SAMJ Vol 104, No 1 (2014) by HMPG

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JANUARY 2014

VOL. 104 NO. 1

Medical male circumcision preventing HIV

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TB in HIV

Percutaneous needle biopsy in extrapulmonary TB

Guideline for use of opioids in chronic non-cancer pain HASA conference unpacked CME: Mental health and psychiatric assessment

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The Health & Medical Publishing Group, the publishing arm of the South African Medical Association, mourns our country's loss of Nelson Mandela, while giving thanks for his special leadership qualities and attributes.

JANUARY 2014

VOL. 104 NO. 1

GUEST EDITORIAL

A South African decade of antiretrovirals W D F Venter

EDITOR’S CHOICE EDITOR Janet Seggie. BSc (Hons), MD (Birm), FRCP (Lond), FCP (SA)

CORRESPONDENCE 5

‘A new dietary paradigm?’ – prove it R Kapp

LCHF: Look at the full picture L Evenpoel, response from the Editor

EDITOR EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG MD (Hon), FCM (Hon) CONSULTING EDITOR JP de V van Niekerk, MD, FRCR

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No sacred cows as private sector embraces society-wide solutions Universal Coverage possible – with private sector support

SAMJ FORUM

HEALTH AND FINANCE 10 A first step towards transparency in pricing of medicines and scheduled substances – publication of guidelines for pharmaco-economic submissions M P Stander, M Bergh, H Miller-Jansön 12

MEDICINE AND THE LAW  Surrogacy commissioning fathers and HIV  D W Jordaan

Disposal of medical waste: A legal perspective K du Toit, J Bodenstein

EDITORIAL SYSTEMS MANAGER Melissa Raemaekers, BSc (Hons), PhD SCIENTIFIC EDITOR Kerry Gordon, MSc, PhD TECHNICAL EDITORS Taryn Skikne, BA (Hons), MA Paula van der Bijl, BA, HDipLib Emma Buchanan, BA NEWS EDITOR Chris Bateman | E-mail: chrisb@hmpg.co.za HEAD OF PUBLISHING Robert Arendse

OPINION  15 Traditional male circumcision: Balancing cultural rights and the prevention of serious, avoidable harm K G Behrens 17

Adult circumcision in the prevention of HIV/AIDS N D Goldstuck

Charting a path along the continuum of PMTCT of HIV-1, to elimination, and finally to eradication A Ramkissoon, H Coovadia

PROFESSIONAL ADVERTISING Bronlyne Granger | Tel. 021-681-7000 E-mail: bronlyne.granger@hmpg.co.za

DTP & DESIGN Anelia du Plessis | Carl Sampson

20 Challenging times for environmental health in South Africa: The role of the Environmental Health Research Network C Y Wright, A Mathee, M A Oosthuizen

RESEARCH

22 Extrapulmonary tuberculosis among adults: Experience at Chris Hani Baragwanath Hospital, Johannesburg, South Africa A S Karstaedt 24 Prevalence and incidence of symmetrical symptomatic peripheral neuropathy in patients with multidrug-resistant TB F Conradie, T Mabiletsa, M Sefoka, S Mabaso, R Louw, D Evans, A van Rie 27 Diagnostic yield of fine needle aspiration biopsy in HIV-infected adults with suspected mycobacterial lymphadenitis R Razack, M Louw, C A Wright 29

Percutaneous core needle biopsies: The yield in spinal tuberculosis J P Watt, J H Davis

The attitudes of medical students to research D Nel, R J Burman, R Hoffman, S Randera-Rees

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ART DIRECTOR Brent Meder

EDITORIALS

DEPUTY EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB

January 2014, Vol. 104, No. 1

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Diabetes mellitus in HIV-infected patients receiving antiretroviral therapy D Moyo, G Tanthuma, O Mushisha, G Kwadiba, F Chikuse, M S Cary, A P Steenhoff, M J A Reid

Parents’ perceptions of HIV counselling and testing in schools: Ethical, legal and social implications R Gwandure, E Ross, A Dhai, J Gardner

Patient-initiated sexual partner notification in Botswana and time taken for sexual contacts to report for treatment T A Tafuma, B C Ntwayagae, C K Moalafhi, J M Bolebantswe

The use of the full blood count and diﬀerential parameters to assess immune activation levels in asymptomatic, untreated HIV infection N Vanker, H Ipp

Sexual lubricants in South Africa may potentially disrupt mucosal surfaces and increase HIV transmission risk among men who have sex with men K B Rebe, G de Swardt, P A Berman, H Struthers, J A McIntyre

CONTENTS LISTED IN Index Medicus (Medline). Excerpta Medica (EMBASE). Biological Abstracts (BIOSIS). Science Citation Index (SciSearch). Current Contents/Clinical Medicine SAMJ SUBSCRIPTION RATES Local subscriptions R1 044.00 p.a. Foreign subscriptions R2 352.00 p.a. Single copies R95.00 Members of the Association receive the SAMJ only on request, as part of their membership beneﬁt. Subscriptions: Tel. 012-481-2071 E-mail: members@samedical.org The SAMJ is published monthly by the Health and Medical Publishing Group (Pty) Ltd, Co. registration 2004/0220 32/07, a subsidiary of SAMA.

Rapid, minimally invasive adult voluntary male circumcision: A randomised trial of Unicirc, a novel disposable device P S Millard, H R Wilson, N D Goldstuck, C Anaso

Surgical outreach in rural South Africa: Are we managing to impart surgical skills? D L Clarke, C Aldous

Relationship between firewood usage and urinary Cr, Cu and As in informal areas of Cape Town M Dalvie, A Africa, S Naidoo

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Critical value reporting: A survey of 36 clinical laboratories in South Africa E Schapkaitz, Z Mafika

Please submit all letters and articles for publication online at www.samj.org.za

CONTINUING MEDICAL EDUCATION

GUEST EDITORIAL 68

Mental healthcare in the community J Parker

REVIEW 69

A broad diagnostic framework to simplify the approach to mental disorders in primary care J Parker

ARTICLES 72

An update on attention deficit hyperactivity disorder (ADHD) W Vogel

Outpatient management of adult alcoholism M F Williams

Psychiatry in primary care using the three-stage assessment C A Draper, P Smith

Adapting the psychiatric assessment for primary care J Parker

De-institutionalisation in psychiatry – both sides of the coin J Parker

Recovery in mental health J Parker

Use of editorial material is subject to the Creative Commons Attribution – Noncommercial Works License. http://creativecommons.org/licenses/bync/3.0 Plagiarism is defined as the use of another’s work, words or ideas without attribution or permission, and representation of them as one’s own original work. Manuscripts containing plagiarism will not be considered for publication in the SAMJ. For more information on our plagiarism policy, please visit http://www.samj.org.za/ index.php/samj/about/editorialPolicies Printed by Creda Communications

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South African guideline for the use of chronic opioid therapy for chronic non-cancer pain M Raff, J Crosier, S Eppel, H Meyer, B Sarembock, D Webb

Nelson Mandela attends ‘46664 Arctic’ concert, at the Rica Hotel on June 11, 2005 in Tromso, Norway. Photo by Dave Hogan/Getty Images

January 2014, Vol. 104, No. 1

FIRST PUBLISHED IN 1884

A South African decade of antiretrovirals It is hard not to call the last decade of antiretroviral (ARV) access anything other than a public health, human rights and political success.[1,2] South African life expectancy has increased by a decade, almost entirely due to effective HIV treatment. The arrest of mother-to-child transmission is one of the most celebrated public health programmes in the country, with transmission rates a fraction of what they were. HIV testing and condom usage rates are among the highest in the world. There are data to suggest that new HIV infection rates are going down and that the 2007 National Strategic Plan for HIV/AIDS goal of reducing new incidence by 50% is within reach. This may be due to a combination of condom access, antiretroviral therapy transmission arrest, or simply the natural trajectory of all infectious diseases, but seemed unattainable just a few years ago.[3-5] Questions of sustainability don’t apply as much to South Africa as much as the rest of Africa. The HIV response is largely funded out of the national tax base, reflecting that political commitment is now more important than donor generosity, although there has been critical US Presidents’ Emergency Fund for AIDS Relief (PEPFAR) and Global Fund technical and resource assistance in HIV programme execution and costing. There are legitimate concerns regarding the escalating cost of the programme. However, the combination of downstream costs averted by decreased hospitalisation and clinic visits, and aggressive negotiation of ARV drug costs with generic and originator manufacturers, has meant a sustained annual decrease in overall health costs over the last few years.[6,7] Monitoring requirements have been eased and, owing to some task-shifting, the treatment cost per patient has decreased. Patients have access to third-line drug treatment, often not available even in developed countries. Complaints that HIV draws more resources than it deserves are also easily countered. The virus, and its co-passenger tuberculosis (TB), used to account for almost half of all deaths in the country. While until 2004 resources allocated to HIV did not mirror the burden of disease, current funding levels now more accurately reflect what should have been allocated. The huge impact on health justifies the spend, with early indications that even TB incidence may be falling. There is a lot to celebrate – there is sustained political and treasury support for a successful programme, thanks, in no small part, to a committed Minister of Health and cabinet. HIV debates have somewhat normalised, while a large number of human rights issues have been unveiled. High profile and precedent-setting court cases and debates have pushed the responsibilities of government, employers and manufacturers into an often-uncomfortable spotlight. HIV has mobilised large sectors of civil society and spawned a human rights focus on other areas, particularly provision of education. But there is much to reflect on, not least the half-million South Africans that died due to the President Mbeki-era obstructionism and the failure of politicians and protection agencies to act. It is important to be honest about the history of ARV access. There were clear heroes. Accolades have been deservedly heaped on the Treatment Access Campaign, Médicins Sans Frontièrs and Section 27 (then the AIDS Law Project), backed up by smaller and less vocal organisations such as the Southern African HIV Clinicians Society and the Rural Doctor Association. There were clear villains also. President Mbeki and his health minister, ‘Manto’ TshabalalaMsimang, other ministers and provincial MECs, were responsible

for irrationality on the part of the National Department of Health. We are owed an explanation for the ‘denialism’ from members of Mbeki’s cabinet who seemingly watched silently while so many died. Doctors will recall the grim role they played in the early 2000s, looking after patients, some of them AIDS activists, who died simply because access to life-saving medicines was prevented by a denialist government and high prices. The Health Professions Council of South Africa and the South African Medical Association allowed the denialism to go unchallenged and were toothless when colleagues were fired for doing their jobs. Academic institutions also seemed cowed. A small group of government health officials toughed it out and are owed an enormous and ongoing debt of gratitude. And the press, often the target of scorn, played their key role in telling the truth in the face of government hostility and disinterested readership. Serial breakdowns of drug supply chains, largely due to weaknesses in provincial health delivery systems, show how the corrosive effect of the ‘Manto era’ continues to undermine the health system as a whole.[8] As the complexity of National Health Insurance unfolds, HIV programmes, with all their established measurements, are well placed to provide a proxy indicator of health system performance. It has been a roller-coaster ride. There are many valuable lessons for HIV and other disease programmes to learn from the last 10 years. The second decade will be every bit as eventful. We will require all our energies to build a health system that can provide the kind of quality of care that the HIV programme has dared us to imagine. W D Francois Venter

Wits Reproductive Health and HIV Institute, and Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa fventer@wrhi.ac.za 1. Mabhena N, Ndirangu J, Mutevedzi P. Track 3: Epidemiology and prevention. 6th SA AIDS Conference. 21 June 2013, Durban, South Africa. 2. Venter WDF. HIV Treatment in South Africa: The Challenges of an Increasingly Successful Antiretroviral Programme. In: Padarath A, English R, eds. South African Health Review 2012/13. Durban: Health Systems Trust, 2013. http://www.hst.org.za/publications/ south-af rican-health-review-2012/13 (accessed 28 November 2013). 3. Pillay Y. Treatment 2013 – Current Issues and Future Directions. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013). June 2013, Kuala Lumpur, Malaysia. http://pag.ias2013.org/session.aspx?s=63 (accessed 20 August 2013). 4. Tanser F, Bärnighausen T, Grapsa E, Zaidi J, Newell ML. High coverage of ART associated with decline in risk of HIV acquisition in rural KwaZulu-Natal, South Africa. Science 2013;339(6122):966-971. [http://dx.doi.org/10.1126/science.1228160] 5. Johnson L, Mossong J, Dorrington R, et al. Life expectancies of HIV-positive adults receiving antiretroviral treatment in South Africa. Actuarial Society of South Africa (ASSA) 2012 Convention. 16-17 October 2012, Cape Town, South Africa. 6. Rehle TM, Hallett TB, Shisana O, et al. A decline in new HIV infections in South Africa: Estimating HIV incidence from three national HIV surveys in 2002, 2005 and 2008. PLoS One 2010;5(6):e11094. [http://dx.doi.org/10.1371/journal.pone.0011094] 7. Meyer-Rath G, Over M. HIV Treatment as prevention: Modelling the cost of antiretroviral treatment – state of the art and future directions. PLoS Med 2012;9(7):e1001247. [http://dx.doi.org/10.1371/ journal.pmed.1001247] 8. Bateman C. Drug stock-outs: Inept supply-chain management and corruption. S Afr Med J 2013;103(9):600-602. [http://dx.doi.org/10.7196/SAMJ.7332]

S Afr Med J 2014;104(1):3. DOI:10.7196/SAMJ.7788

January 2014, Vol. 104, No. 1

EDITOR’S CHOICE

A ‘new-look’ SAMJ

The SAMJ now sports an educational component, resembling the BMJ, NEJM and Lancet, by incorporating CME. A review article[1] introduces readers to this month’s subject matter on mental health and we include summaries of the additional articles that may be accessed online.

The clashing epidemics of HIV and TB

Francois Venter, one of South Africa (SA)’s foremost HIV scientists, reveals in our guest editorial just how far SA has progressed in controlling the epidemic since our ‘AIDS denialism’ days. Progress, arguably, would have been yet greater had SA not had to contend with the two clashing epidemics of HIV and tuberculosis (TB). The relationship between HIV and TB is bi-directional: TB is a catalyst in the progression of HIV and HIV infection is associated with an increased risk of developing TB. HIV infection alters the clinical presentation of TB such that TB progresses more rapidly and aggressively in HIV-positive individuals, making diagnosis difficult. Extrapulmonary TB (EPTB) occurs in 20 - 70% of HIV-infected patients with TB and is most prevalent in the 25 - 44-year age group. Karstaedt[2] demonstrates that the most common sites of EPTB are the pleura, lymph nodes, bacteraemia, meningitis and peritonitis. Disseminated TB occurred in 25% of the patients in this study. Sputum smears, which are the cornerstone of diagnosis in resourcelimited settings, are usually negative in HIV-associated TB, contributing to a delay in commencing treatment. Fine needle aspiration biopsy (FNAB) of accompanying lymphadenitis provides a means of easy access to diagnostic material in many of these pulmonary cases. With this approach, Razack et al.[3] were able to confirm mycobacterial lymphadenitis (bacterial confirmation) in 80% of patients. Of TB infections, 1% affect the spine. Yet, of patients treated for spinal TB, only 55% have a definitive laboratory diagnosis (dependent on the identification of the TB bacilli by Ziehl-Neelsen staining in bone biopsy specimens). Watt and Davis[4] stress that in patients with HIV, and more specifically AIDS, the histological changes can range from the classical caseating granulomas to a non-specific chronic inflammatory reaction without necrosis. Unexpectedly, the highest culture yield observed in their study came from samples showing non-necrotising chronic inflammatory changes and not from samples showing necrotising granulomas. Confirming the diagnosis histologically is but half the battle, as sensitivity to first-line drugs has still to be proven. SA has one of the highest worldwide incidences of multidrugresistant (MDR)-TB, owed significantly to HIV co-infection. Almost

a quarter of patients requiring treatment of their MDR-TB have symmetrical symptomatic peripheral neuropathy (SSPN) as the study by Conradie et al.[5] confirms. To avoid renal failure in such patients, due to the combined nephrotoxicity of aminoglycosides and tenofovir, stavudine is often used. Exposure to stavudine is a welldocumented risk factor for SSPN and Conradie et al. warn that the use of twice-daily stavudine for 6 months could potentially result in the development or exacerbation of SSPN.

Management of chronic pain

Chronic pain affects around one in five patients in primary care, occurring more frequently in older individuals, whose presentation is complicated by age-related physiological changes, comorbidities and multiple medications. Chronic pain impacts quality of life, yet may be difficult to manage, and sufferers are more likely to report anxiety or depression. The South African guideline for the use of chronic opioid therapy for chronic non-cancer pain (CNCP)[6] developed by a multi-disciplinary panel provides recommendations for patient selection and the use of opioids for CNCP. Appropriate patient selection is paramount, requiring a comprehensive physical and biopsychosocial assessment to establish the diagnosis and to guide management decisions. Opioids are well accepted for the treatment of severe acute pain and chronic pain associated with cancer and at the end of life, but less is known about their efficacy and safety with long-term use for CNCP. Nevertheless, limited evidence indicates that they can be effective therapy for a carefully selected group of patients as part of a wider management plan focused on reducing disability and improving quality of life. JS 1. Parker J. A broad diagnostic framework to simplify the approach to mental disorders in primary care. S Afr Med J 2014;104(1):69-71. [http://dx.doi.org/10.7196/SAMJ.7717] 2. Karstaedt AS. Extrapulmonary tuberculosis among adults: Experience at Chris Hani Baragwanath Hospital, Johannesburg, South Africa. S Afr Med J 2014;104(1):22-24. [http://dx.doi.org/10.7196/ SAMJ.6374] 3. Razack R, Louw M, Wright CA. Diagnostic yield of fine needle aspiration biopsy in HIV- infected adults with suspected mycobacterial lymphadenitis. S Afr Med J 2014;104(1):27-28. [http://dx.doi. org/10.7196/SAMJ.7492] 4. Watt JP, Davis JH. Percutaneous needle core biopsies: The yield in spinal tuberculosis. S Afr Med J 2014;104(1):29-32. [http://dx.doi.org/10.7196/SAMJ.6868] 5. Conradie F, Mabiletsa T, Sefoka M, Mabaso S, Louw R, Evans D, van Rie A. Prevalence and incidence of symmetrical symptomatic peripheral neuropathy in patients with multidrug-resistant TB. S Afr Med J 2014;104(1):24-26. [http://dx.doi.org/10.7196/SAMJ.6455] 6. Raff M, Crosier J, Eppel S, Meyer H, Sarembock B, Webb D. South African guideline for the use of chronic opioid therapy for chronic non-cancer pain. S Afr Med J 2014;104(1 Suppl 1):78-89. [http:// dx.doi.org/10.7196/SAMJ.7316]

This month in the SAMJ ... Francois Venter* is currently deputy executive director of the Wits Reproductive Health and HIV Institute (Wits RHI), previously the Reproductive Health Research Unit (RHRU) and Enhancing Children’s HIV Outcomes (ECHO), and an associate professor in the Department of Medicine, University of the Witwatersrand. He is an honorary consultant in infectious diseases at the Charlotte Maxeke Johannesburg Academic Hospital. Dr Venter is past president of the Southern African HIV Clinicians Society, which has over 3 000 members throughout Africa. His interests include access to HIV care in resource-limited settings, clinical syndromes associated with HIV, and treatment of key populations, including sex workers and truckers.

*Venter WDF. A South African decade of antiretrovirals. S Afr Med J 2014;104(1):3. [http://dx.doi.org/10.7196/SAMJ.7788]

January 2014, Vol. 104, No. 1

Save the date! 22 to 24 August 2014

CONFIRMED INTERNATIONAL FACULTY: Prof Sughra Raza, USA Prof Emily Conant, USA Prof Nathalie Duchesne, Canada Prof Elizabeth Morris, USA Prof Per Skaane, Norway

PRE-CONFERENCE WORKSHOPS â&#x20AC;&#x201C; 21 AUGUST 2014 Tomosynthesis Image - guided breast biopsy and localisation

More detail to follow on the website from early December 2013 at www.rssa2014breastcourse.co.za The Radiological Society of South Africa

CORRESPONDENCE

‘A new dietary paradigm?’ – prove it

To the Editor: While I respect Prof. Noakes’ passionate search for a much-needed nutritional nirvana, I wish to mention some of my objections to his article in the November issue of the SAMJ.[1] While conceding his study’s limitations, he could have added a few more: patients generally exaggerate their actual weight loss; no attempt was made to verify these alleged clinical successes by consulting any patient’s clinician; there is no indication that these patients were indeed following the ‘Noakes diet’. Furthermore, these case studies are no more dramatic than the stories of patients we as clinicians experience on a regular basis: people who have experienced significant weight loss as a result of other diets, including the prudent diet. Unlike Noakes’ short-term study, these patients bear testimony to long-term successful weight loss. More alarmingly, I am amazed that the mighty Discovery Health – one of Prof. Noakes’ sponsors – is suddenly too out-of-pocket to fund a randomised control trial (RCT) needed to prove Noakes’ hypothesis. In conclusion, I challenge Prof. Tim Noakes to do the ethical thing: conduct the necessary RCT to prove his hypothesis. Failing which, he should stop using this debate as a platform from which to openly criticise his colleagues and confuse the public. R Kapp

Family physician, Goodwood, Cape Town, South Africa rkapp@deck.co.za 1. Noakes TD. Low-carbohydrate and high-fat intake can manage obesity and associated conditions: Occasional survey. S Afr Med J 2013;103(11):826-830. [http://dx.doi.org/10.7196/SAMJ.7302]

S Afr Med J 2014;104(1):5. DOI:10.7196/SAMJ/7729

LCHF: Look at the full picture

To the Editor: The article ‘Low-carbohydrate and high-fat intake can manage obesity and associated conditions: Occasional survey’[1] by T D Noakes refers. When discussing the health benefits of their diet, low-carbohydrate, high-fat (LCHF) advocates, from Atkins to the acolytes after him, give all the credit to LCHF eating. In their conclusions, they could very well be confusing cause and correlation. When obese people lose weight, their cardiovascular risk parameters improve irrespective of the mode of weight loss, whether it was LCHF, high-carbohydrate, lowfat (HCLF), calorie restriction, or even cocaine abuse or contracting tuberculosis. The weight loss itself is the main contributor to improved health, through a decreased pro-inflammatory state, and although this is a well-established fact in the medical literature, it never gets mentioned in the conclusions of a LCHF article. As medical professionals, we would welcome a magic cure for obesity, even if it is LCHF. This diet certainly performs well over the short term (months), but there are no data on its long-term safety (decades). This short-term/long-term dichotomy never finds its way into the conclusions of the LCHF article. Long-term efficacy is questionable. The attrition rate is very high, much higher than with other diets. LCHF is easy and simple enough, until a plate of cookies is put in front of you. And it is expensive, well outside the budget of the lower socio-economic classes, which is the population group where obesity prevalence is the highest. To be fair to his readers and science, Noakes should have mentioned this in his discussion. Where LCHF is right is in agreeing that we eat and drink too many processed and refined carbohydrates, e.g. white flour, breakfast

cereals, sweets, desserts, cool drinks. Our current sugar consumption is four times higher than a century ago. To illustrate that LCHF’s success is about more than LCHF eating, I refer to the second case study (obese man lost 75 kg). He was one of the patients in our bariatric (weight loss) surgery programme, but scared of the operation. At the end of one of my motivational talks to the bariatric surgery support group, he asked me if what I had presented could be an alternative to the surgery. He then voluntarily withdrew from the bariatric work-up (contrary to what Noakes writes, the anaesthesia had never been deemed too dangerous for him – I know, because I am anaesthetist on this programme) and had a close look at his lifestyle. He decided to change his life: he started attending a support group, took up some physical activity and went on LCHF. LCHF was a stepping-stone, not a miracle cure but one of many interventions that collectively contribute to successful weight control. He continues to attend the support group, makes a point of eliminating all refined carbs, sugar and alcohol from his diet, and limits his portion sizes and fat intake. Endocrinologists and dieticians have for decades been prescribing LCHF for selected patients but if bad habits are not changed, the weight returns. If Noakes had included the full story of Case 2, instead of making LCHF look like a miracle cure, his readers would have benefited from a more realistic look at the diet he believes in. He still wouldn’t have scored high marks for design and methodology, but he would have made more of us reflect on the merit in his message. And that is, after all, reason to read medical journals. It remains puzzling how this article found its way past peer review into the SAMJ. Studies that run over decades do seem to indicate that a high fat content in the diet increases the risk for cardiovascular disease, and that a high consumption of red meat, through some yet unknown mechanism, might increase the risk for diabetes (a disease that Noakes aims to ‘cure’ with his approach). Luc Evenepoel

N1 City Hospital, Cape Town, South Africa luc.evenepoel@gmail.com 1. Noakes, TD. Low-carbohydrate and high-fat intake can manage obesity and associated conditions: Occasional survey. S Afr Med J 2013;103(11):826-830. [http://dx.doi.org/10.7196/SAMJ.7302]

Editors’ note: Prof Noakes’ article was published in our Forum section because it did not meet the criteria required for original research. However, as a case series (a recognised approach to looking at particular clinical problems in medicine) it met the criteria to be included in Forum, specifically to generate discussion around a topic that is generating a lot of debate globally at present (see http://www.bbc.co.uk/news/health-24625808 and http://www. theguardian.com/lifeandstyle/2013/oct/22/butter-cheese-saturatedfat-heart-specialist in response to an editorial in the British Medical Journal (BMJ) recently). Note that Forum articles do not go through the formal review process – the SAMJ is not so well endowed with colleagues willing to offer their time to review every submission. However, all submissions – including these letters to the Editor – are reviewed by an in-house review committee, as is the practice at all other general medical journals (the Lancet, the BMJ, etc.) As to critics’ claims that his paper was published only because of Noakes’ ‘fame’ – this is untrue. S Afr Med J 2014;104(1):5. DOI:10.7196/SAMJ/7793

January 2014, Vol. 104, No. 1

ADVERTORIAL

IZINDABA

No sacred cows as private sector embraces society-wide solutions There were no sacred cows at October’s Hospital Association of South Africa (HASA) conference – all the stark realities of our deeply economically divided society, its regulatory shortcomings and our inequitable health care delivery system were aired, and some solutions offered. That is how both HASA’s chairperson, Melanie da Costa, and one of the world’s leading healthcare economics and policy consultants, Dr Margaret Guerin-Calvert, President of the US-based Center for Healthcare Economics and Policy, summed up the conference. Guerin-Calvert, who chaired a debate on ‘Extracting efficiencies in the healthcare sector’, said what impressed her most was the ‘incredible commitment to access and quality of care’ shown by a cross-section of participants determined to tackle fragmentation in the public and private sectors. Several perspectives were shared on the importance of ‘figuring out’ integrated systems, improving the alignment of incentives and better co-ordinated care, with much emphasis on the private sector working with the public sector to craft solutions. One persistent theme was the need for a private sector that can serve more public sector patients, creating an altogether more robust system. ‘I thought people [at the conference] went out on a limb: physicians were trying to look at relative costs and all available data was put forward, at least taking some issues off the table,’ she added. Da Costa said a highlight of the conference was watching Dr Brigid Strachan, a top government and private sector consultant on healthcare financing and human resources for health, lay out the latest data on the current and projected shortage crisis in specialists – which was then thoroughly debated by some of the country’s top experts.

‘Sacrifice ideology for common purpose’ Netcare’s Friedland

‘I also liked what Dr Richard Friedland [CEO of Netcare] said about the sacrifice of ideology for common purpose,’ said Da Costa. ‘I think that’s critical if a national health insurance (NHI) is to succeed. He’s leading the way with hugely successful

Dr Margaret Geurin-Calvert, President of the Center for Healthcare Economics and Policy. Pictures: Chris Bateman

public/private hospitals in Lesotho and the United Kingdom.’ She pointed out that governance structures within the state health system are ‘crippling delivery at ground level’ with emasculated hospital managers unable to directly fire staff or order drugs. ‘We’ve tied the hands of those at ground level to do their job with very complex governance organograms and reporting structures,’ she added. Da Costa revealed that the National Department of Health’s newly formed Academy for Leadership and Management in Health Care, led by former University of Cape Town Dean of Health Sciences Professor Marian Jacobs, had consulted HASA in preparing for its first hospital-CEO training programme. ‘They steered us a bit into coding and diagnostic related groupings, but Richard [Friedland] said the first thing a hospital manager needs to know in the morning is whether his staff have arrived. They were trying to solve the higher-grade problems, the luxury, easy ones – but we have to deal with the 20% that will give us the 80% benefit! Like investing in a fingerprinting system to rule out people clocking in for their friends. You’d be surprised to find out just who spends a lot of time at work and who doesn’t. Outside of drugs and surgicals, 60 - 70% of operating costs are for nursing or

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payrolls. Doing something as simple as that can save you money and improve the quality of care. If you want to know now to make a hotdog, go and speak to somebody who makes hotdogs!’ she quipped. Da Costa said the academy was startled by Friedland’s direct and uncomplicated input, ‘but that’s a prime example of why public/ private sector dialogue is so important’. She added that her ambition for next year is to include more public sector players to sit on all the HASA conference discussion panels. This year, National Health Minister Dr Aaron Motsoaledi addressed the conference, while Dr Terence Carter, Deputy Director-General: Hospitals Tertiary Service and Workforce Management, took part in Strachan’s panel debate. Da Costa was upbeat about the NHI’s prospects – if more joint-policy planning and pragmatic implementation between the two sectors can be achieved. She gave the example of an actuarial study showing a 19% cost saving via mandatory cover and a risk equalisation fund. She said this meant that, of the R100 billion in medical aid contributions generated annually in South Africa, the resultant near-R20 billion saving could conceivably be funnelled into a ‘government aid’ programme. ‘I mean, Discovery’s [member] contributions are R30 billion for some 2.5 million beneficiaries – imagine what you could realise with another R20 billion!’

An added attraction of the Lesotho project was that the consortium can directly employ doctors, something disallowed in South Africa.

She said such a fund could enable everyone on social grants to see a GP, with money over for medications and the use of a private hospital’s emergency unit. The public sector could be used for the remainder of their needs. The government’s sudden change from a social health insurance scheme to NHI (following the ANC’s Polokwane conference) and the now-truncated medical scheme regulation (side-stepping risk equalisation and mandatory cover) was the equivalent of ‘throwing the baby out with the

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earning above the tax threshold (about 30% of the population, v. the 17% now covered). Elements of the proposed NHI are ‘immediately achievable – we can’t wait 14 years to achieve what must be an absolute non-negotiable tenet of our society – universal health care for all.’

Learning from Lesotho

Melanie da Costa, CEO of HASA.

bathwater; it’s like stopping halfway through a pregnancy – you look fat and funny.’

Delivery model should manage complete pathways of care

Friedland told delegates that a wider social compact between the public and private sectors to create a more equal and effective healthcare system is essential – but that this will mean letting go of the distrust and ideology that currently cloud the debate on both sides. ‘The government needs to acknowledge that it alone cannot provide the panacea for healthcare in South Africa,’ he said. ‘The private sector needs to acknowledge and embrace the willingness to treat public sector patients on an equal basis … we need a plurality of providers, giving universal coverage to all South Africans.’ This would require a different delivery model, which allows providers to manage the complete pathways of care (as opposed to the fragmented, unco-ordinated manner in which primary, tertiary and follow-up care is currently administered). He backed the growing call for mandatory health insurance for all formally employed people

Friedland said that in the hills above Maseru, Lesotho, the former Queen Elizabeth II Hospital, now called the Mamahato Memorial Hospital, situated in one of the poorest areas of southern Africa, had been transformed into a public/private state-ofthe-art tertiary referral hospital, coming well within the government’s health budget. The 425-bed public hospital and three primary care referral clinics, serving more than 1.8 million people, are now managed by the private Tsepong Constortium, of which Netcare is a 40% shareholder. Lesotho has one of the world’s highest per capita incidences of TB (632/100 000) while the 2012 HIV/ AIDS estimates showed a prevalence of 26%. In February this year the World Bank commissioned an independent study by Boston University to evaluate outcomes. They found a 41% reduction in the death rate, a 21% reduction in maternal mortality and a 65% reduction in the paediatric pneumonia death rate. This is in spite of a 51% increase in hospital admissions and outpatient visits surging to 126%. The hospital did not previously have the capacity to handle low-birth-weight infants but now boasts a 100% survival rate for infants under 1 500 g, Friedland added. ‘Imagine if we had 50 of these in South Africa, how we could transform the delivery of healthcare,’ he urged. Quizzed on why the partnership was piloted in Lesotho and not South Africa, Friedland said it was ‘merely a question of the government at the time being willing to work with us’. Elaborating, he said South Africa has yet to put out tenders for clinical services, although private healthcare corporates do have SA public sector facility management contracts, including Netcare’s contracts in Bloemfontein, Grahamstown and Port

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Alfred. An added attraction of the Lesotho project was that the consortium can directly employ doctors, something disallowed in South Africa. A total of R1.2 billion capital expenditure was required for the hospital and its clinics. The Lesotho government put in R400 million, while the consortium borrowed R800 million from the Development Bank of South Africa. Operational costs are calculated against the Lesotho Department of Health’s budget with a consumer price index (CPI) annual increment. Friedland said returns are being calculated over a 20-year-plus period.

Dr Richard Friedland, Netcare’s CEO.

In the United Kingdom, Netcare provides clinical services on a ‘very large’ scale, having grown its National Health Service patient base from 3% to 33% since 2006. ‘Our bona fides in terms of publicly funded work are established and we’d be happy to do that in South Africa,’ said Friedland. ‘We have enormous capacity and capability within the sector which we should be galvanising, and [which] the government should be using to improve outcomes and reduce waiting lists.’ Chris Bateman chrisb@hmpg.co.za S Afr Med J 2014;104(1):6-7. DOI:10.7196/SAMJ.7802

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Universal coverage possible – with private sector support The private healthcare sector could, ‘within a com paratively short time span’, hugely relieve its over burdened public counter part by nearly doubling its current medical scheme coverage of the population from 17% to 30%. This private subsidy would increase the government’s public sector per capita health spend by up to 19%. Healthcare actuary Barry Childs adds that for this much-needed pre-national health insurance (NHI) symbiosis to take place, government should complete its medical scheme regulatory reform and find ways to increase income cross-subsidies for schemes. Medical aid could be a lot more affordable if it could be made mandatory for everyone in formal employment above a specified income to belong to a medical scheme – and by bringing in a risk equalisation fund to create a level playing field between schemes, evening out the financial impact of different risk and demographic profiles. The medical aid schemes also urgently need to collaborate to reduce fraud and abuse, said Childs, and to ‘buy smarter’ by finding the most efficient providers and pathways of care, thus changing their mindset to ‘active purchasing’. ‘If we budget and think very carefully about how we run our medical schemes – how to get the best bang for our buck – and put this all together, I estimate we could lower actual [medical aid] contributions by up to 30%,’ he said. ‘It is going to take some time to achieve universal coverage through the NHI plan, but we can provide much-needed relief to both the public and private sectors in just a few years if we could implement these reforms and initiatives ahead of time.’ If only half of the potential savings were passed on to the existing market, the remainder could be used to significantly cross-subsidise the new tier market at similar benefit levels, which would significantly alleviate the load on the public sector. Addressing the annual Hospital Association of South Africa (HASA’s) annual conference at the Cape Town International Convention Centre on 28 October, Childs said that medical schemes have an unbalanced and incomplete regulatory framework. The foundations for social protection are in place through open enrollment, community rating and prescribed minimum benefits, but there

Healthcare actuary Barry Childs (left) and Stanlib chief economist Kevin Lings.

are none of the regulations required for the sustainability of the industry, such as mandatory membership, risk equalisation, risk-based capital and clarity on demarcation. Childs called the current regulations, which prescribe huge risk solvency reserve levels for medical aid schemes, ‘a significant waste of capital’. ‘Some schemes have massive cash reserves sitting in bank accounts and they can do almost nothing with that money,’ he said. He also took issue with the prescribed minimum benefits (PMBs) – a list of potentially catastrophic conditions which schemes are required to cover on all options and which play an important part of the social protection framework – describing them as a barrier to medical scheme entry for low-income families. He explained that just to cover the PMBs, the average cost of a medical scheme to a family was about R1 064 per month. Without greater income crosssubsidy, those costs are unaffordable for the majority of South Africans. Childs said a lot more could be done to increase healthcare access and affordability. Medical schemes have been a ‘regulatory orphan’ since 2007, when the government turned its attention to NHI. Up until that point, government had been planning to make changes to the medical scheme industry – including a risk-equalisation fund and mandatory scheme membership for all employed people – that would have enabled lower-income workers to access private

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healthcare. However, the Medical Schemes Amendment Bill of 2008, which contained these reforms, was never processed by Parliament and lapsed. The Council for Medical Schemes (CMS), under the stewardship of Dr Monwabisi Gantsho, has since drafted a new amendment bill, but this has yet to be submitted to Parliament or published for comment. Childs said it is highly unlikely that the new bill will contain all the measures needed to stabilise the medical schemes industry. Indeed, Gantsho is on record as saying that a risk equalisation fund is no longer part of the agenda. Such a fund would level the playing field between schemes that have lots of young and healthy members (and therefore lower healthcare costs) and those with more old and sick members. At present, schemes with a better risk profile can charge less and attract more young members. Childs also urged schemes and employers to work hard on preventive (‘wellness’) programmes to get people healthier, as this is one of the only solutions to the long-term trends in healthcare cost escalations.

Healthcare divide mirrors ‘two world’ economy

Echoing an earlier speaker on the costlowering theme, Stanlib’s chief economist, Kevin Lings, Childs said that South Africa has the worst Gini co-efficient in the

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world. The Gini index measures the extent to which the distribution of income (or, in some cases, consumption expenditure) among individuals or households within an economy deviates from a perfectly equal distribution. In South Africa, the unequal distribution of healthcare reflects the rest of the economy. South Africans spent about R11 395 per capita on private healthcare annually, versus R2 835 per capita in the public healthcare sector. Childs said that 70% of South Africans live in households earning less than R7 500 per month, a statistic he called ‘severely problematic’. In his own presentation, Lings told the HASA audience that South Africans are a nation of ‘shoppers – we don’t make stuff or invest’, adding that unsecured credit is growing at 42% per annum, with Capitec at one point last year processing 5 000 loans an hour. Lings said that over the past five years government salaries and wages have doubled, quipping, ‘We can’t shop our way to success – our salaries and wages go to China … it’s not the way to grow an economy; we need a different mix.’ Lings said shopping alone accounted for 92% of South Africa’s economic growth. He felt that the top priority should be to invest in infrastructure and manufacturing to create more jobs and establish a massive middle class that can afford medical cover. ‘First create jobs, then look at how you’re going to distribute socio-economic services,’ he said. At present South Africa has a ‘minute’ tax base, in which 859 000 of the 5.88 million taxpayers pay 53% of the total income tax bill. In order to expand access to medical schemes and hit the symbiotic 30% coverage, the country needs a far bigger, stable middle class that is family-oriented, with technical skills and good opportunities. Lings pointed out that South Africa consists of ‘two worlds’: one is skilled with a higher income, can afford private services, and has formal employment and access to technology; the other has high unemployment, low income, poor education, lack of access to services, low savings and relative youth. ‘We need the two worlds to intersect substantially – the differences are too stark,’ he said. The irony is that South Africa shifts between Number 1 and Number 3 in the Global Competitiveness Ranking, is Number 3 in the soundness of its well-managed and well-regulated banks and is Number 2 in global financial transparency. ‘We stand head and shoulders

above most. Two years ago we were ahead of New Zealand [in the Global Transparency ranking]. Now they are Number 1,’ he said. However, Lings stressed, ‘that does not mean government spends the money wisely. It means it allocates it wisely and transparently. It doesn’t mean we don’t squander the money!’

SA can afford a wellmanaged NHI – Lings

Government debt as a percentage of South Africa’s gross domestic product (GDP) stands at 40%, quite low on a world scale. ‘We can therefore consider national health insurance,’ said Lings. ‘Greece can’t, Japan sits at 200% of GDP and Italy is the next worst. We need to use our advantage wisely.’ Currently, debt servicing costs stand at well below 10%, down from double that figure when the ANC inherited a badly managed fiscal regime. Interest rates have plummeted from 14.6% to 5.2% and remain low (the lowest since 1974), meaning that the cost of starting a business or buying a home is reasonable. The FIFA World Cup, while not a huge money spinner at the time, has led to more people with more money making this country a tourist destination, with record tourism earnings currently, and many visitors from Africa itself. Foreign exchange reserves held by the Reserve Bank stood at about R50 billion, up from about R3 billion in 1997.

‘You can’t survive on a social grant,’ said Lings. ‘We’d like to increase it, but we can’t afford to pay a living income when more people receive a social grant than those who work!’ Lings said that these facts seldom make the newspapers and other media. What did hit the headlines was South Africa being ranked nearly last (146th) in the quality of our education system, with only half a million children writing matric annually (about half the desired number). ‘What happened to these children, where are these kids?’ he asked. They have dropped out of school, yet the government message is that South Africa has a 73% pass rate. The current unemployment rate of people younger than 24 years is 51%, while monthly social grants have risen from about 3 million to 16 million – more than the number of people working.

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‘You can’t survive on a social grant,’ said Lings. ‘We’d like to increase it, but we can’t afford to pay a living income when more people receive a social grant than those who work! If we don’t increase employment, these numbers will just get bigger.’ He described South Africa as the very opposite of China: ‘They achieved spectacular growth by building a lot of stuff. Their fixed investment activity sits at almost 50% of GDP. They’ve overbuilt – they have to slow down on building and pick up on shopping – we must do the opposite. [Finance Minister] Pravin Gordhan knows this. He’s saying we [our government] can’t spend as much money on salaries and wages – we need to spend more on public sector infrastructure.’ Gordhan wants to raise R827 billion over the next three years, which Lings said ‘won’t change the country without anything else happening’, but would take us closer to the 25% of spending on fixed investments as a percentage of GDP, which he said needs to be maintained for a decade.

Corporate ‘cash huggers’ biding their time

Lings said part of the answer lay in unlocking huge corporate sector capital, currently sitting idle in banks – what he described as ‘a massive cash pile, the highest ever recorded’, and estimated at over R550 billion currently. The reason these corporates are ‘hugging their cash, waiting’, is that they have lost confidence. ‘Would you want to invest in a business without electricity or inadequate port capacity?’ he asked. Lings said the first goal is to unlock the infrastructural bottlenecks (e.g. road, rail, electricity) to create business opportunities. As balance sheets begin to work, employment will increase. ‘Name any social or economic problem in South Africa, anything. And I promise you every one gets less, the more you employ. Every job you add systematically diminishes all the problems at the same time. Take the jobless 24-year-old guy in Diepsloot. If you try and change his circumstances before he has a job, you wreck the financial position of the government, because the tax base is far too small,’ he said. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2014;104(1):8-9. DOI:10.7196/SAMJ.7797

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HEALTH AND FINANCE

A first step towards transparency in pricing of medicines and scheduled substances – publication of guidelines for pharmaco-economic submissions M P Stander, M Bergh, H Miller-Jansön Tienie Stander, Margreet Bergh and Helen Miller-Jansön work for HEXOR Pty Ltd, South Africa, a health economics and outcomes research company focused on scientific and robust health research that benefits humanity. Pharmaco-economic studies form the basis of outcomes research. It is therefore relevant for HEXOR to share their views on the recently published National Guidelines on Pharmacoeconomic Submissions. Corresponding author: M P Stander (tienies@hexor.co.za)

The National Department of Health of South Africa recently published guidelines for pharmaco-economic (PE) submissions in accordance with the Medicines and Related Substances Act (Act 101 of 1965), which came into effect on 1 April 2013. These guidelines relate to the compilation of PE submissions for evidence of cost-effectiveness of medicine or scheduled substances. The PE guidelines are a first step towards the creation of a mechanism whereby the value of medicine can be quantified in a transparent manner. The ‘voluntary’ nature of PE submissions speaks to the current lack of knowledge, understanding and capacity related to pharmaco-economics that exists in the private healthcare market. The current disconnect between the PE guidelines and the Medical Schemes Act should be addressed as a matter of urgency to provide a mechanism whereby guidance in terms of cost-effectiveness from a PE evaluation will be supported by guaranteed reimbursement by medical schemes. S Afr Med J 2014;104(1):10-11. DOI:10.7196/SAMJ.7284

Healthcare reform in South Africa (SA) has been an ongoing process since 1994. By 2011, this process had evolved into a broad-based National Health Insurance (NHI) policy with compulsory membership for all citizens, based on a basic benefit package. Yet another milestone was reached with the publication of the Medicines and Related Substances Act (Act 101/1965) guidelines for pharmacoeconomic (PE) submissions.[1] The guidelines attempt to regulate and enhance a transparent pricing system for medicines and scheduled substances and offer structure for PE submissions. These guidelines came into effect on 1 April 2013.

Background

Three components ‘anchor’ the guidelines: • they provide for voluntary submissions • they apply to medicines that are registered by the Medicines Control Council in SA • they apply to the private healthcare sector. In the first part of the guidelines (Process for Submission), three of the stated objectives of the guidelines need to be highlighted. Firstly, there is a clear objective to move towards standardisation of PE evaluations. Secondly, there is an attempt to promote transparency when it comes to the value of medicine. The latter is important, as it is an attempt at medicine value transparency and not price transparency. The third objective is ‘to create a forum which provides an objective review of the value of medicine’, the key word being objective. The Pricing Committee (PC) will be responsible for establishing the ‘terms of reference for a sub-committee to assess pharmacoeconomic submissions’. This is an important guideline, with far-reaching implications, as all medicines that are found to be unreasonably priced will be listed on the National Department of Health website.

This regulation specifically mentions ‘unreasonably priced’ and does not address ‘value of medicine’. Furthermore, the PC may only make three recommendations on the therapeutic value of submitted medicines. Firstly, it may recommend that a medicine does not offer therapeutic value relative to the single exit price (SEP). Secondly, it may recommend that it is unreasonably priced. Lastly, it may make recommendations with regard to its therapeutic value in a specific patient group or prescription by general practitioners or specialist groups, or under specific circumstances. This implies that there is no mechanism or mandate whereby the PC can make a recommendation that a medicine does in fact offer therapeutic value relative to the SEP or that it is reasonably priced. The second part of the guidelines pertains to the content of PE evaluation submissions and addresses some technical issues that need to be complied with. It addresses critical issues such as the availability of SA clinical data v. international data, acceptable evidence (e.g. randomised controlled trials), co-administered drugs, choice of comparator drugs, and, very importantly, clinical evidence of effectiveness. The latter two require special mention as they have far-reaching implications. With regard to the choice of a comparator medicine, the guidelines make it clear that the main comparator should be the current standard of care for local practice and go on to state ‘... such as those described in the Prescribed Minimum Benefits (PMB) and Essential Drugs List (EDL)’. The guidelines related to clinical outcomes (effectiveness) are comprehensive and directive and constitute the most important part of a PE submission. However, some important aspects that should be highlighted are a recommendation to include details of patient adherence to treatment data, SA quality of life measures, and transparency and completeness of search strategies for relevant data.

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One technical aspect that needs to be highlighted is the requirement to perform the PE evaluation from a third-party payer perspective. This implies that only the economic costs that are relevant to a thirdparty payer should be included in the submission. Accordingly, only direct healthcare costs should be included, with exclusion of other societal costs such as direct non-healthcare costs (transport and caretaker costs and loss of income directly associated with the disease treatment and progression) and non-direct healthcare costs (loss of productivity and the macro-economic impact on the SA economy). The guidelines constitute ‘world class’ standards for PE evaluation submission and should be seen as complementary to a world-class private healthcare sector. Furthermore, they are comprehensive and directive and a significant step towards the standardisation of PE evaluation submissions. There is a very strong emphasis on clinical outcomes and the robustness of the supporting evidence, and to what extent the latter is transferable and applicable in SA. Mathematical modelling, when needed to mimic the natural history of the disease and estimate its economic impact by comparing a new medicine to the current practices, appears to be less important.

Implications

Several important implications need to be considered. Firstly, the PE guidelines are published as a Regulation to the Medicines and Related Substances Act (Act 101/1965). They therefore have no direct bearing on medical schemes (third-party payers in the private healthcare sector), which are regulated by the Medical Schemes Act (Act 131 of 1998, as amended). Although a manufacturer might submit a PE evaluation to the PC and receive a ‘non-negative’ outcome, this does not imply reimbursement by third-party payers. Medical schemes may or may not accept the outcome of ‘good value for money’ and will retain the right not to reimburse such new medicines based on arguments of affordability. Although the Regulations clearly state that PE submissions are voluntary, this could be questioned. Paragraph 3, which deals with the criteria for medicines that require PE submissions, states three criteria and under 3(c) states: ‘Where it is the opinion of the Minister, Pricing Committee or the Director-General (DG) that a pharmacoeconomic submission is necessary/required for a particular medicine.’ This implies that a PE submission may become compulsory if it is so decided. The guidelines are merely a first step towards a bigger plan in terms of transparency of the value of medicine in an NHI dispensation. This begs the question whether objectivity in a private healthcare system constitutes objectivity in a more societal system, such as NHI. Can committee members be or remain objective in an ever-changing

health reform agenda, i.e. from a private healthcare focus towards an NHI-focused perspective? The broad statement about the terms of reference that will be provided by the PC to the sub-committee ties in with the question of objectivity. In pharmacoeconomics, cost-effectiveness is based on a society’s willingness-to-pay thresholds for specific benefits. It is considered an indication from society of what constitutes good value for money. On what basis will the PE sub-committee make recommendations in an objective way regarding a submission? What would their threshold for cost-effectiveness be? Given the three recommendations that could be made by the PC, based on a PE submission, what incentives would there be for a pharmaceutical company to voluntarily submit a PE evaluation?

Conclusion

The comprehensive nature of the guidelines implies that it will be a costly project to submit a PE evaluation in line with the Regulations. These additional costs should, however, be considered against the backdrop of a shrinking private healthcare industry that is envisaged as NHI is rolled out. In this scenario, pharmaceutical companies could find it more challenging to remain profitable in SA. This will be dependent on the company’s specific product portfolio and pipeline. Given this challenge, it is quite probable that some pharmaceutical companies will exit the SA market. The publication of the PE guidelines should be considered a first step towards the creation of a mechanism whereby the value of medicine can be quantified in a transparent manner. It can be expected that voluntary submissions of PE studies will progressively move towards compulsory PE submissions. Stakeholders should therefore plan to build and enhance capacity, knowledge and insight related to pharmacoeconomics. Finally, in the future we may witness the progressive conversion of the guidelines in support of the NHI initiative and EDL extensions. Strategically, stakeholders should not only ensure that they understand the content and implications of the PE guidelines, but also plan how they will position themselves in this changing environment. 1. Department of Health. Medicines and Related Substances Act (101/1965) Regulations relating to a transparent pricing system for medicines and scheduled substances: Publication of guidelines for pharmacoeconomic submissions. Government Gazette 1 February 2013. http://www.mediscor. net/docs/GG/Medicines%20and%20related%20Substances%20Act%20101-1965%20-%20 Regulations%20relating%20to%20a%20transparent%20(20130201-GGR-36118-00068).pdf (accessed 4 September 2013).

Accepted 3 September 2013.

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MEDICINE AND THE LAW

Surrogacy commissioning fathers and HIV D W Jordaan Donrich Jordaan is an advocate, member of the Pretoria Bar; and research fellow, Department of Jurisprudence, College of Law, University of South Africa Corresponding author: D W Jordaan (mail@donrichjordaan.law.za)

Surrogacy is not regulated by a single legal instrument only, nor is confirmation of a surrogacy agreement by the High Court an unqualified green light for the surrogacy process to proceed. In the context of the HIV status of the commissioning father, whose gametes are to be used for the conception of the child in pursuance of a surrogacy agreement, the intended in vitro fertilisation of the surrogate mother may only take place on condition that the commissioning father, and his semen, have been tested for HIV; that he has consented to his HIV status being made available to the surrogate mother, and if he is HIV-positive, that sperm washing will be used to minimise the risk of infection and that the surrogate mother has been informed of his HIV status, and given her informed consent. S Afr Med J 2014;104(1):12-13. DOI:10.7196/SAMJ.7498

A person’s HIV status is highly private, mainly due to the way in which it is generally transmitted and the lack of a cure.[1] In NM and Others v. Smith and Others, the Constitutional Court held that ‘an individual’s HIV status deserves protection against indiscriminate disclosure due to the nature and negative social context the disease has, as well as the potential intolerance and discrimination that result from its disclosure’.[2] Our courts have recognised the moral and legal duty of healthcare practitioners to keep their patients’ HIV status confidential.[3] However, this duty is not absolute and both the Health Professions Council of South Africa ethical rules[4] and the South African Medical Association guidelines[5] provide for disclosure of a patient’s HIV status to their intimate partner by a healthcare practitioner under certain circumstances. Consider the following: a surrogacy agreement has been confirmed by the High Court in terms of which the gametes of a certain HIVpositive commissioning father must be used. What is the legal duty of the responsible healthcare practitioners with regards to informing the surrogate mother of the HIV status of the commissioning father, or keeping this confidential? The answer is not found in a single legal instrument, but requires consideration of several legal rules. This analysis is limited to the specific parameters of this question and the conclusions should not be applied outside these parameters.

Surrogate motherhood: Relevant statutes

Chapter 19 of the Children’s Act[6] is dedicated to surrogate motherhood. It deals with aspects such as the criteria that prospective commissioning parents and prospective surrogate mothers must fulfil, confirmation of the surrogacy agreement by the Court, and the enforceability of such an agreement. Regarding the artificial fertilisation of a surrogate mother in the execution of a surrogacy agreement, the Children’s Act[6] explicitly refers to the National Health Act.[7] In 2012, the Minister of Health made the Regulations Relating to Artificial Fertilisation of Persons[8] in terms of the National Health Act. The Regulations apply to all cases of artificial fertilisation of persons, including the artificial fertilisation of surrogate mothers in pursuance of surrogate motherhood agreements.

According to the Regulations, a ‘gamete donor’ is the person whose gametes are to be used for artificial fertilisation, and a ‘recipient’ is the woman who is to be artificially fertilised.[8] The Regulations specifically define a ‘surrogate’ as a species of recipient;[8] therefore the ‘commissioning father’ whose sperm are to be used for the conception of the child in pursuance of a surrogacy agreement would be a species of gamete donor.

Legal duties created by the Regulations

Important in the surrogacy process is the ‘competent person’, who is defined in relation to artificial fertilisation as a person registered as such in terms of the Health Professions Act, (Act No. 56 of 1974) who is: (i) a medical practitioner specialising in gynaecology with training in reproductive medicine; or (ii) a medical scientist, medical technologist or clinical technologist with training in reproductive biology and related laboratory procedures.[8] The first relevant legal duty created by the Regulations is that the commissioning father may not donate his sperm on his own volition without the involvement of a competent person in the donation process: ‘Removal or withdrawal and storage of gametes: 3(1) No person, except a competent person, may remove or withdraw a gamete or cause a gamete to be removed or withdrawn, from the body of a gamete donor for the purpose of artificial fertilisation.’[8] This provision aims to ensure that the artificial fertilisation is done within the Regulations’ regulatory framework. The Regulations further provide that, before the commissioning father may donate his sperm, the involved competent person must first: • confirm that the commissioning father has on two occasions, not more than three months apart and one month before the intended donation, undergone medical tests for HIV and a semen analysis[8] • obtain the commissioning father’s informed consent that the results of these tests may be made available to the surrogate mother and the competent person who will perform the artificial fertilisation on the surrogate mother.[8] Only after successfully performing these actions may the donation take place. Hereafter the involved competent person has a legal duty to make the results available to the surrogate mother.[8] Making information available to a person can entail its direct communication.

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It can also entail that the person is informed of the existence of the information, which should be made readily accessible and the person informed of how to access it. At a minimum, the Regulations require the involved competent person to inform the surrogate mother that the commissioning father’s gamete donor file is available for her information. The Regulations are clear that if the commissioning father’s sperm has not been donated according to the Regulations, his sperm may not be used for the artificial fertilisation of the surrogate mother.[8] Thus the competent person who is to perform the in vitro fertilisation (IVF) on the surrogate mother must ensure that all the legal rules of the Regulations have been complied with before proceeding – even if this competent person was not involved with the donation of the sperm. Thus the competent person who is to perform the IVF on the surrogate mother must have a copy of the commissioning father’s gamete donor file, and verify that it has been documented that the commissioning father has, within the prescribed timeframes, been tested for HIV, his semen has been analysed for HIV, and he has given his informed consent to the results being made available to the surrogate mother; and that the results have been received and have been made available to the surrogate mother.

Legal duties at common law

In the context of making the results available, further legal rules become relevant, namely our common law, as developed by case law, regarding consent to medical treatment. The rule of informed consent states that a healthcare professional must warn a patient of all the material risks of the intended medical treatment, and that the patient must understand such risks but still consent to undergoing the intended medical treatment. This raises the question regarding the risks involved for the surrogate mother should the commissioning father be HIV-positive. In such a situation, it is assumed that sperm washing (to eliminate the chances of HIV infection[9-13]) would be utilised to minimise the chance of infection of the surrogate mother. However, in the locus classicus of informed consent, Castell v. De Greef,[14] the Court expressed itself in favour of a patientorientated approach[14] to determining the materiality of the risks involved in the intended medical treatment, and hence whether the healthcare professional has a legal duty to warn a patient of such a risk. Accordingly, the Court held that a risk is material if, in the circumstances of the particular case, a reasonable person in the patient’s position, if warned of the risk, would be likely to attach significance to it; or the medical practitioner is or should reasonably be aware that the particular patient, if warned of the risk, would be likely to attach significance to it. I suggest that the reasonable surrogate mother would attach significance to the risk of HIV infection, even if statistically reduced to virtually zero by sperm washing. This is because of the life-threatening nature of HIV infection and associated negative emotions. This has been recognised by the Constitutional Court, which held in NM v. Smith that: ‘There is nothing shameful about suffering from HIV/ AIDS. HIV is a disease like any other; however, the social construction and stigma associated with the disease make fear, ignorance and

discrimination the key pillars that continue to hinder progress in its prevention and treatment. These pessimistic perceptions persist to fuel prejudice towards people living with HIV/AIDS’.[2] Accordingly, the competent person who is to perform the IVF on the surrogate mother has a legal duty to disclose the commissioning father’s positive HIV status to the surrogate mother, and to explain to her the risks of HIV infection within the context of the utilisation of sperm washing and this technique’s track record of safety.

The surrogate mother’s dignity

In our constitution the value of autonomy is central.[2,15] Accordingly, the competent person cannot simply decide on behalf of the surrogate mother that the use of sperm washing will render non-material the commissioning father’s HIV-positive status. The surrogate mother should make this decision. Whether the risk of HIV infection materialises or not (and gives rise to a medical negligence claim) is a secondary consideration. The primary consideration is the disregard by the competent person of the surrogate mother’s autonomy. Such disregard of the surrogate mother’s autonomy is belittling and she may feel insulted. Thus, irrespective of whether infection occurs or not, should the competent person omit to obtain the surrogate mother’s informed consent regarding the commissioning father’s HIV-positive status, such omission would constitute an infringement of her dignity, which is a crime and cause of action for a civil claim.

Conclusion

A single act (including an omission) – especially in the medical field – may be regulated by many legal rules. Therefore, in the context of this article, the fact that the High Court has confirmed a surrogacy agreement does not render the other layers of legal rules irrelevant. 1. Le Roux-Kemp A. HIV/AIDS, To Disclose or not to Disclose: That is the Question. Potchefstroom Electronic Law Journal 2013;16(1):200-239. [http://dx.doi.org/10.4314/pelj.v16i1.7] 2. NM and Others v. Smith and Others [2007] (5) SA 250 (CC). 3. Jansen van Vuuren and Another NNO v. Kruger [1993] (4) SA 842 (AD). 4. Health Professions Council of South Africa. Guidelines for Good Practice in the Health Care Professions: Ethical Guidelines for Good Practice With Regard to HIV. Booklet 11. Pretoria: HPCSA, 2008. http://www.hpcsa.co.za/downloads/conduct_ethics/rules/generic_ethical_rules/booklet_11_ hiv.pdf (accessed 22 November 2013). 5. South African Medical Association. Ethical and Human Rights Guidelines on HIV: A Manual for Medical Practitioners of South Africa (2001). http://www1.chr.up.ac.za/undp/domestic/docs/ policies_03.pdf (accessed 22 November 2013). 6. South African Government. Children’s Act No. 35 of 2008. Pretoria: Government Printer, 2008. 7. South African Government. National Health Act No. 61 of 2003. Pretoria: Government Printer, 2003. 8. National Department of Health. Regulations Relating to Artificial Fertilisation of Persons. Government Notice R175/2012. http://www.doh.gov.za/docs/regulations/2012/regr175.pdf (accessed 22 November 2013). 9. Bujan L, Hollander L, Coudert M, et al. Safety and efficacy of sperm washing in HIV-1-serodiscordant couples where the male is infected: Results from the European CREAThE network. AIDS 2007;21(14):1909-1914. [http://dx.doi.org/10.1097/QAD.0b013e3282703879] 10. Hanabusa H, Kuji N, Kato S, et al. An evaluation of semen processing methods for eliminating HIV-1. AIDS 2000;14(11):1611-1616. 11. Nicopoullos JD, Almeida P, Vourliotis M, Gilling-Smith C. A decade of the United Kingdom spermwashing program: Untangling the transatlantic divide. Fertil Steril 2010;94(6):2458-2461. [http:// dx.doi.org/10.1016/j.fertnstert.2010.03.074] 12. Savasi V, Ferrazzi E, Lanzani C, et al. Safety of sperm washing and ART outcome in 741 HIV-1serodiscordant couples. Hum Reprod 2006;22(3):772-777. [http://dx.doi.org/10.1093/humrep/del422] 13. Semprini AE, Macaluso M, Hollander L, et al. safe conception for HIV-discordant couples: Insemination with processed semen from the HIV-infected partner. Am J Obstet Gynecol 2013;208(5):402.e1-402. e9. [http://dx.doi.org/10.1016/j.ajog.2013.02.009] 14. Castell v. De Greef [1994] (4) SA 408 (C). 15. Barkhuizen v. Napier [2007] (5) SA 323 (CC).

Accepted 16 September 2013.

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MEDICINE AND THE LAW

Disposal of medical waste: A legal perspective K du Toit, J Bodenstein Karen du Toit is an honorary associate professor in the Discipline of Pharmaceutical Sciences (Pharmaceutical Chemistry), University of KwaZuluNatal, South Africa and candidate attorney at DMKisch Inc. Johannes Bodenstein is a Senior Lecturer in the Discipline of Pharmaceutical Sciences (Pharmacology), University of KwaZulu-Natal, South Africa. Corresponding author: K du Toit (karend@dmkisch.com)

The Constitution of the Republic of South Africa provides that everyone has the right to an environment that is not harmful to their health and well-being. The illegal dumping of hazardous waste poses a danger to the environment when pollutants migrate into water sources and ultimately cause widespread infection or toxicity, endangering the health of humans who might become exposed to infection and toxins. To give effect to the Constitution, the safe disposal of hazardous waste is governed by legislation in South Africa. Reports of the illegal disposal of waste suggest a general lack of awareness and training in regard to the safe disposal of medical waste. S Afr Med J 2014;104(1):14-15. DOI:10.7196/SAMJ.7175

The Constitution of the Republic of South Africa[1] provides that everyone has the right to an environment that is not harmful to their health and well-being. However, the illegal dumping of hazardous waste poses a danger, not only to the health of scavengers who are directly exposed to it, but also to the environment when pollutants migrate into water sources and ultimately cause widespread infection and toxicity. To give effect to the Constitution, the safe disposal of hazardous waste is governed by legislation. However, constant findings of illegal disposal of waste suggest a general lack of awareness and training in this sector.[2] According to the Hazardous Substances Act,[3] waste is classified as general or hazardous waste according to the risk it poses. General waste is defined as waste which does not pose a significant threat to public health or the environment. Hazardous waste, however, has the potential, even in low concentrations, to have a significant adverse effect on public health and on the environment. Waste is accepted to be hazardous and toxic until proven otherwise.[3] The Act further provides for the classification and control of hazardous substances, which is provided for in the South Africa Bureau of Standards (SABS) Standard 0228.[4] Nine classes of hazardous substances are identified, of which one or more will certainly be found in retail pharmacies, including: class 2 – compressed gases such as oxygen in gas cylinders; class 3 – flammable liquids such as acetone or alcohol; class 6 – toxic and infectious substances such as drugs, cytotoxic substances and sharps; and class 7 – radioactive substances. The SABS Standard determines the minimum requirements for the differential disposal of hazardous waste. Neither the Act nor the SABS Standard specifically provide for healthcare waste generated at healthcare facilities. The management of healthcare waste is envisaged by the draft Health Care Risk Waste Management Regulations of 2008.[5] According to these regulations ‘healthcare risk waste’ is defined as that hazardous portion of healthcare waste which includes infectious waste, infectious sharps, and pharmaceutical waste. Pharmaceutical waste is defined as expired, unused, spilt or contaminated drugs, medicines and vaccines, and includes their packaging materials.

Good pharmacy practice

A generator of waste inter alia refers to a person (including healthcare practitioners and facilities) whose actions or activities result in healthcare risk waste, according to the draft Health Care Risk Waste Management Regulations.[5] Any generator of waste has a ‘duty of care’ to society to handle, store, transport or dispose of waste in an environmentally sound way.[6] This is referred to as the ‘cradle-to-grave’ responsibility,[7] since it lasts throughout the whole process of waste disposal. Therefore, pharmacies and responsible pharmacists have a duty to handle waste in a responsible manner. It is important that every pharmacy has a standard operating procedure for disposal of waste. Waste production should be minimised or avoided where possible, e.g. by checking expiry dates of goods on delivery, supplying older batches first, recycling or re-using packaging materials and returning empty gas bottles to the supplier. Generated waste should be segregated at the point of generation in a pharmacy and healthcare risk waste should not be mixed with general waste or other waste streams.[8] This waste should be contained at the point of generation into specifically designated containers. This entails the use of containers specifically intended for sharps (South African National Standards (SANS) 452),[9] as well as differently colour-coded containers and liners (SANS 10248‑1).[10] Containers must be rigid, leak-proof and puncture resistant. In addition, containers must be sealed and labelled properly and stored in a secure, designated area until released to the transporters. Pharmaceutical waste may not be stored for longer than 90 days from the date the container is sealed to the date of final disposal.[5] The waste generator must ensure that waste is handled only by companies permitted to transport and dispose of it.[5] Disposal must take place through a waste disposal facility that is licensed in terms of the National Environmental Management: Waste Act.[6] Chemical waste undergoes physical, chemical or thermal treatment to minimise or eliminate hazardous characteristics before residues are landfilled. Chemical waste is generally incinerated, although care has to be taken with regard to volatile chemicals.[8] Infectious waste is incinerated and the residual ash evaluated and given a hazard rating, prior to being disposed of at a designated hazardous-waste landfill. According to the draft Rules relating to Good Pharmacy Practice,[11] read together with the Medicines and Related Substances Act,[12] medicines

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must be disposed of in an irretrievable manner but not into municipal sewerage systems. A pharmacist or other authorised person may destroy medicine containing a schedule 1, 2, 3 or 4 substance. However, medicine containing a schedule 5, 6, 7 or 8 substance may only be destroyed after obtaining approval from a person authorised by the Director General of Health; futhermore, it may only be destroyed in the presence of an inspector, an officer of the South African Police Service (SAPS) or any other person authorised by the Director General. Furthermore, the South African Medicines Control Council may authorise the destruction of a schedule 5 or 6 substance by the manufacturer in the absence of an inspector. In all cases, the persons responsible for destroying the medicines and scheduled substances must issue a certificate to confirm the destruction of the medicine. If the medicines have been destroyed by an officer of the SAPS, the case number must be entered into the register. According to the draft Rules relating to Good Pharmacy Practice,[11] a contractor specialising in the disposal of chemical or medicinal waste may be contracted to destruct medicines and scheduled substances. Two pharmacists must, however, witness the removal from the premises of the correct quantities of medicines and scheduled substances authorised for destruction. The contractor must employ a pharmacist whose task is to ensure irretrievable disposal of the goods. If a contractor is not used, two pharmacists must witness both the removal and destruction of the correct quantities of medicines and scheduled substances. Failure of pharmacies to comply with the above legislation is a criminal offence. Furthermore, according to the National Environmental Management Act,[7] a generator of healthcare waste may be held liable for the costs of clearing up waste or of rehabilitating any environmental effects, if the process of waste disposal was not dealt with according to sound principles. The Act provides that not only corporate entities, but also their executives in their personal

capacities, may be held liable for failing to prevent pollution. Therefore, it is in the interest of the generator to obtain information regarding waste disposal and to incorporate it as part of standard operational procedures. Appropriate training programmes will be required to provide employees within pharmacies with knowledge regarding waste management to prevent contravention of applicable laws. Furthermore, according to the Occupational Health and Safety Act,[13] an employer should maintain a working environment that is safe and without risk to the health of employees as far as is reasonably practicable. Acknowledgement. We thank Johan Bothma (Executive Director, Pharmaceutical Society of South Africa) for his kind advice regarding waste management in the health sector. 1. South African Government. Constitution of the Republic of South Africa, No. 108 of 1996. Pretoria: Government Printer, 1996. 2. Love P. Hazardous waste has health risks. Reputation Matters, 14 February 2013. http://www. reputationmatters.co.za/hazardous-waste-has-health-risks/ (accessed 25 November 2013). 3. South African Government. Hazardous Substances Act No. 15 of 1973. Pretoria: Government Printer, 1973. 4. South African Bureau of Standards. SABS 0228-5:2010. Pretoria: SABS, 2010. 5. South African Government. Draft Health Care Risk Waste Management Regulations. Government Notice 452, Government Gazette No. 35405, 1 June 2012. 6. South African Government. National Environmental Management: Waste Act No. 59 of 2008. Pretoria: Government Printer, 2008. 7. South African Government. National Environmental Management Act No. 107 of 1998. Pretoria: Government Printer, 1998. 8. South African Government. Framework Document on the Management of Health Care Waste, May 2000. Pretoria: Government Printer, 2000. 9. South African Bureau of Standards. SANS 452:2008. Pretoria: SABS, 2008. 10. South African Bureau of Standards. SANS 10248-1:2008. Pretoria: SABS, 2008 11. South African Government. Draft Minimum Standards Regarding Destruction and Disposal of Medicines. Government Notice 105 of Government Gazette No. 34330, 27 May 2011. 12. South African Government. Medicines and Related Substances Control Act, No. 101 of 1965. Pretoria: Government Printer, 1965. 13. South African Government. Occupational Health and Safety Act, No. 85 of 1993. Pretoria: Government Printer, 1993.

Accepted 27 June 2013.

OPINION

Traditional male circumcision: Balancing cultural rights and the prevention of serious, avoidable harm K G Behrens Kevin Behrens is a senior lecturer in the Steve Biko Centre for Bioethics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Corresponding author: K G Behrens (kevin.behrens@wits.ac.za)

The right to participate in cultural practices should be protected. However, it is a limited right, and does not entail a right to activities that cause serious and avoidable harms. I argue that the harms currently resulting from traditional circumcision are very serious, and that we have an obligation to ensure that the practice is effectively regulated so as to minimise them. S Afr Med J 2014;104(1):15-16. DOI:10.7196/SAMJ.7493

Traditional male circumcision is regarded as a sacred and indispensable cultural rite intended to prepare initiates for the responsibilities of adulthood.â&#x20AC;&#x160;[1] Each year in South Africa (SA) thousands of youths enter initiation schools. Tragically, scores of these initiates experience medical complications and require treatment for, among other things, septicaemia, gangrene, severe dehydration and genital mutilation. Penile amputations

and deaths also occur.[1,2] With multiple deaths, hundreds of boys and young men requiring hospitalisation, and some having to undergo partial or total amputations, 2013 was a particularly bad year.[3] The situation creates a moral dilemma: on the one hand, the right of people to participate in their cultural practices ought to be protected; on the other, initiates ought to be protected from harm. How do we balance these competing obligations? I argue that, all

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things considered, our obligation to prevent serious harm outweighs the rights of people to cultural practice. The right to traditional circumcision is limited, and should only be protected insofar as it does not result in serious harm. This does not imply that the practice should be abolished. Rather, the practice should be regulated and measures to prevent harm should be taken and enforced. The SA Constitution establishes a right to ‘participate in the cultural life of … choice’.[4] The Children’s Act (No. 38 of 2005) allows for the circumcision of males over 16 years of age, with consent and carried out in the prescribed manner. The intention of the law is to allow for traditional circumcision of boys over 16 who belong to groups in which the practice is customary. This represents a legal concession to particular cultural groups. Traditional circumcision is therefore lawful, but is it morally justified? Our Constitution establishes a right to cultural practice, but this is not uncontroversial. Are there good reasons to protect the right to cultural practice? I want to defend the claim that there are important social goods to be obtained by participation in one’s culture, and that people should not be denied these social goods without good reason. Recently, much attention has been given to cultural rights and to ‘identity politics’. Taylor[5] argues that ‘authenticity’ is a social good that should be protected and that our sense of identity grows out of belonging to a culture. In the face of the dominance of Western culture, it is necessary to protect the distinctiveness of other cultures so that they do not become ‘assimilated to a dominant … identity … This assimilation is a cardinal sin against the ideal of authenticity.’ Kymlicka[6] similarly claims that our individual identity is rooted in our cultural identity. ‘People’s selfrespect is bound up with the esteem in which their national group is held. If a culture is not generally respected, then the dignity and self-respect of its members will also be threatened.’ I broadly agree with these theorists. Cultural identity is important and our sense of self-worth is closely associated with a sense of belonging to a primary social group. We should therefore ensure that people are generally free to practise their culture. In SA, we have particularly strong grounds for ensuring cultural rights, based on our historical experience of oppression. In the past, indigenous cultures were denigrated, suppressed and regarded as primitive. Steve Biko[7] described an ‘inferiority complex’ experienced by black people who internalised the image of themselves portrayed by the oppressor: ‘No longer was reference made to African culture, it became barbarism. Africa was the “dark continent”. Religious practices and customs were … superstition … No wonder the African child learns to hate his heritage.’ For Biko, the oppressed need to first reclaim their dignity and self- image before they can truly be free. The attack on indigenous cultures was an assault on the dignity and identity of many. Given this historical injustice, it is exceptionally important that people have their dignity restored by being able to practise their culture and embrace their identity. It is a matter of restorative justice that traditional cultures should be respected. We ought to protect the right to cultural participation. But this right is conditional and not absolute. Surely where serious and avoidable harm results from the exercise of any right, society has justified grounds for limiting the exercise of that right? Surely the right to culture should be limited to practices that do not cause significant harm? So, the question is: what is the extent and nature of the harms caused by traditional circumcision? If these harms are insignificant, the practice should be allowed to continue just as it is. Unfortunately, this is not so: traditional circumcisions are currently the cause of significant harm to many initiates. I want to defend this claim briefly. According to Kepe,[2] from 1995 to 2005 in the Eastern Cape alone, 5 813 hospital admissions, 281 penile amputations and 342 deaths were reported. This is an annual average of 528.5 admissions, 25.5 amputations and 31 deaths. Since these statistics apply only to one province, this is a serious public health concern. The number of deaths is very worrying, but so is the number of amputations. In addition, badly performed and badly

managed circumcisions can result in serious infections and in scarring and mutilation of the genitals, with many non-trivial implications, including severe pain. There are also concerns regarding potential transmission of infections when traditional practitioners fail to use sterilised instruments.[2] There are a number of factors that contribute to the harm caused. Traditional practitioners are often insufficiently trained to perform these surgeries. Poor postoperative management, binding the wound too tightly, and traditional restrictions on drinking water all lead to complications. Social pressure to complete the initiation without outside medical intervention often results in initiates seeking medical help too late. Initiates may also be the victims of violence. The custom that requires secrecy and restricts contact to other circumcised men makes oversight of the process by medical personnel nearly impossible. What makes these harms even more ethically serious is that they are generally avoidable. It is not circumcisions themselves that place initiates in danger, it is how they are done. The avoidable deaths, penile amputations, genital mutilations, and other health threats are very serious harms, and the right of initiates not to be harmed in these ways surely outweighs the right to cultural practice. This is not only intuitively obvious – ethically it is supported in our law. As with many other rights, the right to practise culture is guaranteed only insofar as it is not exercised in a ‘manner inconsistent with any [other] provision of the Bill of Rights’.[4] There are also rights to human dignity, freedom and security of the person, and to life, all of which are being denied to some initiates. While traditional circumcision, as currently practised, causes serious harm, prohibiting this practice is not the only way to prevent harm. With effective regulation and management, the social good of protecting cultural practice can be achieved at the same time as ensuring that harm to participants is minimised. As Kepe[2] points out, the ‘health crisis in ritual male circumcision … is in fact a government responsibility. Therefore, in addition to its constitutional obligation to protect the health of the people, the government may want to be seen as taking this issue seriously.’[2] So far, attempts to regulate these circumcisions have had limited success. Greater political will, effective monitoring, and prosecution and punishment of offenders are required. Traditional leaders also bear much responsibility and need to be aware that their right to perform traditional surgeries is a privilege granted by society to show respect for culture. The right to keep that privilege may require that some of the customary aspects of the practice need to change, to prevent harm. It has been reported that the Congress of Traditional Leaders of South Africa has called for co-operation between the National Department of Health and itself.[8] This is very welcome news. However, the need for action is urgent. It is surely possible to find a way to protect culture and ensure the health and well-being of initiates. 1. Ntombana L. Should Xhosa male initiation be abolished? International Journal of Cultural Studies 2011;14(6):631-640. [http://dx.doi.org/10.1177/1367877911405755] 2. Kepe T. Secrets that kill: Crisis, custodianship and responsibility in ritual male circumcision in the eastern Cape Province, South Africa. Soc Sci Med 2010;70(5):729-735. [http://dx.doi.org/10.1016/j.socscimed.2009.11.016] 3. Makurdi W. Botched circumcision from initiation rituals fill S. African hospital. The Seattle Times, 9 August 2013. http://seattletimes.com/html/nationworld/2021579230_initiationdeathsxml.html (accessed 26 August 2013). 4. South African National Government. Constitution of the Republic of South Africa, Chapter 2. Pretoria: Government Printer, 1996. http://www.info.gov.za/documents/constitution/1996/96cons2.htm (accessed 1 September 2013). 5. Taylor C. Multiculturalism: Examining the politics of recognition. In: Gutman A, ed. Multiculturalism: Examining the Politics of Difference. Princeton: Princeton University Press, 1994. 6. Kymlicka W. The Rights of Minority Cultures. New York: Oxford University Press, 1995. 7. Biko S. I Write What I Like. Johannesburg: Picador Africa, 2004. 8. Bateman, B. Contralesa to address initiation deaths. Eyewitness News, 2 August 2013. http://www.google.co.za/ url?sa=t&rct=j&q=&esrc=s&frm=1&source=web&cd=1&ved=0CCkQFjAA&url=http%3A%2F%2Fewn. co.za%2F2013%2F08%2F02%2FTraditional-leaders-address-initiation-deaths&ei=wB4vUuWkPITm7Abz4DIAQ&usg=AFQjCNEfDLvr7-VDy36O13QWq5Dp49bWtA&bvm=bv.51773540,d.d2k (accessed 7 September 2013).

Accepted 9 October 2013.

January 2014, Vol. 104, No. 1

EDITORIAL

Adult circumcision in the prevention of HIV/AIDS In this month’s SAMJ, Millard et al.[1] report the results of an innovative study comparing surgical circumcision to that using a Unicirc device plus tissue adhesive. This is a follow-up to their earlier study using a similar non-disposable device (Gomco)[2] This study is timely because South Africa (SA) is not on target to meet its planned objective of circumcising 80% of men between the ages of 15 and 49 or 4.3 million by 2015[3] and points the way toward a faster, easier method that may aid in voluntary medical male circumcision (VMMC) scale-up in areas of Africa with a high prevalence of HIV infection. Three landmark randomised trials carried out in SA, Kenya, and Uganda were published in 2007.[4-6] The trials were all terminated early based on interim analyses that showed a significantly lower rate of newly-acquired HIV infection for the circumcised v. the uncircumcised men. These 3 studies later formed the basis of a Cochrane review, which confirmed the value of surgical circumcision with healing by primary intention as a method for preventing heterosexual HIV transmission. The combined results showed that VMMC reduced incident HIV infection rates by 60%. Some people dismiss circumcision as a beneficial, preventive intervention, claiming that it encourages men to participate in unprotected sexual activity. The truth is that despite counselling and increased knowledge, the use of condoms remains sporadic among men. The differences between the control and circumcised groups would not have become apparent so quickly if the men had been using condoms as advised. Based on this strong scientific evidence, VMMC is a priority intervention for the World Health Organization (WHO) and the President’s Emergency Plan for AIDS Relief (PEPFAR). Circumcised men have a lower risk of acquiring HIV because, following circumcision, the epithelium of the glans penis becomes keratinised, and keratinised epithelium is largely resistant to the passage of HIVinfected T-cells. Uncircumcised men, on the other hand, are at higher risk of HIV acquisition because the inner foreskin layer allows HIV-infected cells to form apical viral synapses with the dendrites of Langerhans cells present on the moist mucosal surface of the glans and inner part of the prepuce. [7] Infected T-cells pass through the epithelial layer and attach to the dendrites of the Langerhans cells. The inner foreskin produces tumour necrosis factor, which stimulates the Langerhans cells via cytokines to produce an influx of CD4+ T-cells. The Langerhans cells produce langerin, which binds HIV and helps the cells degrade it and transport the virus to local lymph nodes. The WHO Global Health sector Strategy on HIV/AIDS for 2011 - 2015 has determined that scale-up of VMMC in Africa constitutes a high-impact, cost-effective intervention. They suggest scaling-up medical male circumcision to 80% coverage for 15- to 49-year-old males in 14 priority countries in sub-Saharan Africa by 2015. This will require 20.5 million circumcisions, and is expected to avert 3.4 million new HIV infections by 2025. It will cost US$1.5 billion, but save US$16.5 billion of healthcare costs. Each of the large African studies used an open surgical method of circumcision. Surgical circumcision has several disadvantages for scaling-up and reaching the above-mentioned ambitious targets: it requires a high level of surgical skill, is time-consuming

(approximately 20 min/procedure) and is costly. Given these disadvantages of surgical circumcision, WHO has requested that new, more cost-effective techniques be developed to facilitate scaleup, which is already well behind schedule in most African countries with a high prevalence of HIV. There are many different circumcision techniques. Development of clamps and rings for circumcision using modern materials began in the 1930s. One of the earlier prototypes came from the Goldstein Medical Company (Gomco). These older instruments allow the circumciser to remove almost the entire inner foreskin. Recently, several disposable plastic devices have been developed. The new plastic ring devices are left in place for 1 week, and then removed in the clinic. The unpleasantness of wearing a plastic ring on the penis for a week, the smell of necrotic material, and the return visit for removal of the device negate many of the benefits. Because healing is by secondary intention, the delayed healing may facilitate new infections if sexual activity is not delayed for up to 6 weeks postoperatively. The approach by Millard et al.[2] using the Gomco device, while avoiding the problems of healing by secondary intention, provided other problems in keeping with the use of a nondisposable device. The single-use disposable Unicirc device[1] also works by clamping the the foreskin, removing it and sealing the wound with cyanoacrylate tissue adhesive avoiding the use of sutures. This novel technique is much faster, simpler to learn, nearly bloodless and heals rapidly by first intention. Circumcision with the Unicirc device is 30 - 40% faster than using standard surgical methods. Adverse events were similar to those of the surgical control group. The intraoperative suture rate for the Unicirc was 17% initially due to the utilisation of inadequate tissue pressure. This rate should come down as the newer modifications of this device generate more tissue compressibility. This device meets all the WHO criteria of a disposable, singleuse device to prevent cross-contamination, as occurred in the early phases of the HIV epidemic.

Norman D Goldstuck Department of Obstetrics and Gynaecology, Tygerberg Hospital, Cape Town, South Africa nahumzh@yahoo.com 1. Millard PS, Wilson HR, Goldstuck N, Anaso C. Rapid, minimally invasive adult voluntary male circumcision: A randomised trial of Unicirc, a novel disposable device. S Afr Med J 2013;104(1):52-57. [http://dx.doi.org/10.7196/SAMJ.7357] 2. Millard PS, Wilson HR, Veldkamp PJ, Sitoe N. Rapid, minimally invasive adult voluntary male circumcision: A randomised trial. S Afr Med J 2013;103(10):736-742. [http://dx.doi.org/10.7196/SAMJ.6856] 3. Malan M. Household survey: HIV prevalence increases. Mail and Guardian, 20 June 2013. http:// mg.co.za/article/2013-06-20-household-survey-hiv-prevalence-increases (accessed 2 July 2013). 4. Advert B, Taljaard D, Legarde E, et al. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: The ANRS 1265 trials. Plos Medicine 2005;2(e218):112-122. [http://dx.doi.org 10.1371/journal.pmed.0020298] 5. Bailey RC, Moses S, Parker CB, et al. Male circumcision for HIV prevention in young men in Kisuma, Kenya: A randomised controlled trial. Lancet 2007;369(9562):643-656. [http://dx.doi.org/10.1016/ S0140-6736(07)60312-2] 6. Gray RM, Kigozi G, Serwadda D, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: A randomised trial. Lancet 2007;369(9562):651-666. [http://dx.doi.org/10.1016/S0140-6736(07)60313-4] 7. Morris BJ, Wamai RG. Biological basis for the protective effect conferred by male circumcision against HIV infection. Int J STD AIDS 2012;23(3):153-159. [http://dx.doi.org/10.1258/ijsa.2011.011228]

S Afr J Med 2014;104(1):17. DOI:10.7196/SAMJ.7216

January 2014, Vol. 104, No. 1

EDITORIAL

Charting a path along the continuum of PMTCT of HIV-1, to elimination, and finally to eradication In this editorial we traverse the continuum of transmission of HIV-1 from mothers to children to highlight the biomedical history of this problem. Treatment has progressed from prevention with antiretrovirals (ARVs) through to a broader set of interventions, including various breastfeeding options and other health system improvements, that have increased the possibility of eliminating mother-to-child-transmission (MTCT) of HIV. At the far end of the continuum, the spectacular findings in the case of the Mississippi ‘cured’ baby indicate that eradication is possible. HIV infections in children are overwhelmingly due to MTCT,[1] intrauterine infections accounting for 10 - 25% of cases and intrapartum infections and those through breastfeeding for 35 - 40%. High- and middle-income countries have had considerable success in preventing new HIV infections in children. All HIV-positive pregnant women in developed countries are treated with ARVs, so they have low viral loads (VLs) before and during delivery. In Europe and the USA, perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1 000 copies/ml. With further suppression of viraemia, perinatal transmission may be eliminated.[2] The World Health Organization (WHO) uses standardised transmission rates:[3] the 2010 WHO-recommended regimens (options A or B) are estimated to be associated with a 2% probability of peripartum transmission and a 0.2% probability of transmission per month of breastfeeding. Peripartum and postnatal transmission probabilities were lowest for women who were taking antiretroviral therapy (ART) before the pregnancy, namely 0.5% peripartum and 0.16% per month of breastfeeding. Intra-uterine and intrapartum transmissions account for the majority of transmissions in industrialised countries, whereas in developing countries breastfeeding (up to 24 months of age) can account for 30 - 40% of all MTCT.[1,4] Interventions directed at all three routes of transmission have been very successful in industrialised countries, where transmission rates have fallen from ~25% to <2% and survival of infants has improved.[4] In many middle-income countries transmission rates are now ~2 - 3%. In South Africa (SA), anecdotal data suggest that the transmission rate in the early 1990s was ~32%. It was 2.5% in 2012.[5] Summarising evidence for three levels of avoiding MTCT, we examine the experience of preventing MTCT globally, and suggest the probability of eliminating transmission, especially in South Africa (SA). Finally, we raise the question of eradicating new HIV infections in children altogether. Elimination and eradication are defined in Table 1. Table 1. Definitions of outcomes in HIV infection Maternal disease progression

Death, WHO stage 4, or CD4+ count <200 cells/µl

Elimination

Absence of clinical signs + undetectable viral particles (in blood and other tissues), without ARV use in a patient previously diagnosed and treated for HIV; MTCT rate <5%

Eradication

Elimination + absence of virus in previously infected latent memory cells; MTCT rate <2%

Amelioration

Substantial improvement of clinical signs and stable viral load in blood

WHO = World Health Organization; ARV = antiretroviral; MTCT = mother-to-child transmission.

We stress that much of the hard scientific data on prevention and elimination are already available; what is required are health service refinements. Eradication demands many more basic science experiments to confirm the results indicating ‘cure’ in the Mississippi baby, and to increase our understanding of the biology of latency and destruction of the replicative capacity of the virus. We need more information on the cellular and molecular environment of the CD4+ memory cells, and specific sites that harbour the virus. Among the prerequisites for eradication are public health studies to enable SA to scale up facilities and personnel for very early diagnosis and treatment.

Prevention

Numerous reviews of trials undertaken to prevent MTCT have demonstrated the efficacy of a number of interventions. In brief, these include ARVs, exclusive breastfeeding, and various health service measures such as ‘baby-friendly hospitals’.[1,4,6,7] The WHO has consolidated these data.[8,9] In 2010, deaths attributable to breastfeeding risk factors remained fairly high globally, suboptimal breastfeeding, for example, accounting for deaths of 293 449 male and 251 368 female infants.[10,11] Figures for discontinued breastfeeding and non-exclusive breastfeeding are similar.[11] A set of ‘four prongs’ as a framework to prevent MTCT of HIV-1 has been recommended by the WHO to tackle the problem comprehensively, and is critical in devising an effective and holistic approach to MTCT. [12] Their implementation is key to both elimination of MTCT and eradication of HIV in children. The first prong aims at prevention of HIV in women, the second at prevention of unintended pregnancies in HIV-infected women, the third at prevention of transmission of the virus from mothers to their babies, and the fourth at care and support for HIV-infected women, their infants and their families. As part of the general progress in HIV health services in SA (see below), for example, the unmet need for family planning (i.e. the second prong) is <5%.[13,14] SA has made considerable progress in confronting and driving back HIV-1.[5] The government has launched an HIV counselling and testing campaign to reach 16 million people, rapidly expanded circumcision rollout, enhanced prevention of mother-to-child transmission (PMTCT) programmes, promoted integration of the treatment of HIV and tuberculosis, and drastically increased its budget to expand ART to 1.7 million people while simultaneously moving thousands of patients from PEPFAR-funded treatment programmes to government services. The impact of PMTCT programmes in SA is now evident at community level. Within 10 years of the start of the country’s PMTCT programme, 95% of all health facilities were providing this service in 2010. SA is also one of four countries that have achieved over 80% coverage with ARV prophylaxis to prevent MTCT. More than 98% of women receive an HIV test during pregnancy, and 91.7% of HIV-positive mothers are receiving ART or prophylaxis.[14] The national survey in SA[5] showed that MTCT rates had fallen to ~2.7% (95% confidence interval 2.1 - 3.2%) in 2011. This was confirmed by recently published global reports[13,14] revealing that new HIV infections in SA children (aged 0 - 14 years) have continued to decline, with a fall of 63% (from 38 000 to 14 000) between 2009 and 2012. Furthermore, 70% of eligible children are receiving ARVs. Transmission rates have fallen throughout the world, including SA, as coverage of MTCT services has increased to nearly 90%.[5]

January 2014, Vol. 104, No. 1

EDITORIAL

SA’s success in dealing with MTCT has been made possible by sound leadership, investments in infrastructure involving personnel, facilities and resources, and wider coverage of PMTCT programmes. In 2009 - 2013, 9 out of every 10 HIV-infected pregnant women received ARVs for PMTCT and 9 out of every 10 infants received ARVs to prevent breastfeeding transmission.[14] At the time of writing, there is universal access to ARVs, with 80% of eligible pregnant women receiving ART for their own health.

Elimination

We have recently drawn together health service changes that will be instrumental in eliminating MTCT.[15] In essence, elimination requires escalation, intensification and improvement of the components of the WHO ‘four prongs’ approach described above. In particular, differential coverage of health services in developing countries has hindered progress, so PMTCT services ought to form part of universal coverage, and the gender-related interventions – primary prevention of HIV in women, family planning counselling, and voluntary and informed termination of unwanted pregnancies – should be integrated into comprehensive PMTCT programmes. Improved advocacy, information and guidance are required to increase public demand and use of these services. Within countries, implementation of recent WHO/UNAIDS ARV Guidelines,[16] promotion of breastfeeding and prevention of breastfeeding transmission, and continuing care of mothers and children are necessary.

Eradication

The news from a highly reputable group of researchers that a baby in Mississippi had been cured of HIV infection was greeted by widespread astonishment, clamorous voices of approval, unrestrained cries of delight and a storm of doubt. For more than 30 years the HIV epidemic has dominated our science and threatened our lives and health, the gloom brigade even questioning our survival. Cure seemed a distant yet ultimate goal – the ‘holy grail’ of modern scientific endeavour. And here was the first glimmer of a solution. The mother presented in labour, so no ARVs were given before or during labour. The premature baby was HIV RNA- and DNApositive, but the VL was moderate when blood samples were tested at 30 and 31 h. Samples from Mississippi were transported to a specialised laboratory, and in utero HIV infection was diagnosed. The virus isolated from the mother was replication competent and behaved like other wild-type or laboratory isolates, and neither mother nor baby had genetic markers typical of elite controllers. Mother and baby were started on ARVs ~30 h before the diagnosis was known, with tests showing a decreasing VL over the baby’s first month of life. Mother and baby were lost to follow-up (but the infant may have received 12 - 15 months of ART). The mother returned after 2 years, with her baby clinically well, not on ARVs, and seronegative. No HIV was identified by standard tests, but more sophisticated tests showed HIV DNA sequences of uncertain significance on occasional peripheral white blood cells. The priority research questions were soon established by experts. For example, the currently available ARVs are not all suited for newborns, so an urgent priority is to work with pharmaceutical manufacturers to define the most useful formulations and to provide existing zidovudine/lamivudine dispersible tablets with score marks to allow them to be broken into quadrants of 15/7.5 mg. Some of us believed that the most suitable country to do the studies required to confirm and extend the findings was SA – and in fact the purpose of a recent symposium[17] was to report on ‘Scientific advances from the “Mississippi baby”: Implications for public health programmes on MTCT of HIV’. There are 12 recommendations, covering a

broad range of fields.[4,18] Some of the public health proposals were to improve health services as laid out in recent WHO documents on elimination of MTCT, and more aggressive management of HIVexposed newborns. Challenges identified were diagnosis of HIV at birth, logistical constraints in testing HIV-exposed newborns, availability of the technology for diagnosis, encompassing better point-of-care tests, and appropriate ART for newborns. A suggested package of interventions to ‘eradicate’ MTCT in South Africa includes optimising implementation of the evidencebased WHO ‘four prongs’ comprehensive strategy for PMTCT, improved health services, especially during the perinatal period, infancy and childhood, specifically addressing measures to reduce under-5 and maternal mortality, and improved diagnostic and therapeutic options.

Additional evidence of ‘cures’

• The first and only reported case of a sterilising cure was Timothy Brown, the ‘Berlin patient’, who was HIV-infected and was given a bone marrow transplant for acute myeloid leukaemia. The donor was naturally resistant to HIV due to a mutation in the CCR5 gene, a critical protein required by HIV to enter and infect cells. Brown stopped ART very soon after transplantation and remains free of HIV after 6 years.[19] • A French report (Visconti cohort) suggests that HIV has been eliminated in adults with chronic infection. This group of patients started treatment within 10 weeks of being infected and adhered to a course of ARV drugs for 3 years, on average, but then stopped. Some have remained under control for a decade.[20] • So-called ‘elite controllers’, who have undetectable VLs in the absence of ARVs, have been recognised for some time.[21] A Ramkissoon H Coovadia Maternal, Adolescent and Child Health, Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: H Coovadia (hcoovadia@match.org.za)

1. Coovadia HM, Newell ML. Effective HIV prevention and treatment for pregnant mothers. Meeting health care needs. In: Heyman J, Sherr L, Kidman R, eds. Protecting Childhood in the AIDS Pandemic: Finding Solutions that Work. New York: Oxford University Press, 2012:169-194. 2. Ioannidis JP, Abrams EJ, Ammann A, et al. Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml. J Infect Dis 2001;183(4):539-545. [http://dx.doi.org/10.1086/318530] 3. Rollins N, Mahy M, Becquet R, Kuhn L, Creek T, Mofenson L. Estimates of peripartum and postnatal mother-to-child transmission probabilities of HIV for use in Spectrum and other population-based models. Sex Transm Infect 2012;88(suppl 2):i44-i51. [http://dx.doi.org/10.1136/ sextrans-2012-050709] 4. Rollins N, Coovadia HM. Breastfeeding and HIV transmission in the developing world: Past, present, future. Curr Opin HIV AIDS 2013;8(5):467-473. [http://dx.doi.org/10.1097/ COH.0b013e3283632ba2] 5. Goga AE, Dinh TH, Jackson DJ; for the SAPMTCTE study group. Evaluation of the Effectiveness of the National Prevention of Mother-to-Child Transmission (PMTCT) Programme Measured at Six Weeks Postpartum in South Africa, 2010. South African Medical Research Council, National Department of Health of South Africa and PEPFAR/US Centers for Disease Control and Prevention, 2012. http://repository.uwc.ac.za/xmlui/bitstream/handle/10566/462/GogaPMTCT2012.pdf?sequence=3 (accessed 5 November 2013). 6. Townsend CL, Cortina-Boria M, Peckham CS, et al. Low rates of mother to child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS 2008;22(8):973-981. [http://dx.doi.org/10.1097/QAD.0b013e3282f9b67a] 7. Pérez-Escamilla R. Evidence based breast-feeding promotion: The Baby-Friendly Hospital Initiative. J Nutr 2007;137(2):484-487. 8. World Health Organization. Rapid Advice: Use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. November 2009. http://www.who.int/hiv/topics/mtct/ (accessed 15 June 2010). 9. World Health Organization. Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants: Towards Universal Access. Recommendations for a Public Health Approach (2010 version). 2010. http://www.who.int/hiv/pub/mtct/antiretroviral2010/en/index. html (accessed 15 November 2010). 10. Lozano R, Naghavi M , Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study. Lancet 2013;380(9859):2095-2128. [http://dx.doi.org/10.1016/S0140-6736(12)61728-0]

January 2014, Vol. 104, No. 1

EDITORIAL

11. Lim SS, Vos TP, 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 2013;380(9859):2224-2260. [http://dx.doi. org/10.1016/S0140-6736(12)61766-8] 12. Sweat MD, Reilly KR, Schmidt GP, et al. Cost-effectiveness of nevirapine to prevent mother to child HIV transmission in eight African countries. AIDS 2004;18(12):1661-1671. [http://dx.doi. org/10.1097/01.aids.0000131353.06784.8f] 13. World Health Organization. Programmatic Update. Use of Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants. Executive Summary April 2012. Geneva: WHO, 2012. http://whqlibdoc.who.int/hq/2012/WHO_HIV_2012.6_eng.pdf (accessed 21 September 2013). 14. World Health Organization. 2013 Progress Report on the Global Plan Towards the Elimination of New HIV Infections among Children by 2015 and Keeping Their Mothers Alive. Geneva: WHO/ UNAIDS, 2013. http://www.unaids.org/en/.../2013/20130625_progress_global_plan_en.pdf (accessed 1 September 2013). 15. Coovadia HM, Govender T. Eliminating mother to child transmission of HIV-1 and keeping mothers alive: Recent progress. J Infect 2013 (in press). [http://dx.doi.org/10.1016/j.jinf.2013.09.015] 16. World Health Organization. HIV/AIDS Programme. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Recommendations for a Public Health Approach. Geneva: WHO, 2013.

17. UNAIDS/CAPRISA. Report on the UNAIDS Symposium on the scientific advances from the ‘Mississippi baby’ and the implications for public health programmes to eliminate mother-to-childtransmission of HIV, 3 - 4 June 2013, Durban, South Africa. https://www.facebook.com/permalink. php?id=327735533989998 (accessed 22 September 2013). 18. UNAIDS. 12 recommendations following a discussion about the ‘Mississippi baby’. http://www. unaids.org/en/resources/documents/2013 (accessed 12 September 2013). 19. Yukl SA, Boritz E, Busch M, et al. Challenges in detecting HIV persistence during potentially curative interventions: A study of the Berlin patient. PLoS Pathog 2013;9(5):e1003347. [http:// dx.doi.org/10.1371/journal.ppat.1003347] 20. Sáez-Cirión A, Bacchus C, Hocqueloux L, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy. ANRS VISCONTI Study. PLoS Pathog 2013;9(3):e1003211. [http://dx.doi.org/10.1371/journal.ppat.1003211] 21. Deeks SG, Walker BD. Human immunodeficiency virus controllers: Mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 2007;27(3):406-416. [http://dx.doi. org/10.1016/j.immuni.2007.08.010]

S Afr Med J 2014;104(1):18-20. DOI:10.7196/SAMJ.7603

Challenging times for environmental health in South Africa: The role of the Environmental Health Research Network Environmental health aims to create environments supportive of good health and to minimise disease. This is achieved by controlling environmental factors that impact adversely on human health. Throughout Africa, modern environmental health hazards, including mercury, lead, air toxins, water contaminants, pesticides, and domestic and hazardous waste,[1] need to be addressed alongside longstanding environmental health concerns such as poor housing, inadequate water and sanitation, and exposure to indoor air pollution from the use of solid and liquid fuels for cooking. In South Africa (SA), public protection against environmental hazards is addressed in Section 24 of the Constitution, which states that everyone has the right to an environment that is not harmful to their health and wellbeing, while Section 27 upholds the right of access to healthcare services and sufficient food and water. Responsibility for the provision of safe and healthy environments in which communities live, learn and play is predominantly vested in the local sphere of government. Local-level environmental (or municipal) health services include water quality monitoring, food control and waste management, vector control, environmental pollution control, surveillance and prevention of contagious diseases, and disposal of the dead. Environmental health practitioners (EHPs) form the backbone of environmental health services in SA, and face a significant challenge to provide the safe and healthy environment all South Africans need to maximise their life potential.

High-level challenges impeding environments for healthy lives

The key environmental health challenges[2] that need to be overcome are closely linked to the history of SA, continuing poverty and inequality,[3] as well as over-consumption. The underlying reasons for current environmental health challenges are complex and fundamental change is necessary to address them. The country also has to grapple with major international forces affecting the environment and health status, such as globalisation and rapid urbanisation, unmatched by optimal levels of service delivery. The upshot is that SA is faced with a quadruple burden of disease including HIV/AIDS, violence and injuries, and communicable and non-communicable diseases.[4]

While progress has undoubtedly been made in environmental health since the advent of democracy, in many respects environmental health policy and legislation in SA is not always clear, and there is sometimes a disconnection between national and local roles and responsibilities. Policy and legislation are also covered by several different Acts, agreements and conventions,[3] making it difficult to address the growing range of environmental health issues efficiently. Transformation of the environmental health service in SA remains incomplete; for example, devolution of environmental health to local government is unfinished in several provinces. Also, while compulsory community-based environmental health service has been instituted as part of training for EHPs, the systems and funding are not always in place to accommodate all trainees, unfairly rendering them unable to graduate or accept work appointments. There is also a well-established shortage of EHPs in the country, with the ratio of EHPs to population falling well below international guidelines (Cele A, ‘Strengthening the provision of MHS within the country’ – unpublished paper presented at the Municipal Health Conference, Pretoria, 20 June 2013). Over and above current environmental health problems, climate change and how it affects temperature, water and air poses another significant challenge in maintaining environmental quality for human health, although adaptation options open the door for innovative solutions beneficial to environmental health.

A trichotomous structure in environmental health

Environmental health may be considered in three parts: governance, the profession and research. The National Department of Health (NDoH)’s Environmental Health Directorate is responsible for governing environmental health operations and procedures in SA, but it is woefully under-capacitated. The Department oversees and implements environmental health operations and procedures via the EHPs, who function within the parameters of a ‘scope of practice’ document at local government level. EHPs are registered with the Health Professions Council of SA, and the South African Institute of Environmental Health (affiliated with the International Federation of Environmental Health) serves as their professional organisation.

January 2014, Vol. 104, No. 1

EDITORIAL

Despite the shortcomings outlined here, mechanisms are in place with regard to governance and operations in environmental health. Where the co-ordination of environmental health research is concerned, however, little is in place. To date no national state of environmental health report has been written for SA. An underlying reason for this is the fragmentation of research data and information across multiple institutions and documents, making the collation of relevant data and the preparation of a coherent report a mammoth undertaking. The need for a repository for SA environmental health research and the linking of researchers in this domain has therefore arisen.

Multi-disciplinary, co-ordinated research and partnerships

In 2009, the Environmental Health Research Network (EHRN) [5] was launched. The NDoH’s Environmental Health Director, Ms Aneliswa Cele, endorsed the EHRN at an inaugural seminar in April 2010. The overall aim of the EHRN is to serve as a network to share knowledge and ideas about environmental health research. It is a ‘community of practice’ in environmental health research in SA. The network is open to academic and research institutions, government departments, non-government organisations (NGOs) and any other interested parties. The principal objective of the EHRN is to develop and co-ordinate research, information and practical resources on environmental health matters at all levels. The EHRN aims to provide networking opportunities to everyone working in any environmental health research field to consolidate existing research and identify gaps in research. The purpose of the network is threefold: (i) to strengthen environmental health research in SA; (ii) to encourage collaboration and idea sharing in environmental health research; and (iii) to gain a better understanding of the state of environmental health in SA. The EHRN is an assembly of people working in environmental health research across different organisations, institutions and agencies. It is an open forum for discussion, and currently comprises >150 members from SA. While most members are researchers and scientists working in environmental health research, EHPs, NGOs and government officials make frequent use of the network to learn more about environmental health research in SA. In 2013, the EHRN bi-monthly lecture series was initiated, in which a prominent scientist prepares lecture materials related to a topical environmental health issue. Lectures are distributed electronically to the EHRN

membership. A further core activity of the EHRN is to motivate for the development of environmental health indicators and the collection of environmental health data at appropriate levels of aggregation and scale, linked to socio-demographic data to support evidence-based research and policy making. The vision of the EHRN is to be the primary point of contact for all those who are interested in environmental health research in SA. It aims to facilitate multidisciplinary research, leading to a more thorough description of the state of environmental health in SA and providing a basis to evaluate change. Within a context of limited capacity and resources, the platform provided by the EHRN is fundamental to environmental health research in this country, and to the strategies, planning and decisions necessary to grapple with current and emerging environmental health challenges, especially those posed by the advent of climate change. C Y Wright Climate Studies, Modelling and Environmental Health Research Group, Council for Scientific and Industrial Research, Pretoria, South Africa A Mathee Environment and Health Research Unit, South African Medical Research Council, Johannesburg, South Africa M A Oosthuizen Climate Studies, Modelling and Environmental Health Research Group, Council for Scientific and Industrial Research, Pretoria, South Africa Corresponding author: C Y Wright (cwright@csir.co.za) 1. Nweke OC, Sanders WH III. Modern environmental health hazards: A public health issue of increasing significance in Africa. Environ Health Perspect 2009;117(6):863-870. [http://dx.doi.org/10.1289/ ehp.0800126] 2. Thomas EP, Seager JR, Mathee A. Environmental health challenges in South Africa: Policy lessons from case studies. Health Place 2002;8(4):251-261. [http://dx.doi.org/10.1016/S1353-8292(02)00006-0] 3. Mathee A. Environment and health in South Africa: Gains, losses and opportunities. J Public Health Policy 2011;32:S37-S43. [http://dx.doi.org/10.1057/jphp.2011.21]. 4. 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] 5. Environmental Health Research Network. http://www.ehrn.co.za (accessed 28 October 2013).

S Afr Med J 2014;104(1):20-21. DOI:10.7196/SAMJ.7287

This month in the SAMJ ... Hoosen Coovadia* is director of Maternal, Adolescent and Child Health (MatCH), a division of the University of the Witwatersrand in Durban Metropolitan; emeritus professor of Paediatrics and Child Health; emeritus Victor Daitz professor of HIV/Aids Research at the University of KwaZulu-Natal (UKZN); and Commissioner for the National Planning Commission for the Presidency of the Republic of South Africa. He currently works as a director for MatCH, implementing the well-documented research findings on maternal, newborn and child health, on which he spent a large part of his career as professor of Paediatrics and Child Health and Victor Daitz professor of HIV/Aids research at UKZN. He was chairperson of the Mandela government’s first Commission on Maternal and Child Health to design appropriate policies for the new South Africa. He had major interests in the pursuit of justice, democracy, development and freedom, during and after apartheid. He has headed the largest International AIDS Conferences brought to South Africa, and conducted research on prevention of mother-to-child transmission of HIV. He was one of a handful of individuals to publicly, and consistently, oppose the Mbeki administration regarding AIDS denialism. He has published more than 327 papers on maternal and child health in international peer-reviewed journals. *Ramkissoon A, Coovadia H. Charting a path along the continuum of PMTCT of HIV-1, to elimination, and finally to eradication. S Afr Med J 2014;104(1):18-20. [http://dx.doi.org/10.7196/SAMJ.7603]

January 2014, Vol. 104, No. 1

RESEARCH

Extrapulmonary tuberculosis among adults: Experience at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa A S Karstaedt, MB BCh, MMed Division of Infectious Diseases, Department of Medicine, Chris Hani Baragwanath Hospital and University of the Witwatersrand, Johannesburg, South Africa Corresponding author: A S Karstaedt (karstaedt@mweb.co.za) Background. Extrapulmonary tuberculosis (EPTB) occurs in 15 - 20% of immunocompetent and 20 - 70% of HIV-infected patients with tuberculosis. There are few recent incidence data for EPTB. Methods. Adults (N=2 963) with culture-proven EPTB seen over 2 years at Chris Hani Baragwanath Academic Hospital, the main referral hospital serving Soweto, Johannesburg, South Africa, were retrospectively studied for pattern and incidence. Results. The commonest sites of EPTB were the pleura (39.1%), lymph nodes (31.0%), blood (21.8%), meninges (7.3%), and peritoneum (2.9%). Disseminated tuberculosis occurred in 25.0%. The median age was 33 years (range 18 - 87 years). Males comprised 53.2% overall, with a female majority in the peritonitis group. For Soweto, the incidence of adult EPTB was 88.6/100 000 population, rising to 139.4/100 000 and 125.7/100 000 in the 25 - 34-year and 35 - 44-year age groups, respectively. There was no secondary peak in the elderly (17.9/100 000). Conclusions. This retrospective cohort showed a high incidence of EPTB, most marked in the 25 - 44-year age group. Culture of extrapulmonary sites is of importance to confirm diagnosis of tuberculosis and to ensure antituberculosis drug susceptibility testing. S Afr Med J 2014;104(1):22-24. DOI:10.7196/SAMJ.6374

Extrapulmonary tuberculosis (EPTB) occurs in 15 - 20% of immunocompetent and 20 - 70% of HIVinfected patients with tuberculosis (TB).[1] There are few recent incidence data for EPTB. In the USA, incidence rates were 5.93/100 000 population in black males in Tennessee and 209/100 000 among Somalis in Minnesota. [2,3] In Sao Paulo, Brazil, the incidence of pleural TB was 3.8/100 000.[4] Incidence rates for EPTB from sub-Saharan Africa, where high rates of co-infection with human immunodeficiency virus (HIV) and TB exist, are lacking. The diagnosis of EPTB is more difficult than that of pulmonary TB because fewer bacilli are present and specimen material in extrapulmonary sites of disease is less easily accessible. While TB diagnosis rests on at least one of the triad of mycobacterial culture, histopathology and suggestive clinical criteria, only culture offers an unequivocal result. Positive mycobacterial culture results are reported as 79% and 82% in separate studies from the USA, and as 14% in Brazil.[2-4] In Soweto in 2001, 30% of 990 patients had EPTB. [5] This paper describes the frequency of culture-proven EPTB over a 2-year study period and documents the incidence of EPTB among adults in Soweto according to age.

Methods Study site

Chris Hani Baragwanath Academic Hospital, a 2 700-bed public sector university hospital, is the main referral hospital serving Soweto, Johannesburg, South Africa.

Patient population

A retrospective cohort study of adult patients ≥18 years of age with culture-confirmed tuberculosis in an extrapulmonary site was

performed from April 2001 to March 2003. Age, gender and address were noted. HIV serostatus was available for patients with TB meningitis and those with TB bacteraemia.

Microbiology

The central TB laboratory of the National Health Laboratory Service, Johannesburg, utilised liquid culture media, namely BACTEC 13A or BACTEC MYCO/F Lytic (Becton Dickinson), or solid media (Lowenstein-Jensen), depending on the source of the specimen.

Ethics

The study was approved by the Committee for Research on Human Subjects of the University of the Witwatersrand, Johannesburg.

Results

Over the 2-year period of the study, 2 963 adults had Mycobacterium tuberculosis cultured from 3 166 extrapulmonary sites (Table 1). The commonest sites were the lymph nodes and pleura, which together accounted for nearly 70% of specimens. A positive TB smear was documented in 370 lymph nodes (40.3%). Disseminated disease (bacteraemia or >1 extrapulmonary organ) was present in 742 patients (25.0%). The site of origin in the ‘pus’ group was not specified and probably comprised peripheral lymph nodes, superficial skin and soft tissue and deep organ abscesses, and empyema. Males predominated, with gender parity among patients with lymphadenitis and a female preponderance in those with peritonitis. The median age of 33 years was similar across all disease groups. Of the 217 patients with meningitis, 127 (58.5%) were HIV-infected (12 were not tested). Of patients with TB bacteraemia for whom hospital records were available, HIV infection was established in 227 (35%); only 1 patient

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was known not to be infected with HIV. (It should be noted that while many more had been tested for HIV, the results had in many cases not been documented and had been deleted from the laboratory database.) There were 37 patients aged ≥65 years (of whom 25 (67.6%) were male); pleural involvement was evident in 22 specimens (59.5%), bacteraemia in 8, lymphadenopathy in 6, and liver involvement, abscess and urinary tract infection in 1 each (2 patients had 2 specimens). The annual incidence of EPTB by age is presented in Table 2. Of the 2 963 patients, 1 283 (43.3%) were documented to have addresses in Soweto and 915 (30.9%) had no address available; the remaining patients had been referred to Chris Hani Baragwanath Academic Hospital for diagnostic work-up. The incidence of EPTB in adults based on culture was 88.6/100 000 population, reaching 139.4 and 125.7/100 000, respectively, for 25 - 34-year-olds and 35 - 44-yearolds. There was no secondary peak in the elderly.

Discussion

In this study in a large urban referral hospital with high tuberculosis and HIV prevalence rates, there was an incidence of EPTB of 88.6/100 000 population based on positive TB culture obtained from extrapulmonary sources. This is a minimum estimate of the incidence of EPTB. It would have excluded patients with EPTB in whom the TB diagnosis was made by other diagnostic criteria, from whom an extrapulmonary specimen was not obtained, or in whom the diagnosis was not suspected. Moreover, culture positivity would have varied according to bacillary load. Rates of EPTB were especially high in the 25 - 44-year age group, in which the highest HIV population rates would be expected. The incidence was nevertheless lower than in Somalis in Minnesota, in whom EPTB was commoner

than pulmonary tuberculosis and HIV seroprevalence was low. The Soweto incidence of pleural tuberculosis is much higher than that in Brazil.[3,4] Culture, the most reliable method of diagnosis, depends on specimens being taken. Histological examination is helpful, but there is a wide differential diagnosis for granulomatous disease. These alternatives are often ignored in an endemic TB area. Clinical insight may be flawed and influenced by clinical context and resource restraints, as evidenced in autopsy studies.[6] In this study, pleural and lymph node tuberculosis rates were similar to those reported from Hong Kong, where 42% had pleural and 37% lymph node tuberculosis.[7] In a composite of several studies of EPTB, lymph node tuberculosis (35%) and pleural tuberculosis (20%) were commonest.[1] Among Somalis in Minnesota, lymph node tuberculosis caused 50% and pleural disease 9% of cases of EPTB. In reports from the USA, TB adenopathy occurred in 40% and pleural disease in 20%, while bacteraemia was the sole proof of disease in 18%.[3,8] The presence of TB bacteraemia has been shown to be an important test in HIV-infected patients, especially those with CD4 counts <100 cells/μl.[9] In a retrospective survey of unselected patients in Soweto who were investigated with mycobacterial blood culture, 19% had TB bacteraemia.[10] HIV infection has been negatively associated with a pleural site of EPTB. [11,12] The lack of documentation of HIV status for the group with pleural disease did not allow us to assess this in the study cohort. The slight male predominance found is similar to that in the USA.[8] There was, however, a marked female predominance in patients with tuberculous peritonitis. Abdominal tuberculosis generally occurs equally in both sexes, although some studies report a higher incidence in women.[13]

Table 1. Frequency of organ involvement, gender and age of adults with extrapulmonary tuberculosis Characteristic

EPTB

Pleural

Lymph node Bacteraemia

Meningitis

Pus

Peritonitis Other*

2 963

1 160

919

646

217

100

39.1

31.0

21.8

7.3

3.0

2.9

1.6

Male, n (%)

1 576 (53.2)

646 (55.7)

465 (50.6)

357 (55.3)

116 (53.5)

50 (57.5)

31 (35.6)

28 (58.3)

Median age (years)

Age range (years)

18 - 87

18 - 83

18 - 77

19 - 60

18 - 86

18 - 59

20 - 82

>1 site, n (%)

207 (7)

86 (7)

104 (11)

119 (18)

28 (13)

11 (12)

18 (21)

13 (27)

*‘Other’ comprised bone and joint (21), urogenital (12), pericardial (8), breast (2), miscellaneous and tissue (5).

Table 2. Incidence rate (/100 000 population/year) by age of adults with extrapulmonary tuberculosis in Soweto Age (years)

Population* N n

EPTB

Pleural n

Rate

540

1 283†

Lymph node n

Rate

379

Bacteraemia n

Rate

270

Meningitis n

Rate

116

Peritonitis n

Rate

All

723 839

641.5

88.6

270

37.3

189.5

26.2

135

18.7

8.0

2.1

15 - 24

199 091

57.5

28.9

10.0

11.1

4.5

5.5

2.8

1.5

0.8

25 - 34

201 152

280.5

139.4

107

53.2

101

50.2

58.5 29.1

24.5

12.2

5.5

2.7

35 - 44

146 733

184.5

125.7

54.5

30.7

47.5 32.4

17.5

11.9

2.0

45 - 54

89 212

63.5

71.2

27.5

30.8

16.5

18.4

12.5 14.0

9.0

2.5

2.8

55 - 64

45 647

14.5

31.8

5.5

12.0

3.5

7.7

4.4

2.2

≥65

42 004

7.5

17.9

14.3

0.5

1.2

2.4

0.0

Unknown

33.5

4.5

EPTB = extrapulmonary tuberculosis. *Population of Soweto and Diepkloof municipalities. Census 2001, Statistics South Africa, Pretoria, available at http://www.statssa.gov.za † Number of patients with known Soweto addresses over the 2-year study period.

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1.5

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Limitations of the study include its retrospective nature, and the fact that resistance to anti-TB therapy and HIV status, other than in patients with meningitis and to a lesser extent bacteraemia, were not available. The results of HIV tests, among others, for the period of the study were removed from the laboratory database (and the archived discs proved unreadable). Some organ systems that rely largely on histology or clinical criteria for diagnosis would have been under-represented, including bone and joint, pericardial, gastrointestinal and genitourinary TB. Although the data are a decade old, they do provide a baseline prior to the advent of widespread provision of antiretroviral therapy at the time of the penultimate published census for South Africa. Furthermore, the numbers of patients with EPTB were similar to those at the hospital in 2006.[10] The high incidence of EPTB, based on culture results, persists. The importance of culture of material or tissue obtained from extrapulmonary disease sites to confirm diagnosis and ensure antiTB drug susceptibility testing is emphasised, at least until molecular techniques are validated and widely available.[14] Acknowledgements. I thank Mani Khoosal and Xoliswa Poswa of the National Health Laboratory Service for provision of culture results and Vanessa Quan of GERMS-SA for assistance with data.

References 1. Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120(4):316-353. 2. Fiske CT, Griffin MR, Erin H, et al. Black race, sex, and extrapulmonary tuberculosis risk: An observational study. BMC Infect Dis 2010;10:16. [http://dx.doi.org/10.1186/1471-2334-10-16] 3. Rock RB, Sutherland WM, Baker C, Williams DN. Extrapulmonary tuberculosis among Somalis in Minnesota. Emerg Infect Dis 2006;12(9):1434-1436. [http://dx.doi.org/10.3201/eid1209.050295] 4. Seiscento M, Vargas FS, Rujula MJP, Bombarda S, Uip DE, Galesi VMN. Epidemiological aspects of pleural tuberculosis in the state of Sao Paulo, Brazil (1998-2005). J Bras Pneumol 2009;35(6):548-554. [http://dx.doi. org/10.1590/S1806-37312009000600008] 5. Edginton ME, Wong ML, Phofa R, Mahlaba D, Hodkinson HJ. Tuberculosis at Chris Hani Baragwanath Hospital: Numbers of patients diagnosed and outcomes of referrals to district clinics. Int J Tuberc Lung Dis 2005;9(4):398-402. 6. Cox JA, Lukande RL, Nelson AM, et al. An autopsy study describing causes of death and comparing clinicopathological findings among hospitalized patients in Kampala, Uganda. PLoS One 2012;7:e33685. [http:// dx.doi.org/10.1371/journal.pone.0033685] 7. Noertjojo K, Tam CM, Chan SL, Chan-Yeung MMW. Extra-pulmonary and pulmonary tuberculosis in Hong Kong. Int J Lung Dis 2002;6(10):879-886. 8. Peto HM, Pratt RH, Harrington TA, LeBue PA, Armstrong LR. Epidemiology of extrapulmonary tuberculosis in the United States, 1993-2006. Clin Infect Dis 2009;49(9):1350-1357. [http://dx.doi.org/10.1086/605559] 9. Jones BE, Young SMM, Antoniskis D, Davidson PT, Kramer F, Barnes PF. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993;148(5):1292-1297. 10. Edginton ME, Rakgokong L, Verver S, et al. Tuberculosis culture testing at a tertiary care hospital: Options for improved management and use for treatment decisions. Int J Tuberc Lung Dis 2008;12(7):786-791. 11. Alvarez GG, Thembela BL, Muller FJ, Clinch J, Singhal N, Cameron DW. Tuberculosis at Edendale Hospital in Pietermaritzburg, KwaZulu Natal, South Africa. Int J Tuberc Lung Dis 2004;8(12):1472-1478. 12. Leeds IL, Magee MJ, Kurbatova EV, et al. Site of extrapulmonary tuberculosis is associated with HIV infection. Clin Infect Dis 2012;55(1):75-81. [http://dx.doi.org/10.1093/cid/cis303] 13. Kapoor VK. Abdominal tuberculosis. Postgrad Med J 1998;74(874):459-467. [http://dx.doi.org/10.1136/ pgmj.74.874.459] 14. Tortoli E, Russo C, Piersimoni C, et al. Clinical validation of Xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis. Eur Respir J 2012;40(2):442-447. [http://dx.doi.org/10.1183/09031936.00176311]

Accepted 24 April 2013.

Prevalence and incidence of symmetrical sympto足matic peri足pheral neuropathy in patients with multidrugresistant TB F Conradie,1, 2 MB ChB; T Mabiletsa;2 M Sefoka;2 S Mabaso;2 R Louw,3 MB ChB; D Evans,4 D Biomed; A van Rie,5 MD, PhD Clinical HIV Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Right to Care, Johannesburg, South Africa 3 Sizwe Tropical Disease Hospital, Gauteng Department of Health, Johannesburg, South Africa 4 Health Economics and Epidemiology Research Office, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 5 Department of Epidemiology, University of North Carolina, Chapel Hill, USA 1 2

Corresponding author: F Conradie (fconradie@witshealth.co.za) Background. Symptomatic symmetrical peripheral neuropathy (SSPN) is common in patients with HIV infection. It is also a common adverse event associated with both tuberculosis (TB) treatment and antiretroviral therapy (ART), particularly stavudine. While tenofovir is the one of recommended first-line nucleotide reverse transcriptase inhibitors (NRTIs), there is a risk of nephrotoxicity when using tenofovir together with the aminoglycosides needed to treat multidrug-resistant (MDR) TB. Thus, stavudine is often chosen as a treatment option for the HIV-infected MDR TB patient. Objective. To assess whether use of stavudine both before and during treatment for MDR TB increased the prevalence and incidence of SSPN. Method. MDR TB patients at Sizwe Tropical Disease Hospital were examined for signs of prevalent SSPN. Age, gender, HIV status, alcohol use, TB and HIV treatment regimens both prior to admission and current, and concomitant medications were recorded. Results. In this cohort of 246 patients, we found that 24.4% of patients with MDR TB had SSPN at time of admission for treatment of MDR TB. They were more likely to be HIV-infected (odds ratio (OR) 3.21; 95% CI 1.25 - 8.21) and tended to have longer (>7 months) exposure to stavudine (OR 1.81; 95% CI 0.90 - 3.63). Incident SSPN occurred in 17% of patients and was associated with older age (hazard ratio (HR) 3.00; 95% CI 1.30 - 6.89) and exposure to terizidone (HR 2.98; 95% CI 0.94 to 4.61) or, to a lesser extent, with stavudine (crude HR 1.62; 95% CI 0.65 - 4.01) in the first 6 months of MDR TB treatment. This common adverse event emphasises the need for the development of less toxic drugs for the treatment of MDR TB. S Afr Med J 2014;104(1):24-26. DOI:10.7196/SAMJ.6455

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South Africa (SA) has the fourth-highest incidence of multidrug-resistant (MDR) TB worldwide[1] with significant numbers of patient co-infected with HIV. At present, treatment of MDR TB is characterised by toxic medications, given for prolonged periods of time, and which have poorer efficacy than those used for drug-sensitive TB. One of the mainstays of MDR TB treatment, the aminoglycosides, can cause tubular necrosis[2] which results in functional nephrotoxicity.[3] For patients who are co-infected with MDR TB and HIV, the National Department of Health guidelines recommend they be started on antiretroviral therapy (ART) irrespective of their CD4+ count. These guidelines also suggest the use of a tenofovir-based first-line ART regimen, which is associated with renal dysfunction. Because tenofovir-related nephrotoxicity is characterised by proximal tubular cell dysfunction,[4] there is concern that the cumulative action of aminoglycosides and tenofovir may put patients at risk of renal failure. Zidovudine can be an alternative for tenofovir but the high incidence of anaemia in this population often precludes its use. Consequently, stavudine is often used in HIV-infected patients with MDR TB. However, the use of 30 mg stavudine twice daily for 6 months during the injectable intensive phase could potentially result in mitochondrial toxicity and symptomatic symmetrical peripheral neuropathy (SSPN). We report on the prevalence and incidence of SSPN in a cohort of MDR TB patients admitted to an inpatient facility in Gauteng Province, and assess the effect of stavudine.

Methods

Sizwe Tropical Disease Hospital is the referral facility for MDR TB treatment in Gauteng Province, South Africa. Patients are admitted here if they have resistance to isoniazid (INH) and rifampicin confirmed either by line probe assay or culture and drug sensitivity testing. All patients receive HIV counselling and testing and are managed according to national guidelines.[5] Criteria for enrolment in this prospective cohort were a confirmed diagnosis of MDR TB, ability and willingness to provide written informed consent and being 18 years or older. At admission, consenting patients were asked about symptoms of, and were examined for signs of, prevalent SSPN. The examination was conducted by the medical officer and included an assessment of finetouch, pin-prick and vibration sense. Participants were considered to have SSPN if they had at least one symptom (burning, pain, numbness, or pins and needles) or one clinical sign of neuropathy (reduced vibration sense or absent ankle reflexes) in both legs. The grading was according to the Division of AIDS Toxicity Table (see Table 1).[6] The results were not confirmed by nerve conduction studies, as the expertise and equipment needed are not available on site, and infection control concerns precluded transporting a patient to another site. Participants were assessed for incident peripheral neuropathy weekly for the first 4 weeks and monthly thereafter.

Age, gender, HIV status, alcohol use, TB and HIV treatment regimens both prior to admission and current, and concomitant medications were recorded. The association between potential risk factors and prevalent SSPN was estimated using odds ratio (OR) with 95% confidence intervals (CIs). Factors associated with incident SSPN were estimated as hazard ratios (HRs) using Cox proportional hazard models. Ethical approval for the study was granted by the Human Research Ethics Committee of the University of the Witwatersrand.

Results

Between August 2009 and August 2011, 284 adults with MDR TB were admitted to Sizwe Tropical Disease Hospital, of whom 246 (87%) consented to participate in the study. Median age was 37 years and 54% were female; 81% were HIV-infected with median CD4+ count of 200.5 cells/μl (interquartile ratio (IQR) 98.75 - 267.25). Few (3.3%) patients reported excessive alcohol use. At admission, 35.7% (n=88) were already on ART. Median duration of exposure to stavudine was 7.4 months (IQR 2.2 - 24.5) and median exposure time to INH was 6 months (IQR 3 - 6). Sixty (24.4%) patients had SSPN at time of admission. In bivariate analysis, prevalent SSPN cases were more likely to be HIV-infected (OR 3.21; 95% CI 1.25 - 8.21) and tended to have longer (>7 months) exposure to stavudine (OR 1.81; 95% CI 0.90 - 3.63). However, they were similar to those without prevalent SSPN with regards to gender (OR 1.36; 95% CI 0.76 - 2.42), excessive alcohol use (OR 1.03; 95% CI 0.23 - 4.58) ), age above 37 years (OR 1.12; 95% CI 0.60 - 2.12), and duration of exposure to INH for >6 months (OR 0.94; 95% CI 0.52 - 1.71) (Table 2). HIV infection remained significantly associated with prevalent SSPN in multivariate analysis (adjusted OR) 3.34; 95% CI 1.19 - 9.36). The 186 patients free of SSPN at baseline were followed up for a median of 452 days, (IQR 312 to 628 days). Thirty-one (16.7%) developed incident SSPN after a median of 40 days (IQR 23 - 108) days), corresponding to an incidence rate of 12.9 per 100 personyears. Incident SSPN was associated with older age (HR 3.00; 95 CI 1.30 - 6.89) and tended to be associated with exposure to terizidone (HR 2.98; 95% CI 0.94 - 4.61) or stavudine (Crude HR 1.62; 95% CI 0.65 - 4.01) in the first 6 months of MDR TB treatment. Incident SSPN was not associated with HIV infection (HR 1.00; 95% CI 0.36 - .91). In multivariate analysis, older age remained an independent risk factor for incident SSPN (adjusted HR 3.174; 95% CI 1.243 - 8.06).

Discussion

SSPN was common among patients admitted for MDR TB treatment, with a prevalence of 24.4% and incidence rate of 12 per 100 personyears. We found that HIV infection was independently associated with prevalent SSPN, but was not associated with incident SSPN. HIV-

Table 1. Division of AIDS Toxicity Table[6] Grade 1: Mild

Neurosensory alteration (including paraesthesia and painful neuropathy). Asymptomatic with sensory alteration on exam or minimal paraesthesia causing no or minimal interference with usual social and functional activities.

Grade 2: Moderate

Sensory alteration or paraesthesia causing greater than minimal interference with usual social and functional activities.

Grade 3: Severe

Sensory alteration or paraesthesia causing inability to perform usual social and functional activities.

Grade 4: Potentially life-threatening

Disabling sensory alteration or paraesthesia causing inability to perform basic self-care functions.

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Table 2. Risk factor for incident and prevalent SSPN Crude OR (95% CI)

Adjusted OR (95% CI)

3.21 (1.25 - 8.22)

3.34 (1.19 – 9.36)

Crude HR (95% CI)

Adjusted HR (95% CI)

1.00 (0.35 - 2.91)

1.12 (0.36 - 3.50)

Prevalent SSPN HIV status (negative v. invected) Gender (female v. male)

1.36 (0.76 - 2.42)

1.40 (0.75 – 2.61)

Age (≤37 years v. >37 years)

1.13 (0.60 - 2.12)

1.26 (0.24 – 1.72)

uration of treatment with stavudine D (≤7 months v. >7 months)

1.81 (0.90 - 3.67)

1.50 (0.72 – 3.11)

uration of treatment with isoniazid D (≤6 months v. >6 months)

0.94 (0.52 - 1.71)

1.41 (0.61 – 2.14)

xcessive alcohol use E (alcohol consumption >3 times/week v. <3 times/week)

1.03 (0.23 - 4.58)

1.17 (0.18 – 5.89)

Incident SSPN HIV status (negative v. invected) Stavudine in first 6 months (no v. yes)

1.62 (0.65 - 4.01)

2.43 (0.84 - 7.03)

TZD in the first 6 months (no v. yes)

2.08 (4.61 - 0.94)

1.76 (0.76 - 4.08)

Age (≤37 years v. >37 years)

3.00 (1.30 - 6.89)

3.17 (1.243 - 8.06)

Gender (female v. male)

1.65 (0.73 - 3.74)

1.46 (0.62 - 3.43)

SSPN = symptomatic symmetrical peripheral neuropathy; OR = odds ratio; CI = confidence interval; HR = hazard ratio; TZD = terizidone.

associated SSPN has been associated with low CD4+ count and a high viral load, suggesting a possible reduction in risk when ART is initiated early.[7] Duration of exposure to INH prior to admission was not associated with increased prevalence of SSPN in our cohort. However, the frequency of INH-associated SSPN has been shown to be mediated by HIV infection, with HIV-infected TB patients having a fourfold higher risk.[8] INH-associated SSPN is also dose-related, with 2 - 12% of patients receiving 3 - 5 mg/kg/day INH developing SSPN, compared with 44% of those receiving 16 - 24 mg/kg/day.[9] We could not assess the effect of INH dosage in this cohort as only 4 patients received a high dose of INH for treatment of MDR TB. Exposure to stavudine is a well-documented risk factor for SSPN[10,11] and tended to increase the risk of SSPN in our study cohort. However, compared with the risk of renal disease, this was not considered to be sufficient reason not to use stavudine. Terizidone may further increase the risk of INH-associated SSPN as it inhibits pyridoxine activity.[9] Terizidone-associated nervous system toxicities have been reported, usually within the first 2 weeks, but rarely include SSPN. In our cohort, exposure to terizidone tended to increase the risk of incident SSPN, but this was not statistically significant.

Study limitations

Very ill and confused patients could not provide consent and were excluded, which may have led to an underestimation of the rate of

SSPN. The diagnosis of SSPN was based on clinical examination only, as we did not have the capacity to perform electrophysiological studies.

References 1. World Health Organization. Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response. Geneva: WHO, 2010. http://whqlibdoc.who.int/ publications/2010/9789241599191_eng.pdf (accessed 28 February 2013). 2. Mingeot-Leclercq MP, Tulkens PM. Aminoglycosides: Nephrotoxicity. Antimicrob Agents Chemother 1999;43(5):1003-1012. 3. Walker RJ, Duggin GG. Drug nephrotoxicity. Ann Rev Pharmacol Toxicol 1988;28:331-345. 4. Fernandez-Fernandez B, Montoya-Ferrer A, Sanz AB, et al. Tenofovir nephrotoxicity: 2011 update. AIDS Research and Treatment. 2011, Article ID 354908. [http://dx.doi.org/10.1155/2011/354908] 5. South African Department of Health. Management of Drug Resistant Tuberculosis: Policy Guidelines. Pretoria: NDoH, 2012. http://www.doh.gov.za/docs/policy/2012/TBpolicy.pdf (accessed 27 August 2013). 6. US National Institute of Allergy and Infectious Diseases Division of AIDS. The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Bethesda: DAIDS, 2004. http:// rsc.tech-res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of_Adult_ Pediatric_Adverse_Events.pdf (accessed 2 September 2013). 7. Childs EA, Lyles RH, Selnes OA, et al. Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology 1999;52(3):607-613. 8. Marks DJ, Dheda K, Dawson R, Ainslie G, Miller RF. Adverse events to antituberculosis therapy: Influence of HIV and antiretroviral drugs. Int J STD AIDS 2009;20:339-345. [http://dx.doi. org/10.1258/ijsa.2008.008361] 9. van der Watt JJ, Harrison TB, Benatar M, Heckmann JM. Polyneuropathy, anti-tuberculosis treatment and the role of pyridoxine in the HIV/AIDS era: A systematic review. In J Tuberc Lung Dis 2011;15(6):722-728. [http://dx.doi.org/10.5588/ijtld.10.0284] 10. Evans, SR, Ellis RJ, Chen H, et al. Peripheral neuropathy in HIV: Prevalence and risk factors. AIDS 2011;25(7):919-928. [http://dx.doi.org/10.1097/QAD.0b013e328345889d] 11. Wadley AL, Cherry CL, Price P, Kamerman PR. HIV neuropathy risk factors and symptom characterization in stavudine-exposed South Africans. J Pain Symptom Manage 2011;41(4):700-706. [http://dx.doi.org/10.1016/j.jpainsymman.2010.07.006]

Accepted 30 October 2012.

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Diagnostic yield of fine needle aspiration biopsy in HIV-infected adults with suspected mycobacterial lymphadenitis R Razack,1 MB ChB, MScMedSc (Cytopathology); M Louw,1 MB ChB, MMed (Anat Path), MScMedSc (Cytopathology); C A Wright,1,2 MB BCh, MMed (Anat Path), FCPath (SA), FRCPath (UK), FIAC, PhD Division of Anatomical Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, and National Health Laboratory Service, Tygerberg Hospital, Cape Town, South Africa 2 National Health Laboratory Service, Port Elizabeth, South Africa 1

Corresponding author: R Razack (rubina@sun.ac.za)

Background. Fine needle aspiration biopsy (FNAB) has been shown to be the diagnostic procedure of choice for superficial lymphadenitis in tuberculosis endemic regions. Methods. We conducted a retrospective laboratory-based study to determine the bacteriological yield of clinically suspected mycobacterial tuberculous lymphadenitis following FNAB in adults, and specifically HIV-positive patients, to determine the need for the introduction of automated nucleic acid amplification tests (NAATs) such as the Xpert MTB/RIF assay as the initial diagnostic modality. Results. A diagnostic yield of 80% was achieved, significantly higher in HIV-positive v. HIV-negative patients (84% v. 52%, respectively; p<0.001). Conclusion. The results justify using automated NAATs such as the Xpert MTB/RIF assay as the initial diagnostic modality to expedite management in HIV-infected patients. S Afr Med J 2014;104(1):27-28. DOI:10.7196/SAMJ.7492

Tuberculous lymphadenitis (LAD) is the most common form of extrapulmonary tuberculosis (TB), accounting for 30 - 52% of cases of peripheral lymphadenopathy in developing countries with a high TB incidence.[1-3] In high-incidence countries, it is usually considered a disease of childhood,[4] while the peak age of tuberculous LAD in developed countries such as the USA has now been shown to be 30 - 40 years.[5] In tuberculous LAD, fine needle aspiration biopsy (FNAB) has proved to be the diagnostic procedure of choice, with diagnostic yields varying from 42% to 83%, the highest yield in any extrapulmonary specimen investigation.[1,2,6] Although FNAB is simple, cost effective and safe, cytomorphology is not specific and microbiological cultures for speciation and drug sensitivity are required. The literature reports a variable detection rate of mycobacteria on cultures acquired by FNAB, with figures ranging between 35% and 83%.[1-3] In South Africa (SA), bacteriological confirmation defined as the identification of mycobacterial organisms, either by positive Ziehl-Neelsen stain, Papanicolaou autofluorescence and/or culture from aspirates in children is high, at 77.1%.[7] Comparative figures for aspirates in the adult population in SA are few and have small sample numbers.[8,9] With this background, a retrospective laboratory-based study was conducted to determine the bacteriological yield of clinically suspected mycobacterial LAD in adults, and specifically, HIV-positive patients, to determine the need for introduction of automated nucleic acid amplification tests (NAATs), such as the Xpert MTB/RIF assay as the initial diagnostic modality.

Methods

The study was conducted from May 2007 to March 2010 at the Tygerberg Hospital FNAB clinic. Ethical approval was received from the Stellenbosch University Health Research Ethics Committee (ref. no. S12/07/202). The study population included adults, ≥14 years of age (as defined in SA), referred to the FNAB clinic for suspected

mycobacterial LAD, where cytomorphology was consistent with mycobacterial disease. FNABs were performed by the trained sister or pathologist using a 23 G or 25 G needle attached to a 10 ml syringe. Two aspirates were performed, and the syringe rinsed in Mycobacterial Growth Indicator Tube (MGIT) medium for mycobacterial culture. Samples inoculated into MGIT were cultured according the standard operating procedure in the automated BACTEC MGIT 960 system (Becton Dickenson, USA). Cultures were incubated at 37°C for up to 50 days or until flagged positive. A positive cytology diagnosis included cytomorphological features consistent with mycobacterial infection and confirmation of the organism on Ziehl-Neelsen stain or Papanicolaou autofluorescence.

Results

A total of 368 patients were included. Of these, 226 (61%) were HIV-positive, 25 (7%) HIV-negative and in 117 (32%) patients the HIV status was unknown. The numbers of women and men in the study population were 233 (63.3%) and 134 (36.4%), respectively. The gender of 1 (0.3%) patient was not recorded. Mycobacterial LAD (bacterial confirmation) was confirmed in 293 (79.6%) patients. Of these, 228 (77.8%) had positive MGIT cultures while in 65 (22%) cases with negative MGIT cultures, 64 (22%) were diagnosed on Ziehl Neelsen stain, and 1 (0.4%) on Papanicolaou autofluorescence. The average time to culture was 18.6 days (range 4 - 50). A significant difference was found between the diagnostic yield in the HIV-positive and -negative populations (84% v. 52%, respectively; p<0.001). The yield in the HIV-unknown population was 77%. Of the 228 positive cultures, 226 were Mycobacterium tuberculosis, 1 M. avium-intracellulare, and 1 M. szulgai. The non-tuberculous organisms were both in HIV-positive patients. A positive culture for M. tuberculosis was obtained in 29/84 (34.5%) patients in whom a sputum sample had been submitted. The HIV status of 2 of these patients was unknown, while 27 patients were HIV-positive.

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Total patients (N=368)

HIV status

HIV-positive (N=226)

HIV-negative (N=25)

HIV unknown (N=117)

Bacteriological confirmation (N=293)

n=190 (84%)

n=13 (52%)

n=90 (77%)

Cytology positive* (N=192) Culture positive (N=228)

n=148

n=36

n=8

n=139

n=78

n=11

Fig. 1. Study flow diagram. *Cytology = cytomorphology and identification of organism on ZiehlNeelsen stain or Papanicolaou autofluorescence.

The mean age of patients diagnosed with mycobacterial LAD was 31.9 years (range 14 - 71); with the mean age in the HIV-positive population being 32.6 years and in the HIVnegative population 28.5 years. Multivariate logistic regression analysis showed positive HIV status to be significantly associated with a positive bacteriological yield (p=0.005), independent of other variables included in the model, namely gender, age and site. The odds ratio indicates that an HIV-positive patient has 4.86 times higher odds of having a positive bacteriological yield (95% confidence interval 1.65 - 9.75) than an HIV-negative patient.

Discussion

The relationship between HIV and TB is bidirectional.[1,2] TB is a catalyst in the progression of HIV, and HIV infection is associated with an increased risk of developing TB. HIV alters the clinical presentation of TB such that TB progresses more rapidly and aggressively in HIV-infected individuals. Sputum smears, which are the cornerstone of diagnosis in resource-limited settings, are usually negative in HIV-associated TB, attested to by the 34.5% sputum culture yield in this study. This contributes to the diagnostic delay in treatment.[1,2] Extrapulmonary TB can occur either alone or in association with pulmonary TB in 40 - 60% of cases.[1,2] FNAB provides a means of easy access to diagnostic material in many of these pulmonary cases.

This study shows that the bacteriological yield of FNAB in suspected mycobacterial LAD in adults is comparable to, and higher than, that found in children in TB-endemic areas. Compounding the problem of HIV and TB co-infection is immune reconstitution inflammatory syndrome (IRIS) where the initiation of antiretroviral treatment (ART) ‘unmasks’ the clinically silent disease. [10] M. tuberculosis is estimated to account for about one-third of HIV-related IRIS events.[10] To avoid IRIS complications, ART is ideally initiated once mycobacterial infection has been excluded, but diagnosing TB using current diagnostic modalities has limitations. In this study, the average time to culture was excellent at 18.6 days, but this delay in initiating treatment increases the contagious risk, particularly in resistant disease. In endemic areas, patients with granulomatous inflammation are often treated empirically with anti-TB drugs, contributing to the generation of multidrugresistant TB. The heavy burden of TB, and HIV, in countries such as SA places a strain on scarce resources, which can be alleviated with a rapid diagnosis that reduces the number of follow-up visits.

Conclusion

Given the high mycobacterial LAD patients on FNAB, expedite diagnosis,

diagnostic yield of in HIV-infected adult and the pressure to we feel this justifies

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recommending new automated NAATs such as the Xpert MTB/RIF test to be used as firstline diagnostic modalities. The Xpert MTB/ RIF test has been shown to be of value in the diagnosis of extrapulmonary TB, including tuberculous LAD.[11,12] The advantages include minimal sample size, and ease and rapidity of diagnosis. The rapid turnaround time will, in turn, reduce the need for hospitalisation, reduce the contagious risk and decrease morbidity and mortality associated with the high TB burden in SA. Acknowledgements. The authors express gratitude to Sr Cupido for her dedicated and eﬃcient service at the Tygerberg Hospital FNAB clinic and to Justin Harvey, Department of Statistics and Actuarial Sciences, Stellenbosch University, for the data analysis. References 1. Reuter H, Wood R, Schaaf HS, Donald PR. Overview of Extrapulmonary Tuberculosis in Adults and Children. In: Schaaf HS, Zumla A, eds. Tuberculosis: A Comprehensive Clinical Reference. Atlanta: Saunders Elsevier, 2009;(34):377-380. 2. Nachega JB, Maartens G. Clinical Aspects of Tuberculosis in HIV-infected Adults. In: Schaaf HS, Zumla A, eds. Tuberculosis: A Comprehensive Clinical Reference. Atlanta: Saunders Elsevier, 2009;(51):524-525. 3. Singh K, Muralidhar M, Kumar A, et al. Comparison of in house polymerase chain reaction with conventional techniques for the detection of Mycobacterium tuberculosis DNA in granulomatous lymphadenopathy. J Clin Pathol 2000;53(5):355-361. [http:// dx.doi.org/10.1136/jcp.53.5.355] 4. Mohaptra PR, Janmeja AK. Tuberculous lymphadenitis. J Assoc Physicians India 2009;57:585-590. 5. Fontanilla JM, Barnes A, von Reyn F. Current diagnosis and management of peripheral tuberculous lymphadenitis. Clin Infect Dis 2011;53(6):555-562. [http://dx.doi.org/10.1093/cid/cir454] 6. Monkongdee P, McCarthy D, Cain K, et al. Yield of acid-fast smear and mycobacterial culture for tuberculous diagnosis in people with human immunodeficiency virus. Am J Respir Crit Care Med 2009;180(9):903-908. [http://dx.doi.org/10.1164/ rccm.200905-0692OC] 7. Marais BJ, Wright CA, Schaaf HS, et al. Tuberculous lymphadenitis as a cause of persistent lymphadenopathy in children from a tuberculous-endemic area. Pediatr Infect Dis J 2006;25(2):142146. [http://dx.doi.org/10.1097/01.inf.0000199259.04970.d1] 8. Wright CA, Hoek KGP, Marais BJ, van Helden P, Warren R. Combining fine-needle aspiration biopsy and high-resolution melt analysis to reduce diagnostic delay in mycobacterial lymphadenitis. Diag Cytopathol 2010;38(7):482-488. [http:// dx.doi.org/10.1002/dc.21223] 9. Wright CA, Bamford C, Prince Y, et al. Mycobacterial transport medium for routine culture of fine needle aspiration biopsies. Arch Dis Child 2010 95(1):48-50. [http://dx.doi.org/10.1136/ adc.2009.164038] 10. Colebunders R, John L, Huyst V, Kambugu A, Scano F, Lynen L. Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources. Int J Tuberc Lung Dis 2006;10(9):946-953. 11. Hilleman D, Rusch-Gerdes S, Boehme C, Richter E. Rapid molecular detection of extrapulmonary tuberculosis by the automated GeneXpert MTB/RIF system. J Clin Microbiol 2011;49(4):1202-1205. [http://dx.doi.org/10.1128/JCM.02268-10] 12. Ligthelm LJ, Nicol MP, Hoek KG, et al. Xpert MTB/RIF for rapid diagnosis of tuberculous lymphadenitis from fine-needle aspiration biopsy specimens. J Clin Microbiol 2011;49(11):39673970. [http://dx.doi.org/10.1128/JCM.01310-11]

Accepted 20 September 2013.

RESEARCH

Percutaneous core needle biopsies: The yield in spinal tuberculosis J P Watt, MB ChB; J H Davis, MB ChB, MMed, FCS (SA) (Orth) Department of Orthopaedic Surgery, Stellenbosch University, South Africa Corresponding author: J H Davis (johanhdavis@gmail.com) Background. Current recommendations for spinal tuberculosis (TB) not requiring open surgery include core needle biopsy to confirm TB and determine drug sensitivity. International figures show the positive culture yield from core needle biopsies is 50 - 83%. Objectives. To (i) assess the yield of percutaneous needle biopsies; (ii) identify factors that may lead to a negative result; and (iii) determine whether, TB being suspected, needle biopsy is justified. Methods. We conducted a multicentre retrospective review of 44 patients treated for suspected spinal TB between January 2009 and April 2012, who did not require open surgery. Data captured included demographics, relevant history, outcome of investigations and histopathological findings in patients. Results. The overall positive TB culture rate was 59%. Age, duration of symptoms, HIV and neurological status, erythrocyte sedimentation rate and core size had no statistical influence. Of the 7 patients receiving TB treatment at the time of biopsy, 3 were culture-positive. Multidrug resistance was evident in 12% of positive cultures. The positive culture yield was 40% at Tygerberg Hospital and 75% at Groote Schuur Hospital, with no difference in histological yield. This was attributed to the practice of decontaminating specimens prior to culture at Tygerberg Hospital. The highest culture yield (32%) came from samples showing non-necrotising chronic inflammatory changes. Conclusion. Percutaneous biopsy remains an important tool to diagnose and manage spinal TB. The yield of transpedicular biopsies in this study was comparable with international figures. Specimen decontamination prior to culture had a direct negative influence on biopsy culture yield, as did prior TB treatment. S Afr Med J 2014;104(1):29-31. DOI:10.7196/SAMJ.6868

It has been estimated by the World Health Organi zation (WHO) that a third of the world’s population is infected with Mycobacterium tuberculosis (MTB), with a tuberculosis (TB) incidence of 981/100 000 in South Africa.[1] Of TB infections, 16% involve extra-pulmonary systems and 1% affect the spine. Alarmingly, of all patients treated for spinal TB, only 55% have a definitive laboratory diagnosis, with 19% being negative and 26% having no traceable results.[2] Although effective chemotherapy has been available for over 50 years, TB remains one of the most challenging diseases to manage. Timely diagnosis and adequate treatment of spinal TB are necessary to prevent serious morbidity, including spinal deformity and, ultimately, neurological sequelae. Spinal cord compression from pus, inflammatory granulation tissue of active disease, or kyphosis deformity in the late stage of disease can result in paraplegia.[3] As the majority of cases are managed medically, a reliable confirmation of spinal TB diagnosis is crucial.

Methods

We performed a retrospective, multicentre review of 44 consecutive patients who presented at Tygerberg Hospital (TBH) or Groote Schuur Hospital (GSH) between January 2009 and April 2012 and had clinical and radiological evidence of spinal TB. All had undergone percutaneous transpedicular needle biopsy to confirm diagnosis and were identified from surgical databases kept by their respective surgeons. All patients had strong clinical and radiological evidence of TB and had magnetic resonance imaging (MRI) scans as part of their workup (Fig. 1). Exclusion criteria included absolute indications for further surgical management and questionable diagnoses where biopsy was undertaken to rule out non-infectious processes.

Patients waited an average of 11.9 days prior to biopsy, allowing for full workup. There were 20 males and 24 females, ranging in age from 16 to 89 years (mean 39 years). All had a history of lower back pain, with an average 6-month duration of symptoms prior to presentation. On examination, 24 (54%) had a neurological deficit ranging from sensory fallout to myelopathy with muscle weakness. Nearly half had constitutional symptoms of TB, including weight loss, night sweats, loss of appetite and general malaise. Fourteen patients were HIV-positive, 21 HIV-negative and the rest refused testing. Seven of the HIV-positive patients were established on antiretroviral treatment (ART), and none had any other AIDS-defining disease. Six patients had a history of previous TB, of whom 4 were HIV-positive. As all subjects were referred from secondary level institutions, 7 had already been started on the 4-drug TB treatment regimen, with a varying duration of treatment at presentation (5 - 70 days). Included in the initial blood workup was the erythrocyte sedimentation rate (ESR), a nonspecific inflammatory marker often elevated in TB, measured using the Westergren method. The ESR ranged from 3 to 150 mm/hour (mean 72 mm/hour). All patients had plain X-rays of the chest and spine in the initial radiological workup. Spinal radiology revealed typical features ranging from osteopenia, paravertebral abscess and disc space reduction to end plate erosions and vertebral body collapse. On MRI, 21 patients had abscess formation, which was epidural in 8 and pre-vertebral in 13. One patient had arachnoiditis. Five patients had disease involving more than 2 vertebrae. At the time of biopsy, patients were given a general anaesthetic and either positioned prone or on their right side. A Jamshidi or Harlow Wood needle was advanced percutaneously under fluoroscopic guidance into the affected vertebral body, utilising the transpedicular

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Fig. 1. Radiographic appearance of tuberculosis of the spine. (A) Plain roëntgen and (B) magnetic resonance imaging.

Fig. 2. Fluoroscopic-guided trans-oral needle biopsy.

approach. Almost all patients had either a thoracic or lumbar biopsy. In 2 patients, cervical spine biopsy was achieved via a trans oral approach for atlantoaxial pathology (Fig. 2). A pus sample and 2 trephine biopsies of bone (average length 7.92 mm) were collected from each patient. All samples underwent histopathological examination, microscopy and culture, and polymerase chain reaction (PCR) analysis for MTB DNA.

Biopsy core length had no significant impact on culture yield. The negative group, in fact, had the largest average core size (mean 9 mm v. 7 mm) (Fig. 5). A possible explanation is that these larger core sizes were due to removing the trocar too soon, thereby sampling a greater proportion of healthy pedicular bone. The potential effect of active TB treatment on culture yield was of concern. Seven patients were receiving TB therapy by the time of spinal biopsy, 3 of which were culturepositive. Although a trend towards positive culture in patients not yet started on TB treatment could be identified, this was not statistically significant (p=0.0518, Fisher’s exact twotailed test). There was a similar histological yield of the biopsies between the individual hospitals (56%). Of the 44 samples, 10 were diagnostic and 13 were suggestive of TB infection (but showing non necrotising granulomatous inflammation). There was, however, a significant difference in the yield from culture despite the biopsies being performed by the same surgeons at both hospitals: positive results at TBH only reached 40% compared with 75% at GSH. On examining the standard operating procedure (SOP) at the TBH National Health Laboratory Service (NHLS) laboratory, it was found that all samples were routinely decontaminated before being prepared for culture, leading to loss of viable bacilli and a lower culture yield. The SOP at GSH NHLS laboratory differed in that core specimens were treated as sterile and only decontaminated when they were flagged as growing other bacteria. This was brought to the attention of the relevant microbiologists, who have since changed their practice.

Results

The gold standard for the definitive diagnosis of TB remains the identification of MTB; therefore, all results were measured against a positive or negative culture.[4] To identify factors influencing the overall culture yield of biopsies, the study population was split into 2 groups: culturepositive and culturenegative. Of the 44 patients, 26 (59%) had biopsies that cultured positive for TB. Age, duration of symptoms, HIV status and neurological status had no statistical influence on this outcome of culture positivity. There was no statistical significance when comparing the average ESR values of the culturepositive and negative groups (mean 69.7, standard deviation (SD) ±37.5 v. 74.8±37.6, respectively). However, there was a definite downward trend in ESR from commencement to completion of treatment in both groups (Fig. 3), with patients being treated for an average of 12.4 months (mean 12; SD ±4; range 12 24). The classic histological finding is one of necrotising granulomas with epithelioid macrophages, multiple giant cells and lymphocytes. Because this picture can change in HIVpositive individuals, non necrotising granulomatous inflammatory changes may also be found in TB culturepositive specimens.[4] Fig. 4 shows the comparison between the histology and the culture results of the same specimen. Unexpectedly, the highest culture yield came from samples showing nonnecrotising chronic inflammatory changes (32%), followed by samples with nonspecific histological findings (27%) and not from samples showing necrotising granulomas. Samples showing classic TB histology were associated with a positive culture in only 23% of cases. Only 2 specimens stained positive for acidfast bacilli and of the 59% of positive cultures, 12% were multidrug resistant (MDR). All drug sensitivities were confirmed with PCR.

Discussion

There is no single test that can be performed for the detection of all musculoskeletal cases of TB. The diagnosis of spinal disease remains a challenge. The treating physician must have a high index of suspicion and has to rely on observation and thorough investigation of clinical signs and symptoms, augmented by the use of various imaging techniques and laboratory methods.[4] Patients may complain of back pain, night sweats, loss of weight and appetite. They may also have neurological symptoms ranging from clumsiness, with

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Fig. 3. Erythrocyte sedimentation rate (ESR) through the course of treatment.

9% Nonspecific findings (6/22)

27%

Non-representative (2/22)

23%

Non-necrotising granuloma (7/22) Necrotising granuloma (5/22) 9%

Positive Ziehl-Neelsen stain (2/22)

32%

Fig. 4. Comparison between histology results and culture of the same specimen.

Fig. 5. Specimen core size with respect to culture result.

subtle myelopathic signs, to complete motor fallout. In active TB, a low haemoglobin level, relative lymphocytosis and a raised ESR may be found.[5,6] Because these are all nonspecific findings, results serve only to support the diagnosis. Ultimately, identification of the TB bacilli in biopsy specimens offers the only definitive diagnosis.[7,8] The gold standard remains the culture of MTB, it is much more sensitive than smear microscopy and can detect as little as 10 viable MTB bascillus per millilitre of sample.[2] In spinal disease, this unfortunately requires the invasive procedure of bone biopsy, the diagnosis being made histologically when necrotising granulomatous inflammation showing epithelioid macrophages, multiple giant cells and lymphocytes are demonstrated. In patients with HIV, and more specifically AIDS, the histological changes caused by MTB can range from the classic caseating granulomas, to a nonspecific chronic inflammatory reaction without necrosis.[4] ZiehlNeelsen staining is then key to the identification of the presence of acid fast bacilli. Regrettably, because of the typically low bacterial loads in TB of the spine, bacteria are only identifiable in ≤50% of cases using minimally invasive techniques.[9] Moreover, confirming the

diagnosis histologically is but half the battle, as sensitivity to first line drugs still has to be proven. In endemic areas, the diagnosis of spinal TB is often made on clinical suspicion, radiographic evidence and bloodtest results alone, and treatment is started empirically.[5,10] Danchaivijitr et al.[3] identified patients with spinal TB based on either histopathological, microbiological or typical radiological findings and showed good response to antiTB treatment in all 3 groups. At a time when drug resistance is growing at an alarming rate, and with TB being the great mimicker, it is important to have a histopathological diagnosis together with a drug sensitivity profile to achieve a definitive diagnosis and treatment.[1012] MDRTB is estimated to account for 1.8% of new TB cases and 6.7% of retreatment cases.[1] The current guidelines for the management of spinal TB include percutaneous vertebral needle biopsy as a diagnostic tool before treatment is started[10] to confirm MTB as the responsible pathogen and its sensitivity to firstline treatment. A recent metaanalysis that focused on core needle biopsy to achieve TB diagnosis revealed an overall TB culture yield of 66% (range 50 83) in 299 biopsies.[13] A retrospective study in 2005 focused on 70 adult patients with clinicoradiological proof of thoracic spinal TB. Computed tomography (CT)guided needle biopsies were performed in 11 cases – 3 yielded positive cultures for TB and 5 showed evidence of TB on histology. All 3 culture specimens showed resistance to firstline drugs. Another 10 of the 70 patients in this study failed to respond to first line TB treatment and were diagnosed with MDRTB by default and subsequently successfully treated.[6] Although systematic followup and continuous monitoring can ensure that such resistant cases are ultimately detected, not testing for drug susceptibility risks a delay of between 7 and 8 months before institution of appropriate therapy.[11] It is important to scrutinise biopsy results and to be aware of the techniques used in the processing of samples by the respective microbiology laboratory. In this study, there was clearly an inconsistency in the results obtained from the respective laboratories, with the difference identified in the TBH NHLS SOP of decontaminating biopsy samples prior to culturing for TB. This procedure is meant to selectively eliminate bacteria other than mycobacteria and makes use of sodium hydroxideNacetylL cysteine to liquify samples. A phosphate buffer is then added to the mixture, which is then concentrated by centrifugation. The supernatant is decanted, leaving the sediment to be cultured. Prior to inoculation into the MTB growth indicator tube (MGIT), an antibiotic mixture, referred to as PANTA, is added to the culture broth.[14] PANTA comprises 5 antimicrobial agents: polymyxin B, amphotericin B, nalidixic acid, trimethoprim and azlocillin. The addition of this antibiotic mixture has been found to increase rather than decrease MTB culture yields.[15] Thus, the most obvious explanation for the loss of viable bacilli would have to be the dilution and increased decanting of the specimen by the addition of PANTA. Extra NacetylLcysteine powder would have had to be added to adequately liquefy the core biopsy sample, which in turn meant more phosphate buffer and consequently more supernatant requiring decanting. Both laboratories now practise direct inoculation into a MGIT tube without adding any PANTA, and decontamination is only performed if the specimen appears to be growing bacteria other than mycobacteria. Compared with published data, the overall yield from needle biopsies performed in this study is commensurate with international experience. The factors that could be identified as having directly influenced biopsy yield were twofold, i.e. that the patient was receiving TB treatment at time of biopsy and the routine practice of decontaminating specimens prior to culture. The results of this study

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suggest that every patient with a clinical and radiological suspicion of spinal TB should undergo core needle biopsy in the diagnostic workup. Where TB treatment has already been initiated, the surgeon should recognise the probability of a negative MTB culture. Such patients may be treated empirically and only be biopsied when there is suspicion of drug resistance or non-infective pathology. Acknowledgements. We acknowledge Professor Robert Dunn for the use of the surgery database at GSH. References 1. Patwardhan SA, Joshi S. Laboratory diagnosis of spinal tuberculosis: Past and present. ASN&J 2011;23(3):120-124. [http://dx.doi.org/10.1007/s12240-011-0023-9] 2. World Health Organization. Global tuberculosis control: WHO report 2010. http://www.who.int/tb/ publications/global_report/en/ (accessed 22 April 2012). 3. Danchaivijitr N, Temram S, Thepmongkhol K, Chiewvit P. Diagnostic accuracy of MR imaging in tuberculous spondylitis. J Med Assoc Thai 2007;90(8):1581-1589. 4. Moon M. Tuberculosis of spine – contemporary thoughts on current issues and perspective views. Curr Orthopaed 2007;21(5):364-379. [http://dx.doi.org/10.1016/j.cuor.2007.09.006]

5. Nene A, Pawar U. Tuberculosis of the spine 2011 update. ASN&J 2011;23(3):105-109. [http://dx.doi. org/10.1007/s12240-011-0021-y] 6. Nene A, Bhojraj S. Results of nonsurgical treatment of thoracic spinal tuberculosis in adults. Spine J 2005;5(1):79-84. [http://dx.doi.org/10.1016/j.spinee.2004.05.255] 7. Cheung W, Luk K. Tuberculosis of the spine. Orthop Trauma 2011;25(3):161-167. [http://dx.doi. org/10.1016/j.mporth.2011.02.002] 8. Dunn R. The medical management of spinal tuberculosis. SA Orthop J 2010;9(1):37-41. 9. Luk KDK. Tuberculosis of the spine in the new millennium. Eur Spine J 1999;8(5):338-345. [http:// dx.doi.org/10.1007/s005860050185] 10. Dunn R, Zondagh I. Spinal tuberculosis: Diagnostic biopsy is mandatory. S Afr Med J 2008;98(5):360-362. 11. Mohan K, Rawall S, Pawar UM, Sadani M, Nagad P, Nene A. Drug resistance patterns in 111 cases of drugresistant tuberculosis spine. Eur Spine J 2012; Jan [online] [http://dx.doi.org/10.1007/s00586-012-2154-x] 12. Monni T, Visser A, Visser HF, Motsitsi SN. Clinical utility of tissue polymerase chain reaction in the diagnosis of spinal tuberculosis. SA Orthop J 2012;11(1):23-27. 13. Colmenero JD, Ruiz-Mesa JD, Sanjuan-Jimenez R, Sobrino B, Morata P. Establishing the diagnosis of tuberculous vertebral osteomyelitis. Eur Spin J 2012; May [online] [http://dx.doi.org/10.1007/s00586012-2348-2] 14. Becton, Dickinson and Company. Manual Mycobacterial Growth Systems. http://www.bd.co/ds/ productCenter/MT-MgitTubes.asp (accessed 7 January 2013). 15. Peres RL, Palaci M, Loureiro RB, Dietze R, Johnson JL, Maciel EL. Reduction of contamination of mycobacterial growth indicator tubes using increased PANTA concentration. Int J Tuberc Lung Dis 2011;15(2):281-283.

Accepted 18 March 2013.

The attitudes of medical students to research D Nel, MB ChB; R J Burman; R Hoffman, MB ChB; S Randera-Rees, MB ChB Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: D Nel (danielnel87@gmail.com)

Background. The workforce of ‘physician-scientists’ is ageing and decreasing in numbers. The responsibility to combat this trend rests on future generations of healthcare professionals and it is therefore valuable to evaluate medical students’ attitudes towards research. Objective. To establish the attitudes of University of Cape Town (UCT) medical students towards research and to investigate the factors influencing these attitudes. Methods. An anonymous, cross-sectional, self-administered questionnaire was administered to medical students from years 1 to 6 studying medicine at UCT in 2011. Questions were primarily closed-ended and consisted of Likert scales. Results. Out of a population of 1 195 medical students, 733 were sampled (63%); 65% were female, 53% were preclinical students (years 1 - 3) and 47% were in their clinical years (year 4 - 6). Overall, 61% of students had a positive attitude towards research and 74% felt that participation in research was important to their medical school education; 22% had been involved in voluntarily extracurricular research, 4% had presented at a scientific meeting and 3% had published in peer-reviewed journals. A number of perceived barriers to student research were identified including a lack of adequate training, time and research opportunities. Conclusion. Students believed that research was important and had a positive attitude towards it. However, few had been involved in voluntary research and produced work worthy of presentation and/or publication. Addressing identified barriers and improving students’ attitudes may begin to reverse the trend in declining numbers of physician-scientists. S Afr Med J 2014;104(1):32-36. DOI:10.7196/SAMJ.7058

Clinical research can be defined as the intent to pursue the understanding of the mechanisms, detection, progression and reversal of disease.[1] The main stakeholders of clinical research are the so-called ‘physician-scientists’: clinicians who are engaged in both the scientific method and clinical application. [2-5] The workforce of physician-scientists actively involved in clinical research is ageing and decreasing in number.[1,6,7] This is a phenomenon that has been noted on global and local fronts since the early 1990s.[1,7] Some of the proposed reasons for this decline include a lack of effective training programmes, unattractive careerpathing, and inadequate exposure to research before career paths are chosen.[1,8,9]

The early introduction of research-focused programmes into medical schools, as well as the encouragement of student participation in research, fosters favourable attitudes towards academically focused careers among medical students.[4,5,6,11] Scaria[4] introduced the ‘four I’s’ framework, which acts as a base upon which one can explain the current poor interest among medical students towards research. The barriers highlighted in this model show a lack of initiative (exposure, experience and knowledge), impulse (time and competitive environment), incentive (presentation/publication opportunities and acknowledgement) and idols (supervisors).[4,5,11-15] The diverse burden of disease within South Africa[1,10] requires physician-scientists to emerge out of future generations of healthcare professionals.

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Objective

To review the attitudes of medical students from the University of Cape Town (UCT) to research as well as to identify barriers which might be addressed to improve students’ attitudes.

Methods

The study was approved by the Ethics Committee of UCT Faculty of Health Sciences (ref. no. 251/2011). The study population was defined as UCT medical students, from years 1 to 6, in the year 2011. Participants were sampled at whole class lectures where they were presented with a paper copy of a questionnaire which they had to complete within 15 min. Through a selfadministered questionnaire, information was obtained on the following: basic demographics, interest in specialising, extent of previous research involvement, general attitude to research, and factors influencing attitudes to research. Research involvement included (i) voluntary; extracurricular research – projects pursued by students in their own time, excluding two compulsory research modules in the current curriculum (i.e. a one month ‘special studies’ project in the 2nd year, which entails conducting a very basic study and serves as a practical introduction to research) and an epidemiology and health promotion project forming part of the public health block in 4th year; (ii) publications and conference presentations (both voluntary, extracurricular research and projects forming part of the compulsory research modules mentioned above). Factors influencing attitudes to research were assessed by presenting students with a list of statements which were identified from the literature as well as by the researchers, and then asking them to express the extent to which they agreed or disagreed with these. Responses were recorded either as yes/no or using a 5part Likert scale. The latter was used to investigate the extent to which participants agreed or disagreed with a number of statements related to attitudes to research, where 1 = strongly disagree, 2 =disagree, 3 = neutral, 4 = agree and 5 = strongly agree. Statistical analysis was performed using OpenEpi (version 3.01) with p<0.05 being considered statistically significant. Categorical variables were compared using the χ2 test.

specialty to be competitive and those that did not, and their attitude to research. The same comparison between preclinical and clinical students yielded a similar nonsignificant result.

Research involvement

As shown in Fig. 3, 23% of respondents reported prior involvement in voluntary, extracurricular research (excluding the two compulsory research modules included in the current curriculum), with no significant difference between preclinical and clinical respondents (11% v. 12%, respectively). Of the students, 5% had presented their work (as voluntary, extracurricular projects as well as projects forming part of the compulsory research modules in the curriculum) at a national or international conference, with no significant difference between preclinical and clinical students. Students who had been involved

19%

22%

17% 19% 11%

1st year 2nd year 3rd year 4th year 5th year 6th year

13%

Fig. 1. Distribution of participants by year of study.

Preclinical

61%

28%

11%

Clinical

61%

31%

Results

Demographics

Of all participants, 94% were interested in specialising, with no statistically significant difference between preclinical and clinical respondents, including those who perceived entry into their specialty to be competitive. There was no statistically significant difference in the numbers of respondents who perceived entry into their chosen

Clinical Preclinical

20 15

12%

10 5 0

11%

2% 3%

3% Published

Interest in specialising

Negative

Presented at conference

There was very little difference in attitude to research between preclinical and clinical respondents with almost equal proportions feeling positive (61% v. 61%, respectively), neutral (28% v. 31%, respectively) or negative (11% v. 8%, respectively) (Fig. 2). There was no statistically significant difference in terms of year of study (preclinical v. clinical) and attitude to research. There was also no difference between gender (male v. female) and overall attitude to research (positive v. negative).

Neutral

Fig. 2. A comparison of the overall attitude to research between preclinical (years 1 - 3) and clinical (years 4 - 6) respondents.

Involved in voluntary extracurricular research

Overall attitude to research

Positive

Respondents, %

There were 1 195 medical students enrolled in years 1 6 in 2011. Of these, 733 were sampled, giving a response rate of 63%. Of those sampled, 65% were female. A total of 53% were preclinical (year 1 3) and 47% were in their clinical years (year 4 6). The distribution of participants by year of study is shown in Fig. 1. The mean age of participants was 21 years (range 17 31).

Fig. 3. Respondents’ previous research involvement.

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Important part of med school education Will get acknowledgement Adequate training in research methods

A number of other factors potentially impacting attitudes to research were identified. Fig. 4 shows both preclinical and clinical students’ responses to these factors while Fig. 5 compares the responses of students who had been involved in voluntary, extracurricular research with those who had not. Responses were initially recorded using a 5point Likert scale and then simplified to a 3point scale (Figs 4 and 5). Both preclinical and clinical students’ attitudes to a number of other factors, which could potentially affect attitude to research, were assessed. The same was done for students who had been involved in voluntary extracurricular research v. those that had not. A large portion of the responses were recorded as ‘neutral’, where students chose neither to agree nor disagree with the statement or were ‘unsure’ that they had enough knowledge to respond (Figs 4 and 5). By comparing the numbers of students actually agreeing and disagreeing with each statement, a number of conclusions could be made. As is shown in Fig. 4, 77% of preclinical and 71% of clinical students agreed that research is an important part of their medical school educations and more students than not felt that they would get deserved acknowledgement for their participation in research. As Fig. 5 shows, slightly more students who had been involved in voluntary research felt this way. The vast majority of students (73% clinical and 79% preclinical) (Fig. 4) felt that they lacked

Preclinical 6%

Preclinical

Difficult to present at a conference

Other factors influencing attitudes to research

Preclinical 5%

Preclinical

Difficult to Unsure what Should be Enough time Difficult to find opportunities more time to in med publish supervisor are available do research school for research

in voluntary, extracurricular research were significantly more likely to report that they had presented at a conference (p<0.001). Of all respondents, 3% had published their work in a peerreviewed journal (which included both voluntary and compulsory projects). Significantly more clinical than preclinical respondents had published their research (p<0.001). Students who had been involved in voluntary, extracurricular research were significantly more likely to have published (p<0.001). An analysis of the data, comparing previous involvement in research and overall attitude to research, yielded the following results: significantly more students who had previously been involved in voluntary, extracurricular research had a positive overall attitude to research. (p<0.05); significantly more students who had presented at a conference had a positive attitude to research (p<0.05). There was no significant difference in terms of having published and attitude to research.

Preclinical

Difficult to get funding

RESEARCH

Preclinical

Clinical

18%

Clinical 7%

Clinical

22%

13%

30%

45% 48%

20% 17%

Clinical

16%

45%

43%

47%

45%

38%

29%

55%

24%

51%

Clinical 12%

Preclinical

13%

25%

58% 79%

12%

73% 62%

31%

Clinical

27%

66%

15%

14%

21%

22%

17%

Clinical

31%

33%

Preclinical

23%

25%

26%

Clinical

Preclinical

42%

Clinical

71% 52%

29%

Preclinical

Disagree Neutral Agree

77%

25% 44%

50% 38%

25% 45% 56%

Fig. 4. Other factors potentially aﬀecting (preclinical v. clinical) respondents’ attitudes to research.

knowledge of what research opportunities were available. Many students were eager to get involved in research, but did not know where to start or how to go about performing a study. This was especially true for preclinical students. This was mirrored by the fact that, although the percentage is smaller (66%), the majority of the group that had actually been involved in voluntary research were still unsure about what opportunities were available (Fig. 5). As only 77% of students had not been involved in voluntary, extracurricular research, a large portion of both clinical and preclinical students responded ‘neutral’ to the question of whether it is difficult to find a supervisor or funding. A slightly greater proportion of the students who had been involved in voluntary research disagreed that it was difficult to find a supervisor, although again, the majority were unsure (52%).

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Discussion

Of the total population of students, 63% (n=733) were sampled, making this the largest study of its kind. Of the participants, 65% were female, reflecting the underlying demographic of the university where the female to male gender balance is currently 60:40. There were almost equal numbers of preclinical and clinical students, representing the UCT medical school population fairly. Encouragingly, the majority of preclinical and clinical students were positive about research (each 61%) with relatively few manifesting an outright negative attitude (11% v. 8%, respectively). Despite this, only 23% of students had actually been involved in voluntary, extracurricular research. It was of concern that very few students had translated either their voluntary extracurricular research, or their work

Important part of med school education

Not involved 6%

Will get acknowledgement

Not involved 9%

Adequate training in research methods

Not involved

Difficult to present at a conference

Not involved

Difficult to Unsure what Should be Enough time Difficult to find opportunities more time to in med publish supervisor are available do research school for research

during the compulsory research modules, into material worthy of presentation at a scientific meeting or publication in a peer reviewed journal (4% v. 3%, respectively). To put this into perspective, Siemans et al.[5] showed that 70% of 4thyear participants had presented at either national or international forums. Cursiefen and Altunbas[16] further showed that 28% of the total research output in a particular medical school had medical student involvement, which included 7.8% of the articles having medical students as 1st authors. In the Siemans et al.[5] study, of those students interested in applying for a competitive specialty programme, 43% of 2ndyear participants and 47% of 4thyear participants had prior research experience. In the current study, most of the participants (94%) were interested in specialising and the majority (73%) believed that entry into their specialty programme was competitive. As research undertaken adds weight to the curriculum vitae and is indeed, in some parts of the world, essential for entry into a specialist programme, it would seem logical that students viewing entry into their specialty of choice to be competitive would feel more positively about research. The results of the current study, however, did not show this. Previous exposure has been identified as a factor affecting student attitudes to research.[46,11,12] Only 11% of preclinical and 12% of clinical students had been involved in voluntary, extracurricular research. A comparison between the students who had been involved in voluntary research and the remaining 77% of students who had not, showed that the aforementioned group had a more positive attitude to research (p<0.05). A reason for this could be that students who pursued voluntary research were able choose a topic of specific interest and to set the pace of their work, as opposed to the compulsory modules where the research topic, supervisor, a group of students to work with and a deadline for completion of the project is prescribed. Those students (5% of participants) who had ever presented at a conference had a more positive attitude to research, having enjoyed the opportunity to present their work and enter into discussion with colleagues with similar interests. Those (3%) who had published a paper did not have a more positive attitude to research (again this included both extracurricular and compulsory projects). The reasons for this are not clear. Significantly more students who had been involved in voluntary, extracurricular

Not involved

Difficult to get funding

RESEARCH

Not involved

Involved

Involved 6%

Involved

13%

37%

22%

38%

37%

30%

19%

32%

38%

24%

Involved

41% 40%

30%

36%

48%

42%

40% 23%

57%

Not involved

13% 15% 7%

18%

Not involved

19%

62%

20%

64% 79%

15%

66% 54%

28%

Involved

36%

24%

13%

Involved

20%

25%

40%

Involved

Not involved

52%

31%

16%

Involved

42%

38%

Involved

Not involved

81% 50%

10%

Involved

Disagree Neutral Agree

73%

22%

27% 52%

46% 38%

20% 49% 54%

Fig. 5. Other factors potentially aﬀecting respondents’ attitudes to research (previously involved in voluntary, extra-curricular research v. not)

research had presented at a conference and published (p<0.001). The reasons for this could be similar to why these students had a more positive attitude to research (as discussed above). It is the authors’ opinion that medical school is the ideal place for students to acquire the necessary skills to conduct proper research, as they are in a teaching environment with exposure to academic role models. It is therefore of concern that only 45% of the ‘more senior’ clinical students felt that there is adequate training in research methodology. Most clinical students also felt that it is difficult as a student to present their work at a scientific meeting or publish in a peerreviewed journal. Fewer students who had been involved in voluntary research felt that it was difficult to present at a conference

January 2014, Vol. 104, No. 1

or publish (Fig. 5). A reason for this could be that significantly more students who had been involved in voluntary research had actually presented or published and were thus familiar with what the process demands, i.e. those who had gone through the process thought it was less difficult than those who had not. However, even in this group, only 30% of students thought it wasn’t difficult to present, and 19% thought that it wasn’t difficult to publish. It is not implausible to suggest that students might be less likely to want to get involved in research during medical school, or indeed after graduating, if they do not feel that they have the required knowledge and skills to design and run a project, as well as present or publish it. Demonstrating the barriers mentioned by Scaria,[4] 51% of clinical and 55% of

RESEARCH

preclinical students did not believe that there was enough time to allow for research, with 58% of clinical and 66% of preclinical students stating that there should be more time allocated in the curriculum to research (Fig. 4). One remarkable difference is that even though both groups thought that there should be more time for research, more students who had been involved in voluntary research felt that was enough time in the curriculum to allow for research (Fig. 5). In this group, 40% thought there was not enough time for research and only 36% thought that there was. At the time of the current study, the only possible time in the UCT curriculum that students had to pursue their own research interests was an elective block during their 5th year, which was only 4 weeks in duration. Personal research interests can only be pursued after hours on top of an already heavy academic load.

endeavour to work together to create medical school environments that encourage, acknowledge and foster passion for clinical research, as this is the only way to begin to reverse this universal and worrying trend. The authors offer the following recommendations to improve student attitudes to research: encourage students to get involved in voluntary, extracurricular research; improve training in research methodology, which should include training on how to present at a scientific meeting, as well as on writing up and submitting a paper for publication; ensure that there is enough time in the curriculum allocated to pursue voluntary research interest; and enable greater access to research opportunities through finding/generating suitable projects, making students aware of these and helping them engage in the research process.

Study limitations

Acknowledgement. The authors acknowledge Professor Bongani Mayosi, and the Groote Schuur Hospital Department of Medicine for financially supporting this project.

A large proportion of students responded ‘neutral’ to a number of statements designed to evaluate ‘other’ factors potentially affecting attitudes to research (Figs 4 and 5). It is likely that a large proportion of these students were ‘unsure’, especially the preclinical students who just hadn’t had enough exposure to research to have an opinion on those statements. Unfortunately, the questionnaire was not designed with this option, resulting in a very high proportion of ‘neutral’ responses. This made statistical analysis of the relationships between various factors impossible to interpret in a meaningful manner and the data from this section are therefore reported and discussed based on proportions alone.

Conclusion

In recent years there has been a marked decline in the number of physician-scientists who are ultimately responsible for bringing scientific discovery to clinical practice. This decline is largely precipitated by a lack of interest in research among medical students. Students at UCT perceive research to be important, have a positive attitude towards it and want to get involved in research activities. However, not many have actually been involved in voluntary research and very few have produced work worthy of presentation or publication. Perceived barriers that were identified in this study include a perceived lack of training, time and opportunities. Addressing such factors and improving student attitudes might begin to reverse the local trend in declining numbers of physicianscientists. It is clear from the literature, however, that this is a global problem. Deans, academic staff, faculties and students in all centres must

References 1. Mayosi BM, Dhai A, Folb P, et al. Consensus Report on: Revitalising Clinical Research in South Africa: A Study on Clinical Research and Related Training. Pretoria: Academy of Science of South Africa. http://www. assaf.co.za/wp-content/uploads/2009/09/ASSAf-Clinical-Report-2009.pdf (accessed 25 October 2013). 2. Roberts SF, Fischhoff MA, SakowskiSA, et al. Perspective: Transforming science into medicine: How clinician-scientists can build bridges across research’s ‘valley of death’. Acad Med 2012;87(3):266-270. [http://dx.doi.org/10.1097/ACM.0b013e3182446fa3] 3. Lemoine NR. The clinician-scientist: A rare breed under threat in a hostile environment. Dis Model Mech 2008;1(1):12-14. [http://dx.doi.org/10.1242/dmm.000752] 4. Scaria V. Whisking research into medical curriculum. Calicut Medical Journal 2004;2(1):e1. 5. Siemans DR, Punnen S, Wong J, et al. A survey on the attitudes towards research in medical school. BMC Med Educ 2010;10(4):1-7. [http://dx.doi.org/10.1186/1472-6920-10-4] 6. Khan H, Khawaja M, Waheed A, et al. Knowledge and attitudes about health research amongst a group of Pakistani medical students. BMC Med Educ 2006;6:54. [http://dx.doi.org/10.1186/1472-6920-6-54] 7. Neilson EG. The role of medical school admissions committees in the decline of physician-scientists. J Clin Invest 2003;111(6):765-767. [http://dx.doi.org/10.1172%2FJCI18116] 8. Lloyd T, Phillips BR, Aber RC. Factors that influence doctors’ participation in clinical research. Med Educ 2004;38(8):848-851. [http://dx.doi.org/10.1111%2Fj.1365-2929.2004.01895.x] 9. Shankar PR, Chandrasekhar, TS, Misha, P. Initiating and strengthening medical student research: Time to take up the gauntlet. Kathmandu Univ Med J 2006;4(1):135-138. 10. Bateman C. SA’s clinical research output in crisis. S Afr Med J 2011;101(9):614-616. 11. Solomon S, Tom S, Pichert J. Impact of medical student research in the development of physician-scientists. J Investig Med 2002;51(3):149-156. 12. Pruskil S, Burgwinkel P, George W, et al. Medical students’ attitudes towards science and involvement in research activities: A comparative study with students from a reformed and a traditional curriculum. Med Teach 2009;31(6):e254-e259. [http://dx.doi.org/10.1080/01421590802637925] 13. Houlden RL, Raja JB, Collier CP, et al. Medical students’ perceptions of an undergraduate research elective. Med Teach 2004;26(7):659-661. [http://dx.doi.org/10.1080/01421590400019542] 14. Zier K, Friedman E, Smith L. Supportive programs increase medical students’ research interest and productivity. J Investig Med 2006;54(4):201-207. [http://dx.doi.org/10.2310/6650.2006.05013] 15. Silcox LC. Residents’ and program directors’ attitudes toward research during anesthesiology training: A Canadian perspective. Anesth Analg 2006;102(3):859-864. [http://dx.doi.org/10.1213/01. ane.0000194874.28870.fd] TM 16. Cursiefen C, Altunbas A. Contribution of medical student research to the Medline ‐indexed publications of a German medical faculty. Med Educ 1998;32(4):439-440. [http://dx.doi.org/10.1046/j.13652923.1998.00255.x]

Accepted 4 October 2013.

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Diabetes mellitus in HIV-infected patients receiving antiretroviral therapy D Moyo,1 BPharm (Hons), PGDPH; G Tanthuma,1 BSc, PGDE, MA; O Mushisha,1 BPharm (Hons); G Kwadiba,1 PharmD; F Chikuse,1 HBMLS; M S Cary,2,3 PhD; A P Steenhoff,3-7 MB BCh, DCH (UK), FCPaed (SA), FAAP; M J A Reid,3,4,7 MD, MA, MRCP (UK) Institute for Health Sciences, Gaborone, Botswana Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, USA 3 Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA 4 Botswana/UPenn Partnership, Gaborone, Botswana 5 Center for AIDS Research, University of Pennsylvania, Philadelphia, USA 6 Department of Pediatrics, Division of Infectious Diseases, The Children’s Hospital of Philadelphia, USA 7 School of Medicine, University of Botswana, Gaborone, Botswana 1 2

Corresponding author: M J A Reid (michael.j.a.reid@gmail.com)

Background. There is little in the literature on HIV and diabetes mellitus (DM) in sub-Saharan Africa. Objective. To assess the characteristics of HIV and DM in patients receiving antiretroviral therapy (ART) in Botswana. Methods. A retrospective case-control study was conducted at 4 sites. Each HIV-infected patient with DM (n=48) was matched with 2 HIVinfected controls (n=108) by age (±2 years) and sex. Primary analysis was conditional logistic regression to estimate univariate odds and 95% confidence intervals (CIs) for each characteristic. Results. There was no significant association between co-morbid diseases, tuberculosis, hypertension or cancer and risk of diabetes. DM patients were more likely to have higher pre-ART weight (odds ratio (OR) 1.09; 95% CI 1.04 - 1.14). HIV-infected adults >70 kg were significantly more likely to have DM (OR 12.30; 95% CI 1.40 - 107.98). Participants receiving efavirenz (OR 4.58; 95% CI 1.44 - 14.57) or protease inhibitor therapy (OR 20.7; 95% CI 1.79 - 240.02) were more likely to have DM. Neither mean pre-ART CD4 cell count (OR 1.0; 95% CI 0.99 - 1.01) nor pre-ART viral load >100 000 copies/ml (OR 0.71; 95% CI 0.21 - 2.43) were associated with a significant risk of diabetes. Conclusions. These findings suggest a complex interrelation among traditional host factors and treatment-related metabolic changes in the pathogenesis of DM inpatients receiving ART. Notably, pre-ART weight, particularly if >70 kg, is associated with the diagnosis of diabetes in HIV-infected patients in Botswana. S Afr Med J 2014;104(1):37-39. DOI:10.7196/SAMJ.6792

The unequivocal success of antiretroviral therapy (ART) in controlling HIV replication and restoring immunity has been tempered by the recognition that metabolic diseases, such as diabetes mellitus (DM), are increasing in incidence among people living with HIV. Studies from high-income countries have reported that the incidence of diabetes in HIV-infected adults receiving ART is between 1% and 10%.[1] Conventional risk factors, such as obesity, ageing and male sex, are important determinants of diabetes.[2,3] However, specific antiretrovirals (ARVs)[3] and ARV-related weight gain and lipodystrophy[4,5] are recognised risk factors. High pre-ART viral loads and low baseline CD4+ counts may also increase the risk of insulin resistance and accelerate the pathogenesis of diabetes.[5] The association between HIV infection and DM in sub-Saharan Africa (SSA) has not been well documented.[6,7] While diabetes incidence is increasing in the general population in southern Africa,[8,9] there is very little describing the incidence and determinants of diabetes among HIV-infected adults in this region.

Objective

To assess the characteristics associated with HIV and DM at the time of ART initiation in patients in Botswana.

Methods

A retrospective case-control study was conducted at 4 sites between February 2011 and November 2012. DM was defined according to the World Health Organization criteria.[10] Cases were identified by searching the medical records of patients who had accessed care at diabetes clinics at 2 semi-urban facilities (in Orapa and Kanye) and 2 urban facilities (in Gaborone and Francistown). Patients who developed diabetes receiving ART or who had pre-existing DM before initiating ART were included if they had either 5 consecutive CD4+ count measurements post-ART initiation or had been taking ART for at least 2 years. Those with confirmed insulin-dependent type 1 diabetes were excluded. At each site, controls were selected by a systematic process – every 20th file in the adult HIV clinic registry was retrieved. Two controls per case were matched preferentially for age (±2 years) and sex. The medical records of all cases and controls were reviewed to extract demographic and clinical data including weight, ART regimen, ART adherence, co-morbid disease and baseline preART CD4+ counts and viral loads. Primary analysis using conditional logistic regression was employed to estimate univariate odds ratios (ORs) for each characteristic. Conditioning was based on 6 age-sex categories (gender within 3 age

January 2014, Vol. 104, No. 1

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groups: <40, 40 - 49, and ≥50 years). Statistical analyses were performed using STATA software version 12. All tests of significance were 2-sided with p≤0.05 designated as statistically significant. This study was approved by the Institutional Review Boards of Princess Marina and Nyangabgwe Referral Hospitals and the Botswana Ministry of Health.

Results

In total, there were 48 cases (28 females, 20 males, age mean 46.4 years ± standard deviation (SD) 9.9) and 108 controls (57 females, 51 males, age mean ±SD 43.6±8 years) who had initiated ART between January 2001 and February 2011. Data were available on prescribed anti-diabetic medications in the majority of cases (n=28): 21% (n=6) were receiving metformin, 60% (n=17) receiving metformin and glibenclamide and 18% (n=5) receiving an insulin-based regimen. Cases were matched with 108 HIV-infected control patients without DM. Table 1 summarises the baseline characteristics of both cohorts. There was no significant association between the risk of having DM and either hypertension, active tuberculosis, cancer or reported adherence of <95%. However, undocumented adherence to ART was associated with an increased diabetes risk. Weight at initiation of ART was significantly associated with increased risk of diabetes. Furthermore, the odds of DM with a pre-ART body weight of >70 kg was over 12 times that for a body weight of <50 kg. Univariate analysis demonstrated that both efavirenz (EFV) and protease inhibitor (PI) therapies were associated with increased odds of diabetes. While multivariate analysis suggested that weight was confounding the effect of the drug regimen, the sample size was too small to draw firm conclusions. Mean CD4+ count at the time of ART initiation was not significantly higher in individuals with DM than controls. However, there was a non-significant trend towards increased risk of diabetes at a higher CD4+ count – patients with pre-ART CD4+ counts of >180 cells/μl were twice as likely to have DM compared with those with pre-ART CD4+ counts of <60 cells/μl. Baseline viral load >100 000 copies/ml was not associated with an increased risk of diabetes.

Discussion

In this case-control study, there were several notable findings. Firstly, diabetic patients with HIV had higher baseline weight compared with non-diabetics. Individuals with pre-ART weights of >70 kg had significantly higher risk of having diabetes,

Table 1. Characteristics of subjects prior to initiation of ART Diabetes cases* (N=48)

Non-diabetes controls (N=108)

OR (95% CI)†

1st NVP

4 (8.3)

34 (31.5)

1st EFV

41 (85.4)

73 (67.6)

4.58 (1.44 - 14.57)

2nd PI

3 (6.2)

1 (0.9)

20.7 (1.79 - 240.02)

>95% (excellent)

26 (54.2)

75 (69.4)

<95%

2 (4.2)

11 (10.2)

0.45 (0.09 - 2.21)

Unknown

20 (41.7)

22 (20.4)

2.28 (1.07 - 4.85)

Total, mean±SD (n)

70.6±13.3 (28)

59.4±10.5 (69)

1.09 (1.04 - 1.14)

<50

1 (2.1)

13 (12)

50 - 59.9

4 (8.3)

22 (20.4)

2.23 (0.22 - 22.44)

60 - 69.9

9 (18.8)

20 (18.5)

5.18 (0.58 - 46.05)

>70

14 (29.2)

14 (13)

12.30 (1.4 - 107.98)

Undetermined

20 (41.7)

39 (36.1)

5.89 (0.71 - 48.68)

Total, mean±SD

148.3±128.3

120.6±72.8

1.003 (0.99 - 1.01)

<60

8 (16.7)

28 (25.9)

60 - 119

11 (22.9)

27 (25.0)

1.45 (0.48 - 4.36)

120 - 179

16 (33.3)

32 (29.6)

1.53 (0.56 - 4.12)

>180

13 (27.1)

21 (19.4)

2 (0.68 - 5.91)

Median

74 750 (18)

108 122 (24)

IQR

11 800 - 43 700

14 000 - 500 000

<100 000

10 (20.8)

12 (11.1)

>100 000

8 (16.7)

12 (11.1)

0.71 (0.21 - 2.43)

Unknown

30 (62.5)

84 (77.8)

0.39 (0.15 - 1)

10.9±2.4 (18)

11±2.6 (24)

0.96 (0.75 - 1.22)

46 (95.8)

99 (91.7)

Yes

2 (4.2)

9 (8.3)

0.54 (0.11 - 2.64)

44 (91.7)

102 (94.4)

Yes

4 (8.3)

6 (5.6)

1.45 (0.38 - 5.49)

39 (81.3)

91 (84.3)

Yes

9 (18.8)

17 (15.7)

1.22 (0.50 - 2.98)

Characteristic ART, n (%) ‡

Adherence, n (%)

Body weight (kg), n (%)

CD4+ count (cells/μl), n (%)

Viral load (copies/ml), n (%)

Log viral load, mean±SD (n) Tuberculosis, n (%)

Cancer, n (%)

Hypertension, n (%)

ART = antiretroviral therapy; OR = odds ratio; CI = confidence intervals;ARV = antiretroviral; NVP = nevirapine; EFV = efavirenz; PI = protease inhibitor; SD = standard deviation; IQR = interquartile range. *Type 2 or unspecified diabetes. † Conditional logistic regression. ‡ Refers to first-line regimen in Botswana – either non-nucleoside reverse transcriptase inhibitor-based regimen (NVP or EFV) or second-line PI-based regimen (lopinavir/ritonavir).

compared with those with baseline weights of <50 kg. This finding is consistent with established data that insulin resistance correlates with increased weight gain and obesity.[5] However, it is an important finding

January 2014, Vol. 104, No. 1

in this population since initiation of ART is itself associated with rapid weight gain. [2] Furthermore, the importance of targeted risk reduction strategies for overweight and obese individuals starting ART is highlighted.

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Secondly, there were associations between both EFV and PI exposures and DM. While there is substantial literature indicating that ART plays a causative or permissive role in the pathogenesis of DM in HIV-infected patients, most research has demonstrated a link between DM and thymidine analogues[3] and PI therapy.[3,11] Our finding that EFV was associated with diabetes is especially notable given that EFV is part of first-line ART regimens across SSA because of its perceived lower toxicity compared with nevirapine. Researchers in Cape Town, South Africa found that EFV was significantly associated with impaired glucose tolerance even after controlling for body mass index and waist circumference.[7] Participants in that study had all been receiving EFV for at least 6 months at the time of enrolment, suggesting that EFV may accelerate insulin resistance. We speculate that the effect of EFV in our analysis was mediated by weight – those with a priori obesity receiving EFV were more likely to have DM. Unfortunately, our sample size was not large enough to prove conclusively that this was the case. More prospective research is warranted to elucidate how EFV influences diabetogenesis, especially in individuals with pre-ART weights >70 kg. Thirdly, our analysis failed to demonstrate an association between HIV-specific factors and DM. Neither baseline CD4+ count, nor preART viral load was associated with risk of diabetes. These findings are consistent with data from prospective analyses that have failed to demonstrate associations between CD4+ nadir or baseline viraemia and diabetes.[2,3] Nevertheless, more research is required to explore the relationship between immune reconstitution and insulin resistance. Our analysis did not demonstrate any association between specific co-morbidities, tuberculosis, hypertension and malignancy, and diabetes. Data concerning co-morbidities such as dyslipidaemia, cardiovascular disease or hepatitis C co-infection that may have provided insights into the pathogenesis of DM in our setting were not collected. No relationship between diabetes and ART adherence emerged. While there is clear evidence that psychosocial factors are important in the pathogenesis of DM in HIV-uninfected adults in southern Africa,[9] more rigorous investigation is necessary to determine the role of psychosocial determinants in both ART adherence and diabetogenesis in HIV-infected adults. The study has several limitations. Because of the cross-sectional study design we were able only to evaluate associations between the examined variables and diabetes. Given the retrospective nature of this study, we were also unable to determine whether patients had developed diabetes before or after the initiation of ART. Consequently, we could not assess whether HIV infection or ARV drug exposure played a causal role in the pathogenesis. Furthermore, despite excluding all confirmed type 1 diabetics, we could not exclude those in whom diabetes may have developed secondary to the use of drugs such as pentamidine or corticosteroids. There were several traditional risk factors for the development of DM, such as family history, waist circumference, ethnicity, sedentary lifestyle, which were not included in our analysis. It would be valuable to

assess the impact of these determinants in our setting, particularly given the increasing number of older, overweight persons living with HIV in southern Africa.[6] We were also unable to assess the potential impact of nucleoside reverse transcriptase inhibitors such as zidovudine and stavudine, both of which have been associated with an increased risk of diabetes.[2,11] Increased visceral fat and lipodystrophy, caused indirectly and directly by ARVs, may also contribute to disordered glucose homeostasis. The impact of lipodystrophy on the development of DM was not evaluated, given the retrospective nature of the study.

Conclusions

This case-control study suggests a complex interrelation among traditional host factors and treatment-related metabolic changes in the pathogenesis of DM. Patients with higher pre-ART weight and those exposed to EFV or a PI were more likely to have DM. Larger prospective studies are needed to delineate the relative contribution of other factors among people living with diabetes in southern Africa. Acknowledgements. The Ministry of Health for granting us access to clinical data in our continued collaboration towards improving our understanding of the HIV epidemic in Botswana. This publication was made possible through assistance from the Institute of Health Sciences in Gaborone and core services and support provided by the Penn Center for AIDS Research (CFAR), a NIH-funded programme (P30 AI 045008). References 1. Yoon C, Gulick RM, Hoover DR, Vaamonde CM, Glesby MJ. Case-control study of diabetes mellitus in HIV-infected patients. J Acquir Immune Defic Syndr 2004;37(4):1464-1469. [http://dx.doi. org/10.1097/01.qai.0000137373.26438.18] 2. Capeau J, Bouteloup V, Katlama C, et al; the ANRS CO8 APROCO-COPILOTE Cohort Study Group. Ten-year diabetes incidence in 1046 HIV-infected patients started on a combination antiretroviral treatment. AIDS 2012;26(3):303-314. [http://dx.doi.org/10.1097/QAD.0b013e32834e8776] 3. De Wit S, Sabin CA, Weber R, et al. Incidence and risk factors for new-onset diabetes in HIV-infected patients: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. Diabetes Care 2008;31(6):1224-1229. [http://dx.doi.org/10.2337/dc07-2013] 4. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 2001;32(1):130-139. [http://dx.doi.org/10.1086/317541] 5. Samaras K. The burden of diabetes and hyperlipidemia in treated HIV infection and approaches for cardiometabolic care. Curr HIV/AIDS Rep 2012;9(3):206-217. [http://dx.doi.org/10.1007/ s11904-012-0124-x] 6. Reid MJA, Mosepele M, Tsima BM, Gross R. Addressing the challenge of the emerging NCD epidemic: Lessons learned from Botswana’s response to the HIV epidemic [unresolved issues]. Public Health Action 2012;2(3):47-49. [http://dx.doi.org/10.5588/pha.12.0014] 7. Dave JA, Lambert EV, Badri M, West S, Maartens G, Levitt NS. Effect of nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy on dysglycemia and insulin sensitivity in South African HIV-infected patients. J Acquir Immune Defic Syndr 2011;57(4):284-289. [http://dx.doi. org/10.1097/QAI.0b013e318221863f] 8. Levitt NS, Steyn K, Dave J, Bradshaw D. Chronic noncommunicable diseases and HIV-AIDS on a collision course: Relevance for health care delivery, particularly in low-resource settings – insights from South Africa. Am J Clin Nutr 2011;94(6):1690S-1696S. [http://dx.doi.org/10.3945/ajcn.111.019075] 9. Peer N, Steyn K, Lombard C, Lambert EV, Vythilingum B, Levitt NS. Rising diabetes prevalence among urban-dwelling black South Africans. PLoS One 2012;7(9):e43336. [http://dx.doi.org/10.1371/journal. pone.0043336] 10. World Health Organization. Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia: Report of a WHO/IDF Consultation. Geneva: WHO, 2006. http://www.who.int/diabetes/ publications/Definition%20and%20diagnosis%20of%20diabetes_new.pdf (accessed 23 July 2013). 11. Brown TT, Li X, Cole SR, et al. Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study. AIDS 2005;19(13):1375-1383. [http://dx.doi.org/10.1097/01.aids.0000181011.62385.91]

Accepted 4 July 2013.

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Parents’ perceptions of HIV counselling and testing in schools: Ethical, legal and social implications R Gwandure, Dip Educ, Adv Cert Educ, BEd Hons (Inclusive Education), MSc Med (Bioethics & Health Law); E Ross, BA (Social Work), MA (Social Work), PhD; A Dhai, MB ChB, FCOG, LLM, PG Dip Int Research Ethics; J Gardner, BA (Law & Industrial Sociology), LLB, MSc Med (Bioethics & Health Law) Steve Biko Centre for Bioethics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: E Ross (eleanor.ross@wits.ac.za)

In view of the high prevalence of HIV and AIDS in South Africa, particularly among adolescents, the Departments of Health and Education have proposed a school-based HIV counselling and testing (HCT) campaign to reduce HIV infections and sexual risk behaviour. Through the use of semi-structured interviews, our qualitative study explored perceptions of parents regarding the ethico-legal and social implications of the proposed campaign. Despite some concerns, parents were generally in favour of the HCT campaign. However, they were not aware of their parental limitations in terms of the Children’s Act. Their views suggest that the HCT campaign has the potential to make a positive contribution to the fight against HIV and AIDS, but needs to be well planned. To ensure the campaign’s success, there is a need to enhance awareness of the programme. All stakeholders, including parents, need to engage in the programme as equal partners. S Afr Med J 2014;104(1):40-42. DOI:10.7196/SAMJ.6645

South Africa (SA) has 5.6 million people estimated to be living with HIV and AIDS.[1] With a prevalence rate of 10.9%, the country is experiencing particular challenges relating to high HIV infection rates among youth aged 15 - 24 years.[2-4] Sexual debuts are reported to occur before the age of 12 years in both girls and boys.[4] The SA Department of Health has planned an extensive HIV counselling and testing (HCT) campaign, which forms part of the ‘basket of services’ offered by the new Integrated School Health Programme.[5] Every learner in secondary school who is over 12 years of age will be offered the option of taking an HIV test. This meets the legal requirement for consent for HCT according to the Children’s Act,[6] which acknowledges that consent for an HIV test on a child may be given by the child, if the child is 12 years of age or older; or, if under the age of 12 years, is of sufficient maturity to understand the benefits, risks and social implications of such a test. However, parents may not be aware of their parental limitations in terms of children’s health rights. Since HCT is going to be performed in schools, children need reassurance that their information will be kept confidential by the implementers of the campaign. This is important, in that lack of trust on the part of children could result in low participation rates. Although the HCT campaign is well intentioned, if implemented by people without proper training and qualifications in managing the emotional well-being of adolescents, the programme could have a damaging effect on parents’ and children’s psychosocial well-being.[7] The main aim of this study was therefore to ascertain how a group of parents of children in high school perceive rollout of the HCT campaign in high schools in terms of ethical, legal and social issues.

Methods

The study adopted an exploratory-descriptive research strategy located within an interpretive qualitative paradigm and was conducted using semi-structured interviews. Objectives were to explore parents’ views about the HCT campaign to be conducted in high schools, to determine whether parents would be in a position to engage with their children on the HCT campaign, to elicit information on parents’

awareness of the Children’s Act with regard to HIV testing, and to ascertain parents’ views about knowing their children’s HIV test results and how they thought they would react to the results. The study population comprised parents with children attending high schools. The sample was purposively selected and Katlehong, Gauteng Province, was chosen as the research site because the population of this area closely represents the majority of the SA population. Snowballing sampling was used until data saturation was reached, namely after interviews with 20 parents. It is acknowledged that the small, non-probability sample precluded generalisation or transferability of the findings to the broader population of parents of high-school children in SA. A pre-test using 5 parents was conducted to assess suitability of the interview schedule. Qualitative data from the interviews were analysed using thematic content analysis. Approval for the study was obtained from the Human Research Ethics Committee (Medical) of the University of the Witwatersrand, Johannesburg.

Results

Profile of participants

There were 20 participants: 13 mothers and 7 fathers, average age was 40 years (range 28 - 53 years), and their children’s ages ranged from 12 to 18 years. Participants belonged to one ethnic group (black), as they were all recruited from a township in Gauteng Province.

Parental views on HCT to be conducted in schools

While 19 parents were in favour of HCT, they also articulated concerns regarding the campaign (Fig. 1). Eleven supported the campaign because it would help children know their status and enable them to act responsibly. Examples of responses encapsulating this theme included: ‘… in order to know how to behave’, ‘… for her own benefit’, ‘… I know my child is safe …’. Six parents, although supportive of the campaign, were afraid to know their children’s HIV status because they anticipated that it would be stressful and would strain their relationships with their children. Five parents expressed concern that children’s performance at school would be negatively

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Theme

affected and that some children might refuse to return to school. Four, also in favour of the campaign, stated that they would need to be prepared for the test results by the counsellors responsible for implementing the campaign, and would want to be consulted by their children before consenting to the children’s participation. Nine parents worried that informing children of their HIV positivity would cause them to commit suicide because it would be difficult for them to cope with news of that nature, while 7 stated that there was a need for proper counselling in order to prevent suicide. Six parents were concerned that their children would be stigmatised at school. Four parents expressed concern about maintenance of confidentiality and privacy; 2 stressed that the correct procedures would have to be followed before implementing the programme, and 2 emphasised that they would support their children’s participation in HCT if the children were able to make their own choices without being coerced or unduly influenced. One parent was concerned about the outcome of HCT, namely that children found to be positive might demonstrate ‘… aggression towards parents and even teachers’ and that they might not change their sexual behaviour but would instead continue to endanger themselves and others. Two parents emphasised that supporting their children if they were found to be HIV-positive was an obligation and not a choice. Lastly, 1 parent argued that school was the wrong setting for HCT, because it is a place of learning and not a healthcare centre.

Engaging with children on the HCT campaign

Stressful/strained relations Aggression towards others/invincibility Voluntary testing Be prepared for the outcome Know their status Children act responsibly Wrong setting Correct procedure Need proper counselling 0

Responses (n)

Fig. 1. Parents’ views about HIV counselling and testing to be conducted in schools (N=20). Open to discussing results

Would be supportive

Inform family and community

Would keep results confidential

8 10

16 18

Responses (n)

Fig. 2. Parents’ views on engaging with children on HIV counselling and testing (N=20). No knowledge of the law Law will not work

Theme

Not in favour of the law

Theme

Parents’ views about knowing their children’s HIV results and their anticipated reactions

Need professional advice

Need parental consent

No parent was aware of the Children’s Act No. 38 of 2005 (Fig. 3).[6] When informed about the sections pertinent to HCT, 11 parents indicated that they disapproved of them. Thirteen were of the opinion that the law would not work because it afforded too much freedom to young children. Twelve parents felt that children needed parental consent to take an HIV test, because the results were potentially traumatising and might cause children to commit suicide. Eleven parents were not in favour of the law, believing that 12-year-olds were too young to be given freedom to engage in sexual activity. While 5 parents were supportive of the law (‘… it is a good law because now even children in primary school get a baby … It is totally acceptable, it is for the children’s own benefit …’), they believed that it would only work if parents were part of the legal process.

In favour of the law Do not need parental consent Law will work 0

Responses (n)

Fig. 3. Parents’ awareness of the Children’s Act with regard to age for and appropriateness of HIV testing (N=20).

Supportive parent-child relations

Parental desire to know

Will be angry/dissapointed

Seventeen parents expressed the wish to retain supportive parentchild relations, 7 anticipated that they would be disappointed and angry if their children tested HIV-positive but that they would find a way to offer moral support, and 2 felt that they would require counselling before they were made aware of the results (Fig. 4). An obvious limitation to these reactions is that they were based on the

Stigma Academic performance deteriorates

Seek child’s consent

All the parents were interested in discussing their children’s results and would maintain supportive parent-child relations irrespective of the outcome (Fig. 2). While 13 parents anticipated that they would not keep the results to themselves but would tell a friend, family member, church or support group in their community, 6 parents emphasised that they would keep the results confidential for fear of being judged. While 4 parents believed that it was the child’s choice whether or not to disclose his/her HIV status, others assumed that they (the parents) were responsible for decisions about disclosure of the HIV status of their children to family and friends. Two parents said that they would seek professional advice.

Awareness of the Children’s Act

Suicide Obligation

Need to be prepared before

Responses (n)

Fig. 4. Parents’ views with regard to knowing children’s HIV status and their reactions (N=20).

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hypothetical possibility of a positive result. It is also possible that some participants might have given socially desirable responses but would react differently when confronted with the real-life situation of a child being declared HIV-positive.

Discussion, conclusions and recommendations

Parents’ views on the proposed HCT campaign show that targeting high-school learners for HIV testing could potentially be very successful, with positive effects in the fight against HIV and AIDS in SA. Parents anticipated that the introduction of HCT in schools could encourage children of all ages who are sexually active to be tested, thereby reducing the prevalence of the disease. If the HCT campaign was implemented successfully, the stigma attached to HIV was likely to be reduced. However, parents also feared that HIV testing in high schools might have repercussions if the programme was not well planned and if parents did not play an integral role in it. They reported that they had received little or no information concerning the HCT campaign, and they felt that their role as parents, in terms of supporting a child who tested positive for HIV, was not considered or respected. They generally felt that they had an important role to play both during and after the campaign. These findings indicate that the parents who participated were not against the campaign, but would need preparation on how to deal with children infected and affected by HIV. The parents’ call for appropriate counselling appeared to stem from a desire to protect their children from social and psychological harms. It is therefore recommended that the Departments of Health and Education ensure that they are in a position to offer counselling to parents. In addition, pre-test counselling by qualified healthcare professionals should be provided in order to afford learners the opportunity to ask questions and make informed decisions.

The success of the HCT campaign is based on potential support from all stakeholders, including parents, educators and healthcare workers. However, we noted that parents were not aware of the Children’s Act No. 38 of 2005.[6] The implementers of the HCT programme therefore need to create awareness of this Act among parents and teachers, including information on children’s rights. There is also a need for qualified professionals to monitor the implementation of HCT and evaluate how effectively it adheres to ethical principles. It must not be forgotten that the HCT campaign has the potential to contribute towards stigmatisation, discrimination against and isolation of children and families living with HIV and AIDS. Parents and learners need to be prepared to cope with discrimination in the event that their children or siblings test positive for HIV. Attention to all these risk factors could ensure that the potential benefits of the HCT programme outweigh the risks. References 1. Joint United Nations Programme on HIV/AIDS. Update on the Global AIDS Epidemic. Geneva: UNAIDS, 2012. 2. Chapman R, White RG, Shafer LA, et al. Do behavioural differences help to explain variations in HIV prevalence in adolescents in sub-Saharan Africa? Tropical Medicine and International Health 2010;15(5):554-566. [http://dx.doi.org/10.1111/j.1365-3156.2010.02483.x] 3. South African National AIDS Council. The National HIV Counselling and Testing Campaign Strategy, 2010. http://www.sanac.org.za (accessed 21 June 2011). 4. Shisana O, Rehle O, Simbayi LC, et al., and SABSSM team III. South African National HIV Prevalence, Incidence, Behaviour and Communication Survey 2008: A Turning Tide among Teenagers? Cape Town: HSRC Press, 2009. 5. Govender P. HIV testing in schools on cards. Sunday Times 2012; 30 September, p. 7. 6. Children’s Act 38 of 2005. Government Gazette No. 28944, 19 June 2006. Pretoria: Government Printer, 2005. 7. Peltzer K, Tabane C, Matseke G, Simbayi L. Lay counsellor-based risk reduction intervention with HIV positive diagnosed patients at public HIV counselling and testing sites in Mupumalanga, South Africa. Evaluation and Programme Planning, 2010;33(4):379-385. [http://dx.doi.org/10.1016/j. evalprogplan.2010.03.002]

Accepted 28 February 2013.

Patient-initiated sexual partner notification in Botswana and time taken for sexual contacts to report for treatment T A Tafuma, MB ChB, MPH; B C Ntwayagae, RN, RM, BSc; C K Moalafhi, RN, RM, BCur Ed et Adm; J M Bolebantswe, RN, FNP Department of HIV/AIDS Prevention and Care, STI/HIV Control Programme, Ministry of Health, Gaborone, Botswana Corresponding author: T A Tafuma (tauadd@gmail.com) Background. Sexually transmitted infections (STIs) are an important public health concern because of their impact on reproductive and other health problems. Initiating treatment at an early stage for both index patients and their partners reduces the risk of reinfections and prevents serious short- or long-term complications for the infected individuals. Sexual partner tracing is one of the means available for reaching and treating asymptomatic sexual partners of index patients. Objectives. To determine the time taken by sexual partners to report to a health facility after they had been notified by the index patient, and the distribution of STI syndromes among the treated index patients who had their sexual partners treated. Methods. All available contact slips of the treated sexual partners from 19 health districts in Botswana were reviewed. The study period was July 2010 to June 2011 inclusive. Results. The partner notification slips showed that 77.9% (1 238/1 590) of sexual contacts sought medical attention at government health facilities within 7 days of treating the index patient. Records showed that 47.3% (752/1 590) of the index patients were treated for vaginal discharge syndrome. Conclusion. A high proportion of sexual contacts were treated within 7 days of treating the index patient. Considering this short period, we conclude that Botswana’s recommended 30-day period for consulting sexual partners needs to be revised downwards, so as to reduce the chances of reinfections, complications and transmission of STIs in the community. S Afr Med J 2014;104(1):42-44. DOI:10.7196/SAMJ.7026

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Sexually transmitted infections (STIs) are an important public health concern because of their negative impact on reproductive and other health problems.[1] Sexual partner tracing (SPT), also referred to as partner notification (PN), is the process by which the sexual contacts of a patient treated for a STI, referred to as the index patient (IP), are informed of their risk of an STI and seek medical examination, treatment, care and support at a health facility.[2-4] Prevention and control of STIs, primarily treatable ones such as gonorrhea and chlamydia, rely heavily on the timely identification, diagnosis and treatment of infected individuals. [1,5] In most developing countries these conditions are treated syndromically. SPT is a very important component of comprehensive STI management and control,[5-7] although the US Centers for Disease Control and Prevention’s (CDC) Sexually Transmitted Disease Treatment Guidelines note that it’s uncertain to what extent PN effectively decreases the prevalence and incidence of these infections. [3] However, SPT is the only means available for reaching and treating asymptomatic sexual partners of IPs.[6] It is important to note that sexual contacts have a high likelihood of similar STIs, and that therefore treating them empirically provides a significant opportunity to reduce the risk of reinfection and transmission in the community.[5] This becomes very relevent to developing countries, where the syndromic approach is still being used. Initiating treatment at an early stage for both contacts and IPs reduces the risk of reinfections and prevents serious short- or longterm complications for the infected individuals.[2,7] It is, however, difficult to select the infected individuals for whom the syndromic approach should be used. In developing countries, the patientoriented method is the most-used model, despite evidence suggesting that only around half of sexual contacts informed in this way receive treatment.[5,8] Among other challenges, the stigma and discrimination attached to STIs makes partner notification difficult.[9] As a result, most sexual contacts do not seek medical help despite being informed by IPs, and in some cases IPs will be afraid to notify their contacts.[7] Furthermore, there are difficulties in identifying and contacting nonregular contacts,[5] especially for commercial sex workers. There are 3 main approaches to PN for STIs: (i) the provideroriented notification method, which uses third parties who specialise in contact tracing (public health personnel); (ii) patient-oriented notification methods that rely on IPs to notify their partners, with or without the medication to actually treat the partner(s) for the putative infection or infectious exposure; and (iii) a contractual approach that enlists IPs to notify their partners, with an understanding that healthcare personnel will notify those partners who do not present for treatment within a given time.[2,7] Between the 3, the provideroriented method was found to be the most effective in reaching partners and getting them treated.[7] However, this is only practical in developed countries[7] due to its associated cost. In developing countries, the World Health Organization (WHO) recommends patient-oriented partner notification.[2,4,7] Botswana provides syndromic STI services in all health facilities and recommends the patient-oriented approach, without the IP delivering medications to the partner.[4] STIs are notifiable conditions in this country and approximately 70 000 and 80 000 new cases were treated in 2010 and 2011 respectively.[12] The patient-oriented approach is relatively cheap and easier to implement.[9] Even though developing countries rely on patient referral, the effectiveness of this approach has not been adequately investigated. [1,3] Furthermore, most studies have not documented the time taken by contacts to report to health facilities after the IP notifies them. Botswana considers contact notification to be successful when contacts

are notified within 30 days,[4] but on an anecdotal basis, the evidence to support this recommendation is not clear. The national contact notification rate has been in the range of 8% - 16%.[4] This study aims to establish the time taken by sexual partners to report to a health facility following notification by the IP, and to determine the distribution of STI syndromes among those IPs whose sexual contacts were seen at a government health facility.

Methods

This was a retrospective descriptive study that analysed the contact slips collected from 19 government health districts (each with approximately 15 health facilities) in Botswana between July 2010 and end of June 2011. These contact slips were collected when consulting sexual contacts who had been notified by the relevant IP. The pooled slips from each government health facility within a district were sent to the Community Health Nurse at the District Health Management Team offices. At the end of each month, the slips were taken to the STI Control Programme at the Ministry of Health head office (STI Control Programme). All contact slips received within the study period were considered for the study as long as they contained the dates of treatment of both the IP and the sexual contact, and a clear diagnosis of the IP. Those missing this information were excluded. The time that contacts took to report to a health facility was calculated as number of days from the date on which healthworkers consulted the IP to the date on which they consulted the contact. The authors formulated 3 categories for the time of presentation: i) within 7 days; ii) 8 to 14 days and iii) >14 days. The patients’ conditions were categorised according to the common syndromes treated in the country. The data were captured on an Excel spreadsheet and Epi-Info 6.3 version was used for descriptive statistical analyses. Ethics approval was obtained from the Health Research Development Division of the Ministry of Health (Botswana).

Results

During the study period, a total of 3 048 contact slips were received and recorded, of which 1 590 slips met all the inclusion criteria. Out of these, 77.9% (1 238) showed that sexual contacts sought medical attention within 7 days and 10.3% (164) after 2 weeks (Table 1). Vaginal discharge syndrome was recorded on 47.3% (752) of the contact slips and other STIs on 3.5% (55/1 590) (Fig. 1).

Discussion

This study shows that the majority of sexual contacts sought medical attention within a week of the IP receiving treatment. Healthcare workers in Botswana are trained in sexual partner management during STI syndromic management training. It has been observed that to discuss an STI diagnosis, individuals need to have confidence in themselves and in their relationship.[10] As such, the quality and appropriateness of the counselling that IPs receive increases the success of contact notification by eliminating the fear and stigma associated with STIs.[7] Such counselling should be encouraged in both private and public health facilities. Botswana also has a highly mobile population, which might have contributed to some contacts being consulted more than 7 days after seeing the IP. It is recommended that all sexual partners within the past 1 to 3 months be contacted and referred for STI treatment,[3] but SPT is less effective over this timeframe as they might have already spread their infections or developed complications. However, this should not deter healthcare workers from practising SPT. The most-treated condition in the study was vaginal discharge syndrome (VDS). Although this is not necessarily related to an

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Table 1. Time taken by sexual contacts to be consulted Period (days)

Frequency, n (%)

≤7

1 238 (77.9)

8 - 14

188 (11.8)

>14

164 (10.3)

Total

1 590 (100)

Pelvic inflamatory disease Urethral discharge syndrome 16.4%

17.9%

Other STIs 3.5%

15% Genital ulcer disease

STI, most women who present with the symptoms are labelled as having an STI. There is anecdotal evidence that clinicians perform risk assessment poorly in patients presenting with VDS. In addition, physical examination is often missed due to lack of appropriate equipment (e.g. examination lamps and speculums), leading clinicians to base their diagnosis on the patient’s symptoms. As a result, a significant number of women with other non-STI conditions end up being treated for STIs that they probably do not have. However, to reduce this massive overtreatment would require specific diagnostic tests.[11] Given the higher costs associated with laboratory investigations, developing countries such as Botswana will be forced to continue using the syndromic approach.

Study limitations

This study used data which had been used for routine reporting. As such, some of the slips might have been missing or incomplete at the time of analysis, leading to selection bias. Secondly, the files were not research specific, thus limiting the strength of the study. Significant confounding variables such as stable relationships and presence of symptoms among the contacts who presented to the facilities within a week were not considered because there was no provision for them in the data-collecting tool. Nevertheless, as the first of its kind in Botswana, this study has provided important information that can be used by clinicians and STI control programs.

47.3%

Vaginal discharge syndrome

Fig. 1. Distribution of STI syndromes.

Conclusion

Since the majority of contacts reported to health facilities within a short period (1 week), we conclude that the consultation period (30 days) of sexual contacts in Botswana needs to be shortened. This will reduce the chances of reinfections, complications and transmission of STIs in the community. The study recommends the revision of VDS algorithms. Those in current use contribute to the overdiagnosis of STIs, which might expose women, or their partners, to unnecessary risk of violence, psychological stress and overtreatment.

4. 5.

Acknowledgements. We acknowledge the support of Dr L Chonzi, who assisted with the review of this manuscript. Ms P T Mogolwane assisted with the data entry.

10.

11.

References 1. Wilson TE, Hogben M, Malka ES, et al. A randomized controlled trial for reducing risks for sexually transmitted infections through enhanced patient-based partner notification. Am J Public Health 2009;99(S1):104-110. [http://dx.doi.org/10.2105/ AJPH.2007.112128] 2. World Health Organisation. Global Strategy for the Prevention and Control of Sexually Transmitted Infections: 2006 – 2015. Geneva: WHO, 2007. http://whqlibdoc.who.int/hq/2006/ WHO_RHR_06.10_eng.pdf (accessed 3 September 2013). 3. Workowski K, Berman S. Sexually Transmitted Diseases Treatment Guidelines. Recommendations and Reports. Atlanta:

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12.

Centers for Disease Control and Prevention, 2010. http://www. cdc.gov/mmwr/preview/mmwrhtml/rr5912a1.htm (accessed 3 September 2013). Botswana Ministry of Health. Botswana National Sexual Partner Tracing Guide. Gabarone: MoH, 2012. Khan A, Fortenberry JD, Juliar BE, et al. The prevalence of chlamydia, gonorrhea, and trichomonas in sexual partnerships: Implications for partner notification and treatment. Sex Transm Dis 2005;32(4):260-264. [http://dx.doi.org/10.1097/01. olq.0000161089.53411.cb] Turner K, Adams E, Grant A, et al. Costs and cost effectiveness of different strategies for chlamydia screening and partner notification: An economic and mathematical modelling study. BMJ 2010;341:c7250. [http://dx.doi.org/10.1136/bmj.c7250] Alam N, Chamot E,Vermund SH, Streatfield K, Kristensen S. Partner notification for sexually transmitted infections in developing countries: A systematic review. BMC Public Health 2010;10:19. [http://dx.doi.org/10.1186/1471-2458-10-19] Shackleton T, Sutcliffe L, Estcourt C. Is Accelerated Partner Therapy partner notification for sexually transmissible infections acceptable and feasible in general practice? Sexual Health 2011;8(1):17-22. [http://dx.doi.org/10.1071/SH10031] Trelle S, Shang A, Nartey L, Cassell JA, Low N. Improved effectiveness of partner notification for patients with sexually transmitted infections: Systematic review. BMJ 2007;334(7589):354357. [http://dx.doi.org/10.1136/bmj.39079.460741.7C] Gursahaney PR, Jeong K, Dixon BW, Wiesenfeld HC. Partner notification of sexually transmitted diseases: Practices and preferences. Sexually Transm Dis 2011;38(9):821-827. [http:// dx.doi.org/10.1097/OLQ.0b013e31821c390b] Romoren M, Sundby J, Velauthapillai M, et al. Chlamydia and gonorrhoea in pregnant Batswana women: Time to discard the syndromic approach? BMC Infectious Diseases 2007;7:27. [http://dx.doi.org/10.1186/1471-2334-7-27] Botswana Ministry of Health. Integrated Disease Surveillance and Response Monthly Reports. Gabarone: MoH, 2012.

Accepted 14 May 2013.

RESEARCH

The use of the full blood count and differential parameters to assess immune activation levels in asymptomatic, untreated HIV infection N Vanker, MB ChB; H Ipp, MB ChB, FCPath (SA)(Haematology) Division of Haematology, Department of Pathology, National Health Laboratory Service and Stellenbosch University, Tygerberg Hospital, Cape Town, South Africa Corresponding author: N Vanker (dr.n.vanker@gmail.com)

Background. A feature of HIV/AIDS is chronic immune activation, which results in a number of complications including inflammationrelated disorders and blood cytopaenias. Immune activation status is not routinely tested in HIV infection. However, the full blood count (FBC) is a commonly performed test. Objective. We hypothesised that FBC parameters would be significantly different in HIV-infected v. -uninfected individuals, and that some of these parameters would correlate with markers of immune activation (i.e. percentage CD38 expression on CD8+ T cells (%CD38onCD8)) and disease progression (i.e. CD4+ counts) in HIV infection. Methods. This was a cross-sectional study with 83 HIV-infected adults who were antiretroviral therapy-naive and clinically well, and 51 HIV-uninfected adults. The %CD38onCD8 and CD4+ counts were determined by flow cytometry and the FBC was performed on a Siemens ADVIA 2120 system. FBC parameters investigated were total white cell count (WCC), haemoglobin (Hb) concentration, platelet count, absolute neutrophil count, absolute lymphocyte count, and percentage of large unstained cells (%LUCs). Results. Significant differences were found between the HIV-infected and -uninfected groups for total WCC, Hb, neutrophil count, lymphocyte count and %LUCs. The mean ± standard deviation (SD) for the total WCC (5.3±1.3 v. 6.9±2.2; p≤0.001) and the %LUCs (2.5±0.9 v. 2.0±0.9; p=0.001) both showed correlations with CD4+ counts and %CD38onCD8. Conclusion. The total WCC and %LUCs showed significant differences in HIV-infected individuals and correlated with markers of immune activation and disease progression. This suggests the potential use of these parameters as markers of immune activation in HIV infection. S Afr Med J 2014;104(1):45-48. DOI:10.7916/SAMJ.6983

HIV invades the human host and replicates preferentially in CD4+ T cells, leading to increasing viral numbers and a failing immune system. An important feature in the pathogenesis of AIDS is [1-4] chronic immune activation and inflammation. Sustained immune activation creates a suitable environment for viral replication, drives the loss of CD4+ T cells and also leads to inflammation-related disorders such as atherosclerosis, neurocognitive deterioration, musculoskeletal abnormalities and certain cancers.[1-3] Another complication related to immune activation in HIV is the development of peripheral blood cytopaenias. Cytopaenias are due, in part, to the stimulated immune system releasing proinflammatory cytokines, which suppress haemopoiesis in the bone marrow. Other contributing factors to low cell counts include the suppression of bone marrow progenitors by HIV-infected T cells, the myelosuppressive effect of certain drugs, infective and malignant bone marrow infiltration, and immune-mediated peripheral destruction of blood cells.[5-7] Antiretroviral therapy (ART) is the most effective treatment for patients with HIV/AIDS.[1,3,5] The current criteria for initiating ART are based on either the presence of an AIDS-defining illness, the quantification of CD4+ T cells (or total lymphocyte counts, in situations where CD4+ counts are not available) or a combination of clinical HIV disease staging and CD4+ (or lymphocyte) counts.[5] Once ART is initiated, patients are followed-up at regular intervals with clinical examinations, CD4+ counts and viral-load testing.[5]

Although the degree of immunodeficiency and viral burden are monitored routinely, immune activation status is not currently tested in HIV infection.[2,4,5] Many serum markers of inflammation or immune stimulation in HIV infection have been identified, including the well-established cellular marker of immune activation, CD8+ T cells that express the activation marker CD38.[1,2,4] CD38 expression on CD8+ cells (CD38onCD8) is an important prognostic marker of HIV disease progression, independent of immunodeficiency and viral burden.[1,4] However, determination of CD38onCD8 expression by flow cytometry is an expensive and technically difficult test to perform in resource-limited settings.[4,8] In 2002, a working group was established to develop an approach to clinical research priorities for ART use in resource-limited settings. Issues addressed included the timing of initiation of therapy, choice of ART agents, adherence to therapy and the monitoring of patients receiving treatment. With regard to the latter, the development of simpler, more cost-effective tests, which could assess viral burden and immune function, to replace viral loads and CD4+ counts was recommended.[9] For HIV-infected patients, either prior to or after initiation of ART, a full blood count (FBC) and differential count are regularly requested owing to the prevalence of cytopaenias, opportunistic infections and adverse drug events.[5] The cytopaenias include anaemia, leucopaenia, neutropaenia, lymphopaenia and thrombocytopaenia, which may exist as isolated features, or in various combinations. [6] Parameters routinely included in an FBC are the total white cell count (WCC), haemoglobin (Hb) concentration and a platelet count as well as a leucocyte differential count. The leucocyte differential count includes

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the neutrophil, lymphocyte, monocyte, eosinophil and basophil counts. On certain haematology analysers, (i.e. the Siemens ADVIA 2120) the percentage of large unstained cells (%LUCs) also forms part of the differential count. LUCs usually encompass virally activated lymphocytes, plasma cells, hairy cells, paediatric lymphocytes and peroxidase-negative blasts.[10] The FBC is an affordable test available in most intermediate (level 2) and central (level 3) laboratories.[5] Furthermore, it is recommended that if CD4+ counts are not available, total lymphocyte counts, performed as part of the differential count on routine haematology analysers[5,10] may be seen as a surrogate marker of immune function.

Objective

To determine whether certain FBC parameters are significantly different in HIV-infected patients v. uninfected individuals, and whether these parameters correlate with markers of HIV disease progression and immune activation in an untreated local population group. We hypothesised that the WCC, platelet count and Hb concentration would be lower in the HIV-infected cohort, and that the %LUCs would be raised. We further hypothesised that these FBC parameters would correlate with CD4+ counts, viral loads and %CD38onCD8. A secondary objective of the study was to determine whether testing of FBC parameters would be more affordable than %CD38onCD8 determination.

Methods

Study design

This was a cross-sectional study of 134 adults recruited from a single HIV counselling and testing (HCT) clinic in Crossroads, Cape Town, South Africa. The prevention clinic employs the national HCT algorithm with accredited rapid tests. Study participants were recruited between May 2010 and June 2012 and were enrolled in the study after confirmation of HIV status and before referral for further management. Exclusion criteria were: individuals <21 years of age, patients receiving ART, features of tuberculosis (TB) or individuals receiving anti-TB therapy or other medications, and symptoms of systemic illness (as assessed by a clinic nurse). Peripheral blood was drawn from all patients and used to measure the FBC and differential count, %CD38onCD8, the CD4+ count and the viral load (the latter tested in the HIV-infected study participants only). The study was approved by the Stellenbosch University Human Research Ethics Committee (ref no. N07/09/197) and the University of Cape Town Research Ethics Committee (ref no. 417/2006), and performed in accordance with the Declaration of Helsinki.

Whole blood analysis

Whole blood was analysed on a Siemens ADVIA 2120 system, which makes use of cytochemistry and flow cytometry systems. Hb was measured by modification of the cyanmethaemoglobin method together with a cell-based method. Platelets were analysed using two angles of light scatter, used to calculate the volume and refractive index. A combination of cell size, myeloperoxidase staining and nuclear lobulation was used to perform the total leucocyte and 6-part differential count. We assessed the following parameters: the total WCC, absolute neutrophil and absolute lymphocyte count, and %LUCs. LUCs are peroxidase-negative cells, which do not fit into the other categories of leucocytes, i.e. neutrophils, monocytes, eosinophils, lymphocytes and basophils. The %CD38onCD8 was determined by flow cytometry. Heparinised whole blood was processed on the same day as the sample was drawn. A total of 50 μl of whole blood was incubated with the following monoclonal antibodies: CD8-PerCP; CD38-APC; CD3-FITC (BD Biosciences) for 20

minutes at room temperature. The red blood cells were lysed in BD FACS Lyse and the remaining cells washed with staining buffer (2% fetal calf serum in phosphate-buffered saline) prior to acquisition and analysis on a BD FACSCalibur instrument using BD Cell Quest Pro (version 2) software. Lymphocytes were gated on forward v. side scatter and CD3 expression, and %CD38onCD8 within the lymphocyte gate was determined. Flow cytometry for CD4+ T cell counts was performed using whole blood. The BD MultiTEST CD3-FITC/CD8-PE/CD45-PerCP/CD4APC reagent together with TruCOUNT tubes (BD Biosciences) was used for determining CD4+ counts. HIV-1 RNA quantifications for viral load testing were performed using 1 ml of plasma with the Nuclisens Easy Q HIV-1 v.1.2 kit (BioMerieux Inc), an assay with a lower detection limit of 40 - 50 copies/ml.

Statistical analysis

The Mann-Whitney U test was used to determine differences between the means, standard deviations and 95% confidence intervals (CIs). The Spearman rank order method was used to identify correlations between the FBC parameters and the established markers, which were %CD38onCD8, CD4+ count and viral load.

Costing

Although a complete cost analysis was not carried out, we compared the pricing of these tests based on how much it would cost the consumer in our setting. In SA, state-funded laboratory testing is performed by the National Health Laboratory Service (NHLS); costs quoted below were taken from the Department of Health website.[8]

Results

The 83 HIV-infected individuals were naive to ART, not receiving anti-TB or other medication and clinically asymptomatic. Their median age was 32 years and there was a female to male ratio of 2.8:1. The 51 HIV-uninfected individuals were from the same population, with a median age of 31.8 years and a female to male ratio of 2:1. Statistically significant differences were found between the HIVinfected and -uninfected groups for %CD38onCD8, CD4+ counts, total WCCs, Hb concentrations, absolute neutrophil counts, absolute lymphocyte counts and %LUCs (Table 1). The 95% CIs for total WCC and %LUCs are shown in Figs 1 and 2, which demonstrate the significant differences, with no overlapping ranges. No statistical difference was observed between the HIV-infected and -uninfected groups for the platelet count (Table 1). There were significant positive correlations between %CD38onCD8 and both %LUCs and total WCC, and there was a significant inverse correlation between %CD38onCD8 and Hb concentration. There were also significant positive correlations between CD4+ counts and the absolute lymphocyte count, the absolute neutrophil count and the total WCC, and an inverse correlation between the CD4+ count and %LUCs (Table 2). Although the %CD38onCD8 is not a routinely performed test, it is possible to request a flow cytometry-based analysis, which would cost R629.40 (~64 USD), based on the number of antibodies used.[8] The FBC costs R50.25 (~5 USD) and the leucocyte differential costs R27.55 (~3 USD).[8] The total cost of a full blood and differential count is R77.80 (~8 USD).[8]

Discussion

Immune activation is an important prognostic factor in HIV infection. [1-4] Affordable markers of immune activation would be of value in the management algorithms of early HIV infection in resource-limited settings. In the current study, of the parameters assessed on the FBC, the total WCC and %LUCs demonstrated

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Table 1. Whole blood analysis of HIV-infected v. -uninfected patients HIV-infected

HIV-uninfected

Variable

Mean±SD

95% CI

Mean±SD

95% CI

p-value*

%CD38onCD8

57.8±19.7

53.5 - 62.1

40.3±16.4

35.7 - 44.9

<0.001†

CD4+ count (cells/μl)

405±177

366 - 444

952±332

859 - 1 045

<0.001†

Total WCC (× 10 cells/l)

5.3±1.3

5.1 - 5.5

6.9±2.2

6.4 - 7.4

<0.001†

Hb concentration (g/dl)

12.7±1.4

12.4 - 13

13.5±1.7

13.1 - 13.9

0.001†

Platelet count (× 10 cells/l)

292±77

278 - 306

301±80

284 - 318

0.429

ALC (× 109 cells/l)

1.7±0.5

1.6 - 1.8

2.1±0.8

1.9 - 2.3

0.010†

ANC (× 10 cells/l)

2.9±1.3

2.6 - 3.2

4.1±1.9

3.7 - 4.5

<0.001†

%LUCs

2.5±0.9

2.3 - 2.7

2±0.9

1.8 - 2.2

0.001†

7.5

2.7

7.0

2.5

6.5

2.3

LUCs (%)

Total WCC (x 109 cells/l)

SD = standard deviation; CI = confidence interval; CD38onCD8 = CD38 expression on CD8+ cells; WCC = white cell count; Hb = haemoglobin; ALC = absolute lymphocyte count; ANC = absolute neutrophil count; LUCs = large unstained cells. *Mann-Whitney U test. † Statistically significant, p<0.05.

6.0 5.5 5.0

2.1 1.9

HIV-infected

1.7

HIV-uninfected

HIV-infected

HIV-uninfected

Fig. 1. Total WCC in the HIV-infected and -uninfected groups (95% CIs).

Fig. 2. LUCs in the HIV-infected and -uninfected groups (95% CIs).

good potential for future use in this context. The total WCC was significantly lower in the HIV-infected group and the %LUCs were significantly higher than in the uninfected group, with both markers showing clearly defined 95% CIs (Figs 1 and 2). Furthermore, both parameters correlated with the CD4+ count (an indicator of HIV disease progression) and %CD38onCD8 (an established marker of immune activation in HIV infection). Leucopaenia in HIV infection is thought to be predominantly due to lymphopaenia and neutropaenia.[6,11] Studies have shown that lymphopaenia and depletion in lymphocyte subsets correlate with markers of immune activation in HIV infection.[11,12] However, total WCC has not been previously studied as a potential marker of generalised immune activation levels in untreated HIV-infection. In this study, we show for the first time that the lower the total WCC, the higher the levels of immune activation (%CD38onCD8). This is likely to be due to a combination of factors, including the proinflammatory environment in HIV infection, which primes activated cells for accelerated death,[1] and suppresses the regeneration of the immune system in the bone marrow, thymus and lymph nodes.[1,6] Very few studies have focused on the clinical implications of LUCs in humans, most assessing LUCs in the context of haematological malignancies and not immune activation.[13,14] A study from Europe reviewed FBC reports to identify and describe cases with raised LUCs. The study found that in the very small percentage (0.007%) of reports that identified high numbers of LUCs, the majority of cases (85%) had associated viral infections (i.e. Epstein-Barr virus and influenza A) while the remaining 15% were associated with chronic renal failure. The HIV status of the patients was not reported. It was suggested

that high numbers of LUCs, where chronic renal failure and acute leukaemia have been excluded as a cause, represent natural killer cells, cytotoxic lymphocytes or other reactive lymphoid cells. [15] This suggests that LUCs represent virally activated lymphocytes, consistent with our hypothesis that circulating LUCs would be present in higher numbers in individuals with chronic immune stimulation. Our study found significantly lower neutrophil and lymphocyte counts and Hb concentrations in the HIV-infected group. Lower blood cell counts/cytopaenias are a common effect of HIV infection and mechanisms include decreased bone marrow production and increased peripheral destruction of cells. Causes are multifactorial, contributing factors include immune activation and release of cytokines, effects of ART and opportunistic infections.[6] As all individuals in our study were ART-naive and did not show clinical features of opportunistic infections, their cytopaenias were most likely due to cytokine-induced myelosuppression, or enhanced destruction due to immune mechanisms. The significantly raised %CD38onCD8 found in these individuals adds support to the concept of ongoing immune activation as contributing to the cytopaenias. Some of our findings were comparable with those in a study conducted in an HIV-infected, predominantly adult population to assess the presence of cytopaenias in relation to CD4+ counts. This study found that lower CD4+ counts (<200 cells/μl) were associated with a higher prevalence of anaemia, neutropaenia and thrombocytopaenia.[7] Our study also found declining CD4+ counts associated with lower Hb concentrations and neutrophil counts but there were no significant findings in relation to platelet counts. Another comparative study, conducted among HIV-positive, ART-

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Table 2. Spearman Rho rank correlation for FBC parameters against the established markers Variable 1

Variable 2

Spearman Rho

p-value*

Total WCC (× 109 cells/l)

%CD38onCD8

-0.228

0.008†

CD4 count

0.484

<0.001†

Viral load

-0.073

0.465

%CD38onCD8

-0.206

0.017†

CD4 count

0.122

0.095

Hb concentration (g/dl)

Platelet count (× 109 cells/l)

ALC (× 109 cells/l)

ANC (× 10 cells/l) 9

%LUCs

Viral load

-0.096

0.336

%CD38onCD8

-0.120

0.168

CD4+ count

0.103

0.160

Viral load

-0.217

0.029†

%CD38onCD8

-0.158

0.089

CD4+ count

0.556

<0.001†

Viral load

-0.111

0.291

%CD38onCD8

-0.166

0.074

CD4+ count

0.353

<0.001†

Viral load

-0.088

0.402

%CD38onCD8

0.397

<0.001†

CD4+ count

-0.248

0.006†

Viral load

0.151

0.208

FBC = full blood count; WCC = white cell count; CD38onCD8 = CD38 expression on CD8+ cells; Hb = haemoglobin; ALC = absolute lymphocyte count; ANC = absolute neutrophil count; LUCs = large unstained cells. *Spearman Rho rank correlation † Statistically significant, p<0.05.

naive adolescents, found lower WCCs, neutrophil counts and CD4+ counts, as well as higher expression of %CD38onCD8.[11] There was a significant positive correlation between both the %LUCs and the total WCC, and %CD38onCD8, the established marker of immune activation. The total cost of a full blood and differential count is R77.80 (~8 USD), compared with the %CD38onCD8 price of R629.40 (~64 USD), the blood parameters costing approximately eight times less.[8] Using total WCC or %LUCs, either independently or together, could serve as relatively inexpensive markers of immune activation in HIV infection. The clinical consequences of chronic immune activation are inflammationrelated conditions, including cardiovascular, neurological, musculoskeletal and malignant diseases.[1-3] In addition, studies have shown that patients receiving ART and with suppressed viral loads remain at risk of inflammation-related morbidity, owing to parameters other than viral burden, which drive immune activation. Clinical trials are being carried out using adjusted ART regimens and anti-inflammatory agents, in an effort to boost CD4+ counts and decrease systemic immune activation.[2,3] The clinical utility of immune activation markers, such as total

WCC and %LUCs, would be to identify HIVinfected individuals who are at a greater risk of inflammation-related co-morbidities. These individuals would then benefit from further investigation for underlying inflammatory conditions and appropriate management. A possible limitation of our study was its cross-sectional nature, which provided a ‘snap-shot’ insight into immune activation levels. In addition, specific investigations for other underlying co-infections were not performed. Longitudinal studies will be of value to determine the predictive power of lower WCCs and raised LUC levels for disease progression, development of complications or response to various treatment interventions.

Conclusion

The total WCC was significantly decreased and %LUCs significantly increased in the HIV-infected study population, substan tiating the relevance of these markers in HIV infection. The correlations observed between both total WCC and %LUCs and the CD4+ count, support the potential use of total WCC and %LUCs as markers of HIV disease progression. Furthermore, there were significant correlations between both total WCC and %LUCs and the %CD38onCD8, suggesting that these FBC parameters may

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serve as useful markers of immune activation. The FBC and differential count are affordable, routinely performed tests, even in resourcelimited settings. Intervention studies will be important to determine whether these FBC parameters are surrogate markers of immune activation in HIV infection. Acknowledgements. This research was supported by the following organisations: the NHLS-K, the Poliomyelitis Research Foundation and the South African HIV/AIDS Research and Innovation Platform. We thank the patients and staff of the Emavundleni Clinic in Crossroads, Cape Town for their participation in this study. We also thank other members of the HIV Activation and Inflammation Group (HAIG) for their assistance with specimen processing and running of tests.

References 1. Appay V, Sauce D. Immune activation and inflammation in HIV1 infection: Causes and consequences. J Pathol 2008;214(2):231241. [http://dx.doi.org/10.1002/path.2276] 2. Nixon DE, Landay B. Biomarkers of immune dysfunction in HIV. Curr Opin HIV AIDS 2010;5(6):498-503. [http://dx.doi. org/10.1097/COH.0b013e32833ed6f4] 3. Deeks SG. Immune dysfunction, inflammation, and accelerated aging in patients on antiretroviral therapy. Top HIV Med 2009;17(4):118-123. 4. Liu Z, Cumberland WG, Hultin LE, et al. CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency. J Acquir Immune Defic Syndr Hum Retrovirol 1988;18(4):332-340. [http://dx.doi.org/10.1097/00042560-199808010-00004] 5. World Health Organization. Guidelines for HIV Diagnosis and Monitoring of Antiretroviral Therapy. New Delhi: WHO. 2005. http://www.aidsdatahub.org/dmdocuments/Guidelines_ for_HIV_Diagnosis_and_Monitoring_of_Antiretroviral_ Therapy_2005.pdf.pdf (accessed 22 July 2013). 6. Opie J. Haematological complications of HIV infection. S Afr Med J 2012;102(6):465-468. 7. De Santis GC, Brunetta DM, Vilar FC, et al. Hematological abnormalities in HIV-infected patients. Int J Infect Dis 2011;15(12):e808-e811 [http://dx.doi.org/10.1016/j.ijid.2011.08.001] 8. National Health Laboratory Service. State Pricing Catalogue 2011/2012. Johannesburg: NHLS, 2012. http://www.doh.gov.za/docs/ programmes/2012/appendixM.pdf (accessed 13 November 2012). 9. Rabkin M, El-Sadr W, Katzenstein D, et al. Antiretroviral treatment in resource-poor settings: Clinical research priorities. The Lancet 2002;360(9344):1503-1505. [http:// dx.doi.org/10.1016/S0140-6736(02)11478-4] 10. Buttarello M, Plebani M. Automated blood cell counts: State of the art. Am J Clin Pathol 2008;130:104-116. [http://dx.doi. org/10.1309/EK3C7CTDKNVPXVTN] 11. Douglas SD, Rudy B, Muenz L, et al. Peripheral blood mononuclear cell markers in antiretroviral therapy-naive HIV-infected and high risk seronegative adolescents. AIDS 1999;13(13):1629-1635. [http://dx.doi.org/10.1097/00002030199909100-00005] 12. Sousa AE, Carneiro J, Meier-Schellershein M, Grossman Z, Victorina RMM. CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J Immun 2001;169:3400-3406. 13. Lilliehook I, Tvedten HW. Errors in basophil enumeration with 3 veterinary hematology systems and observations on occurrence of basophils in dogs. Vet Clin Pathol 2011;40(4):450-458. [http:// dx.doi.org/10.1111/j.1939-165X.2011.00353.x] 14. Bononi A, Lanza F, Ferrari L, et al. Predictive value of hematological and phenotypical parameters on postchemotherapy leukocyte recovery. Cytometry B: Clin Cytom 2009;76(5):328-333. [http:// dx.doi.org/10.1002/cyto.b.20476] 15. Nixon DF, Parsons J, Eglin RP. Routine full blood counts as indicators of acute viral infections. J Clin Pathol 1987;40:673675. [http://dx.doi.org/10.1136/jcp.40.6.673]

Accepted 11 June 2013.

RESEARCH

Sexual lubricants in South Africa may potentially disrupt mucosal surfaces and increase HIV transmission risk among men who have sex with men K B Rebe,1 MB ChB, FCP (SA) DTM&H; G de Swardt,1 BA (MW); P A Berman,2 BSc, MB ChB, MMed (Chem Path); H Struthers,1 MSc, MBA; J A McIntyre,1,3 MB ChB, FRCOG nova Health Institute, Johannesburg and Cape Town, South Africa A Division of Chemical Pathology, Faculty of Health Sciences, University of Cape Town, South Africa 3 School of Public Health and Family Medicine, University of Cape Town, South Africa 1 2

Corresponding author: K B Rebe (rebe@anovahealth.co.za)

Background. Men who have sex with men (MSM) are at high risk for HIV acquisition and transmission. There is a high HIV-transmission potential associated with unprotected anal intercourse (UAI), which requires sexual lubrication for comfortable, non-traumatic anal sex. Lubricant distribution remains poor in many developing nations and MSM have been known to substitute a number of common household or food products to ensure comfortable anal sex. Concern has been raised about the potential toxicity of lubricants used during anal sex. Epithelial injury is related to the osmolality of the lubricant product. Objective. To analyse commercially available water-based sexual lubricant products to ascertain their osmolality and potential to cause rectal epithelial damage. Methods. The osmolality and glycerol concentration was determined for eight of the most frequently purchased water-based sexual lubricants and some commonly used household/food products. Results. Osmolality ranged from 270 - 9 440 mosmol/l (Lubrimaxxx Premium, containing phytosqualane, and JO H2O Water Based Lubricant, respectively). Seven (88%) of the commercial lubricants had high osmolalities, with two products approaching 10 000 mosmol/l, far in excess of serum which has an osmolality of ~280 mosmol/l. Conclusion. The results of this study show that many of the top-selling brands of water-based sexual lubricants available in SA are hyperosmolar. Given that hyperosmolar products have been shown in vitro and in vivo to cause epithelial injury, they may have the potential to increase HIV acquisition and transmission, if they are used during UAI. Awareness needs to be raised about the mucosal safety of lubricants designed for use during anal sex. S Afr Med J 2014;104(1):49-51. DOI:10.7196/SAMJ.7002

Men who have sex with men (MSM) are at high risk for HIV acquisition and transmission and their HIV prevalence is higher than heterosexual men in their specific country settings.[1] The reasons for this are multifactorial but a major risk contributor is the high HIV-transmission potential associated with unprotected anal intercourse (UAI). Receptive UAI is approximately 16 times more likely to result in HIV transmission than unprotected vaginal intercourse due to the fact that the anal mucosa is thinner than vaginal mucosa and does not self-lubricate before or during intercourse.[2] The HIV transmission risk associated with UAI applies equally to women engaging in this sexual behaviour. Sexual lubrication is therefore required for comfortable, non-traumatic anal sex. Lubricant use has also been associated with lower rates of condom failure during anal sex among MSM.[3] The use of lubricants for anal sex by MSM ranges from 0% in some developing world MSM cohorts to >90% reported among MSM communities in the USA.[4,5] Distribution of condoms and water-based sexual lubricants forms a cornerstone of MSM-targeted HIV prevention programmes globally. Since HIV prevention interventions have failed among MSM in many settings, there is a need to scale up existing evidence-based interventions and to explore new prevention technologies that may be effective in this high-risk group of men.[4,5] Lubricant distribution remains poor in many developing nations and MSM have been

known to substitute a number of products to ensure comfortable anal sex. These include saliva, food products such as egg white, yoghurt, jelly and cooking oils and a variety of condom-incompatible products such as hand lotions, moisturisers and petroleum jelly. Since these products are not normally considered as sexual lubricants, they have not been assessed for safety in the rectum. An alternative product containing phytosqualane (derived from olives) as the active ingredient and called Lubrimaxxx Premium has recently been developed by Karl de L’Eau Natural Skincare, Cape Town, as a sexual lubricant. The role of lubricants in preventing HIV gained new prominence after studies demonstrated that topical tenofovir-containing products (microbicides) could reduce HIV transmission.[6,7] Microbicides could be formulated as sexual lubricants and are considered acceptable as a potential HIV risk-reduction intervention by MSM if they can be used safely for anal sex.[8,9] Concern has been raised about the potential toxicity of lubricants used during anal sex.[10] Epithelial injury is related to the osmolality of the lubricant product.[11] The main concern is that hyperosmolar water-based lubricants may denude rectal epithelium and increase secretion of fluid into the bowel (signalling epithelial injury). By compromising the integrity of anal mucosa, lubricant use without condoms may increase the risk of HIV transmission.[12] Complementary work investigating hypo- v. iso-osmolar enemas

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has shown that hyperosmolar products cause epithelial damage and that iso-osmolar products are superior.[13] Additionally, there is concern that the constituents of some commercially available sexual lubricants may increase local HIV replication.[14] These issues are not well publicised among key populations who use sexual lubricants for comfortable and pleasurable anal sex as well as to reduce their risk of HIV infection. Information on the potential toxicity of lubricant substitutes used by African MSM is unavailable, making education of affected key populations difficult.

Objective

We analysed commercially available water-based sexual lubricant products to ascertain their osmolality and potential to cause rectal epithelial damage. A phytosqualane-containing formulation, and low-fat yoghurt and egg white (common lubricant substitutes), were also assessed.

Methods

Eight of the most frequently purchased water-based sexual lubricants were sourced from a leading local adult shop, one of a chain of sex shops in South Africa (SA) and from a local non-profit organisation distributing lubricant to MSM. KY Jelly and common lubricant substitutes (egg white and low-fat yogurt) were also included in the analysis, as was the phytosqualane-containing product, Lubrimaxxx Premium. Lubricants were diluted 1/10 and 1/50 in deionised water for osmolality and glycerol measurement, respectively, using positive displacement pipettes. Samples with extremely high glycerol concentrations were diluted 1/500 to obtain readings within the linear range of the assay employed. Egg albumin and yoghurt were diluted 1/2 for measurement of osmolality. Osmolality was measured by the Division of Chemical Pathology at the University of Cape Town, SA, using a freezing point depression osmometer. Glycerol was measured using the enzymatic triglyceride channel on the Roche Modular analyser (Roche Diagnostics, Switzerland).

Results

Osmolality and glycerol measurements are shown in Table 1. Osmolality ranged from 270 - 9 440 mosmol/l (Lubrimaxxx Premium, containing phytosqualane and JO H2O Water Based Lubricant, respectively). Seven (88%) of the commercial lubricants had high osmolalities, with two products approaching 10 000 mosmol/l, far in excess of serum which has an osmolality of ~280 mosmol/l. Exceptions included Leather Personal Lubricant and Lubrimaxxx

Premium. Egg white and low-fat yoghurt had osmolalities of 276 and 428 mosm/l, respectively. High osmolality could be attributed to glycerol and there was a strong direct correlation between osmolality and glycerol content on Wilcoxon matched pair analysis. (p=0.0033).

Discussion

The results of this study show that many of the top-selling brands of water-based sexual lubricants available in SA are hyperosmolar. Given that hyperosmolar products have been shown in vitro and in vivo to cause epithelial injury, they may have the potential to increase HIV acquisition and transmission, if they are used during UAI. This is particularly concerning since many at-risk MSM utilise these products in the belief that they provide protection from HIV infection by decreasing friction and resultant trauma to the rectal mucosa. Lubricant substitutes vary in their safety. Phytosqualanecontaining lubricants, egg white and plain (unflavoured) low-fat yoghurt are relatively isotonic and are therefore unlikely to cause the same epithelial injury seen following the use of very hyperosmolar lubricants. They could therefore be promoted in countries where proprietary lubricants are not freely available, as is the case in most African countries. Saliva is also commonly used as a lubricant substitute. This is potentially problematic since researchers have suggested that this might result in transmission of saliva-borne pathogens including herpes and hepatitis viruses.[8,15] There is currently very little awareness among MSM in SA regarding lubricant safety. Manufacturers of sexual lubrication products are not required to offer product safety information, which results in the inability of users to assess their suitability. It has been demonstrated that currently available sexual lubricants do not have anti-HIV effects and some may even increase HIV replication.[14] Condom use among high-risk men remains inconsistent and therefore lubricant use in the absence of condoms is probably commonplace, a practice that may increase HIV transmission risk.[16] Knowledge about HIV prevention technologies is generally low among MSM in SA. The work of organisations (such as the Anova Health Institute) that provide free MSM-targeted condoms and lubricants, and knowledge about utilisation of sexual lubricants, is increasing. Lubricant users must understand the risks and benefits of these products. Organisations such as the US Centers for Disease Control and the World Health Organization advocate the promotion of condom and lubricant use among MSM.[17,18] Sexual lubricant safety is likely to gain importance as the search for a marketable microbicide product continues. Microbicides will need

Table 1. Osmolality and glycerol measurements Sexual lubricant product

Manufacturer

Osmolality (mosmol/l)

Glycerol (mmol/l)

JO H2O Water Based

United Consortium Inc, USA

9 440

8 500

New H2O Tangerine Dream

United Consortium Inc, USA

9 340

8 050

Wet Stuff Vitamin E

Gel Works, Australia

7 100

4 025

Lube Original Personal Lubricant

Lockerroom Marketing, Canada

5 270

2 435

Assegai

Tatt2, SA

4 630

3 450

K-Y Jelly

Johnson and Johnson, USA

2 430

1 270

Health4men

Lubrimaxxx, SA

1 480

1 265

Leather Personal Lubricant

Lockerroom Marketing, Canada

270

Plain low-fat yoghurt

Dairy Belle, SA

428

36*

276

0.1

270

Egg white Lubrimaxxx Premium (phytosqualane)

Karl de L’Eau Natural Skincare, SA

*Triglyceride rather than glycerol.

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to be safe for vaginal and rectal use and their osmolality and potential mucosal toxicity are being evaluated. Organisations such as the International Rectal Microbicide Advocates (IRMA) are promoting this agenda.[19]

Recommendations

Awareness needs to be raised about the mucosal safety of lubricants designed for use during anal sex. This should include communitybased work to educate MSM communities who are currently being encouraged to increase lubricant use. Information, education and communication (IEC) materials need to be developed and distributed that explain the medical concerns that arise when waterbased sexual lubricants are used without condoms. Clearly, MSMtargeted HIV-risk-reduction messages must stress that lubricants should be used together with condoms. For MSM who use lubricants alone, advice should be given about the safer use of these products such as using silicone-based lubricants and avoiding high osmolality water-based products. Some lubricant substitutes such as egg white or yoghurt could be promoted, although this will have limited impact in countries where food insecurity is common and food products are more likely to be consumed than used for sexual safety. Phytosqualane-containing, water-based lubricants may offer a safe alternative to those that contain glycerine, provided they are not too costly. Healthcare workers providing sexual health services, inclusive of HIV counsellors, nurses and doctors, need to be sensitised to this issue to enable them to provide correct risk-reduction counselling to their patients. This information for providers and users of lubricants will need to be carefully managed to avoid a backlash against use of lubricant and microbicides in development. Lastly, any future microbicide product that is promoted as an HIVprevention intervention must be fully analysed to ensure safety by assessing any mucosal changes it may induce.

Study limitations

Only lubricant brands available from one major branch of adult shops and selling well in Cape Town during 2012, or available from Health4men, were included in this analysis. Popular lubricants used by MSM in other geographical settings have not been included. No analysis of the ingredients of the various assayed lubricants was performed and it is possible that some ingredients may interfere with osmolality analyses, although this is not likely. The ingredients and preservatives of the various lubricants have not been individually assessed for their mucosal toxicity. It is conceivable that a low osmolality lubricant may contain toxic additives, making it potentially more damaging to anal mucosa than suggested by its osmolality alone.

Acknowledgements. KBR and GdS conceived the idea. KBR undertook the literature search, GdS, JAM and HS contributed additional ideas and contributed to the manuscript. PAB designed and implemented the laboratory component of this work and contributed ideas to the manuscript. KBR, GdS, HS and JAM are supported in part by the US PEPFAR through USAID under the terms of Award No. 674-A-00-08-00009-00. The opinions expressed herein are those of the authors and do not necessarily reflect the views of USAID. References 1. Baral SD. Elevated risk for HIV infection among men who have sex with men in low- and middle-income countries 2000-2006: A Systematic Review. PLoS Med 2007;4(12):1901-1911. [http://dx.doi.org/10.1371/ journal.pmed.0040339] 2. Baggaley RF, White RG, Boily MC. HIV transmission risk through anal intercourse, systematic review, meta-analysis and implications for HIV prevention. Int J Epidemiol 2010;39(4):1048-1063. [http://dx.doi. org/10.1093/ije/dyq057] 3. Stone E, Heagerty P, Vittinghof E, et al. Correlates of condom failure in a sexually active cohort of men who have sex with men. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20(5):495-501. [http://dx.doi. org/10.1097/00042560-199904150-00013] 4. Rebe KB, Struthers H, de Swardt G, McIntyre JA. HIV prevention and treatment for South African men who have sex with men. S Afr Med J 2011;101(10):708-710. 5. Rebe KB, Semugoma P, McIntyre JA. New HIV prevention technologies and their relevance to MARPS in African epidemics. SAHARA J 2012;9(3):164-166. [http://dx.doi.org/10.1080/17290376.2012.744168] 6. Karim QA, Karim SSA, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010;329(5996):1168-1174. [http:// dx.doi.org/10.1126/science.1193748] 7. Chateau ML, Denton PW, Swanson MD, McGowan I, Garcia JV. Rectal transmission of transmitted/founder HIV-1 is efficiently prevented by topical 1% tenofovir in BLT humanized mice. PloS One 2013;8(3):e60024. [http://dx.doi.org/10.1371/journal.pone.0060024] 8. McGowan I. Rectal microbicides: Can we make them and will people use them? Aids Behav 2011;15(Suppl 1):S66-S71. [http://dx.doi.org/10.1007/s10461-011-9899-9] 9. McGowan I. Rectal microbicide development. Curr Opin HIV AIDS 2012;7(6):526-533. [http://dx.doi. org/10.1097/COH.0b013e3283582bc2] 10. Giebel S. Condoms and condiments: Compatibility and safety of personal lubricants and their use in Africa. J Int AIDS Soc 2013;16:18531. [http://dx.doi.org/10.7448/IAS.16.1.18531] 11. Adriaens E, Remon JP. Mucosal irritation potential of personal lubricants relates to product osmolality as detected by the slug mucosal irritation assay. Sex Transm Dis 2008;35(5):512-516. [http://dx.doi. org/10.1097/OLQ.0b013e3181644669] 12. Fuchs EJ, Lee LA, Torbenson MS, et al. Hyperosmolar sexual lubricant causes epithelial damage in the distal colon: Potential implication for HIV transmission. J Infect Dis 2007;195(5):703-710. [http://dx.doi. org/10.1086/511279] 13. Leyva FJ, Bakshi RP, Fuchs EJ, et al. Isoosmolar enemas demonstrate preferential gastrointestinal distribution, safety, and acceptability compared with hyperosmolar and hypoosmolar enemas as a potential delivery vehicle for rectal microbicides. AIDS Res Hum Retroviruses 2013;29(11):1487-1495. [http://dx.doi. org/10.1089/AID.2013.0189] 14. Begay O, Jean-Pierre N, Abraham CJ, et al. Identification of personal lubricants that can cause rectal epithelial cell damage and enhance HIV type 1 replication in vitro. AIDS Res Hum Retroviruses 2011;27(9):10191024. [http://dx.doi.org/10.1089/AID.2010.0252] 15. Butler LM, Osmond DH, Jones AG, Martin JN. Use of saliva as a lubricant in anal sexual practices among homosexual men. J Acquir Immune Defic Syndr 2009;50(2):162-167. [http://dx.doi.org/10.1097/ QAI.0b013e31819388a9] 16. Lane T, Raymond F, Dladla S, et al. High HIV prevalence among men who have sex with men in Soweto, South Africa: Results from the Soweto menâ&#x20AC;&#x2122;s study. Aids Behav 2009;15(3):626-634. [http://dx.doi. org/10.1007/s10461-009-9598-y] 17. US Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines. Atlanta, CDC: 2006;55:1-100. http://www.cdc.gov/std/treatment/2006/default.htm (accessed 21 November 2013). 18. World Health Organization. Prevention and Treatment of HIV and Other Sexually Transmitted Infections Among Men Who Have Sex With Men and Transgender People. Recommendations for a Public Health Approach 2011. 2 July 2012. http://www.who.int/hiv/pub/guidelines/msm_guidelines2011/en/ (accessed 21 November 2013). 19. IRMA. International Rectal Microbicides Advocates. http://www.rectalmicrobicides.org (accessed 21Â November 2013).

Accepted 17 September 2013.

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Rapid, minimally invasive adult voluntary male circumcision: A randomised trial of Unicirc, a novel disposable device P S Millard,1 MD, PhD; H R Wilson,2 BA; N D Goldstuck,3 MB BCh; C Anaso,4 MB ChB raduate Program in Public Health, University of New England, Portland, Maine, USA G Department of Pediatrics, New York University, New York, USA 3 D epartment of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa 4 Simunye Primary Health Care, Mitchells Plain, Western Cape, South Africa 1 2

Corresponding author: P S Millard (pmillard@mac.com)

Background. Voluntary medical male circumcision (VMMC) is a priority HIV preventive intervention. To facilitate VMMC scale-up, the World Health Organization is seeking circumcision techniques that are faster, easier, and safer than open surgical methods. Objective. To compare open surgical circumcision with suturing v. the Unicirc disposable instrument plus tissue adhesive. Methods. We conducted a non-blinded randomised controlled trial at an outpatient primary healthcare clinic in Cape Town, South Africa, with 2:1 allocation ratio of 150 male volunteers who were at least 18 years of age. Our primary outcome was intraoperative time and secondary outcomes were ease of performance, post-operative pain, adverse events, time to healing, patient satisfaction and cosmetic result. Results. The intraoperative time was less with the Unicirc/adhesive technique (median 13 v. 22.6 min, respectively; p<0.001). The intraoperative suturing rate was 17% using the Unicirc device. Other adverse events and wound healing outcomes were similar in both groups, but the cosmetic result was superior in the Unicirc group. Doctors found the Unicirc procedure easier to perform and preferred it to the open surgical technique. Conclusions. This study has important implications for the scale-up of VMMC services. Excising the foreskin with the Unicirc instrument and sealing the wound with cyanoacrylate tissue adhesive in adults is quicker, easier to learn, and is potentially safer than open surgical VMMC. Further studies should be conducted with the optimised device. This new instrument has the potential to facilitate more rapid scale-up and save costs. S Afr Med J 2014;104(1):52-57. DOI:10.7196/SAMJ.7357

Voluntary medical male circumcision (VMMC) reduces female-to-male transmission of HIV by 38% to 66% over 24 months[1] and is a priority preventive intervention for the World Health Organization (WHO)[2] and the US President’s Emergency Plan for AIDS Relief (PEPFAR). [3] In South Africa (SA), the national strategic plan for 2012 to 2016 calls for circumcising 80% of men between 15 and 49 years of age (4.3 million men). If this goal is met, more than 1 million new HIV infections can be averted with overall net savings [4] of US$5.5 billion between 2011 and 2025. Thus far, the health department is behind on its target and is unlikely to achieve these goals unless additional modalities can help to scale up the medical circumcision process.[5] Open surgery with suturing is the standard technique currently used in most VMMC programmes. Unfortunately, it is time-consuming, requires good surgical skills, and minor complications are common under the programmatic conditions existing in Africa.[6] We have previously shown that VMMC using the Gomco instrument to excise the foreskin and sealing the wound with tissue adhesive is faster, easier, and has superior cosmetic results compared with open surgical circumcision. [7]

Objective

To compare conventional open surgical circumcision with suturing to a minimally invasive technique using a single-use-only disposable instrument (Unicirc) plus tissue adhesive. This technique completes the circumcision at the time of surgery, and requires no further visits for device removal. We hypothesised that the new technique would be superior to open surgical VMMC with regard to intraoperative time, ease of performance, and have similar adverse events.

Methods Trial design

This was a single-centre non-blinded randomised controlled trial with 2:1 (Unicirc:surgical) allocation ratio in balanced blocks of 15, following the guidelines of the WHO Framework for Clinical Evaluation of Devices for Adult Male Circumcision.[8] An investigator (HRW), who was not involved in the surgeries, allocated participants in a 2:1 ratio in blocks of 15 using a random number table. Slips of paper with the group assignment were folded and placed in sealed, opaque envelopes. Each envelope was opened only at the time of surgery. We used the sample size recommended in the WHO Framework.[8] The sample size of 150 (50 surgical and 100 Unicirc) gave us >90% power to detect a mean difference of 8 min in duration of surgery. The South African Medical Association’s Ethics Committee (SAMAREC) approved the study. The ClinicalTrials.gov identifier is NCT01877408. All subjects gave informed consent. The study took place between 21 June and 8 August 2013.

Participants

Healthy uncircumcised men of at least 18 years of age were eligible for the study. Participants were recruited via posters at two affiliated primary healthcare clinics in Cape Town, SA. Exclusion criteria were concurrent illness, history of bleeding disorder, past reaction to local anaesthetic, infection, or penile abnormality that would complicate circumcision. Men with complete phimosis were excluded from the study, but we included men with partial phimosis without adhesions. We included men with scarring of the frenulum, because it is a common condition easily corrected at the time of circumcision.

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Participants received HIV prevention counselling. We offered HIV testing, but did not request testing as a study prerequisite. The ethics panel advised us not to require a test for HIV (and therefore exclude HIV-positive men), because this was a study of a surgical procedure, not a study of whether or not circumcision prevents HIV. Participants were advised to abstain from sexual intercourse until the wound was completely healed and for at least 4 weeks after the circumcision. Condoms were made freely available.

Intervention

Four generalist doctors, assisted by registered nurses, performed the circumcisions in individual consultation rooms in a single primary healthcare clinic on four different dates. We used a mixture of 2% lidocaine with marcaine local anaesthesia as a subcutaneous ring block at the base of the penis as per the WHO Manual for Male Circumcision under Local Anaesthesia.[9] One of the following interventions was performed: • Open surgical technique. We used the dorsal slit technique, the sleeve technique, or the forceps-guided technique according to doctor preference as described in the WHO manual.[9] After suturing, the wound was covered with an absorbent gauze dressing. • Unicirc with cyanoacrylate skin adhesive. The Unicirc is a plastic and metal single-use-only disposable instrument designed in SA. The instruments were gas sterilised in sealed packages. After applying the Unicirc instrument to the foreskin, we waited 5 min before excising the foreskin with a surgical scalpel. We then removed the instrument and sealed the apposed skin-mucosal edges with cyanoacrylate skin adhesive. We used four different Unicirc sizes in this study: 2.6 cm, 2.9 cm, 3.2 cm and 3.5 cm. We covered the wound with an adherent tape (Hypafix) and absorbent gauze. We removed the absorbent gauze at the two-day follow-up visit, and instructed participants to keep the wound dry and to leave the adherent tape in place for two weeks. All men were observed for 20 min after the procedure. Subjects were given written post-operative instructions and cellular telephone contact information of the doctor.

Outcome measures

• Primary. Intraoperative time. • Secondary. Doctor-described ease in performing the technique, estimated blood loss, complications (operative and post-operative), post-operative pain, time to healing, patient satisfaction, cosmetic result, and direct costs of expendable materials. • Key adverse events considered were anaesthetic complications, bleeding, haematoma, infection, wound disruption, problems with urination, subsequent procedures conducted to correct complications, and occupational exposure to blood and body fluids. We used standardised definitions to grade adverse events as mild, moderate or severe, using the WHO Framework for Clinical Evaluation of Devices for Adult Male Circumcision.[8] In brief, adverse events were categorised as mild if they required little or no intervention (e.g. mild wound disruption or slight bleeding), moderate if they required active treatment (e.g. antibiotics or suturing), or severe if they required transfusion or hospitalisation, or resulted in permanent damage. • Costs. Direct costs of expendable material. Outcome definitions are shown in our previous publication.[7] Wound healing outcomes were assessed by the principal investigator (PSM), a co-author (NG) and one of the surgeons (Dr Senzo Ntshalintshali).

Follow-up

Follow-up was at 2 days, 7 days, 2 weeks, and 4 weeks. For those men who were not completely healed by 4 weeks, we conducted an additional 6-week follow-up visit.

Data analysis

We collected data from participants on socio-demographics and circumcision knowledge/attitudes, and from participating doctors on ease of performing the surgery. We used a 10-point visual analogue scale for pain evaluation in the first 48 h after circumcision and a 5-point Likert scale to grade satisfaction. We conducted: (i) analysis of baseline data to examine potential confounders; (ii) calculation of descriptive statistics of outcomes; and (iii) statistical tests of operative time, differences in scale (e.g. 5-point Likert and 10-point pain scale) and proportions. We analysed the data with Epi Info (version 7).

Results

Participant flow

We recruited participants from 31 May to 26 June 2013. The flow of participants in the study is shown in Fig. 1. A total of 184 men were interviewed and 150 (81.5%) participated in the study. All participants were circumcised using the method to which they were randomly allocated.

Baseline data

The baseline characteristics of the participants are shown in Table 1. The majority of men gave improved hygiene as their motivation for circumcision, 5% cited reduction in infections. There were no significant differences in the baseline characteristics of the two groups.

Outcomes analysed

Operative outcomes are shown in Table 2; 17 (17%) of the Unicirc circumcisions required intraoperative suturing. Intraoperative time and blood loss (without frenulectomy) were less with the Unicirc/tissue adhesive technique, median 13 v. 22.6 min (p<0.001), respectively, and median 1 v. 5.5 ml (p<0.001), respectively. Adverse events are shown in Table 3. There were no significant differences between the two groups in bleeding, haematoma or infection. Wound disruptions >2 cm occurred in 2 (2%) of the Unicirc circumcisions at one week, and 1 (1%) at 2 weeks. Wound disruptions were <5 mm in width, and none required surgical closure. Post-operative pain, healing time, participant satisfaction and cosmetic results are shown in Table 4. Post-operative pain scores were low in both groups. There were no differences in healing at 4 weeks or in patient satisfaction. All subjects were fully healed at 6 weeks. The cosmetic result was superior in the Unicirc group; a regular scar line was found in 80.6% of the Unicirc subjects v. 40.0% in the surgical group (p<0.001). Cost of expendable material For the surgical VMMCs, we used pre-sterilised disposable kits specified by the WHO in SA at a cost of US$15. For the Unicirc VMMCs, we used pre-sterilised disposable kits that did not contain sutures or suturing instruments, at a cost of US$4, and a single-use tube of tissue adhesive at US$5. The Unicirc device cost US$20. The other costs (e.g. local anaesthesia, bandages) were similar for the two methods. The results from the doctors’ survey are shown in Table 5. Doctors found the Unicirc procedure easier to perform and preferred it to the open surgical technique. Three of the four doctors had significant

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Assessed for eligibility (N=184)

Excluded (34) · Inclusion criteria not met (8) · Declined to participate (26)

Randomised (N=150)

Allocation

Unicirc circumcision (N=100)

Surgical intervention (N=50)

Follow-up Day 2: 100 (100%) Day 7: 100 (100%) Day 14: 98 (98%) Day 28: 98 (98%)

Day 2: 50 (100%) Day 7: 49 (98%) Day 14: 49 (98%) Day 28: 50 (100%) Analysis

Pain and complications (N=100) Day 2: 100 (100%) Day 7: 100 (100%) Day 14: 98 (98%) Day 28: 98 (98%) Exit survey: 98 (98%) Doctor’s survey: 4/4 (100%)

Pain and complications (N=50) Day 2: 50 (100%) Day 7: 49 (98%) Day 14: 49 (98%) Day 28: 50 (100%) Exit survey: 50 (100%) Doctor’s survey: 4/4 (100%)

Fig. 1. Participant flow diagram.

previous experience performing open surgical circumcisions. Among these three doctors, there were two glove perforations during the study. One experienced doctor cut himself with a scalpel while doing an open surgical circumcision. The doctor with limited prior experience reported >10 glove perforations during the study.

Discussion

Circumcision scale-up in sub-Saharan Africa has been constrained by the time needed and technical difficulties of performing open surgical circumcision, the only method approved by PEPFAR. To more effectively scale-up services, we require fundamental improvements in current circumcision techniques. We need techniques that are rapid, easy to learn, performed with standard instruments, inexpensive, result in few complications, and provide excellent patient satisfaction and cosmetic results. New VMMC modalities – plastic rings which all share common characteristics – have recently received a great deal of publicity.[5] They are attractive because they require less skill to place and are more rapid than

open surgery, but have a number of serious drawbacks.[10] They remain in place for 1 week, during which time the men have to tolerate the smell of necrotic tissue. Removal is unpleasant and takes more time than placement (10 min v. 7 min for the Prepex device).[11] Healing is by secondary intention, so it is delayed. A recent study of the Prepex device showed a mean healing time of 38 days post-procedure; 16% of men were not completely healed by 7 weeks.[12] Recent cost-effectiveness analyses concluded that the Prepex device is marginally more costeffective than open surgical circumcision.[11,13] Our prior study showed that removal of the foreskin with the Gomco instrument and sealing the wound with tissue adhesive has important advantages over open surgical circumcision. It requires much less operative time, is easier to perform, has better cosmetic results, and is potentially safer because it does not require suturing.[7] However, the Gomco instrument has drawbacks that make it less than ideal for mass circumcisions in resource-limited settings. Given the history of transmission of blood-borne infections from poorly sterilised instruments, WHO prefers disposable devices, but the Gomco instrument

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is re-usable and sterilisable. Given that the Gomco instrument consists of three different parts, mismatching parts from different-sized instruments or different manufacturers may potentially cause complications. The Unicirc shares the advantages of the Gomco instrument, but it overcomes the above drawbacks. It is a metal and plastic instrument that is designed with threads that self-destruct after a single use, definitively preventing re-use. Because it is pre-packaged, mismatching of parts is not an issue. The generalist doctors in this study were moderately experienced in open surgical circumcision but had not previously used the Gomco or Unicirc instruments. Operative times were much shorter with Unicirc v. surgical VMMC (13 v. 22.6 min, respectively). Using the WHO Models for Optimizing the Volume and Efficiency (MOVE) of task-sharing,[14] the actual time savings should be much greater than is reflected by this difference. It takes 1 2 min to place the instrument, and 2 - 3 min to excise the foreskin, remove the instrument and apply the adhesive. The 5 min of waiting time while the compressive action takes place could be well used in other tasks. The time savings using the Unicirc/adhesive technique are likely to substantially reduce overall cost and assist in mass scale-up. There were no serious adverse events in this study, and post-operative complications were similar in the two groups. However, 17% of the Unicirc subjects required intraoperative suturing, and there was a non-significant trend toward increased post-operative bleeding and haematoma with Unicirc. All post-operative bleeding occurred while the subjects were still in the clinic under post-operative supervision. Nonetheless, it was not an anticipated or desirable result and we did not find this in our prior experience with the prototype Unicirc device. We attribute the bleeding to shrinkage that occurred after the injection moulding of the plastic component of the Unicirc production instruments used in this study. We subsequently made minor revisions to the device to increase the compressive forces. After approval by SAMAREC, we conducted a further 50 Unicirc circumcisions in volunteers who had expressed an interest in the original study. None of the participants required intraoperative suturing, and we found a low rate of post-operative bleeding and haematoma with the revised Unicirc device (Table 6). Unlike our previous study conducted during the rainy season in an impoverished community in Mozambique, adhesive failure was not a problem in this cohort. The SA participants had much more success in keeping the wound adhesive dry in the post-operative period. The inexpensive, Asian-manufactured

RESEARCH

Table 1. Baseline characteristics Unicirc/adhesive* (N=100), n and %

Open surgical* (N=50), n (%)

18 - 25

12 (24)

36 - 35

21 (42)

â&#x2030;Ľ36

17 (34)

Single (in a relationship)

26 (52)

Married

17 (34)

No partner

7 (14)

Christian

33 (66)

Muslim

6 (12)

No religion

11 (22)

Primary

2 (4)

Secondary

45 (90)

Post-secondary

3 (6)

Hygiene

33 (66)

Reduce infections

3 (6)

Social/religious

8 (16)

Other

6 (12)

Age (years)

Marital status

Religion

Education level

and one scalpel) and this nearly compensated for the cost of the Unicirc device. Because the Unicirc procedure requires no follow-up visits, we expect there to be significant cost savings compared with plastic ring devices, such as the Shang Ring and PrePex. Plastic ring devices also require both an application pack and a removal pack, which contains scissors and a device for removing the ring. There were several glove perforations among doctors during the study, and one doctor injured himself with a scalpel. Because the Unicirc/ adhesive technique requires no sutures, there is no possibility of a needlestick injury from a suture needle. All doctors preferred the Unicirc method to the surgical method, citing ease of performance and shorter intraoperative time as advantages of the Unicirc. No one technique will be suitable for all settings. The Unicirc/tissue adhesive procedure is ideal for outpatient settings, where large numbers of circumcisions are performed by mid-level staff using the MOVE model, or for use by private practitioners who have basic surgical skills and wish to add circumcision services to their practice. Because of the potential need for intraoperative and post-operative suturing, the procedure is not suitable for rural clinics that lack a provider skilled in basic surgical techniques.

Study limitations

This study was non-blinded and was performed at a single centre. The estimated blood loss was subjectively estimated by the surgeons. There was no independent, objective measure of wound healing outcomes. Rather, these outcomes were assessed by the three different physicians, with close collaboration. Given the high follow-up rates, long opening hours of the primary healthcare clinic where the study was conducted, and the easy availability of doctors via cell phone, we think it unlikely that any adverse events were missed. Finally, the costs of expendable materials were underestimated in the Unicirc group, because of the unanticipated bleeding complications.

Reason for wanting circumcision

*p>0.05 for all comparisons.

Conclusions

Table 2. Intraoperative outcomes Unicirc/ adhesive (N=100)

Open surgical (N=50)

Intraoperative suturing, n (%)

17 (17)

All by protocol

Frenulectomy performed, n (%)

4 (4)

6 (12)

Intraoperative time (min), median (IQR) With frenulectomy

28.6 (17.7)

25 (18)

Without frenulectomy*

13 (4.5)

22.6 (8.6)

Author contributions. P S Millard was the lead author and made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data; drafting the article and revising it critically for important intellectual content and final approval of the version to be published. H R Wilson and C Anaso participated in data collection, data analysis and drafting the article. N D Goldstuck participated in data collection and drafting the article. All authors approved the final version and agreed to publication.

Estimated blood loss (ml), median (IQR) With frenulectomy

6.5 (3.5)

10 (6.5)

Without frenulectomy*

1 (1)

5.5 (6.5)

IQR = interquartile range. *p<0.001.

cyanoacrylate adhesive that we used was more difficult to apply because it had a lower viscosity than the cyanoacrylate adhesive that we used in our Mozambique study. In future studies, it would be worthwhile to compare the performance of other cyanoacrylate formulations. The cost of expendable materials was similar using the two techniques. The cost of tissue adhesive approximates the cost of suture materials. Unicirc requires fewer disposable instruments (only one haemostat

This study has important implications for the scale-up of VMMC services. Excising the foreskin after applying the Unicirc instrument for 5Â min and sealing the wound with cyanoacrylate tissue adhesive in adults is quicker, easier to learn, has superior cosmetic results and is potentially safer than open surgical VMMC. Further studies should be conducted with the optimised device. Use of this new method should greatly facilitate scale-up of mass circumcision programmes.

Acknowledgements. We thank Drs Justin Shenje, Senzo Ntshalintshali, Siyabonga Nhlumbini and Zainul Parker for performing the circumcisions. Drs Cyril and Elisabeth Parker, Sheena Soudien, Sindiswa Njaba, Sandra Ndimangele, Simone Harris and the rest of the staff at Simunye Primary Health Care assured the success of the study through their hard work and diligence. Conflict of interest. This study was supported by Simunye Primary Health Care. No funding bodies played any role in the design, writing, or decision to publish this manuscript.

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Table 4. Post-operative outcomes

Table 3. Adverse events

Serious post-operative complication

Unicirc/ adhesive (N=100) n and %

Open surgical (N=50) n (%)

p-value

Post-operative bleeding Mild (dressing only)

1 (2)

0.25

Moderate (sutured)

2 (4)

Haematoma

0.15

Post-operative infection (antibiotic required)

6 (12)

0.71

Unicirc/ adhesive (N=100)

Open surgical (N=50)

p-value

In first 24 h

4.2 (±2.7)

3.1 (±2.4)

0.01

At 48 h visit

0.7 (±1.6)

1.2 (±2)

0.04

Pain (10-point scale), mean (±SD)

Wound fully healed, n (%) At 2 weeks

At 4 weeks

89 (90.8)

49 (98)

0.1

22 (22)

6 (12)

0.14

Very satisfied

78 (79.6)

40 (80)

Satisfied

15 (15.3)

8 (16)

Not satisfied

5 (5.1)

2 (4)

0.9

Recommend highly

91 (92.9)

48 (96)

0.46

Recommend

4 (4)

1 (2)

Not recommend

3 (3.1)

1 (2)

Regular

79 (80.6)

20 (40)

Irregular

12 (12.2)

8 (16)

Scalloped

7 (7.1)

22 (44)

Sexually active at 4 weeks, n (%)

Wound disruption at 2 days (cm length)

Satisfaction, n (%)

1 (2)

Wound disruption at 1 week (cm length)

Recommendation, n (%)

1 (2)

0.15

Wound disruption at 2 weeks (cm length)

Cosmetic results, n (%)

2 (4)

0.27

Table 5. Doctors’ survey Generalist physicians (N=4) Circumcisions performed prior to study, median (range) Surgical

150 (10 - 200)

Table 6. Post-study case series of subsequent Unicirc circumcisions (N=50)

Unicirc

0 (0 - 10)

Intraoperative suturing, n

Blood loss (ml), median

1.5 9

Ease of performance, n (%) Unicirc much easier

Operative time (min), median

Unicirc easier

4 (100)

Complete follow-up, n (%)

50 (100)

Neutral

Serious post-operative complication, n

Surgical easier

Post-operative bleeding, n (%)

Surgical much easier

Method of preference, n (%)

Mild (dressing only)

Moderate (sutured)

1 (2)

Strongly prefer Unicirc

2 (50)

Haematoma, n (%)

Prefer Unicirc

2 (50)

Neutral

Post-operative infection (antibiotic-treated), n (%)

Prefer surgical

Strongly prefer surgical

1 (2) 2 (4)

Wound disruption at any point in time (cm length), n (%)

Glove perforations during the study, n (%) 0

1 (25)

2 (50)

>10

1 (25)

2 (4)

Healed at 4 weeks, n (%)

49 (98)

Cosmetic appearance, n Regular

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References

1. Siegfried N, Muller M, Deeks JJ, Volmink J. Male circumcision for prevention of heterosexual acquisition of HIV in men. Cochrane Database Syst Rev 2009;(2):CD003362. [http://dx.doi. org/10.1002/14651858.CD003362.pub2] 2. World Health Organization, UNAIDS, Joint Strategic Action Framework to Accelerate the Scale-up of Voluntary Medical Male Circumcision for HIV Prevention in Eastern and Southern Africa, 20122016. Geneva: WHO, 2011. http://www.unaids.org/en/media/unaids/contentassets/documents/ unaidspublication/2011/JC2251_Action_Framework_circumcision_en.pdf (accessed 22 November 2013). 3. Reed JB, Njeuhmeli E, Thomas AG, et al. Voluntary medical male circumcision: An HIV prevention priority for PEPFAR. J Acquir Immune Defic Syndr 2012;60(Suppl 3):S88-S95. [http://dx.doi. org/10.1097/QAI.0b013e31825cac4e] 4. Njeuhmeli E, Forsythe S, Reed J, et al. Voluntary medical male circumcision: Modeling the impact and cost of expanding male circumcision for HIV prevention in eastern and southern Africa. PLoS Med 2011;8(11):e1001132. [http://dx.doi.org/10.1371/journal.pmed.1001132] 5. Malan M. PrePex could save many lives in SA – with traditional leaders’ help. Mail and Guardian. 18 June 2013. http://mg.co.za/article/2013-06-18-prepex-will-save-many-lives-in-sa-with-traditionalleaders-help (accessed 22 November 2013). 6. Bailey RC, Egesah O, Rosenberg S. Male circumcision for HIV prevention: A prospective study of complications in clinical and traditional settings in Bungoma, Kenya. Bull World Health Organ 2008;86:669-677. [http://dx.doi.org/S0042-96862008000900010] 7. Millard PS, Wilson HR, Veldkamp PJ, Sitoe N. Rapid, minimally invasive adult voluntary male circumcision: A randomised trial. S Afr Med J 2013 2013;103(10):736-742. [http://dx.doi.org/10.7196/ SAMJ.6856]

8. World Health Organization. Framework for Clinical Evaluation of Devices for Adult Male Circumcision. Geneva: WHO, 2011. http://apps.who.int/iris/bitstream/10665/75954/1/9789241504355_eng.pdf (accessed 31 May 2013). 9. World Health Organization. Manual for Male Circumcision Under Local Anaesthesia. Geneva: WHO, 2009. http://www.who.int/hiv/pub/malecircumcision/who_mc_local_anaesthesia.pdf (accessed 31 May 2013). 10. Millard PS. Circumcision – what’s wrong with plastic rings? S Afr Med J 2012;102(3):126-128. 11. Duffy K, Galukande M, Wooding N, Dea M, Coutinho A. Reach and cost-effectiveness of the PrePex device for safe male circumcision in Uganda. PLoS One 2013;8(5):e63134. [http://dx.doi.org/10.1371/ journal.pone.0063134] 12. Mutabazi V, Kaplan SA, Rwamasirabo E, et al. HIV prevention: Male circumcision comparison between a nonsurgical device to a surgical technique in resource-limited settings: A prospective, randomized, nonmasked trial. J Acquir Immune Defic Syndr 2012;61(1):49-55. [http://dx.doi. org/10.1097/QAI.0b013e3182631d69] 13. Obiero W, Young MR, Bailey RC. The PrePex device is unlikely to achieve cost-savings compared to the forceps-guided method in male circumcision programs in sub-Saharan Africa. PLoS One 2013;8(1):e53380. [http://dx.doi.org/10.1371/journal.pone.0053380] 14. World Health Organization. Considerations for Implementing Models for Optimizing the Volume and Efficiency of Male Circumcision Services. Geneva: WHO, 2010. http://www.malecircumcision.org/ programs/documents/mc_MOVE_2010_web.pdf (accessed 22 November 2013).

Accepted 5 November 2013.

Surgical outreach in rural South Africa: Are we managing to impart surgical skills? D L Clarke, MB BCh, MMedSci, MBA, MPhil, FCS (SA); C Aldous, PhD School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa Corresponding author: D L Clarke (damianclar@gmail.com)

Background. The Department of Health in KwaZulu-Natal (KZN) has run a surgical outreach programme for over a decade. Objective. To quantify the impact of the outreach programme by analysing its effect on the operative capacity of a single rural health district. Methods. During 2012, investigators visited each district hospital in Sisonke Health District (SHD), KZN, to quantify surgery undertaken by resident staff between 1998 and 2013. Investigators also reviewed the operative registers of the four district hospitals in SHD for a 6-month period (March - August 2012) to document the surgery performed at each hospital. The number of staff who attended specialist-based teaching was recorded in an attempt to measure the impact of each visit. Results. From 1998 to 2013, 35 385 patients were seen at 1 453 clinics, 5 199 operations were performed and 1 357 patients were referred to regional hospitals. A total of 3 027 staff attended teaching ward rounds and teaching sessions. In the four district hospitals, 2 160 operations were performed in the 6-month period. There were 653 non-obstetric operations and the obstetric cases comprised 1 094 caesarean sections, 55 sterilisations and 370 evacuations of the uterus. Conclusion. The infrastructure is well established and the outreach programme is well run and reliable. The clinical outputs of the programme are significant. However, the impact of this programme on specific outcomes is less certain. This raises the question of the future strategic choices that need to be made in our attempts to improve access to surgical care. S Afr Med J 2014;104(1):57-60. DOI:10.7196/SAMJ.7252

It has been estimated that just over 10% of the global burden of disease requires surgical treatment. However, access to surgical services is unevenly distributed across the world and across regions within the same country.[1-6] Currently, less than one-third of the estimated 234 million operations that take place each year are performed in the developing world. Lack of access to surgical services results in significant morbidity and mortality. Strategies to improve access to surgical services focus on improving the surgical capacity of district hospitals. The Bellagio Essential Surgery Group (BESG) and the World Health Organization (WHO) recommend that services at the district hospital level be strengthened by ongoing surgical training. [7-9] One strategy to achieve this is to take surgical

expertise to the district hospitals with the aim of delivering clinical care and imparting surgical skills – known as the surgical outreach programme.[10-14] The Department of Health (DoH) in KwaZulu-Natal (KZN) has run such a programme since the turn of the millennium. The programme is co-ordinated by the staff of the Red Cross, based initially at the old Durban International Airport and now at King Shaka International Airport, north of Durban. The programme makes use of fixed-wing aircraft to visit the more remote district hospitals in the KZN Province and ground transport to visit the more geographically accessible hospitals. Surgical consultants from Pietermaritzburg and Durban are transported to each hospital in the province on a monthly basis. When available, anaesthetists accompany the visiting surgeons. This audit reviews the outreach programme and attempts to quantify

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its impact by analysing the operative capacity of the rural Sisonke Health District (SHD).

Setting

KZN lies on the east coast of South Africa (SA) and consists of three broad regions, the urbanised coastal area around Durban, the western, inland part, stretching from the coast westwards to the Drakensberg mountains and the northern area which extends up to the border with Mozambique in the north, and westwards to Mpumalanga Province and Swaziland. There are 70 provincial hospitals, two central hospitals, two tertiary hospitals and six regional hospitals in KZN. Both central hospitals and two regional hospitals are in the eThekwini Metropolitan Municipality. The coastal area is highly urbanised and has two other regional hospitals. The inland area has the single city of Pietermaritzburg with a well-developed infrastructure, a tertiary hospital and three regional hospitals. However, the western part of the province is predominantly rural, while the northern region is remote and deeply rural. The urban centre serving the north is the least developed of the three urban conurbations and is centred on the towns of Richards Bay and Empangeni. There is a single tertiary hospital serving the northern part of the province. The population of KZN is approximately 11 million, with half the population living in the rural areas outside the three conurbations of Durban, Pietermaritzburg and Empangeni/Richards Bay. SHD is a rural area in south-western KZN with a population of roughly 500 000 people. Edendale Hospital in Pietermaritzburg serves as the regional referral hospital for the four district hospitals in SHD. Each district hospital is visited once a month by a surgical specialist from Edendale Hospital. KZN thus has a large rural population living in relatively remote areas that are poorly served by transport infrastructure and far from surgical services. The South African Red Cross Air Mercy Service (AMS) is a non-profit organisation that focuses on health support and the upliftment of local communities through health initiatives. In KZN it has two helicopters and one fixed-wing aircraft dedicated to emergency services, two fixed-wing aircraft dedicated to the surgical outreach programme and one vehicle based in Pietermaritzburg and dedicated to the ground-based outreach. The operational costs of the programme are borne by the DoH. The flying doctor outreach programme has run since 1998 and in 2007 was supplemented with a ‘drive clinic’ intended to support areas that could not be reached by air. Doctors and healthcare workers travel daily to the outlying healthcare facilities to assist with clinical consultations, to undertake teaching ward rounds and to perform operations. The following specialist surgical departments at the School of Clinical Medicine, University of KwaZulu-Natal (UKZN) contribute to the programme: General Surgery, Ophthalmology, Orthopaedics, Plastic Surgery and Ear, Nose and Throat (ENT) Surgery. Visits are structured not only to focus on the delivery of clinical care, but to implement ongoing quality improvement initiatives by building clinical governance structures and imparting clinical skills. Each visit attempts to address the following objectives: clinical care by means of a ward round and a dedicated outpatient clinic, clinical teaching, and an operative list. Quality control and clinical governance initiatives are developed by assisting with morbidity and mortality meetings while system and infrastructure development is facilitated by undertaking needs assessments in each hospital. As far as possible, all staff at the district hospitals are directly involved in the outreach visits.

Objective

This audit of the past 12 years of the outreach programme documents the activities of outreach staff and assesses the impact of the programme by auditing the surgical output within a single health district (Sisonke) to determine whether surgical (and anaesthetic) skills have been imparted.

Methods

The AMS staff maintained a log of all flights from the base in Durban. Details of the number of specialist visits undertaken both by air and land transport were captured. Data recorded for each visit included the number of patients seen, the number of operations done and the number of patients transferred to the referral centre. The number of staff who attended specialist-based teaching was recorded in an attempt to qualitatively measure the impact of the visit.

Assessment

During 2012 the investigators visited each district hospital in SHD to quantify the operations undertaken by resident staff at those hospitals between 1993 and 2012. Surgical registers were reviewed for the period between March 2012 and August 2012. The following obstetric procedures were recorded: caesarean section, evacuation of the uterus, and sterilisation. Orthopaedic and general surgical cases were categorised thus: orthopaedic reduction and amputation, hernia repair, laparotomy and split skin graft and ophthalmological procedure. All other cases were classified as miscellaneous.

Results

From 1998 to 2013, 35 385 patients were seen at 1 453 clinics; 5 199 operations were performed and 1 357 patients were referred to regional hospitals. A total of 3 027 staff attended teaching ward rounds and teaching sessions. Tables 1 and 2 summarise the number of flying hours for each year and kilometres travelled each year.

General surgery

The Department of Surgery, UKZN visited 24 hospitals and conducted 332 clinics at which 4 456 patients were seen. A total of 235 patients were referred, 668 operations performed and 2 462 doctors and nursing staff trained.

Plastic surgery

Staff of the Department of Plastic Surgery, UKZN visited eight hospitals, conducted 83 clinics, saw 915 patients, performed 144 operations and trained 31 doctors.

Orthopaedic surgery

Staff of the Department of Orthopaedic Surgery, UKZN visited 21 hospitals and conducted 427 clinics at which they saw 12 438 patients. A total of 519 surgical procedures were performed and 161 doctors and nursing staff were trained.

ENT surgery

Staff of the Department of ENT Surgery, UKZN visited 22 hospitals and conducted 215 clinics; 10 316 patients were seen, of whom 939 were referred; 329 procedures were performed and 242 doctors and nursing staff trained.

Anaesthetics

A total of 28 hospitals were visited by staff of the Department of Anaesthetics, UKZN who conducted 270 clinics. They administered

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880 general anaesthetics and 131 doctors and nursing staff were trained.

Table 1. Flying hours for the outreach programme, 1998 - 2012 Year

Flying hours, n

1998

258.6

1999

272.5

2000

290.2

2001

354.6

2002

469.6

2003

497.4

2004

517.5

2005

505.9

2006

571.8

2007

679.2

2008

689.5

2009

827.1

2010

864.5

2011

794.8

2012

687.4

Total, N

8 280.6

Operative data

Review of the surgical registers at the four district hospitals in SHD revealed that 2 160 operations were performed. There were 653 non-obstetric operations including 58 orthopaedic reductions and amputations, 68 ophthalmology operations, 11 laparotomies, 1 split skin graft, 1 abdominal wall hernia repair and 537 miscellaneous operations. The obstetric cases comprised 1 094 caesarean sections, 55 sterilisations and 370 evacuations of the uterus. These data are summarised in Table 3.

Discussion

The BESG recommended that access to surgical care be increased by strengthening services at the district hospital level through enhanced surgical training programmes.[7-9] Such surgical outreach programmes, if not well planned, may merely deplete the regional referral hospital of skills and expertise and be of little benefit to the district hospital. It is essential to assess both the outputs and the outcomes of such programmes and audit their results. Outputs are generally quantifiable and include easily captured metrics such as the number of patients seen and number of operations performed. Outcomes are more difficult to measure. This report documents the outputs of the outreach system but acknowledges the difficulty with regard to precise measurement of outcomes. The WHO in Surgical Care at the District Hospital states that basic abdominal surgery should be undertaken at district hospitals. [7] Although the exact definition of basic abdominal surgery is unspecified, the following procedures are listed: laparotomy for trauma, laparotomy for the diagnosis and management of intestinal obstruction, peritonitis, complicated peptic ulcer disease and appendicitis. The following trauma procedures are described: splenectomy, packing of liver lacerations, small bowel repair, intestinal anastomosis, fashioning of a colostomy, and repair of a ruptured bladder. There is a chapter that describes the diagnosis and management of the following surgical conditions: small bowel obstruction, complicated peptic ulcer disease, as well as the technique of open cholecystectomy for complicated gallbladder disease, non-surgical management of sigmoid volvulus and the surgical management of inguinal hernias, femoral hernias and

Table 2. Distance driven on the ground for the outreach programme, 2007 - 2012 Year

Distance (km), n

2007

16 206

2008

38 094

2009

37 115

2010

46 105

2011

43 554

2012

49 158

Total, N

193 117

Table 3. Operations over six months in 2012 in the four regional hospitals in SHD Cases per hospital, n SAH

Total, N

CTK

EG Usher

Rietvlei

Non-obstetric

133

333

121

653

Caesarean section

414

451

175

1 094

Sterilisation

Evacuation of uterus

122

175

370

Orthopaedic

Eye

Laparotomy

Skin graft

Hernia

Miscellaneous

126

266

121

537

Total, N

704

976

184

296

2 160

SHD = Sisonke Health District; CTK = Christ the King; EG Usher = EG Usher Memorial; SAH = St Apollinaris Hospital.

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umbilical hernias. Our review of the operative data in SHD suggests that, despite an active surgical outreach programme, there remains a significant gap between the range of surgeries the WHO believes should be performed in a district hospital and what is actually delivered within SHD hospitals. Nevertheless, in terms of the numbers of patients seen, and the large number of operations performed, potential congestion at regional and tertiary hospitals over the 12-year period would have been significantly mitigated. Our results are similar to those published by Voss and Duvenage[15] who audited the surgical output of seven district hospitals in the rural Western Cape. The volume of general surgical procedures undertaken is low and almost no abdominal surgery is undertaken. In their year-long review only 21 appendicectomies were performed (19 in one hospital, 2 in another) at the seven referral hospitals! The situation is similar in SHD and we have reported on the poor outcome of acute appendicitis in our environment.[16] The WHO defines a high priority procedure as one which primarily addresses emergencies such as injuries and obstetric complications. These procedures include laparotomies for trauma and acute abdominal conditions as well as open reduction of fractures, split skin graft and abdominal hernia repair. In our study there was a very low rate of abdominal hernia repair, split skin graft and laparotomy. A large number of smaller miscellaneous procedures are performed that included incision and drainage of abscesses, biopsy and excision of cutaneous and sub-cutaneous lesions and suturing of wounds. Our findings are in keeping with data reported from a review of the unmet surgical need in sub-Saharan Africa.[2,3] It would appear that in the region as a whole, caesarean section is the most commonly performed operation and despite a high prevalence of trauma, burns and intestinal obstruction in the region, the number of fracture reductions, laparotomies and skin grafts is small. Most of the procedures performed are in the so-called miscellaneous category and include incision and drainage of abscesses and wound management and suturing, many of which, if performed in the outpatient department, would not have been formally recorded in the surgical registers. Surgical outreach is proposed as a strategy to increase the surgical output of district hospitals. Although our programme has succeeded in delivering point-of-care need it has been less successful in building operative capacity. This raises specific questions as to the way forward for rural surgical care in SA. The strategic options are to continue working to build up district level surgical capacity by means of enhanced training programmes – involving a fairly massive investment in human resource development – or to deliberately

bypass the district system for pathologies requiring surgery, in favour of referral to regional centres with comprehensive surgical capacity.

Conclusion

The DoH has run an active surgical outreach programme for more than a decade. The infrastructure is well established and the programme is well mananged and reliable, and the clinical outputs are significant. However, the impact on strengthening surgical and anaesthetic capacities, which were key objectives, is less certain. Our audit suggests that the outreach programme has not succeeded in transferring surgical skills to the staff of the district hospitals. This raises the question of which future strategic choices need to be made to improve rural patients’ access to surgical care? Acknowledgement. Jerusha Dorasamay from the AMS helped to collate the details of the AMS visits.

References 1. Tollefson TT, Larrabee WF. Global surgical initiatives to reduce the surgical burden of disease. JAMA 2012;307(7):667-668. [http://dx.doi.org/10.1001/jama.2012.158] 2. Grimes CE, Law RS, Borgstein ES, Mkandawire NC, Lavy CB. Systematic review of met and unmet need of surgical disease in rural sub-Saharan Africa. World J Surg 2012;36(1):8-23. [http://dx.doi. org/10.1007/s00268-011-1330-1] 3. Weiser TG, Regenbogen SE, Thompson KD, et al. An estimation of the global volume of surgery: A modelling strategy based on available data. Lancet 2008;372(9633):139-144. [http://dx.doi. org/10.1016/S0140-6736(08)60878-8] 4. Nordberg E, Holmberg S, Kiugu S. Output of major surgery in developing countries. Towards a quantitative evaluation and planning tool. Trop Geogr Med 1995;47(5):206-211. 5. Nabembezi JS, Nordberg E. Surgical output in Kibaale district, Uganda. East Afr Med J 2001;78(7):379-381. 6. Nordberg E, Mwobobia I, Muniu E. Minor surgery at hospitals and clinics in a Kenyan district. East Afr Med J 2001;78(2):102-106. 7. World Health Organization. Surgical Care at the District Hospital. Geneva: WHO, 2003. http://www. who.int/surgery/publications/en/SCDH.pdf (accessed 1 July 2013). 8. Bellagio Essential Surgery Group. http://essentialsurgery.org/bellagio/ (accessed 1 January 2013). 9. Kwon S, Kingham TP, Kamara TB, et al. Development of a surgical capacity index: Opportunities for assessment and improvement. World J Surg 2012;36(2):232-239. [http://dx.doi.org/10.1007/ s00268-011-1385-z] 10. Mungadi IA. Quality surgical care for rural dwellers: The visiting option. Trop Doct 2005;35(3):151153. [http://dx.doi.org/10.1258/0049475054620897] 11. Wachira J, Nordberg E. Airborne surgical outreach services in eastern Africa. East Afr Med J 1998;75(10):563-566. 12. Gruen RL, Weeramanthri TS, Knight SE, Bailie RS. Specialist outreach clinics in primary care and rural hospital settings. Cochrane Database Syst Rev 2004;(1):CD003798. [http://dx.doi. org/10.1002/14651858.CD003798.pub2] 13. Gruen RL, Bailie RS, Wang Z, Heard S, O’Rourke IC. Specialist outreach to isolated and disadvantaged communities: A population based study. Lancet 2006;368(9530):130-138. [http://dx.doi.org/10.1016/ S0140-6736(06)68812-0] 14. Gruen RL, Weeramanthri TS, Bailie RS. Outreach and improved access to specialist services for indigenous people in remote Australia: The requirements for sustainability. J Epidemiol Community Health 2002;56(7):517-521. [http://dx.doi.org/10.1136/jech.56.7.517] 15. Voss M, Duvenage R. Operative surgery at the district hospital. S Afr Med J 2011;101(8):521-522. 16. Kong VY, Bulajic B, Allorto NL, Handley J, Clarke DL. Acute appendicitis in a developing country. World J Surg 2012;36(9):2068-2073. [http://dx.doi.org/10.1007/s00268-012-1626-9]

Accepted 11 July 2013.

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Relationship between firewood usage and urinary Cr, Cu and As in informal areas of Cape Town M A Dalvie,1 PhD; A Africa,1 BTech; S Naidoo,2 PhD Centre for Occupational and Environmental Health Research, School of Public Health and Family Medicine, University of Cape Town, South Africa 2 Environmental Processes and Systems Engineering, Department of Chemical Engineering, Faculty of Engineering and Built Environment, University of Cape Town, South Africa 1

Corresponding author: M Dalvie (aqiel.dalvie@uct.ac.za) Objectives. The study investigated whether wood usage by informal food vendors and household residents in Cape Town results in the absorption of arsenic (As), chromium (Cr) and copper (Cu) owing to release of these metals in the burning of chromated copper arsenate (CCA)-treated wood. Methods. The participants (N=78) selected included an equal number of food vendors and non-vendors from 2 informal settlements. All participants answered a questionnaire concerning exposure and were tested for urinary Cr, Cu and As, while the urine of 29 participants was also tested for toxic As (As(tox)). Results. Multivariate analysis showed that the time spent in close proximity to the wood, as well as the quantity of wood used for cooking and for household use, was weakly positively associated with urinary levels of As, Cr and the sum of As, Cr and Cu. Conclusions. The study provides evidence that use of wood likely to contain CCA as a fuel for informal food outlets and household purposes may increase the absorption of inorganic As, Cu and Cr. S Afr Med J 2014;104(1):61-64. DOI:10.7196/SAMJ.6451

A previous investigation[1] indicated that the use of wood treated with chromated copper arsenate (CCA) as a fuel for open fires in street cooking in Cape Town posed a potential public health risk. In this study, CCA-treated wood samples were taken from wood used for informal catering activities, with treated wood being more prevalent in urban townships than in peri-urban areas of Cape Town. Subsequently, the present study was undertaken to investigate exposure to CCA-treated wood and measure urinary levels of arsenic (As), chromium (Cr) and copper (Cu) among informal food vendors and household residents in an urban and peri-urban area in the Western Cape. The first part of this study (described in a manuscript currently under review by the South African Journal of Science) found that urinary As, Cr and Cu levels were not significantly different in the 2 areas and among caterers and household residents, after controlling for confounding, but revealed evidence of Cr and As exposure. Urinary Cr and As in both informal caterers and household residents exceeded the environmental exposure limit in 12% and 30% of participants respectively. Additionally, a toxic form of As was detected in 30% of 29 samples analysed; in 21% the environmental exposure limit was exceeded. Exposure to As, Cr and Cu from CCA-treated wood occurs through inhalation of fumes and dust released on combustion of the wood; contact with wood, ash, contaminated water and soil; and ingestion of contaminated water, food and soil.[2] The toxic forms of these elements are Cr (IV), As (III) and As (V), and Cu (II). The toxic forms of As and Cr are known carcinogens at low doses, and are associated with several non-cancerous conditions, while long-term exposure to Cu (II) is associated with respiratory effects.

The aim of this study was to investigate the relationship between firewood and urinary levels of Cr, Cu and As.

Methods

A cross-sectional study of 78 adult street food vendors and household residents from 2 informal settlement areas in Cape Town was conducted. Exposure assessment was based on a short questionnaire and urinary levels of As, Cr and Cu. The questionnaire contained sections on demographics and lifestyle, use of wood during commercial and home cooking (number of hours per day, days per week, quantity and size of container drums), and recent fish consumption. An experienced and trained research assistant collected spot urine samples from participants in plastic containers with plastic caps. Urine samples were delivered to the Ampath N1 City Hospital Laboratory in Cape Town whence they were transferred to their main laboratory, accredited for analysis of As, Cr and Cu (South African National Accreditation System), in Gauteng. Total Cr, Cu and As (As(tot)) was measured in all samples using high inductively coupled plasma (ICP).[3] Additionally, all samples with total As â&#x2030;Ľ20 Âľg/l were analysed for speciated As including arsenobetaine, arsenite, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) and arsinate using high-pressure liquid chromatography (HPLC), and ICP with mass spectrophotometry (MS) analysis.[4] As(tox) was calculated as the sum of arsenobetaine, Ai (arsenite + arsenate), MMA and DMA. Urinary Cr, Cu, As and As(tox) concentrations were adjusted for urinary creatinine concentrations. A zero value was allocated when no metal was detected. Urinary concentrations of Cr, Cu, As(tot) and As(tox) adjusted for urinary creatinine as well as the sum of these metals were the primary outcome variables analysed both as continuous variables

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and as dichotomous variables with cut-offs ≥ the detection limits for the metals and ≥ environmental exposure limits for the metals. The number of hours and quantity of wood (litres) per week specifically used for catering and for household purposes, as well as the total for both purposes, were the primary exposure variables analysed as continuous variables. Univariate and bivariate exploration of the data was performed. Multiple linear regression analysis and logistic regression analysis were performed for the relationships between outcome and exposure variables, adjusting for potential confounders. Confounders were selected on an a priori basis, according to biological plausibility, or using bivariate testing if association with outcome was significant (p<0.1). Data were entered and analysed using Stata 8.

employed while the majority (63%) of household residents were unemployed. Less than 25% of participants had matriculated; one had tertiary education. About a third of the participants had smoked in their lifetime, and more than half consumed alcohol. There was no statistical difference in the median age of the caterers (median age 38, interquartile range (IQR) 26 - 48 years) and that of household residents (median age 35, IQR 23 - 54 years).

Wood usage among caterers and household residents

The study was conducted in accordance with the recommendations outlined in the Declaration of Helsinki,[5] and the proposal was approved by the University of Cape Town’s Research Ethics Committee (reference 286/2011).

Virtually all (95%) vendors operated only one braai-stand. Most participants, and household residents in particular, used wood 7 days per week (Table 2). Both the number of hours per week and the quantity of wood used per week were significantly higher among vendors. The number of hours spent cooking, and the quantity of wood used, was significantly (p<0.05) greater among the 29 participants (median quantity of wood in litres 360, IQR 175 - 3 600; median hours 56, IQR 35 - 72) whose urine was analysed for As(tox) than the remaining participants (median quantity of wood in litres 350, IQR 175 - 1 400; median hours 42, IQR 21 - 56).

Results

Urinary levels of Cr, Cu and As

Ethics

Participants

Demographic and lifestyle details of the 78 participants who produced a urine sample are shown in Table 1. Vendors were all

The Cr, Cu and As urinary levels among participants are described in detail in the previous paper.[2] Table 3 shows that detection and median levels of Cr, Cu and As among household residents and

Table 1. Demographic and lifestyle information Vendor* (n=40), n (%)

Resident* (n=38), n (%)

Total (N=78), n (%)

Female

20 (50)

19 (50)

39 (50)

Male

20 (50)

19 (50)

39 (50)

Vendor

36 (90)

0 (0)

36 (46)

Other job

4 (10)

14 (37)

18 (23)

Unemployed

0 (0)

24 (63)

24 (31)

28 (70)

27 (67)

55 (71)

Matric

9 (23)

6 (16)

15 (19)

Tertiary

1 (3)

0 (0)

1 (1)

Ever smoked

11 (28)

15 (39)

26 (33)

Consume alcohol

26 (65)

20 (53)

46 (59)

Variable Gender

Occupation

Schooling

*p<0.05 when comparing vendors with household residents.

Table 2. Wood usage among vendors and household residents Caterers (n=40), n (%)

Household residents (n=38), n (%)

Total (N=78), n (%)

≤3 days per week

12 (30)

10 (26)

22 (28)

4 - 6 days per week

9 (22)

2 (6)

11 (14)

7 days per week

19 (48)

26 (68)

45 (58)

Median hours per week

49 (18 - 84)

42 (8 -77)

45 (21 - 56)

Median quantity of wood used per week (l)*

1 200 (175 - 3 000)

175 (175 - 700)

288 (175 - 1 400)

Wood used

Days per week operating braai-stand/using wood in house

Wood usage, median (IQR)

IQR = interquartile range. *p-value <0.05 when comparing caterers with household residents.

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caterers were similar, but that those exceeding the Cr and As(tox) exposure limits were higher (although not statistically significant) among household residents. Of the 30 participants who reported eating fish in the previous 3 days, 28 (93%) reported 1 such meal; the other 2 participants reported 2 and 3 meals. More household residents than caterers reported eating fish in the 3 days prior to testing. The sum of urinary Cr, Cu and As levels was not different among household residents and caterers. Multivariate analysis showed that the time spent on using wood, and the quantity of wood used, either specifically for catering and/ or household use, were weakly positively associated with urinary As(tot) levels and As(tot) levels that exceeded the exposure limit once controlled for confounding (Table 4). When urinary Cr was detected, Cr levels and those exceeding the exposure limit were weakly positively associated with wood usage. The sum of urinary As, Cr and Cu levels was weakly positively associated with wood usage. As(tox) levels were also weakly positively associated with the number of hours and total quantity of wood used. As(tox) levels were inconsistently associated with wood usage when specifically used for either catering or household use. Urinary Cu was also inconsistently associated with wood usage. As mentioned, urinary levels of As(tot), As(tox) Cr and Cu were not found to be different among caterers and non-caterers in the first part of the study.

Discussion

To our knowledge, this is the first study of Cu, Cr and As absorption resulting from burning of CCA-treated wood by street vendors in informal communities in Cape Town. While the quantity of CCAtreated wood usage was greatest amongst vendors, the levels of As,

Cr and Cu were not different when food vendors and household residents were compared. The consistent positive association of wood exposure (time spent and total amount of wood used) and urinary levels of As(tot), Cr as well as with As(tox) and the sum of urinary As, Cr and Cu, indicates that exposure to CCA-treated wood could result in absorption of these metals. Confounding factors were controlled for in the analysis. Regarding these, fish consumption is particularly important as eating fish was strongly associated with As(tot) levels in the previous study. The amount of fish consumed is unlikely to have affected results in this study since 28 out of 30 participants who had consumed fish in the 3 days prior to testing, had eaten only 1 fish meal. The absence of an association of Cu with wood usage could be explained by exposure to Cu not being measurable in the study; exposure to this metal is common among household residents and workers.[6] Other exposure to Cr and inorganic As[7,8] is also probable but would have been unlikely to have correlated with wood usage. The small sample size could account for the nonsignificance of the association between wood usage and urinary levels of As and Cr. As levels in this study were higher in CCA-treated wood-exposed than non-exposed persons,[9] but substantially lower than those measured in timber CCA treatment plant workers[10] and other As-exposed industrial workers.[11] It is difficult to comment on the long-term consequences of As and Cr exposure at the levels measured in this study; few epidemiological studies exist that have investigated the health effects at these levels of exposure. The cross-sectional design of the study is a further limitation. Additionally, self-reporting of wood usage might not have been

Table 3. Comparison of urinary Cr, Cu and As among vendors and household residents Household*

Caterers*

Total

Variable

n (%)

N (%)

Ate fish in last 3 days

18 (50)

12 (31)

30 (40)

Detections (n)

n=38

n=40

n=78

10 (25)

9 (23.7)

19 (24.4)

33 (86.8)

37 (92.5)

70 (89.7)

As(tot)

38 (100)

40 (100)

78 (100)

As(tox), n=29

4 (33.3)

6 (35.3)

10 (34.5)

n=30

n=31

n=61

5 (17.2)

2 (6.5)

7 (11.7)

0 (0)

8 (26.7)

10 (32.3)

18 (29.5)

As(tox), n=29

4 (33.3)

3 (17.7)

7 (24.1)

n=30

n=31

n=61

0 (0 - 6.3)

0 (0 - 1.8)

0 (0 - 6.3)

13.7 (2.1 - 24.7)

9.7 (4.3 - 20)

11.7 (0 - 24.7)

As(tot)

16.8 (10.2 - 9.2)

17.8 (10.1 - 51.8)

17.8 (7 - 58.9)

As(tox), n=29

0.0 (0 - 7.4)

0.0 (0 - 13.0)

Sum of As, Cr and Cu

31.1 (20.5 - 47.1)

28.7 (21.5 - 49.2)

29.9 (21 - 49)

Above exposure limit

Creatinine (Îźg/g), median (IQR)

IQR = interquartile range. *p-value <0.05 when comparing vendors with household residents. [12-14] Exposure limit in Îźg/g creatinine for Cr = 4; Cu = 62.8, As(tot) = 30; As(tox) = 8.3 Note: A value of 0 was allocated when no metal was detected.

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0.03 (0.18)

0.004 (0.62) 0.05 (0.37)

5.4 (0.99)

0.04 (0.34) 0.1 (0.99) 1.0 (0.13)

0.3 (0.23) 1.0 (0.14)

Catering and household

Acknowledgements. We thank the UCT Vice-Chancellor’s Strategic Fund, UCT Research Committee and National Research Foundation for their financial support for this study. We extend special thanks to the participants and community development workers from Langa and Kayamandi (Stellenbosch) for arranging access to the study areas.

0.03 (0.29) 0.03 (0.24) 0.18 (0.23)

-0.3 (0.26) -5x10-5 (0.34) 0.4 (0.89) -0.005 (0.92) -0.10 (0.17) 4x10-5 (0.85)

-5x10-5 (0.94) 5x10-5 (0.93) -0.03 (0.96)

4x10-6 (0.18) 1.00 (0.88) 1.00 (0.35) 0.3 (0.75) 0.1 (0.85) 1.0 (0.08) 0.03 (0.15) 1.02 ( 0.13) 1.02 (0.05)

0.3 (0.40) 1.0 (0.22) 0.3 (0.23) 1.0 (0.18) 0.09 (0.34) 1.02 (0.08)

Household Catering Catering and household

The present study provides evidence that use of wood likely to contain CCA-treated timber as a fuel for informal catering and household purposes may increase the absorption of inorganic As and Cr among the Cape Town communities studied. Exposure to CCA-treated wood can potentially contribute to health problems in such informal settlements, which are already recognised in developing countries to be particularly vulnerable. A larger study, having a longitudinal design, would more accurately investigate whether use of CCA-treated wood does indeed lead to increased absorption of inorganic As and Cr and result in adverse health effects. Interventions to prevent the use of CCA-treated wood in informal settlements, and environmental monitoring in these areas, are required.

References 1.

*Confounders: Age, gender, education, smoking, eating fish, eating and drinking while cooking or braaing.

0.13 (0.26) 0.04 (0.76) Sum of As, Cr and Cu Urinary level (µg/g creatine)

-0.09 0.41) 0.03 (0.57) -0.18 (0.18) -0.01 (0.30) As(tox) Urinary level (µg/g creatine) Detected (detected/not detected)

0.03 (0.42) -0.04 (0.35) Copper Urinary level (µg/g creatine)

0.06 (0.04) 1.04 (0.06) 1.00 (0.66) -0.01 (0.72) 0.99 (0.65) 1.01 (0.33) Chromium Urinary level (µg/g creatine) >exposure limit (>limit/≤limit) Detected (detected/not detected)

Arsenic Urinary level (µg/g creatine) >exposure limit (>limit, ≤limit)

0.09 (0.43) 1.02 (0.25)

0.04 (0.70) 1.01 (0.29)

Household

Hours per week

accurate. Regarding this latter point, participants could not report accurately whether they had used wood with the green tint characteristic of CCA treatment. Another possible limitation arises from selection of urine samples for further analysis for As(tox) based on As(tot) levels exceeding 20 µg/g creatinine rather than on quantity of wood used. Nevertheless, wood usage among participants whose urine was sent for As speciation was significantly greater than among the other participants.

Conclusions

Catering

Table 4. Multivariate relationship between wood usage and urinary levels of As, Cr and Cu*

Regression coefficient/odds ratio (p-value)

Quantity of wood per week (l)

RESEARCH

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

N iyobuhungiro R, Naidoo S, Dalvie MA, Von Blottnitz H. Occurrence of CCA-treated timber in caterers’ fuel wood stocks in the Cape Town region. S Afr J Sci 2013;109(1/2). [http://dx.doi.org/10.1590/sajs.2013/1015] Chou AS, Colman BJ, Tylendaa C, De Rosa C. Chemical-specific health consultation for chromated copper arsenate chemical mixture: port of Djibouti. Toxicol Ind Health 2007;23:183-208. [http://dx.doi.org/10.1177/0748233707076810] World Health Organization. Biological Monitoring of Chemical Exposure in the Work Place. Geneva: World Health Organization, 1996. http://whqlibdoc.who.int/hq/1996/ WHO_HPR_OCH_96.1.pdf (accessed 2 February 2012). Lintschinger J, Schramel P, Hatalak-Rauscher, Wendler I, Michalke B. A new method for the analysis of arsenic species in urine by HPLC-ICP-MS. Fresenius Journal of Analytical Chemistry 1998;362:313-318. WMA. Declaration of Helsinki – Proposed International Guidelines for Biomedical Research involving Human Subjects. 59th WMA General Assembly, Seoul, October 2008. http://www.wma.net/en/30publications/10policies/b3/17c.pdf (accessed 4 October 2011). ATSDR. Toxicological Profile for Copper (Update). Atlanta, GA: ATSDR, US Department of Health and Human Services, 2004. http://www.atsdr.cdc.gov/toxprofiles/tp132.pdf (accessed 2 February 2012). ATSDR. Toxicological Profile for Arsenic. Atlanta, GA: ATSDR, US Department of Health and Human Services. 2007. http://www.atsdr.cdc.gov/toxprofiles/tp2.pdf (accessed 2 February 2012). ATSDR. Toxicological Profile for Chromium. Atlanta, GA: ATSDR, US Department of Health and Human Services.2003. http://www.atsdr.cdc.gov/toxprofiles/tp7.pdf (accessed 2 February 2012). Shah AQ, Kazi TG, Arain MB. Accumulation of arsenic in different fresh water fish species – potential contribution to high arsenic intakes. Journal of Food Chemistry 2009;112(2):520-524. [http://dx.doi.org/10.1016/j.foodchem.2008.05.095] Cocker J, Morton J, Warren N, Wheeler JP, Garrod ANI. Biomonitoring for chromium and arsenic in timber treatment plant workers exposed to CCA wood preservatives. Ann Occup Hyg 2006;50(5):517-525. [http://dx.doi.org/10.1093/annhyg/mel009] Vimercati L, Carrus A, Sciannamblo G. A study of factors influencing urinary arsenic excretion in exposed workers. Int J Environ Health Res 2009;369-377. [http://dx.doi. org/10.1080/09603120903079349] Ellingsen DG, Horn N, Aaseth J. Handbook on the Toxicology of Metals. 3rd ed. Waltham, Massachusetts: Academic Press, 2007:529-546. Lauwerys RR, Hoet P. Industrial Chemical Exposure; Guidelines for Biological Monitoring. 2nd ed. New York: Lewis Publishers, 1993. Hays SM, Aylward LL, Gagné M, Nong A, Krishnan K. Biomonitoring equivalents for inorganic arsenic. Regul Toxicol Pharmacol 2010;58(1):1-9. [http://dx.doi.org/10.1016/j. yrtph.2010.06.002]

Accepted 10 January 2013.

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Critical value reporting: A survey of 36 clinical laboratories in South Africa E Schapkaitz, MB BCh, FCPath (Haem), MMed (Haem); Z Mafika, MB ChB Department of Molecular Medicine and Haematology, National Health Laboratory Service and University of the Witwatersrand, Johannesburg, South Africa Corresponding author: E Schapkaitz (elise.schapkaitz@nhls.ac.za)

Objective. Critical value policies are used by clinical laboratories to decide when to notify caregivers of life-threatening results. Despite their widespread use, critical value policies have not been published locally. A survey was designed to determine critical value policies for haematology tests in South Africa. Methods. A survey was carried out on 136 identified laboratories across South Africa in January 2013. Of these, 36 responded. Data collected included critical value policies, critical values for haematology parameters, and critical value reporting. Results. Of the 36 laboratories surveyed, 11.1% (n=4) were private, 33.3% (n=12) were affiliated to academic institutions and 55.6% (n=20) were peripheral or regional National Health Laboratory Service laboratories. All the laboratories confirmed that they had a critical value policy, and 83.3% of such policies were derived from local clinical opinion. Mean low and high critical limits for the most frequently listed tests were as follows: haemoglobin <6 and >20 g/dl, platelet count <41 and >1 000 ×109/l, white cell count <2 and >46×109/l, activated partial thromboplastin time >101 seconds, and international normalised ratio >6. In almost all cases critical value reporting was performed by the technologist on duty (97.2%). The majority of laboratories required that the person notified of the critical value be the doctor who ordered the test or the caregiver directly involved in the patient’s care (83.3%); 73.3% of laboratories indicated that they followed an algorithm if the doctor/caregiver could not be reached. Conclusion. Each laboratory is responsible for establishing clinically relevant critical limits. Clinicians should be involved in developing the laboratory’s critical value policy. The findings of this survey may be of value to local laboratories that are in the process of establishing or reviewing critical value policies. S Afr Med J 2014;104(1):65-67. DOI:10.7196/SAMJ.7057

Critical value policies used by clinical laboratories ensure that caregivers are notified of patients’ lifethreatening results. Lundberg[1] was the first author to define critical values as results that may lead to adverse outcomes for patients if clinicians were not notified urgently of the critical result. He developed a system whereby laboratories identified critical results and contacted the clinician caring for the patient.[1] Critical value reporting has subsequently become an accreditation requirement, with most laboratories having implemented critical value policies as a quality assurance practice. Although critical value reporting is widely accepted, it poses certain challenges. Each laboratory is responsible for establishing critical values policies in conjunction with local clinical opinion, review of laboratory practice and the relevant published literature. A number of international publications have described critical value lists. In the early 1990s, Kost[2-3] published surveys of adult and paediatric critical values from medical centres in the USA, and more recently the College of American Pathologists[4] compared the critical values of 163 of its participants. Although these resources are useful for critical value assessment, they may not be clinically relevant to South Africa (SA). Moreover, local lists are not readily available. A survey was therefore designed to determine the critical value policies for haematology tests in clinical laboratories in SA.

Methods

Study design

A survey form was sent to 136 identified laboratories across SA in January 2013. Of these, 36 (26.5%) responded. Critical values

were defined as results requiring urgent notification. Participating laboratories were asked to provide high and low critical values for haematology tests for adults and children and to document their critical value reporting policy. The results were reviewed against published international studies comparing critical values across a large number of laboratories.

Statistical analysis

The survey findings were recorded on an Excel spreadsheet. The mean, standard deviation and range were calculated for each test.

Results

Data were collected from 36 laboratories, of which 11.1% (n=4) were private, 33.3% (n=12) were affiliated to academic institutions, and 55.6% (n=20) were peripheral or regional National Health Laboratory Service (NHLS) laboratories.

Critical value policies

Table 1 summarises the critical value policies of the laboratories surveyed. All confirmed that they had a critical value standard operating policy based on the following sources: local clinical opinion (63.9%, n=23); the published literature (8.3%, n=3); local opinion and the published literature (19.4%, n=7); and review of laboratory practice (8.3%, n=3).

Critical value reporting

Of the laboratories, 97.2% (n=35) indicated that reporting was commonly undertaken by the technologist on duty. In addition,

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19.4% of the laboratories (n=7) authorised reporting by a call centre. All laboratories reported critical results telephonically as well as via an automated method such as a fax, e-mail or sms (5.6%, n=2). The majority of the laboratories required that the person notified of the critical value be the doctor or nurse directly involved in the patient’s care, and/or the person who ordered the test (83.3%, n=30). A minority of laboratories (16.7%, n=6) permitted reporting of critical values to any nurse, doctor on call or clerical staff member (or did not specify). Of the 15 laboratories that responded to this question, 73.3% (n=11) reported following an algorithm in the event that the caregiver Table 1. Characteristics of critical value policies Laboratories, n (%)

Critical value policies Written policies for establishing critical values Yes

36 (100)

0 (0)

Source Local clinical opinion

23 (63.9)

Published literature

3 (8.3)

Local clinical opinion and literature

7 (19.4)

Review of laboratory practice

3 (8.3)

could not be reached. This resulted in additional time spent. The steps in the algorithms included contacting the departmental head or hospital superintendent (18.1%, n=2) or the doctor on call (45.5%, n=5), delivering the critical values via messenger or automated message (18.1%, n=2), or phoning at least three times (18.1%, n=2).

Critical values for haematology tests

Mean low and high critical limits for the most frequently listed tests were as follows: haemoglobin <6 and >20 g/dl, platelet count <41 and >1 000×109/l, white cell count <2 and >46×109/l, activated partial thromboplastin time (aPTT) >101 seconds, and international normalised ratio (INR) >6 (Table 2). Laboratories also included presence of malaria (72.2%, n=26), haemolysis (16.7%, n=6) and/ or primitive cells/blasts (30.6%, n=11) in their critical value lists on peripheral blood review. A minority of laboratories reported additional critical values for coagulation assays, namely fibrinogen (13.9%, n=5), d-dimer (13.9%, n=5), coagulation factors (2.8%, n=1) and anti-Xa (2.8%, n=1). Specific critical limits for children and neonates were reported by 5.6% (n=2) and 13.9% (n=5) of laboratories, respectively. In addition, 5.6% of laboratories (n=2) reported paediatric critical values that were similar to their adult values. Table 3 shows the comparison of the mean, low and high critical limits of the three laboratory categories. The private laboratories reported a stricter cut-off for the mean lower limit for haemoglobin

Population-specific critical values Yes

4 (11.4)

31 (88.6)

Table 2. Adult and paediatric mean critical values Critical value, mean (±SD)

Critical value reporting

Test

Technologist on the bench

35 (97.2)

S enior staff (lab manager, registrars, pathologists)

12 (33.3)

Call centre

7 (19.4)

Automated method

2 (5.6) 30 (83.3)

Staff nurse, doctor on call or clerical staff

6 (16.7)

High

Haemoglobin (g/dl)

6 (±0.9)

20 (±0.5)

Platelet count (×109/l)

41 (±19.8)

1 000 (±0)

Adult critical values

White cell count (×10 /l)

2 (±0.9)

46 (±7.0)

aPTT* (seconds)

101 (±45.4)

INR

6 (±1.5)

Haemoglobin (g/dl)

9 (±1.1)

29 (±9.2)

Platelet count (×109/l)

40 (±34.6)

White cell count (×10 /l)

4 (±0)

53 (±11.6)

Receiving critical values aregiver (nurse or doctor) directly C involved in the patient’s care and/or doctor who ordered the test

Low

Paediatric critical values

Algorithm in place if the caregiver is unreachable Yes

11 (73.3)

4 (26.7)

SD = standard deviation; aPTT = activated partial thromboplastin time; INR = international normalised ratio. * Laboratories need to consider the aPTT results specific for their reagent and analyser when setting critical limits. Nine of the laboratories reported a prolonged aPTT on heparin therapy as a critical value.

Table 3. Comparison of adult critical value means Critical value, mean (±SD) High

Low Test

Academic

Peripheral

Private

Academic

Peripheral

Private

Haemoglobin (g/dl)

6 (±0.9)

5 (±0.8)

6.8 (±1.0)

20 (±0.8)

20 (±0.3)

20 (±0)

Platelet count (×109/l)

33 (±22.6)

43 (±19.7)

47.5 (±5.0)

1 000 (±0)

White cell count (×109/l)

2 (±1.0)

3 (±0.8)

2 (±0)

44 (±7.4)

48 (±4.1)

37.5 (±17.7)

aPTT (seconds)

104 (±47.5)

115 (±10.0)

121 (±84.1)

INR

6 (±1.6)

6 (±1.0)

4.4 (±0.5)

SD = standard deviation; aPTT = activated partial thromboplastin time; INR = international normalised ratio.

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and platelet count, and for the upper limit for INR compared with the academic and peripheral and regional NHLS laboratories. For example, the mean lower limit for haemoglobin was 6.8 g/ dl for private laboratories, 6.0 g/dl for laboratories affiliated to academic institutions, and 5.0 g/dl for peripheral and regional NHLS laboratories. Similarly, the mean upper limit for the INR was 4.4 for private laboratories and 6 for the laboratories affiliated to academic institutions and the peripheral and regional NHLS laboratories.

Discussion

The national focus is currently on improving laboratory commitment to service, efficiency and patient safety. Critical value reporting is an important laboratory quality indicator. The laboratories surveyed indicated that policies were in place for reporting critical values in accordance with accreditation requirements. In the absence of local published literature, the majority of laboratories have relied on local clinical opinions to develop critical value limits. The findings of this survey may be of value to local laboratories that are in the process of establishing or reviewing their critical values policies. All laboratories surveyed reported adult critical values for the commonly performed haematology tests, namely haemoglobin, platelet count, white cell count, INR and aPTT, that may reflect lifethreatening emergencies. The ranges for the critical values reported were very wide. For example, the lower limits for haemoglobin and platelet count ranged from 4 to 8 g/dl and from 10 to 100×109/l, respectively. Laboratories may wish to review their given critical value(s) for clinical relevance in their specific settings. The variability of the mean critical values between the three laboratory categories is shown in Table 3. The private laboratories reported a stricter cut-off for the mean lower limit for haemoglobin and platelet count and the mean upper limit for INR compared with the academic, peripheral and regional NHLS laboratories. International surveys report similar cut-offs to those reported by the private laboratories. Kost[2] and Wagar et al.[4] reported mean lower limits for haemoglobin of 6.6 and 6.9 g/dl, respectively, as well as a mean upper limit for the INR of 4.0. In addition to being developed in conjunction with the published literature, it is important that critical value policies are reviewed by local clinicians to ensure that cut-off values are clinically relevant. As seen in the landmark Transfusion Requirements in Critical Care trial,[5] a restrictive transfusion trigger of <7 g/dl for younger (<55 years) and less ill (APACHE II score <20) patients is a clinically relevant limit. Clinical trials, however, show a wide variation in triggers for transfusion.[6] Similarly, an INR of >5 is a clinically relevant limit because it is associated with an increased risk of bleeding.[7] An INR >5 requires urgent intervention, such as withholding warfarin doses or administering specific treatment, such as vitamin K, fresh-frozen plasma or prothrombin complex concentrates, to reverse the effect of warfarin. [7] This serves as a further example of the important role clinicians play in developing their local laboratory’s critical value policies.

Critical value policies require notification of the abnormal result to someone who can react appropriately. A minority of laboratories allowed reporting of critical values to someone other than the direct caregiver, e.g. a nurse, a doctor on call or a member of the clerical staff, with the risk that the recipient may know little about the patient’s clinical condition and of the clinical significance of the critical result. The majority, however, required that the person notified of the critical value be the doctor who ordered the test or the caregiver directly involved in the patient’s care, as is recommended in the literature.[8] Furthermore, significantly, the laboratory staff member can interpret the result with the direct caregiver, and suggest further investigations.[9] The reporting of critical values generates a significant workload.[10] Published studies report that 1 - 15% of coagulation tests are critical values requiring urgent notification.[11] Laboratories may therefore need to rely on call centres to perform these administrative functions in the future.

Conclusion

Each laboratory is responsible for establishing clinically relevant critical limits and ensuring that the appropriate caregivers are rapidly notified, so that quality patient care can be administered. Clinicians should be involved in developing the laboratory’s critical value policy. Critical value calls are costly for laboratories, as extensive time is required by skilled staff to handle reporting. Automated notification systems may need to be considered and investigated.

References 1. Lundberg GD. When to panic over an abnormal value. MLO Med Lab Obs 1972;4:47-54. 2. Kost GJ. Critical limits for urgent clinician notification at US medical centers. JAMA 1990;263(5):704-707. [http://dx.doi.org/10.1001/jama.263.5.704] 3. Kost GJ. Critical limits for emergency clinician notification at United States children’s hospitals. Pediatrics 1991;88(3):597-603. 4. Wagar EA, Friedberg RC, Souers R, Stankovic AK. Critical values comparison: A College of American Pathologists Q-Probes survey of 163 clinical laboratories. Arch Pathol Lab Med 2007;131(12):1769-1775. 5. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999;340(6):409-417. [http://dx.doi.org/10.1056/ NEJM199902113400601] 6. Hebert PC, Wells G, Martin C, et al. A Canadian survey of transfusion practices in critically ill patients. Transfusion Requirements in Critical Care Investigators and the Canadian Critical Care Trials Group. Crit Care Med 1998;26(3):482-487. [http://dx.doi.org/10.1097/00003246-199803000-00019] 7. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed.). Chest 2008;133(6 suppl):160S-198S. [http://dx.doi.org/10.1378/chest.08-0670] 8. Genzen JR, Tormey CA. Pathology consultation on reporting of critical values. Am J Clin Pathol 2011;135(4):505-513. [http://dx.doi.org/10.1309/AJCP9IZT7BMBCJRS] 9. Howanitz PJ, Steindel SJ, Heard NV. Laboratory critical values policies and procedures: A college of American Pathologists Q-Probes Study in 623 institutions. Arch Pathol Lab Med 2002;126(6):663-669. 10. Dighe AS, Rao A, Coakley AB, Lewandrowski KB. Analysis of laboratory critical value reporting at a large academic medical center. Am J Clin Pathol 2006;125(5):758-764. [http://dx.doi.org/10.1309/ R53XVC2U5CH6TNG8] 11. Pai M, Moffat KA, Plumhoff E, Hayward CP. Critical values in the coagulation laboratory: Results of a survey of the North American Specialized Coagulation Laboratory Association. Am J Clin Pathol 2011;136(6):836-841. [http://dx.doi.org/10.1309/AJCP8O8GIPPPNUSH]

Accepted 27 May 2013.

January 2014, Vol. 104, No. 1

SAMA

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GUEST EDITORIAL

Mental healthcare in the community During the last decade or so, there has been a growing international recognition of the high burden of disease associated with mental health problems,[1] with local research that supports this view.[2] The most comprehensive study of common mental disorders in South Africa, the South African Stress and Health Study,[3] carried out in 1999, showed a lifetime prevalence for these disorders of 30.3%. Of those who had had a mental disorder in the past year, only 25.2% sought treatment and a tiny number, 5.7%, used any formal mental health service.[4] In the years since that study, the HIV/AIDS and substance abuse epidemics have contributed further to this burden, while at the same time mental health services have seen a reduction in hospital beds with de-institutionalisation, yet little growth in community-based services.[5] Historically, mental health services have been poorly funded and left to a small minority of professionals in dedicated services.[6] The reasons for this are complex and interwoven. However, important themes include the stigmatisation of mental illness, the historical (but relatively modern trend) of excluding those with mental illness in mental asylums (which the philosopher Foucault attributed to the need for social exclusion of the ‘unreasonable’ as a product of Enlightenment thinking),[7] and the origins of psychiatry within these institutions. Additionally, the traditional way of measuring the impact of disease in terms of mortality statistics led to an underestimation of the impact of mental health disorders, which are characterised by long-term disability rather than extensive mortality, something that has been rectified in more recent studies that have used the measure of Disability Adjusted Life-Years (DALYs). We are therefore left with the current situation, where it has become increasingly apparent that mental illness is no longer something that can be hidden from public view and left to a small group of specialists. With only 772 psychiatrists[8] for a population of nearly 53 million[9] in South Africa, it is clear that such an approach will lead to further compromise of an already marginalised yet substantial portion of our society. It is time that we made it clear that mental illness is everyone’s concern, and that all healthcare practitioners recognise that we have a role to play in the care of people living with such illnesses. The good news is that there has been increasing recognition that information on effective, evidence-based interventions for mental health problems needs to be made available for healthcare practitioners at every level of service. Extensive resources have been developed for this purpose, such as those produced by the World Health Organization’s Mental Health Gap Action Program,[10] which

are specifically designed for low- and middle-income settings and are freely available. The evidence shows that there is a great deal that can be done by an array of service providers at the primary level and that mental health services can be upgraded in a manner that is both practical and cost effective. The key therefore is to present mental healthcare in a manner that is accessible to a wide range of non-specialist practitioners and, additionally, to ensure that such care is offered in a manner that acts to counter a legacy of exclusion and discrimination. The articles in this edition of CME have therefore been selected to focus on developing an understanding of the mental health assessment that facilitates its use in a primary setting, on the management of a few key disorders that present at this level, and on the integration of mental health with general principles of primary care. Lastly, in the ‘More about’ articles, an attempt is made to provide some understanding of the recent major changes to the context in which mental healthcare is delivered and to provide some indication of how our attitudes and priorities need to change as we move from an era of exclusion and removal to one of partnership and empowerment. John Parker Guest editor john.parker@westerncape.gov.za

5. 6. 7. 8. 9. 10.

1. Murray CJL, Lopez AD. The global burden of disease: A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Cambridge: Harvard School of Public Health, 1996. 2. Bradshaw D, Groenewald P, Laubscher R, et al. Initial burden of disease estimates for South Africa, 2000. S Afr Med J 2003;93:682688. 3. Stein DJ, Seedat S, Herman A, et al. Lifetime prevalence of psychiatric disorders in South Africa. Br J Psychiatry 2008;188:465471. 4. Seedat S, Williams DR, Herman JJ, et al. Mental health service use among South Africans for mood, anxiety and substance use disorders. S Afr Med J 2009;99:346-352. Van Heerden S, Hering L, Dean C, Stein DJ. Providing mental health services in general medical settings in South Africa. Mental health friendly services in mental health friendly hospitals. S Afr Med J 2008;98:4-6. Jacob KS, Sharan P, Mizra I, et al. Mental health systems in countries: Where are we now? (No. 4 in Global Mental Health Series.) Lancet 2007;370(9592):1062-1077. [http://dx.doi.org/10.1016/S01406736(07)61241-0] Foucault M. Madness and Civilisation: A History of Insanity in the Age of Reason. London: Tavistock, 1971. HPCSA Iregister: Psychiatrists. http://iregister.hpcsa.ca.za/RegisterSearch.aspx (accessed 23 October 2013). Stats SA. SA Population Data. http://www.statssa.gov.za/publications/statsdownload.asp?PPN=P0302&SCH=5500 (accessed 24 October 2013). World Health Organization Mental Health Gap (MHGAP) Action Program. http://www.statssa.gov.za/ publications/statsdownload.asp?PPN=P0302&SCH=5500 (accessed 24 October 2013).

S Afr Med J 2014;104(1):68 DOI:10.7196/SAMJ.7734

January 2014, Vol. 104, No. 1

CONTINUING MEDICAL EDUCATION

REVIEW

A broad diagnostic framework to simplify the approach to mental disorders in primary care J Parker, MB BCh, FCPsych (SA) OPD, Outreach and Medium Term Services, Lentegeur Hospital, Division of Public Mental Health, Department of Psychiatry and Mental Health, University of Cape Town, South Africa Corresponding author: J Parker (john.parker@westerncape.gov.za)

Overemphasis on detailed classification of a psychiatric disorder at a primary level assessment may be unhelpful and prone to error. True rigour demands a continuous process of hypothesis formation that guides further enquiry. A simple categorisation of priority conditions provides a useful framework for such a process. This approach has been set out by the World Health Organization (WHO) Mental Health Gap Action Program (MHGAP) Intervention Guide, which can then be adapted for use in the South African context. This then provides the basis for further enquiry and risk assessment at the initial consultation. S Afr Med J 2014;104(1):69-71. DOI:10.7196/SAMJ.7717

A key barrier to mental health assessment at the primary care level is the limited time available to practitioners owing to high service loads. It is likely that this has served as a deterrent to carrying out any mental health assessment at all. Therefore, a key strategy to developing mental health services at the primary level has been the development of simplified approaches, focusing on priority disorders. In most cases, the very wide variety of diagnostic possibilities in psychiatric classification systems do not constitute much more than syndromes. They are mostly collections of signs and symptoms, with considerable variability within categories and some degree of overlap between categories. While diagnostic reliability in psychiatry has been greatly improved with the use of these systems, this does not automatically infer validity;[1] it is important to be clear about this. What really matters at the clinical level is utility or the extent to which a diagnostic label is of use in helping the patient.[2] Therefore, being overly pedantic about diagnosis, particularly early on in the course of an assessment, is seldom helpful and greatly error prone. True rigour also involves an approach which has at its heart a continuous process of hypothesis formation and revision as further evidence is generated. This is particularly true in psychiatry, and a simple categorisation of the various problems that may present can guide one in terms of investigation and intervention. Such an approach has been developed in the World Health Organization (WHO) Mental Health Gap Action Program (MHGAP) Intervention Guide,[3] which focuses on the following 11 priority conditions: • depression • psychosis • epilepsy/seizures • developmental disorders • behavioural disorders • dementia • alcohol use disorders • drug use disorders • self-harm/suicide • bipolar disorder • other significant or medically unexplained complaints. This has been developed as a model guide, aimed at non-specialists, which can then be further adapted to local conditions. It sets out general

principles of care, key presenting symptoms of each of the conditions and modules on the assessment and management of each. This guide – readily available as a free download from the WHO website – is extremely useful. This approach can easily be adapted to the South African context, with additional emphasis on anxiety disorders, which have been identified as being highly prevalent,[4] and on medical conditions other than epilepsy that may present with mental health symptoms. Common presenting features and critical areas that should be considered for each disorder are set out below.

Disorders associated with an underlying general medical condition including epilepsy/seizures

Common presentations • associated signs or symptoms suggestive of physical illness • evidence of risk factors associated with a particular physical illness • acute or chronic onset • brief or extended periods of disorientation or confusion and, in the case of epilepsy, convulsive movements or seizures • fluctuating level of consciousness • cognitive assessment revealing marked impairment • poor insight, particularly in delirium. Critical considerations • An underlying medical disorder should always be considered in any psychiatric illness and needs to be vigorously excluded. • Manage any disturbed or aggressive behaviour to complete the investigations. • Identify and treat the underlying condition.

Drug and alcohol use disorders

Common presentations • Always screen for these disorders in the history-taking. If there is any suspicion whatsoever that this may be the case, further investigation must be considered, including laboratory or side-room testing. • Always consider the possibility of substance abuse or dependence being the underlying cause for almost any type of psychiatric symptom. • Conversely, substance abuse may occur as a result of distress due to another underlying disorder.

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• Where these are the presenting complaints, either directly or via a third party, they must be handled with appropriate skill and tact, as a particular degree of motivation is required in managing such disorders. Critical considerations • risk of suicide • risk of harm to self and others • medical complications related to intoxication, withdrawal and complications of use.

Self-harm and suicide

Common presentations • current thoughts, acts or plans to harm self or to commit suicide • a recent act of self-harm or a suicide attempt • a history of such thoughts, plans or acts. Critical considerations • In many cases, such information will not be presented spontaneously and must be elicited from the patient. • This must be explored in any presentation where it is a possibility (as set out in other presentations). • Further risk assessment is essential.

Psychotic disorders

Common presentations • Although presentation in these disorders tends to be fairly dramatic, with unusual behaviour, perceptual disturbances or disorders of thinking, this is not invariably the case. • Take note of the fact that, in most cases, insight is poorly preserved. • It is vital to consider these disorders when the complainant is not the patient himself, and the patient seems to have little or no awareness that there may be a problem, or that the problem relates to his own behaviour. • It is essential to pay careful attention to collateral information. • It is useful to exercise some degree of patience when assessing these cases, and to be extremely observant for any inconsistencies in the presentation. • Often information that seems initially to hold together well begins to crumble when placed under careful scrutiny. Critical considerations • Establish the degree of risk to the patient and to others and ensure that collateral information is obtained. • It is likely that scenarios will sometimes arise where it is impossible to establish the truth with any degree of certainty. The key here is to ascertain any possible risks and to err on the side of caution.

Bipolar disorder

Common presentations • Key features are manic behaviour or a history of mania in someone who suffers from depression. • It is critical to note that there are degrees of mania, that manic behaviour may not be expressed in the consultation, and that there is often a loss of insight, so collateral information is vital. • Individuals with symptoms of mania can be extremely selfconfident and even seductive, intimidating or aggressive – so safety considerations are essential. • Lack of sleep is a useful feature in mania, but not generally a complaint as it manifests as increased energy and a decreased need for sleep. Critical considerations • risk of suicide • risk of harm to self or others, either directly or as a result of reckless behaviour • risk to financial interests and reputation.

Depression and generalised anxiety disorders

Common presentations • Patients with this group of disorders usually present themselves as being in need of help, or tend to rapidly recognise that there may be a problem. • In some cultures, however, men in particular may be reluctant to admit to being depressed and tend to present with some of the symptoms of depression or to somatise. • In some cultures where there is little indigenous language for depression, the symptoms are expressed in the form of physical, rather than emotional, complaints. • Although the onset of the problem is often associated with a significant stressor, this is not always the case. • There is often considerable overlap between depression and anxiety symptoms. Critical considerations • Establish whether there is any risk of suicide and whether the patient is at risk of abuse, and establish their current level of function. • Sleep disturbance is a common and distressing feature of these disorders, making individuals with such disorders extremely vulnerable to sedative abuse. A thorough knowledge of sleep hygiene is a critical tool at the primary level.

Other significant or medically unexplained complaints, including specific anxiety disorders

Common presentations Particular disorders in this group may present with particular symptoms, such as the following:

f i g h t h ea rt b u r n w i t h g e lu s i l

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• obsessions and compulsive behaviour in obsessive-compulsive disorder • anxiety symptoms and disturbing recollections following trauma in post-traumatic stress disorder (PTSD) • panic attacks in panic disorder • situation-specific anxiety in the specific phobias • anxiety or panic in social situations in social phobia • in some cases, particularly with panic attacks, the symptoms may not initially be identified as being caused by anxiety, but are often attributed to a physical causation such as asthma attacks, angina, fainting, seizures • one or more somatic symptoms that cannot be explained despite appropriate medical investigation. Critical considerations • Assess the risk of suicide. • Presentations may be extremely dramatic, as in a panic attack, but in other cases may seem rather trivial. However, the impact of anxiety on social and occupational function should not be underestimated and needs to be carefully assessed. • In PTSD, a critical first step is always to ensure that a sense of safety is restored. • Psycho-education is an important primary level tool in managing these disorders and a good understanding of the cycle of panic and of relaxation techniques is essential. • In the case of medically unexplained symptoms, be clear about what degree of investigation can reasonably be expected and try to avoid conflict about this.

Dementia and other mental health problems in the elderly

Common presentations • The obvious key is the age group of the patient concerned, but equally important to consider is the duration and onset of the disorder. • Delirium and depression may present in a similar way or co-exist with dementia, so must be considered and excluded. Critical considerations • The exclusion of medical causes is an urgent priority. • A careful screen is essential in the frail and those with dementia to assess their ability to cope with activities of daily living. • Always consider the possibility of abuse. • Old age and either chronic or terminal illnesses are all-important risk factors for suicide.

Mental health problems/behavioural disorders in children Common presentations • changes in behaviour or performance at school

• • • •

withdrawal and refusal to play with others refusal to attend school constantly getting into trouble or fighting with other children marked restlessness and an inability to pay attention.

Critical considerations • It is important to establish the pattern and onset of the behaviour, and whether it is observed in all areas of the child’s life, or only, for example, at school. This may provide important clues as to the origin of the behaviour. • It is vital in children to always consider medical conditions, particularly those such as epilepsy, which may begin in childhood. • Always explore carefully for the possibility of abuse, to which children are particularly vulnerable, be it physical, sexual, emotional or due to neglect.

Intellectual disability/developmental disorders

Common presentations • The most common presentation is of children with a history of developmental delay or difficulty in performing at school. • Less common presentations include those who present with a history of behaviour inappropriate for their age, but that would be usual in someone who is younger, and individuals who suddenly become unable to cope after being placed in a position requiring greater intellectual ability than was previously required. • Useful areas to focus on include developmental milestones and school career, as well as the person’s ability to manage complex tasks such as handling finances or negotiating with civil authorities. Critical considerations • Exercise caution in coming to a final diagnosis and in sharing this with the patient and his family. • There is usually little treatment that can be offered as a matter of urgency, and the major intervention involves helping social and family systems to adapt to the fact of the disability. • Individuals with intellectual disability are particularly vulnerable to abuse.

References 1. Berk M. The DSM-5: Hyperbole, hope or hypothesis? BMC Med 2013;11:128. [http://dx.doi. org/10.1186/1741-7015-11-128] 2. Kendell R, Jablensky A. Distinguishing between the validity and utility of psychiatric diagnoses. Am J Psychiatry 2003;160:4-12. [http://dx.doi.org/10.1176/appi.ajp.160.1.4] 3. WHO. World Health Organization Mental Health Gap Action Program (MHGAP) Intervention Guide. http:// www.who.int/mental_health/evidence/mhGAP_intervention_guide/en/ (accessed 23 October 2013). 4. Stein D, Seedat S, Herman A, et al. Lifetime prevalence of psychiatric disorders in South Africa. Br J Psychiatry 2008;192(2):112-117. [http://dx.doi.org/10.1192/bjp.bp.106.029280]

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CONTINUING MEDICAL EDUCATION

ARTICLE SUMMARY

An update on attention deficit hyperactivity disorder (ADHD) W Vogel, MB BCh, MMed, FCPsych (SA), Certificate in Child and Adolescent Psychiatry Division of Child and Adolescent Psychiatry, Red Cross War Memorial Children’s Hospital, Cape Town, and University of Cape Town, South Africa Corresponding author: W Vogel (wendy.vogel@uct.ac.za)

Although the diagnosis of attention deficit hyperactivity disorder (ADHD) attracts much media attention and is seen by many to be a disorder of the 20th century, it was already described in the 18th century.[1] This article highlights the latest recommendations in the assessment and treatment of ADHD across the age range. It gives an update on the diagnostic criteria for ADHD, which have been revised in the updated Diagnostic and Statistical Manual of Mental Disorders (DSM 5).[2]

How to diagnose ADHD

There are no diagnostic tests that are pathognomonic for ADHD. A good clinical history and examination are essential. The developmental history should include early childhood development, a psychosocial history and an assessment of comorbid conditions. Collateral information, particularly from the school, is essential to assess whether ADHD symptoms are present in more than one setting. As ADHD tends to run in families, it is useful to explore the mental health of both parents, including asking about ADHD. A history of cardiac disease in the child and family should be explicitly explored. Sudden unexplained death from possible cardiac causes in family members, or a history of exercise syncope, breathlessness or previous cardiac disease in the child will require further detailed cardiac examination prior to starting stimulant treatment for ADHD. Explore the misuse of substances in the child and his/her family. Once the diagnosis of ADHD has been made, always look for comorbid conditions such as learning difficulties, anxiety and autism.

When to refer to a psychiatrist • • • •

If unsure of diagnosis If parents request a second opinion If child is younger than 6 years If complex diagnosis (ADHD with tics/obsessive compulsive disorder/depression) • If maximum daily dose of 1 mg/kg/day methylphenidate has been reached • If poor response to treatment.

Summary

• A DHD is a common neurodevelopmental disorder of children, adolescents and adults. • The three main symptom clusters are hyperactivity, inattention and impulsivity. • It is more common in boys than girls. • Girls more frequently present with inattention symptoms and may be underdiagnosed. • Treatment is a combination of psychological and pharmacological management. • Methylphenidate is the medication of choice. • Review the need for ongoing treatment by giving a trial off medication on an annual basis . • Comorbid conditions are common and may require treatment.

S Afr Med J 2014;104(1):72 DOI:10.7196/SAMJ.7728

Table 1. The predominant symptoms of ADHD and age Preschool year

Primary school years

Adolescence

Adulthood

Inattention

Short play Incomplete activities Not listening

Brief activities Changes activities Forgetful Disorganised Distracted

Less persistence Lack of focus on details Poor planning

Incomplete details Forgetful Lack of foresight Distracted Disorganised

Overactivity

Like a whirlwind

Restless Hyperactive

Fidgety

Subjective feelings of restlessness

Impulsivity

Does not listen No sense of danger

Acts out of turn Interrupts Intrusive Thoughtless

Poor self-control

Accidents Impatience Premature decision making

Reckless risk taking

http://iacapap.org/iacapap-textbook-of-child-and-adolescent-mental-health (accessed 25 October 2013).

References for articles on pp 72 and 73 are available online. Use the QR code for each article to access.

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ARTICLE SUMMARY

Outpatient management of adult alcoholism M F Williams, MB ChB, FCPsych (SA) Department of Mental Health and Psychiatry, University of Cape Town, South Africa Corresponding author: M F Williams (drmfwilliams@gmail.com)

Introduction and epidemiology

Medical treatment

Alcohol consumption is responsible for an estimated 3.8 % of all deaths and 4.6 % of disability-adjusted life-years (DALYs) globally.[1] In 2000, 7.1% of all deaths and 7.0% of total DALYs were attributable to alcohol.[2] Alcohol remains South Africa’s most abused substance.[3] This summary of my article outlines the outpatient management of adult alcoholism. A primary healthcare approach is emphasised.

Assessment and diagnosis History taking

All patients must be explicitly asked about alcohol usage. A collateral history from well-positioned associates is often necessary.[6,7] The key considerations of a good alcohol history are:[8] • amounts and pattern of consumption • evidence of alcohol abuse or alcohol dependence • is there continued drinking despite negative consequences? • history of tolerance or withdrawal • medical and psychiatric comorbidities • previous interventions and treatments. The use of screening questionnaires, particularly the validated AUDIT (alcohol use disorders identification test), is strongly recommended.[7-9] The CAGE questionnaire is also commonly used:[6] • Has the patient had failed attempts to cut down? • Do others get annoyed by the patient’s alcoholism? • Does the patient sometimes feel guilty about his/her drinking? • Does the patient sometimes drink an early morning eye opener/‘Regmaker’?

Physical examination and investigations

A thorough physical examination and relevant investigations, e.g. liver function tests (LFTs) and full blood count, are essential.

Management

A comprehensive biopsychosocial approach is required.

Outpatient detoxification[11] Alcohol withdrawal may carry significant morbidity and mortality. Mild to moderate alcohol withdrawal may occur in outpatient settings. Oral diazepam 5 - 15 mg 8 - 12-hourly is typically given over 5 - 10 days. In cases of liver compromise lorazepam may be considered as an alternative. Daily thiamine (100 mg) and vitamin B complex (2 tablets) are primarily prescribed to prevent Wernicke-Korsakoff syndrome. Pregnant women experiencing alcohol withdrawal require a complex risk-benefit analysis, as benzodiazepines are well-known teratogens. Relapse prevention[8,11] Relapse-preventing medications are best prescribed in conjunction with psychosocial interventions and may benefit some patients. The 3 commonly used agents are disulfiram, naltrexone and acamprosate. Please refer to standard pharmacological texts for detailed information.

Psychological interventions

Advice on safe drinking[6,11] • <14 units/week for women and <21 units/week for men • >2 alcohol-free days/week • avoid binges • never drink before or during driving/swimming/operating heavy machinery, etc. • pregnancy • advised not to drink at all (even small amounts may harm the baby) • larger amounts may cause major complications, e.g. fetal alcohol syndrome • pregnant women who insist on drinking: • advised not drink during the first trimester. • 1 - 2 units of alcohol twice/week in 2nd and 3rd trimesters. Motivational interviewing[6] This style of communication is therapeutically useful. The key features are empathy, avoidance of arguments, developing ambivalence (towards the drinking), and supporting self-efficacy.

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Brief (individual) interventions[6-8] This intervention involves short and regular meetings between the patient and HCP. It is cost and time efficient. One approach to delivery is best captured in the acronym FRAMES: Feedback: This should be given regarding the risks and negative effects of the patientâ&#x20AC;&#x2122;s continued drinking. Responsibility: The HCP non-judgementally emphasises the patientâ&#x20AC;&#x2122;s responsibility for the problem. Advice: Verbal and other forms of advice should be offered, e.g. pamphlets. Menu: Options regarding treatment, e.g. referral to psychotherapy. Empathy: An empathic style is essential. Self-efficacy: This must be facilitated. System therapies Brief couples therapy (BCT)[12] There exists robust evidence for BCT. Patients who receive BCT enjoy more abstinence, fewer alcohol-related problems, and happier relationships than those who receive individual treatments only. BCT is indicated where one member of the couple has a current alcohol problem, if they are married or have been living together for more than a year. Contraindications are current psychosis and severe domestic violence.

Method BCT takes place during 15 - 20 outpatient sessions over 5 - 6 months. The HCP sees the couple together. A daily sobriety contract is drawn up in the session in which the patient agrees not to drink and the partner agrees to support these efforts. The partner may be contracted to witness the use of and adherence to prescribed relapse prevention medications. The partner is also responsible for documenting the daily performance on a calendar. Assignments are designed to share activities and nurture positive communication styles and feelings. Social interventions Employment, family and legal difficulties are not uncommon. Referral from a social worker may be necessary. Self-help groups, e.g. Alcoholics Anonymous (AA), may be helpful. Spiritual, religious and other cultural factors must be considered.

Conclusion

Adult alcoholism is a significant societal problem that warrants a comprehensive management approach. The full-length article outlines some of the major considerations at the primary healthcare level. S Afr Med J 2014;104(1):73-74 DOI:10.7196/SAMJ.7730

ARTICLE SUMMARY

Psychiatry in primary care using the three-stage assessment C A Draper,1 MB ChB, FCFP (SA); P Smith,2 MB ChB, FCPsych (SA) 1 2

School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Lentegeur Hospital and Department of Psychiatry, University of Cape Town, South Africa

Corresponding author: C Draper (cpurdue@gmail.com) The burden of mental illness is immense and cannot be borne exclusively by psychiatrists based in specialist services. The National Department of Health has adopted a model of integrated primary care to address the comprehensive health needs encountered at district level. The integration of psychiatric care into this level of service involves several challenges. Among these, and one that this paper seeks to address, is the need to develop a model of assessment and treatment that is accessible, effective and responsive to the particular needs of psychiatric patients who access these services. Traditionally, psychiatry is taught to medical students by psychiatrists based in psychiatric hospitals or specialist clinics. This tends to create a mismatch between undergraduate training and the nature of psychiatric care at a primary level where clinical presentations are often nonspecific, undifferentiated and accompanied by comorbid medical illness and complex psychosocial and environmental issues.

Compounding these, are the almost inevitable service pressures and time constraints. The three-stage assessment that embraces the core principles of family medicine can be adapted to successfully incorporate the psychiatric needs of patients in primary care. A clinical vignette demonstrates the ease with which this can be achieved in order to formulate a truly holistic assessment and an integrated management plan for a given patient. Ideally, psychiatric management requires continuity of care within an enduring therapeutic relationship. This provides a setting within which hypotheses around definitive diagnoses and the most suitable treatment plan can be processed and refined. It is hoped that through the demonstration of a practical adaptation of the three-stage assessment we have presented a solution to one of the challenges encountered in the integration of psychiatry at a primary level. S Afr Med J 2014;104(1):74 DOI:10.7196/SAMJ.7722

January 2014, Vol. 104, No. 1

CONTINUING MEDICAL EDUCATION

ARTICLE SUMMARY

Adapting the psychiatric assessment for primary care J Parker, MB BCh, FCPsych (SA) OPD, Outreach and Medium Term Services, Lentegeur Hospital, Division of Public Mental Health, Department of Psychiatry and Mental Health, University of Cape Town, South Africa Corresponding author: J Parker (john.parker@westerncape.gov.za) The time available for consultations in primary care settings is extremely limited owing to high workloads. This can be particularly challenging when it comes to the mental health assessment,[1] which has traditionally been taught as an extremely long process. It is important to establish a way of assessment that allows for a short consultation, yet also ensures that the most vital information is not missed. This can be achieved if there is a solid understanding of the purpose of the psychiatric history and examination, and a knowledge base and skill set is developed that is congruent with this purpose. This requires emphasis on a few key areas as set out below.

Identifying the presence of mental illness

The ability to identify the presence of mental illness is critical, because, for a number of reasons, many people with a mental illness will either not initially be willing to identify within themselves the possibility of mental illness, or will not be aware that their symptoms are due to a mental illness. To make this easier it is useful to be aware of when to suspect mental illness and of how to screen for it.

Establishing and maintaining rapport

The most important initial goal in any psychiatric interview is to establish and develop a trusting relationship with the patient. Unless this is done sufficiently well, the information obtained will be of uncertain validity, and the opportunity to effect any improvement at all will be severely compromised. It is crucial to understand that nearly all psychiatric disorders affect the individual in a manner that is highly personal, and that to accept that one may be mentally ill is extremely difficult. Areas that require particular attention relate to one’s own conduct and feelings.

Involving others

While confidentiality is vital, it must be counterbalanced with an understanding of risk assessment and management, and of the complexity of presentation in mental illness. Therefore, the importance of obtaining collateral information cannot be overemphasised. This should be made clear early on in the course of an assessment, but the importance of confidentiality should also be stressed.

The assessment as therapy and as a work in progress

The initial assessment plays a crucial role in the initiation of a collaborative process of problem identification and the development of management strategies. Most mental health disorders are complex and multidimensional in all areas of aetiology, presentation and management. Any approach that involves no more than coming to a categorical, oneline diagnosis and the prescription of a medication is therefore likely to be highly simplistic and doomed to failure.[2] Most effective psychiatric medication involves fairly long-term use – and therefore commitment – and most treatments take some time to take effect. Additionally, the process of uncovering information and framing it in terms of better understanding the problem and its management is in itself therapeutic.

Identifying and managing risk

Having established that a full assessment is unlikely to be completed at the first interview, it becomes imperative that one is clear about what information must be obtained and what kind of management may need to be prioritised. This involves understanding that there is a hierarchy of risks to be considered, beginning with the risk of danger to self and the risk of danger to others, and with those risks that result directly from harmful acts assuming priority over those that may occur as a result of indirect harm or neglect. A risk assessment must always be recorded.

Hypothesis formation and a simplified approach to diagnosis

In psychiatry, achieving a definitive diagnosis after the first interview is seldom either possible or desirable, as it takes time for all the required information to emerge. It is therefore crucial to have a diagnostic framework in place that allows one to work logically and methodically towards a helpful formulation. A useful way of doing this is to think in terms of broad priority syndromes rather than individual diagnoses. One can then organise one’s history taking to enable rapid identification of the most likely syndrome. References

1. Thielke S, Vannoy S, Unutzer J. Integrating mental health and primary care. Prim Care Clin Office Pract 2007;34:571-592. [http://dx.doi.org/10.1016/j.pop.2007.05.007] 2. Bakker PR, Wichers M, van Harten PN, et al. Novel directions for psychiatric diagnosis: From psychopathology to motor functioning to monitoring technology. Epidemiology and Psychiatric Sciences 2013;1-7. [http://dx.doi.org/10.1017/S2045796013000474]

S Afr Med J 2014;104(1):75. DOI:10.7196/SAMJ.7731

f i g h t h ea rt b u r n w i t h g e lu s i l

January 2014, Vol. 104, No. 1

CONTINUING MEDICAL EDUCATION

ARTICLE

De-institutionalisation in psychiatry – both sides of the coin J Parker, MB BCh, FCPsych (SA) OPD, Outreach and Medium Term Services, Lentegeur Hospital, Division of Public Mental Health, Department of Psychiatry and Mental Health, University of Cape Town, South Africa Corresponding author: J Parker (john.parker@westerncape.gov.za) S Afr Med J 2014;104(1):76. DOI:10.7196/SAMJ.7733

De-institutionalisation refers to the depopulation of large psychiatric institutions, which was an important component of mental healthcare policy beginning in Europe and the USA in the middle to late 20th century.

Growth of the psychiatric institution

Interestingly, there seems to have been little need for institutional care in Europe before the 18th century. The first purpose-built psychiatric institution in the UK, The Priory of Saint Mary of Bethlehem (later known as Bethlem or ‘Bedlam’), was founded in 1247, but in 1700 was still the only public asylum in Britain, with 100 inmates. The next two centuries, however, saw a radical change, with the development of institutional confinement as the principal way of dealing with individuals who were deemed to be mentally ill, and by 1900 the total number of inmates in psychiatric institutions in the UK exceeded 100 000.[1] Initially, these places offered little more than confinement. However, in time, more humane treatment began to arise and it has been asserted that the institutions were the birthplace of psychiatry. This has implications for how psychiatry is viewed to this day, with a powerful and negative association of mental illness with removal to the ‘loony-bin’.

De-institutionalisation

With little effective treatment (therefore few discharges) and rapid population growth, the demand for institutions began to exceed available funding by the early to mid-1900s. Conditions deteriorated and the institutions became notorious as places of overcrowding, neglect and abuse. By the end of the 20th century, particularly in the USA and Europe, the number of inpatients in psychiatric hospitals had been radically reduced – in the USA the population of state and county psychiatric hospitals fell from 553 979 in 1954 to 61 722 in 1996, and 120 hospitals were closed.[2] The reasons for this precipitous change in the practice of psychiatry are complex, but a number of factors have been cited:[3] • the advent of effective antipsychotic medication • the growing wave of public antipathy towards psychiatric institutions as the abuses and poor conditions became more widely known • the growth of mental healthcare user/survivor groups and the development of disability activism • an assumption that community-based care would be more humane • a variety of political arguments that span the spectrum – from concerns about the human rights of the mentally ill to financial imperatives driven by growing costs and the perception that community care would be cheaper.

Consequences

Undoubtedly, the most positive outcome of de-institutionalisation was the disappearance of the huge asylums of old and with them the potential for human rights abuses. This coincided with an expanded psychopharmacological armamentarium, a widened scope of practice

outside asylums, and the diversification of care. Delinked from the negative association with the institutions, psychiatry has steadily gained recognition as a medical discipline, and psychiatric treatment has become socially more acceptable. It is clear, however, that the consequences for those suffering from severe mental illness were not entirely positive, as the enthusiasm for cost-cutting hospital closures has not been matched in the development of alternatives to hospitalisation. The most obvious negative consequence has been the emergence of large populations of homeless people with severe mental illnesses,[4] and the increase in the number of mentally ill persons in prisons,[5] or those housed in poorly regulated, smaller facilities outside the healthcare system. In particular, it has been argued that those who were meant to benefit most from the closure of the old institutions, the indigent severely mentally ill, have fared worst as a result of the new reforms.[6] The reasons why this has happened have become clearer in retrospect: • What has emerged is that the successful placement of a person living with a chronic mental illness in a community setting requires substantial effort and resources which, when properly assessed, do not translate into any substantial financial saving over a long-term hospital admission.[7] • Co-morbid substance dependence has emerged as a major problem that complicates rehabilitation. • Social spending has generally been reduced, with fewer funds available for social support. • The emergence of structural unemployment has made vocational rehabilitation extremely difficult. • In some areas community resistance has emerged as a significant factor. • Urbanisation and smaller families also reduced social support.

Lessons learned

Perhaps, more than anything else, we have learned the true meaning of the biopsychosocial approach to mental illness from the experience of de-institutionalisation. It has become clear that real recovery requires more than just attending to the biological needs of an individual, such as medication, food and shelter. It demands that if people with chronic mental illness are to do more than just survive, attention must be paid to their individual circumstances, needs and hopes. Additionally, it demands that we see care from a social context, that attends to the wide range of social factors that affect a person with mental illness, such as stigmatisation and various forms of structural discrimination. References 1. Porter R. Madmen: A Social History of Madhouses, Mad-Doctors and Lunatics. Stroud, Gloucestershire: Tempus, 2006. 2. Geller JL. The last half century of psychiatric services as reflected in ‘Psychiatric Services’. Psychiatr Serv 2000;51(1):41-67. 3. Stroman D. The Disability Rights Movement: From Deinstitutionalization to Self-determination. Lanham, MD: University Press of America, 2003. 4. Scott J. Homelessness and mental illness. Br J Psychiatry 1993;162:314-324. 5. Bloom JD. ‘The incarceration revolution’: The abandonment of the seriously mentally ill to our jails and prisons. Journal of Law, Medicine and Ethics 2010;38(4):727-734. [http://dx.doi.org/101111/j.1748-720X2010.00526.x] 6. Grove B. Reform of mental health care in Europe. Br J Psychiatry 1994;165:431-433. 7. Okin RL. The future of state mental health programs for chronic psychiatric patients in the community. Am J Psychiatry 1978;135:1355-1358.

January 2014, Vol. 104, No. 1

CONTINUING MEDICAL EDUCATION

ARTICLE

Recovery in mental health J Parker, MB BCh, FCPsych (SA) OPD, Outreach and Medium Term Services, Lentegeur Hospital, Division of Public Mental Health, Department of Psychiatry and Mental Health, University of Cape Town, South Africa Corresponding author: J Parker (john.parker@westerncape.gov.za) S Afr Med J 2014;104(1):77 DOI:10.7196/SAMJ.7732

Traditionally, recovery has referred to absence of disease, or cure. This makes sense when applied to a short-lived condition such as tonsillitis, but its relevance in more enduring or chronic conditions, such as high blood pressure, an amputated limb or mental disorders, is questionable. We are all aware of many successful business people with high blood pressure and some very famous Olympians with amputated limbs. In the traditional sense, they can never recover from these conditions, but we don’t think of them as sick people or ‘cripples’. Yet, with mental illness, our understanding and resultant attitude can be very different. This has a powerful effect on how healthcare is provided and it also breeds a sense of hopelessness, which dramatically decreases the chance of the person ever getting better. If there is no hope, why bother even trying? However, long-term follow-up studies increasingly show that the vast majority of people with mental disorders can get better over an extended period of time, particularly when they receive the right kind of support.[1] This applies to even the most severe of disorders, such as schizophrenia.[2] Furthermore, from the perspective of the philosophy of recovery, recovery in the short term is also possible.

A new understanding of recovery

The new understanding of mental illness recovery begins with a conceptualisation of recovery as a journey, rather than an endpoint. This journey begins with recognition of the existence of a mental health problem and the desire to set out on a path to healing. The focus is on acceptance of the reality of the illness, but also on the fact that one is still a whole person, with the possibility of a satisfying life, full of hope and meaning, regardless of whether symptoms are present or not. This also involves the realisation that recovery is about the whole self and not just the illness. As we all have our own way of seeing the world and our own ideas of what it means to live a positive, meaningful life, the definition of recovery is unique for each person. For many people with mental illness, this can be a fundamentally empowering realisation. After all, the struggle to find happiness and meaning in life is a universal one, not something limited to people with mental illness. The idea that there is a clear line between those who are ‘normal’ and those who are not, is therefore immediately challenged. This new understanding of recovery is summarised in the 2004 consensus statement of the US Substance Abuse and Mental Health Services Administration: ‘Mental health recovery is a journey of healing and transformation, enabling a person with mental health problems to live a meaningful life in a community of his or her choice, while striving to achieve his or her full potential.’[3] Such understandings have given rise to a global movement that seeks to make this view of recovery a core principle around which mental healthcare is organised.

Making recovery a reality

The philosophy of recovery views mental illness recovery as a personal process that can be aided by support services. Jacobson and Greenley[4] have emphasised that four ‘internal conditions’ need to be present for recovery to take place: • Hope that recovery is possible, generating a frame of mind that allows this to occur. • Understanding that healing is different to cure, and that the emphasis is on self rather than illness and control. • Empowerment as a corrective for the sense of helplessness and dependency that comes with severe mental illness and with traditionally paternalistic services. • Connection with society and knowledge of one’s roles in it. For these conditions to exist, Farkas[5] adds that services need to promote four key values: • Person orientation. Seeing a patient as a whole person, rather than as simply someone with an illness. • Person involvement. Involving people who have experienced mental illness in the design, planning and delivery of mental health services. • Self-determination or self-choice. Understanding that the patients need to decide the meaning of ‘better’, set their own goals, make their own plans for how to achieve them, and take responsibility for the outcome of their decisions. • Hope. Recognising the tremendous harm that is done when services are provided in a negative, cynical environment, and the enormous healing benefits of a positive atmosphere.

Recovery in South Africa

This vision of recovery is critical for the further development of mental health services in South Africa where resources are poor and levels of public knowledge and concern are even worse. The recovery movement involves a wide range of role-players, including patients, their friends and family, NGOs, and state services, all of whom need to pull together to make the necessary changes. Indeed, as awareness improves and stigma is challenged, it will become apparent that improved mental health is everyone’s business and achieving it involves the kind of empowerment and transformation that is the dream of our young democracy. References

1. Harding CM, Brooks GW, Ashikaga T, et al. The Vermont longitudinal study of persons with severe mental illness: I. Methodology, study sample, and overall status 32 years later. Am J Psychiatry 1987;144:718-726. 2. Bellack AS. Scientific and consumer models of recovery in schizophrenia: Concordance, contrasts, and implications. Schizophr Bull 2006;32(3):432-442. [http://dx.doi.org/10.1093/schbul/sbj044] 3. Substance Abuse and Mental Health Services Administration (SAMHSA). National Consensus Statement on Mental Health Recovery Definition. http://mentalhealth.samhsa.gov/pub-lications/allpubs/sma054129 (accessed 18 July 2012). 4. Jacobson N, Greenley D. What is recovery? A conceptual model and explication. Psychiatr Serv 2001;52(4):482-485. [http://dx.doi.og/10:10.1176/appi.ps.52.4.482] 5. Farkas M. The vision of recovery today: What it is and what it means for services. World Psychiatry 2007;6(2):68-74.

January 2014, Vol. 104, No. 1

PULSE

Largest-ever roll-out of GeneXpert rapid TB test machines in 21 countries

UNITAID and the World Health Organization (WHO) have started the largest-ever roll-out of GeneXpert state-of-the-art test machines for tuberculosis (TB) that shorten the time to diagnose drug-resistant strains of TB from weeks to only a few hours. By allowing health workers to diagnose drug-resistant TB quickly and put patients on treatment immediately, GeneXpert devices can help halt the spread of this deadly form of the disease. UNITAID has invested US$25.9 million in purchasing over 220 GeneXpert machines and 1.4 million test cartridges for 21 countries in Africa, Eastern Europe and Asia. It is estimated that this project, co-ordinated by the WHO and the Stop TB Partnership and known as TBXpert, will save 62 000 lives. Until recently, the high cost of GeneXpert TB cartridges was a barrier to the test’s introduction in low- and middle-income countries. Thanks to an agreement UNITAID finalised a year ago with the device’s manufacturer Cepheid, 145 countries – including all 21 in the TBXpert Project – are now benefiting from a 40% price reduction on cartridges. This global price reduction has helped achieve cost savings of more than US$15 million and has enabled countries not directly supported by UNITAID, like South Africa, to test more people with the same money. The US President’s Emergency Plan for AIDS Relief (PEPFAR), the United States Agency for International Development (USAID), and the Bill & Melinda Gates Foundation joined UNITAID in negotiating this price reduction. The GeneXpert machine provides the platform for the test recommended by the WHO for initial diagnosis of people with suspected drug-resistant TB and for all people living with HIV who are thought to have TB. The test is highly accurate, users require minimal training, and results are obtained within 2 hours. The only technique available to most laboratories in developing countries, until recently, is over a century old and involves detecting the bacteria using a microscope. Testing for MDR-TB requires another cumbersome method: growing the bacteria in laboratory cultures, a process that can take months and requires extensive infrastructure. During this time period, drug-resistant strains can spread from person to person, often in families living in close quarters. TB is also difficult to detect with traditional technologies in children and in people living with HIV, as they tend to have low levels of TB bacteria in their sputum. GeneXpert machines detect resistance to rifampicin and can also detect TB in patients who are co-infected with HIV.

Aspen and Sifiso Nxasana Paediatric Trust provide welcome financial boost to Nelson Mandela Children’s Hospital

Aspen Pharmacare has raised R5 million for the Nelson Mandela Children’s Trust through its Sifiso Nxasana Paediatric Trust for the Children of Africa. On Saturday 17 August, Aspen’s Group Chief

Executive Stephen Saad handed over a cheque for that substantial sum to the Nelson Mandela Children’s Hospital at the inaugural Nelson Mandela Sport and Culture Day, hosted at the FNB Stadium in Johannesburg amid scenes reminiscent of the 1995 Rugby World Cup. Also present were former presidents Thabo Mbeki and F W de Klerk, Deputy President Kgalema Mothlanthe, Minister of Sports and Recreation Fikile Mbalula, and Minister of Arts and Culture Paul Mashatile. Throughout his presidency, Nelson Mandela shared his vision for sport as a powerful and unifying force in society, and the Sport and Culture Day was the culmination of the Unite4Mandela ‘One Man, One Nation, One Celebration’ campaign. The proceeds from the day will go towards the building of the Nelson Mandela Children’s Hospital. The Sifiso Nxasana Paediatric Trust was founded by Saad in 2012 after the tragic death of Sifiso Nxasana, son of Aspen’s Chairman, Dr Judy Dlamini, and her husband Sizwe Nxasana. ‘Sifiso’s untimely demise brought home to me the desperate need in our country for quality healthcare for our children, and I realised that Aspen could make an invaluable additional contribution in its healthcare capacity by supporting the Nelson Mandela Children’s Hospital through this Trust,’ Saad explained. South Africa still has one of the highest disease burdens in the world, and infant and child mortality are disproportionately high. This is not surprising considering the scarcity of specialist paediatric healthcare services in the South African public sector, and as a consequence the Nelson Mandela Children’s Hospital has become a flagship initiative for our country. ‘As Aspen, we aim to help honour Madiba’s wish of providing specialist paediatric healthcare for the children of Africa,’ explained Stavros Nicolaou, Aspen’s Senior Executive. ‘This hospital will strengthen the overall healthcare system and provide hope to many thousands of children who would otherwise be denied access to such healthcare facilities.’ In addition to fundraising, the Nelson Mandela Children’s Trust provides for the sustainability and appropriate resourcing of both the Nelson Mandela Children’s Hospital and the KwaZulu-Natal Children’s Hospital, developing adequate management capacity and human resourcing while contributing to the overall strengthening of the South African public healthcare system. ‘We wish to acknowledge and commend all donors for their contribution, which will provide much-needed impetus to this initiative, and in particular we wish to thank Ministers Motsoaledi (Health), Mbalula (Sports and Recreation) and Mashatile (Arts and Culture) for their vision in conceiving and successfully executing the Mandela Sport and Culture Day. The scenes of nation building in the stands on that day will live long in our memories,’ concluded Nicolaou. Enquiries: Nkini Phasha, Bakone Public Relations, nkini@bakonegroupsa.co.za

January 2014, Vol. 104, No. 1

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CPD

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True (A) or false (B): Extrapulmonary tuberculosis (EPTB) among adults: Experience at Chris Hani Baragwanath Hospital, Johannesburg, South Africa 1. There is a high incidence of EPTB in the elderly age group. 2. The most common sites of EPTB were the pleura, lymph nodes, bacteraemia, meningitis and peritonitis. Diagnostic yield of fine needle aspiration biopsy in HIV-infected adults with suspected mycobacterial lymphadenitis 3. Fine needle aspiration biopsy has been shown to be the diagnostic procedure of choice for superficial lymphadenitis in tuberculosis (TB)-endemic regions. 4. In this study, a diagnostic yield of 80% was achieved, significantly higher in HIV negative than in HIV-positive patients. Percutaneous needle core biopsies: The yield in spinal tuberculosis 5. Spinal cord compression from pus, inflammatory granulation tissue of active disease or kyphosis deformity in the late stage of disease can result in paraplegia. 6. In AIDS, the histological changes caused by Mycobacterium tuberculosis can range from the classical caseating granulomas, to a non-specific chronic inflammatory reaction without necrosis. Prevalence and incidence of symmetrical symptomatic peripheral neuropathy (SSPN) in patients with multidrug-resistant (MDR) TB 7. To avoid renal failure in HIV-infected patients with MDR-TB owing to the combined nephrotoxicity of aminoglycosides and tenofovir, stavudine is often used. Diabetes mellitus in HIV-infected patients on antiretroviral therapy (ART) 8. The success of ART in controlling HIV and restoring immunity is tempered by the increasing incidence among people living with HIV of metabolic diseases, such as diabetes mellitus. South African guideline for the use of chronic opioid therapy for chronic non-cancer pain (CNCP) 9. Clinically meaningful improvement is at least a 30% reduction in pain (or ≥2 points on a 0 - 10 numerical rating scale) and/or a 30% improvement in function.

10. Adverse effects of opioids include nausea/vomiting, constipation sedation and pruritis. A broad diagnostic framework to simplify the approach to mental disorders in primary care 11. The most important goal of a primary level mental health assessment is to reach a definitive diagnosis as set out in an internationally recognised classification system. 12. An underlying medical disorder or a substance use disorder should always be excluded before a diagnosis of a psychiatric disorder is made. An update on attention deficit hyperactivity disorder (ADHD) 13. Children usually outgrow ADHD by adolescence. 14. There is a strong evidence base for the use of methylphenidate in treating ADHD. Psychiatry in primary care using the three-stage assessment 15. The three-stage assessment model is helpful because it requires that all the details of the patient’s current circumstances are captured at the time of the first assessment so that a definitive management plan can be devised. Outpatient management of adult alcoholism 16. Screening for alcoholism is a key aspect of all adult assessments. 17. It is safe for women to drink small amounts of alcohol (<1 unit per day) during pregnancy. Adapting the psychiatric assessment for primary care 18. The rules of confidentiality demand that information is obtained only from the patient. De-institutionalisation in psychiatry – both sides of the coin 19. The effect of the closure of large psychiatric hospitals has not been overwhelmingly positive for those suffering from severe mental disorder. 20. It is much cheaper to care for people with severe mental illness in the community than in large institutions.

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