SAMJ Vol 105, No 8 (2015)

AUGUST 2015

VOL. 105 NO. 8

Anterior chamber paracentesis in Mx of infectious uveitis Contributions of SA’s first black doctors Tobacco use in SA

628 635 637, 648

Time to regard HIV as a chronic condition

638

One NCD begets another

642

Carcinogenic nitrosamines and Ca oesophagus

656

Mental health burden of ‘tik’ users CME: Fits, faints and funny turns

685 689-695

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References: 1. Seema Rani, M.C. Gupta, Prem Verma, Dalbir Singh. A Comparative Study of Clinical Efficacy And Tolerability Of Second Generation (Cetirizine) and Third Generation (Levocetirizine) Antihistaminics in Seasonal Allergic Rhinitis. Available at: http://www.scopemed.org/?mno=30140. (Accessed 23/03/2015 2. Garg G, Thami GP. Comparative efficacy of cetirizine and levocetirizine in chronic idiopathic urticaria.

The journal of dermatological treatment 2007; 18(1):23-4. 3. Kapp A, Demarteau N. Cost Effectiveness of Levocetirizine in Chronic Idiopathic Urticaria. Clin Drug Invest. 2006;26 (1):1-11. Accessed via Medscape 01/06/2014. Available at: http://www.medscape.com/viewarticle/521307 4. Passalacqua G ,Canonica GW. A review of the evidence from comparative studies of levocetirizine and desloratadine for the symptoms of allergic rhinitis. Erratum in.Clin Ther.2005 Oct:27(10):1669 ZA/05/2015/Allerway/001

AUGUST 2015

VOL. 105 NO. 8

SAMJ

FROM THE EDITOR

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SA’s happiness – and misery – index J Seggie

EDITOR-IN-CHIEF Janet Seggie, BSc (Hons), MD (Birm), FRCP (Lond), FCP (SA)

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EDITOR’S CHOICE

DEPUTY EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB EDITORS EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG, MD (Hon), FCM (Hon) JP de V van Niekerk, MD, FRCR

CORRESPONDENCE 618

Cost awareness on the part of health professionals G D Nethathe

619

Myasthenia gravis is a rare but treatable disease B Mombaur, J M Heckmann

ASSOCIATE EDITORS Q Abdool Karim, A Dhai, N Khumalo, R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman

IZINDABA 620 621 623

‘Changing sides’ – SAMA unionist now Limpopo’s Health MEC Pain management – the global sound of silence Snipping away at the HIV pandemic, one foreskin at a time

625

BOOK REVIEW Pharmaceuticals, Corporate Crime and Public Health R S Summers

SAMJ FORUM

TECHNICAL EDITORS Emma Buchanan Paula van der Bijl

Motivational interviewing for smoking cessation M McCaul, T Kredo, J Volmink

HEALTHCARE DELIVERY 628 Anterior chamber paracentesis to improve diagnosis and treatment of infectious uveitis in South Africa E Schaftenaar, K A Lecuona, G S Baarsma, C Meenken, G M G M Verjans, J A McIntyre, R P H Peters 631 Patient support interventions to improve adherence to drug-resistant tuberculosis treatment: A counselling toolkit* E Mohr, J Hughes, L Snyman, B Beko, X Harmans, J Caldwell, H Duvivier, L Wilkinson, V Cox 635

NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za PRODUCTION MANAGER (CMC) Emma Jane Couzens DTP & DESIGN (CMC) Carl Sampson HEAD OF SALES AND MARKETING Diane Smith | Tel. 012 481 2069 Email: dianes@samedical.org JOURNAL ADVERTISING Charles William Duke Benru de Jager Reneé van der Ryst Ladine van Heerden ONLINE SUPPORT Gertrude Fani | Tel. 072 463 2159 Email: publishing@hmpg.co.za FINANCE Tshepiso Mokoena

MEDICAL HISTORY The first black doctors and their influence in South Africa* B M Mayosi

HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Dr M J Grootboom, Mrs H Kikaya, Adv. Y Lemmer, Prof. E L Mazwai, Dr M Mbokota, Mr G Steyn, Dr G Wolvaardt

EDITORIALS 637

CEO AND PUBLISHER Hannah Kikaya | Email: hannah.kikaya@ hmpg.co.za MANAGING EDITOR Ingrid Nye

COCHRANE CORNER 626 Task-shifting from doctors to non-doctors for initiation and maintenance of antiretroviral therapy

T Kredo, M McCaul, J Volmink 627

HMPG

Turbo-charging tobacco control in South Africa D Yach, E Alexander

638 Improving access to antiretrovirals in rural South Africa – a call to action A Gray, F Conradie, T Crowley, B Gaede, T Gils, A Shroufi, B Hwang, D Kegakilwe, J Nash, P Pillay, S C Stende, F Venter, P Matthews

Production and distribution services supplied and managed by Media Outsourcing, a wholly owned subsidiary of Cape Media Corporation. Tel. 021 681 7000 ISSN 0256-9574

RESEARCH 642 Multimorbidity, control and treatment of non-communicable diseases among primary healthcare attenders in the Western Cape, South Africa N Folb, V Timmerman, N S Levitt, K Steyn, M O Bachmann, C Lund, E D Bateman, C Lombard, T A Gaziano, M Zwarenstein, L R Fairall 648 Prevalence of tobacco use among adults in South Africa: Results from the first South African National Health and Nutrition Examination Survey

P Reddy, K Zuma, O Shisana, K Jonas, R Sewpaul

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August 2015, Vol. 105, No. 8

Publisher website: www.hmpg.co.za SAMA website: www.samedical.org Journal website: www.hmpg.co.za

656 Carcinogenic nitrosamines in traditional beer as the cause of oesophageal squamous cell carcinoma in black South Africans C Isaacson, P Mothobi, M Hale, L K Tomar, C Tyagi, P Kumar, Y E Choonara, M Altini, V Pillay 659 Do low levels of physical activity in female adolescents cause overweight and obesity? Objectively measured physical activity levels of periurban and rural adolescents*

I Cook 664 The case for expanding the definition of ‘key populations’ to include high-risk groups in the general population to improve targeted HIV prevention efforts*

O Shisana, N Zungu, M Evans, K Risher, T Rehle, D Celentano 670 K-ras codon 12 and not TP53 mutations are predominant in advanced colorectal cancers* G Zhunussova, L Djansugurova, E Khussainova, B Zhunusbekova, G Afonin, D Khaidarova, M Matejcic, M Iqbal Parker 675 Chromosomal radiosensitivity of lymphocytes in South African breast cancer patients of different ethnicity: An indirect measure of cancer susceptibility*

F Z Francies, O Herd, X Muller, A Cairns, M Murdoch, S Nietz, J P Slabbert, A Baeyens 679 Human papillomavirus genotypes and clinical management of genital warts in women attending a colposcopy clinic in Cape Town, South Africa*

S Tayib, B Allan, A-L Williamson, L Denny 685 The mental health experiences and needs of methamphetamine users in Cape Town:

A mixed-methods study*

M H Watt, B Myers, S L Towe, C S Meade

CONTINUING MEDICAL EDUCATION

689

GUEST EDITORIAL Fits, faints and funny turns N A B Ntusi

690

REVIEW An approach to the clinical assessment and management of syncope in adults N A B Ntusi, C B I Coccia, B J Cupido, A Chin

693

ARTICLES An approach to epilepsy* E B Lee-Pan, L Tucker

694

An approach to acute vertigo* K Bateman, C Rogers, E Meyer

695

An approach to balance problems and falls in elderly persons* L de Villiers, S Z Kalula

*Full article available online only.

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Hippos are more dangerous than they look Photo: Susan Flegg

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August 2015, Vol. 105, No. 8

FIRST PUBLISHED IN 1884

SA’s happiness – and misery – index Measuring a nation’s happiness – Gross National Happiness (GNH) – in the manner of measuring Gross National Product (GNP) would seem frivolous, but is increasingly being taken seriously. [1] Happiness has come to be considered a measure of social progress. Psychologists, economists and sociologists have shown that people’s satisfaction with their lives offers information about a society. National governments have begun to use measures of happiness, or subjective wellbeing, to guide development of policies aimed at improving people’s lives.[1] The idea of measuring GNH, and developing a GNH index,[1] began in the tiny constitutional monarchy of Bhutan, tucked against the Himalayas, with (just) 800 000 citizens.[2] GNH is a complex mathematical construct[1] that provides an overview of performances across nine domains (psychological wellbeing, time use, community vitality, cultural diversity, ecological resilience, living standard, health, education, good governance) each with a number of key indicators, e.g. Health: mental health, self-reported health, healthy days, disability; and Good Governance: government performance, fundamental rights, services, political participation.

The first World Happiness Report was launched in 2012.[1] There was another GNH report in 2013,[3] which covered both the 2010 - 2012 rankings and also the changes from 2005 - 2007 to 2010 2012. The 2015 report[4] is just to hand. South Africa (SA) has been slipping steadily in the ranks with the publication of each report: in 2011[1] Bangladesh was 14 rungs above SA and Zimbabwe 52 rungs below us; in 2014[4] we were ranked at 113/158, in the company of Tunisia, Palestinian Territories, Bangladesh, Iran, Ukraine and Iraq, slightly above us (107 - 112), and Ghana and Zimbabwe just below us (114 - 115). It probably is no accident that ‘Gross national happiness in Bhutan: The big idea from a tiny state that could change the world’[5] attracted interest in 2012 (at the Doha United Nations climate change conference), ‘in a world beset by collapsing financial systems, gross inequity and widescale environmental destruction.’

Which brings one to the World Misery Index, devised by Steve Hanke, professor of Applied Economics at Johns Hopkins University, who factors together a nation’s inflation, lending rates, unemployment figures and year-on-year per capita GDP growth to determine ‘misery’.[6] In 2015, SA is among ‘Les Miserables’, with a ranking of 10/108 (Bhutan ranks 44/108).[7] The chief reason, according to Hanke, is our unemployment, which currently stands at 26% (40%, if people who have given up are counted): ‘when people are unemployed, their wellbeing is low and can be likened to the effect of bereavement or separation. Studies show that it is better to get people into bad jobs rather than no jobs at all.’[1] To add insult to injury, SA occupies second-to-last place – 75/76 – in an analysis[8] based on the Organisation for Economic Cooperation and Development (OECD)’s Pisa[9] test scores in maths and science, according to a report titled ‘Universal Basic Skills: What Countries Stand to Gain’, and subtitled ‘Update of Employment and Educational Attainment Indicators’, which has just been released by the OECD and produced by economists Eric Hanushek and Ludger Woessmann.[10] Science, according to Carl Sagan,[11] is a way of thinking; a way of sceptically interrogating those in authority: ‘if we are not able to ask sceptical questions … then we’re up for grabs for the next charlatan, political or religious, who comes ambling along. Once you give a charlatan power over you, you almost never get it back.’

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Chapter 4 of the Universal Basic Skills report, in offering a comprehensive analysis of the current state of ‘knowledge capital’ in each country and distance from the goal of basic skills for all, reveals that some 80% of SA’s students are at a disadvantage. There is some ‘balm’ in that even the richest countries in the world also have significant populations without basic skills, e.g. Luxembourg (25%), Norway (22%), the USA (24%) and Switzerland (14%), and one in five British students leave school without acquiring these same basic skills.[8] The report shows that poor quality of schooling in a country is a powerful predictor of the wealth that countries will produce in the long run. For countries, such as our own, that are rich in natural resources: ‘the wealth that lies hidden in the undeveloped skills of their populations is far greater than what they now reap by extracting wealth from national resources … the post-2015 agenda is no longer just about providing more people with more years of schooling, but about making sure that individuals acquire a solid foundation of knowledge in key disciplines, that they develop creative, critical thinking and collaborative skills, and that they build character attributes, such as mindfulness, curiosity, courage and resilience … knowledge and skills have become the global currency, the key to better jobs and better lives. And there is no central bank that prints this currency. We cannot inherit this currency, and we cannot produce it through speculation; we can only develop it through sustained effort and investment in people.’[10] Why raise these constructs in the journal? Because, as several papers in this edition show, the country’s poor health has everything to do with the issues that determine happiness: social support, incomes, healthy life expectancy,[1] and misery, principally unemployment.[6] The SA quadruple burden of disease is underpinned by poverty. In this context, readers will resonate with the Prime Minister of Bhutan’s recent warning of the threat to his country’s happiness of ‘ballooning debt that if we’re not careful will not be sustainable; the big rupee shortage; unemployment, in particular youth unemployment; and a perception of growing corruption.’[12] In ‘Multimorbidity, control and treatment of non-communicable diseases among primary healthcare attenders in the Western Cape, South Africa,’ Folb et al.[13] observe that of the 4 500 patients they studied, 75% were unemployed and 58% were recipients of a social welfare grant. Their median income in the month prior to the study date was ZAR1 140, including personal non-grant income plus any household grant that benefited the participant, such as a disability or child grant. The results found poor disease control, high levels of multimorbidity and unmet treatment needs in primary care clinics in the public sector (in two districts in SA).

Poverty is understood to be a driving force behind the HIV/AIDS epidemic in sub-Saharan Africa as both a cause and effect of the disease, and empirical research has pointed to an association between HIV prevalence and lower socioeconomic status.

In ‘The case for expanding the definition of “key populations” to include high-risk groups in the general population to improve targeted HIV prevention efforts’, Shisana et al.[14] confirm that income and social inequality, as also the case in the USA among black Americans, are important, if not the chief social determinants of HIV prevalence and incidence among black South Africans.

Studying ‘The mental health experiences and needs of methamphetamine users in Cape Town’, Watt et al.[15] found high rates of psychological distress, with close to half of participants scoring above the cut-off for depression and more than half

August 2015, Vol. 105, No. 8

FROM THE EDITOR

meeting screening criteria for post-traumatic stress disorder. Many reported using methamphetamine to numb feelings, forget disturbing memories and cope with their daily lives. Yet, very few participants had ever accessed the mental health services that might provide coping and problem-solving interventions to help abusers deal with life stressors.

Janet Seggie Editor janet.seggie@hmpg.co.za 1. Helliwell J, Layard R, Sachs J, eds. World Happiness Report 2012. http://worldhappiness.report/wpcontent/uploads/sites/2/2012/04/World_Happiness_Report_2012.pdf (accessed 17 May 2015).

2. Bhutan. http://en.wikipedia.org/wiki/Bhutan (accessed 16 May 2015) 3. Helliwell JF, Layard R, Sachs J, eds. World Happiness Report 2013. New York: Sustainable Development Solutions Network, 2013. http://unsdsn.org/wp-content/uploads/2014/02/WorldHappinessReport2013_ online.pdf (accessed 17 May 2015).

4. Helliwell JF, Layard R, Sachs J, eds. World Happiness Report 2015. New York: Sustainable Development Solutions Network, 2015. http://worldhappiness.report/wp-content/uploads/sites/2/2015/04/WHR15Apr29-update.pdf (accessed 17 May 2015).

5. Kelly A. Gross national happiness in Bhutan: The big idea from a tiny state that could change the world. http://www.theguardian.com/world/2012/dec/01/bhutan-wealth-happiness-counts (accessed 16 May 2015).

6. Hanke S. The World Misery Index: 108 countries. http://www.businessinsider.com/the-29-mostmiserable-countries-in-the-world-2015-1#ixzz3aIHhoJTO (accessed 16 May 2015).

7. Jamrisko M, Saraiva AC, Tartar A. The 15 Most Miserable Economies in the World. http://www. bloomberg.com/news/articles/2015-03-02/the-15-most-miserable-economies-in-the-world (accessed 16 May 2015).

8. Chang N. Global school rankings: Interactive map shows standards of education across the world. http://www.independent.co.uk/news/education/education-news/global-school-rankings-interactivemap-shows-standards-of-education-across-the-world-10247405.html (accessed 17 May 2015).

9. The Programme for International Student Assessment (PISA). http://www.oecd.org/pisa/aboutpisa/ (accessed 17 May 2015).

10. Hanushek E, Woessmann L. Universal Basic Skills: What Countries Stand to Gain. http://hanushek. stanford.edu/sites/default/files/publications/Universal_Basic_Skills_WEF.pdf (accessed 17 May 2015).

11. Carl Sagan. http://en.wikiquote.org/wiki/Carl_Sagan (accessed 16 June 2015).

12. BBC News. Bhutan PM casts doubts over Gross National Happiness. http://www.bbc.com/news/worldasia-23545641 (accessed 16 May 2015).

13. Folb N, Timmerman V, Levitt NS, et al. Multimorbidity, control and treatment of non-communicable diseases among primary care attenders in the Western Cape, South Africa. S Afr Med J 2015;105(8):642647. [http://dx.doi.org/10.7196/SAMJnew.7882] 14. Shisana O, Zungu N, Evans M, et al. The case for expanding the definition of ‘key populations’ to include high-risk groups in the general population to improve targeted HIV prevention efforts. S Afr Med J 2015;105(8):664-669. [http://dx.doi.org/10.7196/SAMJnew.7918] 15. Watt MH, Myers B, Towe SL, Meade CS. The mental health experiences and needs of methamphetamine users in Cape Town. S Afr Med J 2015;105(8):685-688. [http://dx.doi.org/10.7196/SAMJnew.7910]

S Afr Med J 2015;105(8):615-616. DOI:10.7196/SAMJnew.8217

NOTICE

A publication fee of ZAR5 000 will be levied for all research papers submitted to SAMJ after 1 September 2015, provided they are accepted for publication following peer review.

EDITOR’S CHOICE CME: Fits, faints and funny turns

Fits, faints and funny turns represent a common reason for presentation to the general practitioner or emergency department.

Patients often present a diagnostic dilemma for the clinician, and the consultation is frequently dissatisfying for both doctor and patient. The key to a satisfactory evaluation is a structured approach, premised on a clear and comprehensive history focused on prior comorbidities, the context of the episode, precipitating factors, situational factors before the episode, the onset and evolution of the episode, and events occurring after it. A detailed and carefully elicited medical history allows the clinician to confirm the diagnosis, delineate the underlying mechanism, and identify features that may suggest a high risk of recurrence, injury or death.

In this issue of CME we offer a series of articles on approaches to common causes of fits, faints and funny turns in adults. The underlying mechanisms for such episodes are emphasised, and the busy clinician is provided with a sound and simplified approach to clinical evaluation and management.

Non-communicable diseases in South Africa

The rising prevalence of non-communicable diseases (NCDs) is a major challenge to health systems worldwide, with multimorbidity the norm for people with chronic diseases. Health systems tend, however, to be configured for individual diseases. South Africa (SA) faces a rise in NCDs in both her rural and urban populations, driven by an increase in tobacco use, physical inactivity and unhealthy diets,

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and – yet to fully emerge – HIV (and HAART), that will place a heavy burden on primary care services.

Primary care in the public sector is nurse-led, with nurses seeing over 85% of patients, with support from doctors. Nurses working at primary care clinics often do not have the necessary skills or capacity to deal adequately with NCDs. Chronic diseases and risk factors are often undiagnosed and inadequately treated, resulting in high levels of poor control and morbidity.

Several articles in this issue of SAMJ deal with SA’s looming burden of NCDs now that the HIV/AIDS epidemic nears some sort of control and is becoming just another chronic condition.

Given the ‘drivers’ of HIV, as alluded to in my editorial,[1] it is impossible to publish an edition that does not offer insights into this continuing but preventable infection and the infections it begets. If HIV is to gain chronic condition status, much is required of our nurse-led primary clinics (as pointed out above), and the authors of the ‘Forum’ article[2] on improving access to antiretrovirals (ARVs) in rural South Africa stress that adoption of a chronic disease management model for HIV requires extended task shifting, decentralisation and new approaches to distribution of ARVs. Implementation, particularly in rural clinics, depends on new legal flexibilities for nurse prescribing and breaking the impasse between the national (and provincial) departments of health, which wish to see nurses recognised as authorised prescribers and able to issue prescriptions to be dispensed by pharmacists or pharmacist’s assistants, and the South African Pharmacy Council, which holds that nurses are not authorised prescribers.

August 2015, Vol. 105, No. 8

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EDITOR’S CHOICE

The Medicines Control Council (as custodians of the Medicines Act) and the South African Nursing Council (whose legislation permits public sector nurses to ‘supply’ medicines) need to step up and give clear and positive direction. The SA Pharmacy Council is urged to pragmatically interpret existing legislation to provide for the recognition of nurses as authorised prescribers. Finally, the National Department of Health needs to ensure continuous availability of safe and appropriate regimens and formulations of ARVs for all eligible patients.

Returning to NCDs proper, the issue of tobacco use is unavoidable.

Tobacco is the second leading risk factor for the global burden of disease, causing six million deaths annually. In their editorial ‘Turbo-charging tobacco control in South Africa’, Yach and Alexander[3] confirm SA’s rather proud record regarding its global leadership role in tobacco control since the 1990s. While globally the prevalence of smoking among adults decreased between 1980 and 2012 from 41% to 31% for men and from 11% to 6% for women, tobacco use among girls is increasing in many countries, and unless effectively addressed will result in increased risk for the next generation of women.

The latest study on tobacco use in SA, reported by Reddy et al.,[4] shows that a quarter of adults and young people smoke. While men have a higher prevalence of smoking than women, girls are catching up. Smoking prevalence differs greatly by race: 40% of coloured people smoke tobacco, as do a third of coloured women, nearly five times the prevalence among all SA women.

Tobacco control remains a critical priority, and an aggressive educational programme is required. Attempts to quit smoking tobacco were significantly associated with having been advised to do so during a visit to a healthcare provider or having noticed health warnings on tobacco packages. Disappointingly, surprisingly few current smokers (only 29%) reported having been so advised.

As the South African National Health and Nutrition Examination Survey suggests,[4] health professionals need to redouble their efforts to advise their patients against tobacco use. The SAMJ has carried a debate on e-cigarettes,[5,6] with evidence increasingly showing[3] that they offer an opportunity to improve public health, reduce global deaths attributable to tobacco use, and reduce healthcare expenditure.

Regarding NCD management, the study by Folb et al.[7] on multimorbidity, control and treatment of NCDs among primary care attenders in the Western Cape Province evaluated the effects of the Primary Care 101 programme on the quality and outcomes of care for hypertension, diabetes, chronic respiratory disease and depression in 38 primary clinics. The analysis showed an impressive NCD ‘multiplier’ effect – 47% of participants in the hypertension group also had diabetes, 84% of participants with diabetes also had hypertension, and 22% of participants with hypertension or diabetes also had chronic respiratory disease.

The study confirmed previous reports of poor control and treatment of NCDs. The high levels of multimorbidity signal the need for primary care services to provide integrated NCD care, with management of NCDs and multimorbidity factored into clinical training. After a decade of focusing on scaling up antiretroviral therapy programmes, primary care management of NCDs, including mental health, needs to be prioritised and requires similar investment to address the burden.

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Anterior chamber paracentesis to improve diagnosis and treatment of infectious uveitis

Infectious uveitis is a significant cause of blindness in SA, especially among HIV-infected individuals, who have increased susceptibility to ocular infections and may present with more severe disease. The visual outcome of uveitis depends on early clinical and laboratory diagnosis to guide therapeutic intervention. Schaftenaar et al.[8] show that analysis of aqueous humor, obtained at very limited risk by anterior chamber paracentesis, provides a diagnosis and optimal treatment.

Human papillomavirus genotypes and clinical management of genital warts

It is well known that persistent infection with human papillomavirus (HPV) is the precursor to development of cervical cancer. HPV is also associated with genital warts and other types of anogenital neoplasia, including penile, anal and oropharyngeal tumours. HIV infection is an important risk factor for HPV infection and persistence. In their Cape Town study, Tayib et al.[9] found that almost 80% of patients were HIV-positive. Genital warts are strongly linked to sexual behaviour (in this study the majority of women were sexually active and had had more than one sexual partner), and weakly associated with cigarette smoking (cigarette smoking is biologically associated with decreased antiviral immune cells in the cervical epithelium).

Carcinogenic nitrosamines in traditional beer as the cause of oesophageal squamous cell carcinoma in black South Africans

The abovementioned article[10] is published as a tribute to work pioneered

by Prof. Charles Isaacson (1929 - 2014) and his contributions in the field of anatomical pathology. Fusarium moniliforme, which grows freely on maize, produces a toxin, fumonisin, that reduces nitrates to nitrites and synthesises nitrosamines in the presence of secondary amines.

The aetiological role of carcinogenic N-nitrosamines, just as Isaacson hypothesised in 2005, is confirmed in a study that is the first to demonstrate their presence in six out of six traditional beer samples. The decline in the incidence of carcinoma of the oesophagus to one-fifth of the peak in the 1980s probably reflects diminished consumption of traditional beer.

JS 1. Seggie, J. South Africa’s happiness – and misery – index. S Afr Med J 2015;105(8):615-616. [http:// dx.doi.org/10.7196/SAMJnew.8217] 2. Gray A, Conradie F, Crowley T, et al. Improving access to antiretrovirals in rural South Africa – a call to action. S Afr Med J 2015;105(8):638-640. [http://dx.doi.org/10.7196/SAMJnew.8265] 3. Yach D, Alexander E. Turbo-charging tobacco control in South Africa. S Afr Med J 2015;105(8):637638. [http://dx.doi.org/10.7196/SAMJnew.8032] 4. Reddy P, Zuma K, Shisana O, Jonas K, Sewpaul R. Prevalence of tobacco use among adults in South Africa: Results from the first South African National Health and Nutrition Examination Survey. S Afr Med J 2015;105(8):648-655. [http://dx.doi.org/10.7196/SAMJnew.7932] 5. Allwood. B. Electronic cigarettes: The potential benefits outweigh the risks. S Afr Med J 2013;103(11):832-833. [http://dx.doi.org/10.7196/SAMJ.7434] 6. Van Zyl-Smit RN. Electronic cigarettes: The potential risks outweigh the benefits. S Afr Med J 2013;103(11):833. [http://dx.doi.org/10.7196/SAMJ.7435] 7. Folb N, Timmerman V, Levitt NS, et al. Multimorbidity, control and treatment of non-communicable diseases among primary healthcare attenders in the Western Cape, South Africa. S Afr Med J 2015;105(8):642-647. [http://dx.doi.org/10.7196/SAMJnew.7882] 8. Schaftenaar E, Lecuona KA, Baarsma GS, et al. Anterior chamber paracentesis to improve diagnosis and treatment of infectious uveitis in South Africa. S Afr Med J 2015;105(8):628-630. [http://dx.doi. org/10.7196/SAMJnew.7816] 9. Tayib S, Allan B, Williamson A-L, Denny L. Human papillomavirus genotypes and clinical management of genital warts in women attending a colposcopy clinic in Cape Town, South Africa. S Afr Med J 2015;105(8):679-684. [http://dx.doi.org/10.7196/SAMJnew.7890] 10. Isaacson C, Mothobi P, Hale M, et al. Carcinogenic nitrosamines in traditional beer as the cause of oesophageal squamous cell carcinoma in black South Africans. S Afr Med J 2015;105(8):656-658. [http://dx.doi.org/10.7196/SAMJnew.7935]

August 2015, Vol. 105, No. 8

CORRESPONDENCE

Cost awareness on the part of health professionals

To the Editor: The African region bears more than 24% of the global burden of disease, but has access to less than 1% of the financial resources.[1] Access to healthcare is a significant concern in South Africa (SA), and financial cost is a recognised cause of lack of access to adequate healthcare. Furthermore, increasing healthcare costs affect healthcare decisions taken by poorer households, further decreasing their already limited access.[2] Resource scarcity also determines the standard of care, and higher costs have been shown to have a negative impact on patient outcomes.[3] The cost of healthcare can also affect other aspects of living, and for some members of society can mean the choice between medication and essentials of living such as food.[4] In 2012, SA government expenditure on healthcare amounted to 8.8% of the GDP.[5,6] Compared with other countries of similar development status and some high-income countries, SA’s level of spending is high but health status indicators are much worse,[5] suggesting that equitable and efficient resource utilisation is still a major challenge. In terms of healthcare spending per capita, SA ranks below higher-income countries with a spending of USD982 per person per year in 2012 (calculation based on purchasing power parity), compared with the Organisation for Economic Co-operation and Development (OECD) average of USD3 484 per person per year.[6] The costs of providing medical care are not only high but are escalating, and several measures have been suggested and employed to reduce these expenses.[3] Anstey et al.[7] recently suggested a framework focusing on Talking to patients about their preferences for care, Asking for outside tests, Avoiding Routine and/or Repeated tests, prescribing Generic medications, Education about costs, and appropriate Transfusion practices (TARGET) to reduce intensive care unit costs. In our public health setting in SA, choices such as which medicines to prescribe are limited.

However, in-depth teaching of cost awareness may prove to be an important step in overcoming one of the biggest challenges of the SA health system, lack of resources. It is easy for managers to obtain information on the costs of drugs, equipment, disposables, tests and other expendables that healthcare professionals use in their practice, and it is just as easy to make such information readily available to healthcare workers.

As the public health system is faced with increasing budget constraints, healthcare professionals are in a position to act as stewards in ensuring that healthcare provision is effectively utilised and cost-effective. Providers have an influence on total spending and allocation of limited healthcare resources, and they can act as drivers in the effort to contain costs.

Unfortunately studies done in less resource-limited environments have found that medical professionals have limited understanding of the costs of medical care, and that their knowledge and awareness of costs and the implications thereof are limited.[4,8-11] Glickman et al.[4] in a survey done in the USA on doctors’ knowledge of drug costs found a trend towards underestimation of the prices of expensive drugs and overestimation of the prices of less expensive drugs. Estimates of prices by doctors were also highly variable; younger doctors were more likely than older ones to make correct estimates, and specialists in internal medicine were less likely to make correct estimates than specialists from other disciplines.

A more recent systematic review on doctors’ awareness of drug costs showed a similar pattern.[3] Awareness of costs was lacking, and doctors tended to underestimate the costs of expensive drugs and

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overestimate the costs of less expensive ones. In addition, doctors in this study indicated that they wanted cost information but found it inaccessible – an unnecessary, highly undesirable and easily remedied situation.

Predictors of cost awareness among healthcare staff also vary. Most studies indicate that there is no difference in cost estimation accuracy between health professionals at various levels of training and experience, with a number of studies finding no difference in cost estimation accuracy among medical students, residents, faculty doctors, specialists and doctors from different practice settings, nurses and ward clerks, suggesting that health science education as it currently stands, as well as experience or involvement in private practice, does not significantly influence awareness of costs.[4,12-14] Over-ordering tests, additional costs related to wastage and mishandling of disposables and equipment contribute to escalating healthcare costs, and initiatives and interventions to minimise these costs may reduce expenditure and are particularly pertinent in a setting where resources are limited. Cost-awareness strategies may allow for improved resource management, and may prevent wasteful expenditure through the ordering of unnecessary investigations, tests and therapies. They would enable healthcare workers to be conscious of absolute costs as well to make comparisons between different products and therapies. Staff knowledge of costs also informs the decisions that lead to the most cost-effective treatment options being chosen.

The ability to make a correct estimation has, unsurprisingly, been associated with the ordering of fewer tests.[14] The concern that this may negatively affect outcome is unsubstantiated, although it is a topic that requires further investigation; however, strategies to improve healthcare awareness of costs have been shown to reduce costs. Unfortunately, data describing SA healthcare practitioners’ awareness of costs are lacking, and availability of such information may aid educators and other decision-makers in improving strategies aimed at cost-awareness training.

Gladness Dakalo Nethathe

Intensive Care Unit, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa, and Division of Critical Care, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg gladness.nethathe@wits.ac.za 1. Van Rensburg HC. South Africa’s protracted struggle for equal distribution and equitable access – still not there. Hum Resour Health 2014;12(1):26. [http://dx.doi.org/10.1186/1478-4491-12-26] 2. Castro-Leal F, Dayton J, Demery L, Mehra K. Public spending on health care in Africa: Do the poor benefit? Bull World Health Organ 2000;78(1):66-74.

3. Allan GM, Lexchin J, Wiebe N. Physician awareness of drug cost: A systematic review. PLoS Med 2007;4(9):e283. [http://dx.doi.org/10.1371/journal.pmed.0040283] 4. Glickman L, Bruce EA, Caro FG, Avorn J. Physicians’ knowledge of drug costs for the elderly. J Am Geriatr Soc 1994;42(9):992-996. [http://dx.doi.org/10.1111/j.1532-5415.1994.tb06594.x] 5. World Health Organization. National health accounts. http://www.who.int/nha/country/ZAF.pdf (accessed 31 January 2015).

6. Organisation for Economic Co-operation and Development. OECD Health Statistics 2014. How does South Africa compare? http://www.oecd.org/els/health-systems/Briefing-Note-SOUTH-AFRICA-2014. pdf (accessed 31 January 2015).

7. Anstey MH, Weinberger SE, Roberts DH. Teaching and practicing cost-awareness in the intensive care unit: A TARGET to aim for. J Crit Care 2014;29(1):107-111. [http://dx.doi.org/10.1016/j. jcrc.2013.08.007] 8. Schilling UM. Cost awareness among Swedish physicians working at the emergency department. Eur J Emerg Med 2009;16(3):131-134. [http://dx.doi.org/10.1097/MEJ.0b013e32831cf605] 9. Miller LG, Blum A. Physician awareness of prescription drug costs: A missing element of drug advertising and promotion. J Fam Pract 1993;36(1):33-36.

10. Bade K, Hoogerbrug J. Awareness of surgical costs: A multicenter cross-sectional survey. J Surg Educ 2015;72(1):23-27. [http://dx.doi.org/10.1016/j.jsurg.2014.06.017] 11. Allan GM, Innes G. Family practice residents’ awareness of medical care costs in British Columbia.

Fam Med 2002;34(2):104-109.

12. Fowkes F. Doctor knowledge of the costs of medical care. Med Educ 1985;19(2):113-117. [http://dx.doi. org/10.1111/j.1365-2923.1985.tb01150.x] 13. Shulkin DJ. Cost estimates of diagnostic procedures. N Engl J Med 1988;319(19):1291. [http://dx.doi. org/10.1056/NEJM198811103191920] 14. Long MJ, Cummings KM, Frisof KB. Role of perceived price in physician demand for diagnostic tests.

Med Care 1983;21(2):243-250. [http://dx.doi.org/10.1097/00005650-198302000-00011]

S Afr Med J 2015;105(8):618. DOI:10.7196/SAMJnew.7810

August 2015, Vol. 105, No. 8

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CORRESPONDENCE

Myasthenia gravis is a rare but treatable disease

To the Editor: Myasthenia gravis (MG) is a rare but treatable disease.

Early recognition and treatment can prevent mortality and morbidity, thereby reducing the burden of the disease. In 85 - 90% of cases, the diagnosis is made with an acetylcholine receptor antibody (AChR) radioimmunoprecipitation assay. As a diagnostic test, the assay is 99.9% specific for the presence of MG.[1] We recently reported the incidence of AChR-positive MG in South Africa (SA) based on all the laboratory data over a 2-year period (2011 - 2012).[2] Here, we highlight two issues emanating from that research of importance to specialist services delivery and MG management.

The first issue relates to the need to improve diagnostic capacity for neurological disorders in regions with limited resources. Our results showed an annual crude incident rate of 8.5 per million for AChR-positive MG, which is comparable with the pooled estimate of 7.3 per million from a worldwide systematic study,[3] and represents an apparent increase in incidence from 2.6 per million reported in 2004.[4] Rather than indicating an increased incidence, we believe the observed increase represents improved diagnostic capacity in the form of improved access to the assay, as well as better recognition of the disease. Diagnostic capacity has increased thanks to a number of SA universities establishing outreach programmes, increasing access to specialist services. Still, MG is currently diagnosed mostly in provinces with more resources (Fig. 1).

The second issue relates to the efficient use of resources in MG management. We found that ~10% of requests were repeat antibody tests. Some clinicians are routinely tracking antibody titres to monitor disease activity. There is currently poor evidence to suggest that the AChR antibody test is the preferred biomarker

for disease activity compared with bedside clinical assessments.

Constantly changing conditions in the laboratory, such as variations in temperature, etc., materially affect assay results. Therefore assay result A performed at time 1 cannot accurately be compared with assay result B performed at a different time. Scientific experimental methods would require samples A and B to be performed in the same assay for comparative purposes. In such an experiment using stored samples collected in a prospective MG treatment trial, a fall in antibody titres correlated weakly with improvement as assessed by two validated clinical outcome measures.[5] This study also compared serial measurements of AChR titres in an observational cohort performed at least 6 months apart and at separate times, and found even less correlation between clinical improvement and change in titres. Indeed, the conclusion was that a clinical assessment tool provided a more effective measure to monitor response to therapy. The MG composite score is a good example of a simple clinical tool that can be used to monitor patients. It is a validated instrument that takes 5 minutes to perform, and includes ocular, bulbar, respiratory and proximal muscle strength evaluations.[6] The bulbar and respiratory items are largely based on patient symptoms.

In contrast, each commercial AChR antibody test costs ~ZAR1 000.

In conclusion, our recent work suggests that the overall incidence rate of MG in our population is comparable with rates reported in North American and European studies in keeping with a biological rather than environmental aetiology for MG. The geographical variation of the incidence rate within the country underscores the importance of outreach programmes in regions with limited resources. Finally, when managing a chronic disease such as MG, it is preferable to treat the patient’s symptoms rather than rely on an expensive laboratory test that cannot be accurately interpreted outside a rigorous scientific experiment.

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Fig. 1. Average incidence ratios for AChR-antibody-positive myasthenia gravis in SA between 2011 and 2012, by province. The number of practising neurologists per province as of December 2012 is shown. Incidence rates calculated using denominators from the 2011 census and 2012 adjusted population estimates (www.statssa.gov.sa).

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Busi Mombaur, Jeannine M Heckmann Neurology Research Group, Division of Neurology, Groote Schuur Hospital and University of Cape Town, South Africa busisiwe.mombaur@wits.ac.za 1. Vincent A, Clover L, Buckley C, Grimley Evans J, Rothwell PM. Evidence of underdiagnosis of myasthenia gravis in older people. J Neurol Neurosurg Psychiatry 2003;74(8):1105-1108. [http:// dx.doi.org/10.1136/jnnp.74.8.1105] 2. Mombaur B, Lesosky M, Liebenberg L, Vreede H, Heckmann J. Incidence of acetylcholine receptor positive myasthenia gravis in South Africa. Muscle Nerve 2015;51(4):533-537. [http://dx.doi. org/10.1002/mus.24348] 3. Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol 2010;10(46). [http://dx.doi. org/10.1186/1471-2377-10-46] 4. Bateman KJ, Schinkel M, Little F, Liebenberg L, Vincent A, Heckmann JM. Incidence of seropositive myasthenia gravis in Cape Town and South Africa. S Afr Med J 2007;97(10):959-962.

5. Sanders DB, Burns TM, Cutter GR, Massey JM, Juel VC, Hobson-Webb L; Muscle Study Group. Does change in acetylcholine receptor antibody level correlate with clinical change in myasthenia gravis?

Muscle Nerve 2014;49(4):483-486. [http://dx.doi.org/10.1002/mus.23944] 6. Burns TM. The MG composite: An outcome measure for myasthenia gravis for use in clinical trials and everyday practice. Ann N Y Acad Sci 2012;1274:99-106. [http://dx.doi.org/10.1111/j.17496632.2012.06812.x]

S Afr Med J 2015;105(8):619. DOI:10.7196/SAMJnew.8328

August 2015, Vol. 105, No. 8

New nationally designed Postgraduate Diploma in Family Medicine POSTGRADUATE DIPLOMA IN FAMILY MEDICINE PG Dip (Fam Med) C

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MY

CY

CMY

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The new diploma has been designed nationally through a process overseen by the South African Academy of Family Physicians. It is aimed at existing primary care doctors, from either the private or public sector, to enable them to expand their knowledge and skills in areas relevant to primary care. The programme aims to enhance the quality of general practice by capacitating primary care doctors to fulfil their roles as competent clinicians, change agents, collaborative practitioners, capability builders, critical thinkers and community advocates in the future South African primary health care system.

COURSE CONTENT AND DURATION

This is a 2-year programme with a modularised curriculum (4-6 modules) and a blended approach which will involve campus-based teaching, web-based teaching and work-place based peer learning. During the course of the programme the doctor must work in a clinical setting appropriate to the practice and learning of family medicine, for instance a general practice, community health centre, clinic or district hospital.

ADMISSION REQUIREMENTS

For admission to the Postgraduate Diploma in Family Medicine programme a student must hold a MB, ChB degree, or equivalent qualification deemed to be of an adequate standard, and must be registered with the Health Professions Council of South Africa or with an equivalent licensing body in the country where s/he is practicing.

Application forms can be downloaded from the relevant universities. See contact details below UP – Mr F Sekgwele Department of Family Medicine Tel: +27 (0)12 354 2141 Fax: +27 (0)12 354 1317 Email: frans.sekgwele@up.ac.za Website: www.up.ac.za/family-medicine

SU – Ms N Cordon-Thomas Division of Family Medicine and Primary Care Tel: +27 (0)21 938 9168 Fax: +27 (0)21 938 9704 Email: nicolec@sun.ac.za Website: www.sun.ac.za/fammed

UCT - Ms M Chavda Division of Family Medicine Tel: +27 (0)21 406 6421 Fax: +27 (0)21 406 6667 Email: manisha.chavda@uct.ac.za Website: www.fammed.uct.ac.za

The development of a new national postgraduate Diploma in Family Medicine is one of the goals of the project “Strengthening primary health care through primary care doctors and family physicians” that has been conducted with the financial assistance of the European Union. The contents of this document are the sole responsibility of the authors and can under no circumstances be regarded as reflecting the position of the European Union.

UKZN – Ms S Chumia Department of Family Medicine University of Kwazulu-Natal Tel : +27 (0)31 260 4485 Fax : +27 (0)31 260 4465 Email: chumia@ukzn.ac.za Website: www.familymedicine.ukzn.ac.za

IZINDABA

‘Changing sides’ – SAMA unionist now Limpopo’s Health MEC She’s known countrywide as the strident public health activist voice of the South African Medical Associ­ ation (SAMA), slamming national and provincial health departments wherever there’s dismal patient care, drug stock-outs or non-payment of doctor salaries – you name the dysfunction. Now suddenly she’s the surprise MEC for Health in one of the country’s most bankrupt and historically corruption-ridden provinces – Limpopo.

represented SAMA in COSATU and worked for over a decade in that province’s public sector hospitals – she knows the political players,’ says Mabasa, whose soft-spoken style of leadership has won him wide respect.

However, he does have a few words of advice and caution about running a provincial health department that immediately prior to his appointment saw more than ZAR25 million in health contracts awarded to state officials and the entire province virtually bankrupt (under central government adminis­ tration).

‘We have leadership challenges, if you look at some of the hospitals and clinics. It’s not that they cannot perform, but they’re not given guidance. One needs to make sure what the attitudes are.

If you’re CEO of a hospital, you need to appreciate why you’re there and what you’re doing. Clinical governance is a priority for me.’ – Ramathuba

Mabasa lights her way …

Unionist-turned-Health-MEC, Dr Phophi Rama­ thuba.

Dr Phophi Ramathuba was head-hunted and put on the short-list of candidates by Limpopo Premier Stanley Mathabatha, her appointment this June prompting national Minister of Health Dr Aaron Motsoaledi to quip to her: ‘You’re going from throwing stones to catching them.’ She follows in the footsteps of another SAMA leader, Dr Norman Mabasa (variously former SAMA chair, general manager and president between 2009 and 2012, and Limpopo MEC from 2012 to 2014). Without intending one-upmanship, she genuinely believes she’s uniquely better qualified for the job than Mabasa was. Mabasa, now back in private practice in Krugersdorp, chairing the National Convention on Dispensing and a panellist on one of the Medical and Dental Professions Board disciplinary committees, actually agrees. ‘Unlike me, she’s a political animal, served for a long time as treasurer to the SA Communist Party’s Limpopo branch,

‘Your former allies will become your potential adversaries because they now expect you to deliver what you represented them about.

You’ll have to deliver on what you expected others to do. The other problem is that there are camps based on political differences and you receive different levels of loyalty. This is why in the main, new incumbents bring in their own people. People can cause you embarrassment. You’re also going into a province hungry for service, destitute both financially and by its rural nature. There are clinics you can’t reach by phone, that have no roofs, that you cannot reach comfortably by car, that have no water. Don’t own what was not your creation, but do try to address it,’ he advised, adding: ‘It’ll be hard, if not impossible to turn around [he couldn’t do so in his 18 months there]. Don’t punish yourself for lack of successes, but try to be a messenger of hope. I felt that I’d left before I’d even started. I think you need a longer-term MEC there to have any results.’

Asked by Izindaba to sum up what his main ‘take-home’ message for Ramathuba would be, Mabasa replied: ‘Focus on the work ethic of those entrusted with the

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responsibility of managing the institutions, get the right people in the right places – and get the funding to enable better healthcare.

If you have the money and the people to use it properly, you may succeed.’ Mabasa said he found himself in the political crossfire once elections came along. ‘The job didn’t allow me to do what was within me. I’m not used to defending. I prefer realistically analysing the situation, so it didn’t sit well with me. This was not what characterises my involvement in healthcare.’

Tripartite alliance back­ ground ‘an advantage’

Ramathuba said Mabasa was one of the first colleagues to congratulate her and offer advice. ‘He indicated to me that I come from a stronger position politically – he entered into a terrain where he had no clue of the politics. I’ve worked in the public sector here all my life, I was part of crafting government policy, even though I was representing labour.

One journalist told me he’d collated all my SAMA union statements and was going to take me through each one, asking what I’ll be doing about it,’ she laughed. Quizzed on what her priorities are, Ramathuba said that over the past financial year there’d been a genuine attempt to ‘turn things around’, with the potential for her department to finally receive a qualified audit during her tenure. ‘This current financial year was the first time we’ve had enough money until

Ex-SAMA leader, ex-Health MEC, Dr Norman Mabasa.

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IZINDABA

March 31st – previously funds ran out in November of the previous year, and we ended up borrowing. I think the corruption has changed completely since the province was put under administration in 2013. I must say I’m quite humbled by this honour. One has to take seriously the responsibility of looking after six million people’s health.’ Speaking from the unfamiliar back seat of a chauffeurdriven luxury vehicle, Ramathuba took Izindaba’s ribbing in her stride. Describing it as ‘just practical’, she said she was travelling to all the districts and hearing and reading presentations by various directorates. ‘We have leadership challenges, if you look at some of the hospitals and clinics. It’s not that they cannot perform, but they’re not given guidance. One needs to make sure what the

attitudes are. If you’re CEO of a hospital, you need to appreciate why you’re there and what you’re doing. Clinical governance is a priority for me – you cannot change things on the ground when the leadership attitude is still negative.’ She believed in ‘giving people chances’, not just firing. This would allow her to see ‘who is untrainable and unchangeable’, and only then redeploy them elsewhere. She said that at top leadership level, health was ‘a very specialised sector – you don’t just go in and fire people. Look at Prof. Househam [recently retired ANC-appointed DG of Health in the Western Cape] – when the DA [Democratic Alliance] came in, they kept him.’

SAMA chair Dr Mzukisi Grootboom thanked Ramathuba for her ‘enormous contri­

bution to the public sector and our doctors’ during her tenure on the SAMA Board – and for her service as the President of SAMA’s trade union. ‘More than most, she understands the challenges of healthcare in the public sector.

We believe that she’s well poised to tackle these challenges and to improve the service and lives of our people in her province.’

It’s almost certain she’ll emerge from her new job less willing to ‘throw stones’ – the glass house she’s in could prove quite unforgiving, with no place to hide.

Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(8):620-621.

DOI:10.7196/SAMJnew.8082

Pain management – the global sound of silence Worldwide, and particularly in South Africa (SA), patients are unwittingly forced to suffer in silence because doctor training in formal pain management is almost nonexistent, with the best local medical campus undergraduate pain training consisting of ‘about four hours’ in a student’s fourth or fifth year.

This is according to Cape Town-based anaesthetist Dr Milton Raff, a member of the International Association for the Study of Pain (IASP) and the Developing Countries Working Group and former president of Pain SA, who said that the best country for pain management training is France. ‘It’s absolutely shocking,’ he said on describing the findings of an IASP study of pain education in developing countries (published in the British Journal of Pain in 2012[1]). South America, Africa and the Indian sub-continent proved to have ‘very, very poor pain education at undergraduate level’. Then in 2012 the IASP shifted the survey spotlight to First-World countries, canvassing 242 medical schools in Europe.

(This was the APPEAL (Advancing the Provision of Pain Education and Learning) Study, the first-ever Europe-wide review of pain education for undergraduates in Europe. Conducted by independent research company Adelphi Research in 15 European countries and involving review of publicly available curricula from 242 undergraduate

medical schools, it went beyond existing research by providing a more comprehensive analysis and understanding of pain learning.

The research was conducted from April to September 2013, is part of a Europe-wide initiative aimed at raising the profile and importance of pain education, and was funded by Mundipharma International Ltd.) They found that pain management training consisted on average of about 0.2% of a medical student’s curriculum over their full 6 years of training. A total of 17 European medical schools had no pain education of any kind, while the rest claimed to have integrated the subject into other training blocks – but were unable to quantify this.

North America – animals in pain better off than humans

‘We thought that North America [Canada and the USA] would perhaps be better, but guess what? They were as bad. We actually found that vets in North America get 20 times more attention paid to pain management in their training, meaning that animals get better treated there than human beings.’ On home turf, a survey of SA’s nine medical schools revealed that only the University of the Free State had a dedicated full-time pain unit, backed by a ‘few hours-long’ standalone pain management course, something unique to that campus. ‘The others claimed it was integrated into their other subjects, but the best I could find was via a family

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Dr Milton Raff.

medicine block where undergraduates got three to four hours in their fourth year,’ says Raff. ‘Overall students are absolutely under-equipped to manage both acute and chronic pain when they leave university in SA. Globally and locally, there are no clinical end-points prescribed that enable a newly graduated medical practitioner to deal with pain issues.’ A check on postgraduate training in SA also provided little cause for celebration. It ranged from Bloemfontein’s full-time pain clinic to part-time pain clinics at Stellenbosch University, the University of Cape Town and the University of the Witwatersrand. However, Prof. Richard Hift, chair of the Committee of Medical

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IZINDABA

Medical training: ‘We are more than our diseased organs’ – Dean

In most medical curricula, undergraduate and postgraduate, there is a serious lack of exposure to non-discipline-bound, syndrome-centred experience and instruction such as in pain, depression and disability, admits Prof. Richard Hift, Chair of the Medical Committee of Deans and Dean of the School of Clinical Medicine at the University of KwaZulu-Natal.

This was the consequence of a hundred years of narrowly specialty-based training programmes that by their very nature have tended to focus on organ systems rather than the organism as a whole – in all senses, physical, psychological and social, he adds. ‘Sadly, deans are not being petulant in stating that new topics can only enter into the curriculum if something else drops out – it is no secret that curricula are subject to serious, increasing overload.’ He says the solution did not lie in devoting ‘some extra hours’ to orphan subjects such as pain management. An intermediate step was the reprioritisation of topics within the curricula. However, the only genuine and lasting solution lay in fundamentally redesigning undergraduate curricula so that they were centred around the problems experienced by people, and not the diseases that affect their organs.

This was not a new sentiment. ‘Thinking colleagues have been urging this for decades – but medical schools worldwide have proved themselves extraordinarily resistant to attempts to bring about radical curricular reform in the clinical years, and to shift the focus away from department-led teaching to something much less rigid and more generalist and holistic in nature.’ A number of initiatives were being explored around the world, and at UKZN ‘we’ve just commenced planning our “CCCP” [continuous clinical and community placement programme] curriculum, which will see students working for long, uninterrupted periods in non-specialist hospital, clinic and community settings. Although our specialist departments will have an important contribution, it will be as enhancers of learning in this setting, not as the dominant providers. We hope to move away from organs and their diseases to people and their problems – and this very much includes enhanced competence in dealing with the physically failing body. It is a move away from narrow, technical excellence to another form of excellence – global proficiency in promoting, maintaining and restoring health.’ Among many advan­tages of such a system would be the space to ensure that important issues such as pain management were comprehensively and holistically addressed over periods of months of clinical experience, rather than in the form of ‘a bolus of information injected into an already crowded curriculum’. One of the most ‘crippling fallacies’ in medical education was that brief exposure to a topic (and by brief, Hift means even exposure as long as the typical clinical block of 4 - 6 weeks) was sufficient to result in lasting changes in understanding, performance and behaviour. ‘Sadly, there are many parallels among our traditional system for the training of postgraduates, our specialists.’

In the meantime, Dr Raff and his coll­eagues around the country were to be congratulated on their important initiative. ‘There is little in human experience that is as debilitating as chronic severe pain, and it is indeed an area that deserves a much stronger focus than it has traditionally received,’ says Hift.

Deans, said that there were now also active, enthusiastic interdisciplinary and researchproductive pain clinics at Grey’s Hospital in Pietermaritzburg and Inkosi Albert Luthuli Central Hospital in Durban.

Raff said that unless you were ‘rotating through the pain clinic discipline in your postgraduate training [as an anaesthetist], it’s unlikely that as a specialist in any other discipline you’d have ever worked in a pain clinic’. This meant that doctors were not clinically equipped to diagnose and treat pain states, leading ultimately to poor management and patient dissatisfaction.

Far from just complaining, Raff and his associates at Pain SA (which acts as the local chapter of the IASP) have grasped the nettle, working through the examining body, the SA Colleges of Medicine, to create a postgraduate subspecialty in pain management that will be submitted to the Health Professions Council of South Africa for registration. Asked when this might become available, he said that the aim was to begin training in 2017, but cautioned that with the current pressure on expanded medical training platforms, very few hospitals would be able to do it. Izindaba has established that probably only Helen Joseph Hospital in Gauteng and Pelonomi Hospital in Bloemfontein will be likely to

offer this training. When this was put to Raff, he reluctantly confirmed it.

With pain under-treated, under-managed and poorly managed across the globe, the IASP chapters took on medical deans in their own countries, but the overarching response was that training would have to be at the expense of some other discipline – summed up, Raff said, in the ‘petulant response’ of ‘OK, you want pain, we take out appendicitis.’

‘So it’s recognised, but very little is done about it,’ he added.

Pain SA has garnered some overseas funding to train three African fellows per annum in pain management (two Nigerians and one Mauritian at present), resulting in IASP certification after an intensive 3-month course. Raff began the training in Cape Town with assistance from Dr Rene Krause at St Luke’s Hospice. The current incumbents are being trained at academic hospitals attached to the universities of KwaZulu-Natal and the Free State. Raff has kicked off two other ongoing pain management courses, the first in his current capacity as chair of the Pain Committee of the World Federation of Anesthetists (WFA). Called Essential Pain Management and sponsored by the WFA, the weekend course, split between Cape Town, Johannesburg and Pretoria, usually

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sees between 20 and 30 doctors enrolling. ‘It’s very basic, but more than they’ve ever got,’ says Raff. Focusing on pain as a disease and its diagnosis and management, the course moves doctors away from the traditional view of pain as merely symptomatic. The second course, cleverly entitled ‘Know Pain’ and with the intention of creating a ripple effect via a ‘train the trainer’ programme, is more intensive. Sponsored by Pfizer through a non-restrictive educational grant, the course is delivered pro bono by Pain SA members. The first 20 doctors enrolled in mid-June for the nine modules on various aspects of pain.

Holistic approach to pain sadly lacking

Raff said that the various private initiatives should begin to have some impact, albeit far short of what was required. He says that the average private GP cannot afford to see a patient for more than 14 minutes, which is less than half the time required by a patient in pain. ‘You have to use a biopsychosocial approach, because the disease itself has so many implications, not the least of which is depression.’ Equity in access to pain management remained a huge headache because only the luckier patients would get

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referred to a pain clinic that adopted the correct holistic, multidisciplinary approach.

This meant that 80% of the population would probably remain without any pain management, ‘unless you’re really lucky and end up in the Bloemfontein clinic – which probably reduces the overall burden by about one per cent’. Raff stressed that many state pain patients were Workmen’s Compensation Act cases, which meant that pain management was automatically excluded from any funding benefits. ‘So we’re sitting with a government and parastatals that don’t recognise that pain is a disease entity on its own. So you have people dropping out of work and costing the economy billions every year, not to mention the cost in the quality of family life,’ he said.

Partly because of lack of training, doctors were reluctant to use highly effective opioids such as morphine, particularly with children, whose pain management differed both emotionally and physically from that of adults. ‘Apart from Red Cross Children’s

Hospital [Cape Town], the way kids’ pain is handled countrywide is shocking,’ he added.

Dr Liz Gwyther, chair of the International Hospice and Palliative Care Association and CEO of its local equivalent, said there was no doubt that training in pain assessment and management must be improved and that Pain SA was doing a good job in providing it.

‘It is always difficult to add courses to busy undergraduate curricula. Pain assessment and management is also taught in palliative care, which needs to be strengthened in undergraduate curricula – we find it more effective to provide training to academic lecturers and encourage them to integrate this into their courses. In this way palliative care and pain management become part of current courses without having to find dedicated time in the curriculum. We’re encouraged by the new Comprehensive Pain Management division being set up at UCT by Dr Romy Parker,’ she added.

Prof. Errol Holland, a former chair of the Comm­ittee of Medical Deans, said that curr­­ ent curricula were so full that pain manage­ ment had become an ‘orphan’ discipline. ‘I totally agree that it’s something so fundamental that it needs to be addressed properly,’ he added. His successor, Prof. Hift, said that Dr Raff and his colleagues around the country were to be congratulated on their important initiatives. ‘There is little in human experience that is as debilitating as chronic severe pain, and it is indeed an area that deserves a much stronger focus than it has traditionally received,’ he added (see side-bar story, p. 622).

Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(8):621-623.

DOI:10.7196/SAMJnew.8083 1. Bond M. A decade of improvement in pain education and clinical practice in developing countries: IASP initiatives. Br J Pain 2012, 6(2):81-84. [http://dx.doi.org/10.1177/2049463712444062]

Snipping away at the HIV pandemic, one foreskin at a time Nearly two million South African (SA) men will have been voluntarily circum­ cised by the end of this year, about half of the govern­ ment’s original target – yet even this will have conservatively prevented 133 333 new HIV infections as a timely new public/pri­ vate sector initiative kicks in to boost overall efforts. In spite of this, alarm bells continue to ring as interventions for women, twice as vulnerable biologically and culturally, remain in various stages of trial.

Proven in field trials to reduce the risk of HIV infection by 60% and calculated to prevent one HIV infection for every 5 - 15 men circumcised, voluntary medical male circumcision (VMMC) is uniquely suited to the SA environment, where 1 400 new HIV infections occur daily, the vast majority via heterosexual transmission. The latest private sector intervention comes from Metropolitan Health Risk Management, who have partnered with the Centre for HIV/AIDS Prevention Studies (CHAPS) and the National Department of Health in a bid to halve new HIV infections by next year – via VMMC scale-up. The ZAR55 million United States Agency for International Development (USAID)-funded initiative is two-pronged: training or upskilling 850 general

practi­tioners, and increasing VMMC coverage in the private sector to 100 000 men per year by 2017. Since 2007, what was originally a Metropolitan Health and CHAPS initiative (government endorsed the programme in April this year) has resulted in 170 000 Metropolitan Health members being voluntarily circumcised.

The private sector initiative uptake has slowly accelerated, from 12 000 in 2008 to 20 000 in 2010, through 30 000 in 2012 to 45 000 last year.

Mr Siraaj Adams, General Manager for HIV and TB at Metropolitan Health, said that the ZAR55 million was going towards the volun­ tary training of GPs by CHAPS at government facilities after their practices were identified according to HIV prevalence demographics (Johannesburg, Pretoria, Nelspruit, Uitenhage and Cape Town so far). By early June this year, a total of 150 GPs had undergone the rigorous training and been set up at their practices, where they were provided with free surgical circumcision packs and HIV test kits, and paid either the going medical aid rates for insured patients or a median medical aid rate

by USAID for patients without cover. Doctors had to be covered for adverse events through medical practice insurance and earned ten continuing professional development (CPD) points after being ‘signed off ’ as competent VMMC/CHAPS practitioners. Adams said

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that the theoretical and practical course (plus the in-practice ‘sign-off ’ review) was oversubscribed, with 20 doctors on the waiting list for the next two training weekends (at the time of writing). Up to eight doctors were trained in one government facility at a time.

The training and support service incorporates a comprehensive package of services, including HIV testing, sexually transmitted infection (STI) management, VMMC and condom provision. No sexual contact for 6 weeks after the procedure and condom use are strongly encouraged (circumcision often being perceived as an ‘invisible condom’).

Funder exclusion barriers removed

A significant development in the lead-up to the current public/private partnership was that all medical aid schemes (both open and closed) in the Metropolitan stable removed all exclusions around VMMC (in 2012). Before that, members who applied on non-medical grounds were automatically exclu­ded – a significant barrier to HIV prevention efforts. The offer of no outof-pocket costs for VMMC services by GPs will vastly improve accessibility, with Metropolitan Health data suggesting that 35% of VMMCs were already being done by GPs, up to 65% of circumcisions being conducted as day

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procedures in hospital. To give some idea of the patient savings of the new initiative, a private GP visit for the procedure costs around ZAR1 000 while a private in-hospital procedure could cost well into double figures. Over a 10-year time horizon, it is estimated that VMMC in highprevalence areas will save between ZAR1 650 and ZAR9 900 per infection prevented. Adams said that in Gauteng alone, if 1 000 adult males were circum­cised, ZAR26.4 million could be saved in HIV treatment over 20 years. This comprehensively negated arguments that the money for VMMC budgets could be better used in other HIV prevention strategies.

‘The very opposite is true: VMMC frees up money for other strategies to be enhanced,’ he said. Metropolitan Health schemes include several closed government schemes such as Polmed, Transmed and GEMS, making it the largest administrator in the country with three million lives covered (followed by Discovery and Medscheme). Adams revealed that HIV prevalence among Metropolitan Health members stood at 6.5%. He appealed to other medical schemes to also scrap VMMC exclusions on non-medical grounds, saying that the benefits of the new project accrued to members of any medical scheme and that they were a good example of how the private and public sectors could work together for the benefit of all in the impending National Health Insurance.

Government response

Current government VMMC efforts began 3 years ago after HIV prevention efficacy became clear from the original Orange Farm pilot study in Gauteng and two other sub-Saharan sites. It was initiated after comprehensive consultation with all 19 stakeholders in the South African National AIDS Council and discussion on scientific, social and cultural issues. It is now official policy and part of the 2012 - 2016 National Strategic Plan for HIV, STIs and TB. VMMC is regarded as a ‘game-changer’ in SA’s HIV prevention efforts, and all provinces are prioritising efforts to accelerate access.

Asked about the possible inclusion of the Prepex, a non-surgical three-ringed device that results in the foreskin atrophying and falling off after about seven days and is currently being piloted by government in four provinces, Adams said it was being excluded until officially ‘signed off ’. While the safety and efficacy of the device were very high, ‘we are promoting the surgical technique (forceps guided and dorsal slit) – the intention is that non-surgical techniques will become an option’. Prepex’s greatest contribution to the HIV prevention battle is that is relatively pain-free, and can be

Women remain twice as vulnerable

CAPRISA research associate Dr Cheryl Baxter.

prescribed and fitted by a nurse, enabling task-shifting down from over-burdened GPs. A downside is that a Prepex wound takes 8 weeks to heal, 2 weeks longer than healing after surgical circumcision.

Modelling studies suggest striking impli­ cations of scaling up VMMC in averting millions of infections and deaths and saving billions of rands in the long run. Adams said any further delays would constitute a ‘major failure to capitalise on scientific evidence to save lives and improve the quality of our population’.

A ‘jolly good show’ by (and for) CHAPS

CHAPS, a USAID-funded NGO, is a global leader in implementing and disseminating evidence-based approaches to prevent the spread of HIV in southern Africa such as efficiency models and professional training. It was behind the original sub-Saharan studies that proved the efficacy of VMMC. The main pillars of the new 3-year public-private partnership will include Metropolitan Health initially covering the costs of high-quality VMMC to over 32 000 men, USAID supplying disposable circumcision packs to GPs where needed, and CHAPS assisting GPs to set up their facilities and address emergencies and adverse events, and supporting their accurate recording and reporting of VMMC services.

USAID and CHAPS have also undertaken to help create demand and raise awareness of GP-provided VMMC services.

Meanwhile Dr Cheryl Baxter, an asso­ciate researcher at the Centre for the AIDS Program of Research in South Africa (CAPRISA) in Durban, said there was a paucity of any comparable data for HIV prevention in women. The only currently available HIV prevention options for women were the ABCs of Abstinence, Be faithful and Condomise.

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Prevention options for women, such as microbi­ cides, long-acting vaginal rings and long-acting injectables, while holding promise, were not yet available. HIV treatment of an infected partner would have an impact on HIV prevention for women, but it was not something that a woman could control – the male partner would have to know his HIV status, and if HIV-positive would need to be on antiretrovirals (and take them as prescribed) for the woman to benefit. Oral pre-exposure prophylactics had been shown to work in a number of populations (men who have sex with men, discordant couples and heterosexuals), but again this was not a currently available HIV prevention option in SA. ‘There might be some data on condom scale-up, but most of the condoms distributed are male condoms,’ Baxter added.

‘If we pursue a downward trend in financing AIDS, we see a devastating slide backward by 2020 – an increase in new HIV infections and AIDS-related deaths and escalating costs of controlling the epidemic.’ – Moses-Burton Women bear a disproportionate burden of the HIV epidemic in sub-Saharan Africa (SSA), and account for approximately 60% of all infections in this region. HIV-infected women between the ages of 15 and 24 years represent 76% of total cases in that age group.

The rapid spread of HIV among adolescent girls and young women in SA has been described as ‘explosive’. A survey conducted among high-school students in one KwaZuluNatal health district showed that the HIV prevalence in girls was six times higher than in boys. National, annual, anonymous seroprevalence surveys in pregnant women using public sector healthcare facilities demonstrate that HIV prevalence in SSA has increased from 0.8% in 1990 to 30.2% in 2010. Several factors contribute to the increased vulnerability of young women to acquiring HIV in SSA, among them the fact that biologically, women appear to be more susceptible to acquiring HIV than men.

According to the US Centers for Disease Control and Prevention, the risk of HIV infection is 1/2 000 contacts for the male partner compared with 1/1 000 contacts for the female partner in penile-vaginal sex.

Women are twice as likely to become infected as men after a single sexual encounter.[1]

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Downscaling funding ‘asking for trouble’

The Global Network of People Living with HIV (GNP+) last month applauded the conclusions of the recent UNAIDS-Lancet Commission report, ‘Defeating AIDS – advancing global health’, i.e. that failing to continue funding the AIDS response sufficiently would have ‘grave and immediate consequences’. The Commission was tasked with exploring strategies to ensure that the vision of the global AIDS movement, ‘Zero new HIV infections, zero discrimination and zero AIDS-related deaths’, could be realised in coming decades. The report stresses that a human rights and community mobilisation approach has been central to the successes of the AIDS response to date, emphasising that failure to fund the AIDS response sufficiently,

particularly the contribution of civil society, will have major consequences for continued success and sustainability under the sustainable development goals.

Suzette Moses-Burton, GNP+ executive director, said the report presented two ‘stark and contrasting pictures. If we pursue a downward trend in financing AIDS, we see a devastating slide backward by 2020 – an increase in new HIV infections and AIDS-related deaths and escalating costs of controlling the epidemic.

In the alternative picture, with continued investment in AIDS over the next 5 years, we see HIV transmission at low endemic levels, AIDS-related mortality significantly reduced and children born HIV free.’

Impressively, the UNAIDS-Lancet Commi­ ssion report makes a strong econo­ mic argu-

ment for ambitious investment, showing that robust financial investment in the HIV response now will create significant returns later. Each life-year gained in low- and middle-income countries produces significant gains in GDP. Moses-Burton added: ‘With over 10 million people needing antiretroviral drugs today, now is not the time to backtrack on funding and political commitment. We cannot end the AIDS epidemic without that one last push.’

Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(8):623-625.

DOI:10.7196/SAMJnew.8123 1. Abdool Karim S, Baxter C, Frohlich J, Abdool Karim Q. The need for multipurpose prevention technologies in sub-Saharan Africa.

BJOG 2014;121(Suppl 5):27-34. [http://dx.doi.org/10.1111/14710528.12842]

BOOK REVIEW

Pharmaceuticals, Corporate Crime and Public Health. By G Dukes, J Braithwaite and J P Moloney. Cheltenham, UK: Edward Elgar Publishing Ltd, 2014.

ISBN 978 178471 361 4.

This comprehensive, probing and helpful book can be described as ‘compulsory reading for all responsible healthcare practitioners’. Its three authors have a long history of association with and analysis of the international pharmaceutical industry, having identified and written about a range of its activities for the past half century.

In this book they go one step further than the usual criticisms by offering achievable strategies to improve practices and result in more positive outcomes than those that

have beset the industry over so many years.

The fact that malpractice appears to be on the increase is adequate reason for updating the picture and offering remedies, as they have done.

The book is divided into three parts. In Part 1, the introduction, Graham Dukes, a prominent researcher, academic and author who is both a doctor and a lawyer, sets the scene by referring to some of his personal experiences from employee in the industry to national drug regulation, to the World Health Organization, and ultimately to a university environment where he continues to pursue his studies of the industry.

Part 2 considers pharmaceutical rights and wrongs as they have developed over the past 50 years, by considering in turn the main aspects of the industry’s activities: research, production, information, distribution and pricing. Questionable practices that detract from the industry’s important role in society are also examined. They include the use of anonymous ‘ghost-writers’ to speed up and ‘improve’ clinical trial reports and publications, the promotion of ‘offlabel use’ and other poor practices in drug promotion, cover-ups of serious adverse effects identified in pre- and post-marketing practice, ‘disease-mongering’, ‘evergreening’ to manipulate patent expiry constraints, bribery and corruption. That these practices continue is illustrated by criminal and civil penalties amounting to more than USD12.6 billion over the past 10 years, many of which are related to false claims/advertising by well-known names in the medicines and pharmaceutical industries. One is reminded of one cynical response to the banking

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scandals of the past few years: ‘too big to fail, too big to jail, too big to nail’.

What is critical in this environment is to provide for and encourage a ‘best practice’ approach to all these challenges, so that the industry, regulatory authorities, healthcare professionals, society and patients benefit more and experience fewer negative outcomes than they have in the past.

Part 3 of the book, ‘Transforming the way ahead’, focuses on possible and realistic options to respond to the challenges faced by the industry in an environment that is ever more competitive but in which access to information allows individuals and organisations the opportunity to contribute towards improvement. New thinking and fresh approaches, including responsive regulation, supports and sanctions of the industry and the use of private involvement in enforcement, are suggested and described.

The rise of Brazil, India and China in international affairs and the role of South Africa in Africa offer hope for a so-called new ‘drug diplomacy’. The role of ‘ethical dissenters’, including Bill and Melinda Gates, in reformation is also explored.

While this book highlights many of the challenges that have been described previously, it goes beyond other publications by offering a way ahead so that in the future the pharmaceutical industry can take its rightful place as an ethical producer of medicinal remedies that benefit all.

R S Summers Emeritus Professor, Sefako Makgatho Health Sciences University, Pretoria, South Africa robert.summers@smu.ac.za

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COCHRANE CORNER T Kredo,1 M McCaul,2 J Volmink,1,2 on behalf of Cochrane South Africa 1 2

Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa Centre for Evidence Based Health Care, Stellenbosch University, Cape Town, South Africa

Corresponding author: T Kredo (tamara.kredo@mrc.ac.za)

‘Cochrane Corner’ in the August SAMJ offers evidence relating to articles published in this issue, namely ‘Improving access to antiretrovirals in rural South Africa – a call to action’, ‘Multimorbidity, control and treatment of non-communicable diseases among primary healthcare attenders in the Western Cape, South Africa’ and ‘Prevalence of tobacco use among adults in South Africa: Results from the first South African National Health and Nutrition Examination Survey’, and the editorial by Yach and Alexander, ‘Turbo-charging tobacco control in South Africa’.

S Afr Med J 2015;105(8):626-627. DOI:10.7196/SAMJnew.8271

This ‘Cochrane Corner’ offers evidence relating to articles published in the August issue of SAMJ, namely ‘Improving access to antiretrovirals in rural South Africa – a call to action’,[1] ‘Multimorbidity, control and treatment of non-communicable diseases among primary healthcare attenders in the Western Cape, South Africa’[2] and ‘Prevalence of tobacco use among adults in South Africa: Results from the first South African National Health and Nutrition Examination Survey,’[3] and the editorial by Yach and Alexander, ‘Turbo-charging tobacco control in South Africa’.[4]

Task-shifting from doctors to nondoctors for initiation and maintenance of antiretroviral therapy (Summary prepared by T Kredo, with M McCaul and J Volmink.)

About 30 million people living with HIV worldwide are eligible for antiretroviral therapy (ART), but less than half access treatment. [5]

Healthcare worker shortages are an impediment to increasing patients’ access to ART. This is of particular concern where the burden of disease is greatest and the number of doctors is limited. To improve access, some low- and middle-income countries have initiated programmes that support the delivery of ART by non-specialist healthcare providers.

However, some have raised concerns that this may cause more harm than good. In this Cochrane column, we highlight a Cochrane review[6] that evaluated the quality of initiation and maintenance of HIV/AIDS treatment in models that shift care from doctors to non-doctors. The results of this review informed the recommendations of the WHO consolidated guidelines for ART in 2013.[7] A comprehensive search conducted up to March 2014 identified all relevant controlled trials and cohort studies comparing doctor-led to other health worker-led delivery of ART. Four randomised controlled trials and six cohort studies are included, all conducted in Africa.

When nurses initiate and provide maintenance ART, there is no difference in death at 1 year (risk ratio (RR) 0.96, 95% confidence

Table 1. Summary of findings: task shifting of HIV care for maintenance only – 12 months’ follow-up Population: HIV-infected patients on antiretroviral therapy Settings: Low- and middle-income countries Intervention: Doctor v. nurse or clinical officer for maintenance of antiretroviral therapy Illustrative comparative risks* (95% CI) Outcomes

Doctors

Non-doctors

Relative effect (95% CI)

Number of participants (studies)

Quality of the evidence (GRADE†)

Death (RCTs)

23 per 1 000

20 per 1 000 (14 - 30)

RR 0.89 (0.59 - 1.32)

4 332 (2 studies)

+++– Moderate‡1

Death (cohorts)

15 per 1 000

3 per 1 000 (1 - 12)

RR 0.19 (0.05 - 0.78)

2 772 (1 study)

+––– Very low‡2

Loss to follow-up (RCTs)

28 per 1 000

36 per 1 000 (26 - 49)

RR 1.27 (0.92 - 1.77)

4 332 (2 studies)

+++– Moderate‡3

Loss to follow-up (cohorts)

42 per 1 000

14 per 1 000 (8 - 28)

RR 0.34 (0.18 - 0.66)

2 772 (1 study)

+––– Very low‡2

CI = confidence interval; RCTs = randomised control trials; RR = risk ratio. *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). † GRADE: Working group grades of evidence: High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important effect on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important effect on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate. ‡ 1 Downgraded by 1 for imprecision. There was a low number of events (<300) and the 95% CI includes appreciable harm and benefit.

2 Downgraded by 1 for imprecision owing to low event numbers (<300).

3 Downgraded by 1 for imprecision. There was a low number of events (<300) after adjusting for clustering in the Fairall et al.[8] 2012 study.

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interval (CI) 0.82 - 1.12, one trial, cluster adjusted n=2 770; high-quality evidence), with probably lower rates of loss to followup (RR 0.73, 95% CI 0.55 - 0.97, moderatequality evidence).

When doctors initiate ART and nurses provide maintenance, there is probably no difference in death compared with doctorled care at 1 year (RR 0.89, 95% CI 0.59 1.32, two trials, cluster adjusted n=4 332, moderate-quality evidence), with probably no difference in the rate of loss to follow-up (RR 1.27, 95% CI 0.92 - 1.77, moderatequality evidence).

When maintenance therapy is provided in the community, there is probably no difference in mortality at 1 year when doctors deliver care in the hospital or specially trained field workers provide home-based maintenance of ART (RR 1.0, 95% CI 0.62 - 1.62, one trial, cluster adjusted n=559, moderate-quality evidence), and probably no difference in loss to follow-up (RR 0.52, 95% CI 0.12 - 2.3, moderatequality evidence).

Travel costs for patients are lower where task-shifting occurs closer to patients’ homes. Evidence suggests that the implementation of the strategy may increase health system costs, in particular related to training and supervision.

Conclusion

Shifting responsibility for providing ART from doctors to adequately trained and supported nurses or community health workers probably does not decrease the quality of care and may decrease the number of patients lost to follow-up.

Motivational interviewing for smoking cessation

(Summary prepared by M McCaul, with T Kredo and J Volmink.)

Smoking kills.[9] Fortunately, several pharma­ cological and non-pharmacological inter­ ven­tions are available to help smokers quit. [10] Motivational interviewing is a psycho­ therapeutic approach for effecting behaviour change. It originated in the treatment of alcohol abuse as ‘a directive, client-centred counselling [approach] for eliciting behaviour change by helping clients to explore and resolve ambivalence’.[11] Here we highlight a Cochrane review[12] that updates the original 2007 review investigating whether motivational interviewing promotes

0

SE(log[RR])

0.5

1

1.5

2 0.005

RR 0.1

1

10

200

Fig. 1. Funnel plot of motivational interviewing v. brief advice/usual care: All trials, outcome: smoking cessation: longest duration and strictest definition of abstinence.

smoking cessation compared with simple advice or usual care.

A comprehensive search conducted in August 2014 identified all relevant randomised controlled trials evaluating the effects of motivational interviewing for smoking cessation.

Twenty-nine trials are included (14 added since 2007), all of which provided data for meta-analysis.

Motivational interviewing for smoking cessation is moderately effective compared with brief advice or usual care, using the strictest definition of abstinence and longest follow-up period (at least 6 months) (RR 1.26, 95% CI 1.16 - 1.36, 28 trials, n=16 803, moderate-quality evidence).

Subgroup analysis by type of therapist indicated that interventions delivered by gene­ ral practitioners (RR 3.49, 95% CI 1.53 - 7.94, two trials, n=736) may have larger effects than those delivered by nurses (RR=1.24, 95% CI 0.91 - 1.68, five trials, n=2 256) or counsellors (RR 1.25; 95% CI 1.15 - 1.36, 22 trials, n=13 593).

Larger effects were found with sessions lasting <20 minutes (RR 1.69, 95% CI 1.34 - 2.12, nine trials, n=3 651) than with sessions >20 minutes (RR 1.20, 95% CI 1.08 - 1.32, 16 trials, n=10 306).

The authors noted variations in study quality and treatment fidelity, as well as between study heterogeneity and the possibility of publication or selective reporting bias (Fig. 1).

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Conclusion

Motivational interviewing appears to be modestly successful in promoting smoking cessation, compared with usual care or brief advice.

1. Gray A, Conradie F, Crowley T, et al. Improving access to antiretrovirals in rural South Africa – a call to action. S Afr Med J 2015;105(8):638-640. [http://dx.doi.org/10.7196/SAMJnew.8265] 2. Folb N, Timmerman V, Levitt NS, et al. Multimorbidity, control and treatment of non-communicable diseases among primary healthcare attenders in the Western Cape, South Africa. S Afr Med J 2015;105(8):642-647. [http://dx.doi.org/10.7196/SAMJnew.7882] 3. Reddy P, Zuma K, Shisana O, Jonas K, Sewpaul R. Prevalence of tobacco use among adults in South Africa: Results from the first South African National Health and Nutrition Examination Survey. S Afr Med J 2015;105(8):648-655. [http://dx.doi.org/10.7196/SAMJnew.7932] 4. Yach D, Alexander E. Turbo-charging tobacco control in South Africa. S Afr Med J 2015;105(8):637-638. [http://dx.doi. org/10.7196/SAMJnew.8032] 5. Kredo T, Adeniyi FB, Bateganya M, Pienaar ED. Task shifting from doctors to non-doctors for initiation and maintenance of antiretroviral therapy. Cochrane Database Syst Rev 2014;7:CD007331. [http:// dx.doi.org/10.1002/14651858.CD007331.pub3] 6. Joint United Nations Programme on HIV/AIDS (UNAIDS). Global Report 2013. http://www.unaids.org/en/resources/campaigns/ globalreport2013/globalreport/ (accessed 27 January 2014).

7. World Health Organization (WHO). Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach.

Geneva: WHO, June 2013. http://www.who.int/hiv/pub/ guidelines/arv2013/download/en/ (accessed 15 March 2015).

8. Fairall L, Bachmann MO, Lombard C, et al. Task shifting of antiretroviral treatment from doctors to primary-care nurses in South Africa (STRETCH): A pragmatic, parallel, clusterrandomised trial. Lancet 2012;380:889-898. [http://dx.doi. org/10.1016/S0140-6736(12)60730-2] 9. Keating C. Smoking Kills: The Revolutionary Life of Richard Doll. Oxford: Signal Books, 2009.

10. Coleman T, Králíková E, Himmerová V. ABC of smoking cessation.

Use of simple advice and behavioural support. Cas Lek Cesk 2004;143(10):713-715. [http://dx.doi.org/10.1136/bmj.328.7436.397] 11. Miller WR. Motivation for treatment: A review with special emphasis on alcoholism. Psychol Bull 1985;98(1):84-107. [http://dx.doi.org/10.1037/0033-2909.98.1.84] 12. Lindson-Hawley N, Thompson TP, Begh R. Motivational interviewing for smoking cessation. Cochrane Database Syst Rev 2015;3:CD006936. [http://dx.doi.org/10.1002/14651858.

CD006936.pub3]

Accepted 10 July 2015.

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HEALTHCARE DELIVERY

Anterior chamber paracentesis to improve diagnosis and treatment of infectious uveitis in South Africa E Schaftenaar, K A Lecuona, G S Baarsma, C Meenken, G M G M Verjans, J A McIntyre, R P H Peters Dr Erik Schaftenaar, MD, is a PhD candidate in the Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands, a resident in ophthalmology at Rotterdam Eye Hospital, and an honorary research associate at Anova Health Institute, Tzaneen, South Africa. The clinical studies for his thesis are part of the ‘Mopani Eye Project’, a collaboration between Anova Health Institute and the Department of Viroscience. Dr Karin Lecuona, MD, is an ophthalmologist in the Department of Ophthalmology, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa. Dr Seerp Baarsma, MD, is an ophthalmologist, specialised in uveitis and the medical retina, and works for the Rotterdam Ophthalmic Institute, The Netherlands. Dr Christina Meenken, MD, PhD, is an ophthalmologist with a special interest in uveitis and HIV/AIDS ophthalmology and works at the VU University Medical Center, Amsterdam, The Netherlands. Prof. Georges Verjans, MSc, PhD, is head of the Herpes Research Group at the Department of Viroscience, Erasmus MC, and an affiliated professor at the Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine, Hanover, Germany. Prof. James McIntyre, MB ChB, FRCOG, is Executive Director of the Anova Health Institute and an honorary professor affiliated to the School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town. Prof. Remco Peters, MD, PhD, DLSHTM, works for Anova Health Institute as clinical programme specialist and is an affiliated extraordinary professor in the Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, South Africa.

Corresponding author: E Schaftenaar (e.schaftenaar@gmail.com)

Infectious uveitis is a significant cause of blindness in South Africa, especially among HIV-infected individuals. The visual outcome of uveitis depends on early clinical and laboratory diagnosis to guide therapeutic intervention. Analyses of aqueous humor obtained by anterior chamber paracentesis direct the differential diagnosis in infectious uveitis. However, although safe and potentially cost-effective, diagnostic anterior chamber paracentesis is not common practice in ophthalmic care across Africa. We draw attention to this important procedure, which could improve the diagnosis and prognosis of infectious uveitis.

S Afr Med J 2015;105(8):628-630. DOI:10.7196/SAMJnew.7816

Uveitis is a potentially sightthreatening eye condition with an estimated prevalence of up to 714/100 000 in the developing world.[1] HIV impacts on the burden of uveitis, as HIVinfected individuals have increased susceptibility to ocular infections and may present with more severe disease.[1,2] In Uganda, infectious uveitis is the most common cause (41%) of non-correctable visual impairment among HIV-infected individuals.[3] In sub-Saharan Africa, inclu­ding countries where onchocerciasis is en­demic, up to 25% of all blindness can be attributed to uveitis.[1] Uveitis has a wide range of causes, with an infectious origin in up to 50% of cases in Africa.[1]

Diagnostic challenges in uveitis

Early diagnosis and subsequent initiation of targeted antimicrobial treatment is vitally important for good visual outcome in patients with infectious uveitis.[4-6] However, accurate diagnosis is challenging, especially in resource-poor settings and in HIVinfected individuals.[2,3] Firstly, uveitis is generally clinically underdiagnosed owing to lack of ophthalmological expertise.[2]

Unrecognised uveitis was reported to result in significant visual impairment among Ugandan HIV-infected individuals.[3] Visual impairment in these cases could possibly have been prevented if the condition had been recognised early. Secondly, if uveitis is diagnosed clinically, the presumed cause may be incorrect as the diagnosis is based on the patient’s history and clinical and ophthalmological characteristics. Clinical features have poor predictive value for diagnosing the cause of uveitis, and do not distinguish well between infectious and non-infectious origin. Moreover, in cases of infectious uveitis, clinical features are poorly predictive of the causative pathogen, because different pathogens may present with similar clinical characteristics.[4,5] Based on diagnostic testing in almost a quarter of patients presenting with uveitis in studies from The Netherlands and South Africa (SA), the initial clinical diagnosis was adjusted and treatment altered.[4,5] An exception may be uveitis caused by Mycobacterium tuberculosis where the patient’s history (e.g. recent history of pulmonary tuberculosis) or specific retinal findings (e.g. granuloma) are strongly indicative of infection by this organism. However, tuberculosis cannot

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always be ruled out solely on the basis of clinical symp­toms.[7] Thirdly, empirical treatment of infectious uveitis is difficult because of the wide range of potential uveitogenic pathogens that require targeted treatment (Table 1). Finally, HIV-infected individuals are at an increased risk of specific opportunistic ocular infections (e.g. cytomegalovirus retinitis).[2] Manifestations of infectious uveitis are often atypical, with immunosuppression resulting in a lower degree of inflammation, even in advanced uveitis, compared with HIVuninfected individuals. This makes clinical identification of the triggering pathogen in HIV-infected individuals particularly challenging.[2]

Diagnostic analysis of aqueous humor

The clinical diagnosis of infectious uveitis is increasingly supported in Western countries by analysis of ocular fluid[8] obtained through diagnostic anterior chamber paracentesis and aspiration of aqueous humor (Fig. 1). This is a well-documented procedure that is routinely performed in other aspects of ophthalmological care, e.g. management of acute elevation

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Table 1. Clinical management of the most common pathogens in infectious uveitis Aetiology

Treatment

Viruses HSV and VZV

Topical and oral or intravenous antivirals (e.g. acyclovir), topical corticosteroids (e.g. prednisolone acetate eyedrops), and intravitreal antiviral agents (e.g. ganciclovir)

CMV

Intravenous and/or intravitreal antiviral agents (e.g. ganciclovir)

Bacteria ycobacterium M tuberculosis

Routine treatment for extrapulmonary tuberculosis and topical steroids (e.g. prednisolone acetate eyedrops)

Treponema pallidum

Intravenous antibiotic treatment (e.g. penicillin G or ceftriaxone)

Protozoa Toxoplasma gondii

Oral antimicrobial regimens (e.g. pyrimethamine) and systemic steroids (e.g. prednisolone)

Onchocerca volvulus

Oral ivermectin

Note: This table serves as a general guideline for the clinical management of infectious uveitis. Management of these conditions may differ dependent on local guidelines and availability of drugs.

HSV = human simplex virus; VZV = varicella zoster virus; CMV = cytomegalovirus.

Fig. 1. Photograph and schematic overview of anterior chamber paracentesis for the aspiration of aqueous humor.

of intraocular pressure and diagnosis of suspected intraocular infections, metastasis and lymphoma.[5,6] The two key diagnostic tests of aqueous humor are pathogenspecific serological examination of paired ocular fluid and serum samples, and polymerase chain reaction (PCR) testing of the ocular fluid sample. In serological examination, intraocular pathogen-speci­ fic IgG is measured and compared with serum IgG levels (Goldmann-Witmer co­efficient) to differentiate between intra­ ocular production of antibody and passive leakage from the blood as proxy for infection, whereas PCR identifies pathogenspecific nucleic acids.[9] In infectious uveitis, pathogen-specific nucleic acids and IgG

production are commonly detectable at different times after the onset of disease.

During the early phase, nucleic acids are detectable within days after the onset of disease, followed by detection of intraocular IgG levels. Whereas pathogen nucleic acids commonly become undetectable 2 weeks after the onset of disease, specific antibodies remain detectable for many weeks in aqueous humor.[9] The two assays are therefore complementary, and contribute considerably to the differential diagnosis of infectious uveitis.[4-6,9,10] Identification of the triggering pathogen was established by serological examination and PCR in 60% of HIV-infected individuals presenting with undefined posterior uveitis, whereas PCR

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provided a final diagnosis in 39% of cases in which the initial diagnosis of the causative pathogen was uncertain.[4,10] Furthermore, treatment was altered on the basis of PCR results in 20% of patients with posterior uveitis of suspected infectious origin in a study from the USA.[6]

Anterior chamber para­ centesis in uveitis

Anterior chamber paracentesis is a safe procedure that can be performed in a consultation room with a slit-lamp.[11,12] Three studies have reported on the safety of this procedure in diagnosing uveitis.[11-13] Only a few nonserious complications occurred, including traumatic hyphaema (5 cases/1 000 procedures), referring to bleeding in the anterior chamber that may cause blurred vision, but usually resolves spontaneously or is easily treatable with topical eyedrops (e.g. topical steroids); similarly, injection of air into the anterior chamber (4 cases/1 000 procedures) may cause blurred vision, but is usually selflimiting.[11-13] Uveitis is a serious condition resulting in severe visual impairment and even blindness if not treated promptly and adequately. In SA, referral from lower levels of healthcare to a regional ophthalmology unit for further management and initiation of (empirical) treatment is indicated.

However, even in these units treatment outcomes may be poor owing to the low predictive value of the patient’s history and clinical characteristics for identifying the cause of the uveitis.

Anterior chamber paracentesis, aspiration and analysis of aqueous humor provide a valuable diagnostic procedure that optimises treatment and subsequent prognosis and poses a very limited risk. We believe that this procedure could be performed in most settings, because a well-trained ophthalmic nurse could perform anterior chamber paracentesis safely in situations where qualified ophthalmologists are not available.

Paracentesis is easier to perform than cataract surgery, for which ophthalmic nurses are trained in African countries such as Malawi that lack ophthalmologists.[14] In addition to skills development, strengthening labora­tory infrastructure is warranted. Validation of existing diagnostic assays and provision of other resources required to analyse aqueous humor for the most common uveito­genic pathogens should be considered across SA. Furthermore, logistic systems such as a cold-sample transport chain require optimi­ sation to ensure a short turnaround time and maximum clinical impact of this diag­nostic test. Providing such a diagnostic service

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would be cost-effective, reducing unnecessary use of expensive antimicrobial drugs and avoiding blindness and its associated socioeconomic costs.[15]

Conclusion

We seek to draw attention to the so far unmet need for this valuable diagnostic procedure and to encourage discussion among health­care providers regarding introduction of anterior chamber paracentesis in the routine work-up of patients with uveitis in SA. Ultimately, these efforts should result in the development of clinical guidelines and a training programme that includes anterior chamber aspiration. This would improve clinical management of uveitis and reduce the burden of avoidable visual impairment and blindness.

Authorship. ES: literature search, design, figure, table and writing; KAL: writing; GSB: literature search and writing; CM: writing; GMGMV: writing and figure; JAM: writing; RPHP: literature search, design, figure, table, and writing. All the authors have seen and approved the content of this article.

Acknowledgements. We thank Prof. Aniki Rothova of the Department of Ophthalmology, Erasmus MC, Rotterdam, The Netherlands, for providing the photo in Fig. 1.

1. London NJ, Rathinam SR, Cunningham ET Jr. The epidemiology of uveitis in developing countries. Int Ophthalmol Clin 2010;50(2):1-17. [http://dx.doi.org/10.1097/IIO.0b013e3181d2cc6b]

2. Schaftenaar E, van Gorp ECM, Meenken C, et al. Ocular infections in sub-Saharan Africa in the context of high HIV prevalence. Trop Med Int Health 2014;19(9):1003-1014. [http://dx.doi. org/10.1111/tmi.12350] 3. Otiti-Sengeri J, Colebunders R, Kempen JH, Ronald A, Sande M, Katabira E. The prevalence and causes of visual loss among HIV-infected individuals with visual loss in Uganda. J Acquir Immune Defic Syndr 2010;53(1):95-101. [http://dx.doi.org/10.1097/QAI.0b013e3181c313f0] 4. Scheepers MA, Lecuona KA, Rogers G, Bunce C, Corcoran C, Michaelides M. The value of routine polymerase chain reaction analysis of intraocular fluid specimens in the diagnosis of infectious posterior uveitis. ScientificWorldJournal 2013;2013:545149. [http://dx.doi.org/10.1155/2013/545149] 5. Rothova A, de Boer JH, Ten Dam-van Loon NH, et al. Usefulness of aqueous humor analysis for the diagnosis of posterior uveitis. Ophthalmology 2008;115(2):306-131. [http://dx.doi.org/10.1016/j. ophtha.2007.05.014] 6. Harper TW, Miller D, Schiffman JC, Davis JL. Polymerase chain reaction analysis of aqueous and vitreous specimens in the diagnosis of posterior segment infectious uveitis. Am J Ophthalmol 2009;147(1):140-147. [http://dx.doi.org/10.1016/j.ajo.2008.07.043] 7. Abu El-Asrar AM, Abouammoh M, Al-Mezaine HS. Tuberculous uveitis. Int Ophthalmol Clin 2010;50(2):19-39. [http://dx.doi.org/10.1097/IIO.0b013e3181d2ccb9] 8. Hunter RS, Lobo AM. Current diagnostic approaches to infectious anterior uveitis. Int Ophthalmol Clin 2011;51(4):145-156. [http://dx.doi.org/10.1097/IIO.0b013e31822d6807] 9. De Groot-Mijnes JD, Rothova A, van Loon AM, et al. Polymerase chain reaction and GoldmannWitmer coefficient analysis are complementary for the diagnosis of infectious uveitis. Am J Ophthalmol 2006;141(2):313-318. [http://dx.doi.org/10.1016/j.ajo.2005.09.017] 10. Danise A, Cinque P, Vergani S, et al. Use of polymerase chain reaction assays of aqueous humor in the differential diagnosis of retinitis in patients infected with human immunodeficiency virus. Clin Infect Dis 1997;24(6):1100-1106. [http://dx.doi.org/10.1086/513625] 11. Cheung CM, Durrani OM, Murray PI. The safety of anterior chamber paracentesis in patients with uveitis. Br J Ophthalmol 2004;88(4):582-583. [http://dx.doi.org/10.1136/bjo.2003.027219] 12. Trivedi D, Denniston AK, Murray PI. Safety profile of anterior chamber paracentesis performed at the slit lamp. Clin Experiment Ophthalmol 2011;39(8):725-728. [http://dx.doi.org/10.1111 /j.1442-9071.2011.02565] 13. Van der Lelij A, Rothova A. Diagnostic anterior chamber paracentesis in uveitis: A safe procedure? Br J Ophthalmol 1997;81(11):976-979. [http://dx.doi.org/10.1136/bjo.81.11.976] 14. Palmer JJ, Chinanayi F, Gilbert A, et al. Trends and implications for achieving VISION 2020 human resources for eye health targets in 16 countries of sub-Saharan Africa by the year 2020. Hum Resour Health 2014;12(1):45. [http://dx.doi.org/10.1186/1478-4491-12-45] 15. De Smet MD, Taylor SRJ, Bodaghi B, et al. Understanding uveitis: The impact of research on visual outcomes. Prog Retin Eye Res 2011;30(6):452-470. [http://dx.doi.org/10.1016/j.preteyeres.2011.06.005]

Accepted 31 May 2015.

This month in the SAMJ ...

Priscilla Reddy* is Deputy Executive Director in the Population Health, Health Systems and Innovation programme of the Human Sciences Research Council. She holds a PhD in health promotion and behavioural science from the University of Maastricht in The Netherlands. She has worked and published in the field of tobacco control research since 1992, and her work was used by government to inform its programme of tobacco control measures over the past 23 years. She has conducted controlled trials in smoking cessation in adolescents, and led three Youth Risk Behaviour Surveys and four Global Youth Tobacco Surveys in South Africa. She has also published extensively in behavioural aspects of HIV/AIDS and sexually transmitted disease prevention. She has served on three National Academy of Medicine Committees, reviewing the President’s Emergency Plan for AIDS Relief (PEPFAR) Antiretroviral Programme and Tobacco Control in Africa. *Reddy P, Zuma K, Shisana O, Jonas K, Sewpaul R. Prevalence of tobacco use among adults in South Africa: Results from the first South African National Health and Nutrition Examination Survey. S Afr Med J 2015;105(8):648-655. [http://dx.doi.org/10.7196/SAMJnew.7932]

Dr Erik Schaftenaar,* MD, is a PhD candidate in the Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands, a resident in ophthalmology at Rotterdam Eye Hospital, and an honorary research associate at Anova Health Institute, Tzaneen, South Africa. The clinical studies for his thesis are part of the Mopani Eye Project, a collaboration between Anova Health Institute and the Department of Viroscience. *Schaftenaar E, Lecuona KA, Baarsma GS, et al. Anterior chamber paracentesis to improve diagnosis and treatment of infectious uveitis in South Africa. S Afr Med J 2015;105(8):628-630. [http://dx.doi.org/10.7196/SAMJnew.7816]

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Patient support interventions to improve adherence to drug-resistant tuberculosis treatment: A counselling toolkit E Mohr, J Hughes, L Snyman, B Beko, X Harmans, J Caldwell, H Duvivier, L Wilkinson, V Cox Erika Mohr, drug-resistant tuberculosis (DR-TB) epidemiologist at Médecins Sans Frontières (MSF) Khayelitsha, Cape Town, South Africa, obtained a Master’s in Public Health from Boston University (USA), concentrating in epidemiology. Her special interests include infectious diseases, maternal and child health and developing health care systems. Jennifer Hughes, DR-TB doctor at MSF Khayelitsha, graduated MB BCh and BSc Hons (Public Health) from Cardiff University in Wales and completed a Diploma in Tropical Medicine and Hygiene (DTMH) in Liverpool. Leigh Snyman, DR-TB patient support manager at MSF Khayelitsha, graduated with a Diploma in General Nursing and has completed a short course in palliative nursing care. Busisiwe Beko, a DR-TB counsellor at MSF Khayelitsha, is studying for a degree in social work. Her special interests include patient-centred models of care, particularly for patients with DR-TB. Xoliswa Harmans is also a DR-TB counsellor at MSF Khayelitsha. As a former extensively drug-resistant tuberculosis patient, she is interested in the provision of structured patient support for DR-TB. Judy Caldwell, a registered nurse with a BCur degree, is TB project manager at the Department of Health for the City of Cape Town. Hélène Duvivier, patient and community support advisor at MSF South Africa and Lesotho, is a clinical sexotherapist with a master’s degree in Sciences of Family and Sexuality from Louvain-laNeuve University, Belgium. Lynne Wilkinson, project co-ordinator of the HIV/TB Programme at MSF Khayelitsha, is a qualified attorney with a master’s degree in Global Health. Her special interests include HIV and TB retention and adherence strategies, focusing on community models of care and patient support-related interventions. Vivian Cox, MD, current deputy field co-ordinator of the HIV/TB Programme at MSF Khayelitsha, is particularly interested in infectious diseases and recently completed an MSF mission in Liberia to provide assistance with the Ebola outbreak.

Corresponding author: E Mohr (msfocb-khayelitsha-drtb-epi@brussels.msf.org)

In response to the growing burden of drug-resistant tuberculosis (DR-TB) in South Africa (SA), Médecins Sans Frontières (MSF), with local government health departments, piloted a decentralised model of DR-TB care in Khayelitsha, Western Cape Province, in 2007. The model takes a patient-centred approach to DR-TB treatment that is integrated into existing TB and HIV primary care programmes. One essential component of the model is individual and family counselling to support adherence to and completion of treatment. The structured and standardised adherence support sessions have been compiled into a DR-TB counselling toolkit. This is a comprehensive guide that focuses on DR-TB treatment literacy, adherence strategies to encourage retention in care, and provision of support throughout the patient’s long treatment journey. Along with other strategies to promote completion of treatment, implementation of a strong patient support component of DR-TB treatment is considered essential to reduce rates of loss from treatment among DR-TB patients. We describe our experience from the implementation of this counselling model in a high DR-TB burden setting in Khayelitsha, Cape Town, SA. S Afr Med J 2015;105(8):631-634. DOI:10.7196/SAMJnew.7803

Drug-resistant tuberculosis (DR-TB), defined as TB with at least rifampicin resistance, is increasing in preva­ lence and incidence worldwide.[1] South Africa (SA) has reported some of the highest numbers of DR-TB cases globally: in 2012 alone there were 14 161 laboratorynotified cases of multidrug-resistant TB (MDR-TB) and 1 545 cases of extensively drug-resistant TB (XDR-TB).[2] Regimens available for DR-TB are expensive, toxic, and require a minimum treatment duration of 20 months. In addition, currently available medications often cause multiple side-effects that impact on patients’ ability to maintain their usual daily activities.[3] The burden of treatment regimens contributes to poor DR-TB programme outcomes, including high rates of loss from treatment (LFT) and stagnant treatment success rates. A study conducted in the Western Cape Province, SA, found an LFT rate of 27%, which is comparable to LFT rates observed in other DR-TB treatment cohorts in SA.[4] National Department of Health (NDoH) data from 2012 reflect a 40% treatment success rate for MDR-TB and less than 20% treatment success for XDRTB.[2] It is imperative that strategies to provide structured patient support are developed and implemented to promote retention in care.

Setting

Khayelitsha, a township in the Western Cape, is home to approximately 500 000 people and has one of the highest rates of

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HIV and TB among subdistricts in the country. It was determined that there were 989 cases of DR-TB diagnosed in Khayelitsha from 2003 through 2010, 200 of which were diagnosed in 2010. In response to the growing burden of DR-TB in Khayelitsha, Médecins Sans Frontières (MSF) collaborated with City of Cape Town Department of Health (CCTDoH) and provincial health services in 2007 to pilot a decentralised model of care in which primary healthcare clinicians initiate and manage treatment of patients diagnosed with DR-TB at Khayelitsha-based clinics. The prevailing model of care for DR-TB previously involved centralisation of treatment to 45 specialised hospitals in SA, which hindered the ability to provide longitudinal support to DR-TB patients and their families in their local community. In contrast, decentralisation to primary care enabled patient support to form a major component of the overall model of care.[5] Two dedicated lay DR-TB counsellors were employed to provide education and support to DR-TB patients managed at 11 primary care clinics in the subdistrict. Since 2011 the model has been managed by the CCTDoH, and various aspects of the model have been adopted and implemented across other subdistricts in the Western Cape. In 2012, MSF, together with the CCTDoH, developed a more structured, standardised, patientcentered approach to counselling DR-TB patients, placing equal emphasis on treatment literacy and adherence support.

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Objective

A policy of decentralised management of DR-TB in SA was endorsed by the NDoH in 2011. Although welcomed for its priori­ tisation of decentralisation nationally, it lacks specific information on how to provide structured patient support and counselling despite its recommendation to provide these services to patients. The DR-TB counselling toolkit aims to provide guidance on how to provide patient support to promote adherence to difficult treatment regimens, to encourage retention in care, and to increase the likelihood of successful treatment outcomes.

Treatment start

Session 1

<1 week later

Session 2

<1 month later

2nd-line DST result

XDR session

Milestone

The intervention

The counselling toolkit is a comprehensive guide that provides patients with support throughout the duration of their treatment.

It aims to encourage patients to take owner­ ship of their treatment. Specific counselling session plans have been included in the toolkit that provide structured scripts of simple key points to convey to patients,

Session 3 Home visit

Injectable phase

Session 4

Continuation phase

Treatment interruption >2 weeks at any point through treatment Treatment interruption session

Treatment interruption followup

Treatment failure Palliative session

Fig. 1. Overview of the counselling sessions.[6] (DST = drug susceptibility testing.)

Table 1. Timing of DR-TB counselling sessions[6] Resource materials

Session

Target

Rationale

Timing and location

Session content

Session 1

Newly diagnosed DR-TB patients

Provide the patient with information regarding DR-TB to promote insight about their disease, adherence to treatment, and ownership of their treatment journey

First day of treatment initiation

Treatment literacy Basic TB and DR-TB information including definitions, when and where to take treatment, and clinic visits; basic awareness of sideeffects and other treatment-related challenges; basic infection control Adherence steps Step 1: Getting to appointments Step 2: Dealing with side-effects Step 3: Getting support at home Step 4: Getting support at the clinic Step 5: Audiometry screening Identify three reasons to stay healthy and alive

Session plan – session 1 Flip chart Adherence plan Stickers

Treatment literacy Basic information regarding adherence and what to expect if adherence is poor; discussing the importance of identifying drugs and dosages; definitions of sputum and culture conversion Adherence steps Step 6: Preventing future mistakes and completing the treatment journey Step 7: Identifying a treatment partner Step 8: Communicating with the treatment team Step 9: How to manage weekend doses Step 10: Reminder strategies

Session plan – session 2 Flip chart Adherence plan Stickers

Clinic

To plan with the counsellor how to overcome possible barriers to treatment adherence

Session 2 (may be com­­bined with session 3)

DR-TB patients who have received counselling session 1

Provide the patient with information regarding DR-TB to promote insight into their disease and adherence to treatment, and allow patient to take ownership of the treatment journey as they plan with the counsellor how to overcome possible barriers to adherence to treatment

Within 1 week of treatment initiation Home or clinic

Continued ...

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Table 1. (continued) Timing of DR-TB counselling sessions[6] Resource materials

Session

Target

Rationale

Timing and location

Session content

Session 3 (may be combined with session 2)

DR-TB patients who have received counselling session 2

Provide DR-TB information to the family and the patient, encouraging the family to support the patient; DR-TB contact identification, screening and infection control advice

Within the first month of treatment initiation

Treatment literacy Basic TB and DR-TB information: TB infection control and how TB is spread; time off work or school; patient journey; details of those at risk of DR-TB and contacts in the home; TB and pregnancy; traditional medication and alcohol use with treatment Adherence steps Step 11: How to protect my family Step 12: How to deal with substance abuse Step 13: Managing unplanned trips

Session plan – session 3 Flip chart Adherence plan

Session 4

DR-TB patients who have completed the intensive phase

Congratulate the patient and revise treatment literacy messages and adherence steps to ensure ongoing adherence (also inform patient of potential for selfadministered treatment (SAT) in some settings)

Completion of intensive phase

Revision of treatment literacy messages See sessions 1 - 3 Revisit adherence steps See sessions 1 - 3

Session plan – session 4 Flip chart Adherence plan that was completed post treatment initiation

Patients who interrupted DR-TB treatment for ≥2 consecutive weeks or who frequently interrupt treatment for short time periods

Promote adherence to treatment and prevent LFT

As soon as the patient has interrupted DR-TB treatment for 2 consecutive weeks, or if the patient frequently interrupts treatment for short time periods

Treatment literacy What is adherence, what happens if you take your treatment, and what happens if you stop taking your treatment Adherence steps Step 1: Reminder strategies Step 2: Getting to the clinic Step 3: Getting support at home Step 4: DR-TB support at the clinic Step 5: Dealing with side-effects Step 6: Dealing with substance use Step 7: Completing your treatment journey

Session plan – treatment interruption session Flip chart Adherence plan

Follow-up session Monitor goals achieved, set new goals

Adherence plan Nurse monitoring document

Treatment literacy Adherence assessment Step 1: Confirming the patient’s support system at home Step 2: Reviewing contacts for screening Step 3: SOS plan for emergencies

Session plan – XDR-TB session Adherence assessment

Explanation about current diagnosis; what happens with treatment of other chronic diseases or conditions; how to travel safely if the patient intends to migrate

Session plan – palliative care session Relevant facility contact details Referral letter from clinician

Treatment interruption session

Home (if the patient refuses a home visit, this session can be done in the clinic with a family member joining the patient)

Clinic

Clinic or home

Treatment interruption follow-up sessions XDR-TB session

Palliative care session

Patients who received the treatment interruption session

Monitor adherence on a frequent basis and improve the patienthealthcare worker relationship

One week after the treatment interruption counselling session

Patients with a pre-XDR or XDRTB diagnosis

Educate the patient on pre-XDR and XDR diagnosis, discuss potential future treatment options and limitations (the clinician will continue this discussion), create an awareness of palliative care

As soon as possible after second-line resistance has been detected

Understanding their diagnosis and prognosis, future treatment and psychosocial support options

As soon as the patient is identified by a clinician as a patient in whom DR-TB treatment has failed

Patients in whom DR-TB treatment has failed, and have been identified as such by a clinician

Clinic

Clinic

Home or clinic

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to address very sensitive topics with patients and their families should treatment not yield a successful outcome. Recognising the importance of quality assurance, a counsellor competency assessment for supervisors has also been included in the toolkit.[6] Fig. 1 provides a summary of the timing of the various DR-TB sessions in relation to the patient’s journey towards DR-TB treatment completion. Table 1 provides an overview of the contents of the various counselling sessions provided by the DR-TB counsellor to the patient.

While challenges in the implementation of this patient support model can be anticipated, including human resource needs for skilled lay counsellors and their supervision, the structured nature of the approach supports formalised training and monitoring of counsellors and their supervisors. It is further possible to implement counselling sessions in a phased manner to slowly build capacity towards implementing the more specialised XDR-TB and palliative care sessions.

The infrastructure required for the implementation of this toolkit includes four essential components: DR-TB counselling session guides for both the counsellors and their supervisors; adherence plans for patients (Fig. 2); DR-TB flipcharts to use as supportive educational tools during counselling sessions; and a structured training programme for counsellors that contains the tools and exercises necessary to ensure standardised quality of counselling provided to patients.

Patient name: My three reasons to stay healthy and alive: 1 2 3 Session 1 (date) DR-TB education done Adherence Step 1: Getting to appointments How am I going to get to clinic every day Backup plan to get to appointments daily Adherence Step 2: Dealing with side-effects My plan for minor side-effects is My plan for side-effects that worry me is Adherence Step 3: Getting support at home Members of my support system

Agree to a home visit Yes No

Who else can support me in my treatment Adherence Step 4: Getting support at the clinic Contact details of the clinic Adherence Step 5: Getting to my audiometry screening appointments How to remember audiometry appointments How to get to my audiometry appointments Backup plan to get to appointments Session 2 (date)

Conclusions

DR-TB education done Adherence Step 6: Preventing any future mistakes and completing my treament journey What will I do if I make a mistake, and don’t come to the clinic for a while to take my treament

Adherence Step 7: Treatment partner My treatment partner is Adherence Step 8: Communicating with treatment team My focal person in clinic is Adherence Step 9: How to manage weekend doses How will I remember to take my weekend medication Where will I keep my weekend medication Adherence Step 10: Reminder strategies I will put my reminder stickers on

The counselling toolkit was presented at the 4th Annual South African Tuberculosis Conference held in Durban, SA, on 10 - 13 June 2014. At the conclusion of the conference, the counselling model was recognised for clinical excellence by the organising committee, reinforcing the importance of including a structured patient support component during decentralisation of DR-TB care to primary care level. The DR-TB counsellor is a critical member of the team providing care to patients with DR-TB. It is essential that all DR-TB clinicians, nurses, and counsellors work together to ensure comprehensive support for patients with DR-TB. This support is as essential as the pills patients are required to take every day, and must continue throughout the long DR-TB treatment journey.

I will read my reasons for taking my treatment at My other reminder tools are

Author contributions and funding. EM wrote the article, JH, LS, JC, LW, HD, and VC devised the counselling sessions and toolkit, BB and XH implemented the counselling sessions, and JC, HD, LW and VC assisted with the revision of the article. All the authors reviewed and approved the final article. The counselling toolkit was funded by MSF. Ethics approval statement. Since this was a retrospective description of the counselling toolkit which involved no data analyses, no ethical approval was needed.

Acknowledgements. We thank the CCTDoH, the Western Cape Province, the National Health Laboratory Service, Khayelitsha clinic staff, the DRTB counsellors, and most importantly, our patients suffering from DR-TB and HIV in Khayelitsha.

Session 3 (date) DR-TB education done Adherence Step 11: How to protect my family I will sleep Adherence Step 12: Dealing with substance use My plan to make sure I take my treatment if I used alcohol or drugs is

Adherence Step 13: Managing unplanned trips My folder number My regular travel location The closest clinic at my regular travel location is GOAL: To be sputum–negative

Fig. 2. Sessions 1 - 3 adherence plan for patients.[6] and steps they should follow to overcome commonly experienced barriers to adherence. The initial four sessions are conducted during the intensive phase of treatment (the first three should be conducted within the first 4 weeks of treatment initiation, one of which must be a home visit), with the goals of treatment literacy, stepwise adherence planning, family involvement, contact tracing and infection control advice. In addition to these initial sessions, counselling sessions can occur at any time during treatment to address treatment interruption, the diagnosis of XDR-TB, and treatment failure and palliative care.

These additional sessions are particularly important, as they provide detailed scripts for lay counsellors or professional healthcare workers

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1. World Health Organization. Companion Handbook to the WHO Guidelines for the Programmatic Management of Drug-resistant Tuberculosis, 2014. http://apps.who.int/iris/ bitstream/10665/130918/1/9789241548809_eng.pdf (accessed 1 August 2014).

2. Ndjeka N. Multi-Drug Resistant Tuberculosis: Strategic Overview on MDR-TB Care in South Africa.

National Department of Health, 2014. https://www.msf.org.za/sites/msf.org.za/files/Publications/ Strategic_overview_of_MDR_TB_RSA.pdf (accessed 1 January 2015).

3. Calligaro G, Dheda K. Drug-resistant tuberculosis. CME 2013;31(9):344-346. http://www.cmej.org.za/ index.php/cmej/article/view/2853/3188 (accessed 1 August 2014).

4. Kendall EA, Theron D, Franke MF, et al. Alcohol, hospital discharge, and socioeconomic risk factors for default from multidrug resistant tuberculosis treatment in rural South Africa: A retrospective cohort study. PLoS One 2013;8(12):e83480. [http://dx.doi.org/10.1371/journal.pone.0083480] 5. Médecins Sans Frontières. Scaling-up diagnosis and treatment of drug-resistant tuberculosis in Khayelitsha, South Africa, 2011. http://www.msfaccess.org/sites/default/files/MSF_assets/TB/Docs/ TB_report_ScalingUpDxTxKhaye_ENG_2011.pdf (accessed 1 August 2014).

6. Médecins Sans Frontières. Patient support interventions to improve adherence to drug resistant tuberculosis treatment: Counselling toolkit, 2014. http://samumsf.org/documents/2014/06/ khayelitsha_dr-tb-pt-support.pdf (accessed 1 August 2014).

Accepted 30 May 2015.

August 2015, Vol. 105, No. 8

FORUM

MEDICAL HISTORY

The first black doctors and their influence in South Africa B M Mayosi Prof. Bongani Mayosi is Head of the Department of Medicine at Groote Schuur Hospital and the Faculty of Health Sciences, University of Cape Town, South Africa. He qualified in medicine from the University of KwaZulu-Natal in Durban, trained in internal medicine and cardiology in Cape Town, and graduated with a DPhil in genetics from Oxford University. His research interests include the genetics of cardiovascular traits, treatment of tuberculous pericarditis and prevention of rheumatic fever.

Corresponding author: B M Mayosi (bongani.mayosi@uct.ac.za)

The early black doctors who qualified from foreign medical schools between 1883 and 1940 were pioneers in the history of South Africa. They made seminal contributions to the struggle against colonialism and apartheid, established the principle of fighting against racism in healthcare through the courts, and were trailblazers in academic medicine. They have bequeathed a remarkable legacy to the new South Africa.

S Afr Med J 2015;105(8):635-636. DOI:10.7196/SAMJnew.7821

Before 1940, there were no opportunities for training in medicine in South Africa (SA) for people who were not white. The University of the Witwatersrand (Wits) took the first black medical students in 1941, and was followed shortly by the University of Cape Town (UCT).[1] Before 1940, training was possible overseas either through funding from the church for many black Africans or from family resources for coloured and Indian South Africans.

Glasgow in 1915. Another daughter, Waradea Abdurahman, became the first black woman to qualify as a doctor in SA (Glasgow, 1927).

The dynastic tendency of the first generation of black doctors was also evident among the Sogas. Alexander R B Soga, son of William Anderson, became the seventh black doctor in SA (Glasgow, 1912).

Alexander Soga started his practice in Eliotdale, where his father had worked, and subsequently established a private practice in Idutywa in the Transkei.

Early black medical doctors

The next generation

William Anderson Soga was the first black medical doctor in SA.[2] He was the son of Tiyo Soga from Tamarha near Butterworth in Transkei, who was ordained as the first black SA minister of religion in the United Presbyterian Church of Scotland on 10 December 1856. Soga qualified in medicine from Glasgow in 1883 – about 30 years before the creation of the medical school in Cape Town, and 60 years before UCT and Wits considered black people fit for admission to their hallowed halls. Let us not forget that UCT practised a pernicious form of racism in which local black African students were not admitted to study medicine until about 100 years after Soga’s graduation from Glasgow.

Like his father, Dr Soga was ordained as a minister (in 1885). He was licensed to practise in the Cape from 1890, and worked as a medical missionary at the Miller Mission in Eliotdale, Bomvanaland.

He started private practice in the same area in 1904 and worked there until his death in 1912. Soga’s example was followed by John Mavuma Nembula, who graduated with the degree Doctor of Medicine from Chicago in 1887, and Abdullah Abdurahman, who earned the Scottish Triple in 1893.

Nembula was born in Amanzimtoti, Natal, and educated at Adams Mission Station before he was taken to the USA by American missionaries to translate the Bible into Zulu. He commenced practice as a district surgeon at Umsinga in 1889 and ran a multiracial practice in nearby Pomeroy. He died of tuberculosis in 1897 at the age of 36.

Abdurahman practised in Cape Town between 1895 and 1929.

During this time, he fought for better living conditions for black people as a Cape Town city councillor. His daughter Cissie married Abdul Hamid Gool, who qualified as a doctor from London in 1910, and his brother Ismail Abdurahman qualified as a doctor from

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Whereas only three black doctors had qualified in the final 20 years of the 19th century, there were 29 who qualified from UK and US medical schools between 1900 and 1940, including luminaries such as James Moroka (Edinburgh, 1918), Silas Modira Molema (Glasgow, 1919), Alfred Bitini Xuma, with dual American (1920) and Scottish (1926) qualifications, Monty Naicker and Yusuf Dadoo (both Edinburgh, 1934).

Moroka and Xuma became successive presidents of the African National Congress (ANC) in the 1940s and have suburbs in Gauteng named after them – Kwa Xuma in Springs and Moroka in Soweto.

Naicker revived the Natal Indian Congress (NIC), and Dadoo was initially the president of the Transvaal Indian Congress (TIC) before he became a leader of the South African Communist Party.

Political contributions

The first generation of black doctors made seminal and lasting contributions in at least three areas. The first was their political contribution to the non-racial struggle against apartheid. The famous ‘Three Doctors’ Pact’ bears testimony to their foundational role in the new SA. A ‘Joint Declaration of Cooperation’ was signed by Xuma, President of the ANC, Naicker, President of the NIC, and Dadoo, President of the TIC, on 9 March 1947.[3] The Doctors’ Pact was significant: it provided the basis for unity among Africans and Indians and the principle of non-racialism that was to define the anti-apartheid struggle from the 1950s onwards, and the call for ‘a vigorous campaign to be launched immediately’ inspired the Defiance Campaign of the early 1950s that signalled the change in the tempo of the anti-apartheid struggle from a series of deputations to the Queen pleading for mercy to direct political action against unjust laws.

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The irony of the change and radicalisation of the anti-apartheid struggle is that Moroka and Xuma were faced with a stark choice between political activism carrying the risk of imprisonment, and the continuation of their lucrative medical careers. Indeed, during the Defiance Campaign, Moroka was to testify against his comrades in the ANC and escape prison. Nelson Mandela said that Moroka ‘was unwilling to jeopardise his medical career and fortune for his political beliefs’.

Xuma also fell on his sword. He opposed the 1949 Programme of Action of the ANC Youth League, which envisaged a campaign of mass mobilisation, and resigned from the ANC, continuing to practise in Sophiatown. Mandela commented that ‘his medical practice took precedence ... he made it clear that he was a doctor with a wide and prosperous practice that he would not jeopardise by going to prison’.

There was, however, a new generation of black doctors who had qualified from Wits in the 1940s and 1950s, such as Wilson Conco, Dilizintaba Mji, Ntatho Motlana and James Njongwe, who joined Mandela in the Defiance Campaign and pursued the new radical agenda of the ANC, thus taking over the baton of political leadership from the first generation of ANC doctors.

Molema’s story represents the second major contribution of the early black doctors to our history. He commenced practice in Mafikeng in 1922, and ran a subsidiary practice in Johannesburg.

He had a multiracial practice and observed the custom of the time that provided for separate entrances for white and black patients.

Molema’s practice of liberally prescribing medicine (much liked by his black patients) also found favour among Afrikaner patients, who referred to him as ‘die dokter van die groot bottel’ (the doctor of the large bottle).[1] In 1927, an incident occurred that I believe was the trailblazer for the health-for-all campaign in SA. White nurses resigned after Molema admitted some of his white private patients to Victoria Hospital in Mafikeng. He did not take this affront to decent healthcare for his patients lying down – he took legal action, and won the case for access of his patients to appropriate care unencumbered by racism.

Academic achievements

Finally, the first generation of black doctors were not devoid of academic ability. Dr William Anderson Soga was not only the first black doctor in SA, but he also wrote a Doctor of Medicine thesis after 10 years of practice in Bomvanaland.[2] The thesis has remarkable aspects. First, it emphasised the role of climate, nutrition and housing in the genesis of ill-health among the Bomvana people – Soga foresaw the role of climate change in health and disease that has become a major subject of study and controversy in our time.

Second, he wrote about the epidemiology of local diseases, including the persisting problems of rheumatic fever, tuberculosis and leprosy.

Finally, he provided a mixed assessment of the effectiveness of traditional medicine, praising the methods used to treat fracture but lambasting the wily and deceptive ways of traditional diviners.[2]

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Wilson Zamindlela Conco was a promising successor to William Anderson Soga as the second black academic physician in SA. He was a brilliant medical student who qualified from Wits at the top of his class in 1948. His appointment as demonstrator in histology at Wits provoked a protest among National Party MPs that led to his demotion to demonstrator to black students only.[1] The acquiescence of Wits to academic racism was a harbinger of the Archie Mafeje affair at UCT in 1969, and closed the doors to aspirant black scholars in our university system for decades.

A remarkable legacy

The first generation of black doctors have bequeathed to us a great example that is as relevant to the new SA as it was during their time. Rudolf Ludwig Carl Virchow, the German pathologist and politician, said that medicine is a social science, and politics is nothing other than medicine on a large scale. Our generation of medical doctors accepts the responsibility to play a public role, which may require direct political action from time to time.[4] This we have done, for example when our politicians attempted to cut beds at Groote Schuur Hospital[5] – such public action has ensured that tertiary medicine is recognised as a legitimate component of an effective national health system.[6] The courts that were used effectively by Silas Modiri have been a powerful weapon in ensuring that the government of Thabo Mbeki provided antiretroviral therapy against its own wishes, and that drug companies are forced to provide lifesaving medication at a cost that poor people can afford.

Finally, we are building on the remarkable Doctor of Medicine degree of William Anderson Soga by raising a new generation of scholars in medicine on a large scale. We have started a multitude of schemes to provide opportunities for health professionals to become researchers and scholars as good as any in the world. One ambitious project is to produce 1 000 PhDs in medicine over the next ten years.[7] This and other plans are beginning to bear fruit, and promise to usher SA on to the high road of research and innovation in healthcare and help to overcome the formidable health problems of the people of Africa.

1. Digby A. Early black doctors in South Africa. Journal of African History 2005;46(3):427-454. [http:// dx.doi.org/10.1017/S0021853705000836] 2. Digby A. On the notable thesis of William Anderson Soga, the first black doctor in South Africa. S Afr Med J 2007;97(5):345-346.

3. ‘Three Doctors’ Pact’, March 9 1947. http://www.sacp.org.za/docs/history/dadoo-45.html (accessed 15 March 2015).

4. Bateman C. Academic health complexes bleeding in ‘no man’s land’. S Afr Med J 2010;100(1):17-19.

5. Caelers D. Docs sticking to their guns in cuts row. 2007. http://www.iol.co.za/news/south-africa/ docs-sticking-to-their-guns-in-cuts-row-1.316699?ot=inmsa.ArticlePrintPageLayout.ot (accessed 18 February 2015).

6. Mayosi BM, Benatar SR. Health and health care in South Africa – 20 years after Mandela. N Engl J Med 2014;371(14):1344-1353. [http://dx.doi.org/10.1056/NEJMsr1405012] 7. Nordling L. South Africa invests in health research training. 2012. http://blogs.nature.com/ news/2012/04/south-africa-invests-in-health-research-training.html (accessed 16 March 2015).

Accepted 20 March 2015.

August 2015, Vol. 105, No. 8

EDITORIAL

Turbo-charging tobacco control in South Africa Tobacco use globally and in South Africa

Tobacco continues to be the leading cause of death and disease worldwide.[1] Globally, the prevalence of smoking among adults decreased between 1980 and 2012 from 41% to 31% for men and from 11% to 6% for women, yet the number of smokers increased to nearly 1 billion by 2012.[2] Tobacco use by girls is increasing in many countries, and unless effectively addressed will result in increased risk for the next generation of women.[3] While media attention to global tobacco has waned, the harm it causes is increasing.

The 2015 World Conference on Tobacco or Health (WCTOH) held recently in Abu Dhabi recommended the urgent ratification of the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) by the remaining non-signatories (of which the USA and Indonesia are the most significant), and full implementation of its provisions by all 180 signatory countries.[4] After decades of neglect, South Africa (SA) emerged in the 1990s as a global leader in tobacco control.[5] This began in 1993 with the Tobacco Products Control Act introduced by Rina Venter, the last Health Minister of the National Party government. It addressed smoking in public places, warnings on packaging and modest restrictions on advertising and sponsorship. In 1994, after the election of Nelson Mandela, Minister of Health Dr Nkozasana Zuma, along with Finance Minister Trevor Manuel, established tax and regulatory measures that have reduced the national prevalence of smoking – and saved many lives – in the years since. In doing so, Zuma made true on a pledge she made in the presence of ministers of health of Africa to take strong action on tobacco at the First All Africa Tobacco Control meeting in Zimbabwe in 1993.[5] Thus started a decade of SA leadership steering African governments to play a key role in the drafting of the WHO FCTC negotiating process. SA leadership in tobacco control continues today as the FCTC moves from ‘the books’ to the streets. Policies to prevent tobacco use are proving effective: recent research shows that for each R1 increase in cigarette price, the risk of smoking initiation is reduced between 1% and 2.8% for males in SA.[4] The latest study on tobacco use in SA shows that 17.6% of adults smoke.[6] Men have a higher prevalence of smoking than women: the male smoking prevalence is over three times greater than the female smoking prevalence of 7.3%. Smoking prevalence differs greatly by race: 40.1% of coloured people smoke tobacco, including 34.4% of coloured women. This is nearly five times the prevalence among all SA women. Of students in grades 8 - 11 in SA, 12.7% currently smoke cigarettes, including 10.8% of girls.[7] This emphasises the reality that tobacco control remains a critical priority for the country.

A turbo-charged approach towards a tobacco-free world

A recent review of global approaches to tobacco control concludes that a ‘turbo-charged’ approach is needed, extending beyond the current rather leisurely pace of progress, to prevent the projected 1 billion tobacco deaths expected this century.[3] Several tactics are needed, especially in SA. • Earmark tobacco taxes. Annual increases in tobacco excise taxes are needed that earmark 2 - 5% of such taxes to create a National Health Promotion Foundation as a private-public partnership involving leading insurers, retailers and other sectors committed to health. A model for SA to consider is the Thailand Health

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Promotion Foundation (ThaiHealth), which uses 2% of the alcohol and tobacco excise tax to fund health promotion and raises USD50 - 60 million annually.[8] The Foundation has created a sustainable long-term source of funding to address chronic disease risks, including alcohol, tobacco, physical activity and diet, in settings that include schools, worksites and communities. Without such financing, tobacco control remains subject to the vagaries of policy makers and generally suffers.

• Tighten marketing regulations. Explicit attention is needed to block and weaken the marketing strategies used by the tobacco industry to target girls and women – these include brands with long, slim, low-tar and menthol products, and ads that depict slimness and sophistication.[9] The FCTC provides for genderspecific regulations, but no countries have yet established these.

A second marketing need is for SA to follow the lead shown by Australia and mandate plain packaging of tobacco products. The guidelines for implementation of Article 13 of the FCTC include plain packaging of tobacco products, a strategy that has been called for over a decade.[10] The strength of the industry opposition to these measures, including World Trade Organization disputes, is the best evidence of their probable impact.

• Engage the private sector in tackling tobacco control. The private sector has played a key role in HIV/AIDS prevention and treatment and many other areas of public health, with benefit to their bottom line and society. Partnerships to address smoke-free workplace policies more effectively are just the start of what is possible.[3] Retailers should be encouraged to follow the lead shown

by CVS Health, a pharmacy that ended the sale of tobacco products from its stores in 2014. Rather than this having hurt business, CVS Health’s stock price has increased by over 23% since 1 October 2014, when the policy was implemented.[11] The efforts of Vitality, a health promotion programme, together with health and life insurance companies to support and incentivise members to end tobacco use should become the industry norm.[12] Programmes run by insurers and retailers have the potential to positively benefit non-members and the broader society.

• Develop a harm reduction strategy that distinguishes between tobacco and nicotine. Controversy and misconception surround e-cigarettes, snus and related non-combustible products, driving doubt in the minds of smokers seeking to quit. Evidence suggests that this misinformation can reinforce a view that these products are no better, and possibly more dangerous, than traditional cigarettes.[13] The worst example of this comes from the recent US Centers for Disease Control’s new ‘Tips from Former Smokers’ campaign, and new California Health Department ads, that both fail to mention the simple reality that tobacco kills – before raising theoretical concerns about e-cigs.[14] Evidence is increasingly showing the opportunity for e-cigs to improve public health and reduce the nearly 6 million global deaths due to tobacco use, as well as reduce healthcare spending resulting from tobacco.[1,15] Research presented at the two latest global tobacco control research and policy meetings – the Society for Research on Nicotine and Tobacco meeting in Philadelphia[12] and the World Conference on Tobacco or Health in Abu Dhabi[4] – strengthened evidence of the benefits of e-cigs for smokers seeking to quit, and weakened concerns about young people using e-cigs as a gateway to eventual tobacco use.

The Canadian Standing Committee on Health draft regulatory framework for e-cigs is worth considering.[16] In the interim, SA health leaders – starting with the Minister of Health – would do well

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to emulate the approach taken by Jane Ellison, the UK Secretary of State for Health, when she repeated the recommendation of a statement carried by the Royal College of Physicians encouraging smokers seeking to quit to try e-cigs.[17]

The way forward

SA hosts the 17th WCTOH in Cape Town in 2018, placing a spotlight on the country’s tobacco control policies and progress. SA has an opportunity to show global leadership by accelerating tobacco control in the country, and should use the time from now to 2018 to build a coalition of local players committed to demonstrate how a turbocharged approach can impact millions of smokers. We are ready to play our role.

Derek Yach, Elle Alexander The Vitality Institute, New York, USA Corresponding author: D Yach (dyach@thevitalitygroup.com) 1. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380(9859):2224-2260. [http://dx.doi. org/10.1016/S0140-6736(12)61766-8] 2. Ng M, Freeman MK, Fleming TD, et al. Smoking prevalence and cigarette consumption in 187 countries, 1980-2012. JAMA 2014; 311(2):183-192. [http://dx.doi.org/10.1001/jama.2013.284692] 3. Beaglehole R, Bonita R, Yach D, Mackay J, Reddy KS. A tobacco-free world: A call to action to phase out the sale of tobacco products by 2040. Lancet 2014;385(9972):1011-1018. [http://dx.doi. org/10.1016/S0140-6736(15)60133-7] 4. World Conference on Tobacco or Health, Abu Dhabi, UAE, 17-21 March 2015. http://www.wctoh.org/ body/Abstract-book-23-HD.pdf (accessed 6 April 2015).

5. Chapman S, Yach D, Saloojee Y, Simpson D. All Africa conference on tobacco control. BMJ 1995;308:189. [http://dx.doi.org/10.1136/bmj.308.6922.189]

6. Reddy P, Zuma K, Shisana O, Jonas K, Sewpaul R. Adult tobacco use prevalence in South Africa: Results from the First South African National Health and Nutrition Examination Survey. S Afr Med J 2015;105(8):648-655. [http://dx.doi.org/10.7196/SAMJnew.7932] 7. Global Youth Tobacco Survey Fact Sheet. South Africa 2011. http://www.who.int/tobacco/surveillance/ gyts/en/ (accessed 22 June 2015).

8. World Health Organization. Thai Health Promotion Foundation. http://www.searo.who.int/tobacco/ news_events/thaihealth/en/ (accessed 6 April 2014).

9. World Health Organization. Female Smoking: The Tobacco Atlas. http://www.who.int/tobacco/en/ atlas6.pdf (accessed 6 April 2015).

10. Yach D. Injecting greater urgency into global tobacco control. Tob Control 2005;14(3):145-148. [http:// dx.doi.org/10.1136/tc.2005.011957] 11. Google Finance. CVS Health. https://www.google.com/finance?q=cvs&ei=jiETVYHTDuqysAeX9YH YDA (accessed 25 March 2015).

12. Society for Research on Nicotine and Tobacco (SRNT). 2015. https://www.srnt.org/2015_SRNT_S-aa-G_G.pdf (accessed 23 June 2015).

13. Yach D. E-cigarettes save lives. The Spectator 2015;21 Feb. http://www.spectator.co.uk/health/featureshealth/cover-feature/9442271/e-cigarettes-save-lives/ (accessed 23 June 2015).

14. Alexander E, Yach D. Distorted messages undermine tobacco control. Vitality Institute blog. http:// thevitalityinstitute.org/distorted-messages-undermine-tobacco-control/ (accessed 23 June 2015).

15. Moody JS. E-cigarettes poised to save Medicaid billions. http://tobacco.ucsf.edu/sites/tobacco.ucsf. edu/files/u9/SBSMediciadECigarettes033115.pdf (accessed 6 April 2015).

16. Canadian House of Commons. Report of the Standing Committee on Health. Vaping: Towards a regulatory framework for e-cigarettes. http://www.nsra-adnf.ca/cms/file/files/412_HESA_Rpt09-e.pdf (accessed 6 April 2015).

17. UK Parliament. Electronic cigarettes: Written question – 227133. http://www.parliament.uk/business/ publications/written-questions-answers-statements/written-question/Commons/2015-03-11/227133/ (accessed 6 April 2015).

Further reading Reddy P, James S, Sewpaul R, et al. A decade of tobacco control: The South African case of politics, health policy, health promotion and behaviour change. S Afr Med J 2013;103(11):835-840. [http://dx.doi. org/10.7196/SAMJ.6910] Yach D, Alexander E. Building partnerships for disease prevention and mobilizing resources for the global NCD agenda. In Public Health Approaches to Noncommunicable Diseases 2015 (in press). Wolter Kluwer. Guragon, India.

Yach D. The origins, development, effects, and future of the WHO Framework Convention on Tobacco Control: A personal perspective. Lancet 2014383(9930):1771-1779. [http://dx.doi.org/10.1016/S01406736(13)62155-8]

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Improving access to antiretrovirals in rural South Africa – a call to action South Africa (SA) already has the world’s biggest antiretroviral (ARV) programme. With the introduction of extended criteria for initiating ARVs, the National Department of Health (NDoH) wishes to increase the number of people on ARVs by around two million over the next 2 years. Adoption of a chronic disease management model, with extended task shifting, decentralisation and new approaches to distribution of ARVs, must be embraced if this is to be successfully achieved without huge increases in resources. In this editorial we discuss the need for change, and the current substantial blocks to progress (principally in prescribing and dispensing legislation) that contradict national treatment guidance and should be addressed as a matter of urgency. In addition, we draw attention to threatened regulatory changes that may further worsen the situation.

HIV management as a chronic condition

The implementation of nurse prescribing of ARVs, through nurseinitiated management of antiretroviral treatment, has been a great success and has proved not to be inferior to doctor-monitored ART.[1,2] However, this very success is feeding the challenges. Patients in ever-growing numbers are required to attend nurse-managed clinics monthly, or at best 3-monthly, to obtain their medication –

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whether or not they also need to attend for care. Consequently large workloads have caused a ‘vicious tangle’ of problems in clinics, including high staff stress, turnover, sickness and shortages, and therefore poor-quality care (including reduced attention to adherence and identification of treatment failure[3]). These affect the patient experience through long waiting times and lack of personcentred care, and are likely to contribute to the substantial losses to follow-up and undermine effective disease control.[4,5] Increasing patient numbers will put an additional burden on the infrastructure of health facilities, for example waiting areas and storage space for increasing stocks of ARVs. Regular visits, which may be as frequent as monthly, with faceto-face counselling by a pharmacist, are no longer the gold standard in resource-rich settings, where demedicalisation of patients and efficient use of resources are also drivers for change. In such a setting, 6- or 12-monthly review by a clinician is the norm for stable patients, with resources concentrated on patients with higher clinical needs. This shift has been recognised in SA in part, with 3-monthly supplies being issued where stocks allow, but further flexibility is now essential.

There is a cry for changes, including in our national guidelines,[6] that will see the adoption of a chronic disease management model with demedicalisation of healthy patients and supported self-care. [7-10] Consequent improved efficiencies in respect of nurse time can enable

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an increased clinical focus of attention on those whose need is highest.[11] Such models depend on stable patients being able to obtain a safe and regular supply of medication between clinical reviews. This in turn depends on: (i) having a trained clinician able to determine which patients are clinically stable, and ‘enable’ their future medication to be issued, at appropriate intervals, until the next clinical review; (ii) a pharmacist, pharmacist’s assistant or other trained support person able to provide ‘between-review’ medication for individual patients at appropriate intervals; (iii) ‘between-review’ medication being available at appropriate (convenient and safe) locations; and (iv) clinical review intervals being determined according to clinical need and national guidelines, and not hampered by over-restrictive laws, interpretations of those laws or tertiary legislation (such as Good Practice standards).

All of this, of course, requires intelligent implementation, with the presence of some simple, essential checks and balances such as are standard for chronic disease management, e.g. the ability to identify, and act on, non-attendance.

Barriers to progress in rural clinics

In rural SA, there are barriers to achieving these steps. About 40% of the SA population is rural, and this includes areas with the highest prevalence of HIV in the world. There are concerns about the ability of nurses to prescribe safely when clinics are ‘overloaded with the healthy’[10] and nurses are dispensing medication individually to each patient. The potential for errors would be much reduced if this task were to be systematised, and nurses freed to prioritise their time and attention on the clinically needy, only seeing stable patients at routine review.

Rural nurses work in the absence of ‘individual patient level’ pharmacy and medical support, and are operating in terms of an exceptional permit (section 56(6) of the Nursing Act).[12] Under this Act, they are required to do all of their dispensing, and cannot use other clinic personnel (as listed in (ii) above) to dispense ‘between-review’ repeat medication. Hospital pharmacies are generally remote from their clinics, and providing detailed support for ‘between-review’ prescribing will necessitate substantial additional resources. Rural areas also lack access to private sector community pharmacies, which might otherwise be able to support such programmes.

If nurses are enabled to ‘trigger’ ‘between-review’ prescriptions of medication for patients in a rural setting, the use of centralised pharmacy support using postal or courier delivery will be hampered by the lack of formal postal or residential addresses in rural areas.

There has been a national shift, supported by an NDoH circular (July 2010, unpublished), for at least first-line ARV regimens to be available as 3-monthly supplies (as opposed to monthly), which, locked as it is to attendance, leads to some improvement.

However, medicine stock-outs (threatened or actual) currently pitch nurses and patients backwards from 3-monthly into monthly clinic attendance, with all its negative impacts on quality of care and patient quality of life. In addition, there are concerning reports from some rural clinics that the shift to 3-monthly supplies has met with a negative reaction from clinic managers who are angry because there has been a consequent drop in the clinic attendance head count.

Legislation and guidance on the interval for clinical review are currently contradictory. Conservatively defined, adult, establishedstable ARV patients only require annual clinical review, with blood tests, according to national guidelines[6] – as long as simple problemscreening questions are used when interim medication is collected.

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However, currently section 22A(6)(f) of the Medicines and Related Substances Act[13] indicates that medication should not be repeated beyond 6 months from the original date of the prescription: in other words, a prescriber must sign a new prescription, and the implication is that the patient should be reviewed. There are reports that this requirement is widely circumvented in the private sector for some conditions (such as stable HIV and controlled hypertension) where the evidence, and clinical guidance, supports only annual clinical review.

An additional problem is posed by the status of nurses as authorised prescribers. There is an impasse between the national (and provincial) departments of health, which wish to see nurses recognised as authorised prescribers able to issue prescriptions that can then be dispensed by pharmacists or pharmacist’s assistants, and the South African Pharmacy Council, which holds that they are not authorised prescribers.[14] The Pharmacy Council seems determined to set ever-higher standards for each element of the dispensing and medication supply process. In this regard they risk allowing the perfect to be the enemy of the good. Things may get worse. Draft amendments to the Rules relating to Good Pharmacy Practice would restrict the ability of pharmacies (both community and institutional) to operate mobile services and to deliver medicines once dispensed.[15] These draft rules, as well as rules that have been issued in final form,[16] have also introduced restrictions on the use of technological options such as remote automated dispensing units. These options may not be easily applicable in the public sector, yet should not be discounted as potential future solutions.

This impasse contributes to the impression that the needs of hundreds of thousands of patients a day in rural public sector health clinics, and their nurses, are invisible to some policymakers.

Finding solutions

Chronic disease management systems will require careful piloting and evaluation, with support of the nurses, as well as system changes and safety nets. However, such approaches contain natural incentives for nurses (through the prospect of rationalised and rewarding workloads) and patients (through demedicalisation and reduced attendance) to achieve stable status by paying increased attention to adherence and to viral load results. It is therefore essential to overcome the barriers in their way. A prerequisite for implementation of chronic care models for effective decongestion of primary healthcare facilities is a stable, flexible and patient-centred supply of ARVs, with refills for at least 3 months and delivered close to patients’ homes, supported by national legislation. Underpinning this is dependence on the willingness and flexibility of provincial and hospital pharmacy managers to provide for sufficient buffer stocks of ARVs. A variety of chronic disease management models are being explored or used, both in SA and elsewhere, some endorsed by the WHO and included in national guidelines.[17] Adherence clubs can shift healthy patients out of the clinics, and enable them to collect ‘between-review’ medication that has been prepacked and labelled by pharmacy staff. Some hospital pharmacies are supporting community pick-up points (such as churches), supported by pharmacists’ assistants. A chronic dispensing model has been implemented in National Health Insurance urban and semiurban pilot areas and the Western Cape public sector, successfully delegating ordering, warehousing, prepacking and labelling of chronic medication to a public-private entity that delivers the medicine packs to the facility for fast-tracked collection by patients.

A central chronic medicine dispensing and distribution programme,

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EDITORIAL

providing distribution to designated pick-up points, has also been started in the public sector.

However, for their implementation in rural Department of Health clinics, every one of these solutions depends either on new legal flexibilities for nurse prescribing or the reintroduction of doctors and pharmacists into routine rural HIV care. Clearly the latter is not a viable option. The only existing alternative for those desperate for change is circumvention, reports of which are becoming more widespread.

Tinne Gils, Amir Shroufi Regional Pharmacy Manager and Deputy Medical Coordinator, Médecins Sans Frontières South Africa

Call to action

Jenny Nash Amathole District Clinical Specialist Team, Eastern Cape, South Africa

Those keen to implement efficiency and quality in primary care will not be able to pilot and implement solutions to the above conundrums until SA rural nurses are unlocked from huge-scale dispensing of medication and freed to focus more closely on clinical need, whether for HIV or other chronic diseases.

• The Medicines Control Council (as custodians of the Medicines Act) and the SA Nursing Council (whose legislation permits public sector nurses to ‘supply’ medicines) should give a clear and positive direction.

• The South African Pharmacy Council is urged to support and enable the following essential measures: • Pragmatically interpret existing legislation so as to provide for the recognition of nurses as authorised prescribers (albeit through an exceptional mechanism, until specialist registers are created and populated).

• Allow and encourage patient-centred and decentralised drug supplies with a minimum of 3 months’ refill for stable patients.

• Allow for mobile and decentralised treatment points to be managed with regular support, but without direct personal supervision by pharmacists.

• The NDoH is urged to put in place logistical and legislative measures to: • Ensure continuous availability of safe and appropriate ARVs for all eligible patients.

• Optimise access to these appropriate medicines closer to patients’ homes, through community and mobile dispensing and allowing multiple months’ supplies.

• Consider possible amendments to the Medicines Act to enable clinicians to tailor clinical follow-up, within appropriate medication issuing systems and according to individual clinical need, up to 12 months.

• Ensure responsibility and accountability for a range of systems of medication issuing that can be clearly, if flexibly, defined.

Andy Gray Senior Lecturer, Division of Pharmacology, Discipline of Pharmaceutical Sciences, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Francesca Conradie President, Southern African HIV Clinicians Society Talitha Crowley Lecturer, Division of Nursing, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa Bernhard Gaede Head of Department, Discipline of Family Medicine, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa

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Bella Hwang Programme Manager, Stop Stock Outs Project, South Africa Desmond Kegakilwe Chair, RuDASA, South Africa

Prinitha Pillay Human Resources for Health and Policy Implementation Programme Manager, Rural Health Advocacy Project, South Africa Stacie C Stende Senior Technical Advisor, HIV/TB/ID (based in Cape Town, South Africa), Jhpiego Francois Venter Deputy Executive Director, Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa Philippa Matthews Primary Care Development Facilitator, Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa Corresponding author: P Matthews (pmatthews@africacentre.ac.za) 1. Nyasulu JC, Muchiri E, Mazwi SL, Ratshefola M. NIMART rollout to primary healthcare facilities increases access to ARVs in Johannesburg. S Afr Med J 2013;103(4):232-236. [http://dx.doi. org/10.7196/SAMJ.6380] 2. Sanne I, Orrell C, Fox MP et al. Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): Randomised non-inferiority trial. Lancet 2010;376:33-40. [http:// dx.doi.org/10.1016/SO140-6736(10)60894-X] 3. Mutevedzi P, Lessells RJ, Heller T, Barnighausen T, Cooke G, Newell M-L. Scale-up of decentralized HIV treatment programme in rural KwaZulu-Natal, South Africa: Does rapid expansion affect patient outcomes? Bull World Health Organ 2010;88(8):593-600 [http://dx.doi.org/10.2471/ BLT.09.069419] 4. Rosen S, Fox MP, Gill CJ. Patient retention in antiretroviral therapy programs in sub-Saharan Africa: A systematic review. PLoS Med 2007;4:e298 [http://dx.doi.org/10.1371/journal.pmed.0040298] 5. Lessells RJ, Mutevedzi P, Cooke GS, Newell M-L. Retention in HIV care for individuals not yet eligible for antiretroviral therapy: Rural KwaZulu-Natal, South Africa. J Acquir Immune Defic Syndr.

2011;56:e79-86. [http://dx.doi.org/10.1097/QAI.1090b1013e3182075ae3182072] 6. Department of Health, South Africa. National consolidated guidelines for the prevention of motherto-child transmission of HIV (PMTCT) and the management of HIV in children, adolescents and adults. Section 2.1-2.5, p. 20/ section 6.6.6, p. 70. 2014. http://www.hst.org.za/sites/default/files/HIV_ Guidelines_Jan%202015_YP_0.pdf (accessed 24 June 2015).

7. Mutevedzi P, Lessells RJ, Newell M-L. Disengagement from care in a decentralized primary health care antiretroviral treatment programme: Cohort study in rural South Africa. Trop Med Int Health 2013;18(8):934-941. [http://dx.doi.org/10.1111/tmi.12135] 8. Deeks S, Lewin SR, Havlir DV. The end of AIDS: HIV infection as a chronic disease. Lancet 2013;382(9903):1525-1233. [http://dx.doi.org/10.1016/S0140-6736(13)61809-7] 9. Beaglehole R, Epping-Jordan J, Patel V, et al. Improving the prevention and management of chronic disease in low-income and middle-income countries: A priority for primary health care. Lancet 2008;372(9642):940-949. [http://dx.doi.org/10.1016/S0140-6736(08)61404-X] 10. Ellman T. Demedicalizing AIDS Prevention and Treatment in Africa. N Engl J Med 2015;372(4):303305. [http://dx.doi.org/10.1056/NEJMp1414730] 11. Murray CJL. Maximizing antiretroviral therapy in developing countries: The dual challenge of efficiency and quality. JAMA 2015;313(4):359-360. [http://dx.doi.org/10.1001/jama.2014.16376] 12. Republic of South Africa. Nursing Act (Act 33 of 2005). http://www.sanc.co.za/pdf/Nursing%20 Act%202005.pdf (accessed 24 June 2015).

13. Republic of South Africa. Medicines and Related Substances Act (Act 101 of 1965), as amended. http:// mccza.com/genericDocuments/Act_101_of_1965_published_2003.pdf (accessed 24 June 2015).

14. Gray A. Prescribing and dispensing by nurses – neglected steps in the legislative process. HIV Nursing 2010;1(2):28-31.

15. South African Pharmacy Council. Rules Relating to Good Pharmacy Practice. Board Notice No. 49 of 2015. Government Gazette No. 38511 (27 February 2015).

16. South African Pharmacy Council. Rules Relating to Good Pharmacy Practice. Board Notice No. 50 of 2015. Government Gazette No. 38511 (27 February 2015).

17. Bemelmans M, Baert S, Goemaere E, et al. Community-supported models of care for people on HIV treatment in sub-Saharan Africa. Trop Med Int Health 2014;19(8):968-977 [http://dx.doi.org/10.1111/ tmi.12332]

S Afr Med J 2015;105(8):638-640. DOI:10.7196/SAMJnew.8265

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RESEARCH

Multimorbidity, control and treatment of noncommunicable diseases among primary healthcare attenders in the Western Cape, South Africa N Folb,1,2,3 MB ChB, MRCGP (UK); V Timmerman,1 PhD; N S Levitt,2,3 MB ChB, MD, FCP (SA); K Steyn,2,3 MSc, NED, MD; M O Bachmann,4 MB ChB, PhD, FFPH (UK); C Lund,5 MA, MSocSci, PhD; E D Bateman,1,2,3 MB ChB, MD, FRCP (UK); C Lombard,3,6,7 MSc, PhD; T A Gaziano,3,8 MD, MSc; M Zwarenstein,9 MB ChB, MSc, PhD; L R Fairall,1,2,3 MB ChB, PhD niversity of Cape Town Lung Institute, Cape Town, South Africa U Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 3 Chronic Disease Initiative for Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 4 Norwich Medical School, University of East Anglia, Norwich, UK 5 Alan J Flisher Centre for Public Mental Health, Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa 6 Biostatistics Unit, Medical Research Council, Cape Town, South Africa 7 School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 8 Cardiovascular Medicine, Brigham & Womenâ&#x20AC;&#x2122;s Hospital, Boston, MA, USA 9 Centre for Studies in Family Medicine, Department of Family Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada 1 2

Corresponding author: N Folb (naomi.folb@uct.ac.za)

Background. South Africa (SA) is facing a heavy burden of non-communicable diseases (NCDs). Few studies address multimorbidity, control and treatment of NCDs in patients attending primary healthcare (PHC) clinics.

Objectives. To describe multimorbidity, related risk factors, disease severity and treatment status of patients with four important NCDs attending public sector PHC clinics in two districts in SA. Methods. A cross-sectional sample of patients completed baseline data collection for a randomised controlled trial of a health systems intervention. The study population comprised adults attending PHC clinics in the Eden and Overberg districts of the Western Cape in 2011.

Four subgroups of patients were identified: hypertension, diabetes, chronic respiratory disease and depression. A total of 4 393 participants enrolled from 38 clinics completed a baseline structured questionnaire and had measurements taken. Prescription data were recorded.

Results. Of participants with hypertension, diabetes, respiratory disease and depression, 80%, 92%, 88% and 80%, respectively, had at least one of the other three conditions. There were low levels of control and treatment: 59% of participants with hypertension had a blood pressure â&#x2030;Ľ140/90 mmHg, the mean haemoglobin A1c (HbA1c) value in participants with diabetes was 9%, 12% of participants in the depression group were prescribed an antidepressant at a therapeutic dose, and 48% of respiratory participants were prescribed a b2-agonist and 34% an inhaled corticosteroid.

Conclusion. Considerable multimorbidity and unmet treatment needs exist among patients with NCDs attending public sector PHC clinics. Improved strategies are required for diagnosing and managing NCDs in this sector.

S Afr Med J 2015;105(8):642-647. DOI:10.7196/SAMJnew.7882

South Africa (SA) faces a rise in non-communicable diseases (NCDs) in both rural and urban populations, driven by an increase in risk factors such as tobacco use, physical inactivity and unhealthy diets.[1] These place a heavy burden on public sector primary healthcare (PHC) services. A recent cross-sectional survey of reasons for consultations in PHC in four SA provinces confirmed that management of hypertension was the most common reason for attendance, with NCDs accounting for 14% of visits.[2,3] PHC in the public sector is nurse-led with support from doctors, with nurses seeing over 85% of all patients.[2] However, at present nurses working at PHC clinics often do not have the necessary skills or capacity to deal adequately with NCDs.[1] Chronic diseases and risk factors are often undiagnosed and inadequately treated, resulting in high levels of poor control and morbidity.[1,4-6] There is renewed focus on NCD care in SA. However, despite the magnitude of the NCD burden, there are few recent studies

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addressing multimorbidity, control and treatment of NCDs in this country. In particular, little is known about the multimorbidity of depression with other NCDs. We present an analysis of the clinical characteristics, level of disease control, presence of multimorbidity and treatment of patients with hypertension, diabetes, chronic respiratory disease and symptoms of depression, identified in PHC clinics in the Eden and Overberg districts of the Western Cape Province, SA, as part of the Primary Care 101 trial described below.

Methods

This study describes the characteristics of patients participating in the Primary Care 101 trial at enrolment. The Primary Care 101 programme comprised a customised clinical practice guideline and training programme aimed at assisting healthcare providers, largely nurses, with the primary care management of adults. The pragmatic cluster randomised controlled trial evaluated the effects of the

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programme on the quality and outcomes of care for hypertension, diabetes, chronic respiratory disease and depression. Clinics were randomised either to receive the intervention or not. The main results of the trial will be published elsewhere.

The 33 largest clinics in the Eden district that provided NCD care, and a convenience sample of five clinics in the neighbouring Overberg district, were included in the study. Each clinic had at least 10 000 attendances per year and was staffed by nurse practitioners, doctors, and community health workers who manage clinic patients in the communities. These clinics are the main providers of PHC for local populations with high levels of unemployment and socioeconomic deprivation.

Eligible participants were clinic attenders aged 18 years or older, likely to reside in the area for the next year, and able to engage in an interviewer-administered questionnaire. Patients attending each clinic were interviewed to assess their eligibility for inclusion in the hypertension, diabetes, chronic respiratory and/or depression groups, until the sample size required for each group was reached.

For the hypertension and diabetes groups, a self-reported history of medication use for these conditions was required. For the respiratory group, a self-report of prescription of medications for chronic respiratory disease or symptoms of chronic respiratory disease (cough or difficult breathing for >2 weeks),[7] and no current or recent treatment for tuberculosis, was required. The depression group comprised participants with a score of ≥10 on the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10).[8] Individuals could be included in more than one group. In this article ‘comorbidity’ refers to two coexisting conditions and ‘multimorbidity’ to three or more coexisting conditions.

For trial purposes the sample sizes for each disease group were calculated separately, and were 27 participants per clinic for the chronic respiratory disease group and 60 per clinic for each of the other three groups. These target sample sizes were attained or exceeded for all disease groups except the diabetes group, which reached 48 participants per clinic.

Fieldworkers invited patients attending the trial clinics to be screened for inclusion in the study using a structured questionnaire.

Eligible patients who provided informed consent were enrolled and completed another, baseline, questionnaire. Between March and October 2011, 4 904 patients were screened, of whom 4 393 were enrolled. The questionnaire was available in Afrikaans, isiXhosa and English. It included questions relating to demographic characteristics, socioeconomic factors, medical history and smoking status. Three blood pressure (BP) readings were taken at least 2 minutes apart with an Omron automatic monitor. The first reading was excluded and the values from the second and third readings were averaged.[9] Height, weight and waist circumference were measured using standardised techniques. Height and weight were measured with participants barefoot and wearing light clothing.

A flexible tape was used to measure waist circumference, 2.5 cm above the umbilicus. Haemoglobin A1c (HbA1c) was measured only in 20 randomly selected clinics because of cost and logistical constraints. Diabetic participants in the 20 clinics were referred to a clinic nurse at the end of the interview for an HbA1c test, which was processed by the National Health Laboratory Service.

The severity of respiratory disease was assessed with the Symptom and Activity domains of the St Georges Respiratory Questionnaire (SGRQ)[10] in participants enrolled in the respiratory disease group.

Scores are expressed as percentages, with 100% representing worst and 0% best possible health status. The presence of symptoms of depression was assessed with the CESD-10 scale, which was administered to all participants enrolled in the study.[8] The items

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were scored from 0 (rarely or none of the time) to 3 (most of the time).

Treatment for depression was defined as having received coun­ selling or been referred to psychiatric services within the past year, or currently receiving an antidepressant. Counselling was defined as a consultation that intended to seek solutions to problems or provide emotional support, and not simply give advice on medication use.

Participants who reported receiving counselling from a mental health nurse, clinic counsellor, social worker, psychiatrist or psychologist were considered to have received counselling, and those who reported receiving counselling from a mental health nurse, psychiatrist or psychologist were considered to have been referred to psychiatric services.

Chronic medication prescribed to participants at the time of their interview for depression, hypertension, diabetes and respiratory dis­ ease was recorded. Fieldworkers photocopied all available prescription charts for the year preceding the interview. The trial manager (NF) examined the prescription charts of each participant to identify medications prescribed at the time of their interview. A data capturer entered the prescription data (drug names, doses and frequencies) into an access database, and a total daily dose for each drug was calculated. Prescription charts were available for 99.3% of participants.

Quality control measures included supervision of fieldworkers, electronic alert messages for fieldworkers who entered unusually high or low values, and regular monitoring of the data to identify unusual values or trends. Quality control checks performed on the capturing of prescription data included double entry and checking all unusually high or low doses and frequencies.

The trial was registered with Current Controlled Trials (ISRCTN20283604) and the Office for Human Research Protections Database. Ethical approval was obtained from the University of Cape Town Human Research Ethics Committee and the Western Cape Provincial Department of Health. Participants provided written informed consent for their interview and prescription data to be collected and analysed. All data were anonymised for analysis, and participant identities were revealed only to the fieldworker and a limited number of researchers who received and prepared the data for analysis.

Results

Thirty-eight clinics were included in the study. The median number of nurses per clinic was four. Forty per cent of clinics had daily doctor support, the remainder had sessional support from doctors, and 42% of clinics had an on-site pharmacy.

A total of 4 393 participants were enrolled into the study, of whom 73% were women. The median age was 52 years, and 73% had hypertension, 42% diabetes, 26% chronic respiratory disease and 56% a CESD-10 score of ≥10 and so could be considered to be at risk of depression.

The majority of the participants (84%) were Afrikaans speaking, 75% were unemployed, 7% had never attended school, and 42% had achieved high-school education. Fifty-eight per cent reported receiving a social welfare grant, including 44% of participants under the age of 60 years. The median income in the month prior to the interview date was ZAR1 140, including personal non-grant income plus any household grant that benefited the participant, such as a disability or child grant.

Although 31% of participants were current smokers, their median pack-year history was only 7.5. Twenty-five per cent of participants provided a history of cardiovascular disease (heart attack, angina or stroke), 11% had a history of tuberculosis (TB), 2% reported

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being on medication for TB at the time of the interview, and 2% reported being on antiretroviral drugs.

The NCD-related health characteristics of participants in each of the four disease groups are presented in Table 1.

In the hypertension group (3 227 parti­ cipants), 59% had a BP ≥140/90 mmHg and 10% had a BP ≥180/110 mmHg, indicating poor control. Their mean body mass index (BMI, kg/m2) was 31, 27% were current smokers, and 26% reported a history of cardiovascular disease. Of the 1 166 parti­ cipants not in the hypertension group, 25% had a BP ≥140/90 mmHg and were not on medication for hypertension.

The diabetes group comprised 1 842 participants, of whom 704 had their HbA1c measured. The mean HbA1c value was 9.1% and 77% had an HbA1c above the target of 7%, indicating poor glycaemic control. The mean BMI for all participants with diabetes was 32, 23% were current smokers, and 23% reported a history of cardiovascular disease. An elevated BP (≥140/80 mmHg)[11] was present in 77%, and 8% had a BP ≥180/110 mmHg. The chronic respiratory disease group comprised 1 157 participants, of whom 50% reported being on medication for respiratory disease and 50% were identified by symptoms alone. Eighteen per cent had a previous history of TB and 39% were current smokers. Their median pack-year history was 7.5. The median symptom and activity domain scores of the SGRQ were 60 and 74, respectively.

The depression group comprised a total of 2 466 participants. Their median CESD10 score was 14 (interquartile range (IQR) 12 - 18).

Of participants with hypertension, diabetes, respiratory disease and depression, 80%, 92%, 88% and 80%, respectively, had at least one of the other three conditions, and 34%, 45%, 53% and 42% had at least two other conditions (Fig. 1). Hypertension was the commonest comorbidity in participants with other categories of chronic disease, followed by depression, diabetes and chronic respiratory disease. Forty-seven per cent of participants in the hypertension group also had diabetes, 84% of participants with diabetes also had hypertension, 22% of participants with hypertension or diabetes also had chronic respiratory disease, and 51% of participants with hypertension, diabetes or respiratory disease had a CESD-10 score of ≥10.

Treatment received by participants in the hypertension group at the time of their interview is presented in Table 2. Four per

Table 1. Characteristics of study participants Hypertension group

All participants (N=3 227)

Systolic BP (mmHg), mean (SD) (n=3 220)

139 (23.6)

Diastolic BP (mmHg), mean (SD) (n=3 220)

90 (13.2)

BP ≥140/90 mmHg, n (%)

1 917 (59.4)

BP ≥180/110 mmHg, n (%)

334 (10.4)

BMI (kg/m ), mean (SD) (n=3 066)

31.1 (7.5)

BMI, proportion obese (BMI ≥30), n (%)

1 628 (50.5)

Waist circumference (cm), mean (SD) (n=3 194)

100.5 (15.6)

Waist circumference (cm), proportion greater than ideal,* n (%)

2 293 (71.1)

Current smokers, n (%)

885 (27.4)

Pack-year history for current smokers, median (IQR) (n=756)

8 (4.8 - 13.8)

Cardiovascular disease, n (%)

849 (26.3)

Diabetes group

All participants (N=1 842)

HbA1c (%),‡ mean (SD) (n=704)

9.1 (2.5)

Proportion HbA1c ≥7%, n (%)

544/704 (77.3)

SBP (mmHg), mean (SD) (n=1 840)

137 (23.2)

DBP (mmHg), mean (SD) (n=1 840)

88 (12.4)

BP ≥140/80 mmHg, n (%)

1 414 (76.8)

2

†

BP ≥180/110 mmHg, n (%)

139 (7.5)

BMI, mean (SD) (n=1 742)

32.0 (7.3)

BMI, proportion obese (BMI ≥30), n (%)

1 011 (54.9)

Waist circumference, mean (SD) (n=1 822)

103.6 (14.8)

Waist circumference, proportion greater than ideal,* n (%)

1 436/1 842 (78.0)

Current smokers, n (%)

415 (22.5)

Pack-year history for current smokers, median (IQR) (n=353)

8.25 (4.8 - 16.0)

Cardiovascular disease, n (%)

423 (23.0)

Chronic respiratory disease group

All participants (N=1 157)

Self-reported CRD on respiratory medication, n (%)

699 (60.4)

Self-reported CRD symptoms and not on respiratory medication, n (%)

458 (39.6)

SGRQ symptom domain (% maximum weight), median (IQR) (n=833)

59.50 (36.4 - 74.8)

SGRQ activity domain (% maximum weight), median (IQR) (n=1 054)

73.71 (53.6 - 92.5)

Current smokers, n (%)

454 (39.2)

Pack-year history for current smokers, median (IQR)

7.8 (4.4 - 13.5)

Previous tuberculosis, n (%)

211 (18.2)

Depression group

All participants (N=2 466)

CESD-10 score, mean (SD); median (IQR)

15.3 (4.3); 14 (12 - 18)

Current smokers, n (%)

860 (34.9)

Pack-year history for current smokers, median (IQR) (n=754)

7.2 (3.9 - 13.5)

†

SD = standard deviation. *≥88 cm for women, ≥102 cm for men. † History of heart attack, angina or stroke. ‡ HbA1c measured in a preplanned subgroup of 20 randomly selected clinics.

cent of participants in the hypertension group had no evidence of having received antihypertensive medication, 14% were on one antihypertensive agent, and 15% were

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on three or more antihypertensive drugs at optimal dosages. Fifty-five per cent of participants with hypertension were pre­ scribed aspirin and 34% a statin.

RESEARCH

Hypertension group (N=3 227)

308 (10%) DEP 595 (18%)

Chronic respiratory disease group (N=1 157) DM 21 (2%)

CRD 154 (5%)

25 (2%)

97 (3%)

177 (6%)

97 (8%)

177 (15%)

HPT

DEP 524 (16%)

154 (13%)

240 (21%)

DM

308 (27%)

742 (23%)

HPT

CRD 135 (12%)

630 (20%) Diabetes group (N=1 842)

Depression group (N=2 466) CRD

97 (5%) CRD 21 (1%) HPT

177 (10%)

308 (13%)

25 (1%)

742 (40%)

HPT

177 (7%)

595 (24%) 524 (28%)

DEP

DM 108 (4%)

DEP

148 (8%)

25 (1%)

524 (21%)

108 (6%) DM

240 (10%)

489 (20%)

Fig. 1. Venn diagram of multimorbidity associated with hypertension, diabetes, chronic respiratory disease and depression. (HPT = hypertension; DM = diabetes; CRD = chronic respiratory disease; DEP = depression.)

Table 2. Treatment, hypertension group All participants (N=3 227) n (%)

Controlled BP*† (N=1 303) n (%)

Uncontrolled BP‡† (N=1 917) n (%)

No hypertension medication

129 (4.0)

80 (62.0)

47 (36.4)

1 hypertension medication

436 (13.5)

207 (47.5)

229 (52.5)

≥2 hypertension medications

2 638 (81.7)

1 003 (38.0)

1 631 (61.8)

≥3 antihypertensive

482 (14.9)

140 (29.0)

341 (70.8)

Medications prescribed Hypertension medications

medications at optimal dosage Missing information

24 (0.7)

Aspirin

1 760 (54.5)

711 (40.4)

1 047 (59.5)

Statin

1 093 (33.9)

445 (40.7)

647 (59.2)

*BP <140/90 mmHg. † Frequencies and row percentages exclude 7 participants with missing BP readings. ‡ BP ≥140/90 mmHg.

Treatment received by participants in the diabetes group is presented in Table 3. Sixtyone per cent of participants with diabetes had been prescribed an oral hypoglycaemic agent (without insulin) and 32% were prescribed insulin (with or without oral hypoglycaemic agents). Aspirin had been prescribed for 63% in the diabetes group, and statins for 51%. Seven per cent of participants with diabetes had had no hypoglycaemic agents prescribed. In both the hypertension

and diabetes groups, we observed higher medication use in participants with poorer control.

In the respiratory group, 48% of participants had been prescribed a b2-agonist metered dose inhaler (MDI) or nebuliser, 34% an inhaled corticosteroid (any dose), 8% an ipratropium bromide MDI or nebuliser, and 11% slow-release theophylline as maintenance treatment (Table 4).

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In the depression group, 12% of participants had been prescribed a therapeutic dose of antidepressant and 10% a subtherapeutic dose (<50 mg/d) of amitriptyline or imi­ pramine (Table 5). Twenty-five per cent were receiving treatment for depression, defined as receiving counselling, referral to psychiatric services or being on an antidepressant at a therapeutic dose. Fortyfive per cent were not receiving treatment, and it could not be established whether the remaining 30% were receiving treatment for depression, either because prescription charts were not available (14 participants) or because the participant failed to answer the question regarding counselling and psychiatric referral (729 participants).

Discussion

This study described the clinical profile, disease control, multimorbidity and treatment received by patients with the target conditions attending PHC clinics in two districts in SA. The results indicated poor disease control, high levels of multi­ morbidity and unmet treatment needs in the public sector in these districts.

These findings confirm previous reports of poor control and treatment of NCDs, and demonstrate little improvement in NCD control since these earlier studies were conducted. A study of 1 089 patients in 18 community health centres in 1999 demonstrated poor levels of control of hypertension and diabetes in community health centres in the Cape Peninsula, with 67% of hypertensive patients recording a BP ≥140/90 mmHg and a mean HbA1c of 8.8% in diabetic patients.[4] A study of goldminers in Gauteng Province, SA, in 2009/2010 found that only 42% of patients diagnosed with hypertension received antihypertensive medication, while 69% of patients on antihypertensive medication were poorly controlled.[12] The South African Stress and Health Study, a community survey of 4 351 adult South Africans between 2002 and 2004, found that only one-quarter of patients with depression, anxiety and substance use disorders received treatment. [6] Comorbidity of hypertension and diabetes was found to be high in a cross-sectional study in Cape Town townships in 2008/2009, with 21% of participants with hypertension also having diabetes, compared with 7% of non-hypertensive patients having diabetes. [9] The cross-sectional study in the Cape Peninsula in 1999 found 31% of participants with hypertension to have diabetes and 64% of participants with diabetes to have hypertension.[4] A more recent survey of SA PHC found that 18% of patients with

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Table 3. Treatment, diabetes group All participants (N=1 842) n (%)

Subgroup with HbA1c test (N=704) n (%)

Controlled* (N=160) n (%)

Uncontrolled† (N=544) n (%)

No diabetes medications

119 (6.5)

33 (4.7)

23 (69.7)

10 (30.3)

Metformin and/or sulfonylurea (but not insulin)

1 126 (61.1)

438 (62.2)

112 (25.6)

326 (74.4)

Insulin (with/ without oral agents)

588 (31.9)

230 (32.7)

25 (10.9)

205 (89.1)

Missing information

9 (0.5)

Medications prescribed Hypoglycaemic medications

Aspirin

1 155 (62.7)

477 (67.8)

101 (21.2)

376 (78.8)

Statin

931 (50.5)

407 (57.8)

82 (20.1)

325 (79.9)

ACE inhibitor

1 215 (66.0)

475 (67.5)

108 (22.7)

367 (77.3)

ACE = angiotensin-converting enzyme. *HbA1c <7%. † HbA1c ≥7%.

Table 4. Treatment, chronic respiratory disease group

Medications prescribed No chronic respiratory disease medications

All participants (N=1 157) n (%)

SGRQ symptom domain score Median (IQR)

SGRQ activity domain score Median (IQR)

567 (49.0)

52.6 (29.8 - 68.5)

67.2 (47.7 - 85.8)

Selective b2-agonist

558 (48.2)

64.6 (44.9 - 78.9)

79.8 (59.5 - 92.5)

Inhaled corticosteroids (any dose)

388 (33.5)

64.6 (42.8 - 79.3)

80.3 (60.3 - 92.5)

Inhaled corticosteroid (≥800 µg/d)

346 (29.9)

64.9 (41.8 - 80.2)

80.4 (60.3 - 92.5)

Theophylline

121 (10.5)

70.4 (51.8 - 83.0)

79.8 (60.4 - 92.5)

Ipratropium bromide

91 (7.9)

69.7 (52.2 - 81.6)

85.8 (60.4 - 93.2)

Table 5. Treatment, depression group

Medications prescribed or other management

All participants (N=2 466) n (%)

CESD-10 score Median (IQR)

Antidepressant medications No antidepressant medications

1 902 (77.1)

14 (12 - 17)

Antidepressant at therapeutic dose

294 (11.9)

19 (14 - 22)

Antidepressant at subtherapeutic dose

250 (10.1)

15 (12 - 19)

Missing information

20 (0.8)

Received counselling in past year

402 (16.3)

15 (12 - 20)

Psychiatric referral in past year

175 (7.1)

17 (13 - 21)

Antidepressant at therapeutic dose or counselling in past year or psychiatric referral in past year

614 (24.9)

16 (12 - 20)

hypertension also had diabetes, and 63% of patients with diabetes also had hyper­

tension.[3] Our study demonstrated higher levels of comorbidity than these studies,

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August 2015, Vol. 105, No. 8

with 47% of participants with hypertension also having diabetes, and 84% of participants with diabetes also having hypertension. A study of urban SA women demonstrated high rates of comorbid psychological distress with physical disease,[13] consistent with our finding of 51% of participants with hypertension, diabetes or chronic respiratory disease also having symptoms of depression.

However, the high rates of multimorbidity in our study, particularly in the reporting of diabetes in the hypertension group, may partly be due to the sampling strategy, as explained in ‘Study limitations’ below.

Study limitations and strengths

This study had several limitations. It did not consider other potential comorbid conditions such as osteoarthritis which are likely in such patient populations, so multimorbidity and comorbidity were probably underestimated. The study was not intended to provide estimates of the prevalence of NCDs or depression symptoms, but its inclusion criteria may have influenced the interpretation of results.

Because the inclusion criteria for each condition involved self-reporting, there was misclassification; some participants’ reported diseases were not confirmed, while others were found to be receiving medications for a disease that they had not reported. For example, of 1 166 participants not enrolled in the hypertension group (denying receiving medication for this diagnosis), 13% had received a prescription for antihypertensive medication and 30% had a BP ≥140/90 mmHg. Further, of 3 227 participants who reported being on medication for hypertension, 5% had no evidence of a prescription for hypertension. The inclusion criterion for the diabetes group was self-reported diabetes medication. Patients with diabetes on dietary control alone were therefore not included in the study. The study’s chronic respiratory disease definition was probably more inclusive than usual clinical practice and so may have overestimated disease prevalence. Spirometry was not used to diagnose respiratory disease. We did not distinguish between asthma, chronic obstructive pulmonary disease or other symptomatic chronic lung diseases, and severity was not assessed by lung function tests. For these reasons, the appropriateness of treatments prescribed could not be assessed for individual participants. The study’s definition of possible depression indicates, but does not confirm, clinical depression. In addition, the percentage receiving counselling or referral is an

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underestimate owing to an error resulting in this question not being administered to all participants. Finally, the sampling strategy may have led to over-representation of reported comorbidities. For the randomised controlled trial we estimated that 60 patients were needed per clinic for each disease group except for the respiratory group, which required 27 patients per clinic. Owing to the high prevalence of hypertension in this clinic population, targets were easily met for the hypertension group, although it was more difficult to do the same for the diabetes group.

Fieldworkers were asked to continue recruitment until targets were met for all four groups, with the result that targets were exceeded for all groups except diabetes, where recruitment fell short (81% of target). Since the majority of patients with diabetes also had hypertension, extended recruitment of this group may have led to an over-representation of the proportion of those with hypertension who also had diabetes.

The study had a number of strengths. The sample size was large, data were collected for four disease groups, and prescription data were collected for 99% of participants. There are few other recent studies addressing multimorbidity, control and treatment of NCDs in public sector PHC clinics in SA.

of Health, Department of Health and Human Services, under Contract No. HHSN268200900030C. Funding was also received from United Health, USA; the Department of Health of the Provincial Government of the Western Cape; the Department of Medicine, University of Cape Town; the UK Department for International Development; and the University of Cape Town Lung Institute. The study sponsors did not contribute to the design of the study, to the collection, analysis and interpretation of data, or to the writing of this article or the decision to submit it for publication.

The researchers were independent from funders and sponsors, and researchers involved in the collection, analysis and interpretation of the data had access to all the data.

Acknowledgements. The authors thank all clinic nurses, doctors, managers, pharmacists and pharmacy assistants at participating study facilities; the Department of Health of the Provincial Government of the Western Cape; the Eden and Overberg district management; Primary Care 101 trainers and fieldworkers; and the National Health Laboratory Service.

References

Conclusion

The rising prevalence of NCDs is a major challenge facing healthcare systems worldwide, with multimorbidity becoming the norm for people with chronic diseases. Despite this, health systems tend to be configured for individual diseases.[14] The high levels of multimorbidity demonstrated in this study stress the need for PHC services to provide better-integrated NCD care. Clinicians need to consider potential coexistence of, and interactions between, diseases.

Training of clinicians to manage multimorbidity is essential, and should address both appropriateness of prescribing and adherence to medication. Management of NCDs and multimorbidity need to be addressed at a health systems level and factored into clinical training.

The Integrated Chronic Disease Management[15] and Primary Care 101[16] programmes are important current initiatives aimed at integrating chronic disease care and addressing multimorbidity.

After a decade of focusing on scaling up antiretroviral therapy programmes, management of NCDs in PHC needs to be prioritised and requires similar investment in order to improve outcomes and limit the impact on morbidity and mortality. With limited time and resources in the PHC setting, careful consideration of how to prioritise care is required.

Understanding the causes of poor NCD control will assist in prioritising care and resources. Further research is required into the development and evaluation of interventions to address the burden and unmet treatment needs of NCDs, including mental health.

Funding. This project has been funded in part with Federal funds by the United States National Heart, Lung, and Blood Institute, National Institutes

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1. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of noncommunicable diseases in South Africa. Lancet 2009;374(9693):934-947. [http://dx.doi.org/10.1016/ S0140-6736(09)61087-4] 2. Mash B, Fairall L, Adejayan O, et al. A morbidity survey of South African primary care. PLoS One 2012;7(3):e32358. [http://dx.doi.org/10.1371/journal.pone.0032358] 3. Lalkhen H, Mash R. Comorbidity and multimorbidity in non-communicable diseases in South African primary healthcare. S Afr Med J 2015;105(2):134-138. [http://dx.doi.org/10.7196/SAMJ.8696] 4. Steyn K, Levitt NS, Patel M, et al. Hypertension and diabetes: Poor care for patients at community health centres. S Afr Med J 2008;98(8):618-622.

5. Poyser MA, Nelson H, Ehrlich RI, et al. Socioeconomic deprivation and asthma prevalence and severity in young adolescents. Eur Respir J 2002;19(5):892-898. [http://dx.doi.org/10.1183/0903193 6.02.00238402] 6. Williams DR, Herman A, Stein DJ, et al. Twelve-month mental disorders in South Africa: Prevalence, service use and demographic correlates in the population-based South African Stress and Health Study. Psychol Med 2008;38(2):211-220. [http://dx.doi.org/10.1017/S0033291707001420] 7. English RG, Bateman ED, Zwarenstein MF, et al. Development of a South African Integrated Syndromic Respiratory Disease Guideline for Primary Care. Prim Care Respir J 2008;17(3):156-163. [http://dx.doi.org/10.3132/pcrj.2008.00044] 8. Andresen EM, Malmgren JA, Carter WB, Patrick DL. Screening for depression in well older adults: Evaluation of a short form of the CES-D (Center for Epidemiologic Studies Depression Scale). Am J Prev Med 1994;10(2):77-84.

9. Peer N, Steyn K, Lombard C, Gwebushe N, Levitt N. A high burden of hypertension in the urban black population of Cape Town: The Cardiovascular Risk in Black South Africans (CRIBSA) Study. PLoS One 2013;8(11):e78567 [http://dx.doi.org/10.1371/journal.pone.0078567] 10. Jones PW, Quirk FH, Baveystock CM. The St Georgeâ&#x20AC;&#x2122;s Respiratory Questionnaire. Respir Med 1991;85(Suppl B):25-31. [http://dx.doi.org/10.1016/S0954-6111(06)80166-6] 11. Executive Summary: Standards of Medical Care in Diabetes â&#x20AC;&#x201C; 2013. Diabetes Care 2013;36(Suppl 1):S4-S10. [http://dx.doi.org/10.2337/dc13-S004] 12. Maepe LM, Outhoff K. Hypertension in goldminers. S Afr Med J 2012;102(1):30-33.

13. Mendenhall E, Richter LM, Stein A, Norris SA. Psychological and physical co-morbidity among urban South African women. PLoS One 2013;8(10):e78803. [http://dx.doi.org/10.1371/journal. pone.0078803] 14. Barnett K, Mercer SW, Norbury M, et al. Epidemiology of multimorbidity and implications for health care, research, and medical education: A cross-sectional study. Lancet 2012;380(9836):37-43. [http:// dx.doi.org/10.1016/S0140-6736(12)60240-2] 15. Department of Health, Republic of South Africa. Department of Health Annual Report 2011/2012. http://www.health.gov.za/ (accessed 27 June 2014).

16. Department of Health, Republic of South Africa. Primary Care 101. http://www.health.gov.za/docs/ Policies/2013/Low_res_PC_101_Guideline_v2.pdf (accessed 4 November 2014).

Accepted 15 June 2015.

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Prevalence of tobacco use among adults in South Africa: Results from the first South African National Health and Nutrition Examination Survey P Reddy,1,2 PhD; K Zuma,3 PhD; O Shisana,4,5 BA, MA, ScD; K Jonas,1 MA; R Sewpaul,1 MSc Population Health, Health Systems and Innovation, Human Sciences Research Council, Cape Town, South Africa hild and Family Studies, Department of Social Work, Faculty of Community and Health Sciences, University of the Western Cape, C Bellville, Cape Town, South Africa 3 Research Methodology and Data Centre, Human Sciences Research Council, Pretoria, South Africa 4 Human Sciences Research Council, Cape Town, South Africa 5 Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: P Reddy (preddy@hsrc.ac.za)

Background. Data on tobacco use have informed the effectiveness of South Africa (SA)’s tobacco control strategies over the past 20 years.

Objective. To estimate the prevalence of tobacco use in the adult SA population according to certain demographic variables, and identify the factors influencing cessation attempts among current smokers.

Methods. A multistage disproportionate nationally representative stratified cluster sample of households was selected for the South African National Health and Nutrition Examination Survey, conducted in 2012. A sample of 10 000 households from 500 census enumerator areas was visited. A detailed questionnaire was administered to all consenting adults in each consenting household.

Results. Of adult South Africans, 17.6% (95% confidence interval (CI) 6.3 - 18.9) currently smoke tobacco. Males (29.2%) had a prevalence four times that for females (7.3%) (odds ratio 5.20, 95% CI 4.39 - 6.16; p<0.001). The provinces with the highest current tobacco smoking prevalence were the Western Cape (32.9%), Northern Cape (31.2%) and Free State (27.4%). Among current tobacco smokers, 29.3% had been advised to quit smoking by a healthcare provider during the preceding year, 81.4% had noticed health warnings on tobacco packages, and 49.9% reported that the warning labels had led them to consider quitting.

Conclusion. A large proportion of adult South Africans continue to use tobacco. While considerable gains have been made in reducing tobacco use over the past 20 years, tobacco use and its determinants need to be monitored to ensure that tobacco control strategies remain effective.

S Afr Med J 2015;105(8):648-655. DOI:10.7196/SAMJnew.7932

Smoking is one of the major preventable causes of disease and premature death globally.[1] Tobacco is the second leading risk factor for the global burden of disease, accounting for 6.3% of disability-adjusted life-years lost[2] and causing six million deaths annually.[1] Since 1995 there has been a modest increase in tobacco consumption in low- and middle-income countries (LMICs), but a consistent decline in high-income countries (HICs).[3] By 2030 it is estimated that tobacco will kill more than eight million people annually, with 80% of these deaths occurring in LMICs.[3] Consumers in LMICs such as South Africa (SA) are likely to be less informed about the adverse health consequences of tobacco use than those in HICs, and are therefore likely to bear the major health impact of tobacco unless an aggressive educational programme is mounted.[3,4] SA epidemiological and economic data on tobacco use have in­ formed tobacco control efforts since the 1980s, resulting in a halv­ing of the prevalence of smoking in adults over the past 20 years.[4] Tobacco interventions used have included legislation such as the Tobacco Products Control Amendment Act No. 12 of 1999, hikes in excise duty on cigarettes, and health promotion interventions to educate and improve individuals’ health knowledge.[4,5] Despite initial successes, there have been recent increases in tobacco use between 2008 and 2011 among SA youth, particularly girls.[4] This study provides data on tobacco use among SA adults, and the factors influencing quitting among current smokers. The insights it

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provides into tobacco-related behaviours can be used to strengthen measures and health policies for tobacco control.

Methods

The first South African National Health and Nutrition Examination Survey (SANHANES-1)[6] investigated the smoking status of South Africans aged ≥15 years through an interviewer-administered questionnaire survey and the collection of blood samples to measure serum cotinine levels. SANHANES-1 was a cross-sectional, biobehavioural survey providing baseline data as a foundation for future longitudinal studies. This article focuses on the selfreported tobacco-using behaviour of adults aged ≥18 years. The survey instrument included questions on the respondents’ history of smoking tobacco, current use of other tobacco products, frequency and duration of use, and attempts to stop smoking tobacco or using other tobacco products. SANHANES-1 was conducted by the Human Sciences Research Council (HSRC) in 2012 and received approval from the Research Ethics Committee (REC) of the HSRC (REC 6/16/11/11).

Sampling

The detailed sampling method is described in the main report.[6] Persons in all nine provinces aged ≥18 years were sampled, using a multistage disproportionate, stratified cluster sampling approach to select 10 000 households from a random sample of 500 census enumerator areas. All such adults in the household were interviewed

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in their homes, usually after hours, in a standardised manner by trained interviewers in the preferred language of the respondents.

The reliability of the interviewers’ survey techniques was ensured by reinterviewing 10% of the sample.

Respondents were considered to be current tobacco smokers if they reported that they currently smoked tobacco daily or less than daily. Similarly, current users of other tobacco products were defined as those who reported use of other tobacco products on a daily or less than daily basis. Other tobacco products were defined as handrolled cigarettes, pipes, cigars, cheroots and cigarillos, hookah, hubbly bubbly or water-pipe sessions, electronic cigarettes, snuff, chewing tobacco and smokeless tobacco. Reference to non-smokers in the text includes ex-smokers.

Data management and statistical analysis

Data were double-entered and verified using Census Survey Processing (CS Pro) software version 5.0 (US Census Bureau) and converted to the Statistical Package for the Social Sciences (SPSS) for further exploration. Sampling weights were computed to account for unequal sampling probabilities and benchmarking to 2012 mid-year population estimates. Data on tobacco use were analysed for adults aged ≥18 years. Weighted data were analysed using STATA version 12 (Stata Corporation, USA). Estimates and 95% confidence intervals (CIs) were reported with odds ratios (ORs) as measures and direction of association. Chi-square and t-tests were used for categorical and continuous random variables, respectively. A p-value of <0.05 indicated statistical significance. Logistic regression analyses were conducted on the subsample of current tobacco smokers to determine the factors associated with having tried to stop smoking in the preceding 12 months in this group. The variables found to be significant in the univariate models were used in the multivariate model.

Table 1. Demographic profile of adults aged ≥18 years, SANHANES 2012

%

95% CI

n

National

100.0

15 401

Gender

Males

47.8

46.8 - 48.9

6 366

Females

52.2

51.1 - 53.2

9 021

18 - 24

21.0

19.9 - 22.2

3 253

25 - 34

26.7

25.3 - 28.1

3 381

35 - 44

20.8

19.8 - 22.0

2 750

45 - 54

14.3

13.3 - 15.4

2 539

55 - 64

9.3

8.4 - 10.4

1 918

≥65

7.8

7.0 - 8.7

1 560

Western Cape

11.1

9.6 - 12.7

2 229

Eastern Cape

11.1

9.2 - 13.3

1 675

Northern Cape

1.7

1.4 - 2.2

973

Free State

5.2

4.0 - 6.7

868

KwaZulu-Natal

15.9

13.2 - 19.0

2 666

North West

8.7

7.4 - 10.1

1 849

Gauteng

32.4

27.3 - 38.0

2 626

Mpumalanga

5.3

4.2 - 6.6

1 331

Limpopo

8.7

7.3 - 10.3

1 184

Black African

77.2

73.1 - 80.8

9 961

White

10.7

7.9 - 14.2

727

Coloured

9.3

7.9 - 11.0

3 122

Indian

2.8

1.8 - 4.5

1 414

Age (years)

Province

Race

Results

Demographic profile of the sample

Of the adult sample of 15 401, 52.2% were females (Table 1), 77.2% classified themselves as black Africans, 10.7% as white, 9.3% as coloured and 2.8% as of Indian descent, and 82.8% were aged 18 54 years.

Current tobacco smoking

The tobacco smoking status of the respondents is shown in Table 2.

Of the 15 401 interviewed, 13 897 (90.2%) indicated their tobacco smoking status. The national prevalence of current tobacco smoking among adults was 17.6% (95% CI 16.3 - 18.9), with 15.9% (95% CI 14.7 - 17.2) being daily smokers and 1.7% (95% CI 1.4 - 2.0) less than daily smokers.

The prevalence of current tobacco smoking among males (29.2%) was four times that among females (7.3%) (OR 5.20, 95% CI 4.39 6.16; p<0.001).

The provinces with the highest current tobacco smoking rates were the Western Cape (32.9%), Northern Cape (31.2%) and Free State (27.4%); North West and Limpopo had the lowest rates (12.7% and 12.8%, respectively). Coloured adults had a significantly higher current smoking prevalence (40.1%) than Indians (22.1%) (p<0.001), whites (15.3%) (p<0.001) and black Africans (15.1%) (p<0.001).

Adults aged 18 - 24 (13.6%), and ≥65 years (10.8%) had significantly lower current tobacco smoking prevalences than those aged 25 - 34 (18.5%), 35 - 44 (19.7%), 45 - 54 (21.2%) and 55 - 64 years (19.5%) (p<0.001 for all).

Use of other tobacco products

Nationally, 5.2% of adults reported current use of other tobacco products, with 4.2% being daily users and 1.0% less than daily users

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(Table 3). Significantly (p<0.001) more males (6.8%) than females (3.7%) reported current use of other tobacco products (OR 1.90, 95% CI 1.52 - 2.36).

Among males, there was no significant variation in current use of other tobacco products by age group, whereas among females this increased with age. Females aged 18 - 24 (1.8%) and 25 - 34 years (2.1%) had a significantly lower prevalence of current use of other tobacco products than those aged 35 - 44 (4.6%), 45 - 54 (4.9%), 55 - 64 (6.1%) and ≥65 years (6.2%). The Free State had the highest provincial prevalence of current use of other tobacco products (18.3%), and North West (2.1%) the lowest.

Significantly more coloured adults (7.7%) than Indian (3.0%) (p=0.009) and white (2.2%) (p<0.001) adults reported current use of other tobacco products. Furthermore, significantly more black African adults (5.4%) than white adults (2.2%) reported current use of other tobacco products (p<0.001).

Current use of any tobacco product

Nationally, 20.1% (95% CI 18.7 - 21.5) of adults reported current use of any tobacco product (either smoking or use of other tobacco products).

Males had a significantly higher prevalence of current tobacco use (31.0%) than females (10.3%) (OR 3.90, 95% CI 3.37 - 4.52; p<0.001).

Significantly fewer adults aged 18 - 24 (14.8%) and ≥65 years (15.9%) than those aged 25 - 34 (20.2%), 35 - 44 (22.5%), 45 - 54

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≥65

August 2015, Vol. 105, No. 8

28.5

18.0

47.0

36.8

White

Coloured

Indian

lack B African

Race

26.9

Limpopo

17.3 - 27.1

21.8

22.3

orth N West

28.7

17.8 - 27.6

35.7

Gauteng

41.7 - 52.2

46.9

Free State

KwaZuluNatal

Mpumalanga

28.2 - 49.4

38.3

Northern Cape

27.7 - 46.9

42.0 - 51.9

12.1 - 25.9

25.9 - 31.3

20.8 - 34.2

22.9 - 35.3

31.1 - 40.6

26.1 - 37.2

31.4

Eastern Cape

34.1 - 45.5

39.6

12.7 - 22.1

16.9

Western Cape

Province

24.4 - 35.1

30.8 - 41.1

28.8 - 37.9

29.4

35.8

45 - 54

55 - 64

33.2

35 - 44

26.7 - 35.2

19.5 - 25.5

22.4

30.8

18 - 24

26.9 - 31.6

29.2

National

Age (years)

25 - 34

95% CI

%

Current tobacco smoking

35.6

45.1

17.3

25.5

23.0

27.3

20.6

21.2

31.5

39.3

34.7

27.1

38.0

15.7

27.6

32.5

30.5

28.4

19.3

26.6

%

26.4 - 46.0

40.3 - 50.0

11.4 - 25.2

23.0 - 28.2

17.5 - 29.7

21.6 - 33.8

16.2 - 25.8

16.7 - 26.7

26.7 - 36.7

34.7 - 44.1

25.2 - 45.5

21.4 - 33.8

32.5 - 43.7

11.7 - 20.8

22.7 - 33.0

27.7 - 37.8

26.2 - 35.2

24.4 - 32.7

16.8 - 22.2

24.3 - 28.9

95% CI

Current daily smoking

Males

1.2

1.8

0.8

3.0

3.9

1.4

1.2

1.1

4.2

7.6

3.6

4.3

1.6

1.2

1.9

3.3

2.7

2.4

3.0

2.6

%

364

610

803

472

711

903

963

1 255

1 315

5 619

n

0.6 - 2.5

1.1 - 3.0

0.3 - 2.2

2.3 - 3.9

2.0 - 7.5

0.6 - 3.2

0.5 - 2.6

0.4 - 2.5

2.7 - 6.6

553

1 114

308

3 615

428

478

1 028

656

946

4.4 - 13.0 306

1.9 - 6.5

2.7 - 6.7

0.9 - 2.9

0.5 - 2.8

0.9 - 3.8

2.1 - 4.9

1.7 - 4.3

1.6 - 3.7

2.0 - 4.5

2.1 - 3.3

95% CI

Current less than daily smoking

7.5

34.4

12.9

3.3

2.1

3.6

4.4

5.2

4.1

8.5

24.5

6.7

26.8

7.5

11.3

8.5

7.5

6.9

4.9

7.3

%

5.0 - 11.1

30.3 - 38.7

8.4 - 19.2

2.8 - 4.0

1.1 - 3.8

2.2 - 5.8

3.2 - 6.0

3.6 - 7.4

2.3 - 7.4

5.4 - 13.1

18.3 - 32.0

4.4 - 9.9

21.6 - 32.8

4.3 - 12.7

8.9 - 14.2

6.8 - 10.6

5.9 - 9.5

5.6 - 8.4

3.7 - 6.3

6.4 - 8.4

95% CI

Current tobacco smoking

6.1 - 9.8

5.5 - 9.1

4.2 - 6.8

3.3 - 5.8

5.6 - 7.5

95% CI

4.1 - 12.5

3.7 - 8.6

5.4 - 12.9

2.1 - 3.2

1.1 - 3.7

2.0 - 5.7

2.0 - 4.6

3.4 - 7.0

1.8 - 6.9

4.8

3.0 - 7.5

32.1 28.3 - 36.0

12.8 8.3 - 19.1

2.6

2.0

3.4

3.0

4.9

3.6

8.4

23.1 17.0 - 30.6

5.6

25.6 20.6 - 31.4

7.2

10.1 7.8 - 13.0

7.7

7.1

5.4

4.4

6.5

%

Current daily smoking

Females

2.7

2.3

0.1

0.7

0.1

0.2

1.4

0.3

0.6

0.1

1.4

1.0

1.3

0.3

1.2

0.8

0.4

1.5

0.5

0.8

%

1.2 - 6.1

1.4 - 3.7

0.0 - 0.5

0.5 - 1.1

0.0 - 0.4

0.0 - 1.4

0.8 - 2.3

0.1 - 0.8

0.3 - 1.3

0.0 - 0.9

0.7 - 3.0

0.6 - 1.8

0.7 - 2.2

0.1 - 0.7

0.6 - 2.5

0.4 - 1.6

0.2 - 1.1

0.9 - 2.6

0.2 - 1.4

0.6 - 1.1

95% CI

687

1 661

370

5 537

693

722

1 419

1 094

1 371

441

533

864

1 138

937

1 021

1 383

1 540

1 754

1 640

8 275

n

Current less than daily smoking

Table 2. Prevalence of current tobacco smoking by gender according to age, province and race among adults aged ≥18 years, SA 2012

22.1

40.1

15.3

15.1

12.8

15.3

13.0

12.7

17.8

27.4

31.2

18.4

32.9

10.8

19.5

21.2

19.7

18.5

13.6

17.6

%

16.9 - 28.2

36.5 - 43.8

11.7 - 19.9

13.9 - 16.5

9.7 - 16.6

12.0 - 19.4

10.7 - 15.8

10.5 - 15.4

15.5 - 20.3

23.7 - 31.4

24.1 - 39.4

15.5 - 21.9

28.3 - 37.8

8.1 - 14.4

16.8 - 22.5

18.5 - 24.1

17.4 - 22.2

16.3 - 20.9

11.9 - 15.4

16.3 - 18.9

95% CI

Current tobacco smoking

20.1

38.0

14.9

13.3

11.0

14.6

11.8

12.1

15.6

23.6

28.8

15.9

31.4

10.2

18.0

19.2

18.2

16.5

11.8

15.9

%

15.2 - 26.1

34.6 - 41.6

11.3 - 19.5

12.2 - 14.6

8.3 - 14.6

11.3 - 18.6

9.6 - 14.4

9.8 - 14.8

13.3 - 18.2

20.6 - 26.9

21.9 - 36.8

12.8 - 19.5

27.0 - 36.2

7.5 - 13.8

15.4 - 20.9

16.7 - 22.1

15.9 - 20.7

14.4 - 18.9

10.3 - 13.4

14.7 - 17.2

95% CI

Current daily smoking

Total

2.0

2.1

0.4

1.8

1.7

0.8

1.3

0.7

2.2

3.8

2.5

2.6

1.4

0.6

1.5

1.9

1.5

2.0

1.8

1.7

%

1.1 - 3.5

1.5 - 2.9

0.2 - 1.1

1.4 - 2.2

0.9 - 3.3

0.4 - 1.6

0.8 - 2.1

0.3 - 1.2

1.4 - 3.2

2.2 - 6.5

1.4 - 4.2

1.7 - 3.8

1.0 - 2.1

0.3 - 1.2

0.9 - 2.5

1.4 - 2.8

1.0 - 2.3

1.4 - 2.7

1.2 - 2.6

1.4 - 2.0

95% CI

1 240

2 776

678

9 152

1 121

1 201

2 448

1 750

2 317

747

897

1 475

1 941

1 409

1 733

2 288

2 503

3 009

2 955

13 897

n

Current less than daily smoking

RESEARCH

651

7.4

7.7

45 - 54

55 - 64

15.2

August 2015, Vol. 105, No. 8

7.5

7.8

Mpumalanga

Limpopo

10.8 7.8 - 14.8

5.4

Coloured

Indian

2.5

8.0

2.1

5.8

5.3

6.3

5.0

2.2

95% CI

0.9 - 6.9

5.2 - 12.1

1.0 - 4.3

4.9 - 6.9

3.1 - 8.9

3.8 - 10.4

3.6 - 6.8

0.9 - 5.6

2.9 - 7.2

10.5 - 21.3

4.7 - 16.5

3.9 - 9.1

2.5 - 8.0

4.8 - 11.4

5.4 - 10.8

4.1 - 8.5

3.1 - 6.5

4.3 - 8.5

2.7 - 6.2

4.7 - 6.4

%

2.9

2.8

0.0

1.3

2.5

1.2

0.6

0.4

2.0

3.6

1.2

1.2

1.9

0.6

0.0

1.5

1.2

1.5

2.0

1.4

95% CI

0.7 - 11.4

1.7 - 4.6

0.9 - 1.9

1.1 - 5.5

0.5 - 2.8

0.2 - 1.7

0.1 - 2.3

1.1 - 3.6

1.8 - 7.4

0.4 - 3.0

0.5 - 2.7

1.0 - 3.3

0.1 - 2.4

0.7 - 3.4

0.5 - 2.8

0.9 - 2.5

1.2 - 3.2

1.0 - 1.8

530

1 115

296

3 533

425

468

1 007

616

911

302

370

607

796

457

693

880

939

1 233

1 300

5 502

n

%

95% CI

3.2 - 6.5

2.8 - 8.5

4.5 - 8.5

4.1 - 8.9

3.7 - 6.5

3.3 - 6.5

1.4 - 3.2

0.8 - 3.9

3.1 - 4.5

0.5

5.1

2.3

3.9

5.0

2.7

1.7

1.7

2.1

0.2 - 1.4

3.5 - 7.3

0.7 - 7.5

3.1 - 4.7

2.8 - 8.7

1.3 - 5.6

1.0 - 2.9

0.8 - 3.7

1.2 - 3.6

17.9 13.4 - 23.5

10.2 5.5 - 18.2

4.6

4.9

6.2

6.1

4.9

4.6

2.1

1.8

3.7

%

95% CI

4.4 - 16.9

2.4 - 5.8

2.0 - 7.8

4.0 - 7.7

3.4 - 6.7

3.0 - 5.4

2.7 - 5.8

1.2 - 2.9

0.4 - 3.7

2.6 - 3.8

0.2

4.3

1.4

3.3

4.4

2.7

1.2

1.7

1.7

0.0 - 0.7

2.8 - 6.5

0.2 - 8.1

2.7 - 4.1

2.6 - 7.2

1.3 - 5.6

0.7 - 1.9

0.8 - 3.7

0.9 - 3.0

15.9 11.6 - 21.5

8.8

3.8

4.0

5.5

4.8

4.1

4.0

1.9

1.2

3.1

0.4

0.8

0.9

0.5

0.6

0.0

0.6

0.0

0.4

2.0

1.4

0.8

0.9

0.6

1.3

0.8

0.6

0.2

0.5

0.6

%

0.1 - 1.2

0.5 - 1.4

0.2 - 3.8

0.4 - 0.9

0.2 - 1.9

0.2 - 1.5

0.1 - 1.5

1.0 - 3.7

0.7 - 2.9

0.4 - 1.9

0.4 - 1.9

0.3 - 1.7

0.4 - 4.1

0.3 - 2.1

0.3 - 1.4

0.1 - 0.6

0.3 - 1.2

0.4 - 0.9

95% CI

653

1 640

356

5 382

668

710

3.0

7.7

2.2

5.4

6.2

4.9

2.1 3.7

1 045

4.1

18.3

10.2

5.8

5.6

6.8

6.8

6.1

5.1

4.7

3.9

5.2

%

1.3 - 6.9

5.6 - 10.4

1.1 - 4.5

4.7 - 6.2

3.9 - 9.7

3.2 - 7.5

2.8 - 4.8

1.0 - 4.4

2.9 - 5.6

14.1 - 23.5

6.0 - 17.0

4.5 - 7.5

3.7 - 8.4

5.1 - 9.0

5.1 - 9.0

4.7 - 7.8

4.0 - 6.5

3.7 - 6.0

2.9 - 5.3

4.6 - 5.9

95% CI

Current use of other tobacco products

1 395

1 301

425

535

846

1 126

899

988

1 348

1 507

1 710

1 599

8 051

n

Current less than daily use of other tobacco products

*Other tobacco products include hand-rolled cigarettes, tobacco smoked in pipes, cigars, cheroots, cigarillos, hookah, hubbly bubbly, water pipe, electronic cigarettes, snuff, chewing tobacco, and smokeless tobacco.

2.2 - 12.6

1.0 - 4.3

2.1

6.1 - 8.3

7.1

White

4.9 - 12.0

4.7 - 11.7

Black African

5.6

Gauteng

Race

1.1 - 5.9

2.6

North West

4.1 - 7.6

4.7 - 9.1

KwaZulu-Natal 6.6

4.6

9.0

18.8 12.9 - 26.5

Free State

4.5

Northern Cape 10.2 5.7 - 17.6

4.0 - 9.9

7.4

7.7

5.9

4.5

6.1

4.1

6.0

7.2

Eastern Cape

5.1 - 12.2

5.4 - 10.8

5.3 - 10.3

4.1 - 7.9

5.7 - 9.9

4.4 - 8.3

5.0 - 10.4

6.4

Western Cape

5.7

35 - 44

Province

7.5

25 - 34

8.0

6.1

18 - 24

≥65

Age (years)

5.5

%

5.9 - 7.9

95% CI

%

6.8

National

Current daily use of other tobacco products

Current use of other tobacco products

Current daily use of other tobacco products

Current use of other tobacco products

Current less than daily use of other tobacco products

Females

Males

Table 3. Prevalence of current use of other tobacco products* by gender according to age, province and race among adults aged ≥18 years, SA 2012

95% CI

4.9 - 15.8

3.6 - 6.5

2.5 - 7.1

4.6 - 8.2

4.7 - 8.0

3.8 - 6.4

3.2 - 5.5

2.9 - 5.2

1.7 - 4.0

3.7 - 4.8

1.4

5.9

1.7

4.5

4.8

4.4

3.1

1.9

3.0

0.5 - 3.6

4.0 - 8.7

0.7 - 4.1

3.9 - 5.1

3.0 - 7.5

2.7 - 7.0

2.3 - 4.0

0.9 - 4.3

2.1 - 4.2

15.5 11.9 - 20.1

8.9

4.9

4.2

6.2

6.1

4.9

4.2

3.9

2.6

4.2

%

Current daily use of other tobacco products

Total

1.7

1.7

0.5

0.9

1.4

0.5

0.6

0.2

1.1

2.8

1.3

1.0

1.3

0.6

0.7

1.1

0.9

0.8

1.3

1.0

%

0.4 - 6.0

1.1 - 2.6

0.1 - 2.0

0.7 - 1.2

0.7 - 3.1

0.2 - 1.3

0.3 - 1.2

0.0 - 1.0

0.6 - 1.9

1.6 - 4.8

0.8 - 2.2

0.6 - 1.7

0.8 - 2.2

0.3 - 1.4

0.2 - 2.3

0.6 - 2.1

0.5 - 1.7

0.5 - 1.3

0.8 - 2.0

0.8 - 1.2

95% CI

1 183

2 756

652

8 915

1 093

1 179

2 403

1 661

2 212

727

905

1 454

1 922

1 356

1 682

2 230

2 446

2 943

2 899

13 556

n

Current less than daily use of other tobacco products

RESEARCH

RESEARCH

Table 4. Advice to stop tobacco smoking, cessation attempts and the effects of warning labels on cessation attempts among current tobacco smokers aged ≥18 years by gender, age, province and race, SA 2012 Advised to quit using tobacco during any visit to a doctor/other healthcare provider (past 12 months) %

95% CI

n

Tried to stop smoking tobacco during the past 12 months %

n

95% CI

Noticed health warnings on tobacco packages during the past 30 days %

95% CI

n

Warnings labels on tobacco packages led one to think about quitting smoking %

95% CI

n

National

29.3

26.3 - 32.4

2 543

47.8

44.9 - 50.7

2 561

81.4

78.5 - 83.9

2 513

49.9

46.7 - 53.1

2 442

Gender

Males

26.5

23.2 - 30.1

1 699

47.4

44.0 - 50.8

1 720

81.3

78.1 - 84.2

1 684

50.8

47.1 - 54.4

1 633

Females

39.3

33.9 - 45.0

844

49.2

43.4 - 54.9

841

81.5

76.6 - 85.5

829

46.8

41.0 - 52.7

809

Age (years) 18 - 24

14.7

10.5 - 20.3

432

45.0

37.9 - 52.3

438

79.6

72.7 - 85.0

431

49.1

42.8 - 55.5

422

25 - 34

24.3

20.0 - 29.2

599

45.6

40.5 - 50.7

606

82.3

77.6 - 86.3

596

52.1

46.7 - 57.4

581

35 - 44

30.2

23.9 - 37.3

493

47.6

41.0 - 54.3

494

81.7

75.9 - 86.4

489

45.2

38.5 - 52.1

472

45 - 54

35.8

28.4 - 43.9

504

52.7

45.5 - 59.9

508

83.7

78.1 - 88.1

498

56.2

48.8 - 63.4

486

55 - 64

41.6

34.5 - 49.1

361

49.0

41.8 - 56.3

360

80.2

72.8 - 86.0

347

47.0

39.1 - 55.1

334

≥65 Province

52.3

39.0 - 65.3

154

50.5

35.4 - 65.5

155

74.0

60.9 - 83.9

152

47.2

32.8 - 62.1

147

Western Cape

36.0

31.7 - 40.6

703

49.3

43.9 - 54.7

702

86.5

81.7 - 90.1

690

47.3

41.2 - 53.5

684

Eastern Cape

27.3

20.2 - 35.8

290

54.2

47.1 - 61.0

291

80.7

72.2 - 87.1

281

59.5

49.3 - 68.9

275

Northern Cape

31.4

24.2 - 39.6

307

40.8

31.2 - 51.2

306

93.2

88.0 - 96.3

305

61.1

55.0 - 66.8

293

Free State

21.9

15.2 - 30.5

187

51.2

43.4 - 59.0

187

75.8

67.3 - 82.6

187

48.0

40.7 - 55.4

182

KwaZulu-Natal

32.1

21.8 - 44.3

349

53.8

45.6 - 61.8

356

88.0

83.1 - 91.6

350

58.3

51.0 - 65.2

339

North West

38.9

32.2 - 46.0

171

42.2

35.5 - 49.2

172

74.8

64.5 - 82.9

168

50.4

43.2 - 57.7

164

Gauteng

26.2

19.5 - 34.2

278

44.5

37.5 - 51.7

281

78.6

69.1 - 85.8

274

45.1

36.6 - 53.8

258

Mpumalanga

18.9

10.2 - 32.4

134

41.9

29.2 - 55.7

139

71.0

58.1 - 81.2

135

48.0

32.9 - 63.5

126

Limpopo Race

22.3

15.2 - 31.5

124

38.4

27.7 - 50.4

127

74.6

66.6 - 81.2

123

35.7

27.1 - 45.2

121

Black African

25.3

21.8 - 29.0

1 158

47.7

43.8 - 51.5

1 178

78.4

74.6 - 81.9

1 150

51.8

47.6 - 56.0

1 111

White

33.3

23.1 - 45.4

120

47.0

36.2 - 58.2

120

84.2

70.9 - 92.1

120

37.1

26.3 - 49.4

119

Coloured

36.2

32.6 - 40.0

1 052

47.8

43.3 - 52.4

1 053

88.0

84.7 - 90.7

1 036

49.3

44.2 - 54.5

1 014

Indian

53.7

28.9 - 76.8

205

52.9

47.0 - 58.8

203

89.2

76.4 - 95.4

199

54.0

47.4 - 60.6

190

(24.4%) and 55 - 64 years (22.8%) currently used tobacco (p<0.05 for all).

The highest prevalence of current tobacco use was observed in the Free State (36.7%) and Western Cape (35.8%), and the lowest in North West (14.2%). The prevalence was significantly higher among coloured adults (43.1%) than among Indians (23.5%) (p<0.001), black Africans (17.7%) (p<0.001) and whites (17.1%) (p<0.001).

Factors affecting tobacco smoking cessation attempts

Among current tobacco smokers, 29.3% reported that they had been advised to quit smoking tobacco during a visit to a healthcare practitioner during the 12 months preceding the survey, and 47.8% had tried to quit smoking during that time (Table 4).

Significantly fewer male (26.5%) than female (39.3%) current tobacco smokers reported being advised to quit smoking (OR 0.56, 95% CI 0.42 - 0.74; p<0.001). The proportions of respondents who had been advised to quit increased with age group. Significantly more current tobacco smokers aged 55 - 64 (41.6%) and ≥65 years (52.3%) were advised to quit smoking by a healthcare practitioner than those aged 35 - 44 (30.2%) (p=0.020 and p=0.005, respectively), 25 - 34 (24.3%) (p<0.001 and p<0.001, respectively) and 18 - 24

652

years (14.7%) (p<0.001 and p<0.001, respectively). Of the provinces, Mpumalanga (18.9%) had the lowest proportion of current smokers who had been advised to quit smoking, and North West (38.9%) the highest. Significantly more Indian (53.7%) and coloured (36.2%) current smokers than black Africans (25.3%) (p=0.035 and p<0.001, respectively) reported being advised to quit smoking.

Attempts to quit tobacco smoking in the past year did not differ significantly by gender (OR 0.93, 95% CI 0.71 - 1.22; p=0.607), or by race or age for all within-group pairwise tests. The prevalence of having tried to quit smoking was highest in the Eastern Cape (54.2%) and KwaZulu-Natal (53.8%) and lowest in Limpopo (38.4%).

Among current tobacco smokers, 81.4% reported that they had noticed health warnings on tobacco packages during the 30 days preceding the survey, and 49.9% reported that these labels had led them to think about quitting smoking.

There was no significant association of gender (OR 0.99, 95% CI 0.71 - 1.37; p=0.955) or age in the likelihood of having noticed health warnings on tobacco packages among current smokers.

The Northern Cape (93.2%) had the highest proportion of current smokers who had noticed health warnings on tobacco packages.

Significantly more coloured (88.0%) and Indian (89.2%) than black

August 2015, Vol. 105, No. 8

RESEARCH

Table 5. Logistic regression of factors associated with having tried to stop smoking tobacco among current tobacco smokers aged ≥18 years, SA 2012 Tried to stop smoking tobacco during the past 12 months Univariate regression

OR

95% CI

p-value

Males

0.93

0.71 - 1.22

0.607

Females

Ref

-

-

18 - 24

Ref

-

-

25 - 34

1.02

0.71 - 1.47

0.899

35 - 44

1.11

0.75 - 1.66

0.596

45 - 54

1.37

0.91 - 2.05

0.135

55 - 64

1.18

0.77 - 1.79

0.449

≥65

1.25

0.63 - 2.48

0.529

Black African

Ref

-

-

White

0.98

0.6 - 1.58

0.918

Coloured

1.01

0.79 - 1.27

0.960

Indian

Multivariate regression OR

95% CI

p-value

Gender

Age (years)

Race

1.24

0.92 - 1.65

0.154

Advised to quit using tobacco during any visit to a doctor/ other healthcare provider during the past 12 months

3.97

2.94 - 5.34

<0.001

3.79

2.8 - 5.14

<0.001

Noticed health warnings on tobacco packages during the past 30 days

2.00

1.43 - 2.79

<0.001

1.71

1.21 - 2.41

0.002

African (78.4%) (p<0.001 and p=0.032, respectively) current smokers had noticed health warnings on tobacco packages.

There was no significant variation by gender in the prevalence of current smokers who reported that warning labels on tobacco packages led them to think about quitting smoking (OR 1.17, 95% CI 0.89 1.54; p=0.248). Significantly more current smokers aged 45 - 54 (56.2%) than those aged 35 - 44 years (45.2%) reported that warning labels on tobacco packages led them to think about quitting smoking (p=0.042). The Northern Cape had the highest proportion of current smokers who reported that warning labels led them to think about quitting (61.1%), and Limpopo the lowest (35.7%). Significantly more black African (51.8%) and Indian (54.0%) current smokers than white current smokers (37.1%) reported that warning labels led them to think about quitting (p=0.022 and p=0.015, respectively).

Among current tobacco smokers, no statistically significant univariate associ­ ations were found between having tried to stop smoking tobacco in the past 12 months

and each of the categories gender, age group and race (Table 5). Having been advised to quit using tobacco during a visit to a healthcare provider during the past 12 months and having noticed health warnings on tobacco packages in the past 30 days were significantly associated with attempts to stop smoking tobacco in both the univariate (OR 3.97, 95% CI 2.94 5.34 and OR 2.00, 95% CI 1.43 - 2.79, respectively) and multivariate (OR 3.79, 95% CI 2.80 - 5.14 and OR 1.71, 95% CI 1.21 - 2.41, respectively) logistic re­gres­ sion models.

Prevalence of exposure to secondhand smoke

Among current users of any tobacco products, 56.4% reported that someone smoked in their home (either daily or less than daily), while among non-current users of tobacco products this figure was 13.0% (Table 6).

Among current tobacco users, daily exposure to tobacco smoke in the home did not vary significantly by gender (OR 1.11, 95% CI 0.86 - 1.44; p=0.409)

653

August 2015, Vol. 105, No. 8

or age group. The Northern Cape and Western Cape had the highest proportions of current smokers who reported that someone smoked daily in their homes (64.9% and 64.3%, respectively) while the Eastern Cape and Mpumalanga had the lowest proportions (41.9% and 42.5%, respectively). Significantly fewer black African (45.1%) than coloured (67.1%) and white (59.9%) current tobacco users reported daily exposure to tobacco smoke in their homes (p<0.001 and p=0.049, respectively).

Among adults who did not currently use tobacco, significantly fewer males (8.4%) than females (11.8%) (OR 0.69, 95% CI 0.58 - 0.82; p<0.001) reported that someone smoked daily in their homes.

Significantly more 18 - 24-year-old noncurrent users of tobacco (13.8%) than those aged 25 - 34 (9.0%), 35 - 44 (9.4%), 45 54 (9.9%) and ≥65 years (8.3%) reported that someone smoked daily in their homes (p<0.001, p=0.002, p=0.008 and p=0.001, respectively). The Western Cape had the highest proportion of non-current tobacco users who reported that someone smoked daily in their homes (18.6%), and North West the lowest (6.9%). Significantly more coloured (24.5%) and Indian (20.3%) than black African (9.3%) (p<0.001 and p=0.005, respectively) and white (8.5%) (p<0.001 and p=0.007, respectively) non-current tobacco users reported that someone smoked daily in their homes.

Discussion

The SANHANES-1 study collected selfreported data on tobacco-using behaviour among 13 897 SA adults aged ≥18 years. The study revealed significantly greater use of tobacco products by males than by females, perhaps because tobacco use is believed to be more socially acceptable among men than women in many SA communities, and because men often have more disposable income to buy tobacco products.[4] There were considerable variations in tobacco use between the provinces and different racial groups in SA, perhaps reflecting differences in sociocultural and demographic determinants. For example, tobacco smoking rates are very high among coloured people, who comprise a high proportion of the Western Cape and Northern Cape populations – tobacco smoking rates in the Western Cape were 39.6% for men and 26.8% for women, and in the Northern Cape 38.3% for men and 24.5% for women. High rates of smoking among pregnant women in the Western Cape have been reported in other studies.[7] Surprisingly

Females

high prevalences of use of other tobacco products were observed among both males and females in the Northern Cape and Free

654

State, and further investigation is needed to ascertain the factors driving these high rates.

August 2015, Vol. 105, No. 8

62.0 44.2 - 77.1

Indian

3.4 - 9.6

3.1 - 11.5

0.6 - 3.8

1.8 - 11.9

5.4

3.1

2.9 - 9.7

1.5 - 6.4

2.3 - 28.5

4.2 - 6.9

24.4 - 35.0 15.9 - 51.2

30.8

20.1 - 44.7

42.9 - 51.6

1.8

0.4

0.4

2.2

2.6

6.5

20.9 - 35.8

0.9

32.7 - 57.7

0.8

2.5

1.1

3.2

2.7

0.1

1.3

1.2

0.3

1.5

2.7

2.0

0.9

2.0

1.7

%

39.7 - 57.9

34.5 - 58.9

31.8 - 50.8

38.5 - 60.4

22.4 - 35.5

41.2 - 58.6

25.4 - 40.0

29.9 - 53.1

27.3 - 42.2

31.2 - 47.0

36.3 - 49.0

39.2 - 50.8

36.6 - 51.7

36.8 - 48.5

37.8 - 45.5

38.3 - 45.5

95% CI

Never

29.4

31.0

47.2

27.8

44.9

48.8

46.5

41.0

49.4

28.5

49.9

32.3

41.0

34.3

38.8

42.5

44.9

44.0

42.5

41.6

41.9

%

*Currently use any tobacco product, i.e. smoking tobacco or other tobacco products. † Do not currently use any tobacco product.

59.8 45.4 - 72.6

67.1 61.2 - 72.5

White

8.8

2.9 - 10.0 1.9 - 6.2

11.1 6.9 - 17.4

6.1

5.4

1.6 - 6.9

10.4 5.1 - 20.1

5.8

45.1 40.8 - 49.5

Coloured

Black African

Race

58.6 50.7 - 66.1

Limpopo

1.5

48.8 39.6 - 58.1

42.5 29.7 - 56.5

Gauteng

46.0 35.8 - 56.6

48.0 35.7 - 60.5

KwaZulu-Natal

North West

Mpumalanga

4.8

43.7 33.9 - 54.0

Free State

3.4

41.9 33.9 - 50.5

64.9 57.8 - 71.4

Eastern Cape

5.5

3.3

64.3 56.0 - 71.8

4.5 - 12.1

2.4 - 7.4

2.9 - 8.8

1.3 - 4.4

3.8 - 10.2

4.3 - 12.3

3.3 - 6.0

4.0 - 6.9

14.7 5.1 - 35.4

7.4

4.2

5.1

2.4

6.2

Northern Cape

Western Cape

43.0 30.8 - 56.1

≥65

Province

56.7 49.0 - 64.1

57.0 49.3 - 64.4

45 - 54

55 - 64

49.9 44.0 - 55.7

50.8 44.4 - 57.2

25 - 34

47.7 39.8 - 55.8

7.3

49.2 43.2 - 55.3

35 - 44

18 - 24

Age (years)

4.5

5.2

95% CI

Less than daily %

51.9 47.9 - 56.0

Gender

Males

51.2 47.5 - 54.9

National

Daily

95% CI

%

284

125

336

242

328

312

694

195

376

521

524

602

418

988

1 648

2 636

n

0.5 - 6.4

0.2 - 0.9

0.1 - 2.7

1.3 - 3.6

0.8 - 8.1

184

1 042

113

1 290

162

2.5 - 15.6 153

0.1 - 6.4

0.1 - 5.5

1.1 - 5.9

0.2 - 5.4

1.4 - 7.4

0.9 - 7.3

0.0 - 0.6

0.4 - 3.8

0.4 - 3.5

0.1 - 1.2

0.7 - 3.4

1.3 - 5.7

0.8 - 5.1

0.4 - 2.1

1.2 - 3.3

1.1 - 2.6

95% CI

Don’t know

Among current users of any tobacco product* How often does anyone smoke inside your home?

20.3

24.5

8.5

9.3

9.3

8.5

8.4

6.9

12.1

15.3

13.1

11.0

18.6

8.3

11.1

9.9

9.4

9.0

13.8

11.8

8.4

10.4

%

13.8 - 29.0

20.1 - 29.5

5.1 - 13.9

7.9 - 10.8

6.9 - 12.5

5.7 - 12.6

6.2 - 11.4

4.7 - 10.1

8.5 - 16.7

11.4 - 20.3

9.0 - 18.7

8.4 - 14.3

14.1 - 24.2

6.1 - 11.1

8.9 - 13.9

7.9 - 12.3

7.5 - 11.8

7.5 - 10.8

11.6 - 16.3

10.4 - 13.4

7.0 - 10.0

9.2 - 11.8

95% CI

Daily

1.3

1.2

1.5

2.8

4.8

2.3

1.4

4.0

3.9

1.9

0.7

2.9

1.4

3.0

2.4

2.7

2.6

2.3

2.6

2.9

2.0

2.6

%

0.8 - 2.3

0.7 - 2.0

0.6 - 4.0

2.3 - 3.5

2.8 - 8.1

0.9 - 5.6

0.8 - 2.4

2.7 - 5.8

2.6 - 5.9

0.8 - 4.2

0.2 - 2.3

1.7 - 4.8

0.8 - 2.7

2.0 - 4.4

1.4 - 4.0

1.8 - 4.2

1.8 - 3.8

1.6 - 3.4

1.9 - 3.7

2.3 - 3.6

1.5 - 2.7

2.1 - 3.1

95% CI

Less than daily

77.1

73.0

89.3

84.7

84.4

83.6

88.4

82.9

82.2

81.1

83.8

80.5

79.0

86.7

84.0

84.9

85.2

85.1

81.4

82.6

86.8

84.3

%

69.3 - 83.3

68.1 - 77.4

83.7 - 93.1

82.9 - 86.4

79.1 - 88.5

76.3 - 89.0

85.5 - 90.9

78.3 - 86.6

77.2 - 86.3

76.2 - 85.1

79.2 - 87.6

75.5 - 84.7

73.4 - 83.7

83.6 - 89.2

80.6 - 86.9

81.7 - 87.7

82.5 - 87.6

82.9 - 87.1

78.5 - 84.0

80.8 - 84.2

84.7 - 88.6

82.7 - 85.8

95% CI

Never

1.3

1.3

0.7

3.2

1.5

5.6

1.8

6.3

1.8

1.8

2.3

5.6

0.9

2.1

2.5

2.4

2.8

3.6

2.2

2.7

2.8

2.7

%

1 122

1 108

1 222

1 605

1 835

2 237

2 377

6 800

3 581

10 384

n

1 778

459

541

2 047

0.5 - 3.2

0.6 - 2.8

0.2 - 2.0

2.3 - 4.3

0.7 - 3.0

937

1 559

517

7 328

902

2.3 - 13.1 985

0.8 - 3.8

3.7 - 10.5 1 451

1.1 - 3.1

0.6 - 4.8

0.8 - 6.6

3.0 - 10.3 1 099

0.3 - 2.8

1.2 - 3.5

1.5 - 4.0

1.3 - 4.4

1.8 - 4.2

2.6 - 5.0

1.4 - 3.3

2.0 - 3.7

1.9 - 4.0

2.0 - 3.6

95% CI

Don’t know

Among non-users of tobacco† How often does anyone smoke inside your home?

Table 6. Prevalence of current and non-current users of tobacco aged ≥18 years who had someone smoke in their homes, by gender, age, province and race, SA 2012

RESEARCH

Economic factors are also important in determining smoking prevalence rates, as tobacco use in LMICs such as SA is often

RESEARCH

highest among poorly educated, urban men and women who have low incomes.[8-11] These sociocultural and geographical differences in tobacco use and prevalence suggest that tailored culture- and contextspecific interventions need to be designed for smoking prevention and cessation among SA’s heterogeneous and rapidly changing populations. Tobacco control interventions such as hikes in excise taxes are likely to be more effective in citizens with lower disposable income. A case can be made for increasing excise duty on cigarettes from the current 51% of total price to nearer the 75% employed by countries with progressive tobacco control policies such as Canada.[12] The recent increase in smoking rates among young people and girls from 2008 to 2011, seen in the Global Youth Tobacco Surveys,[4] has occurred despite the initial success of tobacco control legislation and public health policies of the past 20 years that resulted in a 30% reduction in smoking prevalence among school learners during that time. This suggests that the strategies the tobacco industry uses to encourage young people (particularly girls) to smoke have been successful. Research shows that tobacco use is most often initiated and established during adolescence and young adulthood, with nearly nine out of ten smokers starting the habit by the age of 18 years, and 99% starting by the age of 26.[13] Surprisingly few current smokers (29.3%) reported that they had been advised to quit the use of tobacco products. Health professionals therefore need to escalate their efforts in advising users to quit, so as to avoid missed opportunities for prevention (in over 70% of smokers). Of current smokers, 47.8% had tried to quit and 49.9% reported that the health warning labels on tobacco packages made them think about quitting, suggesting that health warning labels may be effective in encouraging smoking cessation. This effect may be augmented when combined with plain packaging, as is done in Australia. Those who noticed warning labels on tobacco packages were 1.7 times more likely to attempt to quit smoking than those who did not notice warning labels.

Respondents who received advice to quit smoking from a healthcare provider were 3.8 times more likely to attempt to quit than those who did not receive advice. Women received advice to quit smoking much more often than men.

Of concern is the high prevalence of non-smokers who are exposed to environmental tobacco smoke (ETS). It is estimated that of the six million deaths that tobacco causes annually, 10% (600 000 deaths) occur among non-smokers who have been exposed to ETS.[14] ETS is particularly harmful for children who live in homes with smokers.

Notably, the SA government has introduced legislation to ban smoking in cars in which children under the age of 12 are travelling.

Conclusion

The efficacy and cost-effectiveness of a well-tested set of tobacco control policies and interventions have been clearly established over several decades in many countries around the world, at various income levels and in many different cultures. SANHANES-1 shows that this is also true of SA, where national smoking prevalence rates fell from 32% in 1994 to 16.4% in 2011,[6] during a time when the government was introducing a host of tobacco control legislation and hiking excise duties on cigarettes. However, research and

655

monitoring of tobacco control must continue to develop policies and interventions to decrease smoking prevalence rates further. In addition, research is needed to counter the ever-evolving strategies the tobacco industry uses to market its products, especially to young people and girls.

Lastly, longitudinal studies such as SANHANES-1 should be repeated at regular intervals in the future to monitor the course of the tobacco epidemic, in accordance with the guidelines of the World Health Organization’s Framework Convention on Tobacco Control,[15] to which SA is a signatory. These studies should form part of comparative datasets with other LMICs and HICs aimed at strengthening transnational co-ordination in tobacco control while facing an industry that is transnational in structure and marketing methods.

Acknowledgements. We wish to express our gratitude to the respondents who participated in the survey by completing the questionnaire. We appreciate the work done by our colleagues, the HSRC researchers who developed the questionnaires and collected the data that made it possible for us to prepare the paper.

Funding. The SANHANES-1 survey was funded by the Department for International Development, UK, and the South African National Department of Health.

References 1. World Health Organization (WHO). Global Health Risks Report: Mortality and Burden of Disease Attributable to Selected Major Risks. Geneva: World Health Organization, 2009. http://www.who.int/ healthinfo/global_burden_disease/GlobalHealthRisks_report_full.pdf (accessed 20 January 2015).

2. Lim S, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380(9859):2224-2260. [http://dx.doi. org/10.1016/S0140-6736(12)61766-8] 3. World Health Organization. WHO Report on the Global Tobacco Epidemic 2011: Warning About the Dangers of Tobacco. Geneva: WHO, 2011. http://whqlibdoc.who.int/ publications/2011/9789240687813_ eng.pdf (accessed 14 May 2014).

4. Reddy P, James S, Sewpaul R, et al. A decade of tobacco control: The South African case of politics, health policy, health promotion and behaviour change. S Afr Med J 2013;103(11):835-840. [http:// dx.doi.org/10.7196/SAMJ.6910] 5. Reddy P, Meyer-Weitz A, Yach D. Smoking status, knowledge of health effects and attitudes towards tobacco control in South Africa. S Afr Med J 1996;86(11):1389-1393.

6. Shisana O, Labadarios D, Rehle T, et al., and the SANHANES-1 Team. South African National Health and Nutrition Examination Survey (SANHANES-1): 2014 Edition. Cape Town: HSRC Press, 2014. http://www.hsrc.ac.za/uploads/pageNews/72/SANHANES-launch (accessed 20 January 2015).

7. Chopra M, Lawn JE, Sanders D, et al. Achieving the health Millennium Development Goals for South Africa: Challenges and priorities. Lancet 2009;374(9694):1023-1031. [http://dx.doi.org/10.1016/ S0140-6736(09)61122-3] 8. Blakely T, Hales S, Kleft C, Wilson N, Woodward A. The global distribution of risk factors by poverty level. Bull World Health Organ 2005;83(2):118-126. [http://dx.doi.org/10.1590/S004296862005000200012] 9. Bobak M, Jha P, Nguyen S, Jarvis M. Poverty and smoking. In: Jha P, Chaloupka F, eds. Tobacco Control in Developing Countries. Oxford, UK: Oxford University Press, 2000.

10. Pampel FC. Patterns of tobacco use in the early stage of the epidemic: Malawi and Zambia 2000-2002.

Am J Public Health 2005;95(6):1009-1015. [http://dx.doi.org/10.2105/AJPH.2004.056895] 11. Blecher EH, van Walbeek CP. Cigarette affordability trends: An update and some methodological comments. Tob Control 2009;18(3):167-175. [http://dx.doi.org/10.1136/tc.2008.026682] 12. Gabler N, Katz D. Contraband Tobacco in Canada: Tax Policies and Black Market Incentives. Studies in Risk and Regulation, Fraser Institute, 2010. http://www.fraserinstitute.org/uploadedFiles/fraser-ca/ Content/research-news/research/publications/contraband-tobacco-in-canada%281%29.Pdf (accessed 20 January 2015).

13. US Department of Health and Human Services (USDHHS). Preventing Tobacco Use Among Youth and Young Adults: A Report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2012. http://www.surgeongeneral. gov/library/reports/preventing-youth-tobacco-use/full-report.pdf (accessed 20 January 2015).

14. World Health Organization. WHO Report on the Tuberculosis Epidemic. Global Tuberculosis Control Reports, 2014. http://www.who.int/tb/publications/global_report/en/ (accessed 20 January 2015).

15. World Health Organization. WHO Framework Convention on Tobacco Control. A56/8. Geneva: WHO, 2003. http://whqlibdoc.who.int/publications/2003/9241591013.pdf (accessed 31 April 2015).

Accepted 15 June 2015.

August 2015, Vol. 105, No. 8

RESEARCH

Carcinogenic nitrosamines in traditional beer as the cause of oesophageal squamous cell carcinoma in black South Africans C Isaacson,1,2 MB BCh, PhD (Med) (deceased); P Mothobi,3 BSc, MSc (Pharmaceutics); M Hale,1,2 MB ChB, LRCP&S, FCPath; L K Tomar,3 BSc, MSc, PhD; C Tyagi,3 BSc, MSc, PhD; P Kumar,3 BPharm, MPharm; Y E Choonara,3 BPharm, MPharm, PhD; M Altini,1 BDS, MDent, DSc; V Pillay,3 BPharm, MPharm, PhD Department of Anatomical Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa N ational Health Laboratory Service, Johannesburg, South Africa 3 Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1 2

Corresponding author: V Pillay (viness.pillay@wits.ac.za)

Background. Before the 1930s, squamous cell carcinoma (SCC) of the oesophagus was almost unknown among black South Africans. From the 1930s the annual frequency rose. A dietary cause was sought, the staple diet of black people having changed from sorghum to maize (corn), with traditional beer being brewed from maize. Carcinogenic N-nitrosamines in traditional beer were suggested as a cause of SCC of the oesophagus, with Fusarium moniliforme, a corn saprophyte, thought to play a role.

Objectives. To confirm the presence of N-nitrosamines in traditional beer and demonstrate a mechanism for the oncogenesis of oesophageal carcinoma.

Methods. Analysis by high-performance liquid chromatography was conducted for the identification of nitrosamines in traditional beer samples, and molecular docking studies were employed to predict the affinity between N-nitrosamines and the S100A2 protein.

Results. Carcinogenic N-nitrosamines were identified in all six samples of traditional beer examined (N=18 analyses), and docking studies confirmed a high affinity of the nitrosamine N-nitrosopyrrolidone with the S100A2 protein. This may result in the altered expression of the S100A2 protein, leading to tumour progression and prognosis.

Conclusion. It is suggested that carcinogenic N-nitrosamines in traditional beer are a major factor in the causation of SCC of the oesophagus in black South Africans. N-nitrosamines have been shown to produce cancer experimentally, but there has not been conclusive epidemiological evidence that N-nitrosamines are carcinogenic to humans. This study is the first to demonstrate the potential link between N-nitrosamines and a human tumour.

S Afr Med J 2015;105(8):656-658. DOI:10.7196/SAMJnew.7935

Squamous cell carcinoma (SCC) of the oesophagus dominates the oesophageal cancer landscape in the Middle East, Africa, Asia and parts of Europe. The global incidence rates are highest in Northern China, South Africa (SA), Turkey and Iran. In the USA, black people have a five times higher incidence than whites.[1] SCC of the oesophagus is common among black South Africans.â&#x20AC;&#x201A;[2] From 1912 to 1927, no case of SCC of the oesophagus was recorded in the files of the South African Institute for Medical Research.[2] The tumour started to appear in small numbers in the 1930s, reached a peak in the 1980s and then started to decline, so that today the numbers are one-fifth of what they were at their highest. Based on the premise that a carcinogen exerts its tumorigenic effect for approximately 30 - 40 years for a tumour to manifest, a cause was sought dating from 30 years prior to the 1930s when the tumour first appeared. Among various potential causes considered, a dietary change emerged as a potentially significant factor.[2] A major dietary alteration at the turn of the 20th century was the change of the staple diet of black Africans from sorghum to maize. This is considered a pivotal factor in the causation of SCC of the oesophagus.[3] The probable reason for the change was that agricultural production of maize was more profitable, and although sorghum can grow in harsh environments, the yields are lower. Of note, sorghum is the staple diet of Nigeria, where SCC of the oesophagus is infrequent. [4] SA, where maize is the staple diet, has a high incidence of SCC of the oeso­phagus.[3]

656

The fungus Fusarium moniliforme grows freely on maize, but poorly on sorghum.[5] Mouldy cereals containing the fungus F. moniliforme have been suggested to play a significant role in the causation of oesophageal cancer.[6] Fusarium produces a toxin, fumonisin, which reduces nitrates to nitrites and in the presence of secondary amines synthesises nitrosamines. Nitrosamines are the suggested carcinogens.[7] Traditional beer was produced by fermenting maize (often with sorghum added) in iron containers that, as they rusted with the passage of time, released large quantities of iron into the beer, which was deposited in tissues as haemosiderin.[8] A postmortem series demonstrated that the level of iron overload, reflected in the amount of haemosiderin in the tissues in males and females dying of natural causes, correlated with traditional beer consumption.[9] A subsequent postmortem study of patients dying of oesophageal carcinoma showed much higher tissue haemosiderin levels, indicating that they had consumed considerably more traditional beer than control patients dying of other illnesses. This suggested the possibility of carcinogens in traditional beer. Haemosiderin levels can therefore be used as a surrogate marker of traditional beer consumption. It has been proposed that the fall in the incidence of SCC of the oesophagus among black South Africans reflects diminished consumption of traditional beer.[8,9] The current study focused on highlighting the number of cases of SCC of the oesophagus from 1912 to 2010, as well as confirming the presence of carcinogenic N-nitrosamines via high-performance liquid chromatography (HPLC) and the interaction of N-nitrosamines

August 2015, Vol. 105, No. 8

RESEARCH

Detection of N-nitrosamines in traditional beer

Six samples of traditional beer were obtained from four traditional brewers (brewers A, B, C and D) in rural areas in the proximity of Kimberley, a town in the Northern Cape Province of SA. Three specimens were obtained from brewer A and one each was obtained from brewers B, C and D. For statistical robustness, each of the six samples was analysed in trip­ licate (N=18) by HPLC (Waters Model 1525 Breeze, USA) using a fluorescence detector (Acquity UPLC Fluorescence FLR, USA) with excitation and emission wavelengths at 350 nm and 530 nm, respectively.

Reference standard and sample preparation

A nitrosamine mix stock solution containing seven N-nitrosamines, namely N-nitroso-nmethy­­l­ethylamine (NMEA), N-nitrosodi-nbutylamine (NDBA), N-nitrosodi-n-propyl­ amine (NDPA), N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), N-nitrosopiperidine (NPIP) and N-nitroso­ pyrrolidine (NPYR), was purchased from Sigma Aldrich, Germany. Individual reference standards of NDBA, NDEA, NDMA and NPYR, known oesophageal carcinogens, were also purchased from Sigma Aldrich. A mix

240 224 227

218

200

216 190

160

166

150

175

170

225 210

193

192 190

182

170

161

160

140 140 128 104

Data unavailable

0

Data unavailable

50

Data unavailable

Data unavailable

96

56

50

41 41 26

Data unavailable

100

Data unavailable

112

Study design and data collection

At the turn of the 20th century, pathology services at most SA public hospitals were provided by the South African Institute for Medical Research (SAIMR). In 1951, the SAIMR established the Department of Anatomical Pathology at Baragwanath Hospital, Johannesburg. Subsequently the National Health Laboratory Service administered the public sector pathological services in SA. The data reported in this study were obtained retrospectively from the records of the Department of Anatomical Pathology situated at Johannesburg and Chris Hani Baragwanath hospitals to assess the frequency of SCC of the oesophagus in black South Africans from 1912 to 2010.

255

250

42

56 53 50

1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Methods

300

Cases, n

with S100A2 protein to determine the actual mechanisms of this interaction using molecular docking studies. The S100A2 protein is an endogenous protein that is a normal component of the oesophageal wall, and its altered expression has been associated with ‘tumor progression and prognosis’.[10] We proposed that the carcinogenic property of N-nitrosamines in the oeso­phagus may alter the expression of the S100A2 protein by changing its 3D confor­mation and hence its normal function­ing.[11,12] To date, however, there have been no robust studies to quantitatively prove this interaction.

Years

Fig. 1. Annual number of cases of SCC of the oesophagus, 1970 - 2010.

Table 1. Potentially carcinogenic nitrosamines identified in traditionally brewed beer samples Nitrosamines Samples*

NDMA

NDEA

NDPA

NPYR

NDPhA

Brewer A1

+

+

-

+

-

Brewer A2

-

-

-

+

-

Brewer A3

+

-

-

-

-

Brewer B

+

-

-

-

-

Brewer C

+

+

-

-

-

Brewer D

+

-

-

+

-

NDPhA = N-nitrosodiphenylamine. *All samples analysed in triplicate (N=18).

standard solution containing 0.1 mg of each of the seven N-nitrosamines was prepared from the stock according to the method established by Wang et al.[13] Individual reference standards of NDBA, NDEA, NDMA and NPYR were also prepared separately for identification purposes.[11]

Molecular docking studies

Quantitative molecular docking studies were performed to determine the degree of N-nitosamine-S100A2 interaction and the affinity of the N-nitrosamines for the S100A2 protein. All computations were completed online at www. dockingserver. com, hosted

by Virtua Drug Ltd, Hungary. Gasteiger partial charges were added to the ligand atoms. Non-polar hydrogen atoms were merged, and rotatable bonds were defined.

Docking calculations were carried out on the NPYR-S100A2 model using the Lamarckian genetic algorithm. Each docking experiment was derived from ten different runs that were set to terminate after a maximum of 250 000 energy evalua­ tions. The population size was set to 150.

During the search, a translational step of 0.2 Å, and quaternion and torsion steps of 5 were applied.[14]

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Results

An analysis of the results presented in Fig. 1 shows a dramatic increase in the frequency of SCC of the oesophagus from the 1970s to the 1990s. The tumour started to manifest in the 1930s with an average of four cases per annum, increasing rapidly to nine cases per annum in 1940 - 1949 and 167 cases per annum in 1970 - 1979. Fig. 1 depicts the rising frequency, showing the numbers from 1970 to 2010 in greater detail. The frequency reached a peak of 255 in 1987. The numbers then started to decline, and for the past 10 years have averaged 41 cases per annum.

Results of HPLC analysis

The traditional beer specimens were analysed for the presence of potentially carcinogenic N-nitrosamines by HPLC (Table 1). The chromatogram of the reference standard displayed the elution of NDMA, NPYR, NDEA and NPIP at a concentration of 0.1 mg/mL. All 20 mL aliquots of the traditional beer samples revealed the presence of the experimental carcinogens NDMA, NDEA and/or NPYR. The HPLC chromatograms revealed the clear separation of five of the nitrosamines at their respective retention times.

RESEARCH

Molecular docking of N-nitrosamines with the S100A2 protein

The molecular stability of a ligand/protein complex was determined by calculating the final binding energy on the complex, where a negative energy of binding confirms that the complex is stable and its formation is favoured. These NPYR/S100A2 complexes represented a negative established free energy of binding (–4.92 kcal/mol) resulting from the various intermolecular energies. The binding mode of NPYR and the S100A2 protein had an established inhibition constant with a concentration value of 247.28 μM and a large interaction surface at a frequency of 100%.

These results confirm the high affinity and interaction of NPYR with the S100A2 protein.

Molecular docking analysis of the N-nitrosopyrrolidine-S100A2 interaction complex

The binding mode achieved in the molecular docking studies is presented in Fig. 2. An established inhibition constant and a large interaction surface with a frequency of 100% occurrence was displayed in accordance with the modelling parameters. This confirmed the high affinity of NPYR towards the S100A2 protein. Furthermore, it was predicted that owing to the high affinity of the molecular complex for S100A2, NPYR is able to alter the expression of S100A2. This leads to failure of the functional complex and its complementary derivatives, cell differentiation and node metastasis, and cell cycle progression, and eventually induces carcinogenesis.[10,11]

Fig. 2. The best conformational binding mode between NPYR (blue) and S100A2 (yellow).

Discussion

From 1912 to 1927, not a single case of SCC of the oesophagus was documented in the files of the SAIMR.[2] The tumour started to appear in small numbers in the 1930s, increasing annually to reach a peak of 255 cases in 1987.

The frequency then started to decline to the current average of 40 per annum.

The recent fall in the number of SCCs of the oesophagus is probably a result of diminished consumption of traditional beer. In the apartheid era, the black people of SA were not permitted by statute (the Natives (Urban Areas)

Act No. 21 of 1923) to buy regular liquor, and were permitted only to drink traditional beer.

It is hypothesised that SA blacks now have free access to regular liquor and are drinking less traditional beer. The tumour has fallen in frequency to one-fifth of its highest level, without any input from the medical profession or the pharmaceutical industry.

The premise of the current study is that carcinogenic nitrosamines in fungal-infected traditional maize-brewed beer are the cause of SCC of the oesophagus. Segal et al.[15] concur with this view. The hypothesis receives support from studies in HPLC and molecular docking. It was possible to separate all seven N-nitrosamines found in the N-nitrosamine mix standard.[13] Based on a comparison with the N-nitrosamine mix standards, NDMA, NPYR and NDEA, all carcinogenic nitrosamines, were identified in the traditional beer samples. The critical interaction between NPYR and the S100A2 protein demonstrates the role these nitrosamines may play in the development of SCC of the oesophagus. Molecular docking analysis confirms the potential mechanism of N-nitrosamines in the pathogenesis of oesophageal SCC. Nitrosamines may act on the S100A2 protein, causing conformational changes in the protein that alter its normal functioning.[10,11] The current research is the culmination of a sequence of earlier studies. In 1950 Walker and Arvidsson[16] demonstrated that there was excess iron in the diet from iron utensils used during the preparation of traditional beer. In 1962, Bothwell and Isaacson[9] quantitatively assessed the postmortem haemosiderin content of organs of patients dying of natural causes, and Isaacson et al.[8] showed in 1985 that the organs of patients dying of SCC of the oesophagus contained considerably more haemosiderin, as a marker of traditional beer consumption, than control patients, indicating that they had consumed more traditional beer than the controls.

In 2005 Isaacson[3] postulated that the change of the staple diet from sorghum to maize at the turn of the 20th century played a significant role in the causation of SCC of the oesophagus.

In the current study, HPLC identified carcinogenic N-nitrosamines in traditional beer, while molecular docking elucidated the probable mechanism of oesophageal carcinogenesis by N-nitrosamines.

The data presented in this article support the hypothesis presented by Isaacson[3] in 2005, and demonstrate a lag period of approximately 30 years between the change in the staple diet and the increase in the incidence of SCC, supporting a dietary cause.[3] Furthermore, the current decrease in incidence may reflect a reduced consumption of traditional beer in favour of commercially brewed products.

N-nitrosamines have been shown experimentally to produce cancer, but there

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has been no conclusive epidemiological evidence to show that they are carcinogenic to humans.[17] In October 2009, the US Environmental Protection Agency listed five nitrosamines as ‘probably carcinogenic to humans’: NDEA, NDMA, NDPA, NPYR and N-nitrosodiphenylamine (NDPhA). [18] Our study has identified carcinogenic N-nitrosamines in six out of six beer samples, and is the first to demonstrate carcinogenic N-nitrosamines in traditional beer. It is suggested that these N-nitrosamines play a major role in the causation of SCC of the oesophagus.

Conclusion

This study may be the first to demonstrate a link between carcinogenic N-nitrosamines and a human tumour.

Acknowledgements. This work was pioneered

by Prof. Charles Isaacson (1929 - 2014), and is a tribute to his contributions as a leading researcher in the field of anatomical pathology.

References 1. Lawrence L, Charles RT. Squamous cell cancer of the oesophagus: The forgotten one. Gastrointest Cancer Res 2011;4(1):22-23.

2. Isaacson C. Pathology of a black African population. In: Berry CL, Grundman E, Kirsten WH, eds. Current Topics in Pathology. Berlin: Springer Verlag, 1982.

3. Isaacson C. The change of the staple diet of black South Africans from sorghum to maize (corn) is the cause of the epidemic of squamous carcinoma of the oesophagus. Med Hypotheses 2005;64(3):658-660. [http://dx.doi.org/10.1016/j.mehy.2004.09.019] 4. Pindiga HU, Akang EE, Thomas JO, et al. Carcinoma of the oesophagus in Ibadan. East Afr Med J 1997;74(5):307-310.

5. Moretti A, Bennett GA, Logrieco A, et al. Fertility of Fusarium monilliforme from maize and sorghum related to fumonisin production in Italy. Mycopathologia 1995;131(1):25-29. [http:// dx.doi.org/10.1007/BF01103900] 6. Marasas WFO, van Rensburg SJ, Mirocha CJ. Incidence of Fusarium species and the mycotoxins deoxynivalenol and zearalenone in corn produced in oesophageal cancer areas in Transkei. Agric Food Chem 1979;27(5):1108-1112. [http://dx.doi.org/10.1021/jf60225a013] 7. Melhado RE, Alderson D, Tucker O. The changing face of oesophageal cancer. Cancers 2010;2(3):1379-1404. [http:// dx.doi.org/10.3390/cancers2031379] 8. Isaacson C, Bothwell TH, MacPhail AP, et al. The iron status of urban black subjects with carcinoma of the oesophagus. S Afr Med J 1985;67(15):591-593.

9. Bothwell TH, Isaacson C. Siderosis in the Bantu: A comparison of incidence in males and females. BMJ 1962;1(5277):522-524. http://www.jstor.org/stable/20356782 (accessed 19 June 2015).

10. Chen H, Xu C, Jin Q, et al. S100 protein family in human cancer. Am J Cancer Res 2014;4(2):89-115.

11. Haneef M, Lohani M, Dhasmana A, et al. Molecular docking of known carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)1-butanone (NNK) with cyclin dependent kinases towards its potential role in cell cycle perturbation. Bioinformation 2014;10(8):526-532. [http://dx.doi.org/10.6026/97320630010526] 12. Morales P, Arranz N, Haza AI. Apoptosis induced by n-nitrosamines in two cancer cell lines. Journal of Environmental Protection and Ecology 2010;1(3):314-323. [http://dx.doi.org/10.4236/jep.2010.13037] 13. Wang Z, Xu H, Fu C. Sensitive fluorescence detection of some nitrosamines by precolumn derivatization with dansyl chloride and high performance liquid chromatography. J Chromatogr 1992;589(12):349-352. [http://dx.doi.org/10.1016/0021-9673(92)80044-U] 14. Kumar P, Choonara YE, Pillay V. In silico affinity profiling of neuroactive polyphenols for post-traumatic calpain inactivation: A molecular docking and atomistic simulation sensitivity analysis. Molecules 2015;20(1):135-168. [http:// dx.doi.org/10.3390/molecules20010135] 15. Segal I, Reinach SG, de Beer M. Factors associated with oesophageal cancer in Soweto, South Africa. Br J Cancer 1988;58(5):681-686.

16. Walker ARP, Arvidsson UB. Iron overload in the South African Bantu. Trans R Soc Trop Med Hyg 1953;47(6):536-548.

17. Jakszyn P, Gonzalex CA. Nitrosamine and related food intake and gastric and oesophageal cancer risk: A systematic review of the epidemiological evidence. World J Gastroenterol 2006;12(27):42964303. [http://dx.doi.org/10.3748/wjg.v12.i27.4296] 18. Selin NE. Environmental Guidelines and Regulations for Nitrosamines: A Policy Summary. Cambridge, MA: Massachusetts Institute of Technology, 2011.

Accepted 4 April 2015.

RESEARCH

Do low levels of physical activity in female adolescents cause overweight and obesity? Objectively measured physical activity levels of periurban and rural adolescents I Cook, PhD Physical Activity Epidemiology Laboratory, Kinesiology Discipline, Faculty of Humanites, University of Limpopo, Sovenga, Limpopo, South Africa Corresponding author: I Cook (ian.cook@ul.ac.za)

Background. The increase in obesity levels in South African adolescents is attributed to an energy imbalance such that physical inactivity is causally related to adiposity. However, in some settings obesity occurs in spite of high physical activity levels.

Objectives. To examine objectively measured physical activity levels of rural black female and male adolescents from periurban to rural settings in relation to weight status, and specifically the direction and strength of the associations.

Methods. Seven-day accelerometry-derived pedometry data (step counts and activity energy expenditure) were collected for 178 adolescents (85 females, 93 males; age 13.7 - 18.0 years) living in six demographic surveillance site villages. Anthropometric measures were body mass index (kg/m2), waist circumference (cm) and sum of skinfolds (mm). Weight status was determined using international growth standards for stunting, underweight (UW), normal weight (NW), overweight (OW) and obesity (OB).

Results. Females had greater adiposity and lower 7-day average step counts and activity energy expenditure, and achieved fewer days at ≥10 000 steps and more days at <5 000 steps (p<0.05). The age and gender-weighted prevalences for female/male stunting, UW-NW, OW-OB, <5 000 steps/day and ≥12 500 steps/day were 12.4%/20.7%, 74.3%/99.1%, 25.8%/0.9%, 12.3%/0.9% and 50%/64.9%, respectively (females v. males, p<0.05). In multivariate models (weighted and adjusting for age, gender, village, season), step counts and activity energy expenditure were positively related to adiposity measures (p<0.05).

Conclusion. Both UW-NW and OW-OB periurban to rural adolescents were active to highly active on most days of the week. Physical activity was directly associated with adiposity measures.

S Afr Med J 2015;105(8):659-663. DOI:10.7196/SAMJnew.7791

Recently Mokabane et al. asserted that black female periurban adolescents exhibited low levels of physical activity and high levels of sedentary behaviour, and that there is a causal, unidirectional, inverse relationship between physical activity and adiposity.[1] However, contrary to their conclusions, the data they presented show female adolescents who are active to highly active and not overly sedentary.[1] First, the physical activity levels reported are in excess of the daily 60 minutes of recommended healthenhancing physical activity (HEPA) for adolescents.[2] Moreover, their estimate of HEPA did not include active commuting (cycling, walking).[1] Second, the sedentary time reported[1] is not in excess of the limit recommended for adolescents.[2] Third, acknowledging that association does not prove causality, an association should be robust, significant and in the expected direction to even consider that a causal relationship may exist. In this regard, there is evidence for reverse and bidirectional causal relationships between physical activity and adiposity.[3] The Dikgale Health and Demographic Surveillance System (HDSS) site in Limpopo Province, South Africa,[4] provides objectively measured physical activity data to examine: (i) whether female and male adolescents from periurban to rural settings are indeed physically inactive; and (ii) whether significant, robust inverse relationships exist between physical activity and adiposity measures.

Methods

The methodology behind these cross-sectional data is described in detail elsewhere.[4] Briefly, 7-day accelerometry-based pedometry

659

data and anthropometric measures were obtained from 178 male and female adolescents (age range 13.7 - 18.0 years) residing in the Dikgale HDSS site across six villages varying in infrastructure and amenities. Only 26 participants were recruited from three villages (Ntsima, Ga-Tjale, Moduane), and because these three villages are geographically closely linked they were combined. The study was approved by the Ethics Committee of the University of Limpopo.

Anthropometric outcomes were body mass index (BMI, kg/m2), waist circumference (WC, cm) and sum of two skinfolds (triceps + subscapular, SSKF, mm). BMI was classified as underweight (UW), normal weight (NW), overweight (OW) or obese (OB), depending on the adolescent’s age and gender, based on adult BMI cut-offs at 18 years as recommended by the International Obesity Task Force (IOTF).[5,6] Height-for-age z-scores (HAZ) were generated using the 2007 World Health Organization (WHO) growth standards.[7] HAZ <–2 was classified as stunted. Daily step counts and activity energy expenditure were summed and averaged for 7 days. Standard step count categories that complemented adolescent cut-points were used.[8] Descriptive statistics comprised means and one standard deviation (SD), quartiles and prevalence. Post-stratification weights by age and gender were derived from the Dikgale HDSS site population[4] to adjust for bias introduced through convenience sampling and applied to all subsequent procedures except basic descriptive statistics, independent t-tests and repeated measures with post hoc analyses which were used to compare variables across gender, weight status and days. Where required, corrections were applied for multiple comparisons. Relationships between categorical variables and differences between proportions were examined through

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Pearson’s χ2 and z-tests with correction for multiple comparisons. Forced multiple linear regression models were constructed with adiposity and pedometry variables as dependent variables and report the association between variables with zeroorder correlation coefficients. Explanatory variables that were forced into the model were gender, age, village, season, adiposity (BMI, WC, SSKF) and average 7-day step count. Appropriate data transformations and non-parametric statistical procedures were used to confirm parametric results if data were not normally distributed. Data were analysed using appropriate statistical software (IBM SPSS Statistics Release 22.0.0.0 (IBM Corporation, USA, 2013) and GraphPad Prism version 6.04 (GraphPad Software, USA, 2014)). Significance for all inferential statistics was set at p<0.05.

Results and discussion

Females displayed significantly greater adi­ posity and lower 7-day average step count and activity energy expenditure, and achieved fewer days at ≥10 000 steps and more days at <5 000 steps (p<0.05) (Table 1). Signifi­cantly more males achieved an average of ≥12 500 steps/day (p<0.05), and signifi­ cantly more females fell into the sedentary category (<5 000 steps/day) (p<0.05) (Table 2). The level of activity of the Dikgale adolescents was remarkable, with some achieving two to three times the recommended levels[8] (Fig. 1, A) and nearly 60% of the sample achieved an average daily step count of ≥12 500 steps (Table 2). One obese female (BMI 46.3) achieved >10 000 steps on 5 days, of which 2 days approached 20 000 steps (Fig. 1, A). The very high step volumes achieved in the Dikgale sample are in good agreement with the high objectively measured volumes of physical activity in rural black adolescents in another HDSS site.[9] In fact the accelerometrymeasured volumes were nearly three times higher than those for adolescents in the UK,[9] and Dikgale sample achieved average daily step counts more than 1.5 times higher than those reported for North American children and adolescents.[8] OW-OB adolescents often accrued some of the highest daily step counts, and there was no clear pattern of consistently lower daily step counts in the OW-OB group (Fig. 1, A). Daily step counts were not signifi­cantly lower for the OW-OB group compared with the UW-NW group (p>0.05) (Fig. 1, B). Because 92% of the OW-OB group consisted of females, with only two OW males, the female step profile was similar to the OW-OB profile. However,

Table 1. Descriptive statistics of participant characteristics Variables

Female (N=85)

Male (N=93)

All (N=178)

Age (years), mean (SD)

16.3 (1.1)

16.1 (1.1)

16.2 (1.1)

10 - 14

12 (14.1)

14 (15.1)

26 (14.6)

15 - 19

73 (85.9)

79 (84.9)

152 (85.4)

Age distribution (years), n (%)

BMI (kg/m ), mean (SD)

23.1 (5.1)

19.3 (2.4)

21.1 (4.4)

Waist circumference (cm), mean (SD)

73 (9)‡

67 (7)

70 (9)

SSKF (mm), mean (SD)

30 (10)‡

23 (8)

26 (10)

2

‡

Average 7-day pedometry, mean (SD) Ambulation (steps/day)

12 672 (4 923)†

15 268 (5 436)

14 028 (5 343)

Activity energy expenditure (kcal/day)

423 (168)

522 (200)

475 (192)

Days <5 000 steps/day

0.8 (1.5)*

0.4 (1.2)

0.6 (1.3)

Days ≥10 000 steps/day

4.4 (2.4)*

5.3 (2.0)

4.9 (2.2)

Quartile 1 (1 294 - 10 752)

7 298 (2 537)

8 128 (2 460)

7 640 (2 512)

Quartile 2 (10 753 - 13 713)

12 292 (806)

12 221 (709)

12 263 (759)

Quartile 3 (13 714 - 17 461)

15 676 (1 345)

15 639 (1 126)

15 657 (1 223)

Quartile 4 (17 462 - 35 534)

21 836 (2 636)

21 296 (3 424)

21 421 (3 235)

Mantheding

26 (30.6)*

15 (16.1)

41 (23.0)

Madiga

26 (30.6)

32 (34.4)

58 (32.6)

Ntsima, Ga-Tjale, Moduane

7 (8.2)*

19 (20.4)

26 (14.6)

Sefateng

26 (30.6)

27 (29.0)

53 (29.8)

Spring

19 (22.4)

19 (20.4)

38 (21.3)

Summer

34 (40.0)

33 (35.5)

67 (37.6)

Autumn

12 (14.1)

15 (16.1)

27 (15.2)

Winter

20 (23.5)

26 (28.0)

46 (25.8)

‡

S tep count distribution (steps/day), mean (SD)

Resident village, n (%)

Season during measurement, n (%)

Female v. male: *p<0.05, †p<0.001, ‡p<0.0001.

there was a noticeably lower step count for the OW-OB group on Wednesdays and especially on Saturdays, suggesting reduced participation in usual sporting/ recreational activities in OW-OB females (Fig. 1, B). In contrast, males achieved significantly higher step counts on weekend days and some weekdays (p<0.05) (Fig. 1, B). The significant gender-specific patterns midweek and over weekends were probably due to females attending less active social activities on Wednesdays and males participating in sport (mainly soccer) on Saturdays, so that overall Saturday step counts were significantly higher than Tuesday and Wednesday step counts (p<0.05) (Fig. 1, B).

Micklesfield et al.[10] categorised their self-reported physical activity data for adolescent rural black African females,

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nearly identical in age and BMI to the Polokwane group, such that a comparison was possible with the physical activity data reported by Mokabane et al.[1] Assuming 5 days per week for moderate to vigorous physical activity (MVPA, e.g. organised school and club sport), the Agincourt HDSS sample would be more sedentary (+52 minutes per day) and participate in less MVPA (–50 minutes per day) and less home-based informal play/recreation (–21 minutes per day), resulting in a total physical activity volume of 1.1 hours per day, excluding the 40 minutes per day, 5 days per week active travel to school. In contrast, the Polokwane group reported double the amount of physical activity, 2.2 hours per day.[1] Considering that the HEPA recommendation[2] for adolescents is 60 minutes per day and the reported

RESEARCH

Table 2. Prevalence statistics for health-related anthropometric and pedometry indices* Female (N=85)

Variables

Male (N=93)

All (N=178)

Anthropometry Stunted (HAZ <–2)†

12.4 (7.1)

20.7 (20.4)

16.8 (14.0)

UW (BMI <18.5)

1.9 (3.5)

12.6 (20.4)

7.3 (12.4)

86.5 (77.4)

79.6 (73.6)

‡

§

NW (BMI 18.5 - 24.9)‡ 72.4 (69.4)§ OW (BMI 25 - 29.9)

21.0 (15.3)

0.9 (2.2)

10.6 (8.4)

OB (BMI ≥30)‡

4.8 (11.8)§

0.0 (0.0)

2.5 (5.6)

‡

§

Step count distribution (steps/day) Sedentary (<5 000)

12.3 (5.9)§

0.9 (2.2)

6.3 (3.9)

ow active (5 000 L 7 499)

4.7 (10.6)

0.9 (2.2)

2.7 (6.2)

Somewhat active (7 500 - 9 999)

9.4 (10.6)

9.9 (12.9)

9.5 (11.8)

Active (10 000 - 12 499) 23.6 (22.4)

23.4 (17.2)

23.8 (19.7)

Very active (≥12 500)

64.9 (65.6)

57.7 (58.4)

50.0 (50.6)§

*Values reported as adjusted (unadjusted) %, adjusted to adolescent age-gender profile of the Dikgale HDSS site. † WHO growth standards. ‡ IOTF categories based on adult BMI cut-offs at 18 years.

Female v. male for adjusted prevalence: §p<0.05.

daily sedentary time was no more than 2 hours, it seems likely that the Polokwane group did not ‘spend a significant amount of time in sedentary activities’ or ‘spend very little time being physically active’.[1] Even allowing for significant over-reporting in the Polokwane group it would be difficult to classify them, on the basis of the data provided, as being sedentary and physically inactive.

The Dikgale results for weight status category prevalence are in good agreement with national estimates for Limpopo adolescents[11] and rural black adolescents (Table 2).[12] Kimani-Murage et al.[13] reported that 3% of their sample displayed concurrent stunting and OW-OB, which is in contrast to the Dikgale weighted prevalence (OW-OB 21.4%). Estimates of the prevalence of OW-OB among male adolescents in the Agincourt HDSS site show a peak of approximately 5%, which is in agreement with the Dikgale weighted estimate of 0.9% (Table 2).[13] Likewise, estimates of the prevalence of OW-OB among female adolescents in the Agincourt HDSS site peak at 20 - 25%, which is similar to the present estimate of 25.8% (Table 2).[13] The weight status prevalence for females reported by Mokabane et al.[1] yielded some anomalous results. Irrespective of weighting, the present results (Table 2) stand in contrast to their UW category prevalence (1.9 - 3.5% v. 16.1%, respectively) and OW-OB prevalence (25.8 - 27.1% v. 16.1%, respectively). The weight status prevalence of the Dikgale sample was also determined using the adult BMI definitions without computing IOTF BMI categories and yielded a similar elevated female UW prevalence (10.6%). Consequently there is uncertainty as to the methodology used by Mokabane et al.[1] to evaluate the weight status of their sample.

Overall there was no significant difference between UW-NW and OW-OB for active to very active weighted prevalence (83.5% v. 71.4%, respectively). In Madiga, Ntsima, Ga-Tjale, Moduane and Sefateng, just as many OW-OB as UW-NW subjects were active to very active (>80%), yet in Mantheding, more UW-NW than OW-OB

661

Under- to normal weight (n=153) Overweight to obese (n=25)

Female, BMI=46.3 kg/m2 All (n=178)

Male (n=93) Female (n=85)

Fig. 1. Accelerometry-based pedometer assessment of physical activity across 7 days for periurban and rural adolescents. A: Scatterplot of raw pedometry data by weight status; B: Unadjusted step count means plot by weight status (IOTF) and gender (male > female, *p<0.05; Saturday > Tuesday, Saturday > Wednesday, ** p<0.05).

subjects were active to very active (57.1% v. 18.2%; p<0.05). Similarly, overall there was no significant difference in sedentary weighted prevalence (7.4% v. 2.4%, respectively) or step count quartile 1 weighted prevalence (23.2% v. 27.9%, respectively) between UW-NW and OW-OB subjects. Only in Mantheding was step count quartile 1 weighted prevalence higher in the OW-OB group than the UW-NW group (81.8% v. 41.7%, respectively; (p<0.05). Since village residence status appears to modulate the expected prevalence profile (OWOB prevalence lower in active to very active groups and higher in sedentary to low active groups), this suggests that a unidirectional inverse relationship between physical activity and adiposity may not hold in all circumstances.

Independent of gender, age, village and season, adiposity measures were positively associated with step counts, albeit weakly so (Table 3). In other words, higher walking volumes were associated with higher levels of adiposity. The increase in adiposity was higher in females, increased with age, was higher during colder months and was directly associated with step counts (models 1 - 3, Table 3). An increase in step counts was higher in males, in villages with less infrastructure, during warmer months and with increasing adiposity (models 4 - 6, Table 3). Interestingly, step counts decreased but adiposity increased with decreasing seasonal temperature (p<0.01).

However, overall, adiposity increased as step counts increased once other contributing factors were held constant (Table 3). The same analyses were run using activity energy expenditure instead of step counts, because in addition to purposeful walking accelerations, non-walking, low-intensity, incidental accelerations are also

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RESEARCH

Table 3. Multiple linear regression models for anthropometric indices and physical activity in 178 adolescents Goodness of fit Model*

Adjusted R2

p-value

Outcome

1

0.2487

<0.0001

BMI

2

3

4

5

6

0.2124

0.2922

0.1805

0.1797

0.2606

<0.0001

<0.0001

<0.0001

<0.0001

<0.0001

WC

SSKF

Steps

Steps

Steps

Factors

Model parameter β-coefficient (SE)

Significance p-value

Correlation Zero

Collinearity VIF

Gender

3.44 (0.46)

<0.0001

0.44

1.0389

Age

0.8 (0.2)

0.0001

0.26

1.0087

Village

0.01 (0.22)

0.9476

0.05

1.1800

Season

0.03 (0.2)

0.8922

-0.04

1.0380

Steps

0.00009 (0.00004)

0.0414

0.05

1.1964

Gender

7.23 (1.11)

<0.0001

0.37

1.0389

Age

0.61 (0.49)

0.2096

0.08

1.0087

Village

–0.68 (0.52)

0.1924

-0.09

1.1800

Season

2.17 (0.49)

<0.0001

0.25

1.0380

Steps

0.00021 (0.00011)

0.0469

0.00

1.1964

Gender

7.95 (1.17)

<0.0001

0.33

1.0389

Age

0.53 (0.51)

0.3061

0.06

1.0087

Village

–0.1 (0.55)

0.8633

0.04

1.1800

Season

3.14 (0.52)

<0.0001

0.30

1.0380

Steps

0.00059 (0.00011)

<0.0001

0.22

1.1964

Gender

–2 589.24 (783.32)

0.0011

-0.17

1.2506

Age

–243.43 (323.06)

0.4520

0.00

1.0812

Village

1 714.15 (314.94)

<0.0001

0.37

1.0344

Season

–281.32 (316.22)

0.3747

-0.11

1.0342

BMI

217.87 (106.17)

0.0414

0.05

1.3358

Gender

–2 477.41 (764.10)

0.0014

-0.17

1.1888

Age

–123.71 (313.25)

0.6933

0.00

1.0155

Village

1 779.08 (314.87)

<0.0001

0.37

1.0328

Season

–466.20 (329.69)

0.1588

-0.11

1.1231

WC

87.84 (43.94)

0.0469

0.00

1.2757

Gender

–3 220.17 (714.71)

<0.0001

-0.17

1.1539

Age

–166.46 (296.92)

0.5757

0.00

1.0122

Village

1 568.19 (300.70)

<0.0001

0.37

1.0450

Season

–864.74 (320.39)

0.0075

-0.11

1.1767

SSKF

196.21 (37.46)

<0.0001

0.22

1.2795

Steps = average 7-day step count (steps/day); Gender: 1 = male, 2 = female; Age = years; Village: 1 = Mantheding, 2 = Madiga, 3 = Ntsima-Ga-Tjale-Moduane, 4 = Sefateng; Season: 1 = spring, 2 = summer, 3 = autumn, 4 = winter; SE = standard error; VIF = variance inflation factor. *Models constructed using Dikgale HDSS adolescent age-sex weighting. Significant factors are in bold font.

detected and recorded in this measure.

Very similar models and coefficient significance and directions were found, although zero-order correlations between activity energy expenditure and adiposity measures were slightly stronger (r=0.10 to r=0.30; p<0.01) (data not shown). These results suggest a more nuanced explanation of causal pathways, as opposed to a strictly unidirectional approach.[1]

Conclusion

It is difficult to concur with Mokabane et al.[1] that their data are evidence of an energy imbalance through a sedentary, physically inactive lifestyle. Moreover, the

methodology employed to ascertain weight status was of concern. Insufficient details were provided, and the results suggested that the appropriate growth standards were not applied to their raw data. Consequently, there appears to be a disjoint between the data they reported and the subsequent conclusions and recommendations.[1] The results reported here are certainly not conclusive, yet do provide some interesting anomalous associations in light of the traditional energy balance hypothesis,[1] i.e. an inverse relationship between physical activity and adiposity levels. This should at least suggest that other explanations may be considered as to

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August 2015, Vol. 105, No. 8

why there is increasing adiposity in some communities where physical activity levels are very high and food insecurity and poverty are elevated.

The investigation of physical activity, inactivity and sedentary behaviour must move beyond the widely accepted uni­ directional causality and consider the alternative hypothesis that increasing adiposity, especially in rural and periurban populations that are active to highly active, may be due to factors related to diet quality and energy partitioning rather than energy balance.[14] In this regard, there is agreement with Mokabane et al.[1] that certain macronutrients are over-emphasised

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in the adolescent diet. Indeed, in the Dikgale HDSS adult and child populations, consumption of carbohydrates is very high and protein/ fat intake is low.[15,16] In the Dikgale setting, the data suggest that being obese does not deterministically result in lower physical activity levels.[17] Rather, obligatory subsistence requirements coupled with social and environmental factors[18] appear to override the purely biological/endocrinological drives[17] that reduce physical activity, provided the integrity of biological systems/organs is not threatened.

Funding disclosure. The Research Development and Administration Division of the University of Limpopo and the Thuthuka Programme of the National Research Foundation supported this study References 1. Mokabane M, Mashao M, van Staden M, Potgieter M, Potgieter A. Low levels of physical activity in female adolescents cause overweight and obesity: Are our schools failing our children? S Afr Med J 2014;104(10):665-667. [http://dx.doi.org/10.7196/SAMJ.8577] 2. Botha C, Wright H, Moss S, Kolbe-Alexander TL. ‘Be active!’ Revisiting the South African food-based dietary guideline for activity. S Afr J Clin Nutr 2013;26(3):S18-S27.

3. Richmond RC, Smith GD, Ness AR, et al. Assessing causality in the association between child adiposity and physical activity levels: A Mendelian randomization analysis. PLoS Med 2014;11:e1001618. [http:// dx.doi.org/10.1371/journal.pmed.1001618] 4. Cook I, Alberts M, Brits JS, Choma S, Mkhonto SS. Descriptive epidemiology of ambulatory activity in rural, black South Africans. Med Sci Sports Exerc 2010;42(7):1261-1268. [http://dx.doi.org/10.1249/ mss.0b013e3181ca787c] 5. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: International survey. BMJ 2000;320:1240. [http://dx.doi.org/10.1136/ bmj.320.7244.1240] 6. Cole TJ, Flegal KM, Nicholls D, Jackson AA. Body mass index cut offs to define thinness in children and adolescents: International survey. BMJ 2007;335:194. [http://dx.doi.org/10.1136/ bmj.39238.399444.55]

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7. De Onis M, Onyango AW, Borghi E, et al. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ 2007;85(9):660-667. [http://dx.doi.org/10.2471/ blt.07.043497] 8. Tudor-Locke C, Craig C, Beets M, et al. How many steps/day are enough? For children and adolescents.

Int J Behav Nutr Phys Act 2011;8:78. [http://dx.doi.org/10.1186/1479-5868-8-78] 9. Craig E, Bland R, Reilly J. Objectively measured physical activity levels of children and adolescents in rural South Africa: High volume of physical activity at low intensity. Appl Physiol Nutr Metab 2013;38(1):81-84. [http://dx.doi.org/10.1139/apnm-2012-0115] 10. Micklesfield LK, Pedro TM, Kahn K, et al. Physical activity and sedentary behavior among adolescents in rural South Africa: Levels, patterns and correlates. BMC Public Health 2014;14:40. [http://dx.doi. org/10.1186/1471-2458-14-40] 11. Reddy SP, James S, Sewpaul R, et al. Umthente Uhlaba Usamila – the South African Youth Risk Behaviour Survey 2008. Cape Town: South African Medical Research Council, 2010:37-38, 106-107, 156-157. http://www.mrc.ac.za/healthpromotion/yrbs_2008_final_report.pdf (accessed 18 December 2014).

12. Reddy SP, Resnicow K, James S, et al. Rapid increases in overweight and obesity among South African adolescents: Comparison of data from the South African National Youth Risk Behaviour Survey in 2002 and 2008. Am J Public Health 2012;102(2):262-268. [http://dx.doi.org/10.2105/ ajph.2011.300222] 13. Kimani-Murage EW, Kahn K, Pettifor JM, et al. The prevalence of stunting, overweight and obesity, and metabolic disease risk in rural South African children. BMC Public Health 2010;10:158. [http:// dx.doi.org/10.1186/1471-2458-10-158] 14. Willett WC, Leibel RL. Dietary fat is not a major determinant of body fat. Am J Med 2002;113(Suppl 9B):47S-59S. [http://dx.doi.org/10.1016/s0002-9343(01)00992-5] 15.

Mamabolo RL, Alberts M, Steyn NP, Delemarre-van de Waal HA, Levitt NS. Prevalence and determinants of stunting and overweight in 3-year-old black South African children residing in the Central Region of Limpopo Province, South Africa. Public Health Nutr 2005;8(5):501-508. [http:// dx.doi.org/10.1079/phn2005786] 16. Steyn NP, Burger S, Monyeki KD, Alberts M, Nthangeni G. Seasonal variation in dietary intake of the adult population of Dikgale. S Afr J Clin Nutr 2001;14(4):140-145.

17.

Ludwig DS, Friedman MI. Increasing adiposity: Consequence or cause of overeating? JAMA 2014;311(21):2167-2168. [http://dx.doi.org/10.1001/jama.2014.4133] 18. Panter-Brick C. Issues of work intensity, pace, and sustainability in relation to work context and nutritional status. Am J Hum Biol 2003;15(4):498-513. [http://dx.doi.org/10.1002/ajhb.10189]

Accepted 30 May 2015.

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The case for expanding the definition of ‘key populations’ to include high-risk groups in the general population to improve targeted HIV prevention efforts O Shisana,1,2 BA, MA, ScD; N Zungu,1 BA, BA Hons, MA, DPhil; M Evans,1 BMus, MA; K Risher,3 BA, MHS; T Rehle,1,4 MD, MPH, PhD; D Celentano,3 MHS, ScD Human Sciences Research Council, Cape Town, South Africa Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa 3 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA 4 School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: O Shisana (oshisana@hsrc.ac.za)

Background. Two additional key populations within the general population in South Africa (SA) that are at risk of HIV infection are black African women aged 20 - 34 years and black African men aged 25 - 49 years.

Objective. To investigate the social determinants of HIV serostatus for these two high-risk populations.

Methods. Data from the 2012 South African National HIV Prevalence, Incidence, and Behaviour Survey were analysed for black African women aged 20 - 34 years and black African men aged 25 - 49 years.

Results. Of the 6.4 million people living with HIV in SA in 2012, 1.8 million (28%) were black women aged 20 - 34 years and 1.9 million (30%) black men aged 25 - 49 years. In 2012, they constituted 58% of the total HIV-positive population and 48% of the newly infected population. Low socioeconomic status (SES) was strongly associated (p<0.001) with being HIV-positive among black women aged 20 - 34 years, and was marginally significant among black men aged 25 - 49 years (p<0.1).

Conclusion. Low SES is a critical social determinant for HIV infection among the high-risk groups of black African women aged 20 34 years and black African men aged 25 - 49 years. Targeted interventions for these key populations should prioritise socioeconomic empowerment, access to formal housing and services, access to higher education, and broad economic transformation.

S Afr Med J 2015;105(8):664-669. DOI:10.7196/SAMJnew.7918

South Africa (SA) has an HIV epidemic that is driven by heterosexual transmission and characterised by dynamic risk groups and profiles.[1,2] Key populations refers to groups that are at high risk of HIV infection, stigmatised by society because of their identities or behaviours, and less likely than other groups to be reached by interventions;[2] traditionally, these include men who have sex with men (MSM), sex workers, people who inject drugs[3] and transgender persons.[4] These traditional key populations have been important for understanding HIV in industrialised countries with low-level or concentrated epidemics, and in recent years it has been determined that traditional key populations represent a major portion of the global epidemic. In reviewing the national response to HIV/AIDS, SA has identified traditional key populations such as MSM as critical to reach with interventions, owing to the high HIV prevalence in this group.[5] The current National Strategic Plan on HIV, STIs and TB (2012 - 2016) now includes MSM and recommends a more targeted approach to reducing infections in this group.

While focusing on traditional key populations, it is important to recognise that within the general population there are groups that are vulnerable and at particular risk of being infected with HIV, particularly in the unique context that is SA.[1-3] With a generalised epidemic, large segments of the general population rather than traditional key populations are likely to be driving the epidemic. These larger subpopulations can be identified through national surveys, whereas traditional key populations are smaller, often hard-to-reach groups that can be studied through sampling approaches such as respondent-driven sampling. The reasons for

664

the vulnerability among groups within the general population vary, and may include factors such as occupation, living arrangements, personal behaviour and behaviour of partners. Groups that have been suggested as additional key populations are migrant populations (the migrants themselves and their partners), truckers, prisoners, soldiers, internally displaced people, refugees, and orphans and vulnerable children.[3] There is therefore a need to expand the definition of key populations and not limit it to distinct traditional groups.[1-3] Shisana et al.,[1] for example, define key populations as groups that have a higher HIV prevalence than the general population. This is in line with the UNAIDS definition, which puts more emphasis on ‘communities most likely to be living with HIV or those disproportionately affected by it when compared with the general population’.[6] The definition of key populations therefore depends on the epidemiological profile of the country and the social dynamics that operate in relation to HIV infections in that country, and in SA, the definition of key populations at risk of HIV should be tailored to the local context.

In hyperendemic countries, typically economically constrained low- and middle-income countries, groups that do not fall within the traditional definition of key populations are often not the focus of targeted HIV prevention interventions. The challenge is that these large subpopulations are part of the general population and not easily distinguishable by a unifying social criterion. Such large population groups are likely to be heterogeneous and hence difficult to target for specific interventions. However, it is necessary to identify both these groups and their social determinants, because the general HIV prevalence in a country is unlikely to be reduced unless these high-

August 2015, Vol. 105, No. 8

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risk groups are targeted with appropriate interventions that meet specific risks and needs.

Human Sciences Research Council researchers[1,2] have identified key popu­ lations within the general population to include, inter alia, black African women aged 20 - 34 years and black African men aged 25 - 49 years, among whom the prevalence of HIV infection in 2012 was found to be 31.6% and 25.7%, respectively.[2] The HIV incidence estimates based on assays (% per year) was also found to be high at 4.54% and 1.84%, respectively, in these same populations.[2] Although there is a breadth of research in SA focusing on HIV and women more generally, little is known about the social factors that shape the risk profiles of these key populations, particularly in respect of their demographic information, including employment, residence and socioeconomic status (SES).

Methods

The data used in this study are part of a larger population-based survey conducted in SA in 2012 using a multistage stratified survey design. The detailed metho­ dology of the study is described else­ where. [2] In short, a probability sample of 15 households was drawn from each of the randomly selected 1 000 enumeration areas (EAs). The selec­tion of EAs was stratified by province and locality type, defined as urban formal, urban informal, rural formal (including commercial farms), and rural informal localities. All household members were invited to participate in the 2012 survey.

Dried blood spot specimens for HIV testing were collected from consenting participants. A detailed questionnaire soliciting information related to demo­ graphic characteristics, knowledge, atti­ tudes, practices and behaviours was administered. Participants were guaranteed anonymity, and all questionnaires and blood samples were linked using a unique bar code. This article is based on a subsample of unweighted adult data, and the analysis focused on black adults aged 20 - 49 years who participated in the survey. Separate analyses of black women aged 20 - 34 years and black men aged 25 49 years were conducted in order to assess the associations between social factors and HIV status in key populations.

The survey protocol was approved by the HSRC’s Research Ethics Committee (REC: 5/17/11/10), as well as by the Associate Director of Science of the National Center for HIV and AIDS, Viral Hepatitis, STD and

TB Prevention at the US Centers for Disease Control and Prevention (CDC).

An SES scale was developed using 13 items from the questionnaire related to possession of and/or access to toilet facilities; cooking energy; access to electricity, radio, television, telephone, cell phone (mobile phone), refrigerator, personal computer and washing machine; number of rooms in the dwelling; extent to which the household has sufficient money; and drinking water source.

Each item ranged from 1 to 4, and the scale ranged from 13 to 52. Reliability of the SES scale was assessed using Cronbach’s alpha (Table 1).

Bivariate analyses and multiple logistic regression analyses were conducted to assess the relationship between SES and HIV status, stratified by gender. The SES scale

was treated as a continuous variable in the regression analyses.

Results

Of the 6.4 million people living with HIV in SA in 2012, 1.8 million were black women aged 20 - 34 years and 1.9 million were black men aged 25 - 49 years. In total, they constituted 58% of the HIV-positive population and 48% of the newly infected population in 2012 (percentages recalculated from the earlier study[2]).

Table 2 presents demographic charac­ teristics of the sample by gender. Among black men aged 25 - 49 years, the greatest proportion (30.3%) of respondents were 25 - 29 years old, lived in urban formal areas (41.6%), and were employed full-time (42.4%), although a large proportion (30.7%)

Table 1. Items and scoring of the SES scale Item

Scores

Toilet facilities

4

Flush toilet (own or shared)

3

Pit latrine with ventilation

2

Pit latrine without ventilation or bucket

1

No facility/other

4

Electricity or gas

3

Coal

2

Paraffin (kerosene)

1

Wood, dung, or other

4/1

Electricity (yes/no)

4/1

Radio (yes/no)

4/1

Television (yes/no)

4/1

Landline (yes/no)

4/1

Cellphone (yes/no)

4/1

Refrigerator (yes/no)

4/1

Personal computer (yes/ no)

Cooking fuel

Household access to

Number of rooms in dwelling

Household rating

Drinking water source

665

4/1

Washing machine (yes/no)

4

≥2 rooms per person in household

3

1 - 2 rooms per person in household

2

0.5 - 1 rooms per person in household

1

<0.5 rooms per person in household

4

Money for extra things such as holidays and luxury goods

3

Money for most of the important things but few luxury goods

2

Money for food and clothes, but short on many other things

1

Not enough money for basic things like food and clothes

4

Piped water (tap) in dwelling

3

Piped water (tap) in site/yard

2

Public/communal tap

1

Water carrier/tanker, rainwater tank, borehole/well/ spring, dam/river/stream, or other

August 2015, Vol. 105, No. 8

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in time (94.8%), and 9.3% had received a tertiary education. Nearly half of the male respondents (48.1%) reported being the head of their household.

Among black women aged 20 - 34 years, the largest unweighted proportion was

were unemployed. Most men reported that their main source of income was a formal salary (63.8%), although a third of them reported that they had received no income in the past month (34.9%). The vast majority of men had attended school at some point

Table 2. Social and demographic characteristics of key populations, SA 2012 Black men aged 25 - 49 years n

Black women aged 20 - 34 years

Column %*

n

Column %*

Age (years) 20 - 24

-

-

1 320

38.7

25 - 29

1 028

30.3

1 180

34.6

30 - 34

770

22.7

910

26.7

35 - 39

596

17.6

-

-

40 - 44

535

15.8

-

-

45 - 49

465

13.7

-

-

Locality type Urban formal

1 412

41.6

1 345

39.4

Urban informal

719

21.2

636

18.7

Rural informal

870

25.6

1 147

33.6

Rural formal

393

11.6

282

8.3

1 160

42.4

525

17.3

Employment status Full-time employment Part-time employment

529

19.3

332

10.9

Student

34

1.2

303

10.0

Unemployed

840

30.7

1 522

50.1

Homemaker/sick/disabled/other

173

6.3

357

11.7

Main source of income in past month Formal salary

1 033

63.8

536

39.0

Family contributions

59

3.6

116

8.4

Grants/pensions

115

7.1

435

31.7

Other

412

25.4

286

20.8

928

34.9

1 532

51.7

Income in past month No income <ZAR 2 500

993

37.3

1 136

38.3

≥ZAR 2 500

741

27.8

296

10.0

Never attended school

160

5.2

85

2.8

Ever attended school

2 899

94.8

2 991

97.2

Highest education level Primary

737

24.3

356

11.5

Secondary

2 016

66.4

2 475

80.2

Tertiary or higher

283

9.3

256

8.3

Relationship to head of household Head

1 606

48.1

459

13.7

Husband/wife/partner

165

4.9

600

18.0

Son/daughter

860

25.8

1 267

37.9

Other

705

21.1

1 015

30.4

*Column totals may not sum to 100% owing to rounding.

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August 2015, Vol. 105, No. 8

aged 20 - 24 years (38.7%). The greatest proportion of respondents were living in urban formal localities (39.4%), and were unemployed (50.1%). Only a minority (17.3%) reported full-time employment. Less than half reported that their main source of income in the past month was from a formal salary (39.0%), with nearly a third (31.7%) reporting that their main source of income was grants or pensions. The majority of women (51.7%) reported no income in the past month. Almost all women reported having some schooling (97.2%), and 8.3% had received tertiary education or higher. A minority of women reported being the head of their household (13.7%), and the greatest proportion reported being the daughter of the head of household (37.9%).

Table 3 shows the household character­ istics of black men aged 25 - 49 years and black women aged 20 - 34 years. About half of men and women reported not having access to a flush toilet (45.5% and 50.2%, respectively).

A minority of participants reported using a cooking fuel besides electricity or gas (17.8% for men and 18.1% for women). The majority of men and women reported having household access to electricity and owning a radio, television, cell phone and refrigerator.

A small proportion of individuals reported household access to a landline telephone (8.1% for men and 8.7% for women), a personal computer (16.6% for men and 15.8% for women) or a washing machine (26.7% for men and 26.9% for women). A minority of participants reported living in one-room dwellings (10.4% for men and 7.1% for women), while a higher proportion reported that they had only one room in the dwelling used for sleeping (23.0% for men and 17.6% for women). Half of the respondents reported not having enough money for access to necessities such as food and clothing (52.9% of men and 51.9% of women). A minority of respondents (11.0% of men and 12.4% of women) reported using rainwater tanks, wells/springs and rivers/ streams as sources of drinking water.

The Cronbach’s α for the SES scale was 0.82. The median SES score for black women aged 20 - 34 years was 36 (inter­ quartile range (IQR) 31 - 41), and for black men aged 25 - 49 years the median was 36 (IQR 31 41). SES scores differed significantly by HIV status among 20 - 34-year-old black women (mean among positive 33.0, mean among negative 35.6; p<0.001) and among 25 49-year-old men (mean among positive 33.3, mean among negative 34.8; p=0.002).

Table 4 shows the associations of SES, age, behavioural risks and social factors with HIV status among black men aged 25 - 49

RESEARCH

Table 3. Household characteristics of key populations, SA 2012 Black men aged 25 - 49 years n

Column %*

Black women aged 20 - 34 years n

Column %*

Toilet availability No facility/other

207

6.2

199

6.0

Pit latrine without ventilation/bucket latrine

812

24.4

887

26.7

Pit latrine with ventilation

497

14.9

585

17.6

Flush toilet (own or shared)

1 813

54.5

1 656

49.8

291

8.9

356

10.9

Cooking fuel Wood, dung, or other Paraffin (kerosene)

234

7.2

186

5.7

Coal

54

1.7

48

1.5

Electricity or gas

2 679

82.2

2 676

81.9

Household access to Electricity

2 841

85.3

2 885

86.7

Radio

2 490

75.4

2 459

74.2

Television

2 546

76.9

2 655

80.0

Landline telephone

265

8.1

285

8.7

Cell phone

3 028

91.8

3 089

93.7

Refrigerator

2 351

70.9

2 499

75.6

Personal computer

547

16.6

522

15.8

Washing machine

882

26.7

891

26.9

Number of rooms in dwelling 1

345

10.4

238

7.1

2-3

854

25.6

772

23.2

4-5

1 221

36.7

1 288

38.6

≥6

910

27.3

1 036

31.1

Number of rooms for sleeping 1

764

23.0

587

17.6

2

1 133

34.1

1 147

34.5

≥3

1 425

42.9

1 595

47.9

ot enough money for basic things like food N and clothes

1 553

52.9

1 549

51.9

oney for food and clothes, but short on M many other things

1 007

34.3

1 080

36.2

e have most of the important things, but W few luxury goods

320

10.9

295

9.9

oney for extra things such as holidays and M luxury goods

57

1.9

61

2.0

Household situation description

Main source of drinking water Piped water (tap) in dwelling

1 427

44.4

1 393

43.9

Piped water (tap) in site/yard

1 008

31.3

952

30.0

Public/communal tap

429

13.3

436

13.7

Other

353

11.0

392

12.4

*Column totals may not sum to 100% owing to rounding.

years. In bivariate analyses, the SES scale, age, condom use at last sexual encouter, and

self-perception of HIV risk were statistically significantly associated with HIV status

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August 2015, Vol. 105, No. 8

among black men. In adjusted analyses, SES scale was only weakly (p=0.097) inversely associated with HIV status among men, with a one-point increase in the SES scale (higher SES) being associated with a small decrease (1.7%) in adjusted odds of being HIV-positive. Condom use at last sexual encouter and self-perception of HIV risk were both strongly positively associated with HIV status among black men.

Table 5 shows the associations with HIV status among black women aged 20 - 34 years. In bivariate analyses, SES, age, locality type, condom use at last sexual encounter, lifetime number of sexual partners and selfperception of HIV risk were all statistically significantly associated with HIV status.

In the multiple logistic regression analysis, a statistically significant strong inverse relationship was found between SES and HIV status (p<0.001). Each one-point increase in the SES scale (higher SES) was associ­ated with a 3.9% (95% confidence interval 2.2 5.6) decrease in adjusted odds of being HIVpositive among black women. Women who were older (25 - 34 years), reported using a condom at last sexual encounter, reported more than one lifetime sexual partner, and perceived themselves to be at risk for HIV were more likely to be HIV-positive.

Discussion

In contemporary SA, racial inequalities remain interwoven with economic in­equality, and wealth continues to reflect apart­ heid hierarchies, with whites at the top of the pyra­mid and black Africans at the bottom. [7] The HIV epidemic has developed in this inequitable social context and has thrived among black communities, especially in overcrowded, poor urban areas where there are poor sanitation and living conditions and the basic necessities of life are scarce.[8] A series of national surveys have shown that HIV affects black Africans disproportion­ ately,[1,2] with no respite apparent. The goal of this article is to move beyond generalisations at the population level and instead present a deeper understanding of the epidemic by focusing on two subpopulations most affected by HIV. The findings presented in the report published earlier[2] suggested that the epidemic is concentrated among black African women aged 20 - 34 years and men aged 25 - 49 years. These two groups, accounting for the majority of the country’s HIV-positive population (57.3%) and nearly half of the newly infected population (48%) in 2012, constitute additional key populations for HIV risk. If they are not the main target of HIV prevention programmes, SA is unlikely to significantly reduce new infections in the

RESEARCH

Table 4. Associations with HIV status among black men aged 25 - 49 years, SA 2012

OR

95% CI

aOR

95% CI

SES scale

0.98‡

0.96 - 0.99

0.98*

0.96 - 1.00

25 - 29

Ref

Age (years) Ref

Ref

Ref

30 - 34

1.59

‡

1.20 - 2.10

1.32

0.91 - 1.92

35 - 39

1.75‡

1.30 - 2.34

1.36

0.92 - 2.03

40 - 44

1.31*

0.95 - 1.79

0.99

0.63 - 1.53

45 - 49

1.03

0.73 - 1.47

1.10

0.69 - 1.76

Locality type Urban formal

Ref

Ref

Ref

Ref

Urban informal

1.23

0.94 - 1.61

1.17

0.78 - 1.74

Rural informal

1.06

0.82 - 1.36

0.99

0.68 - 1.44

Rural formal

1.21

0.89 - 1.63

1.22

0.77 - 1.93

1.41 - 2.21

1.69

1.28 - 2.23

Condom use at last sex

1.77

‡

‡

Lifetime number of sex partners 1

Ref

Ref

Ref

Ref

2-3

1.33

0.86 - 2.04

1.04

0.56 - 1.95

4-5

1.40

0.91 - 2.16

1.06

0.57 - 1.98

≥6

1.42

0.93 - 2.15

1.16

0.63 - 2.13

1.84 - 2.78

2.11

1.59 - 2.80

Self-perceived to be at risk for HIV

2.26

‡

‡

OR = odds ratio; CI = confidence interval: aOR = adjusted odds ratio. *0.05≤p<0.1. ‡ p<0.001.

Table 5. Associations with HIV status among black women aged 20 - 34 years, SA 2012

OR

95% CI

aOR

95% CI

SES scale

0.96*

0.95 - 0.972

0.96*

0.94 - 0.98

20 - 24

Ref

Ref

Ref

Ref

25 - 29

1.98*

1.61 - 2.44

1.66*

1.25 - 2.20

30 - 34

3.06*

2.46 - 3.79

2.32*

1.71 - 3.14

Urban formal

Ref

Ref

Ref

Ref

Urban informal

1.74*

1.37 - 2.21

1.26

0.88 - 1.81

Rural informal

1.42*

1.15 - 1.73

1.30

0.95 - 1.77

Rural formal

1.85*

1.38 - 2.50

1.13

0.72 - 1.78

1.53*

1.26 - 1.84

1.98*

1.56 - 2.52

1

Ref

Ref

Ref

Ref

2-3

1.99*

1.58 - 2.51

2.25*

1.63 - 3.10

4-5

2.67*

2.02 - 3.52

2.71*

1.84 - 4.00

≥6

2.76*

1.96 - 3.88

2.67*

1.66 - 4.31

2.42*

2.04 - 2.88

2.07*

1.63 - 2.63

Age (years)

Locality type

Condom use at last sex Lifetime number of sex partners

Self-perceived to be at risk for HIV

OR = odds ratio; CI = confidence interval: aOR = adjusted odds ratio. *p<0.001.

coming years. It is important to understand the demographic characteristics of these groups and the social determinants associated with their increased HIV risk.

The results presented add to the body of knowledge suggesting that SES and specifically inequality (both social and income) are important social determinants

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for HIV risk and infections, particularly among women. SES not only reflects social standing of an individual or group, but also denotes social class, privilege, power and control. The findings suggest that social determinants such as social inequality, income inequality and lack of economic opportunities are associated with being HIVpositive in the two key populations studied, with a much stronger effect observed among black women aged 20 - 34 years. Evidence shows that HIV is a disease that is associated with social and economic inequity and poverty.[9,10] High rates of unemployment in SA can be understood as a significant factor driving the HIV epidemic,[11] and empirical evidence has pointed to increased educational attainment as a method of lowering the incidence.[12] The subject of race and HIV, and who is susceptible to HIV and why, remains a sensitive and controversial issue. Researchers have focused on sociocultural and behavioural aspects in explaining the observed HIV disparities by race.[10] However, data from the USA are beginning to challenge some of these assumptions by showing that it is the individual’s socioeconomic environ­ ment (‘place’), rather than race alone, which may influence behaviour that increases or decreases the likelihood of contracting HIV.[10] In a country like SA, with a history of racial segregation and race-based oppression, race should be understood as a determinant of one’s SES, and it is SES coupled with other factors that protects one from or puts one at risk of HIV. Research has shown a strong association between HIV, SES, race and locality.[1,2] Income and social inequality in particular are emerging as important social determinants for predicting not only risk behaviour but also HIV prevalence and incidence among black South Africans. This is also the case among black Americans in the USA.[10] In the current article, an analysis of socioeconomic factors showed that the two groups (black African women aged 20 - 34 years and men aged 25 - 49 years) are likely to fall into the lower SES rungs and face significant challenges with regard to accessing formal employment, income, education (especially higher education), formal housing, and basic household services and items.

Poverty is understood to be a driving force behind the HIV/AIDS epidemic in subSaharan Africa as both a cause and effect of the disease,[9] and empirical research has pointed to an association between HIV prevalence and lower SES.[13,14] Women globally, and black African women in particular, tend to fall into the lower socio­ economic stratum

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and are disproportionately affected by HIV.[15] There is also evidence that the association between HIV, SES and gender varies depending on income inequality in the general population. Where income per capita is high and intracountry inequalities are high, HIV risk increases.[14] With regard to employment status, black women were more likely than black men to be unemployed and looking for work. Full-time employment rates were higher for men than for women. An analysis by income showed that black men were more likely to have a formal source of income, while women were more likely to have no income and tended to be dependent on welfare, namely grants and charity.

While the study found that both genders are disadvantaged, black women were found to be more socioeconomically disadvantaged than their male counterparts. Among women, lower social standing and the experience of life stress have been associated with risky sexual practices such as transactional sex and lack of consistent condom use.

Access to resources and power determines vulnerability to diseases and poor health outcomes. Poor access to or lack of socioeconomic resources can lead to riskier health behaviours, as individuals belonging to groups with lower SES may not always have access to resources or interventions that they can use to protect themselves.

There is evidence to suggest that race or ethnicity and social class are critical factors in the increased risk of HIV. SES determines where one lives and the conditions to which one is exposed.

Residential settlements in SA remain segregated by race and SES. The link between locality and HIV is poorly understood; however, evidence from the USA suggests that residential segregation, which is characterised by white-black dissimilarity, and black isolation, is a very strong predictor of HIV incidence among blacks.[10] This has led to some researchers arguing that institutional and structural racism is a neglected factor contributing to HIV infection among blacks.[10] The findings presented in this article are in line with a study of 80 cities in the USA that found that income inequality, poverty, and racial segregation of black individuals was a significant predictor of HIV incidence. It was further observed that high income inequality, low incomes, high unemployment, high poverty, low home ownership and a high cost of living correlated positively with HIV incidence.[10] With regard to access to formal income, employment and education, the results of this article suggest that HIV-positive men and HIV-positive women were in a worse position than their male and female counterparts who were HIV-negative. The analysis by gender shows that increases in SES had a stronger protective effect against HIV for black women.

Among both key populations analysed, condom use at last sexual encounter and self-perceived HIV risk were statistically significantly associated with HIV status. Additionally, among 20 - 34-year-old black women, older age and multiple lifetime sexual partners were statistically significantly associated with HIV status. These predictors are investigated in greater detail in the study report.[2] It should be noted that black Africans had the highest HIV testing response rate in the survey, 73.3% as opposed to 67.5% in the total population. A detailed analysis comparing HIV risk-related characteristics among survey respondents who were interviewed and tested with those who were interviewed but refused HIV testing found no evidence that the HIV survey results were biased as a result of HIV testing refusal.[2] Owing to the limitations of a cross-sectional study, it was not possible to determine the causal sequence between HIV infection and SES; as previously stated, low SES has been understood as both a cause and effect of the HIV epidemic in sub-Saharan Africa. Existing research suggests that HIV status often has a negative impact on SES by limiting the individual’s ability to work and earn income.[16] For those who are already positive, being poor and unemployed may also create challenges to accessing healthy food and antiretroviral

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treatment, leading to a faster progression from HIV to AIDS. Positive HIV status may further entrench a cycle of social and income inequality that leads to poverty.[9]

Conclusion

It is not surprising that low SES appears to be a risk factor for HIV infection, especially for the key population of black African women aged 20 - 34 years, with marginal significance for black African men aged 25 - 49 years, as socioeconomic and racial inequalities have a direct impact on these populations. Gender inequality further disadvantages black African women. Additional research is necessary to expand under­ standing of these additional key populations and determine the social and structural characteristics that increase their risks of HIV infection.

Although biomedical prevention and behaviour change interventions are critical for combating the HIV epidemic in SA, it is equally important that energy is directed towards shifting the core structural drivers of HIV, namely economic, racial, and gender inequalities. Targeted interventions for black African key populations should prioritise socioeconomic empowerment, access to formal housing and services, and access to higher education, especially for women. Access to antiretroviral therapy and health services for these communities also needs to be scaled up, and racial disparities in access and quality addressed. The government’s decision to move towards universal healthcare should be lauded; however, implementation remains a pressing challenge. Policy shifts should support the goal of economic transformation and the redistribution of wealth to address racial disparities.

Acknowledgements. This article was supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) through the CDC under the terms of 3U2GGH000570. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC. The Johns Hopkins University Center for AIDS Research (1P30AI094189) and the National Institutes of Health (T32AI102623) are also acknowledged.

References 1. Shisana O, Rehle T, Simbayi LC, et al. South African National HIV Prevalence, Incidence, Behaviour and Communication Survey, 2008: A Turning Tide Among Teenagers? Cape Town: HSRC Press, 2009.

2. Shisana O, Rehle T, Simbayi LC, et al. South African National HIV Prevalence, Incidence and Behaviour Survey, 2012. Cape Town: HSRC Press, 2014.

3. Beyrer C, Baral S, Kerrigan D, et al. Expanding the space: Inclusion of most-at-risk populations in HIV prevention, treatment, and care services. J Acquir Immune Defic Syndr 2011;57(Suppl 2):S96-S99. [http://dx.doi.org/10.1097/QAI.0b013e31821db944] 4. Baral SD, Poteat T, Strömdahl S, et al. Worldwide burden of HIV in transgender women: A systematic review and meta-analysis. Lancet Infect Dis 2013;13(3):214-222. [http://dx.doi.org/10.1016/S14733099(12)70315-8] 5. Rispel LC, Metcalf CA, Cloete A, et al. HIV prevalence and risk practices among men who have sex with men in two South African cities. J Aquir Immune Defic Syndr 2011;57(1):69-76. [http://dx.doi. org/10.1097/QAI.0b013e318211b40a] 6. UNAIDS. UNAIDS Guidance for Partnerships with Civil Society Including People Living with HIV and Key Populations. Geneva: Joint United Nations Programme on HIV/AIDS, 2012.

7. Statistics South Africa. Census 2011. Pretoria: Statistics South Africa, 2012.

8. Mayosi BM, Lawn JE, van Niekerk A, et al. Health in South Africa: Changes and challenges since 2009.

Lancet 2012;380(9858):2029-2043. [http://dx.doi.org/10.1016/S0140-6736(12)61814-5] 9. Shisana O, Zungu N, Pezi S. Poverty and HIV and AIDS. In: Rohleder P, Cameron E, Swartz L, et al., eds.

HIV/AIDS in South Africa 25 Years On. New York: Springer, 2009:89-104.

10. Buot MLG, Docena JP, Ratemo BK, et al. Beyond race and place: Distal sociological determinants of HIV disparities. PLoS One 2014;9(4):e91711. [http://dx.doi.org/10.1371/journal.pone.0091711] 11. Hunter M. The changing political economy of sex in South Africa: The significance of unemployment and inequalities to the scale of the AIDS pandemic. Soc Sci Med 2007;64(3):689-700. [http://dx.doi. org/10.1016/j.socscimed.2006.09.015] 12. Bärnighausen T, Hosegood V, Timaeus IM, Newell ML. The socioeconomic determinants of HIV incidence: Evidence from a longitudinal, population-based study in rural South Africa. AIDS 2007;21(Suppl 7):S29-S38. [http://dx.doi.org/10.1097/01.aids.0000300533.59483.95] 13. Buve A, Bishikwabo-Nsarhaza K, Mutangadura G. The spread and effect of HIV-1 infection in subSaharan Africa. Lancet 2002;359(9322):2011-2017. [http://dx.doi.org/10.1016/S0140-6736(02)08823-2] 14. Wojcicki JM. Socioeconomic status as a risk factor for HIV infection in women in East, Central and Southern Africa: A systematic review. J Biosoc Sci 2005;37(1):1-36. [http://dx.doi.org/10.1017/ S0021932004006534] 15. UNAIDS. Global Report: UNAIDS Report on the Global HIV Epidemic 2013. Geneva: Joint United Nations Programme on HIV/AIDS, 2013.

16. Rabkin JG, McElhiney M, Ferrando SJ, et al. Predictors of employment of men with HIV/AIDS: A longitudinal study. Psychosom Med 2004;66(1):72-78.

Accepted 15 June 2015.

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K-ras codon 12 and not TP53 mutations are predominant in advanced colorectal cancers G Zhunussova,1 PhD; L Djansugurova,1 PhD; E Khussainova,1 PhD; B Zhunusbekova,1 BSc; G Afonin,2 MD; D Khaidarova,2 MD; M Matejcic,3 PhD; M Iqbal Parker,3 PhD aboratory of Molecular Genetics, Institute of General Genetics and Cytology, Almaty, Kazakhstan L Almaty Oncology Centre, Almaty, Kazakhstan 3 International Centre for Genetic Engineering and Biotechnology, Cape Town Component, South Africa, and Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding authors: M Iqbal Parker (iqbal.parker@icgeb.org), L Djansugurova (leylad@mail.ru)

Background. Colorectal cancer (CRC) is one of the most common types of cancer, affecting 3 - 5% of the global population. K-ras protooncogene and TP53 tumour suppressor gene mutations are among the most common genetic alterations detected in advanced colorectal tumours.

Objective. To investigate the role of K-ras codon 12 and TP53 exons 5 - 9 mutations in late-stage CRC patients.

Methods. Blood samples were collected from 249 CRC patients, of whom 147 presented with advanced carcinoma. K-ras codon 12 mutations were analysed using polymerase chain reaction-restriction fragment length polymorphism, while direct sequencing was used in screening for TP53 exons 5 - 9 mutations.

Results. No significant changes were observed in TP53 exons 5 - 9, except for two cases in which nucleotide replacements were observed in the non-coding regions in intron 4 (c.376-19C>T) and intron 9 (c.993+12T>C). Heterozygous mutations in K-ras codon 12 were observed in 79 individuals suffering from advanced CRC (53.7%). Colon and rectal tumours were equally distributed among the heterozygotes, but colon tumours were mostly present in wild-type homozygotes (84.6%). There was also a predominance of Caucasians among heterozygotes and a predominance of Asians among the wild-type homozygotes.

Conclusion. Analysis of peripheral blood samples of CRC patients suffering from advanced carcinoma has prognostic value only for K-ras codon 12 mutations, and not for TP53 mutations.

S Afr Med J 2015;105(8):670-674. DOI:10.7196/SAMJnew.7886

Colorectal cancer (CRC) is one of the most common cancers, affecting 3 - 5% of the population, with an incidence peak in the age range 50 - 70 years.

CRC is the third leading cause of cancer death in both men and women worldwide, and continues to be one of the most common fatal types of cancer. Worldwide, approxi­mately 1.5 million individuals are diagnosed with CRC and 500â&#x20AC;&#x201E;000 die from the disease annually.[1] Among Eurasian countries, Kazakhstan has the seventh-highest incidence of CRC. CRC develops slowly over several years and progresses through cytologically distinct benign and malignant stages of growth, ranging from single-crypt lesions through adenoma to malignant carcinoma with the potential for invasion and metastasis. The majority of CRC cases are sporadic, with 20 30% being familial.[1] The classic model of colorectal tumourigenesis includes several genetic changes that are required for cancer initiation and progression.

The earliest genetic trigger is the inactivation of the APC pathway.

Mutations in other tumour suppressor genes (APC, SMAD2, SMAD 4, DCC, TP53) and oncogenes (K-ras) and several other genes/pathways accompany the transition of the tumour towards malignancy and metastasis. In addition to the gene mutations, deregulated expression of oncogenes and/or tumour suppressor genes can also be mediated via epigenetic modifications such as DNA methylation and histone acetylation. Rapidly developing insights into the molecular genetics of CRC have led to the identification of predictive and prognostic biomarkers for CRC.[2]

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K-ras proto-oncogene and TP53 tumour suppressor gene mutations are among the most common genetic alterations in advanced colorectal tumours. The Ras genes code for a family of membrane-bound small guanosine triphosphate-bound proteins that play a key role in the transduction of extracellular mitogenic signals. Constitutively activating Ras mutations are present in a significant proportion of colorectal adenomas and carcinomas.[1-2] Approximately 40% of CRCs harbour K-ras mutations, 90% of which occur in codons 12 and 13; these mutations occur less frequently in codons 61, 63, and 146.

Mutations in any of these codons lead to a constitutively activated RAS protein.[3-6] The relationship between K-ras mutations and the clinical/ morphological parameters of CRC has been extensively investigated.

Some epidemiological studies show a prevalence of K-ras codon 12 mutations over mutations in codon 13 in CRC tumours.[7] A study of more than 1 000 colorectal cancers showed that K-ras codon 12 mutations (in particular c35G>T, pG12V), but not codon 13 mutations, are associated with poor prognosis in wild-type CRCs.[3] The prognostic value of codon 12 mutations was revealed in a functional study that showed that malignant transformation of NIH3T3 cells with mutant codon 12 K-ras had a more aggressive phenotype when compared with mutant codon 13 K-Ras.[3] A recent study of Chinese CRC patients revealed that a high frequency of codon 12 K-ras mutations was associated with poorly differentiated tumours, liver metastasis and poor survival.[6] Although the role of K-Ras mutations in tumour tissues is widely accepted to be associated with poor prognosis and antiepidermal growth factor receptor (EGFR) therapy,[4,12] the predictive value of K-ras mutations in blood samples remains uncertain.

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The TP53 gene product is a nuclear phosphoprotein that is expressed at low levels in most normal tissues and plays a key role in the control of cell cycle progression, genome stability and apoptosis.

TP53 is one of the most frequently mutated genes in human cancers.

Somatic mutations of TP53 are associated with more advanced stages of the disease, with loss of TP53 gene heterozygosity being a marker for the conversion of adenoma to carcinoma. In CRC tumours, more than 50% of mutations occur in the TP53 gene. The most common mutations are single-base substitutions that alter protein function.

However, in contrast to the activating K-ras gene mutations, which are concentrated in only a few positions, mutations in the TP53 gene are scattered over a large region of the gene.[8] Most TP53 gene mutations in CRC tumours occur in exons 5 - 9, which contain four highly conserved domains that are important in the clinical outcome of CRC and have been associated with increased malignant potential.[8,9] TP53 mutations occur with a higher frequency in distal colon and rectal tumours and with a lower frequency in proximal, mucinous and microsatellite instability-positive CRCs. Alterations to this gene are likely to have very little or no prognostic significance in CRC patients treated with surgery alone, but may be associated with marginally worse survival for patients treated with chemotherapy.

There is some evidence that different TP53 mutations are associated with different clinical properties, including prognosis and response to therapy. TP53 status appears to have predictive value for the survival benefit of CRC patients on 5-fluorouracil (5FU) chemotherapy.[10] Several studies have reported combined mutations in K-Ras and TP53 genes in CRC tumours,[7] but the clinical usefulness of K-ras and/or TP53 gene mutations is still somewhat controversial. The data on K-ras and TP53 aberrations and their relationship to patient survival and prognosis are insufficient to recommend the use of such mutations as prognostic indicators.[9] It is therefore clear that prospective studies to assess the prognostic utility of these genetic abnormalities are required. Although most reports indicate that altered K-Ras and TP53 genes in tumour tissues present at advanced stages, it would be interesting to assess the status of these genes in peripheral blood samples of CRC patients, because the gene heterozygosity can have a predictive value for determining prognosis.

The Kazakhstan National Screening Program for malignant neoplasms of the colon and rectum, initiated in 2011, showed that most cases were diagnosed at a very late stage when treatment is expensive and ineffective. The prediction of malignant potential and resistance to EGFR or 5FU chemotherapy at earlier stages of CRC development before surgery may improve patient survival.

Objective

Because the K-ras codon 12 and TP53 mutations are the most promising biomarkers of CRC tumour progression, the objective of this study was to assess K-Ras and TP53 gene status in blood samples of patients with advanced colorectal carcinoma.

Methods Sampling

Blood samples were collected from 249 CRC patients at Almaty Oncology Centre, Almaty, Kazakhstan. Informed consent and detailed demographic information were obtained. Histological testing showed that 147 of these patients (59.0%) had presented with advanced CRC, and they were chosen as subjects for this study. The study protocol was approved by the Ethics Committee of the Asfendiyarov Kazakh National Medical University.

DNA isolation

Genomic DNA was isolated from peripheral blood leucocytes of the 147 patients with advanced CRC (stages III and IV) using the standard phenol-chloroform method with modifications in the composition of the lysis buffer (0.2M sodium acetate and 1% sodium dodecyl sulphate, pH 8.0) and precipitated in ice-cold ethanol.[9] The quantity and quality of the DNA samples were evaluated spectrophotometrically using an Eppendorf BioPhotometer (Eppendorf, Germany), and they were stored at –20°C until required.

Detection of K-ras mutations in codon 12

All known nucleotide mutations in codon 12 were screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). One hundred nanograms of total DNA was amplified in a 20 μL reaction mixture containing 10 pM of each specific primer (sense-5ʹ-ACTGAATATAAACTTGTGGTAGTTGGACCT-3ʹ, anti-sense-5ʹ-TCAAAGAATGGTCCTGGACC-3ʹ), 10 mM of each deoxy­nucleotide triphosphate (dNTP), 1 mM MgCl2, 0.5 KCl, 0.1% gelatin and 1 U Taq-polymerase (Sigma-Aldrich, USA). Denaturation was performed at 95oC for 5 minutes, followed by 40 cycles at 95oC for 30 seconds, at 54oC for 40 seconds and at 72oC for 1 minute, with a final elongation step at 72oC for 7 minutes.[11] Five microlitres of each PCR product (157 bp) was digested with 1 U MvaI (BstN1, ThermoScientific, USA) at 60oC for 3 hours. Digestion products were analysed on 1.4% agarose gels. The normal K-ras allele is indicated by the presence of a 114-bp fragment as opposed to the 143-bp fragment in the mutant K-ras allele. Heterozygotes display both the 143- and 114-bp fragments.

Sequencing of exons 5 - 9 of the TP53 gene

Direct sequencing was used to screen for mutations in exons 5 - 9 of TP53.[9] The PCR was performed in a final volume of 20 μL containing 50 ng template DNA, 1 × PCR buffer, 0.2 mM of each dNTP, 1.5 mM MgCl2, 0.4 μM of each primer (Table 1) and 0.5 U of FastStart Taq DNA polymerase using the Veriti Dx 96-well Thermal Cycler (Applied Biosystems, USA). PCR products were visualised by electrophoresis on 1.5% agarose gels.

PCR products were purified using Nucleofast 96-well PCR plates (Macherey-Nagel, Germany). Sequencing reactions were performed

Table 1. The PCR amplification primers and parameters used for direct sequencing of TP53 exons 5 - 9 Amplified regions of TP53 gene

Primer pairs (5ʹ→3ʹ)

Exons 5 - 6

f-TGTTCACTTGTGCCCTGACT r-TTAACCCCTCCTCCCAGAGA

Exon 7

f-CTTGCCACAGGTCTCCCCAA r-AGGGGTCAGAGGCAAGCAGA

Exons 8 - 9

f-TTGGGAGTAGATGGAGCCT r-AGTGTTAGACTGGAAACTTT

PCR conditions

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1 cycle of 2 min at 94°C, 20 cycles (94°C for 30 s, 63°C for 45 s with –5°C per cycle, 72°C for 1 min), followed by 30 cycles (94°C for 30 s, 60°C for 45 s, 72°C for 1 min), and a final cycle of 10 min at 72°C

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Length of PCR products 467 bp 237 bp 445 bp

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using specific primers and the BigDye Terminator v3.1 sequencing kit (Applied Biosystems) and an ABI 3730xl Genetic Analyser (Applied Biosystems). The cycle sequencing reactions contained 50 100 nmol of purified PCR product, 2 μl of BigDye Terminator, 1 μL of Sequencing Buffer and 3.2 pmol of primer in a total volume of 20 μL. Cycle sequencing was per­ formed using 55 cycles at 96°C for 5 minutes, 60°C for 5 minutes and 96°C for 5 minutes. After cycle sequencing, sodium dodecyl sulphate was added and the samples were purified on Sephadex columns using a Tecan EVO150 robotic workstation (Agilent Technologies, USA). The purified sequencing products were dried, suspended in Hi-Di (Life Technologies, USA) and denatured at 95°C for 2 minutes before sequencing electrophoresis. Electrophoresis was performed on an ABI 3730xl using a 50 cm capillary array and POP7 (Applied Biosystems).

DNA sequencing data were analysed using ChromasPro version 1.7.4 software, confirmed by reverse sequencing and com­ pared with the Leiden Open Variation and Universal Mutation databases to search for mutations.

Table 2. Localisation and stage of the tumours in the CRC cohort used in this study TNM stage, n (%)

Localisation of tumours

Patients n (%)

I

II

III

IV

Rectum

115 (47.7)

8 (3.2)

44 (17.7)

48 (19.3)

15 (6.0)

Colon

48 (19.3)

3 (1.2)

14 (5.6)

21 (8.4)

10 (4.0)

Cecum

18 (7.5)

0 (0)

7 (2.8)

7 (2.8)

4 (1.6)

Sigmoid

57 (22.9)

5 (2.0)

17 (6.8)

28 (11.2)

7 (2.8)

Rectosigmoid

11 (4.6)

0 (0)

4 (1.6)

4 (1.6)

3 (1.2)

Total

249 (100.0)

16 (6.4)

86 (34.5)

108 (43.4)

39 (15.7)

Statistical analysis

Student’s t-test was used to compare the distribution of variables between groups, with a p-value of <0.05 considered signi­ ficant.

Results

Characteristics of the study population

Adenocarcinoma was the predominant tumour type among the 249 CRC patients first diagnosed with CRC in the period 2012 - 2014, and 55.8% of the tumours were well or moderately differentiated. Table 2 summarises the data on tumour localisation and stage, showing that rectal tumours predominated at 47.7% of all sites.

For the analysis of K-ras codon 12 mutations and TP53 exons 5 - 9 mutations as potential markers of cancer progression, the advanced carcinoma cases were chosen after histological verification. A total of 147 patients (59.0%) had advanced CRC (stages III and IV by TNM criteria). In this cohort there were 73 women (49.7%) and 74 men (50.3%), and the ethnic distribution was as follows: Kazakhs n=39 (26.5%), Russians n=86 (58.5%), other Asians (Turks, Uzbeks, Tatars, Uighurs, Koreans, Dungans) n=17 (11.6%), and other Caucasians (Armenians, Ukrainians, Belarusians, Germans) n=5 (3.4%). There were 50 cases of rectal cancer

Fig. 1. Genotyping of the K-ras codon 12 mutations. Blood DNA was isolated and subjected to PCR amplification, digestion with the restriction MvaI (BstN1) and separation of the digestion products on 3% agarose gels as described under ‘Methods’. The 114-bp fragment indicates the normal K-ras while the 143-bp fragment indicates the mutant K-ras codon 12 allele. Lane M is a 100-bp DNA ladder, while lanes 1, 4, 6 and 8 are the undigested 157-bp PCR products; lanes 2, 5 and 9 show the normal homozygous individuals represented by the 114-bp band, while lanes 3, 7, 10, 11, 12 and 13 show the heterozygous individuals. The gel shows only a sample of 13 of the 147 patients with advanced carcinoma investigated in this study.

(34.0%) and 97 of colon cancer (66.0%), with 126 cases of stage III cancer (85.7%) and 21 of stage IV cancer (14.3%). Among patients suffering from advanced CRC there were 5 smokers (3.4%), 14 ex-smokers (9.5%), and 128 non-smokers (87.1%).

K-ras mutations in codon 12 in patients with advanced CRC

The 147 selected CRC patients with advanced carcinoma were screened for K-ras codon 12 mutations (Gly12Asp (GGT→GAT), Gly12Ala (GGT→GCT), Gly12Val (GGT→GTT), Gly12Ser (GGT→AGT), Gly12Arg (GGT→CGT), Gly12Cys (GGT→TGT)).

The genotyping data for the K-ras codon 12 mutations (Fig. 1) revealed 79 heterozygous individuals (53.7%), while 68 (46.3%) of the patients were homozygous wild type. Some differences were observed

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Table 3. Differences in the stage of CRC in individuals with homozygous and heterozygous K-ras codon 12 genotypes TNM stage Genotype

III

IV

Mutant heterozygous, n (%)

53 (67.1 )

26 (32.9)

Normal homozygous, n (%)

58 (85.3)

10 (14.7)

Odds ratio

1.25

1.76

p-value

>0.05

>0.05

in the stage of cancer progression between individuals who were mutant heterozygous and normal homozygous for K-ras codon 12 (Table 3). The percentage of patients who had progressed to stage IV was higher among the mutant allele carriers than

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among the normal homozygotes (32.9% v.

14.7%).

The heterozygous genotype was present in 50% of patients with rectal tumours and in 50% of those with colon tumours. Most of the normal homozygotes were diagnosed with colon tumours (84.6%), and only 15.4% with rectal tumours. These differences were statistically significant (for colon tumours odds ratio (OR) 2.7; p<0.01 and for rectal tumours OR 2.84; p<0.01).

The prevalence of Caucasians among mutant allele carriers (70% Russians and other Caucasians), and the prevalence of Asians among normal homozygotes (53.9% Kazakhs and other Asians) were observed as significant (for Caucasians OR 2.09; p<0.05 and for Asians OR 2.32; p<0.05).

The percentage of smokers and ex-smokers among heterozygotes was 13.4%, while among normal homozygotes there were only ex-smokers (11.5%). Distribution by gender was similar between heterozygotes (40 males and 39 females) and normal homozygotes (34 males and 34 females).

Analysis of TP53 mutations

No TP53 exon 5 - 9 mutations were observed by direct sequencing, as shown in A. Heterozygous T/C substitution in intron 9 (c.993+12T>C)

C

T

G

T

Y

T

C

C

Fig. 2. However, three cases of nucleotide replacements were noticed in intron 9 (c.993+12T>C) (Fig. 2, A), and another two cases in intron 4 (c.376-19C>T, Fig. 2, B), all in the heterozygous state. Table 4 summarises the DNA sequencing data in individuals with TP53 mutations. Two different types of mutations were detected in five patients from among the 147 patients with advanced carcinoma.

Discussion

It is well known that mutations in the tumour suppressor gene TP53 and K-ras oncogene are not responsible for initiation of the development of CRC, but are critical for tumour progression and metastasis.[1-2,8-9,12] The most common TP53 gene mutations are single-base substitutions that alter protein function. While loss-of-function mutations are generally inherited or early events, some of the oncogenic mutations that confer gain-of-function properties are latestage events, mostly exon 5 - 9 mutations, that play an important role in the clinical outcome of CRC.[1,9] Our study on peripheral blood samples of 147 patients with advanced CRC did not show any significant changes in TP53 B. Heterozygous T/C substitution in intron 4 (c.376-19CT>T)

T

T

G

T

C

T

Y

G

G

G

A

Fig. 2. DNA sequence analysis of the TP53 gene. Blood DNA was isolated and subjected to PCR amplification using the primers defined in Table 1, and the PCR products were subjected to direct sequence analysis. A: Nucleotide change observed in intron 9 in three patients; B: Nucleotide change observed in intron 4 in two patients.

Table 4. Nucleotide changes detected by direct PCR sequencing TP53 exons 5 - 9 detected in five of the 147 CRC patients investigated Nucleotide substitution

Gene

Exon/intron

Affected patients

TP53

9i

c.993+12T>C, rs1800899

One female (born 1967), rectal, stage III T3NxMo One male (born1937), rectal, stage IV T3NxM1 One male (born1937), colon, stage IV T3NoM1

TP53

4i

c.376-19C>T

One female (born 1983), rectal, stage III T4NxMo One female (born1952), colon, stage IV T4NxM1

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exon 5 - 9 mutations, except for two novel heterozygous nucleotide replacements in the non-coding regions of the gene. One change in intron 4 (c.376-19C>T) was observed in two patients, and another nucleotide substitution was detected in intron 9 (c.993+12T>C) in three patients.

No information on the significance of these mutations detected in CRC patients from Kazakhstan is available in the literature. It should also be noted that the TP53 mutations were examined in the peripheral blood DNA of the patients and not in the tumours; these are therefore inherited mutations. However, it cannot be ruled out that additional genetic events may occur along the way. Although intronic mutations do not alter the amino acid sequence of a gene product, they can influence the regulation of gene activity by altering the binding of regulatory proteins or miRNA, leading, for example, to aberrant splicing (IARC TP53 Database).

The most common K-ras codon 12 muta­ tions result in the substitution of glycine for valine, thus changing the spatial conforma­ tion of RAS, leading to a consti­ tutively activated form where the RAS signalling cascade to other partici­ pants occurs regardless of EGFR status. This explains why the predictive value of K-ras mutations in determining whether or not patients will respond to anti-EGFR therapy is of much interest.[13,14] Screening of all known K-ras codon 12 mutations (Gly12Asp, Gly12Ala, Gly12Val, Gly12Ser, Gly12Arg, Gly12Cys) in the blood DNA of 147 CRC patients with advanced CRC showed heterozygous mutations in more than 50% of the patients (79/147). Our data are in agreement with the published data showing K-ras codon 12 mutation frequencies ranging from 30% to 60% in tissue samples from rectal and colon tumours.[10,13-14] We could not find any significant differences regarding gender, age or smoking habit between patients carrying the K-ras codon 12 mutation and the wild-type homozygotes. The percentage of patients with stage IV cancer carrying the mutant allele was higher than among the normal homozygotes (32.9% v. 14.7%), but this was not statistically significant. Tumours of the rectum and colon were equally distributed among heterozygous patients; however, the prevalence of colon tumours (84.6%) in normal homozygous patients was statistically significant. The relationship between K-ras mutations and the clinical/morphological parameters of CRC has been extensively investigated.[5] There is some evidence that K-ras codon 12 mutations are significantly

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associated with poor survival at all stages of cancer progression.

Estimated event-free survival correlates with poor tumour differentiation status, pericolic fat invasion and metastasis.[5] CRCs with K-ras mutations are associated with distinctive morphological features. K-ras codon 12 mutations are more frequently observed in carcinomas of the proximal-distal axis of the colorectum, mucinous differentiation, and contiguous polyps. Our findings are in agreement with these findings.

Some ethnic differences were observed in the Kazakhstan patients: there was a higher prevalence of mutant allele carriers among the Caucasians (Russians and others) and a higher prevalence of normal homozygotes among the Asians (Kazakhs and others). It is well established that ethnic differences and lifestyle have a strong influence on the frequency of K-ras mutations.[15] K-ras codon 12 mutation is a good biomarker in stage IV CRC, predicting lack of benefit from the anti-EGFR targeted antibodies cetuximab (Erbitux) and panitumab (Vectibix).[4,15] It is possible that the findings on K-ras codon 12 carriers in our population will help in the choice of adjuvant therapy.

Several studies have detected compound mutations in the K-ras and TP53 genes in CRC.[4,15] A Tunisian CRC study reported the detection of a K-ras somatic mutation in 31.5% of patients, with 81.2% having a single mutation at codon 12 and 23% having a single mutation at codon 13; 43.75% of the patients harboured combined K-ras and TP53 mutations, with 71.42% of them showing TP53 over-expression.[7] In our study two of the five patients (a woman born in 1967, rectal carcinoma, stage III T3NxMo, and a man born in 1937, rectal carcinoma, stage IV T3NxM1) with TP53 intron mutations were also heterozygous for the K-ras codon 12 mutation.

In both cases the mutation was in intron 9 of TP53 (c.993+12T>C).

Because the percentage of TP53 mutations among advanced CRC patients from Kazakhstan is very low (3.4%) and nothing is known about the pathological significance of these intronic mutations, there is no evidence for an association with poor prognosis. However, our observation of the prevalence of inherited K-ras codon 12 mutation carriers in advanced CRC patients (53.7%), together with the literature data, supports the idea that these mutations may be a predictive marker of cancer progression and anti-EGFR therapy.

Conclusion

The study demonstrates that the analysis of peripheral blood samples of patients suffering from advanced CRC may have

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prognostic value only for K-ras codon 12 mutations, and not for TP53 mutations.

Acknowledgements. This work was supported by grant N.0067/GF from the Committee of Science MES of Republic of Kazakhstan. MIP was funded by grants from the ICGEB, the South African Medical Research Council and the University of Cape Town. We are sincerely grateful to all the patients who participated in this study, to the doctors of Almaty Oncology Centre for collecting tissue samples and histological testing, and to the Head of the Department of Oncology at the KazNMU Bakhyt Khaidarov, who managed the research.

References 1. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet 2014;383(9927):1490-1502. [http://dx.doi. org/10.1016/S0140-6736(13)61649-9] 2. Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: One step closer to targeted therapy. Oncologist 2010;15(7):699-731. [http://dx.doi.org/10.1634/theoncologist.2010-0025] 3. Imamura Y, Morikawa T, Liao X, et al. Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers. Clin Cancer Res 2012;18(17):4753-4763. [http:// dx.doi.org/10.1158/1078-0432.CCR-11-3210] 4. Roock WD, Vriendt VD, Normanno N, Ciardiello F, Tejpar S. KRAS, BRAF, PIK3CA, and PTEN mutations: Implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 2011;12(6):594-603. [http://dx.doi.org/10.1016/S1470-2045(10)70209-6] 5. Zlobec I, Bih MP, Schwarb H, Terracciano L, Lugli A. Clinicopathological and protein characterization of BRAF- and K-RAS-mutated colorectal cancer and implications for prognosis. Int J Cancer 2010;127(2):367-380. [http://dx.doi.org/10.1002/ijc.25042] 6. Li Z, Chen Y, Wang D, Wang G, He L, Suo J. Detection of KRAS mutations and their associations with clinicopathological features and survival in Chinese colorectal cancer patients. J Int Med Res 2012;40(4):1589-1598.

7. Aissi S, Buisine MP, Zerimech F, et al. KRAS mutations in colorectal cancer from Tunisia: Relationships with clinicopathologic variables and data on TP53 mutations and microsatellite instability. Mol Biol Rep 2013;40(3):6107-6112. [http://dx.doi.org/10.1007/s11033-014-3030-z] 8. Naccarati A, Polakova V, Pardini B, et al. Mutations and polymorphisms in TP53 gene – an overview on the role in colorectal cancer. Mutagenesis 2012;27(2):211-218. [http://dx.doi.org/10.1093/mutage/ ger067] 9. Robles AI, Harris CC. Clinical outcomes and correlates of TP53 mutations and cancer. Cold Spring Harb Perspect Biol 2010;2(3):a001016. [http://dx.doi.org/10.1101/cshperspect.a001016] 10. Iacopetta B. TP53 mutation in colorectal cancer. Hum Mutat 2003;21(3):271-276.

11. Levidou G, Saetta AA, Gigelou F, et al. ERK/pERK expression and B-raf mutations in colon adenocarcinoma: Correlation with clinicopathological characteristics. World J Surg Oncol 2012;10:47. [http://dx.doi.org/10.1186/1477-7819-10-47] 12. Vakiani E, Solit DB. KRAS and BRAF: Drug targets and predictive biomarkers. J Pathol 2011;223(2):219-229. [http://dx.doi.org/10.1002/path.2796] 13. Heinemann V, Stintzing S, Kirchner T, Boeck C, Jung A. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev 2009;35(3):262-271. [http://dx.doi.org/10.1016/j.ctrv.2008.11.005] 14. Deeb KK, Sram JP, Gao H, Fakih MG. Multigene assays in metastatic colorectal cancer. J Natl Compr Canc Netw 2013;11(Suppl 4):S9-S17.

15. Lee DW, Kim KJ, Han SW, et al. KRAS mutation is associated with worse prognosis in stage III or highrisk stage II colon cancer patients treated with adjuvant FOLFOX. Ann Surg Oncol 2015;22(1):187194. [http://dx.doi.org/10.1245/s10434-014-3826-z]

Accepted 15 June 2015.

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Chromosomal radiosensitivity of lymphocytes in South African breast cancer patients of different ethnicity: An indirect measure of cancer susceptibility F Z Francies,1,2 BHSc Hons; O Herd,1 PhD; X Muller,1 MSc; A Cairns,3 MB BCh, FCS (SA); M Murdoch,4 MB BCh, FCPlastSurg (SA); S Nietz,4 MB BCh, FCS (SA); J P Slabbert,1 PhD; A Baeyens,1,2 PhD i Themba LABS/National Research Foundation, Somerset West, Western Cape, South Africa Radiobiology, Department of Radiation Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 Department of Surgery, Donald Gordon Medical Centre, Johannesburg, South Africa 4 Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1 2

Corresponding author: A Baeyens (ans.baeyens@wits.ac.za, ansbaeyens@hotmail.com)

Background. Breast cancer is the leading cancer among South African (SA) women. SA has citizens from diverse ethnic groups, and the lifetime risk of breast cancer differs according to ethnicity. Candidate genes for increased breast cancer risk are those involved in DNA damage repair pathways, and mutations in these genes are characterised by increased chromosomal radiosensitivity. Several European studies have shown that breast cancer patients are more sensitive to ionising radiation than healthy individuals.

Objectives. To investigate the in vitro chromosomal radiosensitivity of SA women with breast cancer and the possible influence of ethnicity and clinical parameters on chromosomal radiosensitivity.

Methods. Chromosomal radiosensitivity was analysed with the micronucleus assay using lymphocytes of breast cancer patients and healthy individuals of different ethnic groups. Lymphocytes were irradiated in vitro with 2 Gy or 4 Gy, and micronuclei (MN) were scored 70 hours after irradiation. These MN frequencies were correlated with the ethnicity and clinical parameters of the breast cancer patients.

Results. MN values were higher in breast cancer patients than in healthy controls. This was noted for black and white breast cancer patients at the different radiation doses. No correlations could be demonstrated between MN values and clinical parameters of the breast cancer, except that MN values were significantly higher in oestrogen receptor (ER)-positive breast cancers.

Conclusion. SA breast cancer patients have elevated chromosomal radiosensitivity compared with healthy controls. ER positivity also influences chromosomal radiosensitivity.

S Afr Med J 2015;105(8):675-678. DOI:10.7196/SAMJnew.8266

According to South Africa (SA)â&#x20AC;&#x2122;s most recent cancer registry, breast cancer is the leading cancer among SA women, with a lifetime risk of 1 in 34.[1] SA is a country with citizens of diverse ethnicity: black African (80.2%), white Caucasian (8.5%), mixed/ coloured (8.9%) and Indian/Asian (2.4%).[2] The lifetime risk of breast cancer differs according to ethnicity: 1/52 in black women, 1/22 in coloured women, 1/19 in Indian women and 1/18 in white women.[1] While the incidence is lowest among black women, it is rising as a result of increased life expectancy and urbanisation, which leads to lifestyle changes that elevate exposure to known risk factors for breast cancer such as dietary changes, decreased exercise, delayed and decreased parity, and reduction in breastfeeding.[3] Although there is a lower incidence of breast cancer in SA in comparison with developed countries, the mortality rate of existing breast cancer patients is higher owing to limited access to diagnostic centres, particularly in rural areas, lack of awareness, low standards of healthcare facilities and limited screening.[4] Familial breast cancer caused by mutations in high-penetrance genes such as BRCA 1 and BRCA 2 accounts for only 5% of all breast cancers.

The majority of breast cancers are sporadic and are due to mutations in a number of low-penetrance genes. Candidate genes for breast cancer risk include those involved in DNA damage repair pathways. Mutations in genes regulating these pathways are characterised by increased chromosomal radiosensitivity.[5] Measurement of chromosomal radiosensitivity has been used as an indirect measure of cancer

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susceptibility. The association between chromosomal radiosensitivity and cancer risk is supported by the following facts: cancer-prone disorders such as ataxia telangiectasia present with high chromosomal radiosensitivity; elevated chromosomal radiosensitivity is an indicator of defects in DNA repair that could lead to the chromosomal instability often observed in cancer; and chromosomal radiosensitivity is linked with early events in carcinogenesis.[6] Several studies (reviewed in Cardinale et al.[7]) on European, Asian and American populations have shown breast cancer patients to have elevated chromosomal radiosensitivity compared with healthy individuals. Studies on the chromosomal radiosensitivity of breast cancer patients have never been performed in SA. Chromosomal radiosensitivity can be measured using the cytokinesis-block micronucleus assay. Micronuclei (MN) are small nuclei that form in the cytoplasm when chromosomes or chromosome fragments are not incorporated into the daughter nuclei subsequent to cell division. MN can contain whole chromosomes (mis-segregated during mitosis) or acentric fragments, which are usually the result of misrepaired or unrepaired DNA double-strand breaks. MN are counted in cells that have undergone a single division; however, cytokinesis is blocked by adding cytochalasin B, which results in binucleated (BN) cells. This assay is well established, robust and can be performed on lymphocytes, which are easily obtained through venepuncture. The automation of MN scoring with the Metafer 4 platform (MetaSystems, Germany) has minimised the variability of the assay and rendered it rapid and less subjective.

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Objective

To measure the chromosomal radiosensitivity of SA breast cancer patients in a case-control study design with the micronucleus assay and the Metafer 4 scoring system. Recent studies have shown how tumour characteristics of breast cancer can differ among different ethnic groups.[8,9] The differences between the ethnic groups point to differences in the underlying biology of the disease and led to the idea of comparing chromosomal radiosensitivity in different ethnic groups. We also assessed whether there was an influence of clinical parameters on chromosomal radiosensitivity.

Materials and methods Subjects

Blood samples were collected from 68 breast cancer patients (mean age (standard deviation (SD)) 52 (12)) recruited from Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), a public hospital in Johannesburg, Gauteng Province, South Africa, and Donald Gordon Medical Centre, a private hospital in Johannesburg. We included 30 black breast cancer patients (mean age 47 (12) years), 25 white breast cancer patients (mean age 59 (11) years), 7 Indian breast cancer patients (mean age 45 (8) years) and 6 coloured breast cancer patients (mean age 49 (8) years).

Exclusion criteria included prior chemo- and/ or radiotherapy. Clinical and biographical information on the patients was obtained through questionnaires and hospital files.

All patients were categorised by race (black, white, Indian, coloured) based on patients’ selfreported data from the questionnaires. Most of the breast cancer patients (80.0%) had inva­ sive ductal carcinomas, of which 31.1% were stage 0 - I, 53.3% stage II and 15.6% stage III. Overall 74.1% were oestrogen receptor (ER)-positive, 63.8% were progesterone receptor (PG)-positive and 78.6% were human epidermal growth factor receptor 2 (HER2)negative. No participant was HIV-positive.

Blood samples from 70 healthy controls (mean age (SD) 35 (12) years), including 20 black women (mean age 36 (15) years), 35 white women (mean age 36 (10) years), 8 Indian women (mean age 32 (6) years) and 7 coloured women (mean age 31 (13) years), were also collected. The healthy donors were staff members and students from CMJAH, where the study was undertaken. All donors signed informed consent. Ethical approval for the study was obtained through the Human Research Ethics Committee, University of the Witwatersrand, Johannesburg (M110248).

study. In brief, 0.5 mL of heparinised blood was added to 4.5 mL of RPMI 1640 (Bio­ Whittaker, USA) supplemented with 13% fetal bovine serum (Gibco-Invitrogen, USA), and antibiotics (50 U/mL penicillin and 50 mg/mL streptomycin; Gibco-Invitrogen, USA). The medium was pre-warmed to 37°C and gassed (5% CO2/95% air). Culture flasks with blood and medium were irradiated with doses of 2 Gy or 4 Gy of X-rays using a 6 MV photon beam from a medical linear accelerator (Siemens Healthcare, Germany).

A 0 Gy dose was used as a sham-irradiated control. For each dose point, two cultures were set up. Immediately after irradiation the lymphocytes were stimulated with 100 µL phytohaemagglutinin (stock solution 1 mg/ mL; Sigma-Aldrich, USA), and 23 hours

Table 1. Spontaneous and radiation-induced MN values in breast cancer patients and healthy controls, according to ethnicity Group

Patients

Controls

30

20

14 (8)*

10 (4)

Black

p-values

n MN/1 000 BN cells, mean (SD) 0 Gy

0.0087

2 Gy

179 (30)*

159 (31)

0.0273

4 Gy

498 (91)*

449 (66)

0.0324

25

35

White

n MN/1 000 BN cells, mean (SD) 0 Gy

16 (7)*

11 (4)

0.0083

2 Gy

172 (24)*

158 (23)

0.0253

4 Gy

507 (79)*

443 (35)

0.0006

6

7

Coloured n MN/1 000 BN cells, mean (SD) 0 Gy

12 (9)

12 (7)

0.6043

2 Gy

193 (49)

169 (20)

0.4697

4 Gy

487 (103)

444 (51)

0.5281

7

8

11 (6)

11 (5)

Indian n MN/1 000 BN cells, mean (SD) 0 Gy

0.8427

2 Gy

172 (28)

177 (34)

0.8000

4 Gy

467 (91)

470 (74)

0.9305

68

70

14 (7)*

11 (5)

All groups n MN/1 000 BN cells, mean (SD) 0 Gy

Irradiations and micronucleus assay

The protocol for the micronucleus assay described by Herd et al.[10] was used in this

later 20 µL cytochalasin B (stock solution of 1.5 mg/mL; Sigma-Aldrich) was added to block cytokinesis. Cells were harvested at 70 hours after stimulation using a cold (4°C) hypotonic shock with 7 mL 0.075M KCl (Merck, Germany). This was followed by fixation in methanol:acetic acid:Ringer (0.9% NaCl) solution (4:1:5) (Merck).

Fixed cell suspensions were dropped on coded slides and stored at 4°C. Slides were mounted with Vectashield containing DAPI (4,6-diamidino-2-phenylindole; Vector Lab­ oratories, USA) before being scanned auto­ matically with the Metafer 4 system. The classifier and scoring method was based on Herd et al.[10] Each dose point was scored by at least two scorers. All results were normalised to an MN frequency in 1 000 BN

2 Gy

177 (30)*

161 (27)

0.0014

4 Gy

497 (86)*

448 (52)

0.0001

*Significantly different from controls.

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0.0012

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12

6

10 8

Individuals, n

Individuals, n

8

4 2 0

6 4 2

32 0 36 0 40 0 44 0 48 0 52 0 56 0 60 0 64 0 68 0

32 0 36 0 40 0 44 0 48 0 52 0 56 0 60 0 64 0 68 0

0 MN/1 000 BN cells

MN/1 000 BN cells

Coloured population

Indian population 4 Individuals, n

4 3 2 1

3 2 1 0

0 MN/1 000 BN cells

32 0 36 0 40 0 44 0 48 0 52 0 56 0 60 0 64 0 68 0

Individuals, n

The results obtained with the micronucleus assay on the samples of 68 breast cancer patients and 70 healthy individuals are presented in Table 1. The mean spontaneous MN yields of all the breast cancer patients were significantly higher than those of the healthy controls (p<0.005). The spontaneous MN yields were significantly correlated with the age of the healthy individuals, but this correlation could not be observed in the breast cancer patient group (p<0.005).

To investigate whether ethnicity had an influence on chromosomal radiosensitivity, we split the breast cancer patients and the healthy controls into four subgroups (black, white, coloured and Indian). When the patients and controls were grouped according to their ethnicity, the significantly higher number of spontaneous MN was only seen in the black and white patients compared with the healthy individuals of the same ethnicity.

The radiation-induced MN yield was calculated by subtracting the spontaneous yield from the yield in the irradiated cells. For the whole group of breast cancer patients, the mean MN yields were significantly higher than in the whole group of healthy individuals for both 2 Gy and 4 Gy irradiations. Grouping the samples according to their ethnicity revealed significantly higher radiation-induced MN values in the black and white breast cancer patients for both 2 Gy and 4 Gy. This could not be observed in the coloured and Indian subgroups (Table 1). Histograms of radiation-induced MN after 4 Gy for the four ethnic subgroups are presented in Fig. 1. The MN distribution after 2 Gy showed similar patterns for the four subgroups (data not shown). Although no significant differences

White population

32 0 36 0 40 0 44 0 48 0 52 0 56 0 60 0 64 0 68 0

Results

Black population

MN/1 000 BN cells

Fig. 1. Distribution of MN yields after 4 Gy of breast cancer patients and healthy individuals. (Dark blue bars = breast cancer patients; light blue bars = healthy individuals.)

600 500 MN/1 000 BN cells

cells. Radiation-induced MN values were obtained by subtracting baseline (0 Gy dose) values from those obtained in irradiated samples.

Statistical analysis was performed with Graphpad Prism 6. Differences between means of MN yields of patients and controls in black and white populations were tested for significance with the unpaired Student’s t-test. For comparison of differences in MN values in the Indian and coloured subgroups, and between ER receptor subgroups, the Mann-Whitney U-test was applied. This test is used for small sample sizes. To analyse the correlations between age, clinical parameters and MN values, we used Pearson’s correlation coefficient. The confidence level of the statistical tests was 95%, and statistical significance was set at p<0.05.

400 300

Receptor-negative Receptor-positive

200 100 0

2 Gy

4 Gy ER

2 Gy

4 Gy PR

2 Gy

4 Gy

HER2

Receptor status Fig. 2. Radiation-induced MN values of breast cancer patients grouped according to receptor status. (*Significantly different from the receptor-negative group.)

in mean MN values could be seen in the coloured group, there was a shift of values towards the higher range. This shift was not noted in the Indian population.

All the breast cancer patients were also split into groups according to clinical parameters, and MN values in these groups were compared. No significant correlation

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August 2015, Vol. 105, No. 8

could be found between clinical parameters (tumour histological type, size and staging) and MN yields of the breast cancer patients.

There was an effect of ER positivity on the MN yields (Fig. 2). Breast cancers positive for ER receptors had significantly higher radiationinduced MN values than ER-negative breast cancers for both 2 Gy and 4 Gy (ER-positive

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185 MN/1 000 BN cells (2 Gy), 518 MN/1 000 BN cells (4 Gy); ER-negative 159 MN/1 000 BN cells (2 Gy), 468 MN/1 000 BN cells (4 Gy)) (p=0.0031 and p=0.044, respectively).

Discussion

This study investigated whether SA breast cancer patients are more sensitive than healthy individuals to DNA damage caused by ionising radiation. Since differences in breast tumour characteristics are noted between ethnic populations, we also evaluated the possible differences of chromosomal radiosensitivity in the four SA ethnic groups.

Higher spontaneous mean MN frequencies, which were seen in breast cancer patients in this study, have been linked with higher levels of genetic instability. These significantly higher mean MN values occurred mainly in the white and black patients, who had significantly higher MN values than controls of the same ethnicity.

The higher ages of the cancer patients, which is a limitation in our study, could have played a role in the elevated spontaneous MN values; Thierens et al.[11] have suggested an increase of 0.58 MN/ year. The higher levels of spontaneous MN in the breast cancer patients could also suggest higher chromosomal instability, which is associated with an increased risk of cancer.

The higher chromosomal radiosensitivity observed in the whole group of SA breast cancer patients and in the white patients in this study is in agreement with several international studies. It is interesting that the significantly higher MN values were also seen in black breast cancer patients, who have never been studied for chromosomal radiosensitivity with the micronucleus assay. This trend is in contrast with a study performed by Wang et al.,[12] who looked at chromatid breaks in young breast cancer patients and noted significantly higher chromatid breaks in white American breast cancer patients than white controls, but not in African-American breast cancer patients compared with black controls.

The MN values of the coloured patients and controls were not significantly different, although higher MN values were observed in the patients. However, the small sample size of this subgroup limits conclusions. The other small subgroups were the Indian patients and controls, between whom no differences in mean MN values were found.

Black African breast cancer patients are known to have more aggressive tumour phenotypes than white women, and a higher prevalence of triple-negative and premenopausal breast cancers.[8,9] These differences were not reflected in differences in chromosomal radiosensitivity of white and black breast cancer patients in our study. We found no correlation between the MN values and most of the clinical parameters investigated, which is in agreement with Baeyens et al.[13] There was an effect of ER status on MN values, with ER-positive women having significantly higher MN values. A similar trend was observed in the study of Riches et al.,[14] where patients with increased G2 radiosensitivity had a higher proportion of ER-positive tumours. The underlying reason for the higher radiation-induced MN in this type of breast cancer is unknown, but it could be based on interactions between the double-strand break repair kinase DNA-PK and ERs.[15] The link between ERs and MN could suggest

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a prognostic value of the micronucleus assay for ER-positive breast cancers. Black and coloured women with breast cancer have a higher incidence of ER-negative cancers,[8,9] which could have led to lower MN values in these groups. However, we did not observe this in our study. Enlarging the sample sizes and subgrouping the cancer patients into ethnic groups and into ER-positive and negative patients could provide greater insight.

Conclusion

Our results showed that SA breast cancer patients have elevated chromosomal radiosensitivity compared with healthy controls. The presence of ER positivity also influenced this radiosensitivity. More rigorous extended studies on the different ethnic groups are needed to validate our findings and to unravel the underlying mechanisms.

Acknowledgments. This research was supported by a grant of the South African Medical Research Council, by a ‘VLIR Own Initiative Programme’ between Belgium and SA (ZEIN2011PR387), and by a grant under the Nuclear Technologies in Medicine and the Biosciences Inititiative (NTeMBI), a national technology platform developed and managed by the SA Nuclear Energy Corporation and supported by the Department of Science and Technology, SA. The authors thank all the patients and healthy individuals who participated in this study.

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2. Statistics South Africa. Mid-year population estimates. 2014. http://beta2.statssa.gov.za. (accessed 29 October 2014).

3. Porter P. ‘Westernizing’ women’s risks? Breast cancer in lower-income countries. N Engl J Med 2008;358(3):213-216. [http://dx.doi.org/10.1056/NEJMp0708307] 4. Igene H. Global health inequalities and breast cancer: An impending public health problem for developing countries. Breast J 2008;14(5):428-434. [http://dx.doi.org/10.1111/j.15244741.2008.00618.x] 5. Jeggo P, Lavin MF. Cellular radiosensitivity: How much better do we understand it? Int J Radiat Biol 2009;85(12):1061-1081. [http://dx.doi.org/10.3109/09553000903261263] 6. Bonassi S, Znaor A, Ceppi M, et al. An increased micronucleus frequency in peripheral blood lymphocytes predicts the risk of cancer in humans. Carcinogenesis 2007;28(3):625-626. [http://dx.doi. org/10.1093/carcin/bgl177] 7. Cardinale F, Bruzzi P, Bolognesi C. Role of micronucleus test in predicting breast cancer susceptibility: A systematic review and meta-analysis. Br J Cancer 2012;106(4):780-790. [http://dx.doi.org/10.1038/ bjc.2011.567] 8. Herd O, Francies F, Cairns A, Muller X, Slabbert JP, Baeyens A. Ethnical differences in breast cancer characteristics in South African population. Breast J 2015;21(4):447-449. [http://dx.doi.org/10.1111/ tbj.12434] 9. Dickens C, Duarte R, Zietsman A, et al. Racial comparison of receptor-defined breast cancer in Southern African women: Subtype prevalence and age-incidence analysis of nationwide cancer registry data. Cancer Epidemiol Biomarkers Prev 2014;23(11):2311-2321. [http://dx.doi.org/10.1158/10559965.EPI-14-0603] 10. Herd O, Francies F, Kotzen J, et al. Chromosomal radiosensitivity of HIV positive/negative cervical cancer patients in South Africa. Molecular Oncology Reports 2015 (in press).

11. Thierens H, Vral A, Morthier R, Aousalah B, de Ridder L. Cytogenetic monitoring of hospital workers occupationally exposed to ionizing radiation using the micronucleus centromere assay. Mutagenesis 2000;15(3):245-249. [http://dx.doi.org/10.1093/mutagen/15.3.245] 12. Wang LE, Han CH, Xiong P, et al. Gamma-ray-induced mutagen sensitivity and risk of sporadic breast cancer in young women: A case-control study. Breast Cancer Res Treat 2012;132(3):1147-1155. [http:// dx.doi.org/10.1007/s10549-011-1940-1] 13. Baeyens A, Thierens H, Claes K, et al. Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition. Br J Cancer 2002;87(12):1379-1385. [http://dx.doi. org/10.1038/sj.bjc.6600628] 14. Riches AC, Bryant PE, Steel CM, et al. Chromosomal radiosensitivity in G2-phase lymphocytes identifies breast cancer patients with distinctive tumour characteristics. Br J Cancer 2001;85(8):11571161. [http://dx.doi.org/10.1054/bjoc.2001.2086] 15. Medunjanin S, Weinert S, Schmeisser A, Mayer D, Braun-Dullaeus RC. Interaction of the doublestrand break repair kinase DNA-PK and estrogen receptor-alpha. Mol Biol Cell 2010;21(9):1620-1628. [http://dx.doi.org/10.1091/mbc.E09-08-0724]

Accepted 1 April 2015.

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Human papillomavirus genotypes and clinical management of genital warts in women attending a colposcopy clinic in Cape Town, South Africa S Tayib,1,2 MB ChB, MMed (O&G), Fellowship in Gynaecology Oncology (Malaysia); B Allan,3 MSc; A-L Williamson,3,4 PhD; L Denny,2 MB ChB, MMed (O&G), PhD, FCOG (SA) epartment of Obstetrics and Gynaecology, Hospital Pulau Pinang, Penang, Malaysia D Gynaecological Oncology Unit, Department of Obstetrics and Gynaecology, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 3 Institute of Infectious Disease and Molecular Medicine and Division of Medical Virology, Faculty of Health Sciences, University of Cape Town, South Africa 4 National Health Laboratory Service, Cape Town, South Africa 1 2

Corresponding author: S Tayib (syarq@yahoo.com)

Background. Genital human papillomavirus (HPV) infection is the most common sexually transmitted viral disease in the world. HPV infection of the genital epithelium is associated with genital warts and malignancies of the lower genital tract.

Objectives. To describe the distribution, phenotypic appearance and HPV type associated with genital warts in women.

Methods. This was a prospective observational study of all women with genital warts who attended the Colposcopy Clinic, Groote Schuur Hospital, Cape Town, South Africa, during 2010 and fulfilled the inclusion and exclusion criteria. One hundred and thirteen women were tested for HPV using the Roche Linear Array HPV genotyping kit to determine the HPV genotypes causing genital warts.

Results. The median age of the women was 27 years (range 15 - 53); 90 (79.6%) were HIV-positive, and two-thirds were on antiretroviral treatment. Treatment involved ablation with topical agents, cauterisation or carbon dioxide laser. At 3 months’ follow-up after treatment, 56.6% of the women, the majority of whom were HIV-positive, had recurrent/persistent disease. In both HIV-positive and HIV-negative women, HPV was detected in over 90% of cases. However, over half the HIV-positive women as opposed to 2/18 of the HIV-negative women were infected with multiple HPV genotypes. The commonest HPV genotypes in HIV-positive and HIV-negative women were types 11, 6, 89, 61, 55 and 62 and types 11 and 6, respectively.

Conclusions. The majority of the patients were HIV-positive and had multiple HPV infections. While this did not alter the phenotypic appearance of the warts, recurrence/persistence after treatment was more common.

S Afr Med J 2015;105(8):679-684. DOI:10.7196/SAMJnew.7890

Genital human papillomavirus (HPV) infection is the most common sexually transmitted viral disease in the world.[1,2] HPV infection of the genital epithelium is associated with a range of diseases, including genital warts and cancers of the cervix, vagina, vulva, anus and penis and their precursors. However, HPV infection may exist in the latent form in apparently normal epithelium.[3,4] Genital warts are typically associated with low-risk HPV genotypes, most commonly HPV types 6 and 11.[5] However, recent studies have shown that 20 - 50% of genital warts may be co-infected with high-risk HPV types associated with malignancy.[6,7] Although genital warts are not life-threatening, they cause significant psychosocial harm, including low self-esteem, negative self-perception, embarrassment and anxiety.[8,9] Genital warts represent a health problem for the individual, and carry a significant economic burden for society owing to their generally poor response to conventional therapies and the need for multiple therapeutic interventions.[9] Immunisation against high-risk HPV types to prevent cervical cancers is likely to have a positive public health impact in the future. In addition, the quadrivalent vaccine, which has been approved for use in males and females aged 9 - 26 years, protects against the HPV types that cause 90% of genital warts (i.e. types 6 and 11).[4] Genital warts are a common reason for referral to the Colposcopy Clinic at Groote Schuur Hospital (GSH), a tertiary hospital serving

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the Cape Town area and the Western Cape Province, South Africa.

We undertook this study to examine the nature of the disease, seeking particularly to determine the rate of recurrence after treatment, the response to various therapies using trichloroacetic acid (TCA), electrocautery and carbon dioxide laser, and the HPV genotypes associated with genital warts in women referred to our clinic.

Objectives

To describe the demographic features of women diagnosed with genital warts, the characteristics of genital warts seen and treatment modalities used, and to determine the type of HPV infections associated with warts according to HIV status and response to treatment at 3 months.

Methods

Study design

This was a prospective observational study performed over a 6-month period (1 April - 30 September 2010). Subjects were recruited from women diagnosed with genital warts referred to the Colposcopy Clinic at GSH. Those who were pregnant or unable to undergo gynaecological examination were excluded.

Written informed consent was obtained from all participants in their home language (English, Afrikaans or Xhosa), with subsequent back-translation to ensure accuracy. Approval for the study was

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obtained from the Human Research Ethics Committee of the University of Cape Town and the GSH Bioethics Unit. Separate consent was sought for photographing the warts.

At enrolment, each participant was interviewed using a structured questionnaire. A urine pregnancy test was performed prior to clinical examination if the patient had been amenorrhoeic for more than a month and/or was not using contraception. All participants had a detailed examination of the anogenital area, and a macroscopic photograph of the lesions was taken. Cervical and anal smears were taken during colposcopy, which was followed by detailed examination of the cervix, vagina, vulva and anus. Any acetowhite areas observed during colposcopy of the cervix and any macroscopically visible anogenital warts were biopsied for histological investigation. The anal smears were not examined for this study. All patients received serological screening for HIV and syphilis. Those confirmed as HIV-positive had CD4 cell counts and HIV viral load determined in accordance with HIV management guidelines at the time of the study.

HPV analysis

HPV DNA analysis was performed at the Institute of Infectious Disease and Molecular Medicine, University of Cape Town. All biopsy specimens for HPV DNA analysis were given a unique identification number that was matched to the participant’s data and was only known to the principal investigator. The specimens were each placed in a separate container with the specific identification number and collected by the testing laboratory on a daily basis. When the sample was appropriately sized, the Qiagen DNA extraction mini-kit (cat. 51304) was used to complete extraction. For biopsy samples in excess of the recommended size, the Qiagen protocol was used only to provide a first-step digestion lysate of tissue. Anogenital wart biopsy DNA was subjected to HPV typing employing the Roche Linear Array HPV genotyping kit (testing for HPV types 11, 16, 18, 26, 31, 33, 35, 39, 40, 45, 51, 52, 53, 54, 55, 58, 59, 61, 62, 66, 68, 70, 72, 73, 81, 82, 83, 84 and 89) according to the manufacturer’s instructions (Roche Molecular Systems, USA).

The HPV target DNA for amplification was a 450-bp fragment of the L1 region. To confirm sample quality and the DNA extraction process, a second target was a 268-bp fragment of the human β-globin gene. A sample was considered adequate if it was β-globin-positive (internal control) or β-globin-negative but HPV DNA-positive.

Pathology

Cervical cytology and biopsy specimens for histological confirmation were interpreted by pathologists at the GSH pathology laboratory.

The pathologists examining the specimens were not blinded as to the HIV status of the participants.

Treatment modalities

All participants received treatment based on the morphology and distribution of lesions. The lesions were classified as small, moderate, and large or extensive. Small lesions referred to multiple small warts around the genitalia of diameter <0.5 cm, moderate lesions to warts with diameter 0.5 - 1.0 cm, and large or extensive lesions to a perineum infiltrated by warts.

Treatments involved topical application of TCA; electrocautery or excision under local or general anaesthesia; or ablation with a CO2 laser under general anaesthesia, depending on the size of the warts.

Women with small warts received topical treatment with TCA and were advised to attend weekly until no visible lesions were seen.

Women with warts of moderate size were treated with electrocautery under local anaesthesia in the clinic setting. Women requiring

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general anaesthesia for excision of large or extensive warts or CO2 laser were given a date for admission to the ward for laser ablation and surgery.

All patients were seen after treatment for follow-up assessment of their response. The wart(s) were categorised as recurrent if recurring 3 months after treatment, or persistent if recurring less than 3 months after treatment. Patients who were found to be HIV-positive were referred to a social welfare officer for post-test counselling and subsequently referred for management at their local HIV clinic for initiation of antiretroviral treatment (according to the 2010 Clinical Guidelines on the Management of HIV and AIDS in Adults and Adolescents of the National Department of Health, SA[10]).

Data collection and statistical analysis

To guarantee confidentiality, all participants were allocated a unique study number. Data obtained were entered into an anonymous database and data analysis was performed using SPSS Statistical Software, version 19.

Ethical considerations

Ethical approval was obtained from the Research Ethics Committee of the Faculty of Health Sciences, University of Cape Town (Ref. 131/2010).

Results

A total of 156 patients (mean age 27 years, range 15 - 53) partici­ pated in the study. Ninety-four patients (60.3%) were new cases, 40 (25.6%) were recurrent cases and 22 (14.1%) had been treated previously but had persistent disease. Table 1 summarises the demographic and clinical characteristics of the participants. More than 50% of the women were single (not legally married) but sexually active. The majority (n=128, 82.1%) had had their first sexual encounter before the age of 20 years, often between the ages of 15 and 19.

The majority of the women (123/156, 78.8%) were HIV-positive (Table 1). Four patients declined HIV screening and were categorised as ‘HIV status unknown’. Of the HIV-positive women, 83/123 (67.5%) were already on antiretroviral therapy with a median CD4 count of 356 cells/µL (range 22 - 483).

Table 2 shows the modalities of treatment administered. Local ablation with TCA and electrocautery under local anaesthesia were performed on patients with lesions of small to moderate size. Patients with large and extensive lesions received CO2 laser. The average length of hospital stay for these patients was 5.1 days (range 1 - 7) owing to poor home circumstances and requirement for wound care.

Histological examination confirmed genital warts in 154 patients.

Two of the 156 specimens (1.3%) were reported as invasive squamous cell carcinoma, and these patients were treated with radical wide local excision of the lesions and groin node dissection. Both were HIV-positive.

One hundred and thirteen of the 156 specimens were successfully investigated for HPV with positive β-globin tests.

Of these 113 specimens, 7 (6.2%) had no detectable HPV DNA. Table 3 shows the relationship between HPV DNA detection and HIV status. Of 106 HPV DNA-positive patients, 85 (80.2%) were HIV-positive.

Table 4 shows the association between HPV DNA status and cervical cytological abnormalities. Seventy of 106 HPV DNApositive women (66.0%) had cervical cytological abnormalities noted: high-grade squamous intraepithelial lesions (HSILs) in 8.5% (9/106) and low-grade squamous intraepithelial lesions (LSILs) in

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Table 1. Demographic features and clinical parameters of study participants* New (N=94) n (%)

Demographics/clinical parameters

Recurrent (N=40) n (%)

Persistent (N=22) n (%)

Total (N=156) n (%)

Marital status

p-value 0.118

Single, not sexually active

19 (63.3)

6 (20.0)

5 (16.7)

30

Single, sexually active

56 (60.9)

27 (29.3)

9 (9.8)

92

Married

13 (62.0)

4 (19.9)

4 (19.0)

21

Separated/divorced/widow

6 (46.2)

3 (23.0)

4 (30.8)

13

â&#x2030;¤14

9 (75.0)

2 (16.7)

1 (8.3)

12

15 - 19

69 (59.5)

33 (28.4)

14 (12.1)

116

â&#x2030;Ľ20

16 (59.3)

5 (18.5)

6 (22.2)

27

Virgo intacta

-

-

1 (100.0)

1

Primary

13 (81.3)

-

4 (18.7)

16

Secondary

67 (57.8)

36 (31.0)

13 (11.2)

116

Tertiary

14 (58.3)

4 (16.7)

6 (25.0)

24

Yes

9 (56.3)

3 (18.8)

4 (24.9)

16

No

77 (61.1)

34 (27.0)

15 (11.9)

126

Previously

8 (57.2)

3 (21.4)

3 (21.4)

14

Age at first sexual exposure (years)

0.184

Level of education

0.034

Smoking

0.579

Alcohol consumption

0.273

Yes

13 (54.2)

5 (20.8)

6 (25.0)

24

No

76 (60.3)

35 (27.8)

15 (11.9)

126

Previously

5 (83.3)

-

1 (16.7)

6

Use of drugs/snuff

0.836

Yes

1 (100.0)

-

-

1

No

92 (60.1)

39 (25.5)

22 (14.4)

153

Previously

1 (50.0)

1 (50.0)

-

2

HIV status

0.305

Positive

71 (57.7)

36 (29.3)

16 (13.20

123

Negative

21 (72.4)

3 (10.3)

5 (17.3)

29

Unknown

2 (50.0)

1 (25.0)

1 (25.0)

4

*Other than level of education (p=0.034), there were no significant associations between marital status, age at first sexual exposure, smoking, alcohol consumption, use of drugs/snuff and HIV status, and new, recurrent or persistent disease.

Table 2. Treatment modalities administered

Treatment

New (N=94) n (%)

Recurrent (N=40) n (%)

Persistent (N=22) n (%)

Total (N=156) n (%)

Local ablation with TCA

7 (63.6)

2 (18.2)

2 (18.2)

11 (7.1)

Electrocautery under LA

68 (62.4)

28 (25.7)

13 (11.9)

109 (69.9)

Electrocautery/CO2 laser under GA

17 (51.5)

9 (27.3)

7 (21.2)

33 (21.2)

LA = local anaesthesia; GA = general anaesthesia.

52.8% (56/107). Thirty-six of 106 patients with HPV DNA-positive warts (34.0%) had normal cervical cytological findings.

Women with cervical abnormalities

were subsequently recalled and managed according to standard clinical protocols.

Of the 7 women with no HPV DNA detectable from biopsied genital warts, 2 had

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LSILs, 4 had normal cytological findings, and 1 had no cervical cytology performed (virgo intacta).

Table 5 shows the HPV genotypes detected from anogenital warts. The ten most frequent types detected were HPV 11, 6, 89, 61, 55, 62, 81, 16, 18 and 45. HPV genotypes 6 and 11 were the most common genotypes encountered in both HIV-positive and negative women. In addition to the most prevalent genotypes 6 and 11, HIV-positive cases yielded types 16, 18, 31, 33, 35, 39, 40, 45, 51, 52, 53, 54, 55, 58, 59, 61, 62, 66, 68, 70, 72, 73, 81, 82, 83, 84 and 89.

Fifteen of 85 HIV-positive women who were HPV DNA-positive (17.6%) were co-infected with HPV 16 and 18, among other types.

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Of the 106 women who were positive for HPV DNA, 58 (54.7%) had a single genotype identified. Co-infection with more than one genotype was detected in 43/85 HIV-positive women (50.6%) as opposed to 3/18 HIVnegative women (16.7%). This difference was statistically not significant (p=0.771), possibly owing to the small number of HIVnegative cases. Among the HIV-positive cases, 15 genotypes were detected from one patient and 11 genotypes from two patients.

The maximum number of HPV genotypes detected from HIV-negative women was three, detected in two specimens. One of the two specimens with histological confirmation of invasive squamous cell carcinoma was available for HPV typing and had seven HPV types detected (HPV 11, 16, 53, 55, 61, 62 and 89).

Fifty-three of 113 women for whom HPV analysis could be performed (46.9%) returned for follow-up 3 months after treatment. Of this group, 35 (66.0%) were HIV- and HPV DNA-positive and 13 (24.5%) were HIV-negative but HPV DNA-positive (Table 6). The majority of recurrences at 3 monthsâ&#x20AC;&#x2122; follow-up were in HIV-positive women (26/30, 86.7%). In the HIV- and HPV DNA-positive group, 25 women (71.4%) had recurrent genital warts compared with three women (23.1%) in the HIV-negative, HPV DNA-positive group (p=0.114). Recurrent genital warts were seen more often in women with more than one HPV genotype initially detected (40%, 10/40) than in those with a single detectable genotype (60%, 15/25) (p=0.172).

The most common HPV types detected were HPV 11 (54.7%, 58/106) and HPV 6 (39.6%, 42/106). Three women had dual HPV 6 and HPV 11 infection. Of note, 39/106 (36.8%) of women were infected with high-risk HPV types such as 16, 18, 31, 33, 35, 39, 45 and 51. Only nine women (8.5%) had no infection with either HPV 6 or 11.

Discussion

It is well known that persistent infection with HPV is a necessary precursor for the development of cervical cancer. Infection with HPV is also associated with genital warts and other types of anogenital neoplasia, including penile, anal and oropharyngeal tumours.[11] Although genital warts are not life threatening, they are common and cause considerable psychosocial and sexual morbidity.[9] Genital warts in both men and women are readily transmitted, have a high recurrence rate after treatment, and cause local pain and discomfort.[9,12] Treatment for genital warts also requires multiple clinical visits associated with increased cost. In the

Table 3. HPV DNA detection in genital warts according to HIV status*

HPV DNA

HIV-positive (N=90) n (%)

HIV-negative (N=20) n (%)

HIV status unknown (N=3) n (%)

Total (N=113) n (%)

HPV DNA-positive

85 (80.2)

18 (17.0)

3 (2.8)

106 (93.8)

HPV DNA-negative

5 (71.4)

2 (28.6)

-

7 (6.2)

*p=0.684 (statistically not significant).

Table 4. Correlation of HPV DNA detection with cervical cytological findings

Cytological results

HPV DNA-positive (N=106) n (%)

HPV DNA-negative (N=6) n (%)

Total (N=112)* n (%)

Normal

36 (34.0)

4 (66.7)

40 (35.7)

LSIL

56 (52.8)

2 (33.3)

58 (51.8)

HSIL

9 (8.5)

-

9 (8.0)

ASCUS

5 (4.7)

-

5 (4.5)

ASCUS = atypical squamous cell of undetermined significance. *Number of Pap smears was 112 because one patient was virgo intacta and did not have a Pap smear performed.

Table 5. HPV genotypes identified in genital warts Commonest HPV genotypes isolated

HIV-positive (N=85) n (%)

HIV-negative (N=21) n (%)

Total (N=106)* n (%)

11

46 (82.1)

10 (17.9)

56

6

32 (78.0)

9 (18.0)

41

89

19 (100.0)

-

19

61

16 (94.1)

1 (5.9)

17

55

12 (100.0)

-

12

62

12 (100.0)

-

12

81

9 (90.0)

1 (10.0)

10

16

8 (100.0)

-

8

18

8 (100.0)

-

8

45

8 (100.0)

-

8

53

8 (100.0)

-

8

83

8 (100.0)

-

8

66

6 (100.0)

-

6

51

5 (100.0)

-

5

52

5 (100.0)

-

5

58

5 (100.0)

-

5

59

5 (100.0)

-

5

72

5 (100.0)

-

5

39

4 (100.0)

-

4

68

4 (100.0)

-

4

40

3 (100.0)

-

3

73

3 (100.0)

-

3

31

2 (100.0)

-

2

33

2 (100.0)

-

2

84

2 (100.0)

-

2 Continued ...

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Table 5. (continued) HPV genotypes identified in genital warts Commonest HPV genotypes isolated

HIV-positive (N=85) n (%)

HIV-negative (N=21) n (%)

Total (N=106)* n (%)

35

1 (100.0)

-

1

54

1 (100.0)

-

1

70

1 (100.0)

-

1

82

1 (100.0)

-

1

26

-

1 (100.0)

1

*The 3 patients with unknown HIV status are excluded from this table; 2 of them had HPV 11 and 1 HPV 6.

Table 6. Follow-up at 3 months according to HIV and HPV DNA status

HPV DNA

HIV-positive n (%)

HIV-negative n (%)

HIV status unknown

Total (N=53) n (%)

Positive

35/53 (66.0)

13/53 (24.5)

-

48 (90.6)

Negative

3/53 (5.7)

2/53 (3.8)

-

5 (9.4)

USA, the cost was highest in young adults (USD 1 717/1 000 person-years) for women aged 15 - 24 years.[13]

Main findings

In this study, the mean age of the patients recruited was 27 years; 63 (40.4%) were aged ≤25. This is consistent with the known prevalence of HPV infection, which peaks at age 15 - 25 years.[4] A number of studies show that the occurrence of genital warts is strongly linked with sexual behaviour, and more weakly associated with cigarette smoking.[14] More than 80% of patients in this study were sexually active, and 80.1% had had more than one sexual partner. However, only 19.2% were current or ex-smokers. It has been postulated that cigarette smoking is associated with more risky sexual behaviours, and biologically with decreased S-100 and CD1a-positive Langerhans cells in the cervical epithelium. [14] It is well known that HIV infection is an important risk factor for HPV infection and persistence. HIV-seropositive women are at increased risk of contracting HPV infection and developing HPV-related preinvasive and invasive lesions compared with their seronegative counterparts.[3,4] In addition, HIV-seropositive women have a high rate of persistent HPV infection with high-risk HPV genotypes (16 and 18),[5] which are responsible for 70% of cervical cancers.

In this study, the majority of the patients (n=123, 78.9%) were HIV-positive. HIV seropositivity and HIV-induced immune suppression are known to be associated with an increased prevalence of anogenital

HPV infections in men and women. This association involves HPV infection of all types, as well as infections with multiple types of HPV, including the oncogenic types.[15] Our study showed that HIVinfected women not only had genital warts with more HPV genotypes, with the maximum number being 15 in one patient, but also had multiple oncogenic types of HPV. HPV types 6 and 11 were detected in most cases (85.8%). The role of the other HPV types in the pathogenesis of genital warts is unknown. It is also not clear what the implications are in terms of HPV vaccination, as this raises the question as to whether the other types will also cause genital warts.

Study strengths and limitations

The strength of this study is that it was conducted prospectively, with detailed documentation of the clinical diagnosis of genital warts by one clinician. Limitations include the short follow-up period of only 3 months, with a significant number of patients lost to follow-up. Furthermore, these data refer to a group of women referred specifically for genital warts and cannot be considered to be representative of the general population.

Interpretation

Our data show that HIV-infected women have a high incidence of HPV infection and infection with multiple types of HPV, including high-risk types. Recently, some investigators have suggested that HPV infection is a risk factor for HIV transmission. Lissouba et al.,[16] in their

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systematic review and meta-analysis of 2 601 abstracts, six observational studies and 6 567 participants, found that HIV acquisition was significantly associated with HPV infection (summary odds ratio (OR) 1.96; 95% confidence interval (CI) 1.55 - 2.49). HIV incident infection was significantly associated with high-risk HPV in five of six studies and with low-risk HPV in two out of five. The association was significant for high-risk HPV (summary OR 1.92; 95% CI 1.49 - 2.46) and borderline for low-risk HPV. However, our study was not designed to evaluate the impact of HPV infection on HIV transmission. This study showed that HIV co-infection is a risk factor for infection with multiple HPV genotypes.

Conclusions

There was a high rate of HIV positivity among women with genital warts recruited into the study. HPV-associated disease is likely to become a major clinical issue in HIV-positive women, because: (i) both HPV and HIV viruses are transmitted sexually; and (ii) clearance of HPV infection relies on functional cell-mediated immunity, precisely the immune system attacked by HIV infection. There is an urgent need for effective strategies for management of HPV-associated disease in HIV-positive women. This may be achieved through extensive public education programmes on the prevention and transmission of HPV, as well as HIV and HPV vaccination. HPV vaccination with the quadrivalent vaccine (Gardasil; Merck, USA) has recently been shown to significantly reduce the incidence of genital warts in individuals less than 21 years of age in Australia and New Zealand.[17,18] Acknowledgements. We thank all staff members of the GSH Colposcopy Clinic.

Conflict of interest. ST: none; BA: none; ALW: none; LD: has received honoraria for appearing on various speaker forums on HPV vaccination from GlaxoSmithKline and MSD/Merck and has received research funding from both organisations.

Contributions to authorship. ST: study design, data collection and analysis, data interpretation, writing of manuscript and literature search; BA: performed HPV typing tests, data collection and analysis, data interpretation, writing of manuscript; ALW: head of HPV testing laboratory, data interpretation and writing of manuscript; LD: study design, data collection and analysis, data interpretation and writing of manuscript

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Funding. This study was supported by a research grant from InvestigatorInitiated Studies Program of Merck Sharp & Dohme. The opinions expressed in this article are those of the authors and do not necessarily represent those of Merck Sharp & Dohme. This work was also partially based upon research supported by the South African Research Chairs Initiative of the Department of Science and Technology and the National Research Foundation.

References 1. Kjaer SK, Tran TN, Sparen P, et al. The burden of genital warts: A study of nearly 70000 women from general female population in the 4 Nordic countries. J Infect Dis 2007;196(10):1447-1454. [http:// dx.doi.org/10.1086/522863] 2. Hagensee ME. Infection with human papillomavirus: Update on epidemiology, diagnosis and treatment. Curr Infect Dis Rep 2000;2(1):18-24. [http://dx.doi.org/10.1007/s11908-000-0083-z] 3. Singer A, Monaghan JM, Quek SC, Deery ARS. Human papillomaviruses in pathogenesis of lower genital tract neoplasia (chapter 2). In: Singer A, Monaghan JM, Quek SC, Deery ARS, eds. Lower Genital Tract Precancer: Colposcopy, Pathology and Treatment. 2nd ed. London: Blackwell Publishing, 2000:15-33. [http://dx.doi.org/10.1002/9780470760093] 4. Lacey CJ. Genital warts and anogenital papillomavirus disease. Medicine 2010;38(6):271-275. [http:// dx.doi.org/10.1016/j.mpmed.2010.02.003] 5. Sun XW, Kuhn L, Ellerbrock TV, Chiasson MA, Bush TJ, Wright TC. Human papilloma virus infection in women infected with the human deficiency virus. N Engl J Med 1997;337(19):1343-1349. [http:// dx.doi.org/10.1056/NEJM199711063371903] 6. Lacey CJ. Therapy for genital human papillomavirus-related disease. J Clin Virol 2005;32(Suppl.

1):S82-S90. [http://dx.doi.org/10.1016/j.jcv.2004.10.020] 7. Vandepapeliere P, Barrasso R, Meijer CJ, et al. Randomised controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine: Infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination. J Infect Dis 2005;192(12):2099-2107. [http://dx.doi. org/10.1086/498164]

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8. Persson G, Dahlf LG, Krantz I. Physical and psychological effects of anogenital warts on female patients. Sex Transm Dis 1993;20(1):10-13. [http://dx.doi.org/10.1097/00007435-199301000-00003] 9. Wiley D, Masongsong E. Human papillomavirus: The burden of infection. Obstet Gynecol Surv 2006;61(Suppl 1):S3-S14. [http://dx.doi.org/10.1097/01.ogx.0000221010.82943.8c] 10. National Department of Health, South Africa. Clinical Guidelines on the Management of HIV and AIDS in Adults and Adolescents. 2010. http://www.sahivsoc.org/upload/documents/Clinical_ Guidelines_for_the_Management_of_HIV_AIDS_in_Adults_Adolescents_2010.pdf (accessed 4 July 2015).

11. Onon TS. History of human papillomavirus, warts and cancer: What do we know today? Best Pract Res Clin Obstet Gynaecol 2011;25(5):565-574. [http://dx.doi.org/10.1016/j.bpobgyn.2011.05.001] 12. Von Grogh G. Management of anogenital warts (condyloma cuminata). Eur J Dermatol 2001;11(6):589-603.

13. Insinga RP, Dasbach EJ, Myers ER. The health and economic burden of genital warts in a set of private health plans in the United States. Clin Infect Dis 2003;36(11):1397-1403. [http://dx.doi. org/10.1086/375074] 14. Lacey CJN, Lowndes CM, Shah KV. Chapter 4: Burden and management of non-cancerous HPVrelated conditions: HPV-6/11 disease. Vaccine 2006;24(Suppl 3):S35-S41. [http://dx.doi.org/10.1016/j. vaccine.2006.06.015] 15. Sun XW, Kuhn L, Ellerbrock TV, Chiasson MA, Bush TJ, Wright TC. Human papillomavirus infection in women infected with the human immunodeficiency virus. N Engl J Med 1997;337(19):1343-1349. [http://dx.doi.org/10.1056/NEJM199711063371903] 16. Lissouba P, van de Perre P, Auvert B. Association of genital human papillomavirus infection with HIV acquisition: A systemic review and meta-analysis. Sex Transm Infect 2013;89(5):350-356. [http:// dx.doi.org/10.1136/sextrans-2011-050346] 17. Read TR, Hocking JS, Chen MY, Donovan B, Bardshaw CS, Fairley CK. The near disappearance of genital warts in young women 4 years after commencing a national human papillomavirus (HPV) vaccination programme. Sex Transm Infect 2011;87(7):544-547. [http://dx.doi.org/10.1136/ sextrans-2011-050234] 18. Oliphant J, Perkins N. Impact of human papillomavirus (HPV) vaccine on genital warts diagnosed at Auckland Sexual Health Services. N Z Med J 2011;124(1339):51-58.

Accepted 15 June 2015.

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The mental health experiences and needs of methamphetamine users in Cape Town: A mixed-methods study M H Watt, 1 PhD; B Myers, 2 PhD; S L Towe,1,3 PhD; C S Meade,1,3 PhD uke University, Duke Global Health Institute, Durham, NC, USA D Alcohol, Tobacco and Other Drug Research Unit, South African Medical Research Council, Tygerberg, Cape Town, South Africa 3 Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Duke Global Health Institute, Durham, NC, USA 1 2

Corresponding author: M H Watt (melissa.watt@duke.edu)

Background. South Africa (SA) has a burgeoning problem of methamphetamine use, particularly in the Western Cape Province. Although methamphetamine has been associated with elevated psychological distress, there has been little examination of the mental health needs of out-of-treatment methamphetamine users in SA. Objective. To describe the mental health experiences and needs of out-of-treatment methamphetamine users in Cape Town.

Methods. Active methamphetamine users were recruited using respondent-driven sampling techniques. Eligible participants (N=360) completed a computer-assisted assessment and clinical interview, where they provided data on mental health symptoms and treatmentseeking behaviour. A subset of 30 participants completed qualitative in-depth interviews in which they provided narrative accounts of their mental health experiences and needs. Analysis of the mixed-methods data was conducted using a concurrent triangulation strategy whereby both methods contributed equally to the analysis and were used for cross-validation.

Results. About half of the participants met screening criteria for depression and traumatic stress, and there were some indications of paranoia. Using substances to cope with psychological distress was common, with participants talking about using methamphetamine to numb their feelings or forget stressful memories. One-third of women and 13% of men had previously tried to commit suicide. Despite the huge mental health burden in this population, very few had ever received mental health treatment.

Conclusion. The data indicate a need for integrated care that addresses both substance use and psychiatric needs in this population. Mental health and drug treatment services targeting methamphetamine users should include a concerted focus on suicide prevention.

S Afr Med J 2015;105(8):685-688. DOI:10.7196/SAMJnew.7910

Since early 2000, there has been an exponential rise in the use of methamphetamine, locally called ‘tik’, in the Western Cape Province, South Africa (SA).

Studies consistently show that methamphetamine use is associated with poor mental health, including depression, psychosis and suicidality.[1] In SA, research has demonstrated an increased risk of mental health problems among methamphetamine users, including aggressive behaviour[2] and symptoms of depression and anxiety.[3] The relationship between methamphetamine and mental health is complex. On the one hand, poor mental health may be a risk factor for the initiation of substance use, as people may ‘self-medicate’ as a way to deal with psychiatric distress.[4] On the other hand, substance use results in numerous psychosocial sequelae, including isolation, family breakdown and loss of employment, which can contribute to mental health problems. Chronic methamphetamine use is associated with structural and functional changes in the brain that may account for the increased rate of psychiatric disturbance in this population.[5] Furthermore, the cycle of addiction (including intoxication, bingeing, withdrawal and craving) may lead to depressed mood, lethargy and anhedonia.

Regardless of whether psychiatric disturbances precede or follow the initiation of methamphetamine use, understanding the mental health experiences and needs of methamphetamine users in SA is important, as poor mental health may be a barrier to drug cessation and harm reduction efforts. Psychological distress impacts on motivation to initiate drug treatment services,[3] and

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ongoing distress may contribute to attrition from treatment. In addition, mental health problems may serve as barriers to reducing harms such as risky sexual behaviours that are associated with continued substance use. Despite the potential impact of untreated mental disorders on treatment seeking and outcomes, there has been little research on how methamphetamine users experience symptoms of psychological distress. This gap needs to be addressed so that appropriate intervention programmes can be developed for methamphetamine users in SA.

Methods Overview

The results presented here come from a mixed-methods study that included a cross-sectional survey of 360 current methamphetamine users and in-depth interviews (IDIs) with a subset of 30 participants.

Data collection was completed between May and October 2013 in Delft, a township on the Cape Flats, Western Cape.

Sample

Participants were recruited into the cross-sectional survey using a respondent-driven sampling strategy, described elsewhere.[6] Individuals were eligible to participate if they were ≥18 years old and positive for methamphetamine use on a urine drug screen. A subset of 30 participants were selected to participate in IDIs to explore the study topics in greater depth. The IDI participants were purposefully selected to provide a balance of race and gender representation and to include individuals who the staff felt would be articulate and reflective.

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Data collection

Quantitative procedures and measures Participants completed an audio computer-assisted self-interview, followed by a clinical interview. Data collection was conducted by trained staff in a private room. The visit took approximately 2 hours, and assessments were completed in the language of the participants’ choice (Afrikaans, Xhosa or English).

Mental health symptoms. The nine-item Patient Health Question­ naire (PHQ-9) measured frequency of depressive symptoms in the past 2 weeks. Scores range from 0 to 27, and a dichotomous measure was created for moderate depression (≥10).[7] The seven-item Breslau Post-Traumatic Stress Disorder (PTSD) screener was used to capture traumatic stress symptoms in the past month. The yes/no responses were summed to create composite scores ranging from 0 to 7; a recommended cut-off of 4 was used as an indication of PTSD symptoms.[8] Addiction Severity Index Lite (ASI-L). The ASI-L is a semi­ structured interview for substance-abusing populations that assesses several different areas of functioning, including substance use and mental health.[9] Participants reported the number of days they had used methamphetamine in the past 30 days, as well as the number of years they had used methamphetamine regularly. They also reported the number of days they had experienced psychological problems in the past 30 days, whether they had ever experienced particular psychiatric symptoms, including hallucinations, suicidal ideation, suicide attempt and aggressive behaviour, and whether they had experienced these symptoms in the past 30 days. Participants were asked whether they had ever received treatment for psychological problems, whether they had ever been hospitalised for psychological problems, and whether they had ever been prescribed psychiatric medications. Participants rated how troubled they were by psychological symptoms and how important they perceived psychiatric treatment to be for them (with responses ranging from ‘not at all’ to ‘extremely’).

Substance use coping. Participants responded to the four-item substance use subscale of the COPE[10] to assess how often they used substances as a coping mechanism. Response options ranged from ‘never or rarely’ to ‘almost always.’

Qualitative procedures The IDIs were conducted by local interviewers with extensive training in qualitative methods in the language of the participant’s choice, and lasted approximately 60 - 90 minutes. A semistructured interview guide included broad opening questions and more specific follow-up probes. The mental health content included questions and probes about chronic and acute stressors, areas of emotional distress, distress symptoms including suicidal ideation and suicide attempts, coping behaviours, and any mental health treatment sought or received.

Ethical concerns

Given the sensitive nature of the interviews, the team received extensive and ongoing training by a local clinical psychologist on how to support participants, how and when to offer active referrals to local service agencies, and how to assess for risk of suicide. A list of referrals was provided to all participants, and the interviewer offered to make active referrals when participants were in distress. The psychologist was on call to advise staff on steps that needed to be taken with distressed participants. The study protocol was approved by ethical review boards at Stellenbosch University and Duke University.

Analysis

Analysis was conducted using a concurrent triangulation strategy, whereby qualitative and quantitative data contributed equally to

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the analysis and were used for cross-validation. For the quantitative analysis, descriptive statistics were used to characterise the mental health symptoms, needs and treatment-seeking behaviour of the sample. For the qualitative analysis, audio recordings of the interviews were transcribed and translated into English. Narrative memos were written to organise the content of the transcripts, make connections across the transcript content, and begin to achieve meaningful insights into the data. NVivo software was used to conduct content analysis. The quantitative and qualitative data were then combined to provide a full picture of the mental health experiences and needs of the population.

Results

The sample included 201 men and 159 women, described in Table 1.

The 17 men and 13 women who completed IDIs had demographic and drug-related characteristics similar to the full sample.

Presentation of mental health symptoms

In the survey data, 49.3% of respondents met the criteria for moderate depression and 54.0% the screening criteria for PTSD. On average, individuals reported experiencing 11.7 days (range 0 - 30, standard deviation (SD) 12.8) of psychological problems in the past 30 days. Almost half of the sample (47.9%) reported being ‘extremely’ bothered by psychological symptoms in the past month. Women reported more days of psychological problems than men (13.5 v.

10.2; p<0.05).

In the IDIs, most participants expressed psychological distress.

Depressive symptoms included crying during the interview, loneliness, lethargy, and lack of interest in life. For men, feelings of regret and low self-worth were dominant, as this man expressed: ‘My mind is suffering, because I had my own plans, but none of them are successful.’ Several women talked about symptoms consistent with PTSD, typically related to histories of sexual or physical abuse. One woman, in recounting her sexual abuse history, said, ‘When you are asking me about that I just feel like vomiting … I don’t want to talk about my difficult memories.’

Participants spoke about the impact of methamphetamine on their psychological state. Several said that methamphetamine made them more ‘emotional’. One man stated that smoking methamphetamine ‘puts you more in touch with your feelings. You are not 100% in control when it comes to thoughts or actions, but you are more emotional.

You feel more. You sense more.’ Hallucinations and paranoia also seemed to be common during periods of methamphetamine use.

When not intoxicated, people spoke about feeling extreme lethargy and lack of interest in life.

Methamphetamine as a coping mechanism

Using substances to cope with stressors was common, with nearly half of the survey sample saying that they used substances to feel better, lose themselves, avoid thoughts and get through difficult situations (Table 2). In the IDIs, participants spoke about methamphetamine as a ‘comfort zone’ and a way to ‘calm down’. Many reported using methamphetamine to numb feelings, forget disturbing memories, and cope with their daily lives. A woman who had severe depression and a history of multiple traumas said that she used methamphetamine to cope with her emotional symptoms: ‘The moment I increased my daily intake (of methamphetamine), my body felt much better.

I could also manage emotionally.’ A man spoke about how he used methamphetamine to deal with daily stressors: ‘If the pressure gets too much, or I can’t handle things, then I have a fix. I do that to cut myself off from everything and not focus. I just want to be narrow minded.’ Five people specifically talked about initiating

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Table 1. Characteristics of the sample (N=360) Men (N=201)

Women (N=159)

Statistic

Age, mean (SD)

28.92 (7.59)

29.04 (6.95)

t (358) = 0.15

Race, coloured v. black African, n (%)

125 (62.2)

138 (86.8)

c2(1) = 27.30**

Currently married, n (%)

22 (10.9)

28 (17.6)

c2(1) = 3.30

Employed (part or full time), n (%)

46 (22.9)

21 (13.2)

c2(1) = 5.49*

Completed secondary school, n (%)

22 (10.9)

20 (12.6)

c2(1) = 0.23

Years of regular use, mean (SD)

7.15 (4.04)

6.95 (3.08)

t (358) = 0.52

Days of use in past 30 days, mean (SD)

24.26 (8.73)

22.52 (9.05)

t (358) = 1.86

Depression symptoms (PHQ-9 ≥10), n (%)

96 (47.8)

81 (50.9)

c2(1) = 0.31

PTSD symptoms (Breslau ≥4), n (%)

107 (53.2)

88 (55.3)

c2(1) = 0.11

Days of problems, past 30 days, mean (SD)

10.16 (12.17)

13.47 (13.23)

t (329) = 2.37*

Felt extremely bothered by problems, n (%)

89 (44.3)

78 (49.1)

c2 (1) = 0.87

Hallucinations, lifetime, n (%)

104 (51.7)

63 (39.6)

c2 (1) = 5.24*

Hallucinations, past 30 days, n (%)

98 (48.8)

60 (37.7)

c2(1) = 4.38*

Suicidal ideation, lifetime, n (%)

50 (24.9)

68 (42.8)

c2(1) = 12.90**

Suicidal ideation, past 30 days, n (%)

26 (12.9)

25 (15.7)

c2(1) = 0.57

Suicide attempt, lifetime, n (%)

26 (12.9)

53 (33.3)

c2(1) = 21.56**

Suicide attempt, past 30 days, n (%)

9 (4.5)

16 (10.1)

c2 (1) = 4.29*

Aggressive behaviour, lifetime, n (%)

148 (73.6)

89 (56.0)

c2(1) = 12.31**

Aggressive behaviour, past 30 days, n (%)

118 (58.7)

84 (52.8)

c2(1) = 1.25

reatment perceived as extremely T important, n (%)

91 (45.3)

77 (48.4)

c2(1) = 0.44

Demographics

Methamphetamine use and addiction

Mental health

**p<0.01, *p<0.05.

Table 2. Frequency of substance use as a coping mechanism to deal with stressors (N=360) Never/rarely n (%)

Occasionally n (%)

Often n (%)

Almost always n (%)

Use alcohol or drugs to feel better*

37 (10.3)

132 (36.7)

123 (34.2)

67 (18.6)

Try to lose myself by drinking or taking drugs

50 (13.9)

151 (41.9)

97 (26.9)

62 (17.2)

Drink or take drugs to think about it less

49 (13.6)

138 (38.3)

108 (30.0)

65 (18.1)

Use alcohol or drugs to help get through it

60 (16.7)

145 (40.3)

97 (26.9)

58 (16.1)

*One answer missing.

methamphetamine for the first time as a way to cope with feelings or events in their lives.

Suicidality

In the survey data, 32.8% of the sample said that they had ever had suicidal thoughts, and 21.9% said that they had ever attempted suicide. Women were significantly more likely to have ever had suicidal thoughts (42.8% v.

24.9%; p<0.001) and to have ever attempted suicide (33.3% v. 12.9%; p<0.001). In the IDIs, 10 of the 30 participants recounted suicide attempts, with many of those individuals reporting multiple attempts. The reasons that men expressed for attempting suicide were feeling rejected by family as a result of drug use, breaking up with a girlfriend, and feeling in a ‘dark place’. Among women, four

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attributed their suicide attempts to traumas (sexual abuse, partner abuse and husband’s murder), and the others spoke about general distress and problems in relationships. The most common way that people attempted suicide was via medication overdose, followed by hanging and cutting. Suicidal ideation was also common, with participants talking about feeling that they would be ‘better off dead’.

Treatment-seeking behaviour

Only 7.2% of the survey sample had ever received treatment for a psychological problem. The majority (69.2%) of those who reported that that they had received treatment said that they had been hospitalised for psychiatric reasons. Despite low uptake of mental health treatment, almost half (47.1%) said that receiving psychological treatment was ‘extremely important’ to them. In the qualitative data, there was little discussion of mental health treatment. Five participants said that they had received some psychiatric treatment after being hospitalised for a suicide attempt, but none had follow-up after discharge. One woman explained that she felt that providers were not interested in treating drug users: ‘After I came back from the hospital [after suicide attempt], they said they would check on me sometimes, but they never did. I told you before, not everyone is interested in us.’

Only one of the IDI participants had received outpatient mental health counselling, which she apparently received through the HIV clinic where she was receiving care. Notably, several participants spoke about the study contact as a therapeutic experience, indicating a desire and need for mental health counselling. As this woman explained: ‘I am feeling a great relief after talking to you. A heavy weight is lifted from my shoulders.’

Discussion

While previous studies in SA have documented the high prevalence of mental health problems among methamphetamine users,[2,3] none have explored how users understand the relationship between methamphetamine use and psychological distress. We combined quantitative and qualitative methods to document the mental health experiences and needs of out-oftreatment methamphetamine users from one township in Cape Town. This study yields information that could potentially inform the development of mental health services for methamphetamine users in SA. We found high rates of psychological distress in this population, with close to half of the participants scoring above the cut-off for depression and more than half meeting screening criteria for PTSD. Despite the high

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burden of mental disorders, very few participants had ever accessed mental health services, indicating a large unmet need for mental health treatment. This is not surprising, given evidence of a 75% treatment gap for common mental disorders in SA.[11] Further complicating matters for a substance-using population, substance abuse and other mental health services are delivered by distinct service systems, with neither system equipped to address both problems effectively in an integrated manner,[12] although our findings indicate that a substantial proportion of methamphetamine users could benefit from integrated substance abuse and mental health services. Some might argue that the depressive symptomatology in this population is likely to be a consequence of the physiological effects of methamphetamine,[5] and may resolve after a period of abstinence. However, this explanation does not account for the high rates of PTSD observed in this sample.

Our qualitative data suggest that traumatic experiences are likely to have preceded the initiation of methamphetamine use, with many participants reporting that they used methamphetamine as a way of coping with negative feelings associated with these experiences.

For these participants, effective treatment requires addressing their traumatic experiences, particularly as unresolved trauma is associated with poor drug treatment outcomes.[13] In addition to using methamphetamine as a way of coping with traumatic experiences, participants reported using metham­ phetamine to handle their everyday stressors. This is likely to be the result of poor problem-solving and coping skills. We also observed gender differences in how methamphetamine use was used to help people cope with stressful events. Womenâ&#x20AC;&#x2122;s narratives suggest that methamphetamine is used as an avoidance strategy to block, numb or dull negative psychological distress. In contrast, men reported using methamphetamine to facilitate emotional discharge or catharsis, a form of emotion-focused coping. The reliance on these maladaptive coping styles highlights the need for interventions to help methamphetamine users develop more adaptive problemfocused coping strategies.

Addressing psychological distress is particularly important in view of the alarmingly high rates of suicide attempts in this population.

More than a third of women and more than 10% of men reported prior suicide attempts, higher than the national prevalence of 3%.[14] This finding provides further evidence of the need to integrate mental health services into existing substance abuse programmes. At the very least, all patients reporting methamphetamine use should be screened for risk of suicide, and programming for methamphetamine dependence should include a focus on suicide prevention.

These findings have several other implications for the prevention and treatment of methamphetamine use. First, universal prevention programmes should consider equipping young people with problem-focused coping skills to help delay initiation of substance use. Second, prevention programmes indicated for individuals who are using methamphetamine but are not yet dependent should include a focus on developing adaptive coping and problemsolving styles, particularly given emerging evidence that brief, problem-solving therapies are effective for reducing substance use involvement in high-risk SA populations.[15] Third, as mental health problems and problem-solving deficits are risk factors for poor treatment outcomes,[15] substance abuse services should screen all methamphetamine users for co-occurring mental health problems and provide patients with coping and problem-solving interventions to help them deal with life stressors. Finally, the low use of mental health services in this population indicates a need for improving community awareness of mental health problems and resources, which may hinder uptake and consistent use of available community-based services.

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Study strengths and limitations

While this study has several strengths, including the largest sample of community-recruited methamphetamine users in SA, it does have some limitations. First, findings may not generalise to the entire population of methamphetamine users or to methamphetamine users in other communities. Second, our sample may have been skewed towards regular methamphetamine users, as we only included participants with a positive urine screen that detects methamphetamine in the urine for 3 - 5 days. Although we may have excluded less frequent users, our results do reflect the need for mental health services among regular methamphetamine users. Finally, we did not undertake clinical interviewing to determine mental health diagnoses, but rather relied on symptom checklists.

Conclusion

This study clearly demonstrates that mental health services should be made more readily available to methamphetamine users. The high prevalence of suicide attempts and psychological distress in this sample highlights the need for evidence-based substance abuse prevention interventions that also promote mental health through developing adaptive coping strategies. Additionally, to improve drug treatment outcomes, programmes should screen methamphetamine users for suicide risk and psychological distress, deliver services that treat their substance use and underlying mental health conditions in an integrated manner, and teach adaptive coping strategies to prevent relapse to substance use.

Acknowledgements. This study was funded by the National Institute of Drug Abuse (R03-DA033282) and further supported by additional training and institutional grants from the National Institutes of Health (K23-DA028660, T32-AI007392, P30-AI064518, R25-DA035692), USA. We are grateful to all the men and women who participated, and to our collaborators and staff in SA (Donald Skinner, Desiree Pieterse, Albert Africa, Tembie Mafikizolo, and Mariana Bolumbe).

References 1. Marshall BD, Werb D. Health outcomes associated with methamphetamine use among young people: A systematic review. Addiction 2010;105(6):991-1002. [http://dx.doi.org/10.1111/j.13600443.2010.02932.x] 2. Pluddemann A, Flisher AJ, McKetin R, Parry C, Lombard C. Methamphetamine use, aggressive behavior and other mental health issues among high-school students in Cape Town, South Africa.

Drug Alcohol Depend 2010;109(1-3):14-19. [http://dx.doi.org/10.1016/j.drugalcdep.2009.11.021] 3. Myers B, Kline TL, Doherty IA, Carney T, Wechsberg WM. Perceived need for substance use treatment among young women from disadvantaged communities in Cape Town, South Africa. BMC Psychiatry 2014;14:100. [http://dx.doi.org/10.1186/1471-244x-14-100] 4. Robinson J, Sareen J, Cox BJ, Bolton J. Self-medication of anxiety disorders with alcohol and drugs: Results from a nationally representative sample. J Anxiety Disord 2009;23(1):38-45. [http://dx.doi. org/10.1016/j.janxdis.2008.03.013] 5. Rusyniak DE. Neurologic manifestations of chronic methamphetamine abuse. Psychiatr Clin North Am 2013;36(2):261-275. [http://dx.doi.org/10.1016/j.psc.2013.02.005] 6. Kimani SM, Watt MH, Merli MG, et al. Respondent driven sampling is an effective method for engaging methamphetamine users in HIV prevention research in South Africa. Drug Alcohol Depend 2014;143:134-140. [http://dx.doi.org/10.1016/j.drugalcdep.2014.07.018] 7. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: Validity of a brief depression severity measure. J Gen Intern Med 2001;16(9):606-613. [http://dx.doi.org/10.1046/j.1525-1497.2001.016009606.x] 8. Breslau N, Peterson EL, Kessler RC, Schultz LR. Short screening scale for DSM-IV posttraumatic stress disorder. Am J Psychiatry 1999;156(6):908-911.

9. McLellan AT, Luborsky L, Woody GE, Oâ&#x20AC;&#x2122;Brien CP. An improved diagnostic evaluation instrument for substance abuse patients. The Addiction Severity Index. J Nerv Ment Dis 1980;168(1):26-33.

10. Carver CS, Scheier MF, Weintraub JK. Assessing coping strategies: a theoretically based approach. J Pers Soc Psychol 1989;56(2):267-283.

11. Seedat S, Stein DJ, Herman A, et al. Twelve-month treatment of psychiatric disorders in the South African Stress and Health Study (World Mental Health Survey Initiative). Soc Psychiatry Psychiatr Epidemiol 2008;43(11):889-897. [http://dx.doi.org/10.1007/s00127-008-0399-9] 12. Myers B, Fakir N. Provision of Mental Health Services in South African Substance Abuse Treatment Facilities. Int J Ment Health Addict 2009;7(3):441-449. [http://dx.doi.org/10.1007/s11469-009-9205-5] 13. Norman SB, Tate SR, Anderson KG, Brown SA. Do trauma history and PTSD symptoms influence addiction relapse context? Drug Alcohol Depend 2007;90(1):89-96. [http://dx.doi.org/10.1016/j. drugalcdep.2007.03.002] 14. Joe S, Stein DJ, Seedat S, Herman A, Williams DR. Non-fatal suicidal behavior among South Africans: Results from the South Africa Stress and Health Study. Soc Psychiatry Psychiatr Epidemiol 2008;43(6):454-461. [http://dx.doi.org/10.1007/s00127-008-0348-7] 15. Sorsdahl K, Myers B, Ward CL, et al. Adapting a blended motivational interviewing and problemsolving intervention to address risky substance use amongst South Africans. Psychother Res 2015;25(4):435-444. [http://dx.doi.org/10.1080/10503307.2014.897770]

Accepted 15 June 2015.

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CONTINUING MEDICAL EDUCATION

REVIEW

An approach to the clinical assessment and management of syncope in adults N A B Ntusi, FCP (SA), DPhil; C B I Coccia, MB ChB; B J Cupido, FCP (SA); A Chin, FCP (SA), MPhil Division of Cardiology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa Corresponding author: N A B Ntusi (ntobeko.ntusi@gmail.com)

Syncope, defined as a brief loss of consciousness due to an abrupt fall in cerebral perfusion, remains a frequent reason for medical presentation. The goals of the clinical assessment of a patient with syncope are twofold: (i) to identify the precise cause in order to implement a mechanism-specific and effective therapeutic strategy; and (ii) to quantify the risk to the patient, which depends on the underlying disease, rather than the mechanism of the syncope. Hence, a structured approach to the patient with syncope is required. History-taking remains the most important aspect of the clinical assessment. The classification of syncope is based on the underlying pathophysiological mechanism causing the event, and includes cardiac, orthostatic and reflex (neurally mediated) mechanisms. Reflex syncope can be categorised into vasovagal syncope (from emotional or orthostatic stress), situational syncope (due to specific situational stressors), carotid sinus syncope (from pressure on the carotid sinus, e.g. shaving or a tight collar), and atypical reflex syncope (episodes of syncope or reflex syncope that cannot be attributed to a specific trigger or syncope with an atypical presentation). Cardiovascular causes of syncope may be structural (mechanical) or electrical. Orthostatic hypotension is caused by an abnormal drop in systolic blood pressure upon standing, and is defined as a decrease of >20 mmHg in systolic blood pressure or a reflex tachycardia of >20 beats/minute within 3 minutes of standing. The main causes of orthostatic hypotension are autonomic nervous system failure and hypovolaemia. Patients with life-threatening causes of syncope should be managed urgently and appropriately. In patients with reflex or orthostatic syncope it is important to address any exacerbating medication and provide general measures to increase blood pressure, such as physical counter-pressure manoeuvres. Where heart disease is found to be the cause of the syncope, a specialist opinion is warranted and where possible the problem should be corrected. It is important to remember that in any patient presenting with syncope the main objectives of management are to prolong survival, limit physical injuries and prevent recurrences. This can only be done if a patient is appropriately assessed at presentation, investigated as clinically indicated, and subsequently referred to a cardiologist for appropriate management.

S Afr Med J 2015;105(8):690-693. DOI:10.7196/SAMJnew.8065

Syncope refers to a brief loss of consciousness (LOC) due to an abrupt fall in cerebral perfusion. It remains a frequent reason for medical presentation and accounts for a large proportion of emergency department and outpatient clinic visits. While there are no population-based epidemiological studies of syncope in South Africa, it accounts for up to 3% of hospital admissions in western countries. There are many causes of syncope (discussed below) – some benign and others more serious. The goals of the clinical assessment of a patient with syncope are twofold: (i) to identify the precise cause in order to implement a mechanism-specific and effective therapeutic strategy; and (ii) to quantify the risk of recurrence or death, which depends on the underlying disease rather than the mechanism of the syncope. Hence, a structured approach to the patient with syncope is required. History-taking is the most important aspect of the clinical assessment. The patient’s history guides both appropriate selection of investigations and best management strategy.

Definition of syncope

Syncope is a transient loss of consciousness (T-LOC) caused by transient global hypoperfusion of both cerebral hemispheres or focal hypoperfusion of the reticular activating system. Cerebral hypoperfusion may be secondary to decreased cardiac output, peripheral vascular resistance or a combination of both. Four cardinal clinical features characterise the syncopal episode: (i) it is transient; (ii) it has a rapid onset; (iii) it has a short duration (lasting seconds

to several minutes); and (iv) there is spontaneous complete recovery requiring no resuscitative efforts.[1] Appropriate orientation and behaviour is restored after the syncopal episode and there is complete return of pre-existing neurological function. Retrograde amnesia may occur in older adults. Syncopal patients may have brief, involuntary clonic movements, but do not report tongue biting or incontinence.

T-LOC encompasses all disorders characterised by self-limited LOC, irrespective of mechanism. Other causes of T-LOC include trauma, epileptic seizures and psychogenic LOC. Syncope is differ­ entiated from other causes of T-LOC by its mechanism of global cerebral hypoperfusion.

Presyncope indicates symptoms and signs that occur before LOC in syncope. It is often used interchangeably with ‘dizziness’ and ‘light-headedness’ to describe a situation in which the individual thinks he or she may have a blackout, but consciousness is maintained.

Is the cause of the syncopal episode life threatening?

The primary responsibility of the emergency department doctor or general practitioner is to ensure that a life-threatening cause of syncope is excluded. The four main life-threatening causes of syncope are: (i) cardiac syncope (arrhythmia related or structural); (ii) massive haemorrhage with haemodynamic instability; (iii) pulmonary embo­ lism; and (iv) subarachnoid haemorrhage (which should be suspected if a patient presents with syncope after a headache).

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Classification of transient loss of consciousness

T-LOC is divided into traumatic and nontraumatic forms. T-LOC related to trauma is usually the result of concussion. Non-

Table 1. Classification of transient loss of consciousness Traumatic T-LOC • Concussion Non-traumatic T-LOC • Syncope • Epileptic seizure • Psychogenic pseudosyncope • Hypoglycaemia • Hypoxia • Hyperventilation with hypocapnia • Intoxication • Vertebrobasilar TIA T-LOC = transient loss of consciousness; TIA = transient ischaemic attack.

traumatic causes of T-LOC include syncope, epileptic seizures, intoxication, vertebrobasilar transient ischaemic attack (TIA) and metabolic disorders, such as hypoglycaemia, hypoxia and hyperventilation with hypocapnia (Table 1).

Other disorders without LOC may also be incorrectly diag­nosed as syncope; these include cata­ plexy, drop attacks, falls, psychogenic pseudo­ syncope and a TIA of vertebrobasilar origin.[1] Differentiating syncope from seizure and TIA is not always easy, and Table 2 provides useful pointers.

Classification of syncope

The classification of syncope is based on the underlying patho­ physiological mechanism causing the event, emphasising collections of disparate disorders with a common presentation but different risk profiles (Fig. 1). Syncope is classified into cardiac syn­ cope, orthostatic hypotension (OH) and reflex (neurally mediated) mechanisms.[2] Reflex syncope is the most frequent cause of syncope in any setting and is particularly common in young

Table 2. Differentiating syncope from seizure and TIA Syncope

Seizure

TIA

Onset

Abrupt (but may have warning)

Aura is typical (but LOC is abrupt)

Abrupt

Prompt waking

Yes

Post-ictal state

Slow waking

Seizure

No

Yes

No

Pallor

Yes

No

No

Hyperaemic flush

Yes

No

No

Associated symptoms

No

Aura

Other neurological symptoms

Tongue biting

No

Yes

No

Urinary incontinence

No

Yes

No

LOC = loss of consciousness; TIA = transient ischaemic attack.

Outflow tract obstruction

Decreased cardiac output

Pump failure

Decreased systemic vascular resistance

Conduction defect

Decreased intravascular volume

females. The most common cause of syncope is cardiac related. OH is rare in patients <40 years of age, whereas it is prevalent in older patients (Table 3). Of note, 5 - 15% of syncopal episodes are medication related (from orthostasis or cardiotoxicity).

Reflex syncope

Cardiovascular reflexes play an important role in maintaining blood pressure (BP) in normal individuals, but can cause a signi­ficant decrease in BP with subsequent syncope in those with an inappropriate response. The syncope may be due to a vasodepressor or cardio-inhibitory type of reflex – the former causing a loss of vasoconstriction and the latter resulting in significant bradycardia or asystole.[1] Reflex syncope can be further categorised into vasovagal syncope (from emotional or orthostatic stress); situational syncope (due to specific situational stressors such as micturition, vomiting and defecation); carotid sinus syncope (from pressure on the carotid sinus, e.g. shaving or a tight collar); and atypical reflex syncope (episodes of syncope or reflex syncope that cannot be attributed to a specific trigger or syncope with an atypical presentation).

Cardiac syncope

Cardiovascular causes of syncope may be structural (mechanical) or electrical.[3] Structural heart disease results in global cerebral hypo­ perfusion by decreasing the cardiac output and subsequently the systemic BP. Syncope occurs when the circulatory demands outweigh the ability of the heart to maintain an adequate cardiac output. In conditions with a fixed ventricular outflow obstruction it is not only the decreased cardiac output that plays a role, but also a reflex vasodilation or

Haemodynamically significant arrhythmia

Decreased arterial pressure

Global cerebral hypoperfusion

Syncope Fig. 1. The pathophysiology of syncope.

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Impaired cerebral autoregulation

Abnormal metabolic regulation vascular tone

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orthostatic hypotension. The main causes of structural syncope are highlighted in Table 3 and include acute myocardial infarction/ ischaemia, hypertrophic cardiomyopathy (HCM), arrhyth­mogenic cardiomyopathy, valvular heart disease (e.g. aortic stenosis and mitral stenosis) and pericardial disease. Arrhythmias causing syncope can be either brady- or tachyarrhythmias, and may be acquired or caused by congenital defects. Acquired bradyarrhythmias include sick sinus syndrome, which causes pauses due to sinus arrest and a subsequent fall in cardiac output. The atrioventricular (AV) blocks causing syncope include Mobitz I and II AV block, high-degree AV blocks (2:1 AV block and greater) and complete AV block – the mechanism being either ventricular asystole (i.e. an absent escape rhythm) or torsades des pointes due to prolongation of the QT interval. For many cardiovascular causes of syncope the pathogenesis is multifactorial, Table 3. Pathophysiological classification of syncope Cardiac (cardiovascular) syncope Structural • Cardiac • Valvular heart disease (including aortic stenosis) • Acute myocardial infarction/ischaemia • Hypertrophic cardiomyopathy • Arrhythmogenic cardiomyopathy • Cardiac masses (atrial myxoma, tumours, thrombus) • Pericardial disease/tamponade • Congenital anomalies of the coronary arteries • Prosthetic valve dysfunction • Non-cardiac • Pulmonary embolism • Acute aortic dissection • Pulmonary hypertension Arrhythmic • Bradycardia • Sinus node dysfunction • Atrioventricular node disease • Implanted device malfunction • Tachycardia • Supraventricular • Ventricular (primary or secondary to structural heart disease or channelopathy) • Implanted device malfunction • Drug induced • Bradycardia • Tachycardia Reflex-mediated (neurogenic) syncope Vasovagal • Mediated by emotional stress, fear, pain, instrumentation, blood phobia • Induced by orthostatic stress Situational • Cough, sneeze • Gastrointestinal stimulation (swallow, defecation, visceral pain) • Micturition/post-micturition • Post-exercise • Postprandial • Others (laugh, brass instrument playing, weightlifting) Carotid sinus syncope Atypical forms • Without an apparent trigger and/or atypical presentation Continued ...

Table 3. (continued) Pathophysiological classification of syncope Orthostatic syncope • Primary autonomic failure • Pure autonomic failure • Multisystem atrophy • Parkinson’s disease with autonomic failure • Dementia with Lewy bodies • Secondary autonomic failure • Diabetes • Amyloidosis • Uraemia • Spinal cord injury • Drug-induced orthostatic hypotension • Alcohol • Vasodilators • Diuretics • Phenothiazines • Antidepressants • Volume depletion • Haemorrhage • Diarrhoea • Vomiting • Dehydration

e.g. in HCM, where the syncope may be secondary to outflow obstruction, ventricular or atrial arrhythmias or neurally mediated mechanisms.

Orthostatic hypotension

OH is due to an abnormal drop in systolic BP upon standing, and is defined as a decrease of >20 mmHg in systolic BP or a reflex tachycardia of >20 beats/minute within 3 minutes of standing.[2] The main causes of OH are autonomic nervous system (ANS) failure and hypovolaemia.

Other causes are illustrated in Table 3. In older patients, especially those with diabetes, mild autonomic neuropathy is common and may easily be aggravated by diuretic treatment, medication prescribed for hypertension or tricyclic antidepressants. Vasodilator therapy or diuretics that were recently added as treatment are common pre­ cipitants of new-onset OH and syncope in the elderly.

Prognosis of syncope

The prognosis of syncope relates to: (i) the risk of death and lifethreatening events; and (ii) the risk of recurrence of the syncope and physical injury.[1,3] The prognosis depends on the underlying cause of the syncope. Higher mortality is associated with life-threatening cardiac causes of syncope. Furthermore, there is a high morbidity in patients with a risk of recurrence of syncope and subsequent physical injury.[4] Structural heart disease and primary cardiovascular electrical disease are major risk factors for sudden cardiac death (SCD) in syncope. OH results in a twofold higher risk of mortality in syncope.

Mortality is often related to the severity of the underlying disease rather than to syncope per se. However, young persons without structural or electrical heart disease have an excellent prognosis.[5] In up to one-third of adults there is recurrent syncope within 3 years of follow-up. Psychiatric disease and age <45 years predict higher rates of pseudosyncope. Major injury, including fractures and motor vehicle accidents, is reported in 6% of patients with syncope. Minor and softtissue injuries occur in 12% of patients. Morbidity is particularly high in the elderly. Moreover, recurrent syncope may have serious effects on the quality of life.[1]

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Clinical evaluation of syncope History and examination

As syncope is a symptom or clinical presentation of an underlying disorder, attempting to establish the cause is essential and relies heavily on the history and physical examination. On history, the diagnosis of syncope can be confirmed by asking four key questions:

• • • •

Was the LOC complete?

Was the LOC transient, with rapid onset and short duration?

Did the patient recover spontaneously and completely, without sequelae?

Did the patient lose postural tone?

The answer to all these questions should be positive.

Table 4. History in a patient with syncope* History

Likely diagnosis

Precipitating factors • • • • • • • •

Warm/crowded area, pain, emotional distress, fear Activities such as coughing, laughing, urination/defaecation, eating Unexplained fall Head movement, tight collars, shaving During exertion Shortly after exertion Prolonged sitting/standing up Addition or use of medication

• • • • • • •

• Antiarrhythmics • Antihypertensives • Macrolides, anti-emetics, antipsychotics, tricyclic antidepressants

• Cardiac (arrhythmia, prolonged QT interval) • Orthostatic, cardiac (prolonged QT interval) • Cardiac (prolonged QT interval)

Neurally mediated (vasovagal), orthostatic Neurally mediated (situational) Neurally mediated (carotid sinus) or cardiac (arrhythmia, structural heart disease) Neurally mediated (carotid sinus) Cardiac (arrhythmia, structural heart disease) Neurally mediated (vasovagal), cardiac (arrhythmia) Orthostatic

• Hand or upper-extremity exercise

• Neurogenic (steal syndrome)

Prodrome • Light-headedness, dizziness, blurred vision, vertigo • Nausea, diaphoretic, abdominal pain • Focal neurological deficit • Chest pain, shortness of breath, dyspnoea

• • • •

• • • • •

• • • • •

Auras Fluttering or palpitations Slow pulse Tonic-clonic movement/posturing None

Neurally mediated (vasovagal), orthostatic Neurally mediated (vasovagal) Neurogenic (cerebrovascular accident or TIA) Cardiac (structural heart disease, pulmonary embolus, acute myocardial infarction) Seizure Cardiac (arrhythmia) Neurally mediated (vasovagal), cardiac (bradyarrhythmia) Seizure Vasovagal or cardiac in older patients, cardiac in younger patients

Position before syncope • Prolonged standing • Sudden change in posture • Supine

• Neurally mediated (vasovagal), orthostatic • Orthostatic • Cardiac (arrhythmia, structural heart disease)

Post-syncope • • • • • • • • • • • • • • •

Nausea, vomiting, fatigue Immediate complete recovery Pallor, sweating Focal neurological deficit Myoclonic movement Tonic-clonic movement posturing Eyes open during event Eyes closed during event Prolonged confusion Transient disorientation Amnesia regarding loss of consciousness Incontinence Tongue biting Significant trauma Chest pain, shortness of breath

• Prolonged syncope • Slow pulse

• • • • • • • • • • • • • • •

Neurally mediated (vasovagal) Cardiac (arrhythmia), psychogenic Likely syncope (any cause) v. seizure Neurogenic (cerebrovascular accident or TIA) Neurally mediated (vasovagal) Seizure Seizure or syncope (any cause) Pseudoseizure, psychogenic Seizure Neurally mediated (vasovagal) Seizure or neurally mediated (vasovagal) in older patients Seizure, uncommon in syncope (vasovagal most likely) Seizure Syncope (any cause), unlikely seizure Cardiac (structural heart disease, pulmonary embolus, acute myocardial infarction) • Seizure, neurogenic, metabolic, infectious • Cardiac (bradyarrhythmia) Continued ...

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Table 4. (continued) History in a patient with syncope* History

Likely diagnosis

Pre-existing disease • Heart disease • Psychiatric illness • Diabetes mellitus, Parkinson’s disease, alcoholism, renal replace­ ment therapy • Family history of sudden cardiac death • Frequent and long history of syncopal events • Older age with dementia *

• Cardiac • Psychogenic • Orthostatic • Cardiac (long QT syndrome, Brugada syndrome, arrhythmogenic right ventricular dysplasia/cardiomyopathy, structural heart disease) • Psychogenic, neurally mediated (vasovagal) • Orthostatic, cardiac

These historical features are a useful guide, but are not absolutely definitive.

Table 5. Electrocardiographic features of arrhythmic syncope • Non-sustained VT • Bifascicular block (LBBB or RBBB combined with left anterior or left posterior fascicular block) or other intraventricular conduction delay with QRS >120 ms • Sinus bradycardia (<50 bpm or sinoatrial block in absence of negative chronotropic medications or physical training) • Pre-excited QRS complex • Prolonged or shortened QT interval • RBBB pattern with ST elevation in V1 - V3 (Brugada pattern) • Negative T waves in the right praecordial leads, epsilon waves, and ventricular late potentials suggestive of ARVC ARVC = arrhythmogenic right ventricular cardiomyopathy; LBBB = left bundle branch block; RBBB = right bundle branch block; VT = ventricular tachycardia.

In the majority of patients the diagnosis of syncope may be confirmed based on the history alone. Obtaining a detailed history from a witness such as a partner or family member is important to describe the LOC. History-taking must be comprehensive and include details of the situation, precipitating factors, prodrome, LOC episode and postprodrome. Important aspects to glean from the history include whether the syncope is postural, exertional, situational and associated with palpitations or cardiovascular symptoms. Additionally, the clinician must take into account the use of medications, a family history of SCD, and a personal history of cardiac disease. Table 4 includes features on the history that may be useful to distinguish a cause. The history should always aim to answer three important questions: • Was this a syncopal episode?

• If indeed syncope, what is the cause?

• Are there features suggesting high risk of cardiovascular events or death?[4] On examination, the vital signs must be assessed, including pulse, BP, pallor and bruits, and OH must be checked. The BP needs to be measured in the supine position, followed by BP in the erect position after 3 minutes of standing. A cardiovascular examination includes evaluation of features of underlying cardiac disease, such as impaired systolic function arrhythmias and murmurs suggesting conditions such as mitral or aortic stenosis or HCM. Neurological examination focuses on ascertainment of muscle weakness, paraesthesia, cranial nerve abnormalities and peripheral neuropathy. Gastrointestinal tract (GIT) examination should exclude a GIT source of blood loss.[4]

Special investigations

An ECG is recommended in all patients who present with syncope, checking for evidence of abnormal rhythm, prolonged intervals (PR, QRS,

and QTc), severe bradycardia, pre-excitation, myo­car­dial infarction, low voltage in standard limb leads suggestive of effusion, and abnormal conduction. The ECG plays a crucial role in diagnosing arrhythmia, ischaemia, pulmonary embolism, and HCM (Table 5).

Additional assessments may be performed, but must be directed based on the findings of the initial evaluation. Importantly, <2 - 3% of patients evaluated for syncope have abnormal laboratory results.[1,6] Therefore, the routine use of a broad panel of laboratory tests is not recommended and tests should only be requested when clinically indicated. Further investigations (Table 6) are usually the domain of cardiologists, as the performance and interpretation there­of require specialised training.

Echocardiography is useful in the evaluation of left ventricular systolic function and delineation of structural heart disease, including abnormal valves, chamber enlargement, hypertrophy, wall motion and pericardial disease. However, in patients with an unremarkable clinical examination, normal ECG, and no cardiac history the value of echocardiography is minimal. Transoesophageal echocardiography, cardiovascular computed tomography or cardiovascular magnetic resonance imaging may be considered for evaluation of structural heart disease when the transthoracic echocardiogram is abnormal or the index of suspicion of myocardial, valvular, pericardial or coronary artery disease is high.[2] Tilt-table testing may be useful when there is an intermediate probability of reflex syncope or to demonstrate OH in a controlled environment. In a patient with a typical history suggestive of reflex syncope a tilt-table test is not indicated, as a negative test does not exclude reflex syncope. The sensitivity and specificity of tilt-table testing are 65% and 93%, respectively. The patient is attached to a cardiac and BP monitor, lies flat for 10 minutes and is then tilted 60 - 70° head-up and observed for 30 minutes for symptoms and signs of syncope. At 15 minutes, a sublingual nitrate is administered if no symptoms have occurred. The test is considered positive if the patient’s symptoms are reproduced in the presence of hypotension, bradycardia or both. Contraindications to performing tilt-table testing include a recent myocardial infarction, stroke or tight carotid stenosis.[7] Carotid sinus massage (CSM) to diagnose carotid sinus hyper­ sensitivity (CSH) is only recommended in patients >40 years of age with syncope or unexplained falls without a clearly identified cause. CSM is positive when it causes a pause of >3 seconds in the heartbeat (cardio-inhibition) or lowering of the BP by >50 mmHg (vasodepression). Complications that may arise from the procedure are TIAs or strokes (both rare). It is therefore recommended that CSM be avoided in patients with a previous TIA or stroke or in those with carotid bruits.

ECG monitoring (telemetry, Holter monitoring and implant­ able loop record­ ers (ILRs)) is used to detect an underlying

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Table 6. Special investigations in a patient with syncope Test

Indication

Comments

Basic laboratory testing

As clinically indicated, including human chorionic gonadotropin in women of childbearing age

Laboratory evaluation rarely helpful; complete blood count for anaemia

Carotid sinus massage

Syncope of unknown aetiology in patients >40 years of age

Diagnostic if ventricular pause is >3 seconds or if a decrease in systolic BP >50 mmHg Contraindicated in patients with bruits or a history of transient ischaemic attack/cerebrovascular accident within the past 3 months

Electrocardiography

All patients with syncope

Can aid in diagnosing arrhythmia, ischaemia, pulmonary embolus (increased pulmonary pressures or right ventricular enlargement), and hypertrophic cardiomyopathy Findings suggestive of arrhythmia include presence of bundle branch block, intraventricular conduction delay, sinus bradycardia (<50 beats/min), prolonged QT interval, QRS pre-excitation, Q waves

ECG monitoring

Recurrent syncope with unremarkable initial evaluation; clinical or ECG features suggestive of arrhythmic syncope; patients with unexplained falls

Holter monitor for 24 - 48 hours, event recorders for 30 - 60 days, implantable recorders for up to 14 months Consider testing in patients suspected of having epilepsy not responsive to therapy

Echocardiography

When history, examination, and ECG do not provide a diagnosis or if structural cardiac disease is suspected

Diagnostic in aortic stenosis, pericardial tamponade, obstructive cardiac tumours or thrombi, aortic dissection, hypertrophic cardiomyopathy, congenital anomalies of the coronary arteries

Electrophysiology

Patients with coronary artery disease after ischaemic evaluation, non-ischaemic dilated cardiomyopathy, bundle branch block, syncope preceded by palpitations, Brugada syndrome, arrhythmogenic right ventricular dysplasia/cardiomyopathy, or high-risk occupations

Not recommended in patients without underlying heart disease Consider in high-risk patients with recurrent unexplained syncope

Exercise testing

Haemodynamic and ECG abnormalities present with syncope during exercise, syncope reproduced with exercise, syncope precipitates a Mobitz type II secondor third-degree block during exercise

Inadequate rise of BP in younger patients is suggestive of hypertrophic cardiomyopathy or left main disease; similar findings in older persons may suggest autonomic dysfunction

Neurological testing

Suspicious for seizures, cerebrovascular event, neurodegenerative disorders, increased intracranial pressure

Seizure can be confirmed with electroencephalography Cranial imaging studies as clinically indicated

Orthostatic BP

Evaluate neurally mediated syncope from orthostatic hypotension

Diagnostic if decrease in systolic BP ≥20 mmHg; if systolic BP <90 mmHg; or if decrease in diastolic BP ≥10 mmHg with symptoms Consider diagnostic even when patient is asymptomatic

Psychiatric testing

When syncope is suspected to be psychogenic

Consider with concurrent electroencephalography and video monitoring

Tilt-table testing

Evaluate neurally mediated syncope, distinguish between neurally mediated and orthostatic hypotension, recurrent unexplained falls, differentiate syncope with jerking movements from seizure, frequent syncopal episodes and psychiatric disease

Used when initial evaluation findings are negative, normal cardiac structure, and no evidence of ischaemia Contraindicated in patients with ischaemic heart disease, uncontrolled hypertension, left ventricular outflow tract obstruction, or aortic stenosis

arrhythmia when initial cardiac or neural­ ly mediated syncope investi­gations are negative and an arrhythmia is suspected. In-hospital telemetry and 24-hour Holter monitoring have a typical, very low yield but may be considered for frequent syncopal episodes.

An ILR is a very useful diagnostic tool in patients with unexplained syncope; it has a

battery life of 2 - 3 years. When syncope occurs, the device can be retrospectively activated by the patient and subsequently interrogated to establish whether there were any arrhythmias at the time of the syncopal episode. Documenting no arrhythmia during a syncopal episode is very useful to exclude an arrhythmic cause of syncope.

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ILRs should be considered when there is recurrent unexplained or high-risk syncope, frequent episodes affecting quality of life, recurrent and unpredictable episodes putting the patient at risk of trauma, or when syncope occurs during high-risk activity, e.g. operating machinery or driving.

Occasionally, electrophysiological studies

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Table 7. Risk stratification in a patient with syncope High risk (hospital admission recommended) • Clinical history suggestive of arrhythmia-induced syncope (e.g. syncope during exercise, palpitations at time of syncope) • Comorbidities (e.g. severe anaemia, electrolyte imbalances) • Electrocardiographic history suggestive of arrhythmia-induced syncope (e.g. bifascicular block, sinus bradycardia <40 beats/min in absence of sinoatrial block or medications, pre-excited QRS complex, abnormal QT interval, ST segment elevation leads V1 - V3 (Brugada syndrome), negative T wave in right praecordial leads and epsilon wave (arrhythmogenic right ventricular dysplasia/cardiomyopathy)) • Family history of SCD • Older age • Significant structural heart disease or coronary heart disease Low risk (outpatient evaluation recommended) • Age <50 years • No history of cardiovascular disease • Normal ECG • Symptoms consistent with neurally mediated or orthostatic syncope • Unremarkable cardiovascular examination ECG = electrocardiogram; SCD = sudden cardiac death.

may be indicated in patients with a high index of suspicion for ventricular tachycardia, bundle branch block, or supraventricular tachycardia.

Risk stratification

The prognosis varies among the different categories of syncope and in many cases the diagnosis remains uncertain from history and examination alone. Between 20% and 50% of patients have unexplained syncope after intensive diagnostic evaluation. Therefore, risk stratification tools have been designed to assist differentiation between low- and high-risk patients. These tools aid in deciding whether a patient qualifies for hospital admission and further investigation or if they can be reassured and discharged from an emergency unit. Ultimately, it is imperative that the final decision remains that of the attending practitioner, based on his/her clinical discretion.[1,6,7] Table 7 illustrates the findings that categorise patients according to risk.

Management principles

As syncope is a symptom of disease, management depends on the underlying cause.

Establishing the diagnosis should largely be based on a thorough history and examination and the use of basic investigations, e.g. an ECG. Further investigations should only be used when clinically indicated.

Discussion of specific treatment options in individual diseases is beyond the scope of this article. Patients with life-threatening causes of syncope should be managed urgently and appropriately. In patients with reflex or orthostatic syncope it is important to address any exacerbating medication and provide general measures to increase BP, such as physical counter-pressure manoeuvres. A small proportion of

patients with severe cardio-inhibitory carotid sinus hypersensitivity may require a dual-chamber pacemaker. Where heart disease is found to be the cause of the syncope a specialist opinion is warranted and where possible the problem should be corrected.

Conclusion

It is important to remember that in any patient presenting with syncope the main objectives of management are to prolong survival, limit physical injuries and prevent recurrences. This can only be done if a patient is appropriately assessed at presentation, investigated as clinically indicated, and subsequently referred to a cardiologist for appropriate management. In patients in whom the diagnosis remains uncertain, risk stratification tools can be utilised to assist in deciding whether patients need admission or further evaluation.

Funding. This review is not funded. Dr N A B Ntusi acknowledges funding from the National Research Foundation and Medical Research Council of South Africa.

References 1. Task Force for the Diagnosis and Management of Syncope; European Society of Cardiology (ESC); European Heart Rhythm Association (EHRA); Heart Failure Association (HFA); Heart Rhythm Society (HRS); Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J 2009;30(21):2631-2671. [http://dx.doi.org/10.1093/eurheartj/ ehp298] 2. Brignole M, Hamdan MH. New concepts in the assessment of syncope. J Am Coll Cardiol 2012;59(18):158315-158391. [http://dx.doi.org/10.1016/j.jacc.2011.11.056] 3. Ungar A, del Rosso A, Giada F, et al.; Evaluation of Guidelines in Syncope Study 2 Group. Eur Heart J 2010;31(16):2021-2026. [http://dx.doi.org/ 10.1093/eurheartj/ehq017] 4. Parry SW, Tan MP. An approach to the evaluation and management of syncope in adults. BMJ 2010;340:c880. [http://dx.doi.org/0.1136/bmj.c880] 5. Ganzeboom KS, Colman N, Reitsma JB, Shen WK, Weiling W. Prevalence and triggers of syncope in medical students. Am J Cardiol 2003;91(8):1006-1008. [http://dx.doi.org/org/10.1016/S00029149(03)00127-9] 6. Gauer RL. Evaluation of syncope. Am Fam Physician 2011;84(6):640-650.

7. Seger JJ. Syncope evaulation and management. Tex Heart Inst J 2005;32(2):204-206.

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ARTICLE

An approach to epilepsy E B Lee-Pan, MB ChB, MMed (Neurology); L Tucker, MB ChB, MSc, FCP (Neurology) (SA), PhD Division of Neurology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa Corresponding author: E B Lee-Pan (eddy.leepan@uct.ac.za)

The key to understanding and managing epilepsy is to decide whether seizures are genetic/idiopathic or caused by focal brain pathology.

The classification of seizures was modified in 2010 after many variations of the original 1981 system and inconclusive debate. Major changes included abandoning many entrenched words and complete rejection of the Focal subsystem. While most of the reasoning is rational, the focal system is described in a long list of terms; general clinicians are therefore faced with a more challenging task than that required for understanding the old classification system. Some of the difficulties include using common words with non-intuitive neurological definitions, ambiguous words and the tendency to merge seizure categorisation with epilepsy. This article highlights some of the fundamental principles in trying to categorise seizures and offers a simplified way of using descriptive words to structure the organisation of Focal seizures. Focal seizures are broken down to A, B and C – an easy-to-remember schema for general clinicians, patients and carers. Words such as ‘Aura’ and ‘Blank stare’ are strategically used to represent old seizure types and how they may be linked in the same patient. Awareness or the lack thereof is explained and how the same patient may have different seizure types and combinations of these. There is less change in the Generalised seizures category, but these are often confused with Focal seizures. Absences are confused with blank stares, while Generalised Tonic-Clonic seizures (GTCSs) are confused with ‘Focal-onset evolving rapidly to GTCSs’. Diagrams to illustrate the concepts of Generalised and Focal are included, as well as tables to demonstrate the differences between seizures that appear similar and points to consider in separating them. Focal seizures may mimic almost any human behaviour. Sorting and grouping the symptoms of Focal seizures with awareness (auras) is covered, along with sorting both the former and those without awareness seizures (As and Bs) by brain lobes. Distinguishing between Generalised and Focal seizures is not merely an academic exercise. It assists in determining the aetiology and has a material impact on the choice of management. Appropriate management of seizures starts with identifying the various seizure types. Time will tell whether or not this new descriptive approach to organisation of seizures makes the task easier and more effective.

S Afr Med J 2015;105(8):693. DOI:10.7196/SAMJnew.8039

A new organisation of epileptic seizures

(Note: because of the difficulty of using neurologically defined English words, these have been capitalised, e.g. ‘Absence’ is a neurologically defined word, whereas ‘absence’ is a normal English word. Where old terms are being replaced with new ones, both may be used together for clarity. Older discouraged terms are in square brackets. While descriptive words may change, the correct concepts need to be communicated accurately.)

The key to understanding and managing epilepsy is to decide whether the seizures are genetic [idiopathic] or caused by focal brain pathology.

Unfortunately, the clinical description (semiology) of a seizure often fails to inform the clinician of this distinction and may be misleading. For example, a 60-year-old man presenting for the first time with a sudden Generalised Tonic-Clonic Seizure (GTCS), should be viewed as suffering from a possible Focal-onset seizure with secondary generalisation rather than a genetically predisposed Generalised seizure type, and an underlying structural intracranial lesion should be excluded.

How best to distinguish and classify different seizure types has challenged the world’s top epileptologists for decades and, after many years of heated debate and unsatisfactory variations, the most recent classification, as well as many well-used terms, was finally abandoned in 2010, leaving a partial vacuum. The new organisation of seizures suggests that Focal seizures be described rather than pigeonholed.

Generalised seizures

Ambiguities with regard to terminology and confusion concerning neurological definitions of commonly used terms were largely responsible for the abovementioned decision. Conceptually, for instance,

the word ‘Generalised’, e.g. a Generalised seizure, implies a disorder in which the entire cortex instantly becomes epileptiform (Fig. 1). Thus, a patient may be functioning entirely normally and, within a fraction of a second, epileptic activity may cause abrupt mass dysfunction of numerous neuronal systems throughout the brain, including memory and awareness. This virtually instantaneous shutdown of memory means that the patient will have no recall of anything that is ‘happening or about to happen’, i.e. no recollection of the seizure onset (i.e. no aura) and amnesia for the duration of the seizure. The two most common types of Generalised seizures are Absence seizures and GTCSs. These are both descriptive rather than aetiological terms, and have previously been termed ‘idiopathic’. As used in epilepsy, idiopathic does not simply mean an ‘unknown’ aetiology, but implies ‘in and of itself ’ (i.e. presumed genetic). Apart from abandoning the term idiopathic, there have been few significant recent changes in Generalised seizure categorisation.

Focal seizures

Compared with Generalised seizures, Focal seizures (the term ‘Partial’ has been formally abandoned) mostly occur after previous focal brain injury (e.g. meningitis as a baby or a significant head injury) or occasionally with an active lesion (e.g. tumour, parasite or abscess).

With retained awareness

Categorising Focal seizures has always been problematic, and one must keep in mind that individual patients may suffer from more than one Focal seizure type. When a Focal seizure starts, only that discrete region of the cortex is involved and rendered dysfunctional. For instance, if only a portion of the primary motor cortex is affected by epileptic activity, the patient may experience clonic jerking confined to the contralateral arm,

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while memory and awareness remain intact.

Thus, the patient is able to experience and recall the manifestations of the focal seizure.

This subjective recall of focal seizure activity may be regarded as an aura or warning of imminent extension to loss of awareness and/ or secondarily GTCSs.

Cortex

Thalami

With altered awareness

The focal epileptic activity described above may either remain confined or spread ‘deeper’ into the brain, rendering the patient ‘unaware’. When regions of the brain that mediate awareness are affected, but the seizure has no generalised tonicclonic manifestations, it was previously termed a ‘Focal Complex Seizure’ or a ‘Complex Partial Seizure’, Complex indicating altered awareness or consciousness. The semiology of Focal Complex seizures may include a ‘blank stare’, a ‘motor arrest’ (sudden freezing), stereotyped non- or semi-purposeful movements, ‘fidgeting’ and ‘lip-smacking’. These are often termed automatisms and usually take the form of simple, repetitive actions as described, but may occasionally be more complex, such as repetitive recitation of a phrase or walking in circles (post-ictal confusion is common after these seizures and may also be responsible for some behavioural components).

Evolving to GTCSs [secondarily GTCSs]

Ultimately, if the seizure spreads deep into the reticulothalamic circuits and then projects upwards to affect the entire brain, the patient will experience secondarily generalised tonicclonic activity (Fig. 2). However, if the epileptic focus is situated in a clinically ‘silent’ area of the cortex, or if the spread from focus to generalisation is rapid, the patient may not experience or recall an aura. This means that it may be extremely difficult to distinguish Generalised seizures from Focal-onset seizures with rapid secondarily generalisation, as in the example at the beginning of the article. Postictal confusion is common after GTCSs and some patients may be transiently confused or psychotic.

Distinguishing between Generalised and Focal seizures is not merely an academic exercise. It assists in determining the aetiology and impacts materially on the choice of management.

Simplifying Focal seizures

The new descriptive categorisation of Focal seizures may sound simple and rational, but the current lack of clearly defined unambiguous terms and absence of an acceptable classification structure are problematic and make teaching difficult for healthcare professionals. Furthermore, patients and their carers need to categorise

Reticular formation

Seizure activity

Fig. 1. Schematic representation of a Generalised Tonic-Clonic Seizure, with rapid activation of seizure activity involving the entire cortex.

A

A

B 1. Focal seizure starts

2. Focal seizure spreads to loss of awareness

Seizure activity

A

B 3. Focal seizure continues to deep midline structures

4. Focal seizure becomes a Generalised Tonic-Clonic Seizure

C

Fig. 2. Schematic representation of a Focal seizure (A) with secondarily generalisation (B and C) to a Generalised Tonic-Clonic Seizure.

Table 1. Core changes in the new organisation of seizures, with customised adaptations for the old Focal subtypes Old

Generalised

Partial

New

Generalised

Focal

Old

Absence

Other types

GTCS

Simple

Complex

2° GTCS

New

Absence

Other

GTCS

Aura->

Blank->

->GTCS

seizures to diarise them correctly. Understand­ ably, most general clinicians are reluctant to invest the time necessary to adopt new complex classifications, as they deal with seizures infrequently. As a compromise, we use the descriptive words aura and blank stare instead of Focal Simple and Focal Complex seizures, respectively. By abbreviating this

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further to A (aura) and B (blank stare) and adding C (for secondarily GTCS), a clinically useful A->B->C mnemonic is available for patients and medical staff (Table 1). This also satisfies the current recommendation of describing the semiology.

For Generalised seizures, a similar A and C mnemonic represents A for Absence and

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Table 2. Differences between (Generalised) Absence seizures and Focal seizures with loss of awareness (Blank stare) on the EEG Differences

Absence

Blank stare

Age

5 - 15 years

Any age

Duration

Short seconds

Longer minutes

Automatisms

Less/simpler

More/varied/complex

Post-ictal confusion

No

Yes

EEG

Generalised 3 Hz spike and wave

Focal

EEG = electroencephalogram.

Table 3. Differences between Generalised Tonic-Clonic and Focal-onset Seizures evolving to Generalised Tonic-Clonic Seizures Differences

GTCS

->GTCS

Aura

No

A->B->C, A->C/B->C

Focal brain lesion

No

Active or scar lesion

Inter-ictal EEG

Brief Generalised spike and wave

Focal spike and wave

Ictal EEG

Generalised spike and wave

Focal evolving spiky rhythm

A = Aura; B = Blank; C = GTCS.

C for GTCS, with a gap in between for all the other, much less common, Generalised seizure subtypes. Of these, ‘myoclonic’ is probably the next most common subtype.

Some Generalised seizure subtypes are seen mostly in children, e.g. an atonic seizure.

Separating the description of a seizure from its cause is intuitively difficult. For instance, although the concept of Generalised seizures is strongly linked to a presumed genetic [idiopathic] aetiology, Generalised seizures may also occur owing to underlying nongenetic metabolic disorders. Similarly, certain focal-onset seizures subtypes are presumed to have a genetic basis. Consequently, this review is necessarily simplistic and covers the more commonly encountered and more easily separated seizure types.

Pragmatically, it may be useful to tabulate some differences between clinically similar, yet physiologically and aetiologically distinct, seizure types. For instance, Generalised Absence seizures are often confused with Focal [Complex] blank stare seizures as both involve altered awareness. However, Absences only very rarely occur in adults, especially for the first time, while onset of Focal [Complex] blank stare seizures may occur at any age (Table 2). The two kinds of GTCSs are compared in Table 3.

To complicate matters, as is the case with Focal seizures, some patients with [idiopathic] Generalised seizures may experience more than one seizure type; most commonly Absence seizures and GTCSs. However, these generalised seizure types occur independently – even at different times in a patient’s life. Patients with juvenile myoclonic epilepsy may have three

seizure types (myoclonic, Absence and GTCSs).

These may occur independently, but some patients feel their myoclonus ‘warns’ them of an impending GTCS. This does not imply a focal onset, but indicates that the concept of instantaneous loss of awareness in Generalised seizure types is not always the case, as these patients are fully aware of their myoclonus.

The ‘hallmark’ of Focal complex/blank stare-type seizures is their consistent stereotypy, irrespective of whether the clinical manifestations of the seizure are subtle (e.g. fidgeting or lip-smacking) or dramatic (e.g. overt bizarre behaviour), their electrical and clinical evolutions are consistently locked – every detail happens in the same way and order every time.

Grouping Focal seizure symptoms

Focal seizures are of special interest to all clinicians, as they may closely mimic almost any non-epileptiform paroxysmal event.

With this in mind, it is useful to group the Focal seizures with retained awareness and memory (i.e. auras) into four categories: motor, sensory, autonomic or psychic.

The motor category may seem simple to identify but may range from unilateral tonic and clonic elements to a wide range of more complex actions. Sensory symptoms also have a wide spectrum involving all sensory modalities, from primary sensations such as paraesthesia, pain and even rarely numbness, to the special senses such as smell, taste, vision and hearing. Autonomic seizure symptoms may also be quite varied, but most commonly involve gastrointestinal symptoms best described as ‘a rising epigastric sensation’. These epigastric

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auras may remain confined to the abdominal area. Psychic symptoms are less common and often the most difficult to recognise as a seizure.

Examples include an unexplained feeling of inappropriate intense fear or ‘impending doom’ or the more common déjà vu. Whatever the seizure symptom, its episodicity, clinical context and stereotypy help to identify it as a seizure.

One may also group Focal seizures according to the lobe in which the seizure occurs, whether or not they involve loss of awareness (auras and blank stares). This is because the nature of the Focal seizure onset (i.e. the semiology of the aura) is often closely linked to the anatomical site of the seizure focus. Statistically, the majority of focal seizures have their onset in the temporal lobe. The next most common site is the frontal lobe, while the parietal and occipital lobes have a much lower propensity to cause Focal seizures. This regional propensity for Focal seizure onset is reflected electrophysiologically.

A potentially epileptic spike (i.e. electrical discharge) identified in the temporal lobe on an electroencephalogram (EEG) is much more likely to be associated with seizures than an identical spike in the occipital lobe. Apart from being the most frequent type, temporal lobe auras may also involve a wide range of symptom types – from autonomic to psychic, but also sensory, such as olfactory, gustatory, visual illusions, hallucinations and even vertigo. Once awareness is impaired, temporal lobe seizures are also involved in the blank stare or motor freeze, oral automatisms (i.e. lip smacking) and aphasia. Electrical seizures do not recognise lobe boundaries; hence, there may be some overlap.

Frontal lobe seizures host a wide variety of complex motor actions as well as strange alterations of awareness and ‘bizarre behaviour’, often with little or no post-ictal confusion. It is not uncommon for patients with frontal lobe seizures to be referred for psychiatric assessment before the ictal nature of their symptoms is recognised. The recent discovery of an association between some strange seizures (e.g. brachiodystonic) and autoantibodies (e.g. against the NMDA (N-methyl-D-aspartate) or AMPA (α-amino3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors is important, because this has resulted in the recognition of encephalitides, some of which are paraneoplastic, and most of which are treatable with immunosuppression if identified in the early stages. The seizures associated with these autoimmune encephalitides are generally immune to standard anti-epileptic drugs.

Appropriate management of seizures starts with identifying the various seizure types. Time will tell whether or not the new descriptive approach to organisation of seizures makes this task easier and more effective.

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ARTICLE

An approach to acute vertigo K Bateman,1 MB ChB, FCP Neurol (SA); C Rogers,2 MSc (Audiology); E Meyer,3 MB ChB, FCS (ORL) Division of Neurology, Department of Medicine, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa Division of Communication Sciences and Disorders (Audiology), Department of Health and Rehabilitation Sciences, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa 3 Division of Otolaryngology, Department of Surgery, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa 1 2

Corresponding author: K Bateman (kathleen.bateman@uct.ac.za)

There can be few physicians so dedicated to their art that they do not experience a slight decline in spirits when they learn that their patient’s complaint is giddiness. This frequently means that after exhaustive enquiry it will still not be entirely clear what it is that the patient feels wrong and even less so why he feels it. (W B Mathews)[1] Contrary to this prevalent view, in recent years advances in the diagnosis and management of common vestibular disorders have made the clinical evaluation of the dizzy patient more rewarding. An accurate diagnosis may be possible in the majority of patients presenting with acute vertigo when a directed history is taken and an examination is performed. Specific and effective treatments are available for many patients. This article describes the clinical evaluation of a patient with acute vertigo, and highlights selected common and important conditions.

S Afr Med J 2015;105(8):694. DOI:10.7196/SAMJnew.8097

Vertigo, the illusion of movement, is usually due to peripheral vestibular disease of the end-organ or nerve. Acute vertigo or dizziness in isolation is usually benign. Despite recent consensus definitions of potential vestibular symptoms, such as vertigo, dysequilibrium and presyncope, it can be difficult to tease out a clear history of vertigo in a patient presenting with dizziness.[1] However, it is important to make a specific diagnosis to appropriately manage serious underlying conditions such as stroke and common conditions such as benign paroxysmal positional vertigo (BPPV), which respond well to immediate treatment. It is possible to make an accurate diagnosis in most patients and the history is the main tool.

The clinical evaluation must answer the following questions: Firstly, is it vertigo? Secondly, is the lesion central (i.e. involving the parts of the central nervous system concerned with balance and vision) or peripheral (involving the vestibular nerve or apparatus of the inner ear)? Thirdly, does the patient require urgent brain imaging?

We discuss the clinical approach to a patient with acute vertigo, and thereafter highlight selected common or important causes of vertigo, outlining management strategies.

Clinical approach to a patient with acute vertigo Is it vertigo?

Vertigo has been defined as the sensation of motion when no motion is occurring.[2] The conventional diagnostic approach to vertigo or dizziness focuses on the nature of the symptom, whether vertigo, presyncope (impending faint), dysequilibrium (unsteadiness with eyes open), or nonspecific dizziness, to direct efforts towards investigating for vestibular (if vertigo), cardiac (if presyncope), neurological (if dysequilibrium), psychiatric or metabolic causes.

However, ‘dizziness’ or ‘vertigo’ are used by patients for a range of subjective experiences that may not imply vertigo. Therefore, it is important to ask the patient to describe in detail the different sensations they experience, without asking leading questions. Is it

rotatory/spinning (merry-go-round), rocking (as on a boat) or linear (like falling)? A rotational component to vertigo makes it highly likely that there is a disorder of the semicircular canals or their central pathways. It can be helpful to ask a patient if the problem is ‘in their legs or in their head’ (spinal cord/cerebellar v. vestibular causes) or if they feel ‘as if they are about to faint’ (presyncope).[3] Recent studies, however, have shown that the timing (especially duration) and triggers of symptoms of dizziness may be more helpful in diagnosing the underlying disorder than the quality of the symptoms.[4] Determining whether vertigo is episodic or persisting, or provoked by positional changes, is very helpful for the diagnosis.

Paroxysmal positional vertigo may be due to BPPV or, rarely, central positional causes. Recurrent spontaneous attacks of vertigo over several years are often due to migrainous vertigo or Ménière’s disease.

Acute persisting vertigo may be caused by vestibular neuritis or posterior fossa stroke. Very frequent short-lived spells of dizziness or imbalance might be due to vestibular paroxysmia or superior canal dehiscence syndrome. Postural imbalance without other neurological symptoms may, for example, commonly be secondary to chronic subjective dizziness or bilateral vestibulopathy following gentamicin toxicity.[5] More details of the timing of symptoms, possible triggers, associated features, and a broader differential diagnosis of acute vertigo are set out in Fig. 1. A complete medical history is essential, as many medications used to treat seizures, depression, anxiety and pain may affect the vestibular system.

Is the lesion central or peripheral?

Once a history of the timing and triggers has narrowed down the differential diagnosis, careful examination should focus on dividing central from peripheral causes. Unidirectional nystagmus, where the direction of nystagmus is unchanged by change in direction of gaze (slow phase towards the dysfunctional labyrinth), is typical of peripheral vestibular disease, and will be most evident when looking in the direction of the fast phase. Unidirectional nystagmus may infrequently be seen in central vestibular lesions involving the brainstem; however,

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accompanying neurological signs make localisation fairly straightforward. The ability to suppress nystagmus in the light (i.e. with visual fixation) suggests intact central mechanisms.[3] The vestibular ocular reflex is impaired in peripheral vestibular disorders, and thus the head impulse (or head thrust) test will be abnormal. This test is fairly easy to perform, and is particularly useful to confirm peripheral dysfunction.[6] Smooth pursuit movements of the eyes are intact in peripheral vestibular syndromes, although the assessment may be difficult owing to the presence of marked nystagmus. With central causes of vertigo, pursuit movements of the eyes are typically broken or jerky. Positional nystagmus (triggered by rapid changes to the head position) is commonly seen and may be due to either peripheral (BPPV) or central causes. However, when caused by BPPV, it has characteristic features of latency, adaptibility, and fatigability (discussed below) that are not present in central disease. The Dix-Hallpike test should be performed on all dizzy patients, whether symptomatic or not.

Table 1 summarises the key eye features of peri­pheral v. central vertigo.

A neurological examination should be performed, looking carefully for brainstem and cerebellar signs. Posterior fossa strokes may rarely cause isolated (central) vertigo, and infarction of the labyrinth may even more rarely mimic a peripheral vestibular disorder with vertigo and deafness (discussed below). Cardiac and aural examinations (usually including an audiogram) are necessary in this setting.

Does the patient require brain imaging?

Brain imaging is required in cases of acute vertigo, with one or more of the following:[3] • new-onset (especially occipital) headache

• • • •

• any central neurological symptoms or signs (including central nystagmus) • acute hearing loss • an intact head impulse test.

Common causes of acute vertigo • Benign paroxysmal positional vertigo BPPV is the most common cause of acute vertigo and has a characteristic history and examination. It is, however, frequently missed, because the patient does not spontaneously describe the position-induced nature of the vertigo or the attending doctor fails to perform a Dix-Hallpike test.

Patients typically have brief attacks of rotatory vertigo that are triggered by movements such as lying down or rolling over in bed, extending the neck, e.g. when inserting eye drops or reaching for an item on a shelf, or when flexing and extending the neck on bending over to lift and hang washing. Each episode lasts only seconds; however, it is not unusual for patients to complain of persisting

Table 1. Peripheral v. central eye signs in acute vertigo Sign

Key feature

Peripheral

Central

Nystagmus

Direction

Unidirectional only Mixed horizontaltorsional

Uni- or bidirectional* Purely vertical, horizontal or torsional

Suppression with visual fixation

Yes

No

Smooth, i.e. intact

Broken or jerky towards side of lesion

Smooth pursuit Positional nystagmus

Features of latency, adaptibility, fatigability present?

Yes

No

Vestibular ocular reflex

Head thrust test

Impaired

Intact

*

Direction changing.

Vertigo: probable vestibular lesion Light-headedness Presyncope/syncope Dysequilibrium

• Movement: BPPV, exclude postural hypotension, central mimics

symptoms of disturbed gait, blurred vision or ‘wooziness’, which may be misleading.

Episodes of vertigo usually occur in clusters over a few weeks to months and then remit – only to return weeks, months or years later.

Examination reveals rotatory-linear nystagmus provoked by rapid changes to head position during the diagnostic positioning test – the Dix-Hallpike manoeuvre (Fig. 2). The nystagmus has a short latency (2 - 15 seconds), builds to a maximum, lasts <40 seconds, and is fati­gable (wears off after repeated tests). The Dix-Hallpike test should be performed routinely in all patients who complain of dizziness (up to one-third of patients with BPPV may not give a typical history). In nearly all patients there are no other demonstrable clinical signs of auditory or vestibular dysfunction.

The cause of BPPV is mechanical, owing to the movement of loose otoconial particles within one semicircular canal, most often the posterior one. Particle positioning manoeuvres

Nature of sensation

Time course and likely aetiology

Triggers

Associated symptoms

• URTI: vestibular neuritis • Noise: semi-circular canal dehiscence

• Seconds to minutes, episodic: BPPV • Minutes to hours, episodic: vestibular migraine, Ménière’s disease, cardiac arrhythmia • Days to weeks, persistent: vestibular neuritis, posterior fossa stroke or demyelination, medication toxicity • Chronic unsteadiness: bilateral vestibular failure, spinal cord lesion, cerebellar degeneration, chronic subjective dizziness

• Aural: hearing loss, tinnitus, fullness, pressure, hyperacusis

• Neurological • Cardiac • Vegetative: anxiety, depression

syndrome, fistula

• Medication: ototoxicity • Dietary/lifestyle: migraine, psychological

Fig. 1. Key aspects of the vestibular history (BPPV = benign paroxysmal positional vertigo; URTI = upper respiratory tract infection).

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Fig. 2. The Dix-Hallpike test to the right ear. With the patient seated on the couch, rotate the head 45° to the right. Warn the patient that they may become vertiginous, and ask them to keep their eyes open and report any symptoms. Move the patient rapidly into the supine position, with the neck extended at 30° and the head over the end of the couch. Vertical upwards-rotational nystagmus beating towards the ground may appear after a few seconds (latency) and last 5 - 10 seconds. This may be accompanied by symptoms of vertigo, signifying a positive test (right posterior canal BPPV). If nystagmus does not appear, wait at least 30 seconds before returning the patient to the upright position as latency may be longer than usual. A negative test does not exclude BPPV.

are therefore the mainstay of diagnosis (Dix-Hallpike test) and treatment (Epley or Semont manoeuvres). Video tutorials of these procedures are readily found on the internet, and the manoeuvres are very successful, safe and easy to administer.[7,8] One treatment with the Epley or Semont manoeuvre is often sufficient, as complete recovery is reported in 50 - 70% of patients.[9] Patients should be informed that the procedure is a treatment and not a cure, and that relapse is common, occurring in up to one-third of patients over the next 5 years. Education lessens patient anxiety and subsequent episodes can be retreated successfully.

• Vestibular neuritis Vestibular neuritis presents with a subacute onset over hours of incapacitating vertigo, nausea and vomiting because of unilateral loss of vestibular function. Thought to be caused by the herpes simplex virus, it has been variably called ‘vestibular neuronitis/neuritis’ or ‘labyrinthitis’. However, as evidence for viral infection is limited, some prefer the term ‘acute idiopathic unilateral peripheral vestibulopathy’.[6] Unlike BPPV, spinning vertigo persists for hours to days. The sense of movement is present even with the eyes closed and is worsened by head movement; yet, it is not fully suppressed by keeping the head motionless.

On examination, typical unidirectional nystagmus is seen, as described above. The head impulse test is invariably abnormal. With the eyes open, the patient is unsteady but can stand without support.[6] Importantly, hearing is normal and no other neurological signs are present.

Management consists of supportive treatment (intravenous fluids, anti-emetics) and a vestibular suppressant, such as prochlorperazine or diazepam (preferably not for longer than a few days). The patient should be encouraged to mobilise as soon as possible to improve clinical recovery, which is largely achieved via central compensation.[10] Steroids appear to hasten complete recovery of the caloric function on testing, but no clinical or long-term benefits have been shown to justify their use in this setting.[11] Antiviral agents have not been proven to work.[12] In most patients the symptoms resolve over weeks, but a feeling of dysequilibrium and dizziness with sudden head movement may last for months. Patients who have residual symptoms at 6 weeks may benefit from vestibular rehabilitation therapy. Although vestibular neuritis tends not to recur, it may be followed by BPPV (in 5%), which may prove more difficult to treat than usual.[13,14] If hearing loss is present, the likely diagnosis is labyrinthitis, and patients should be referred for specialist ear, nose and throat evaluation.

• Cerebellar stroke In a patient with a first-ever attack of acute spontaneous vertigo persisting for several hours, the main differential diagnosis of acute vestibular neuronitis is cerebellar infarction. There are several clues to the diagnosis. First, the onset is hyperacute in stroke, whereas vestibular neuronitis usually develops over hours (rarely minutes). Second, if the head impulse test is positive, the patient has vestibular neuritis; if it is negative, the patient may have a cerebellar infarct. Third, vertigo ascribed to a cerebellar infarction may reveal nystagmus that is bilateral (i.e. direction changing), or vertical, or does not suppress well on fixation, suggesting a central cause. Patients have a sense of self-movement, even when their eyes are closed, and while this may worsen with head movement, it is not fully suppressed by keeping the head completely still. Last, a patient with cerebellar infarction often cannot stand without support, whereas one with acute vestibular neuronitis usually can.

Cerebellar infarction is important to diagnose, as life-threatening posterior fossa brain swelling may ensue, needing emergency surgical decompression.

Recurrent short-lived vertiginous episodes are rarely caused by vertebrobasilar ischaemia, and if they occur almost always have additional brainstem symptoms or signs. Acute peripheral vertigo with a positive head impulse test and deafness may even more rarely be caused by vertebrobasilar ischaemia (specifically, infarction of the labyrinth); these patients require brain imaging if they lack a typical history of Ménière’s disease.

• Vestibular migraine Migrainous vertigo is an increasingly recognised cause of vertigo. As in the case of classic migraine, it is a clinical diagnosis according to consensus definitions.[15] Patients may be dizzy for minutes, hours or even days, with a range in their symptoms from mild dysequilibrium or motion intolerance to severe spinning sensations. When the vertigo occurs concurrent with a migraine, the diagnosis is fairly straightforward. However, migraineurs may quite often have episodes of vertigo, with or without other features of migraine such as photoor phonophobia, in the absence of headache. Adding complexity to the diagnosis, some patients may have symptoms or signs – including nystagmus – that suggest central dysfunction. Consequently, brain imaging may be necessary in patients with a first presentation of acute migrainous vertigo. Standard antimigraine prophylactic drugs (e.g. sodium valproate, propranolol and amitriptyline) are used with good success, although robust evidence for the specific treatment of migrainous vertigo is lacking.[16]

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• Ménière’s disease Patients with repeated attacks of spontaneous vertigo, each lasting >1 hour, are likely to have either vestibular migraine or Ménière’s disease, but the latter is probably overdiagnosed with this presentation. A sense of pressure or fullness in the ipsilateral ear usually precedes the onset of vertigo by a few minutes. Vertigo lasts 20 minutes to a few hours (<24), and may or may not be accompanied by low-frequency ipsilateral tinnitus and fluctuating hearing loss that may persist for several days. Fatigue is common after the episodes.

Attacks occur intermittently over years, and after the first few attacks vestibular and auditory function return to normal. Some patients remit spontaneously. However, in those who have ongoing attacks of vertigo, permanent loss of function may initially only be detected by audiogram or caloric testing. Over time, this may become clinically evident, with the added misery of tinnitus and hearing loss with unpleasant sound distortion persisting between attacks.

The diagnosis of Ménière’s disease rests primarily on a meticulous history. Audiograms are useful, particularly when serial tests are performed, to document the low frequency and fluctuating hearing loss over time. Video nystagmography-caloric testing can confirm unilateral loss of vestibular function (usually incomplete), but this is nonspecific. Imaging is generally not helpful. However, when the history of vertigo is not typical, then unilateral tinnitus and moderate to severe hearing loss require magnetic resonance imaging of the internal auditory meatus to exclude a vestibular schwannoma.[2] Bilateral hearing loss should prompt referral to a specialist.

There are no proven treatments to prevent the progressive innerear damage that is presumed to be due to episodic endolymphatic hypertension. Symptomatic relief may be obtained with the use of vestibular suppressants, which may be administered rectally when nausea is severe. Betahistine (16 mg 3 times daily) or a low-salt diet, either alone or with a diuretic, is frequently used as prophylaxis, but remains unproven.[17] Betahistine given in higher doses (48 mg 3 times daily) may be more effective.[18,19] When intense attacks are frequent, more invasive procedures such as instillation of gentamicin or steroids via intratympanic injection or a grommet may be considered or, very rarely, vestibular nerve section or labyrinthectomy. Surgery on the endolymphatic sac is of questionable value.[20] However, all of these procedures treat symptoms of vertigo without preserving hearing or vestibular function.

Conclusion

When faced with a patient with vertigo, focus on the timing and triggers of symptoms, particularly if episodic, persisting or provoked by positional head changes. It is important to discriminate between central and peripheral causes by a careful, directed examination, including a Dix-Hallpike test which, if positive (signifying BPPV), may result in specific treatment with the Epley manoeuvre. An audiogram is particularly useful in a patient with vertigo; if normal in the setting of episodic vertigo, one might consider migraine rather than Ménière’s disease. In the first-ever attack of acute spontaneous vertigo, a normal head impulse test raises concern of a cerebellar infarct. Although specific management of vertigo depends on the aetiology, all patients with vertigo benefit from vestibular rehabilitation exercises where the emphasis is on movement. Vestibular suppressants should be avoided in the long term as they may impede recovery.

References 1. Halmagyi G, Cremer P. Assessment and treatment of dizziness. J Neurol Neurosurg Psychiatry 2000;68(2):129-134.

2. Lempert T. Recurrent spontaneous attacks of dizziness. Continuum (Minneap Minn) 2012;18(5):10861101. [http://dx.doi.org/10.1212/01.CON.0000421620.10783.ac] 3. Seemungal BM, Bronstein AM. A practical approach to acute vertigo. Pract Neurol 2008;8:211-221. [http://dx.doi.org/10.1136/jnnp.2008.154799] 4. Newman-Toker DE. Symptoms and signs of neuro-otologic disorders. Continuum (Minneap Minn) 2012;18(5):1016-1040. [http://dx.doi.org/10.1212/01.CON.0000421618.33654.8a] 5. Brandt T, Strupp M, Dieterich M. Five keys for diagnosing most vertigo, dizziness, and imbalance syndromes: An expert opinion. J Neurol 2014;261(1):229-231. [http://dx.doi.org/10.1007/s00415-013-7190-x] 6. Halmagyi GM. Diagnosis and management of vertigo. Clin Med 2005;5(2):159-165.

7. Hilton M, Pinder D. The Epley (canalith repositioning) manoeuvre for benign paroxysmal positional vertigo. Cochrane Database Syst Rev 2004;(2):CD003162.

8. Hilton M, Pinder D. The Epley (canalith repositioning) manoeuvre for benign paroxysmal positional vertigo. Cochrane Database Syst Rev 2014;(12):CD003162.

9. Brandt T. How to do it: Exercise away vertigo. Pract Neurol 2001;1(1):36-41.

10. Goudakos JK, Markou KD, Psillas G, Vital V, Tsaligopoulos M. Corticosteroids and vestibular exercises in vestibular neuritis. Single-blind randomized clinical trial. JAMA Otolaryngol Head Neck Surg 2014;140(5):434-340.

11. Fishman JM, Burgess C, Waddell A. Corticosteroids for the treatment of idiopathic acute vestibular dysfunction (vestibular neuritis). Cochrane Database Syst Rev 2011;(5):CD008607.

12. Strupp M, Zingler VC, Arbusow V, et al. Methylprednisolone, valacyclovir, or the combination for vestibular neuritis. N Engl J Med 2004;351(4):354-361.

13. Huppert D, Strupp M, Theil D, Glaser M, Brandt T. Low recurrence rate of vestibular neuritis: A longterm follow-up. Neurology 2006;67(10):1870-1871.

14. Balatsouras DG, Koukoutsis G, Ganelis P, et al. Benign paroxysmal positional vertigo secondary to vestibular neuritis. Eur Arch Otorhinolaryngol 2014;271(5):919-924. [http://dx.doi.org/10.1007/s00405-013-2484-2] 15. Lempert T, Olesen J, Furman J, et al. Vestibular migraine: Diagnostic criteria. J Vestib Res 2012;22(4):167-172. [http://dx.doi.org/10.3233/VES-2012-0453] 16. Obermann M, Strupp M. Current treatment options in vestibular migraine. Front Neurol 2014;5:1-5. [http://dx.doi.org/10.3389/fneur.2014.00257] 17. Gordon A. Menière’s disease. Lancet 2006;367:984.

18. James AL, Burton MJ. Betahistine for Menière’s disease or syndrome. Cochrane Database Syst Rev 2001;(1):CD001873.

19. Strupp M, Krause E, Lezius F, Canis M, Ihler F, Gürkov R. Betahistine for Menière’s disease.

Audiological Medicine 2012;10(4):167-170.

20. Thomsen J, Kerr A, Bretlau P, Olsson J, Tos M. Endolymphatic sac surgery: Why we do not do it. The non-specific effect of sac surgery. Clin Otolaryngol Allied Sci 1996;21(3):208-211.

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CONTINUING MEDICAL EDUCATION

ARTICLE

An approach to balance problems and falls in elderly persons L de Villiers, MB ChB, FCP (SA); S Z Kalula, MB ChB, FRCP, PhD Division of Geriatric Medicine, Albertina and Walter Sisulu Institute of Ageing in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa Corresponding author: S Z Kalula (sebastiana.kalula@uct.ac.za)

Gait instability and falls are common in elderly persons and have devastating consequences, with substantial morbidity and mortality.

Furthermore, they are a precipitant for functional decline, increasing frailty and institutionalisation. The rate of falls and severity of complications increase with age and frailty. A consequence of falls with or without injury is that at least a third of persons develop a fear of falling, which leads to functional decline and a progressive decline in gait. The causes of falls in elderly persons are multifactorial and include physiological changes of ageing, frailty, pathologies, and environmental and situational factors. Maintaining postural control requires a complex integration of sensory input, central processing, motor co-ordination and musculoskeletal function, which decrease with ageing.

This change, combined with sarcopenia, leads to slowed and weakened postural control and muscle responses, resulting in gait instability and falls.

The assessment and management of a patient who is at risk of falls or who has fallen require a multidisciplinary approach to identify and address factors contributing to the fall. The assessment, which includes history, physical examination, and evaluation of gait, postural control and mental function, is aimed at identifying situational and associated factors surrounding a fall, intrinsic impairments in gait or pathologies that increase the risk of falls. The components of the assessment comprise a full medical evaluation for pathologies, including vision, medication review (including over-the-counter medication) with regard to polypharmacy and high-risk medications, psychogeriatric review, functional status (instrumental activities of daily living (IADLs) and activities of daily living (ADLs)), functional assessment of gait and balance, and assessment of environmental hazards in the home. Laboratory investigations are guided by clinical suspicions or diagnoses arising from the medical assessment and screening for common conditions that may increase the risk of falls.

Management and prevention of falls focus on maintaining mobility and balance, and identifying those at risk of a fall for multidisciplinary assessment and intervention. Intervention to reduce the risk of subsequent falls is targeted at modification of the contributory factors.

Intervention includes management of underlying pathologies, strength and balance training by a physiotherapist, assessment and modification of environmental hazards in the home by an occupational therapist, medication review and rationalisation of high-risk medications and polypharmacy, and supplementation of vitamin D where indicated.

S Afr Med J 2015;105(8):695. DOI:10.7196/SAMJnew.8037

Gait instability and falls are common in elderly persons and have devastating consequences, with substantial morbidity and mortality. Furthermore, they are a preci­ pitant for functional decline, increasing frailty and institutionalisation.[1] The rates of falls and severity of complications increase with age and frailty. In persons ≥65 years, the prevalence of falls is as high as 30% per year.[2] Among institutionalised persons aged >75 years, mean fall rates are ≤1.7 per bed annually, with half of affected persons having multiple falls, and 10 - 25% of the latter leading to fractures or lacerations requiring hospitalisation.[3] An important consequence of falls is that at least a third of persons develop a fear of falling after the event, resulting in functional decline and a progressive decline in gait.[4] The causes of falls in the elderly are usually multifactorial, with a combination of intrinsic factors, including the physiological changes of ageing, frailty, pathologies, and extrinsic, environmental and situational factors. In up to 10% of patients presenting with a fall the underlying cause is an acute medical condition.[5]

Pathophysiology

Maintaining postural control requires a complex integration of sensory input, central processing, motor co-ordination and musculoskeletal function to perceive environmental stimuli and respond accordingly to perturbations to control body movement (Fig. 1). The sensory information required includes vision, vestibular input and proprioception. With ageing there is a decrease in

depth perception and dark-light discrimination, a high prevalence (≤40%) of decreased vibration and position sense and frequent vestibular impairment. Central processing is slower, both in the interpretation and weighting of sensory information and in motor output and co-ordination. Higher-order cortical processes linking motor and sensory systems are required for planning movements, solving problems, divided attention and environmental scanning and response.[5] Peripheral nerve conduction is slower, there is a decrease in the number of motor units in the spinal cord, and an increase in the number of myocytes with increased excitability thresholds innervated by each motor unit.[6] This change, when combined with sarcopenia (progressive and generalised loss of skeletal muscle mass and strength), leads to slowed and weakened postural control and muscle responses.[7] Slow postural reflexes are seen as increased postural sway (back and forth movement of head and upper trunk exacerbated by removing visual input by closing the eyes) when evaluating gait and balance.[6,8] The assessment and management of a patient who is at risk of falls, or who has fallen, require a multidisciplinary approach to identify and address factors that contribute to a fall. Such an assessment should be considered for elderly persons who have sustained injuries after a fall, have had a single fall, have an abnormal gait, or have had ≥2 unexplained falls in a 12-month period. The history, examination and assessment of gait and postural control are aimed at identifying situational factors surrounding the falls and associated factors,

August 2015, Vol. 105, No. 8

CONTINUING MEDICAL EDUCATION

as well as intrinsic impairments in gait or pathologies that increase the risk of falls.[9] The evaluation of an elderly person who has fallen or has a fear of falling requires a multidimensional assessment of all factors that can contribute to the risk of falls, and is best performed by a multidisciplinary team. These components include a full medical assessment for pathologies, medication review (including over-the-counter medication) with regard to polypharmacy and high-risk medications,[10] psychogeriatric review, functional status, functional assessment of gait and balance and an evaluation of environmental hazards in the home. The interventions to reduce the risk of subsequent falls are targeted at modifying the contributory factors.[9,11]

Motor co-ordination • Frontal lobe motor planning and focusing attention • Motor cortex, basal ganglia and cerebellar integration and coordination • Peripheral nerve function

Biomechanics • Skeletal integrity • Joint stability, integrity and flexibility • Muscle strength

Medical history, examination and investigation

The history of previous falls should include the frequency, environmental factors such as time, location, floor surface, lighting, obstacles and precipitants, as well as associated factors such as footwear, use of walking aids, glasses, and substances or medications (Table 1). The systemic enquiry and physical examination are aimed at identifying causative or contri­ butory cardiovascular, neurological, sensory, musculoskeletal or other impairments and pathologies. The value of documenting the functional status of a patient with falls is that functional impairments should be accounted for by cognitive, psychiatric and physical pathologies.[9,11] Impairments identified in the history, examination and investigation of a patient and the success of interventions to treat and manage these problems can be gauged by improvements in functional status. Functional status is measured in terms of instrumental activities of daily living (IADLs) (activities required for independent living in the community, such as housekeeping, cooking, shopping, use of transportation, management of finances, and maintaining hobbies and social contact) and activities of daily living (ADLs) (activities that enable a person to care for him/herself, such as bathing, grooming, dressing, toileting, continence and mobility on a level surface and stairs, and ability to transfer from bed to chair) (Fig. 2).

The physical examination should include visual acuity assessment, supine and erect blood pressure, an ECG and a chest radiograph. The physical assess­ment focuses on the identification of cardiovascular, vestibular and central nervous system causes of dizziness/vertigo, identification of visual,

Sensory inputs and organisation • Visual • Vestibular • Proprioception

Fig. 1. Maintaining postural stability.

Table 1. Medical history and examination: symptoms, signs and possible associated pathology Symptoms

Pathologies to consider

Light-headed on standing

Postural hypotension

Light-headed with head turning

Carotid sinus hypersensitivity

Chest pain/dyspnoea/palpitations

Congestive cardiac failure, arrhythmia, aortic stenosis

Drop attacks

Vertebrobasilar insufficiency

Dizziness/vertigo

Medication side-effects

Brief vertigo

Benign paroxysmal positional vertigo

Episodic vertigo and tinnitus

Ménière’s disease

Back pain relieved by flexion

Lumbar spinal stenosis

Acute confusion

Delirium

Signs Asymmetrical spasticity

Cerebrovascular disease

Hyperreflexia, instability

Cervical myelopathy, vitamin B12 deficiency

Bradykinesia, rigidity, tremor

Idiopathic Parkinson’s disease

Dementia

Alzheimer’s disease

• Plus: hyperreflexia/pseudobulbar palsy

Vascular dementia

• Plus: parkinsonism and visual hallucination

Lewy body dementia

• Plus: incontinence and abnormal gait

Normal pressure hydrocephalus

Proximal myopathy

Hypothyroidism, polymyalgia rheumatica, statins, dermatomyositis

Peripheral sensory loss

Peripheral neuropathy

proprioceptive and peripheral nervous system sensory input impairments, central nervous system motor, extrapyramidal and cerebellar pathology and musculoskeletal problems.

Attention should specifically be paid to

August 2015, Vol. 105, No. 8

identifying proximal muscle weakness, as core stability is important in maintaining postural stability, especially in the event of external stress such as stumbling. Core muscle weakness is a common consequence

CONTINUING MEDICAL EDUCATION

Falls

Circumstances

Frequency, time, location, circumstances, surface, obstacles

Associated factors

Footwear, walking aids, glasses, substances/drugs, precipitants

HISTORY

Associated symptoms

Dizziness, vertigo, tinnitus, legs giving way, palpitations, disequilibrium, musculoskeletal pain, instability Cardiovascular, neurological, musculoskeletal and orthopaedic symptoms, foot problems, visual impairments, disequilibrium, fear of falling, systemic symptoms of frailty, malaise, weight loss

Chronic problems Past history New symptoms

Polypharmacy, drugs increasing fall risk (all psychotropics), anti-epileptic drugs (phenytoin and phenobarbitone), narcotic analgesics, diuretics, α-blockers (doxazosin), drugs with anticholinergic side-effects (oxybutynin, tricyclics and over-the-counter drugs)

Full drug history

Functional status is the best indicator of impairments and disabilities. Instrumental activities of daily living (management of finances, shopping, housekeeping, cooking and transport) and activities of daily living (basic self-care – grooming, bathing, toileting, continence, mobility on a flat surface and stairs and transfer from bed to chair) should be documented

Functional status

Fig. 2. Relevant history in fall assessment.

CVS EXAMINATION

CNS

MSS

Bradycardia, postural hypotension, aortic stenosis, ECG: heart block, ischaemia, chest radiograph Screen for dementia and delirium, pseudobulbar palsy and spasticity (vascular), hemiparesis, cervical myelopathy, extrapyramidal rigidity, proximal myopathy, lumbar radiculopathy, peripheral neuropathy, cerebellar signs

Osteoarthritis/deformity hips and knees, synovitis Bursitis – trochanteric and anserine Feet – gout, deformities, painful conditions such as corns and ingrown toenails

Fig. 3. Relevant physical examination (CVS = cardiovascular system; CNS = central nervous system; MSS = musculoskeletal system).

Table 2. Routine investigations Investigation

Condition

Electrolytes and renal function

Hyponatraemia, hypokalaemia, renal impairment

Calcium

Primary hypoparathyroidism

Full blood count and white blood cell differential

Anaemia, chronic lymphocytic leukaemia, myelofibrosis

Erythrocyte sedimentation rate

Polymyalgia rheumatica, myeloma, tuberculosis, malignancy, rheumatoid arthritis, vasculitis (neuropathy)

Thyroid-stimulating hormone

Hypothyroid proximal myopathy

Vitamin B12

Deficiency with central nervous system and peripheral nerve dysfunction

Syphilis serology

Neurosyphilis, central nervous system and peripheral nerve pathology

Vitamin D levels

Deficiency – increased risk of falls

August 2015, Vol. 105, No. 8

of deconditioning and frailty. If there is proximal muscle weakness in the hips from sitting to standing position in the assessment of gait and balance, shoulder muscle strength on shoulder abduction should be assessed. If there is proximal muscle weakness of both upper and lower limbs, the patient needs to be evaluated for causes of myopathy.

Degenerative joint disease and osteoarthirits of the hips and knees are common in the elderly, as are foot problems such as corns, bunions and ingrown toenails.[11] Pain and deformity result in an abnormal gait, which increases the risk of falls, especially if there are multiple contributing factors. In the event of abnormal findings on the musculoskeletal examination, osteoarthritis, gout and rheu­ matoid arthritis should be considered (Fig. 3).

Cognitive and psychiatric evaluation

Cognitive assessment should be done to identify cognitive deficits of dementia or delirium, and to enquire about symptoms of depression and sleep disturbance and the presence of substance or alcohol abuse, all of which increase the risk of falls. There are numerous formal, validated screening instruments for cognitive and psychiatric disorders. A problem with the Mini-Mental State Examination (MMSE) is that it does not evaluate executive (frontal lobe) function, unlike the Montreal Cognitive Assessment (MOCA),[12] the latter therefore being a better screening tool for the busy clinician.

The recognition of delirium rests on the recognition of the fluctuating character of this disorder in terms of concentration and arousal, presence of inattention (poor concentration/ distractibility), disorientation for time and place and inability to interpret sensory stimuli (such as if someone in a nurse’s uniform is at the bedside, the person believes he/she is in a hospital).

Major depressive disorder is characterised by the presence of vegetative features such as sleep and appetite disturbances, low energy levels, diurnal mood disturbance, nihilistic thoughts, suicidal ideation and pervasive sadness.

Laboratory investigations include those guided by clinical suspicions or diagnoses arising from the medical assessment and screening for common conditions that may increase the risk of falls[11] (Table 2).

Gait and balance assessment

Gait and balance are assessed to determine whether there is a balance problem, predict the risk of falls from the impairments identified, and establish the underlying

CONTINUING MEDICAL EDUCATION

Stand without using arms

walk 3 m

turn around 180˚

Sit down

walk back

Knees at 45˚

Pathologies/gait abnormalities Use arms to stand = proximal weakness Stagger/>3 steps in 180˚ turn = Sway/stagger = poor postural control poor postural control • • • •

Characteristic abnormal gait patterns Spastic hemiparetic, spastic, frontal lobe gait apraxia, parkinsonian, antalgic Foot drop/motor neuropathy (slapping feet), high stepping (dorsal columns) Waddling (hip weakness), vestibular (swaying, falling to one side), ataxic Fear of falling – slow, wide based, small stride, shuffling, foward centre of gravity

Fig. 4. The Get Up and Go test.

Table 3. System components for balance assessment System components Balance assessment Biomechanical

• • • •

Motor co-ordination

• Maintain stability with postural perturbations (external forces, anticipatory movement, walking) • Co-ordination strategies for recovering stability (latency, sequence, scaling on sensory information) • Strategy selection for context (magnitude of force, expectation, initial conditions) • Adaption of postural strategy (immediate, with experience, long-term motor learning)

Sensory organisation

• • • • •

Strength Range of motion Stiffness/compliance Alignment

Stability in altered sensory conditions (visual/surface) Limits of stability Perception of vertical orientation Motor perception Attention to and suppression of sensory cues

causes of the balance problem so that effective intervention may be offered. The value of functional assessment of gait and balance is that, by direct observation, one can assess the impact that physiological changes of ageing and pathologies iden­ tified in the history and examination have on gait and postural control, and subsequently on the risk of falls. The assessment of balance should include the identification of impairments between the different types of balance control, including ability to respond to external perturbations (forces), anticipation of postural responses necessitated by voluntary motions, and effective and safe movement (controlling and moving the centre of the body mass over the base of support when moving

through space). If the gait and balance are normal and there are recurrent falls, the underlying problem is most likely cardiovascular or related to medications or substances.

There are three approaches to the assess­ ment of balance: functional assessment, a systems approach and quantitative postu­ ro­ graphy. Functional assessment seeks to estab­ lish whether there is a balance problem and predict the risk of falls, while the systems approach tries to identify which of the elements of postural control are impaired. Functional assessment tools seek to rate performance across various tasks requiring balance control to identify functional limitations or the capacity to perform various tasks. This information can

August 2015, Vol. 105, No. 8

then be used to target medical and physical interventions at the impaired components.[8] There are several validated tools such as the Tinetti Performance-Orientated Assessment of Mobility, the Berg Functional Balance Scale[13,14] and the Timed Get Up and Go test[15] (Fig. 4).

The systems approach to the assessment of balance seeks to identify impairments in the various subcomponents of postural control and compensatory strategies used to compensate for these impairments. The components assessed are described in Table 3.

Compensatory strategies commonly employed by elderly persons with impaired and slowed postural control include excessive trunk/hip motion to maintain postural equilibrium, actively locking the head to the trunk to compensate for dizziness, compensating for muscle weakness by locking the knee and forward positioning of the centre of muscle mass, and widening the base of the gait and shortening the stride length to compensate for a feeling of disequilibrium.

A combination of elements of the various functional balance assessment tools suitable for a busy clinician would include the Timed Get Up and Go test, Romberg’s test (identifies vestibular and proprioception impairments by removing visual compensation), assessing for postural sway with eyes open and closed (slowed postural reflexes), the sternal nudge (postural response to external force) and the functional reach test.

Management of persons at risk of falls and those with fear of falling

Principles of managing elderly persons at risk of falls, those who have fallen and those with a fear of falling are similar. Prevention of falls focuses on maintaining mobility and balance in functional, independent communitydwelling elderly persons and identifying those at risk of falls for multidisciplinary assessment and intervention.[16,17] In independent community-dwelling elderly persons without impairments in gait and balance, the focus is on maintaining physical function, optimally managing chronic diseases, screening, ensuring good nutrition and avoiding prescription of drugs that increase the risk of falls, if possible. Exercise recommendations for maintaining physical function include 30 minutes of aerobic activity 3 times a week (e.g. walking at a brisk pace) and static strength and balance exercises such as callanetics and Tai Chi. Screening for vitamin D deficiency is expensive and the prevalence of suboptimal levels is high, even in South Africa, especially in the winter months. Some health professionals advocate that supplementation for all the elderly is more cost effective.

CONTINUING MEDICAL EDUCATION

In elderly persons with impaired gait and balance that puts them at risk of falls, a multidisciplinary intervention programme is required. Interventions that are effective in reducing subsequent falls, hospitalisation and functional decline include strength and balance training by a physiotherapist, assessment and modification of environmental hazards in the home by an occupational therapist, medication review and rationalisation of high-risk medications and polypharmacy, and the supplementation of vitamin D if indicated.[16,18] References 1. Tinetti ME. Clinical practice: Preventing falls in elderly persons. N Engl J Med 2003:348(1):42-49.

2. Hausdorff JM, Rios DA, Edelberg HK. Gait variability and fall risk in community-living older adults: A 1-year prospective study. Arch Phys Med Rehabil 2001;82(8):1050-1056.

3. Rubenstein LZ. Falls in older people: Epidemiology, risk factors and strategies for prevention. Age Ageing 2006;35(Suppl 2):ii37-ii41.

4. Zijlstra GA, van Haastregt JC, van Eijk JT, van Rossum E, Stalenhoef PA, Kempen GI. Prevalence and correlates of fear of falling, and associated avoidance of activity in the general population of community-living older people. Age Ageing 2007;36(3):304-309.

5. Ambrose AF, Hausdorff JM. Risk factors for falls among older adults: A review of the literature.

Maturitas 2013;75(1):51-61. [http://dx.doi.org/10.1016/j.maturitas.2013.02.009]

6. Horak FB. Postural orientation and equilibrium: What do we need to know about neural control of balance to prevent falls? Age Ageing 2006; 35(Suppl 2):ii7-ii11.

7. Manini TM, Clark BC. Dynapenia and aging: An update. J Gerontol A Biol Sci Med Sci 2012;67(1):2840. [http://dx.doi.org/10.1093/gerona/glr010] 8. Lord SR, Menz HB, Tiedemann A. A physiological profile approach to falls risk assessment and prevention. Phys Ther 2003;3:237-252.

9. Salzman B. Gait and balance disorders in older adults. Am Fam Physician 2010;82(1):61-68.

10. Woolcott JC, Richardson KJ, Wiens MO, et al. Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Arch Intern Med 2009;169(21):1952-1960.

11. Moylan KC, Binder EF. Falls in older adults: Risk assessment, management and prevention. Am J Med 2007;120:493-497.

12. Dag E, Örnek N, Örnek K, Günay F, Türkel Y. Mini mental state exam versus Montreal cognitive assessment in patients with age-related macular degeneration. Eur Rev Med Pharmacol Sci 2014;18(20):3025-3028.

13. Bogle-Thorbahn LD, Newton RA. Use of the Berg Balance Test to predict falls in elderly persons. Phys Ther 1996;76(6):576-583.

14. Whitney SL, Poole JL, Cass SP. A review of balance instruments for older adults. Am J Occup Ther 1998;52(8):666-671.

15. Shumway-Cook A, Brauer S, Woollocott M. Predicting the probability of falls in community-dwelling older adults using the Timed Get Up & Go test. Phys Ther 2000;80:896-903.

16. Karlsson MK, Vonschewelov T, Karlsson C, Coster M, Rosengen BE. Prevention of falls in the elderly: A review. Scand J Public Health 2013;41:442-454.

17. Chang JT, Morton SC, Rubenstein LZ, et al. Interventions for the prevention of falls in older adults: Systematic review and meta-analysis of randomized clinical trials. BMJ 2004;328:676-679.

18. Murad MH, Elamin KB, Abu-Elnor NO, et al. The effects of vitamin D on falls: A systematic review and meta-analysis. J Clin Endocrinol Metab 2011;96(10):2997-3006. [http://dx.doi.org/10.1210/ jc.2011-1193]

August 2015, Vol. 105, No. 8

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Artist rendition

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References: 1. Fosavance approved package insert. 2. Data on le, MSD South Africa.

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CPD

AUGUST 2015

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True (A) or false (B): SAMJ Anterior chamber paracentesis to improve diagnosis and treatment of infectious uveitis in South Africa 1. Analyses of aqueous humor, obtained by anterior chamber paracentesis, direct the differential diagnosis in infectious uveitis.

2.

HIV-infected individuals have an increased risk for specific opportunistic ocular infections (e.g. cytomegalovirus retinitis) and tend to present with more severe disease.

3.

While clinical features are poorly predictive of the causative pathogen in most cases of infectious uveitis, uveitis caused by Mycobacterium tuberculosis (TB) is the exception, a recent history of pulmonary tuberculosis and retinal granulomata confirming the diagnosis of TB. 4. Manifestations of infectious uveitis in HIV-positive persons are often atypical, with a higher degree of inflammation, especially in advanced uveitis.

Improving access to antiretrovirals in rural South Africa – a call to action 5. The implementation of nurses prescribing antiretrovirals (ARVs), through nurse-initiated management of antiretroviral treatment (NIMART) has been a great success and has proven to be noninferior to doctor-monitored ART. Multimorbidity, control and treatment of non-communicable diseases among primary healthcare attenders in the Western Cape, South Africa 6. Half of the participants with hypertension also had diabetes, while 80% of diabetes participants also had hypertension.

Carcinogenic nitrosamines in traditional beer as the cause of oesophageal squamous cell carcinoma in black South Africans 7. Fusarium moniliforme, a corn saprophyte of maize, produces a toxin, fumonisin, which reduces nitrates to nitrites and leads to formation of carcinogenic nitrosamines.

8. The decline in incidence to one-fifth of the peak in the 1980s probably reflects diminished consumption of traditional beer.

The case for expanding the definition of ‘key populations’ to include high-risk groups in the general population to improve targeted HIV prevention efforts 9. Traditional key populations (referring to groups that are at high risk of HIV infection) include men who have sex with men (MSM), sex workers, injection drug users and transgendered persons.

10. In SA, low socioeconomic status is a critical social determinant for HIV infection among the high-risk groups of black African women and men (aged 20 - 34 years and 25 - 49 years, respectively).

CME An approach to the clinical assessment and management of syncope in adults 11. Two features of syncope are that it is transient and of rapid onset.

12. Transient loss of consciousness (syncope) related to trauma is usually the result of concussion.

13.

Structural heart disease and primary cardiovascular electrical disease are major risk factors for sudden cardiac death in syncope.

An approach to epilepsy 14. The key to understanding and managing epilepsy is to decide whether the seizures are genetic (idiopathic) or due to focal brain pathology.

15. It is not uncommon for patients with frontal lobe seizures to be referred for psychiatric assessment before the ictal nature of their symptoms is recognised.

An approach to acute vertigo 16. Acute vertigo or dizziness in isolation is usually benign.

17. Unidirectional nystagmus, where the direction of nystagmus is unchanged by change in direction of gaze, is typical of peripheral vestibular disease.

An approach to balance problems and falls in elderly persons 18. Falls are a precipitant for functional decline, increasing frailty and institutionalisation in the elderly.

19. In the elderly, peripheral nerve conduction is faster owing to a decrease in the number of motor units in the spinal cord.

20. Visual acuity is not an important part of the physical examination of an elderly person who reports having suffered a fall.

Readers please note: articles may appear in summary/abstract form in the print edition of the journal, with the full article available online via www.hmpg.co.za

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Accreditation number: MDB015/167/02/2015

August 2015, Vol. 105, No. 8

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