SAMJ Vol 105, No 11 (2015) by HMPG

NOVEMBER 2015

VOL. 105 NO. 11

The power of vaccination 881, 892, 917 Efavirenz as a cause of ataxia in children 897 Screening for hearing impairment in children 901, 927 Time for ‘basic antenatal care plus’? 902 Missing essentials and desirables for family planning 904 HPV vaccine roll-out continues 912 Anti-vaccination lobbying on the South African internet 922 First report from the South African Children’s Tumour Registry 930 CME: Adolescent health 948-954

NOVEMBER 2015

VOL. 105 NO. 11

GUEST EDITORIAL

SAMJ

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Vaccination saves lives – dare we allow the anti-vaccine lobbyists to prevent it? L Baker

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

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EDITOR’S CHOICE

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

CORRESPONDENCE

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

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Modelling cost-effective therapies R P Abratt

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Junior medical researchers: A neglected community with great academic potential J Bovijn, A Jacobs, M T Boswell, E du Bruyn, L Bovijn, N Berkowitz

IZINDABA 886 887 889 890

Motsoaledi on ‘tide-turning’ new HIV treatment guidelines Medical aids often their own worst enemies with fraud Council for Medical Schemes braves the tightrope between funders and the poor Private hospitals could turbo-boost public sector reform

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BOOK REVIEW The Practitioner’s Guide to Medical Malpractice in South African Law

SAMJ FORUM

COCHRANE CORNER 892 Interventions for improving childhood vaccination coverage in low- and middle-income countries C S Wiysonge, T Young, T Kredo, M McCaul, J Volmink 894

HEALTHCARE DELIVERY Appropriate indications for positron emission tomography/computed tomography: College of Nuclear Physicians of the Colleges of Medicine of South Africa M Sathekge, J M Warwick, A Doruyter, M Vorster

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CLINICAL ALERT Efavirenz as a cause of ataxia in children M P K Hauptfleisch, D P Moore, J L Rodda

899

OPINION Child research in South Africa: How do the new regulations help? A E Strode, C M Slack

EDITORIALS 901

Screening for childhood hearing impairment in resource-constrained settings: Opportunities and possibilities L Petersen, L Ramma

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Time for ‘basic antenatal care plus’ in South Africa? G J Hofmeyr, L Mentrop

904

Family planning in South Africa: Missing essentials and desirables N D Goldstuck

905

Patents and the quality, safety and efficacy of medicines K du Toit, W du Preez, S Padayachee

REVIEW 907

Pre-exposure prophylaxis for South African adolescents: What evidence? L-G Bekker, K Gill, M Wallace

RESEARCH 912

School-based human papillomavirus vaccination: An opportunity to increase knowledge about cervical cancer and improve uptake of screening G Dreyer, F H van der Merwe, M H Botha, L C Snyman, D Constant, C Visser, J Harvey

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November 2015, Vol. 105, No. 11

ASSOCIATE EDITORS Q Abdool Karim, A Dhai, N Khumalo, R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman HMPG CEO AND PUBLISHER Hannah Kikaya Email: hannahk@hmpg.co.za MANAGING EDITOR Ingrid Nye TECHNICAL EDITORS Emma Buchanan Paula van der Bijl NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za PRODUCTION MANAGER Emma Jane Couzens DTP & DESIGN Carl Sampson HEAD OF SALES AND MARKETING Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za JOURNAL ADVERTISING Charles Duke Benru de Jager Reneé van der Ryst Ladine van Heerden ONLINE SUPPORT Gertrude Fani | Tel. 072 635 9825 Email: publishing@hmpg.co.za FINANCE Tshepiso Mokoena HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Dr M J Grootboom, Mrs H Kikaya, Adv. Y Lemmer, Prof. E L Mazwai, Dr M Mbokota, Mr G Steyn, Dr G Wolvaardt ISSN 0256-9574 SAMA website: www.samedical.org Journal website: www.samj.org.za

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Missed opportunities for immunisation in health facilities in Cape Town, South Africa* N Jacob, D Coetzee

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A profile of anti-vaccination lobbying on the South African internet, 2011 - 2013* R J Burnett, L J von Gogh, M H Moloi, G François

927

Age of diagnosis of congenital hearing loss: Private v. public healthcare sector* I R T Butler, D Ceronio, T Swart, G Joubert

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Evaluation of fetal MRI in a South African referral centre* A Daire, S Andronikou, A Boutall, S Constantatos, C Stewart, S E Candy

934

939

Childhood cancer incidence in South Africa, 1987 - 2007* D C Stefan, D K Stones, R D Wainwright, M Kruger, A Davidson, J Poole, G P Hadley, D Forman, M Colombet, E Steliarova-Foucher

CONTINUING MEDICAL EDUCATION

948

GUEST EDITORIAL Adolescent health Q Abdool Karim

948

REVIEW Improving adolescent maternal health C Baxter, D Moodley

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ARTICLES Understanding and responding to HIV risk in young South African women: Clinical perspectives* R Dellar, A Waxman, Q Abdool Karim

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 248.00 p.a. Foreign subscriptions R2 832.00 p.a. Single copies R104.00 local, R236.00 foreign 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. Suites 9 & 10, Lonsdale Building, Gardner Way, Pinelands, 7405 Tel. 072 635 9825 E-mail: publishing@hmpg.co.za Please submit all letters and articles for publication online at www.samj.org.za

953 Adolescent antiretroviral management: Understanding the complexity of non-adherence* K Naidoo, A Munsami, M Archary 953

Adolescent HIV treatment issues in South Africa* H Dawood

954

Human papillomavirus (HPV) vaccination of adolescents in the South African private health sector: Lessons from the HPV demonstration project in KwaZulu-Natal* N Tathiah, M Naidoo, I Moodley

*Full article available online only.

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© Copyright: Health and Medical Publishing Group (Pty) Ltd, a subsidiary of the South African Medical Association 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 TANDYM PRINT

Zebra mother and foal. Photo: Susan Flegg

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GUEST EDITORIAL

Vaccination saves lives – dare we allow the anti-vaccine lobbyists to prevent it? Vaccines are one of the safest and most effective tools available in efforts to control and prevent many infectious diseases.[1] When the Expanded Programme on Immunization (EPI) was established by the World Health Assembly (WHA) in 1974, only about 5% of the world’s children were immunised against polio, diphtheria, tuberculosis, measles, pertussis and tetanus. In 2014, 40 years later, 83% were immunised, and the World Health Organization (WHO) estimates that this programme saves the lives of two to three million children every year.[2] There are a number of other success stories … the complete eradication of smallpox, the near-elimination of polio, and the many countries that have reported elimination of measles (although there have been recent outbreaks in some of these). South Africa (SA) introduced the EPI in 1974 and since then has included a number of additional vaccines. Hepatitis B vaccine was introduced in 1995 and Haemophilus influenzae type b in 1999, and SA was the first country in Africa to introduce vaccines against pneumococcal infections and diarrhoeal disease caused by rotavirus (in 2008). These vaccines have already had a significant impact on the burden of rotavirus infections and infections caused by Streptococcus pneumoniae. Another success story is that the last case of polio in SA occurred in 1989! The most recent addition was a vaccine against human papillomavirus (HPV) in 2014, which is offered to all grade 4 schoolgirls in public schools.[3] Moreover, all these vaccines are provided free of charge to all children. It is, however, vaccination and not vaccines that saves lives, and high vaccine coverage is required to have a positive impact on the burden of disease. 2011 - 2020 has been declared ‘The Decade of Vaccines’ by the WHA, and their vision is to achieve universal access to immunisation with life-saving vaccines. The WHO has recently voiced its concerns regarding vaccine hesitancy, defined as people delaying or refusing vaccines for their children or themselves. Globally one in five children still do not get routine immunisations, and an estimated 1.5 million children die every year from vaccine-preventable diseases. The issue is complex and is influenced by factors such as misinformation, concerns regarding vaccine safety, myths, mistrust, complacency and convenience.[4] Much of this is fuelled by the anti-vaccine lobbyists, and evidence suggests that in North America, Europe and other parts of the world, public confidence in vaccines is decreasing, from both safety and efficacy perspectives, and anti-vaccine movements are becoming stronger.[5] Even though SAGE (the Strategic Advisory Group of Experts in Immunization) has stated that scientific reports indicate that there is no evidence of adverse events following immunisation, the public needs more convincing. There appears to be a discrepancy between scientific evidence and perception of risk.[6] The anti-vaccine contingent largely has the privilege of living in places where many deadly communicable diseases are rare, and as a result has a good chance of never contracting the diseases. This is a luxury not afforded to those living in many areas of the world.[2] However, poor vaccination coverage leads to loss of herd immunity, which may then result in an outbreak, irrespective of where one lives. The Disneyland measles outbreak earlier this year attests to this.[7] Among the 110 California patients, 49 (45%) were unvaccinated; 12 were infants too young to be vaccinated, and 28 were intentionally unvaccinated because of personal beliefs.

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Vaccination is often the victim of its own success – for example, high coverage of oral polio vaccination has resulted in the number of polio cases dropping from >350 000 in 1989 to <400 cases worldwide in 2014. Now the rare adverse event of vaccine-associated paralytic polio is seen as a considerable risk, and a number of vaccine-derived polio cases are seen. Internet-based anti-vaccination lobbying has been acknowledged for many years, but most has originated from the USA. The websites are usually hosted by sophisticated organisations that appear to be official and authoritative. Many of the top internet search results for vaccine safety question or dispute the scientific consensus about safety and efficacy of vaccines.[1] The study by Burnett et al.[8] investigated anti-vaccination lobbying on SA webpages over three years (2011 - 2013), looking at the characteristics of these. Website articles and blogs/forums constituted the two leading platforms, with the largest portion of authors being lay people – mostly parents. These would appeal emotionally to readers of these blogs as they are able to identify with the authors. The majority of the claims were that vaccines were not safe, and most of them originated from the USA. One has to wonder what the motivation for these anti-vaccine lobbyists is. From the study, it appears to be overwhelmingly profit driven. The proportion of commercial web pages increased each year during the study, making up 55% of the final analysis, and 67.6% of these were sponsored by organisations with financial interests in discrediting vaccines. The irony is that many of the anti-vaccine lobbyists claim that vaccination is profit driven, while their sponsors work in an industry that was worth USD 61 - 68 million (in 2009) and the global vaccine market was only worth USD 24 million. Scepticism and rejection of vaccines is not new, but issues in the 21st century play an important role. These include the accelerated introduction of additional vaccines into routine programmes. The Global Advisory Committee on Vaccine Safety monitors the safety of vaccines closely and is concerned that allegations of harm accruing from vaccines that are based on weak evidence will lead to real harm when, as a result, safe effective vaccines cease to be used. This is vividly illustrated by the story of HPV vaccination in Japan: HPV vaccination was offered free of charge to young girls and was added to the immunisation programme; the rate of completion (of three doses of the vaccine) was 74%, but following unconfirmed reports of adverse reactions to the vaccine, the Ministry of Health suspended proactive recommendations for the vaccine. This led to a drop in HPV vaccination to 0.6% in spite of an investigation that concluded that there was no causal association between the vaccine and events. We do not know the actual vaccine coverage rates in SA, owing to some confusion regarding the denominator. Rates are not optimal, however, for a number of reasons that include vaccine shortages and lack of accessible clinics. It would be a travesty if this was exacer bated by the effect of the anti-vaccine lobbyists. Fortunately, because vaccination is voluntary in SA, the ethical and religious concerns that are touted in the USA are less of an issue. The number of people in SA who have access to the internet has increased substantially, so potentially many more people have access to the anti-vaccine websites. The question now is what impact this SA based anti-vaccination lobbying might have on the uptake of vaccines in the country, and what can be done to overcome the problem. It is also important to acknowledge that anti-vaccination lobbying can

November 2015, Vol. 105, No. 11

GUEST EDITORIAL

also occur through all social media channels, as well as sources seen as trusted, but that may be misinformed. Effective communication is key to dispelling fears, addressing concerns and promoting acceptance of vaccination.[4] One way of countering people’s anti-vaccine attitudes is to make them appreciate the consequences of failing to vaccinate their children. Conflict of interest. The author does talks for Aspen GSK, Sanofi Pasteur and MSD, but there is no conflict of interest with regard to this invited editorial.

Lee Baker Amayeza Info Services, Weltevreden Park, South Africa lee@amayeza-info.co.za

1. Hickler B, Guirguis S, Obregon R. Vaccine special issue on vaccine hesitancy. Science Direct 2015;33(34):4155-5416. [http://dx.doi.org/10.1016/j.vaccine.2015.04] 2. Chan M. Beyond expectations: 40 years of EPI. Lancet 2014;383(9930):1697-1698. http://dx.doi. org/10.1016/S0140-6736(14)60751-0] 3. Dreyer G, van der Merwe FH, Botha MH, et al. School-based HPV vaccination: An opportunity to increase knowledge about cervical cancer and improve uptake of screening. S Afr Med J 2015;105(11):912-916. [http://dx.doi.org/10.7196/SAMJ.2015.v105i11.9814]. 4. Addressing Vaccine Hesitancy. http://www.who.int/immunization/programmes_systems/vaccine_ hesitancy/en/ (accessed 7 September 2015). 5. Dube E, Gagnon D, MacDonald NE. Strategies intended to address vaccine hesitancy: Review of published reviews. Vaccine 2015;33(34):4191-4203. [http://dx.doi.org/10.1016/j. vaccine.2015.04.041] 6. Schuster M, Eskola J, Duclos P. Review of vaccine hesitance: Rationale, remit and methods. Vaccine 2015;33(34):4157-4160 [http://dx.doi.org/10.1016/j.vaccine.2015.04.035] 7. Measles Outbreak – California, December 2014 - February 2015. http://www.cdc.gov/mmwr/preview/ mmwrhtml/mm6406a5.htm?s_cid=mm6406a5_w (accessed 2 October 2015). 8. Burnett RJ, von Gogh LJ, Moloi MH, François G. A profile of anti-vaccination lobbying on the South African internet, 2011 - 2013. S Afr Med J 2015;105(11):922-926. [http://dx.doi.org/10.7196/ SAMJ.2015.v105i11.9654]

S Afr Med J 2015;105(11):881-882. DOI:10.7196/SAMJ.2015.v105i11.10175

EDITOR’S CHOICE CME: Adolescent health

Hot off the press (released on 30 September) is the news that the World Health Organization has revised its HIV guidelines to recommend that anyone who tests positive for the virus should be treated immediately irrespective of CD4 count,[1] with the aim of averting 21 million AIDS deaths and preventing 28 million new infections by 2030. We shall have to wait to see whether our National Department of Health and Treasury decide that this can be afforded, given that South Africa (SA) is home to 5.51 million of the world’s population infected with HIV[2] (out of 37 million), accounting for a third of all HIV-related deaths annually.[2]

Vaccination saves lives

Few would argue that vaccines protect children against illnesses that cause death and disease. In the wake of the news of the success of a vaccine against Ebola,[3,4] we learn in this month’s guest editorial[5] (‘Vaccination saves lives – dare we allow the anti-vaccine lobbyists to prevent it?’) of SA’s proud record of availability of vaccination of her children.[5] Most recently, human papillomavirus vaccination of girl children (boys too, it is hoped, when the vaccine is cheaper) has been rolled out.[6] Fortunately too, according to Jacob and Coetzee,[7] missed opportunities for immunisation in health facilities are low, at least in the Western Cape metro, reflecting good immunisation coverage among those children who do access health facilities. According to the latest census (October 2011), 35.2% of SA inhabitants have access to the internet and, as in the USA, might be expected to ‘Google’ for health information. Against this background, Burnett et al.[8] advise in ‘A profile of anti-vaccination lobbying on the South African internet’ that the South African Vaccination and Immunisation Centre is constantly exercised by requests to explain the validity of internetbased anti-vaccination claims, when immunisation is in fact one of the best public health measures ever invented. Local web pages for antivaccination lobbying exist, created by those with financial interests in discrediting vaccines and who have largely taken their misinformation from web pages originating in the USA. The concern is that young parents are using a search engine like Google to seek information about vaccination, and are encountering misinformation instead. The craziness of failure to vaccinate infants and children against common infections is a hangover of the 1998 fraud that vaccines cause autism, perpetrated by Dr Andrew Wakefield and published in, and later

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retracted by, The Lancet. In 2010, the General Medical Council ordered him struck off the medical register, barring him from practising medicine in the UK.[9] Wakefield’s full ‘dishonest’, ‘unethical’ and ‘callous’ behaviour is revealed in an article by investigative journalist Brian Deer[10] that won him the 2011 Pulitzer Prize for his ‘tremendous righting of a wrong’. A recent study published in JAMA[11] that surveyed >95 000 children confirms that no link exists between measles, mumps and rubella (MMR) vaccine and an increased risk of autism spectrum disorder (ASD), even among children whose older siblings have ASD and were already at an increased risk of ASD. However, as Jacob and Coetzee show in Table 4 of their article[7] (reproduced below), immunisation-related challenges remain. Apropos the above, a measles epidemic rages in equatorial Africa,[12] attributed by the Médecins Sans Frontières team in Katanga to the difficulty vaccinators face in reaching the population over impassable roads, while trying to prevent inactivation of the vaccine in the torrid equatorial temperatures. There are reports of death rates of up to 19% (v. the global average of 1.7%) among children who not only have measles but also respiratory diseases, malaria and malnutrition. Also cited are ‘poorly trained health personnel, a population constantly on the move, the refusal of some groups to accept vaccination on religious or cultural grounds, and armed conflicts in several areas’. Table 4. Immunisation-related challenges Vaccine stock-outs Hospital pharmacies do not stock certain vaccines Unavailability of vaccines after hours at all levels of care Staff shortages and high workloads, particularly among nursing staff Uncertainties among doctors regarding dosages and prescription format for immunisations Pervasive nursing perspective that immunisations are only for primary level facilities Poor staff training on immunisations, management of adverse events and cold-chain management Staff conflict on appropriate hospital area where immunisations should be allocated Lack of resources, e.g. EPI fridge

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EDITOR’S CHOICE

Childhood cancer

From Stefan et al.[13] comes a first report from the South African Children’s Tumour Registry (SACTR), a paediatric cancer registry that covers the entire country. The article provides estimates of cancer incidence and discusses the challenges of cancer surveillance and control in childhood populations in a middle-income country like ours, and constitutes an invaluable resource of information for policy planning and research. The report challenges us to improve the diagnosis and notification of childhood cancer to both the National Cancer Registry and the SACTR, and to tackle the ethnic inequalities in access to appropriate care. JS 1. World Health Organization. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/ (accessed 2 October 2015). 2. Statistics South Africa. Statistical Release P0302. Mid-year population estimates 2014. http://www. statssa.gov.za/publications/P0302/P03022014.pdf (accessed 2 October 2015). 3. Callaway E. Successful Ebola vaccine provides 100% protection in trial. Study also demonstrates ability to develop a vaccine quickly during an outbreak. 31 July 2015. http://www.nature.com/news/successfulebola-vaccine-provides-100-protection-in-trial-1.18107 (accessed 19 September 2015).

4. Henao-Restrepo AM, Longini IM, Egger M, et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: Interim results from the Guinea ring vaccination cluster-randomised trial. Lancet 2015;386(9996):857-866. [http://dx.doi.org/10.1016/S01406736(15)61117-5] 5. Baker L. Vaccination saves lives – dare we allow the anti-vaccine lobbyists to prevent it? S Afr Med J 2015;105(11):881-882. [http://dx.doi.org/10.7196/SAMJ.2015.v105i11.10175] 6. Dreyer G, van der Merwe FH, Botha MH, et al. School-based HPV vaccination: An opportunity to increase knowledge about cervical cancer and improve uptake of screening. S Afr Med J 2015;105(11):912-916. [http://dx.doi.org/10.7196/SAMJ.2015.v105i11.9814] 7. Jacob N, Coetzee D. Missed opportunities for immunisation in health facilities in Cape Town, South Africa. S Afr Med J 2015;105(11):917-921. [http://dx.doi.org/10.7196/SAMJ.2015. v105i11.10194] 8. Burnett RJ, von Gogh LJ, Moloi MH, François G. A profile of anti-vaccination lobbying on the South African internet, 2011 - 2013. S Afr Med J 2015;105(11):922-926. [http://dx.doi.org/10.7196/ SAMJ.2015.v105i11.9654] 9. Godlee F. Wakefield’s article linking MMR vaccine and autism was fraudulent. BMJ 2011;342:c7452. [http:// dx.doi.org/10.1136/bmj.c7452] 10. Deer B. Exposed: Andrew Wakefield and the MMR-autism fraud. http://briandeer.com/mmr/lancetsummary.htm (accessed 19 September 2015). 11. Jain A, Marshall J, Buikema A, et al. Autism occurrence by MMR vaccine status among US children with older siblings with and without autism. JAMA 2015;313(15):1534-1540. [http://dx.doi. org/10.1001/jama.2015.3077] 12. DRC: Katanga measles epidemic keeps worsening. http://www.msf.org/article/drc-katanga-measlesepidemic-keeps-worsening (accessed 19 September 2015). 13. Stefan DC, Stones DK, Wainwright RD, et al. Childhood cancer incidence in South Africa, 1987 - 2007. S Afr Med J 2015;105(11):939-947. [http://dx.doi.org/10.7196/SAMJ.2015.v105i11.9780]

Worldmapper: HIV prevalence. The size of the territories shows the proportion of all people aged 15 - 49 years with HIV worldwide, living there. All ten territories with the highest prevalence of HIV are in Africa. (http://www.worldmapper.org/display.php?selected=227)

This month in the SAMJ ... Lucretia Petersen* is a senior lecturer in audiology in the Division of Communication Sciences and Disorders at the University of Cape Town. She holds a master’s degree in audiology. Her research interests include hearing screening, ototoxicity and the improvement of early detection of hearing loss. She was deputy programme manager for the Ivan Toms Hearing Screening project in the Western Cape (2008 - 2010) and was involved in the implementation and evaluation of the project, as well as the training of primary healthcare nurses to conduct the screening.

Lebogang Ramma* is the current Head of the Division of Communication Sciences and Disorders at UCT. He completed his undergraduate and postgraduate training in audiology in the USA, and also worked for four years in both public and private healthcare facilities in California, USA. He holds a clinical doctorate in audiology (AuD), is a Master of Public Health (MPH) and has a postgraduate diploma in health economics. His research focuses on applying public health principles to the practice of audiology. * Petersen L, Ramma L. Screening for childhood hearing impairment in resource-constrained settings: Opportunities and possibilities. S Afr Med J 2015;105(11):901-902. [http:// dx.doi.org/10.7196/SAMJ.2015.v105i11.10082]

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CORRESPONDENCE

Modelling cost-effective therapies

To the Editor: In the present era of rapidly increasing medical costs, there is a need for doctors to assist in controlling these costs, in addition to providing quality care to all patients. This requires inclusion of the parameter of ‘value’ in medical practice. Value has been defined as ‘outcome divided by costs’.[1] In Fig. 1, a model of the changes in outcome with increasing costs is proposed. According to the model, the change follows a sigmoid curve pattern. This pattern is widely observed in biology, e.g. the dose-response effect to irradiation or chemotherapy in oncology, and is also seen in the diffusion of innovation in economics. The model is semiquantitative and does not specify the endpoint for outcome on the vertical axis or the cost in numbers on the horizontal axis. The endpoint used for outcomes will vary depending on the disease being treated. For example, in oncology the endpoints may be overall survival or quality of life parameters. The cost will vary depending on the therapeutic options available. As can be seen in the model, value is initially low (A - B in Fig. 1), then increases (B - C), and then decreases again (C - D). In cost-effective practice, doctors would seek to use the relatively high-value therapies between the threshold points on Fig. 1 (B - C) and avoid the low-value therapies. There would be a ‘sweet spot’ with maximum outcome and a high value at point C.

Threshold to decreasing value

Outcome

B A

Threshold to increasing value Increased costs

Fig. 1. A model for the change in outcome with increasing costs. (Value = outcome/costs.)

This model has been helpful in discussions by the author and others on the inclusion of different therapeutic interventions in treatment protocols, as it provided a framework for debate. Although the model is semiquantitative, agreement could readily be arrived at regarding on which part of the curve a proposed therapeutic intervention might fit. The decision to include a therapeutic intervention in available treatment protocols will also need to include other factors, such as affordability. For example, the new biological therapies for melanoma[2] prolong survival, but are too expensive to use on a population-wide basis. Funding in medicine is most often described from the perspective of medical schemes, government and industry. This needs to be complemented by the perspective of doctors who use their available resources to formulate cost-effective treatment protocols. The model may be helpful to doctors in joint undertakings with funders to provide quality care to patients and control costs. Raymond P Abratt

Head of Clinical Governance, Independent Clinical Oncology Network, and Professor Emeritus, University of Cape Town raymond.abratt@cancernet.co.za

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1. Porter ME. What is value in health care? N Engl J Med 2010;363:2477-2481. [http://dx.doi.org/10.1056/ NEJMp1011024] 2. Robert C, Schachter J, Long GV, et al Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372:2521-2532. [http://dx.doi.org/10.1056/NEJMoa1503093]

S Afr Med J 2015;105(11):884. DOI:10.7196/SAMJ.2015.v105i11.9880

Junior medical researchers: A neglected community with great academic potential

To the Editor: Medical research capacity development is a national priority to improve healthcare in South Africa (SA).[1] The 2011 National Health Research Summit set a target of training 1 000 doctoral candidates in health sciences over the next 10 years.[2-3] We advocate revitalised research training opportunities for junior clinicians to help achieve this target and to contribute to the creation of a thriving medical research network across SA. We acknowledge the need for community input to overcome challenges such as funding, adequate supervision and the time periods required to fulfil quality clinical and research training. We have created an organisation, the Junior Clinicians Research Initiative of South Africa (JUCRISA – www. jucrisa.co.za), to build a supportive community for junior clinicians who would like to be involved in research. We welcome support from the SA medical community to develop this movement further. Challenges. While efforts have been made to provide structured research programmes for undergraduate health science students,[4] little has been done for junior medical graduates (medical interns, community service medical officers (CSMOs) and junior medical officers). At present, medical graduates complete 3 years of public service in various medical fields, often in settings not conducive to academic development. An additional impediment is the perception that part-time studies such as the undertaking of honours or master’s degrees are prohibited during this period. Junior clinicians usually have little training in research proficiencies, leading to missed opportunities for otherwise motivated and capable graduates. Rural research: A unique opportunity. SA’s healthcare has the unique challenge of the HIV/tuberculosis syndemic intersecting with an increasing burden of non-communicable disease and trauma.[5] During CSMO training, junior clinicians are posted to rural areas where the need for medical personnel is dire and the above challenges are often at their greatest. Rural populations and healthcare sectors are seldom studied despite the value of clinical research in this setting. An example is the 2004 extensively drug-resistant tuberculosis outbreak in the rural Msinga area of KwaZulu-Natal, served by the Church of Scotland Hospital. Had it not been for the research initiated by the clinicians of this small hospital (later built on by the University of KwaZulu-Natal in collaboration with Yale University), the true burden of this fatal disease might have gone unchecked for many years.[6] Junior clinicians are uniquely positioned to contribute towards filling critical knowledge gaps in such areas. Suggestions for creating an environment conducive to junior clinicians’ research capacity development: 1. Engage the Department of Health (DoH), the Health Professions Council of South Africa (HPCSA) and academic institutions to actively encourage research training and involvement for junior clinicians. The creation of an academic track for internship and community service is one potential solution. 2. Obtain clarity from the HPCSA and DoH, as published policy, on whether research and part-time postgraduate studies are officially permitted during internship and community service.

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CORRESPONDENCE

3. I ncentivise and promote the pursuit of academic health sciences careers in SA for all medical graduates interested in such a career path. An incentive could be that undertaking postgraduate dissertation-based studies, e.g. a PhD, immediately after undergraduate studies be considered as community service.[4] 4. Implement a pilot study to test the feasibility of linking research projects to interns and CSMOs: • Create a limited number of specific internship and CSMO posts for medical graduates who wish to pursue a career in academic medicine. • Link these junior clinicians to feasible research protocols designed by willing supervisors at academic institutions. • Provide ongoing support and training throughout the internship and CSMO years to bring these studies to completion. We hope to initiate discussion around this matter and the benefits it can bring to the SA health sector. J Bovijn Medical intern, Tygerberg Hospital, Cape Town, South Africa info.jucrisa@gmail.com

A Jacobs

Global Health Research Fellow, Imperial College London, UK, and previous medical officer, Department of Medicine, Groote Schuur Hospital, Cape Town, South Africa

M T Boswell

Community service medical officer, Tshwane District Hospital, Pretoria, South Africa, and Department of Immunology, School of Medicine, Faculty of Health Sciences, University of Pretoria

E du Bruyn, L Bovijn, N Berkowitz

Research medical officers, Clinical Infectious Diseases Research Initiative, University of Cape Town, South Africa 1. The South African Health Improvement Plan. 2009. http://www.healthlink.org.za/uploads/files/ ks_1V2_10pointplan.pdf (accessed 19 August 2015). 2. Mayosi BM, Mekwa NJ, Blackburn J, et al. National Health Research Summit Report: Strengthening Research for Health, Development and Innovation in South Africa. 2011. http://www.rmchsa.org/wpcontent/uploads/2014/04/National-Health-Research-Summit-Report-2011.pdf (accessed 19 August 2015). 3. Purposeful support for health research in South Africa. S Afr J Sci 2012;108(5/6):Art. #1268, 1 page. [http://dx.doi.org/10.4102/sajs.v108i5/6.1268] 4. Katz A, Futter M, Mayosi B. The intercalated BSc (Med) Honours/MB ChB and integrated MB ChB/ PhD tracks at the University of Cape Town: Models for a national medical student research training programme. S Afr Med J 2013;104(2):111-113. [http://dx.doi.org/10.7196/SAMJ.7639] 5. Mayosi BM, Benatar SR. Health and health care in South Africa – 20 years after Mandela. N Engl J Med 2014(14);371:1344-1353. [http://dx.doi.org/10.1056/NEJMsr1405012] 6. The Msinga experience. 2009. http://www.kznhealth.gov.za/tbmsinga.pdf (accessed 19 August 2015).

S Afr Med J 2015;105(11):884-885. DOI:10.7196/SAMJ.2015.v105i11.10179

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Motsoaledi on ‘tide-turning’ new HIV treatment guidelines Minister of Health Dr Aaron Motsoaledi says that implementing the highly lauded new World Health Organization (WHO) HIV treatment guidelines will require careful fine-tuning to South Africa (SA)’s most vulnerable groups, with some aspects easier to implement than others. In an exclusive interview with Izindaba he was upbeat and clearly in favour of both the WHO’s ‘test and treat’ recommendation that all HIV-positive people be put on treatment as soon as they are diagnosed, and the recommendation that a pre-exposure prophylaxis (PrEP) pill be made available to all at-risk groups. He nevertheless urged caution, saying that a very clear set of pragmatic policies would need to be thrashed out with the country’s top experts at the South African National AIDS Council as a matter of urgency, so that ‘we can take everybody with us’. A ‘test and treat’ policy would be a radical departure from SA practice over the past 2 years, where HIV-positive people only qualify for treatment when their condition worsens to a CD4 cell count of 500/µL (previously set at 350/µL). Only HIV-positive pregnant women currently enjoy the benefits of treatment on diagnosis, something that has contributed hugely to the major success in reducing the mother-to-child HIV transmission rate, now estimated at below 2%. In theory, this means that the number of people in SA who currently qualify for antiretroviral treatment (initiation at a CD4 count of 500/µL) could more than double from 3.1 million on ART (measured in July 2015) to the total HIV-positive SA population of 6.4 million. Worldwide, the 15 million who are currently on treatment could increase to all 37 million people living with HIV. In SA, initiating the new measures would lend real weight to the assertion that HIV treatment is now merely another chronic disease, and give non-communicable diseases the attention they deserve. The UNAIDS global target of 15 million on ART by 2015 has been achieved. The new United Nations goalpost is to get 90% of people who test positive on ART – and then to get 90% of those same people down to an undetectable viral load by 2020. Dr Gilles van Cutsem, Médecins Sans Frontières (MSF, Doctors Without Borders) Chief for SA, told Izindaba that most of the 3.1 million South Africans currently on antretroviral therapy commenced

treatment during the past 5 years, when Motsoaledi initiated a massive detection and treatment scale-up, redressing the scandalously slow progress made between 2004 and 2009. The WHO PrEP recommendation is that all people at risk of contracting HIV be given a pill that prevents them from being infected. This is already recommended in the USA, but Motsoaledi said that HIV pandemic profiles differed from country to country, moving quickly to outline some of the local implementation difficulties while strongly rejecting any notion of cost being a barrier to implementation.

MSF started providing HIV treatment to people in developing countries in 2000, and today more than 200 000 people receive treatment through MSF programmes. Says Motsoaledi: ‘The difficult decision to make [regarding PrEP] is around those populations that are vulnerable, even if they are HIV-negative. It’s not that difficult when it comes to HIV-positive people (‘test and treat’), sex workers (of whom there are an estimated 150 000), and men who have sex with men (MSM) – but I can’t just walk into a classroom tomorrow and say to a million or so HIV-vulnerable youths between 15 and 24 that they must start taking PrEP pills – you can only imagine what the response will be.’ Singling out the country’s sex workers, he said 70% of them were already known to be HIV-positive, making it easier to reach the remaining 30% with PrEP – and easier to treat any of them who had recently seroconverted. It was the general HIV-negative population that was exercising his mind most. He said people who were already HIV-positive would be likely to have health problems at some stage – ‘that’s not a difficult decision to take, regardless of cost and numbers’. ‘But how many HIV-negative people will have that motivation to take treatment every day? For vulnerable women (a subset population most at risk in the 15 - 24 age cohort where HIV/AIDS is still growing), we’d have to design programmes specifically,’ Motsoaledi said, adding that nothing was ‘cut and dried’ in the complex application of the recommendations.

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‘We’ll have to debate and weigh this against other forms of prevention, like education and condoms,’ he said. PrEP is seen by treatment advocacy groups as probably the most effective prophylaxis for young women, for whom few HIV prevention options are available, leaving them at the mercy of male whim when it comes to protection. Motsoaledi said that major awareness and education campaigns would have to be devised to accompany roll-outs. Dr Francois Venter, former head of the Southern African HIV Clinicians Society and Deputy Executive Director of the Wits Reproductive Health and HIV Institute, said it was ‘great’ that SA was likely to follow the WHO guidelines, ‘although we need to sort out PrEP for adolescent girls. Condoms and behaviour lectures clearly are not enough – we’ve had them for 20 years and new incident infections are still extremely high. It’s going to be politically uncomfortable and operationally difficult, but we really need to be urgently thinking about PrEP as part of the prevention package for young girls.’

Keep the funding tap open – and use peer volunteers

Meanwhile, the highly respected global volunteer body at the forefront of HIV/ AIDS treatment in SA, MSF, applauded the latest updated treatment guidelines, saying they could ‘turn the tide’. MSF warned that turning the recomm endations into reality would require signifi cantly increased donor and govern ment support, especially in HIV-impacted communities, adding that governments and international donor organisations were already ‘prematurely’ cutting back on their AIDS budgets. Dr Tom Ellman, director of MSF’s Southern Africa Medical Unit, said that while ‘test and treat’ could turn the tide on HIV, in order for it to work as a tool to control the epidemic it would require ‘drastic changes and greatly increased investment’. ‘HIV care has to move out of clinics and into the communities with mobilised, empowered and engaged people living with HIV that actually are part of the response. This will need effort and money.’ He said that almost simultaneously with the WHO announcement on 30 September, world leaders at the United Nations agreed to a sustainable development goal to make AIDS ‘history’ within 15 years. They would

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now need to show that they were serious about it. ‘Nobody’s going to end AIDS with business as usual,’ he added. The Global Fund to Fight AIDS, TB and Malaria will hold its replenishment conference next year, making it the first real test of donors’ commitment to using the best science to treat all people living with HIV and further decrease rates of HIV transmission worldwide.

Founded in 1995, AVAC is a non-profit organisation that uses education, policy analysis, advocacy and a network of global collaborations to accelerate the ethical development and global delivery of AIDS vaccines, male circumcision, microbicides, PrEP and other emerging HIV prevention options as part of a comprehensive response to the pandemic.

Some very real red flags

Experience from MSF’s HIV programmes shows that over the past ten years, onethird of people who were diagnosed with HIV, but not eligible to start treatment, never returned to the health facility. Offering such individuals treatment as soon as they test positive could substantially reduce the number of people who may never return. Dr Marc Biot, MSF’s operational co-ordinator for HIV, said that in order to reach as many people as possible, as soon as possible, simplified models of care and self-management strategies were needed that allowed people to take more control over their own treatment and care.

‘It’s no longer only a question of when to start people on treatment, but also how to help people stay on treatment for life and to maintain “undetectable” levels of virus in their blood. We need to make sure HIV treatment fits into people’s lives better, just like with any other chronic disease in industrialised countries.’ Antiretroviral therapy ‘on demand’ was a wholly new concept in many parts of the world, where people had long been told to wait until they were sick or approaching low CD4 cell counts to begin treatment. Much work was needed to ensure that this guidance was understood and implemented. The recommendation of PrEP for all people at substantial risk replaces previous WHO guidance that focused on MSM and on heterosexual couples in which one partner is HIV-positive and the other negative.

PrEP steps into the gap to protect vulnerable young women

MSF confirmed that, perhaps most impor tantly, the recommendation vastly expands the likelihood that oral PrEP will be offered to young women, offering them a longneeded prevention option that they can use discreetly, not at the time of sex – a profoundly important development. Yvette Raphael, a human rights activist who recently completed a year-long project focused on addressing the HIV prevention, treatment, and sexual and reproductive health needs of young SA women, had this to say: ‘In SA, many young women have expressed the need for PrEP to be available as an option that will work for them. PrEP can help young women and girls take more control of their sexual and reproductive health rights and be more empowered to control their own sex lives.’ Mitchell Warren, AVAC Executive

Director, said that the WHO was paving the way for a fundamental shift in the world’s response to HIV – abandoning the partial or piecemeal use of antiretroviral medicines in favour of full access for men and women in need. ‘Both science and conscience demand that we put these recommendations into effect as quickly as possible.’ Carol Njoroge, a rights activist with the Kenya Sex Worker Alliance and a 2015 AVAC Fellow, focused on expanding PrEP access, said that as a woman who has lived with HIV for 15 years ‘I know the importance of taking control of all aspects of your life and health. I see that most of the people at high risk of HIV who know about PrEP and how effective it is, want it. There is demand from male, female and transgender sex workers and others at high risk for HIV, and we have PrEP demonstration studies looking at how best to provide PrEP in the real world.’ Kenya had developed a ‘prevention revolution roadmap’, but there’s still a lot more needed: clear clinical guidelines, regulatory approval, civil society partnership and funding commitments to make PrEP a reality. Warren stressed that continued research into additional prevention options remained ‘critical’. Two efficacy trials of a monthly vaginal ring with a different antiretroviral called dapivirine, phase II trials of two different injectable antiretrovirals, used every two or three months, a phase II daily rectal microbicide gel, ongoing HIV vaccine trials and new passive antibody studies may eventually provide additional options for young people and others at high risk of HIV. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(11):886-887. DOI:10.7196/SAMJ.2015.v105i11.10200

Medical aids often their own worst enemies with fraud Less than a third of medical schemes in South Africa (SA) (29.4%) use estimates of their losses to fraud, waste and abuse to decide how much they will invest in countering these practices. Most try to negotiate with offenders to mitigate their losses, making countrywide quantification almost imposs ible, while individual schemes fail to collaborate sufficiently, enabling crooked syndicates and individuals to move

between schemes with virtual impunity. Only a minority (also 29.4%) of schemes ensure that the people they hire to counter these practices have received professional training and accreditation for their roles. These figures, extracted from a retrospective KPMG survey conducted 5 years ago, were cited by Jim Gee, Director of Counter Fraud Services at BDO LLP (a UK-based business and accounting firm) and Visiting Professor and Chair of the Centre for Counter Fraud Studies at the University of Portsmouth, UK. His

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paper, entitled ‘The resilience to fraud of medical schemes in South Africa’, was among three expert presentations on fraud to the annual Board of Healthcare Funders (BHF) conference in Cape Town this July. They estimate the total of annual private healthcare fraud in SA to be roughly ZAR13 billion, based on the international norm of 10% of country total spend (ZAR130 billion in SA), but readily concede that insufficient data make this little more than a thumb-suck. Dr Hleli Nhlapo, Deputy Chairman of the BHF’s Healthcare Forensic Management

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Unit (HFMU), an information- and resourcesharing group in which most medical schemes, administrators, management and admini stration entities and some insurers participate, said that most service providers were ‘honest, healing scientists’, but that there were ‘outliers who mess it up for everyone’, mainly by filing high volumes of false or improper low-cost claims – very hard to detect unless schemes have proper systems in place. He urged individual medical schemes to share fraud, waste and abuse data with the HFMU to enable more efficient identification of syndicates, which shape-shifted, moving from scheme after scheme when they were detected or got wind of someone on their trail. ‘The only time we’ll get accurate percentages of fraud losses (and a higher prosecution rate) is when we all come together and work as a unit. This working in silos is a problem.’ Asked how many cases the HFMU had successfully prosecuted last year, he replied ‘Not a lot, there were three or four matters – which is exactly why we want better collaboration for greater success.’ Nhlapo later estimated that private healthcare fraud in SA ‘could be at least 7% and at most as much as 15% of the total spend, but it’s all thumbsuck, the truth is we don’t know.’ He said that the HFMU continued to work closely with the National Prosecuting Authority and the police to try to ensure more efficient prosecutions by giving them a better understanding of how the medical schemes industry worked, singling out KwaZulu-Natal as the most knowledgeable and efficient law enforcement province in this field.

‘50 shades of fraud ...’

Nhlapo, a dentist whose specialty has been tracking the worst offenders (dental therapists) in his field, shared the findings of an HFMU probe into the highest-claiming dental thera pists (treating pain and sepsis). Consolidating and analysing data from participating medical schemes, they found examples of dental therapists working 45 hours in a single day (v. an 8-hour day). By putting an investigator and a clinician into the field to actually question patients of suspect therapists and comparing their stories with actual claims, they found billing for services not provided to be the most common offence. ‘You couldn’t see what was being claimed for in the mouth,’ he explained. Up-coding (doing a single filling and billing for three) and submitting dental claims under one patient’s name when services were actually provided for another were also very common. There was also billing for non-covered services, falsely changing dates of service to compensate for annual benefits having run out, and abusing co-payments by (for example) taking an intraoral X-ray and charging for two, in lieu of the co-payment. Implanting of diamond and

Dr Hleli Nhlapo.

gold studs under false coding was common, while dismal infection control with re-used equipment was rife. (Medical aids use codes that support the avoidance of cross-infection.) One of the most common abuses was the use of ‘specials’, where entire families were encouraged to come in for dental treatment and received a gold inlay for free – the proviso being that four or more family members had to be on the principal member’s medical aid. ‘Some of the people in the pictures we took were supposed to get 16 fillings, but all we saw was cosmetic gold inlays.’ He showed mouthfuls of diseased teeth that were billed for as having been cleaned, adding that many therapists often practised well beyond their scope. Others took advantage of medical schemes holding ‘wellness days’ to treat patients in a corner of an office, or set up practice in substandard amenities such as Wendy houses with no lights or running water and just a hair salon chair. Nhlapo’s colleague Herman Havenga, Chief Operating Officer of Qubeka Forensic Services, said that one case study of collusion between pharmacists, GPs and medical aid members uncovered four main offending pharmacies (which he declined to identify), linked to another 11 pharmacies and involving 432 medical aid members. Using data analytics, they were able to show how pharmacies were being used as ‘ATM machines’. ‘You take a ZAR30 000 float in the morning when you open your pharmacy. The member brings his medical aid card and gets cash and groceries … but the plot thickens when you look at GPs. What we realised is that there are false consults and prescriptions written for scheduled medication. Basically they collude to defraud the schemes.’

Busted? Just change your practice number!

When they were confronted and pay ments were stopped, crooked GPs and pharmacists often opened up new practices with a new practice number. ‘In one particular case where

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a GP entered a plea agreement and agreed to appear as a state witness, we had success – but if we had worked together as an industry (the wider medical aid industry), the case wouldn’t have taken us 5 years to solve,’ he emphasised. Explaining the modus operandi further, he said the pharmacy customer took a basket, put in some baby food and groceries (such as soap, Dettol, skin cream). When they went to pay they were given cash to the value of a claim for (for example) inhaler medication worth ZAR1 400. ‘They even put a mark-up on the goods,’ he added. Showing a spreadsheet to depict a crooked drug rehabilitation clinic falsely charging for the transport of patients to a pathology lab, Havenga said that the secretary who recruited medical scheme members and then turned state witness on the scam was murdered. ‘This was syndicate stuff. If you don’t address it collectively, we won’t win. Yes, we got the Asset Forfeiture Unit in and we did get a conviction eventually here, but it would have been far quicker and better had all the medical aids worked together.’ One BHF conference delegate said it was his impression that schemes tended mostly to want to negotiate with providers and recover money: ‘It’s used as a stick – if you’re willing to negotiate a settlement, then you don’t get reported as a fraudulent case. I’m of the view that this distorts the actual fraud. We just don’t know what the tolerance level is!’ Nhlapo replied that this practice of ‘settling’ differed between schemes, ‘but your view is true of many schemes. Some schemes are not helping us by negotiating separately.’ He and Havenga described a suggestion from the floor that a symposium be held to thrash out the issue as ‘a brilliant idea’. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(11):887-888. DOI:10.7196/SAMJ.2015.v105i11.10197

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Council for Medical Schemes braves the tightrope between funders and the poor A new regulatory framework will in January 2016 enable medical schemes to offer low-cost, limited-benefit pri mary care medical aid, expanding private healthcare coverage by an extra 12.7 million people (from the current decade-long-stagnant 8.7 million higher-income members). It’s being touted as a potential trigger for private health access reform, complementing the impending National Health Insurance aimed at more equitable healthcare access for the other 84% of the population, most of whom depend on the overloaded, often dysfunctional public sector. Paresh Prema, Head of Benefit Management at the Council for Medical Schemes (CMS) and Johan Pretorius, CEO of Universal Health, told the Board of Healthcare Funders annual conference in Cape Town this July that the key to keeping low-income benefit option costs down lay in having healthcare provider networks that charged agreed-upon rates. Pretorius proposed to the CMS guideline architects that scheme members so covered should fall below the tax threshold (R5 296 per month). The CMS is considering restricting membership of the lowcost options to people with an income below R6 000 a month (but possibly up to R12 000), or prohibiting members from moving from more expensive options to the new low-cost options and/or limiting membership to those who have not been a member of a scheme before. The hope is also that not offering full private hospital cover will deter some members of more expensive options from moving to them or ‘buying down’. The Council is also reviewing a proposal to exempt the new options from having to hold reserves equal to 25% of contributions. Pretorius said administrators of medical schemes had proved that it cost more to provide membership to individuals than to groups.

Marrying cost-efficiency with decent benefits

At its August 2015 sitting, the CMS approved the exemption framework and principles allowing for the introduction and registration of low-cost benefit options in the medical schemes industry effective from 1 January 2016 – in an attempt to marry cost efficiency with decent benefits. Prema said that the guidelines for exemption from the Act were drawn up after consultation with

two scheme administrators, two medical aid schemes and some specialist provider groups and would be published soon after approval by the CMS’s 13-member governing board. This should enable schemes to get their low-income options in place by January next year. However, individual schemes would first have to make their submissions to the CMS for approval based on the exemption guidelines. Delays might occur, because most schemes would simultaneously be planning their overall benefits for next year. Each of the 12 guideline submissions from the industry had laid out the costs of two primary care options. The most basic offered three GP visits, basic dentistry and optometry, and basic pathology and radiology services – but no emergency or private hospital care. The benefits were based on feedback from households surveyed a decade ago in research commissioned by the CMS. Sacrificed on the altar of cost-efficiency are prescribed minimum benefits (PMBs), an extensive set of medical conditions, chronic diseases and emergency care that the Medical Schemes Act says must otherwise be provided by all medical schemes.

Prema said the guidelines for exception from the Act were drawn up after consultation with two scheme administrators, two medical aid schemes and some specialist provider groups and would be published soon after approval by the CMS’s 13-member governing board.

Costs of PMBs rising

Pretorius said it cost schemes R508 per person per month to provide cover for PMB benefits in 2013, a figure he estimates has risen to about R600 per month. Prema said of the guidelines his team have drawn up: ‘It will motivate the exceptional case for all schemes. It’s around affordability. We want to simplify it so that schemes know what is expected when they apply – and it’s entirely around primary healthcare products,’ he explained. One idea was to see if it was costeffective to have higher minimum benefits: ‘We don’t want it to be too onerous to [prevent it] reach[ing] the target market.’ The original lower-income medical schemes survey was done in 2005, so subsequent salary hikes and

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Paresh Prema, Head of Benefit Management at the Council for Medical Schemes.

inflation needed to be taken into account to avoid running the risk of prescribing a minimum benefit not valued by the market. ‘We’re hoping that specialties like radiology and pathology will buy into it and provide benefits at a lower cost, because they realise that this is aimed at a lower-income market. It’ll take time for everybody to buy into – that’s why the exemption process is a good start.’ He said that the generic benefit package being proposed was ‘more about what the benefits are and not what diseases are covered’. ‘We have to change the way in which we sell or structure this product to deal with what benefits will be used. It doesn’t make sense to have a PMB package covering 270 conditions at a cost that is unaffordable – and not dealing with the immediate needs.’ Asked to elaborate on the ‘package’, he said it would deal with the day-to-day immediate needs of members such as consultations and acute and chronic medications. ‘It’s what people in the market are willing to pay for to avoid a [public sector] queue or miss a day’s work.’ The idea was to help schemes grow their memberships and increase access to healthcare. Only about one million medical scheme members (10.87% of total lives covered) currently belong to low-cost options that offer benefits via provider networks. Pretorius called on providers to offer more low-cost services that could be included in the new options, suggesting that the Council might consider allowing schemes to restrict membership of the low-cost options to people who live in areas where there were provider networks to service them. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(11):889. DOI:10.7196/SAMJ.2015.v105i11.10199

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Private hospitals could turbo-boost public sector reform A renowned global authority on national healthcare systems says the South African (SA) government should shift its focus from only supporting public hospitals to lever aging the skills and expertise of their private counterparts to turbo-boost state reform in preparation for a universal healthcare system.

Prof. Bill Hsiao, Harvard University health economist.

Speaking at the Hospital Association of South Africa (HASA) conference on 21 September this year, Prof. Bill Hsiao, a Harvard University health economist who has provided analysis and consulting services to 30 countries in Europe, Africa, Asia and Australasia, said that the longterm goal would be to harmonise the public and private health sectors. Hsiao has served as an advisor to three US presidents, the US Congress, and other global health and economic organisations such as the International Monetary Fund, World Bank and International Labour Organization. He told delegates that until now the government’s efforts have been aimed mostly

at supporting public hospitals when more short-term solutions could be found by leveraging private hospitals, most of which are HASA members. HASA’s members, with 37 000 acute hospital beds, 220 hospitals and 150 000 employees, could use its knowledge, experience and innovation to help contribute to better quality healthcare, access to treatment and efficiency if the two sectors could find a way to work together. ‘In the short run the challenge remains how to leverage the strengths of the private sector to strengthen the healthcare system of SA.’ Giving some pragmatic pointers, Hsiao said that the state could contract hospital management companies to transfer know ledge and operational systems to public hospitals, and that Singapore had done just this. Selected functions such as food and laundry, and the management of public hospitals or administration of social health insurance, could also be outsourced. ‘From an international perspective, up to this point, the National Health Insurance pilot system has only tried to strengthen the delivery system in the public sector. There needs to be more active piloting and trying out of alternatives,’ said Hsiao. ‘I liken the long-term aim of harmonising the healthcare system to an orchestra. One not only needs to include the various sections of an orchestra, to create a whole, but also to teach them how to work together. In this sense, the public and private hospitals have different strengths that need to work together. On the one hand, the public hospitals offer universal access and are publicly funded, while on the other, private hospitals attract private investment and are targeted at those who are willing and able to pay. Public hospitals were far more bureaucratic when compared to the far more

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agile and dynamic private hospitals that are driven by market forces. ‘In this type of environment, private hospitals are driven by competition and have to respond by appealing to what patients want and their willingness to pay as well as to be alert and innovate. This is not always the case with public hospitals.’

‘If you unlock people’s imagination and technical knowhow, you can develop highly specialised services at much less cost,’ he added. Public hospitals could benefit by using pri vate sector hospital managers and gain the latest international knowledge and experience in managing hospitals. Globally the private sector offered a source of capital investment and services not provided by the public sector, and was a source of knowledge and management skills for social health insurance plans and hospitals and health centres. ‘This can be leveraged to the benefit of everyone – if you unlock people’s imagin ation and technical know-how, you can develop highly specialised services at much less cost,’ he added. Dumisani Bomela, Chief Executive of HASA, said that his organisation was comm itted to ongoing discussions with the Department of Health with a view to strengthening healthcare delivery. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(11):890. DOI:10.7196/SAMJ.2015.v105i11.10198

Alexander Forbes

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IZINDABA

BOOK REVIEW

The Practitioner’s Guide to Medical Malpractice in South African Law

By Ian Dutton. Cape Town: Siber Ink, 2015. ISBN 978-1-920025-93-9 There is no doubt that a book that clearly sets out the principles of malpractice law would be helpful to the medical profession. The question is – is this the book? In the second sentence of his introduction the author states that the book, by virtue of the subject material, is primarily a legal work, and he is correct. He is obviously an expert in the field, and the subject of litigation is extensively and well covered. While academic

in nature this is clearly not a reference book, making it less likely to be of use to those lawyers already experienced in the field. For lawyers it seems aimed primarily at undergraduates or those considering or entering the field. Would I advise doctors to acquire the book? I found one of the forewords a little misleading in stating that layman’s language is used. The language used in the book is laboured, legalistic and difficult to follow. It is perhaps unfair to quote out of context, but a sentence among many that illustrates the point reads: ‘Conduct may therefore be described as delictually unlawful only if it has as its consequence the factual infringement of an individual interest.’ I think that for the average practitioner the principles, while set out, are opaque and difficult to understand. I suspect that most would not be able to distinguish the difference between negligence and malpractice. In addition, the book concentrates on litigation and is virtually silent on the regulatory consequences of malpractice or possible criminal involvement of the practitioner. The Health Professions Council of South Africa is a very important player in the South African medicolegal arena, and it is virtually unmentioned. Would I suggest that doctors who give expert opinions acquire the book? Latin terminology, foreseeability and lawfulness, while doubtless of legal significance, have little to do with where medicine meets the law, as opposed to the

UNIVER SITY OF C AP E TOW N D E PA R T M E N T O F M E D I C I N E

law meeting medicine. The vast majority of opinions that we seek revolve around evaluating the standard of care in a case, causation, prognosis, costs or life expectancy. Does the care given fall within the recognised and accepted practices of the profession? If it doesn’t and the patient suffered harm, was the harm suffered as a result of the lapse in care or not? If experts can opine on these issues, the lawyers can take the arguments back to the law and legalese. The book gives little pragmatic advice in these important areas for medical experts. It is not a book that I would recommend to a medical practitioner expressing an interest in giving expert opinions. So in answer to the question whether this is the book to answer the medical profession’s quest to understand malpractice law in South Africa, the answer is sadly probably in the negative. While it is packed with facts and written by an expert, the principles and pragmatic advice that doctors (even experts who give medicolegal opinions) need are probably too well hidden. To my mind the book is primarily for lawyers, and of limited interest to the medical profession. Graham Howarth Head of Medical Services in Africa, Medical Protection Society, Victoria House, 2 Victoria Place, Leeds, UK graham.howarth@medicalprotection.org

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COCHRANE CORNER

Interventions for improving childhood vaccination coverage in low- and middle-income countries C S Wiysonge,1,2 MD. PhD; T Young,1,2 MB ChB, MMed; T Kredo,1 MB ChB, MMed; M McCaul,2 BHSc, MSc; J Volmink,1,2 FRCP, DPhil; on behalf of Cochrane South Africa 1 2

ochrane South Africa, South African Medical Research Council, Tygerberg, Cape Town, South Africa C Centre for Evidence-Based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa

Corresponding author: C S Wiysonge (charlesw@sun.ac.za)

‘Cochrane Corner’ in the November SAMJ highlights a Cochrane review that evaluated the effects of interventions for improving childhood vaccination coverage in low- and middle-income countries. Question: Which interventions increase the uptake of childhood vaccines in low- and middle-income countries? Bottom line: Health education, home visits and reminders probably increase the uptake of childhood vaccines in low- and middle-income countries. S Afr Med J 2015;105(11):892-893. DOI:10.7196/SAMJ.2015.v105i11.10177

Worldwide, vaccination prevents three million child deaths annually and could do more if optimal coverage were attained.[1-3] However, vaccination coverage remains suboptimal in low- and middleincome countries (LMICs). We highlight a Cochrane review that evaluated the effects of interventions for improving childhood vaccination coverage in LMICs.[4] Fig. 1 shows a logical framework for thinking through interventions for increasing coverage. The review included six studies (with 7 922 participants) conducted in Ghana, Georgia, Honduras, India, and Pakistan. Three studies focused on health education interventions: evidencebased discussions in communities on the importance of childhood vaccination; information campaigns in communities using audiotape messages and printed materials; and education in health centres on the importance of completing the vaccination schedule. Two studies assessed the effects of home visits to identify unvaccinated children and refer them to health centres and the training of immunisation managers to provide supportive supervision for healthcare providers, respectively. The sixth study evaluated effects of Barriers

Factors affecting demand for services

Factors affecting supply of services

Factors affecting both demand for and supply of services

Tailored interventions

withdrawing monetary vouchers from mothers who did not vaccinate their children and a multifaceted intervention targeting recipients (monetary incentives), providers (quality assurance) and health system (provision of equipment, drugs and materials). These studies show that health education (moderate-quality evidence) and home visits (low-quality evidence) can increase childhood vaccination coverage (Table 1), while recipient disin centives, training immunisation managers to provide supportive supervision, or multifaceted intervention lead to little or no difference in coverage (low-quality evidence). This is a well-conducted systematic review with only minor limitations. We consider that there was a high risk of selection bias in one of the included studies, because participants were not allocated to interventions at random. Two other studies were judged to have a high risk of detection bias, because people assessing outcomes were aware of the interventions to which participants were allocated. Review authors excluded parental reminders, as these interventions were already covered by an existing Cochrane review.[6] The latter conducted comprehensive searches up to May 2007 for controlled trials conducted in any setting, and identified 47 studies. Sixteen of

Outputs

Outcomes

Impacts

Recipient-orientated: • • • •

Information & education Behaviour change support Prompts & reminders Incentives

Provider-orientated: • Education • Audits & feedback • Supervision • Prompts & reminders • Incentives

Direct: • Improved interest in vaccination • Improved knowledge, attitudes & practices • Motivation & behaviour change • Reduced vaccine wastage

• Increased vaccination coverage • Reduced vaccinepreventable diseases

Indirect:

Health system orientated: • Supply chain management • Vaccine stock management • Provision of equipment, drugs & materials

• Expansion & integration of services • Improved quality of services • Better-quality immunisation data

• Reduced time lost from school due to vaccinepreventable diseases

Fig. 1. Conceptual framework of interventions for enhancing childhood vaccination coverage (adapted from Abdullahi et al.[5]).

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November 2015, Vol. 105, No. 11

• Reduced child mortality • Improved childhood vaccination policies • Strengthened immunisation programmes

SAMF

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The ESSENTIAL MEDICAL REFERENCE for every healthcare professional! The convenient pocket-sized design enables you to fit it comfortably into your hospital bag or coat pocket, so it can always be at hand for ready reference. South African Medicines Formulary (SAMF), produced by the Division of Clinical Pharmacology of the University of Cape Town, provides easy access to the latest, scientifically accurate information, including full drug profiles, clinical notes and special prescriberâ&#x20AC;&#x2122;s points. The thoroughly updated 11th edition of SAMF is your essential reference to the rational, cost-effective and safe use of medicines.

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FORUM

Table 1. GRADE summary of findings table for the effects of interventions compared with usual care Population: Parents of children aged 0 - 4 years Settings: Ghana, Georgia, Honduras, India, Pakistan Intervention: Any single intervention intended to improve vaccination coverage in children Comparison: Usual care Illustrative comparative risks (95% CI) Intervention

With usual care

Evidence-based discussion

244/1 000

With specified intervention DTP3 coverage 529/1 000 (349 - 803)

Measles vaccine coverage 324/1 000 Information campaign

Uptake of at least one vaccine 94/1 000

Facility-based health education

528/1 000 (334 - 836) 134/1 000 (95 - 190) DTP3 coverage

547/1 000

Home visits

645/1 000 (574 - 728) OPV3 coverage

730/1 000

890/1 000 (760 - 1 000)

Relative effect (95% CI)

No. of participants (trials)

Quality of the evidence (GRADE)

RR 2.17 (1.43 - 3.29)

957 (1 study)

Moderate

RR 1.63 (1.03 - 2.58)

957 (1 study)

Moderate

RR 1.43 (1.01 - 2.02)

1 025 (1 study)

Moderate

RR 1.18 (1.05 - 1.33)

750 (1 study)

Low

RR 1.22 (1.05 - 1.42)

419 (1 study)

Low

CI = confidence interval; RR = risk ratio; DTP3 = three doses of diphtheria-tetanus-pertussis-containing vaccines; OPV3 = three doses of the oral polio vaccine. GRADE Working Group grades of evidence: high quality = further research is very unlikely to change our confidence in the estimate of effect; moderate quality = further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality = further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very low quality = we are very uncertain about the estimate.

the studies focused on reminders to parents about their children’s routine vaccinations. One study was excluded from meta-analysis owing to potential errors in analysis. Of 15 remaining studies (with 15 704 participants), 14 were conducted in the USA and one in Australia. Eight studies sent reminders through letters and seven used postcards, telephone calls, and home visits. This review found that reminders probably increase vaccination coverage (odds ratio 1.47, 95% confidence interval 1.28 - 1.68; moderate-quality evidence).[6]

Conclusion

The evidence shows that educating parents on the benefits of vaccinating their children, sending reminders to parents prior to planned vaccination visits, and contacting parents whose children have missed vaccination appointments all improve childhood vaccination coverage. However, there is a paucity of controlled trials from LMICs on interventions for improving childhood vaccination

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coverage. Future studies of parental reminders should include modern technologies such as mobile-phone text-messages.[7] 1. World Health Organization. Global immunization coverage in 2014. http://www.who.int/immunization/ monitoring_surveillance/Global_Immunization_Data.pdf?ua=1 (accessed 6 October 2015). 2. Machingaidze S, Wiysonge CS, Hussey GD. Strengthening the Expanded Programme on Immunization in Africa – looking beyond 2015. PLoS Med 2013;10(3):e1001405. [http://dx.doi.org/10.1371/journal.pmed.1001405] 3. Wiysonge CS, Ngcobo NJ, Jeena PM, et al. Advances in childhood immunisation in South Africa – where to now? Programme managers’ views and evidence from systematic reviews. BMC Public Health 2012;12:578. [http://dx.doi.org/10.1186/1471-2458-12-578] 4. Oyo-Ita A, Nwachukwu CE, Oringanje C, Meremikwu MM. Interventions for improving coverage of child immunization in low- and middle-income countries. Cochrane Database Syst Rev 2011, Issue 7. Art. No. CD008145. [http://dx.doi.org/10.1002/14651858.cd008145.pub2] 5. Abdullahi LH, Kagina BMN, Wiysonge CS, Hussey GD. Improving vaccination uptake among adolescents. Cochrane Database Syst Rev 2015, Issue 9. Art. No. CD011895. [http://dx.doi. org/10.1002/14651858.cd011895] 6. Jacobson Vann JC, Szilagyi P. Patient reminder and patient recall systems for improving immunization rates. Cochrane Database Syst Rev 2005, Issue 3. Art. No. CD003941. 7. Kalan R, Wiysonge CS, Ramafuthole T, et al. Mobile phone text messaging for improving the uptake of vaccinations: A systematic review protocol. BMJ Open 2014;4:e005130. [http://dx.doi.org/10.1136/ bmjopen-2014-005130]

Accepted 7 October 2015.

November 2015, Vol. 105, No. 11

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HEALTHCARE DELIVERY

Appropriate indications for positron emission tomography/computed tomography: College of Nuclear Physicians of the Colleges of Medicine of South Africa M Sathekge, J M Warwick, A Doruyter, M Vorster Prof. Mike Sathekge is a nuclear physician in the Department of Nuclear Medicine at Steve Biko Academic Hospital and the Faculty of Health Sciences, University of Pretoria, South Africa, and president of the College of Nuclear Physicians of South Africa (CNP). He has an interest in positron emission tomography/computed tomography (PET/CT) and targeted radionuclide therapy. Prof. James Warwick is a nuclear physician in the Division of Nuclear Medicine at Tygerberg Academic Hospital and the Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa, and secretary of the CNP. He is responsible for clinical operations at the Western Cape Academic PET/CT Centre. Dr Alex Doruyter is a nuclear physician and Medical Research Council clinical PhD scholar in the Division of Nuclear Medicine at Tygerberg Academic Hospital and Stellenbosch University, and Prof. Mariza Vorster is a nuclear medicine physician at the Department of Nuclear Medicine, University of Pretoria. She has a special interest in PET/CT and is a council member of the CNP. Corresponding author: M Sathekge (mike.sathekge@up.ac.za)

Individualised patient treatment approaches demand precise determination of initial disease extent combined with early, accurate assessment of response to treatment, which is made possible by positron emission tomography/computed tomography (PET/CT). PET is a non-invasive tool that provides tomographic images and quantitative parameters of perfusion, cell viability, proliferation and/or metabolic activity of tissues. Fusion of the functional information with the morphological detail provided by CT as PET/CT can provide clinicians with a sensitive and accurate one-step whole-body diagnostic and prognostic tool, which directs and changes patient management. Three large-scale national studies published by the National Oncologic PET Registry in the USA have shown that imaging with PET changes the intended patient management strategy in 36.5% to 49% of cases, with consistent results across all cancer types. The proven clinical effectiveness and growing importance of PET/CT have prompted the College of Nuclear Physicians of South Africa, in collaboration with university hospitals, to develop a list of recommendations on the appropriate use of fluorine-18-fluorodeoxyglucose (18F-FDG) and non-18F-FDG PET/CT in oncology, cardiology, neurology and infection/inflammation. It is expected that other clinical situations will be added to these recommendations, provided that they are based upon solid clinical evidence. These recommendations are intended to offer advice regarding contemporary applications of PET/CT, as well as indicating novel developments and potential future indications. The CNP believes that these recommendations will serve an important and relevant role in advising referring physicians on the appropriate use of 18F-FDG and non-18F-FDG PET/CT. More promising clinical applications will be possible in the future, as newer PET tracers become more readily available. S Afr Med J 2015;105(11):894-896. DOI:10.7196/SAMJ.2015.v105i11.10180

A patient-tailored treatment approach demands precise determin ation of initial disease extent combined with early, accurate assessment of response to treatment. Positron emission tomography/com puted tomography (PET/CT) is currently the most widely used molecular imaging technology and is central to the advancement of patient care and biological research.[1,2]

PET/CT whole-body imaging

PET is a non-invasive tool that provides tomographic images and quantitative parameters of perfusion, cell viability, and proliferation and/or metabolic activity of tissues. These images result from the use of various biological compounds (such as sugars, amino acids, metabolic precursors and hormones) labelled with positronemitting radionuclides (PET radiopharmaceuticals).[1] Fusion of the functional information with the morphological detail provided by CT as PET/CT can provide clinicians with a sensitive and accurate one-step whole-body diagnostic and prognostic tool, which directs and changes patient management.[1,3] Several studies have demonstrated the superiority of combined PET/CT over either modality alone, and for many indications this is

894

generally accepted as the gold standard for imaging in oncology. [4] The value of PET/CT imaging has been best demonstrated in the setting of oncology with the use of fluorine-18-fluorodeoxyglucose (18F-FDG). FDG is an analogue of glucose and is taken up by cells via the first stages of the normal glucose pathway and trapped inside cells with high glucose transporter expression and/or glycolytic activity. Tumour uptake therefore correlates with tumour growth and viability, providing metabolic quantification and frequently useful information for tumour characterisation, patient prognosis and monitoring of therapeutic response.[1]

Impact on the management of oncology patients

Current data suggest that in as many as one-third to one-half of cancer cases, physicians without access to PET are at an increased risk of selecting the wrong management/treatment strategy for their patients. Three large-scale national studies published by the National Oncologic PET Registry in the USA have shown that PET imaging changes the intended patient management strategy in 36.5%, 38% and 49% of cases, respectively.[5-7] Results were consistent across all cancer types.[6] A recent study by Worsley et al.[8] found that the information derived from PET

November 2015, Vol. 105, No. 11

FORUM

imaging resulted in a change in intended treatment plans in 50% of cases.[8] In up to 90% of cases, referring physicians indicated that PET/ CT enabled them to avoid additional imaging tests or procedures.[7] It is largely on this basis that PET can significantly reduce the number of tests performed, with substantial healthcare savings if it is done at the beginning of the diagnostic pathway rather than as a last resort. PET imaging has enabled physicians to avoid costly biopsy and surgery in as many as 70% of cases.[5] This can also result in significant cost savings and prevent patients from undergoing high-risk surgical procedures.

The South African context

South Africa (SA) is recognised as a world leader in the provision of medical isotopes and has centres of global excellence in PET for oncology, infection, neurology and personalised medicine.[9] SA is among a minority of countries that can provide both 18F-

FDG and non-18F-FDG tracers, including 18F-NAF, 18F-choline, 68 Ga-DOTATATE/DOTATOC, and 68Ga-PSMA for clinical use. We have already observed the significant clinical impact of 18F-FDG PET/ CT in the management of cancer patients, similar to that published by Hillner et al.[6,7] and Worsely et al.[8] Evidence is also rapidly accumulating for multiple non-oncological indications in the fields of cardiology,[10] neurology[11] and infection imaging.[12] This growth is expected to continue with existing tracers, and with the numerous possibilities created by new tracers.[13] The proven clinical effectiveness and growing importance of PET/ CT have prompted the College of Nuclear Physicians (CNP) of the Colleges of Medicine of South Africa, in collaboration with university hospitals, to develop a list of recommendations on the appropriate use of 18F-FDG and non-18F-FDG PET/CT in oncology, cardiology, neurology and infection/inflammation. This has resulted in a well-

Table 1. Summary of the appropriate indications for PET/CT Staging

Restaging/response post therapy C

Thymus

Breast

Lymphoma

Disease

Screening

Diagnosis

CNS tumours

Head & neck Thyroid

Langerhans cell histiocytosis

Surveillance

Radiotherapy planning R

Multiple myeloma

Carcinoma unknown primary

Paraneoplastic syndrome

Suspected recurrence

Melanoma Lung cancers

Pleural/mesothelioma

Oesophagus

Gastric & pancreas

Colorectal and anal

Hepatobiliary

Sarcoma

GIST

Genitourinary tract cancers

Male reproductive system

Female reproductive system

Non-FDG PET C

Neuroendocrine tumours (68Ga-DOTATATE) Neuroendocrine tumours (18F-FDG)

Sodium fluoride ( F-NaF)

Prostate cancer (18F-choline, 68 Ga-PSMA)

Paediatric oncology

Neurology

Cardiology

R = recommended; Rs = recommended in select cases; C = may be considered; GIST = gastrointestinal stromal tumour.

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established list of recommendations on the use of both 18F-FDG and non-18F-FDG PET/CT in these fields. The CNP has focused on defining those clinical conditions particular to the SA context, and where PET/CT could potentially result in the highest patient impact, with the intention of optimising the cost-effectiveness of its utilisation.[14,15] In addition, emphasis has been placed on the need for clinical benefit to be demonstrated together with accuracy. This principle has also been expressed by Schuenemann et al.:[16] ‘If a test fails to improve patient-important outcomes, there is no reason to use it, whatever its accuracy.’ This idea is not new, and remains one of several steps in establishing diagnostic procedures.[17,18]

Explanation of recommendations

Our recommendations on the appropriate use of PET/CT are based on the search for the best clinical evidence in the medical literature. In order to achieve consistency and avoid ambiguity, recommendations on the use of PET/CT for individual indications have been categorised as: 1. R ecommended: PET/CT is generally appropriate for this indi cation. There is a strong base of evidence supporting its use and/or it is currently recommended by international clinical guidelines. 2. Recommended in select cases: PET/CT is appropriate for this indication in cases meeting clearly defined criteria. In this specific context there is a strong base of evidence supporting its use and/or it is currently recommended by international clinical guidelines. 3. M ay be considered: PET/CT is generally not appropriate for this indication; however, it may be appropriate in individual cases with a strong motivation. Typically there may be some evidence or a strong rationale to support the use of PET/CT in special circumstances. 4. N ot recommended: PET/CT is generally not appropriate for this indication. Typically there is a low level of evidence and/or weak rationale for its use, and it is not endorsed by international clinical guidelines. The recommendations and practical guidelines developed by the CNP for the use of 18F-FDG and non-18F-FDG PET/CT are summarised in Table 1, and the full details will be available in part 2 of the January 2016 issue of SAMJ.[19]

Conclusion

It is important to note that it is expected that other clinical situations will be added to these recommendations, provided that they are based upon solid clinical evidence. Although the availability of metabolic functional imaging has greatly enhanced our understanding of a range of pathological processes, and provided new opportunities for incorporation of this information into patient management protocols, growth of PET globally and in SA is constrained by cost, infrastructure and education.[20] The World Heath Organization recommends that countries adopt a PET scanner ratio of two scanners per million people.[21] This suggests that SA would require approximately 100 PET scanners – ten times the current number. Attaining this goal would require a financial commitment commensurate with policy priorities that include resources for equipment, radiotracer production and distribution, infrastructure, and the education of physicians and healthcare consumers. Currently this is not achievable.

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The cost of PET/CT in SA ranges from ZAR12 000 in the public sector to ZAR20 000 in the private sector. With the limited resources we have, it is therefore important to avoid the inappro priate use of PET/CT. The limited knowledge of PET on the part of many referring physicians is a growing concern, and is a commonly cited factor contributing to the underutilisation of existing PET scanners in some departments. SA doctors tend to use PET imaging at the end of the diagnostic pathway, which may prevent cost-effective care. Similarly, the inappropriate use of PET/ CT is not cost-effective. There is therefore a need for education and training of caregivers, doctors, patients and healthcare officials. The CNP recommendations[19] are intended to offer advice regarding contemporary applications of PET/CT, as well as indicating novel developments and potential future indications. The CNP believes that these recommendations will serve an important and relevant role in advising referring physicians on the appropriate use of 18 F-FDG and non-18F-FDG PET/CT, which can be a powerful tool in patient management in oncology, cardiology, neurology and infection/inflammation. More promising clinical applications will be possible in the future, as newer PET tracers become more readily available. 1. Boellaard R, O’Doherty MJ, Weber WA, et al. FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. Eur J Nucl Med Molec Imaging 2010;37(1):181-200. [http://dx.doi. org/10.1007/s00259-009-1297-4] 2. Royal College of Physicians and Royal College of Radiologists. Evidence-based Indications for the Use of PET-CT in the UK. London: RCP, RCR, 2013. www.rcr.ac.uk/docs/radiology/pdf/2013_PETCT_ RCP_RCR.pdf (accessed 6 January 2015). 3. PET Professional Resources and Outreach Source. NCCN Practice Guidelines Tabular Summary PET and PET/CT. 2011. http://www.snm.org/docs/PET_PROS/NCCNPracticeGuidelinesI.pdf (accessed 22 November 2011). 4. Gao G, Gong B, Shen W. Meta-analysis of the additional value of integrated 18F-FDG PET-CT for tumor distant metastasis staging: Comparison with 18F-FDG PET alone and CT alone. Surg Oncol 2013;22(3):195-200. [http://dx.doi.org/10.1016/j.suronc.2013.06.004] 5. Hillner BE, Siegel BA, Liu D, et al. Impact of positron emission tomography/computed tomography and positron emission tomography (PET) alone on expected management of patients with cancer: Initial results from the national oncologic PET registry. J Nucl Med 2008;49(13):1928-1935. [http:// dx.doi.org/10.2967/jnumed.108.056713] 6. Hillner BE, Siegel BA, Shields AF, et al. Relationship between cancer type and impact of PET and PET/CT on intended management: Findings of the national oncologic PET registry. J Clin Oncol 2008;26(13):2156-2161. [http://dx.doi.org/10.2967/jnumed.108.056713] 7. Hillner BE, Siegel BA, Shields AF, et al. The impact of positron emission tomography (PET) on expected management during cancer treatment. Cancer 2009;115(2):410-418. [http://dx.doi. org/10.1002/cncr.24000] 8. Worsley DF, Wilson DC, Powe JE, et al. Impact of F-18 fluorodeoxyglucose positron emission tomographycomputed tomography on oncologic patient management: First 2 years’ experience at a single Canadian cancer centre. Can Assoc Radiol J 2010;61(1):13-18. [http://dx.doi.org/10.1016/j.carj.2009.07.005] 9. Sathekge M, Maes A, van der Wiele C. FDG-PET imaging in HIV infection and tuberculosis. Semin Nucl Med 2013;43(5):349-366. [http://dx.doi.org/10.1053/j.semnuclmed.2013.04.008] 10. Flotats A, Knuuti J, Gutberlet M, et al. Hybrid cardiac imaging: SPECT/CT and PET/CT. A joint position statement by the European Association of Nuclear Medicine (EANM), the European Society of Cardiac Radiology (ESCR) and the European Council of Nuclear Cardiology (ECNC). Eur J Nucl Med Mol Imaging 2011;38(1):201-212. [http://dx.doi.org/10.1007/s00259-010-1586-y] 11. Tripathi M, Damle N, Kushwaha S, et al. Differential diagnosis of neurodegenerative dementias using metabolic phenotypes on F-18 FDG PET/CT. Neuroradiology 2014;27(1):13-21. [http://dx.doi. org/10.15274/NRJ-2014-10002] 12. Israel O, Keidar Z. PET/CT imaging in infectious conditions. Ann N Y Acad Sci 2011;1228(1):150-166. [http://dx.doi.org/10.1111/j.1749-6632.2011.06026.x] 13. Núñez MR, Pozo MA. Non-FDG PET in oncology. Clinical and Translational Oncology 2011;13(11):780-786. [http://dx.doi.org/10.1007/s12094-011-0733-7] 14. Sathekge M, Maes A, Kgomo M, Pottel H, Stolz A, van de Wiele C. FDG uptake in lymph-nodes of HIV+ and tuberculosis patients: Implications for cancer staging. Q J Nucl Med Mol Imaging 2010;54(6):698-703. 15. Simonds HM, Warwick J, Ellmann A. Introduction of PET/CT scanning impacts treatment decisions in the management of cervix carcinoma patients in a public hospital. World J Nucl Med 2010;9:S152. 16. Schuenemann HJ, Oxman AD, Brozek J, et al. GRADE: Assessing the quality of evidence for diagnostic recommendations. ACP J Club 2008;149(6):2. 17. Fryback DG, Thornbury J. The efficacy of diagnostic imaging. Med Decis Making 1991;11(2):88-94. [http://dx.doi.org/10.1177/0272989X9101100203]. 18. Köbberling J, Trampisch H, Windeler J. Memorandum for the evaluation of diagnostic measures. J Clin Chem Clin Biochem 1990;28(12):873-879. 19. Vorster M, Doruyter A, Brink A, et al. Appropriate indications for positron electron tomography/ computed tomography, 2015. S Afr Med J 2016;106(1)(in press). [http://dx.doi.org/10.7196/SAMJ.2015. v105i11.10181] 20. Sathekge MM, Warwick J, Vangu MDT, Ellmann A, Mann M. A case for the provision of positron emission tomography (PET) in South African public hospitals. S Afr Med J 2006;96(7):598. 600-601. 21. MEDEC. Positron Emission Tomography (PET) Task Force Report for Ontario. Toronto: MEDEC, 2010.

Accepted 8 October 2015.

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CLINICAL ALERT

Efavirenz as a cause of ataxia in children M P K Hauptfleisch, D P Moore, J L Rodda Dr Marc Hauptfleisch is a paediatric neurologist in the Department of Paediatrics, Chris Hani Baragwanath Academic Hopsital (CHBAH) and the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. He has a special interest in neuromuscular disorders. Dr David Moore is a paediatric infectious disease consultant in the same department. He has a special interest in respiratory pathogens. Prof. John Rodda is a paediatric neurologist in the same department. The Paediatric Neurology Unit was established and has grown under his leadership over the past 28 years. He has a special interest in cerebral palsy and neuromuscular disorders. Corresponding author: M P K Hauptfleisch (marc.hauptfleisch@wits.ac.za)

Acute ataxia in childhood is often caused by toxin ingestion. With the increasing number of paediatric patients on antiretroviral medication, we are seeing more side-effects of these drugs. We report two cases of efavirenz toxicity causing ataxia. S Afr Med J 2015;105(11):897-898. DOI:10.7196/SAMJ.2015.v105i11.9451

A child presenting with ataxia may pose a diagnostic dilemma. After excluding the common causes, including toxins, infection and tumours, one needs to look carefully for a possible genetic cause. With limited genetic testing available in South Africa (SA), a definitive answer is not always found. It is estimated that there are 360 000 HIV-positive children under 15 years of age in SA,[1] 44% of whom are on antiretroviral therapy (ART).[2] These young patients often pose unique diagnostic challenges. We highlight an important differential to consider in HIV-positive paediatric patients presenting with ataxia.

(v. reference 1 000 ng/mL as the minimum target trough concen tration). On stopping the EFV, the patient showed signs of clinical improvement with resolution of vomiting and ataxia. A protease inhibitor was not started at this time as the elevated EFV levels were expected to act as the third antiretroviral agent. A repeat EFV level done 7 days after stopping the drug showed persistently high levels (49 000 ng/mL), but the patient was able to walk unsupported and the dysmetria and dysdidadokinesia had improved. The decision was made to change the patient to lopinavir/ ritonavir, and a month after stopping the EFV she showed no residual cerebellar signs.

Case reports

Case 2

Case 1

A 6-year-old girl presented with an acute onset of confusion, vomiting and difficulty in walking. She was HIV-positive and had been on ART for the past year. She was on the standard first-line regimen comprising abacavir, lamivudine and efavirenz (EFV), each of which was dosed appropriately according to her weight and the Southern African HIV Clinicians Society guidelines. Her viral load a month before admission had been <100 RNA copies/mL and her CD4 count was 250 cells/µL. There was no history of toxin ingestion. On examination she was markedly ataxic and unable to walk or sit unsupported. She was also noted to have titubation, dysmetria and dysdiadochokinesia. Investigations for a possible infectious cause were undertaken. The findings on lumbar puncture (LP) were normal and serological investigations for varicella virus were negative. However, a computed tomography brain scan was suggestive of possible inflammation of the cerebellum (‘cerebellitis’). Magnetic resonance imaging (MRI) of the brain, to better delineate the posterior fossa structures, revealed a normal brain. While the signs of cerebellar dysfunction had started acutely, their continuation for more than 2 weeks prompted further investigation for an inherited cause of progressive chronic ataxia (our differential diagnosis included ataxia telangiectasia (no telangiectasia were present clinically and the immunoglobulin levels were normal), abetalipoproteinaemia, Friedreich’s ataxia and spinocerebellar ataxia. Genetic testing was negative. The vomiting, with the persistent ataxia, led to consideration of possible medication toxicity. The EFV level was 69 110 ng/mL

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A 13-year-old girl was referred to the paediatric neurology clinic at Chris Hani Baragwanath Academic Hopsital, Johannesburg, SA, with an acute onset of ataxic gait. She had been diagnosed with HIV infection 3 years previously and staged as World Health Organization clinical stage IV, but was only started on ART (abacavir, lamivudine and EFV) 18 months before her referral. The doses were all appropriate for weight according to the Southern African HIV Clinicians Society guidelines. She was virally suppressed, with an HIV viral load of 28 RNA copies/mL and a CD4 count of 554 cells/µL. On examination she had a broad-based ataxic gait. Other cerebellar signs included dysmetria, dysdiadochokinesia and mild staccato speech, but no nystagmus. Initial investigations were done to look for a possible infective cause. The findings on LP were normal, and serological investigations for varicella were negative. An MRI scan of the brain showed no intracranial lesions, structural changes or features of infection. Before investigating further, and on the basis of experience in case 1, we looked for possible EFV toxicity. The level was 16 274 ng/mL. Three weeks after stopping the drug, and relying on the elevated EFV levels to continue to act as the third antiretroviral agent, the EFV level had dropped to 1 002 ng/mL with clinical improvement in the patient’s gait and resolution of her dysmetria. It was decided to opt for lopinavir/ritonavir as her third antiretroviral agent, and EFV was discontinued.

EFV drug level methodology

EFV is administered as a once-daily dose given at night to limit side-effects, and blood samples for measurement of steady-state drug

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levels were collected from our patients during the day before 12h00. Samples were collected in a 5 mL heparinised BD Vacutainer vial (BD Plymouth PL6 7BP, UK) and stored at 2 - 8oC until analysed. Analysis was performed using liquid chromatography-tandem mass spectrometry (LC-MS MS) at Ampath Laboratory in Johannesburg. An LC-MS MS TQD (triple quad detector) instrument from Waters in electrospray positive ionisation mode was used, employing an external standard from ChromSystems (6PLUS1 Multilevel Plasma Calibrator Set Anti-HIV Drugs) for quantification. EFV is identified according to its molecular mass of parent ion 316 as well as one daughter ion of molecular mass 244 and retention time.

Discussion

Acute ataxia is defined as unsteadiness of walking or of fine motor movement with a duration of <72 hours. The most common causes are post-infectious acute cerebellar ataxia, toxin ingestion and Guillain-Barré syndrome.[3] However, the possibility of a mass lesion must always be excluded. The reported prevalence of neurological abnormalities in HIVpositive children ranges from 10% to 68%.[4] An SA study found the prevalence of neurological complications to be 59%, the most common being HIV encephalopathy and long-tract motor signs; however, no cases of cerebellar dysfunction were documented in that study.[4] The occurrence of ataxia in an HIV-positive individual is rare, with the chronic sequelae being neurocognitive impairment and polyneuropathy.[5] Ataxia in the setting of HIV is generally secondary to an infectious, vascular or neoplastic cerebellar lesion. Most infections are opportunistic and unlikely to occur in the setting of a sufficient CD4 count.[5] Vascular or mass lesions are readily excluded with neuroimaging. EFV is a non-nucleoside reverse transcriptase inhibitor that dis rupts HIV replication by inhibiting the reverse transcriptase enzyme. EFV is known to have good central nervous system (CNS) penetration,[6] and owing to its long half-life is administered as a once-daily dose. EFV forms part of the SA first-line ART regimen for children >3 years of age and >10 kg in weight.[7] CNS symptoms are the most frequently reported side-effects in HIVpositive patients on EFV, and include dizziness, headache, confusion, stupor, impaired concentration, agitation, amnesia, depersonalisation, hallucinations, insomnia and strange dreams.[6,8-14] The frequency of CNS side-effects is estimated to be 20 - 40%.[10] The majority of patients who develop CNS and psychiatric adverse effects do so in the first 6 weeks of treatment,[11] with most symptoms resolving by 6 - 10 weeks after treatment initiation.[6] One article documented neurocerebellar side-effects – self-reported dizziness, ataxia, insomnia, bad dreams and hallucinations, without objective assessment of ataxia – in patients using EFV, occurring most frequently in the first month after initiating EFV and declining with time.[12] Many studies have looked at the effect of the EFV drug level on the frequency of side-effects. Marzolini et al.[10] reported a 24% increase

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in CNS side-effects if the plasma level was >4 000 ng/mL. However, other researchers have found no correlation between adverse effects and plasma concentrations.[8,9] Gutierrez et al.[13] nevertheless found that CNS side-effects associated with long-term EFV administration were related to plasma levels. Wide variations in the plasma levels of patients on the same weight-appropriate dose of EFV have been demonstrated. One factor attributing to this individual variation in levels is polymorphism of the CYP2B6 enzyme on cytochrome P450, as EFV is a substrate of this enzyme.[9] The prevalence of the slow-metabolising genotype was 30% in a Botswana study, and other studies have also shown a relatively higher incidence of this genotype in African populations.[14]

Conclusion

Ataxia in both our patients was attributable to the high plasma concentration of EFV, which was at least four times greater than the toxic level (4 000 ng/mL) described by Marzolini et al.[10] and improved when the drug was discontinued. Polymorphism of the CYP2B6 enzyme may explain the very high plasma levels seen. When a child known to be on EFV presents with acute progressive ataxia, after excluding the common causes, the EFV plasma levels should be checked; if they are toxic, stopping the agent and substituting it with an alternative class of antiretroviral drug should be considered. 1. UNAIDS. HIV and AIDS estimates 2012 [January 2015]. http://www.unaids.org/en/regionscountries/ countries/southafrica/ (accessed 23 January 2015). 2. UNAIDS. The GAP report 2014 [January 2015]. http://www.unaids.org/sites/default/files/en/media/ unaids/contentassets/documents/unaidspublication/2014/UNAIDS_Gap_report_en.pdf. (accessed 23 January 2015). 3. Whelan HT, Verma S, Guo Y, et al. Evaluation of the child with acute ataxia: A systematic review. Pediatr Neurol 2013;49(1):15-24. [http://dx.doi.org/10.1016/j.pediatrneurol.2012.12.005] 4. Govender R, Eley B, Walker K, Petersen R, Wilmshurst JM. Neurologic and neurobehavioral sequelae in children with human immunodeficiency virus (HIV-1) infection. J Child Neurol 2011;26(11):13551364. [http://dx.doi.org/10.1177/0883073811405203] 5. Anand KS, Wadhwa A, Garg J. A case of cerebellar ataxia associated with HIV infection. J Int Assoc Provid AIDS Care 2014;13(5):409-410. [http://dx.doi.org/10.1177/2325957414531620] 6. Treisman GJ, Kaplin AI. Neurologic and psychiatric complications of antiretroviral agents. AIDS 2002;16(9):1201-1215. [http://dx.doi.org/10.1097/00002030-200206140-00002] 7. Department of Health, South Africa. National consolidated guidelines for the prevention of mother-tochild transmission of HIV (PMTCT) and the management of HIV in children, adolescents and adults 2014. http://www.hst.org.za/publications/national-consolidated-guidelines-prevention-mother-childtransmission-hiv-pmtct-and-man (accessed 23 January 2015). 8. Van Luin M, Bannister WP, Mocroft A, et al. Absence of a relation between efavirenz plasma concentrations and toxicity-driven efavirenz discontinuations in the EuroSIDA study. Antivir Ther 2009;14(1):75-83. 9. Takahashi M, Ibe S, Kudaka Y, et al. No observable correlation between central nervous system side effects and EFV plasma concentrations in Japanese HIV type 1-infected patients treated with EFV containing HAART. AIDS Res Hum Retroviruses 2007;23(8):983-987. [http://dx.doi.org/10.1089/ aid.2006.0193] 10. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001;15(1):71-75. [http://dx.doi.org/10.1097/00002030-200101050-00011] 11. Kappelhoff BS, van Leth F, Robinson PA, et al. Are adverse events of nevirapine and efavirenz related to plasma concentrations? Antivir Ther 2005;10(4):489-498. 12. Hoffmann CJ, Fielding KL, Charalambous S, et al. Antiretroviral therapy using zidovudine, lamivudine, and efavirenz in South Africa: Tolerability and clinical events. AIDS 2008;22(1):67-74. [http://dx.doi. org/10.1097/QAD.0b013e3282f2306e] 13. Gutierrez F, Navarro A, Padilla S, et al. Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis 2005;41(11):16481653. [http://dx.doi.org/10.1086/497835] 14. Gross R, Aplenc R, Tenhave T, et al. Slow efavirenz metabolism genotype is common in Botswana. J Acquir Immune Defic Syndr 2008;49(3):336-337. [http://dx.doi.org/10.1097/QAI.0b013e31817c1ed0]

Accepted 2 June 2015.

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OPINION

Child research in South Africa: How do the new regulations help? A E Strode, C M Slack Ann Strode is a lawyer and Catherine Slack a clinical psychologist. They have worked with the HIV/AIDS Vaccines Ethics Group in the School of Applied Human Sciences, University of KwaZulu-Natal, Pietermaritzburg, South Africa, since 2000 to explore and strengthen the ethical-legal framework for the conduct of HIV vaccine trials. Both have a special interest in the participation of children and adolescents in research. Corresponding author: A E Strode (strodea@ukzn.ac.za)

Child research is governed by legal norms in the National Health Act (2003) and the Regulations. There is increasing harmony between the two on many issues, including the conditions under which children should be enrolled in research. The most striking disjuncture in the ethical-legal framework remains the allowable consent strategy for child research, where the law requires mandatory parental or legal guardian consent for all child research, while ethical guidelines afford research stakeholders the discretion to implement exceptions to this approach in specific justifiable circumstances. S Afr Med J 2015;105(11):899-900. DOI:10.7196/SAMJ.2015.v105i11.9838

Several legal norms regarding South African child health research are contained in section 71 of the National Health Act[1] (hereafter referred to as the NHA), which became operational on 1 March 2012.[2] On 19 September 2014, the Minister of Health published Regulations Relating to Research with Human Participants.[3] These regulations complete the phasing in of the new legal framework for regulating health research as established by the NHA. In the past few months, revised national ethical guidelines have been released.[4] This article describes the relevant sections of the Regulations that deal with minors, and discusses their implications for research ethics committees (RECs) reviewing research involving persons under the age of 18 years.[5]

Research with minors

Section 71 of the NHA[1] sets norms for research involving human subjects who are minors. These include that ‘therapeutic research’ must be in the best interests of the minor.[1] Also, ministerial consent must be obtained for ‘non-therapeutic research’ with minors,[1] critiqued elsewhere as overly broad in scope.[6] Furthermore, mandatory parental consent should be obtained. Minors who demonstrate ‘understanding’ should consent alongside the person providing proxy consent and not merely assent to the study. The latter consent strategy has been criticised elsewhere as overly restrictive because other consent approaches endorsed by ethical guidelines are excluded.[4,7] The new Regulations Relating to Research with Human Participants[3] helpfully confirm some of the principles that had hitherto only been provided for in the national ethical guidelines, and provide some clarity on the norms in section 71 of the NHA; however, in other instances they do little to resolve competing approaches to consent.

Vulnerability, indispensability and risk standards

The new Regulations address three general issues relating to human subjects research with children. Firstly, minors should be consi dered a vulnerable population.[3] ‘Vulnerable persons’ are defined as

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research participants who are at ‘increased risk of research-related harm, or who are limited in their freedom to make choices, or relatively incapable of protecting their own interests’.[3] This is in line with the current approach in the national ethical guidelines.[4] The Regulations require RECs to pay special attention to protocols involving such persons, while, however, emphasising that it would be a form of unfair discrimination to unjustifiably exclude such persons from research, since they are deserving beneficiaries of its outcomes. [3] This approach encourages RECs to balance child protection and research facilitation. Secondly, the participation of minors must be scientifically indispensable to the study design.[3] This confirms the position in the national ethical guidelines.[4] Thirdly, minors can only participate in research when they will be exposed to particular levels of risk, an approach that corresponds well with the risk categories described in national ethical guidelines. The above suggests that RECs seeking to ascertain the conditions under which minors could be enrolled in research will find fairly good harmonisation between legal and ethical norms on this issue.

‘Therapeutic research’ with minors

Section 71(2)(a) of the NHA provides that therapeutic research with minors may only be undertaken if the study ‘is in the best interests of the minor’.[1] The Regulations provide some direction by defining both the terms ‘therapeutic research’ and ‘best interests’. Therapeutic research is defined as being research ‘that holds out the prospect of direct benefit’ to the participant,[3] which corresponds to the national ethical guidelines.[4] The ‘best interests’ of the minor is defined as ensuring that ‘significant decisions affecting a minor’s life should aim to promote, amongst others, the minor’s physical, mental, moral, emotional and social welfare’.[3] This suggests that RECs reviewing research that holds out the prospect of direct benefit to the child/ children should consider the degree to which of the abovementioned domains of welfare might be promoted by the study.[4]

‘Non-therapeutic research’ with minors

Section 71(3)(2)(ii) of the NHA provides that non-therapeutic research with minors can only take place with the consent of the

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Minister of Health.[1,6] The Regulations provide some direction by, firstly, defining non-therapeutic research as ‘research that does not hold out the prospect of direct benefit to the participant but holds out the prospect of generalizable knowledge’.[3] This definition is consistent with the approach taken in the national ethical guidelines[4] and helps RECs to consistently determine which child protocols fall into this category. Secondly, the Regulations help operationalise two of the criteria for ministerial consent. The ‘research should improve understanding of the minor’s “condition”’ and ‘it must not pose more than a “significant risk”’. A ‘condition’ is defined quite broadly as including ‘physical and psycho-social characteristics understood to affect health’, which accommodates protocols with healthy but at-risk children, while significant risk is defined as being a ‘substantial risk of serious harm’. This definition clearly indicates that the risk posed cannot be equated with minimal risk, a term used in the ethical guidelines. Thirdly, the Regulations address some of the procedural complexities of this new requirement by providing: 1. That a delegated authority may provide consent on behalf of the Minister, and 2. Clarity on the procedure to be followed to obtain ministerial consent. Form A has been attached to the Regulations and must be completed by all applicants for ministerial consent. It elaborates the criteria for such consent, by reframing them in standard research ethics terminology. It should be noted that subsequent to the publication of the Regulations, the Minister of Health delegated his power to grant ministerial consent to selected RECs (personal communication, Prof. D R Wassenaar, November 2014). This suggests that registered RECs will perform an additional review of child research that holds out no prospect of direct benefit based on the information contained in Form A. This will be done on behalf of the Minister but at the same time as the routine ethics review.

Other gaps and concerns

Section 71(2)(c) of the NHA[1] restricts consent for child research to parents or guardians, whereas national ethical guidelines allow a broader range of consent approaches in certain defensible circumstances.[4-7] The regulations do little to resolve the tension between the law and ethical guidelines in this regard, stating only that research with human participants should be undertaken with ‘appropriate consent processes’. This leaves RECs with an unresolved dilemma between obligations to approve research that they find to be ethical, as set out in section 73 of the NHA, and ensuring that research complies with the legal standards set out in section 71.

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Conclusions

On the one hand, the publication of the Regulations is welcome because it ends a long period of flux, beginning in 2005 with the partial introduction of the NHA, and has facilitated greater harmonisation regarding many issues between section 71 of the NHA and the national ethical guidelines. On the other hand, the publication of the Regulations means that the disjuncture regarding allowable consent strategies is in its sharpest focus yet, leaving RECs in a difficult situation. While the legal and ethical framework appears to cohere far better around the background conditions for child research, it continues to clash over allowable consent strategies for child research. The main consequence may be that RECs will need to justify and document much more carefully the consent approach they approve for child research. Overall, this tension is akin to the dilemma presented by overly rigid legal reporting requirements for underage consensual sex v. a more nuanced ethical approach.[3,8] Acknowledgements and disclaimer. This article is based on a presentation made by AS at the 3rd Annual ARESA Research Ethics Seminar. It is a joint effort by both authors. The work described was supported by award number 1RO1 A1094586 from the US National Institutes of Health (NIH) entitled CHAMPS (Choices for Adolescent Methods of Prevention in South Africa). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, or represent the views of any committee or council with which the authors are affiliated. 1. South African Government. National Health Act 61 of 2003. http://www.gov.za/sites/www.gov.za/files/ a61-03.pdf (accessed 20 February 2015). 2. Proclamation No. 11 in Government Gazette No. 35081 of 27 February 2012. http://www.greengazette. co.za/documents/national-gazette-35081-of-27-february-2012-vol-560_20120227-GGN-35081.pdf (accessed 1 October 2015). 3. South African Government. Regulations Relating to Research with Human Participants. Government Gazette No. R 719 of 19 September 2014. http://research.ukzn.ac.za/Libraries/Research_Document/ National_Regulations_Relating_to_Research_With_Human_Participants_R719_of_2014.sflb.ashx (accessed 25 February 2015). 4. Department of Health, South Africa. Ethics in Health Research: Principles, Structures and Processes (2015 at 59). http://www.nhrec.org.za/docs/Documents/EthicsHealthResearchFinalAused.pdf (accessed 1 September 2015). 5. ARESA (2014). Vol 4, number 2. http://sun025.sun.ac.za/portal/page/portal/Health_Sciences/English/ Centres%20and%20Institutions/Bioethics1/ARESA/newsletter/ARESA%202014%20December%20 Newsletter_final.pdf (accessed 1 January 2015). 6. Strode A, Slack C, Wassenaar D, Singh J. One step forward, two steps back: Requiring ministerial approval for all ‘non-therapeutic’ health research with minors. S Afr Med J 2007;97(3):200-202. 7. Strode A, Richter M, Wallace M, Toohey J, Technau K. Failing the vulnerable: Three new consent norms which will undermine health research with children. South Afr J HIV Med 2014;15(2):46-49. [http://dx.doi.org/10.4102/hivmed.v15i2.18] 8. Strode A, Slack C. Sex, lies and disclosures: Researchers and the reporting of under-age sex. South Afr J HIV Med 2009;10(2):8-10.

Accepted 13 June 2015.

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EDITORIAL

Screening for childhood hearing impairment in resourceconstrained settings: Opportunities and possibilities Hearing impairment is viewed as the silent epi demic, because of its invisible nature and because routine clinical examinations often fail to detect it. It is the most prevalent sensory disorder in deve loped countries such as the USA and UK, with at least 1 in every 500 newborns having bilateral permanent hearing impairment.[1] Data on the prevalence of childhood hearing impair ment in developing countries are scarce. However, estimates based on pilot studies suggest that childhood hearing impairment may be more prevalent in developing than developed countries. For instance, the prevalence of hearing impairment among neonates was found to be 5.3 - 28/1 000 in Nigeria and 5.0 - 5.6/1 000 in India.[2] In South Africa (SA) it is estimated that at least 6 116 babies are born with permanent bilateral hearing impairment every year.[3] Up to 75% of prelingual hearing impairment has some genetic origin.[1] Untreated hearing impairment can lead to delays in speech, language, and cognitive and social development that may have a devastating impact on a child’s life with regard to academic achievement, employment and social integration in later life.[4] This negative impact may be even greater in developing countries that have limited support services for individuals with hearing impairment. From a societal perspective, failure to detect hearing impairment and provide intervention early in a child’s life means that the child will require special schooling, which is likely to be more expensive than mainstream schools. In addition, an individual with late/non-diagnosed hearing loss is likely to be reliant on social programmes.[4] In contrast, if permanent congenital hearing loss is detected and managed early in life, outcomes are better than when it is detected and managed after 6 months of age.[5] In the USA it was shown that the use of neonatal and infant hearing screening programmes lowers the age of hearing loss identification and intervention.[6] The value of early detection of hearing loss in children is only tangible if appropriate intervention is put in place timeously.[7] Methods of detecting childhood hearing impairment have developed tremendously over the years. Modern technology and refinements in procedures for early childhood hearing screening have now made it possible to screen for hearing impairment in neonates within the first 12 - 24 hours of life. Quick, reliable and non-invasive hearing screening tests such as otoacoustic emissions and automated auditory brainstem responses now enable healthcare workers to screen a newborn’s hearing in less than 2 minutes. Furthermore, such tests can be performed effectively by well-trained non-audiologists without compromising their sensitivity. Neonatal hearing screening is now a routine exercise in most developed countries such as the USA and the UK. For instance, in the USA at least 95% of neonates are screened for hearing loss shortly after birth, and at least 77% of neonates with confirmed hearing loss are enrolled in intervention programmes by 6 months of age. In the UK, 99% of parents opt for neonatal hearing screening, conducted either in hospital or during a home visit by the health visitor nurse.[8] This is in contrast to SA, where only a few healthcare facilities offer limited neonatal hearing screening, i.e. 7.5% of public healthcare institutions[9] and 53% of private.[10] Universal screening takes place at 1% of public institutions[9] and 14% of private facilities.[10] As a result children are often diagnosed late, with the reported age of diagnosis ranging from 2 years[11] to almost 4 years.[12] In addition,

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intervention often takes place at least 8 months after diagnosis of the hearing impairment,[11] thereby missing out on the period for optimal development. One lesson that can be drawn from countries that have successfully implemented programmes for early childhood hearing screening is that there has to be support from a policy/legislation perspective. For instance, in the USA universal neonatal hearing screening is legislated and mandatory in at least 43 states. Furthermore, these countries have also adopted efficient and effective means of testing using non-audiology personnel. Most developing countries do not have legislation that mandates universal neonatal hearing screening,[8] and the majority of these countries still use risk-based screening for hearing impairment (risk-based screening is ineffective, as it fails to detect congenital hearing impairment in 50% of those who are screened). However, most of these countries do have successful expanded immunisation programmes or some form of neonatal screening initiatives that could be used to implement neonatal hearing screening programmes. For instance, in SA neonates are supposed to have some subjective developmental screening that includes hearing during routine immunisation visits, while in Egypt there is a national screening programme for metabolic conditions such as hypothyroidism among children.[7] These are all platforms that can be used to implement neonatal hearing screening as part of a comprehensive neonatal care package of services. Resource constraints such as lack of equipment and trained personnel, poor follow-up of babies in whom screening picks up a problem, and the high proportions of babies who are not born in hospital have been cited as some of the challenges encountered when implementing neonatal screening in most developing countries. However, the technology used in developed countries is now available in most developing countries, and there is a need to explore how this technology can be sourced and to ensure that neonatal hearing screening is offered as part of the package of services for postnatal care. There is also a need to integrate services for neonatal hearing screening into existing postnatal services (instead of setting them up as parallel programmes) to ensure efficient use of resources. Specific to SA, while there is no national legislation/policy per se that mandates neonatal hearing screening, there are some initiatives in the form of existing policies and guidelines that provide an excellent launch pad from which neonatal hearing screening can be implemented across the country. The National Department of Health developmental screening (as part of the Road to Health) includes a requirement for screening for hearing impairment (albeit using very ineffective methods), as does the Health Professions Council of South Africa position statement on neonatal screening,[13] which advocates such services (among others). At present, the few hearing screening programmes in SA operate from hospitals, which is not ideal. However, our primary healthcare (PHC) facilities have been identified as viable platforms through which hearing screening can be implemented, and a pilot study has demonstrated the feasibility of introducing neonatal hearing screening at PHC level in SA.[14] Moreover, SA is one of the few countries in sub-Saharan Africa with relatively well-developed audiology services in respect of infrastructure, available technology and specialist audiology personnel to design PHC-based hearing screening programmes.

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Acknowledging the shortage of audiologists in SA and also the uncomplicated nature of the screening technology, there is a need for a change in mindset and an opportunity to have hearing screening undertaken by well-trained non-audiologists. Standardised training programmes to ensure competence to conduct hearing screening on the part of non-audiologists need to be developed, with the aim of building capacity within neonatal healthcare teams. Clearly, the acquired skills of these screeners would need to be recognised by the relevant authorities. Audiologists would manage the hearing screening training programmes, but be free to focus on confirmation of the diagnosis of hearing impairment in infants who screen positive, and then to undertake subsequent appropriate intervention(s). Given the successful implementation of universal neonatal hearing screening and the value of such services in developed countries, we in developing countries should be asking ourselves ‘how’, and not ‘whether’, such services should be delivered in our contexts.[4] Lucretia Petersen, Lebogang Ramma Division of Communication Sciences and Disorders, Department of Health and Rehabilitation Sciences, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: L Petersen (lucretia.petersen@uct.ac.za)

1. Hilgert N, Smith J, van Camp G. Forty-six genes causing nonsyndromic hearing impairment: Which ones should be analyzed in DNA diagnostics? Mutat Res 2009;681(2-3):189-196. [http://dx.doi. org/10.1016/j.mrrev.2008.08.002] 2. Olusanya BO, Wirz SL, Luxon LM. Hospital-based universal newborn hearing screening for early detection of permanent congenital hearing loss in Lagos, Nigeria. Int J Pediatr Otorhinolaryngol 2008;72(7):991-1001. [http://dx.doi.org/10.1016/j.ijporl.2008.03.004] 3. Swanepoel D, Störbeck C, Friedland P. Early hearing detection and intervention in South Africa. Int J Pediatr Otorhinolaryngol 2009;73(6):783-786. [http://dx.doi.org/10.1016/j.ijporl.2009.01.007] 4. Olusanya BO. Neonatal hearing screening and intervention in resource-limited settings: An overview. Arch Dis Child 2012;97(7):654-659. [http://dx.doi.org/10.1136/archdischild-2012-301786] 5. Ching TYC, Dillon H, Marnane V, et al. Outcomes of early- and late-identified children at 3 years of age: Findings from a prospective population-based study. Ear Hear 2013;34(5):535-552. [http://dx.doi. org/10.1097/AUD.0b013e3182857718] 6. Yoshinaga-Itano C. Levels of evidence: Universal newborn hearing screening (UNHS) and early hearing detection and intervention systems (EHDI). J Commun Disord 2004;37(5):451-465. [http:// dx.doi.org/10.1016/j.jcomdis.2004.04.008] 7. Kamal N. Newborn hearing screening: Opportunities and challenges. Egypt J Ear Nose Throat Allied Sci 2013;14(2):55-58. [http://dx.doi.org/10.1016/j.ejenta.2013.01.002] 8. World Health Organization. Newborn and Infant Hearing Screening: Current Issues and Guiding Principles for Action. Geneva: WHO, November 2009:9-10. 9. Theunissen M, Swanepoel D. Early hearing detection and intervention services in the public health sector in South Africa. Int J Audiol 2008;47(Suppl 1):S23-S29. [http://dx.doi.org/10.1080/14992020802294032] 10. Meyer ME, Swanepoel DW, le Roux T, van der Linde M. Early detection of infant hearing loss in the private health care sector of South Africa. Int J Pediatr Otorhinolaryngol 2012;76(5):698-703. [http:// dx.doi.org/10.1016/j.ijporl.2012.02.023] 11. Van der Spuy T, Pottas L. Infant hearing loss in South Africa: Age of intervention and parental needs for support. Int J Audiol 2008;47(Suppl 1):S30-S35. [http://dx.doi.org/10.1080/14992020802286210] 12. Butler IRT, Basson S, Britz E, de Wet R, Korsten GB, Joubert G. Age of diagnosis for congenital hearing loss at Universitas Hospital, Bloemfontein. S Afr Med J 2013;103(7):474-475. 13. Health Professions Council of South Africa. Early Hearing Detection and Intervention Programmes in South Africa: Position Statement. Pretoria: HPCSA, 2007. 14. Friderichs N, Swanepoel D, Hall JW. Efficacy of a community-based infant hearing screening program utilizing existing clinic personnel in Western Cape, South Africa. Int J Pediatr Otorhinolaryngol 2012;76(4):552-559. [http://dx.doi.org/10.1016/j.ijporl.2012.01.015]

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Time for ‘basic antenatal care plus’ in South Africa? Antenatal care is a unique preventive public health intervention, offered routinely to healthy pregnant women. The overall objectives include health education, routine dietary supplementation, and, most importantly, to improve pregnancy outcomes for mother and child by detecting complications, particularly those without obvious symptoms, early. The principle of antenatal care is firmly entrenched in most health services. For many decades, the South African (SA) National Department of Health followed the schedule of routine antenatal visits implemented in the UK in the 1920s.[1] Similar schedules were implemented in North America at around the same time.[2] This included visits every 4 weeks to 28 weeks, every 2 weeks to 36 weeks, then weekly to delivery. In recent years, the need for such frequent routine antenatal visits, which were introduced arbitrarily and without evidence of effectiveness and represent a significant cost to both women and health services, has been challenged. In 2001, the results of a landmark cluster randomised trial comparing a package of antenatal care with reduced, goal-orientated visits v. standard antenatal care were published in The Lancet.[3] Although perinatal mortality was increased in the reduced-visit package (234/11 672, 2.0% v. 190/11 121, 1.7%), the conclusion arrived at by the authors was that provision of antenatal care using the new model seemed not to affect maternal and perinatal outcomes. This article and derivative publications such as the World Health Organization (WHO) manual for the implementation of the new model[4] have impacted on antenatal care practice in low-income countries such as Thailand,[5] and in SA, where the model was implemented in 2008.[6] A subsequent reanalysis of the original

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data from the WHO antenatal care trial confirmed that perinatal mortality was increased with the reduced-visit model (risk ratio (RR) 1.20, 95% confidence interval (CI) 1.04 - 1.38), and that this increase persisted after adjustment for potential confounding factors (RR 1.18, 95% CI 1.01 - 1.37).[7] The authors indicated that the increased risk of fetal death between 32 and 36 weeks’ gestation could be due to heterogeneity in study populations or differences in quality of care, or to the reduced number of visits per se. This finding was consistent with trends in two cluster randomised trials conducted in Zimbabwe, summarised in a Cochrane systematic review.[8] The limited information on women’s views in the Cochrane review indicates that women may feel anxious about the reduction in routine antenatal visits, and prefer more frequent visits. Experience from our weekly mortality meetings since imple mentation of the ‘basic antenatal care’ (BANC) programme in SA is that infrequent antenatal visits in late pregnancy are commonly identified as an avoidable cause of perinatal or occasionally maternal mortality. This is not surprising, as infrequent visits in the third trimester may lead to missed opportunities to intervene in response to diagnoses such as pre-eclampsia, fetal growth impairment and reduced fetal movements. The following cases serve as illustrations: A 22-year-old nulliparous woman was seen antenatally at 26 weeks’ and 35 weeks’ gestation and was well. Her blood pressure was 110/60 mmHg, urine tests were normal, and fetal movements were felt. Her next visit was booked for 6 weeks later. After 23 days she presented at 08h30 in labour with severe pulmonary oedema. Her blood pressure was 189/93 mmHg, and oxygen saturation 70% on room air and 85% on 40% oxygen by mask. After stabilisation, caesarean section was performed for fetal distress under general

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anaesthesia. A male baby was delivered at 09h50, with an Apgar score of 6/10 at 5 minutes. During closure of the uterus the mother had a cardiac arrest. Resuscitation was carried out and she was transferred to the intensive care unit. Her condition deteriorated despite intensive care and she died at 15h40. The most important avoidable factor was the long interval between routine BANC antenatal visits. Under the traditional antenatal model, she would have been seen 2 weeks after her visit at 35 weeks, and it is very likely that early pre-eclampsia would have been diagnosed and managed with delivery before she progressed to severe pre-eclampsia with pulmonary oedema. A 29-year-old primigravid woman was seen antenatally at 12, 21, 26 and 32 weeks’ gestation and was well. Her subsequent visit was booked for 6 weeks later. Three weeks later she presented with abdominal pain for 8 hours, having last felt fetal movements on the previous day. Her blood pressure was 151/97 mmHg and proteinuria was present. The uterine symphysis-fundus measurement had fallen from 31 cm to 28 cm. The fetal heart was not heard, and ultrasound confirmed intrauterine death, severe growth impairment and a retroplacental clot. Antihypertensives were administered and labour was induced with an extra-amniotic Foley catheter bulb. Labour progressed to delivery of a macerated infant. The mother was well after delivery. The avoidable factor identified was the 6-week interval between BANC visits. A traditional visit 2 weeks after the visit at 32 weeks would probably have detected early pre-eclampsia and fetal growth impairment, and fetal death might have been avoided.

The importance of early booking

The WHO report[8] highlighted the lack of early antenatal booking in low-resource settings, with loss of the opportunity for early gestational age determination, treatment of infections such as syphilis, dietary supplementation and early institution of antiretroviral therapy. Uncertain gestational age is an important cause of pregnancy morbidity, being linked to missed diagnosis of fetal growth impairment, iatrogenic preterm delivery and unnecessary labour induction for suspected post-dates pregnancy, leading to increased use of caesarean section. Previous research in SA has indicated that many women attend private or public health services for early pregnancy confirmation, but the crucial information from this visit is not linked to subsequent late booking at the antenatal clinic.[9] Many women who have early ultrasound scans by private practitioners do not have the crucial information from the early scan available to assist decision-making in late pregnancy. We have previously recommended a policy

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whereby every woman who attends a public or private facility and is diagnosed to be pregnant is issued with a patient-held antenatal record.[10]

Recommendations

The cost of antenatal visits, both to the state and to individual women, is an important consideration. However, too few visits result in missed opportunities to detect and treat asymptomatic pregnancy complications. We recommend that for a middle-income country such as SA, a reasonable compromise would be to continue to implement the WHO BANC model with reduced, goal-orientated visits up to 32 weeks’ gestation, and thereafter to revert to routine visits every 2 weeks to 36 or 38 weeks, followed by weekly checks. We call this model ‘BANC plus’. Secondly, we recommend that copies of the national patient-held antenatal records be made available at all public and private health facilities, with a directive that every pregnant woman who does not yet have a record be issued with one and that relevant information be recorded on it, irrespective of the reason for her attendance. These two practical public health interventions have the potential to improve outcomes for pregnant women and their babies. G J Hofmeyr, L Mentrop Frere and Cecilia Makiwane hospitals, Eastern Cape Department of Health, Walter Sisulu University, Eastern Cape, South Africa Corresponding author: G J Hofmeyr (justhof@gmail.com) 1. Oakley A. The origins and development of antenatal care. In: Enkin M, Chalmers I, eds. Effectiveness and Satisfaction in Antenatal Care (clinics in Developmental Medicine Nos 81/82). Lavenham, UK: Spastics International Medical Publications, 1982:1-21. Alexander GR, Kotelchuck M. Assessing the role and effectiveness of prenatal care: History, challenges, and directions for future research. Public Health Rep 2001;116 (4):306-306. [http://dx.doi.org/10.1016/S0033-3549(04)50052-3] 2. Villar J, Ba’aqeel H, Piaggio G, et al., WHO Antenatal Care Trial Research Group. WHO antenatal care randomised trial for the evaluation of a new model of routine antenatal care. Lancet 2001;357(9268):15511564. [http://dx.doi.org/10.1016/S0140-6736(00)04722-X] 3. World Health Organization, Department of Reproductive Health and Research. WHO Antenatal Care Randomized Trial: Manual for the Implementation of the New Model. http://www.who.int/ reproductivehealth/publications/maternal_perinatal_health/RHR_01_30/en/index.html (accessed 30 September 2015). 4. Lumbiganon P, Winiyakul N, Chongsomchai C, Chaisiri K. From research to practice: The example of antenatal care in Thailand. Bull World Health Organ 2004;82(10):746-749. 5. Ngxongo TS, Sibiya MN. Challenges regarding the implementation of the basic antenatal care approach in eThekwini District, Kwazulu-Natal. J Nurs Manag 2014;22(7):906-913. [http://dx.doi.org/10.1111/ jonm.12036] 6. Vogel JP, Habib NA, Souza JP, et al. Antenatal care packages with reduced visits and perinatal mortality: A secondary analysis of the WHO Antenatal Care Trial. Reprod Health 2013;10:19. [http://dx.doi. org/10.1186/1742-4755-10-19] 7. Dowswell T, Carroli G, Duley L, et al. Alternative versus standard packages of antenatal care for lowrisk pregnancy. Cochrane Database Syst Rev 2010, Issue 10. Art. No.: CD000934. [http://dx.doi. org/10.1002/14651858.CD000934.pub2] 8. Jeffery BS, Tsuari M, Pistorius LR, Makin J, Pattinson RC. The impact of a pregnancy confirmation clinic on the commencement of antenatal care. S Afr Med J 2000;90(2):153-156. 9. Gulmezoglu AM, Hofmeyr GJ. Commentary on ‘Antenatal care programmes in low-resource settings’. BJOG 2007;114(7): 810-811. [http://dx.doi.org/10.1111/j.1471-0528.2007.01372.x]

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Family planning in South Africa: Missing essentials and desirables In common with most developing countries, South Africa (SA) has a rapidly expanding population. Family planning has a central role in slowing population growth. Successful use of birth control relies on many factors, including economic, medical and social. One of the many difficulties faced in supplying adequate birth control is the growing lack of availability of a number of birth control options. Some of these options are vital for ensuring optimal contraception for all who need and want it, while others are useful alternative options for those who experience problems with their current method(s). Ulipristal acetate 30 mg (Ella, EllaOne) has been available on prescription in Europe and the USA for about 5 years and is now available without prescription in most of the European Union, the UK, the USA and Canada. Ulipristal acetate is a selective pro gesterone receptor modulator.[1] It is used as an oral emergency contraceptive up to 120 hours after unprotected intercourse and is reasonably effective because of its powerful effect on delaying ovulation.[1] It is more effective than the levonorgestrel (LNG) 1.5 mg regimen currently available in SA. Like LNG, ulipristal acetate is also less effective in women with an increased body mass index (BMI) (>30).[1] The increased BMI effect, however, is not as pronounced as for LNG or the combined oestrogen/progestin (Yuzpe) method.[1] Ulipristal acetate is estimated to be about 60 - 70% effective in women exposed to pregnancy during the fertile window. This is because it is not effective once ovulation has taken place. Owing to its weaker ovulation-delaying mechanism, LNG is only 30 - 40% effective in those who are exposed during the fertile phase, again because it is not effective after ovulation has occurred.[1] Ulipristal acetate 5 mg (Fibristal) daily for 3 months is also used to treat fibroids.[2] Our second missing family planning essential is desogestrel 75 µg (Cerazette), a progestin-only contraceptive pill (POP). While desogestrel is available in SA in combination with ethinyloestradiol as Marvelon and Mercilon, it is not available as a POP. Cerazette is unique in that it is the only POP that reliably suppresses ovulation. [3] All other POPs, irrespective of the progestin, do not achieve this, their main mechanism of action being their effect on cervical mucus. Desogestrel is not as useful in combination with oestrogen where, in common with other third-generation progestins, it increases resistance to activated protein C and leads to a higher incidence of thrombosis compared with second-generation progestins.[4,5] Desogestrel is the parent compound of etonogestrel, which is the progestin used in the NuvaRing vaginal ring in combination with oestrogen, where it [5] is also associated with an increased tendency to thrombosis. Etonogestrel is also the progestin used in the Implanon NXT implant. Orally or parenterally, desogestrel and its metabolites alone do not cause clotting problems.[5] The third missing essential is an intrauterine device (IUD) or intrauterine system (IUS) the dimensions of which will accommodate the nulliparous or smaller uterus to provide a more anatomical fit. [6] The CHOICE project in St Louis, USA, has provided evidence of the success rate of a family planning programme that focuses on the use of long-acting reversible contraception (LARC) to obtain better long-term outcomes.[7] While ‘one size fits all’ may apply perfectly to the Implanon NXT and other implants when used as part of an LARC programme (they are also independent of BMI),

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it most certainly does not apply when the IUD or IUS is the LARC method being used. The discontinuation rate of the use of IUDs or IUSs in nulliparous or adolescent women is high.[8,9] The reason for this is that the IUD or IUS works best and gives fewer problems if it is situated wholly within the endometrial cavity.[6] This may not be possible if the device is too large for the uterine cavity being fitted. The endometrial cavity is functionally an isosceles trapezoid[10] in which the mean transverse width in multiparous women is 28 mm, while in nulliparous women the mean is 24 mm – or as low as 17 mm.[8] This latter transverse diameter is clearly too small for the transverse arms of the Nova-T, Mirena and Copper-T 380A devices that are available in the private and/or public sectors in SA. LARC methods, including the IUD and IUS, are approved for nulliparous women by the World Health Organization, the American College of Obstetricians and Gynecologists and the Royal College of Obstetricians and Gynaecologists of Great Britain. In order to reliably accommodate nulliparous women, devices such as the Jaydess (a smaller Mirena), with smaller transverse arms, or the GyneFix-200, which is frameless and has no transverse arms, which is attached to the uterine fundus, are needed.[8] Long-term continuation rates with the GyneFix IUD in nulliparous women are usually far higher than with framed devices.[8] Counselling has been advised to help reduce the poor IUD continuation rates in young women.[9] It is difficult to see how this can overcome anatomical disparities. It would be desirable to have the combined oral contraceptive pill Allesse or a generic equivalent available. Allesse contains 100 µg LNG and 20 µg ethinyl-oestradiol. This is a lower dose than that found in Nordette or its generic counterpart (150 µg LNG and 30 µg ethinyloestradiol), which is the lowest-dose monophasic LNG-containing pill currently available. The combined oral contraceptive pills containing third- (and fourth-) generation progestins (e.g. desogestrel, gestodene, cyproterone acetate and drospirinone) are clearly second choice behind the second- and first-generation progestins. LNG and the other first-generation progestins, e.g. norethisterone, are now first choice. The manufacturers of the third-generation progestins have paid out many millions of dollars in compensation to women who experienced thrombosis while using these products, which now contain specific Food and Drug Administration warnings. Also desirable would be the availability of medroxy-progesterone by the subcutaneous route (Depo-SubQ Provera 104 in the Uniject system), which would be a boon for those women interested in and capable of administering their own injectable contraception. Our wish list would be completed by having Jadelle or Sinoplant available. These are implants that contain LNG as the progestin, and are an alternative for women who experience problems with Implanon, a single-rod subdermal contraceptive implant that is inserted just under the skin of a woman’s upper arm and contains etonogestrel, a third-generation progestin. Jadelle or Sinoplant are not as easy to insert or remove as Implanon, however. We can only hope that some, or even all, of these birth control options will soon become available to practitioners in SA. Norman D Goldstuck Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa

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Corresponding author: N D Goldstuck (nahumzh@yahoo.com) 1. Gemzell-Danielsson K, Rabe T, Cheng L. Emergency contraception. Gynecol Endocrinol 2013;29(S1):1-14. [http://dx.doi.org/10.3109/09513590.2013.774591] 2. Croxtall JD. Ulipristal acetate: in uterine fibroids. Drugs 2012;72(8):1075-1085. [http://dx.doi. org/10.2165/11209400-0000000000000-00000] 3. Korver T, Kipping C, Heger-Mahn D, et al. Maintenance of ovulation inhibition with the 75-microg desogestrel only contraceptive pill (Cerazette) after scheduled 12-h delays in tablet intake. Contraception 2005;71(1):8-13. 4. Gris J-C, Jamin C, Bemnifla J-L, et al. APC resistance and third generation contraceptives. Hum Reprod 2001;16(1):3-8. [http://dx.doi.org/1093/humrep/16.1.3] 5. Rott H. Thrombotic risks of oral contraceptives. Curr Opin Obstet Gynecol 2012;24(4):235-240. [http://dx.doi.org/10.1097/GCO.0b013e328355871d] 6. Steyn PS, Goldstuck ND. Contraceptive needs of the adolescent. Best Pract Res Clin Obstet Gynaecol 2014;28(6):891-901. [http://dx.doi.org/10.1016/j.bpobgyn.2014.04.012]

7. Winner B, Peipert J, Qiuhong Zhao MS, et al. Effectiveness of long-acting reversible contraception. N Engl J Med 2012;366(21):1998-2007. [http://dx.doi.org/10.1056/NEJMoa1110855] 8. Wildemeersch D, Pett A, Jandi S, et al. Precision intrauterine contraception may significantly increase continuation of use: A review of long term clinical experience with frameless copper-releasing intrauterine contraceptive devices. Int J Womens Health 2013;5(3)215-25. [http://dx.doi.org/10.2147/ IJWH.S42784] 9. Aoun J, Dines VA, Stovall DW, et al. Complications and continuation of intrauterine device use among commercially insured teenagers. Obstet Gynecol 2014;123(3):585-592. [http://dx.doi.org/10.1097/ AOG.0000000000000144] 10. Hasson HM, Dershin H. Assessment of uterine shape by geometric means. Contracept Deliv Syst 1981;2(1):59-57.

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Patents and the quality, safety and efficacy of medicines A patent represents a right or title conferred by a government authority granting an inventor a limited period of exclusive use of a patented invention, in return for full public disclosure of the invention.[1] The premise is to stimulate innovation by ensuring that the inventor has a limited monopoly as a reward for advancing the industry.[2] Innovative research in the pharmaceutical industry is extremely costly and time consuming. It is generally accepted that the resulting innovations are better rewarded in countries with advanced patent systems than in countries where patent protection is still lacking. Innovation leads to innovation when other inventors have the opportunity to advance the technology disclosed in patents further, and patent their own innovations in turn. However, sometimes the working of these patents may require cross-licensing between the patentees (Patents Act,[3] section 55).

Patent requirements and applications

To be patentable an invention must be new, involve an inventive step, and have the capability of being used or applied in trade, industry or agriculture (Patents Act,[3] section 25). The specific form and requirements of a patent application vary for each country. Generally, all patent applications can be divided into two major parts. Firstly, a patent will contain a detailed disclosure in order to enable a person of ordinary skill in the pertinent area to make and use the invention without extensive experimentation.[4] Secondly, and most importantly, a patent contains a set of worded claims that defines the scope of the monopoly and thus the protection applied for. Whether or not a patent is granted almost always depends on whether the subject matter of the claims is novel and inventive in comparison with what came before (Patents Act,[3] section 25). In the pharmaceutical field, groups of patents may be granted starting with the development of a novel active pharmaceutical ingredient. For example, an active ingredient and its synthesis may be patented, followed by patents protecting the formulation of the final product containing the active ingredient and the manufacturing process of the final product. Even after the initial patent has expired, the formulation and manufacturing process of the final product may therefore still be protected, impacting on generic manufacturers.

Abuse of the patent system

South Africa (SA) is not an examining country, which means that the content of patent applications is not examined to determine whether they meet the requirements for patentability. However, lack of patentability is grounds on which an application for revocation of

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a patent may be lodged (Patents Act,[3] section 61). A patent may also be revoked on grounds that the invention as illustrated or exemplified in the patent document cannot be performed or does not lead to the results and advantages set out (Patents Act,[3] section 61). A patent has to fully disclose the invention in return for the monopoly granted. Furthermore, the Patents Act makes provision for any interested person who is able to show that the rights in a patent are being abused to apply to the commissioner for a compulsory licence under the patent (Patents Act,[3] section 56). The rights in a patent are deemed to be abused for various reasons. An example is that the patented invention is not being worked in SA on a commercial scale or to an adequate extent, after the expiry of a period of 4 years subsequent to the date of the application for the patent, or 3 years subsequent to the date on which that patent was sealed, whichever period expires last, and if in the opinion of the commissioner there is no satisfactory reason for such non-working (Patents Act,[3] section 56). The Patents Act therefore contains provisions to prevent the abuse of patents.

Patent infringement v. circumvention

In SA, as in most countries around the world, a patent is infringed when a product or process that falls within the scope defined by the claims is made, used, offered for sale, sold or imported, without permission, in the country where the patent has been granted (Patents Act,[3] sections 45 and 65). In order to determine whether a product falls within the defined scope of a patent, a list of essential features are isolated within the wording of the claims in the patent, and if all these essential features are present in the product or process under consideration, the patent has been infringed.[5,6] The patentee has the right to institute proceedings for infringement in these circumstances. The model set out above creates an interesting conundrum in the pharmaceutical industry, where competitors are provided with a detailed description of all the products that are developed, as well as a list of essential features that defines the scope of patent protection. Players in this industry sometimes devote time and money to analyse the inventions of their competitors in order to determine whether they can produce similar products with similar effects, by doing without one of the essential features that defines the scope of patent protection. If this can be achieved, a company can piggy-back on the research of a competitor without investing the same time and resources. This is known as competitive patent circumvention, which, if successfully conducted, does not lead to patent infringement and is not unlawful but may affect the medicineâ&#x20AC;&#x2122;s quality, safety and/or efficacy.

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Circumvention of patents and its effect on quality, safety and efficacy of medicines

Registration of a medicine in SA provides the assurance that the medicine meets the quality and safety requirements and is effective for its intended purpose. The quality of a medicine includes attributes such as identity, strength and purity, which are incorporated into an approved set of standards against which the medicine is tested.[7] If a medicine consistently meets these standards, it is a quality medicine. Furthermore, medicines should be safe and efficacious in order for them to be acceptable for patient use. Safety is the ability of the medicine not to cause unprecedented harm or serious side-effects, when measured against the risk-benefit profile of the medicine. Side-effects of a medicine are often due to the inherent properties of the active pharmaceutical substance/s it contains.[8] Efficacy, on the other hand, is simply an expression used to determine whether the medicine is useful for its intended purpose.[9] Efficacy therefore means that the medicine meets its therapeutic claim.[10] A combi足 nation of carefully designed, and conducted in vitro, animal and clinical studies assist in identifying undesirable and toxic effects of a medicine, and also its efficacy.[11] Quality, safety and efficacy studies are conducted to support the registration of a medicine. The medicines regulatory authority (MRA) in SA ensures that all the requirements for quality, safety and efficacy are met before granting registration. The requirements set by the MRA often give rise to the development of innovative formulations and manufacturing procedures, which are patented separately from the active pharmaceutical ingredient. This creates a challenge for generic manufacturers who wish to manufacture a generic medicine after the expiry of the patent that protected the active pharmaceutical ingredient/s of the medicine. A new and innovative formulation or process has to be established for the generic medicine which is qualitatively and quantitatively similar to the innovator medicine without infringing the patent protecting this formulation or process. In practice the development of these new formulations may prove troublesome. For example, a pharmaceutical patent may stipulate a specific excipient, and in an effort to circumvent the patent a generic medicine manufacturer will have to use another excipient. If an effective excipient cannot be found during product development, the product may present with both safety and efficacy issues following poor-quality formulation. Another example is that a specific impurity limit may be claimed for an active ingredient. An effort to circumvent such a patent may result in the intentional contamination of the active ingredient to raise the quantity of the impurity above the patented limits. This intentional contamination compromises quality and violates good manufacturing and regulatory process, even if the quantity of the impurity introduced is not significant and will not present safety or efficacy concerns. Compromising quality may result in safety concerns and efficacy problems, especially in cases where patients respond differently to the same active substance and in drugs with a narrow therapeutic index.

Conclusion

The impact of patent circumvention potentially has serious impli足 cations with regard to medicine quality, safety and efficacy, even

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if it was intended to improve accessibility and affordability of these medicines. Although the MRA does not have any man足 date with regard to patents, it has a mandate to protect the public. Efforts to circumvent patents sometimes increase the regulatory burden of monitoring product quality, safety and efficacy. Furthermore, a lack of efficacy caused by efforts to circumvent patents protecting formulations or processes may result in subtherapeutic levels of medicines, resulting in obvious health risks. For example, ineffective asthma medication may result in death, and subtherapeutic levels of antiepileptics or antibiotics will result in relapses and drug resistance, respectively. The impact of patent circumvention has far-reaching effects on public health. Companies should therefore conduct adequate research in order to understand the effect of patent circumvention on the quality, safety and efficacy of medicine. Sufficient research is necessary to develop alternative formulations and processes, which have to be appropriately validated using production scale batches. Further足 more, sufficient stability data (including stress testing) has to be generated. These steps are necessary to ensure production of a quality product that will not during any stage of its life cycle fail in terms of quality, compromise patient safety, or be ineffective. Karen du Toit Honorary Associate Professor, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa, and owner, Pharmalaw (Pty) Ltd, Pretoria, South Africa Willem du Preez Intellectual Property Development Manager, Westfalia Fruit, Tzaneen, Limpopo, South Africa Silverani Padayachee Pharmacist, Pretoria, South Africa Corresponding author: K du Toit (dutoitk@ukzn.ac.za) 1. World Intellectual Property Office (WIPO). http://www.wipo.int/patents/en/ (accessed 15 June 2015). 2. World Intellectual Property Office (WIPO). http://www.wipo.int/patent-law/en/developments/ research.html (accessed 15 June 2015). 3. Patents Act, Act No. 57 of 1978. http://www.cipc.co.za/files/9513/9452/7965/Patent_Act.pdf (accessed 15 June 2015). 4. United States Patent and Trademark Office. http://www.uspto.gov/patents-getting-started/patentbasics/types-patent-applications/nonprovisional-utility-patent#heading-18 (accessed 15 June 2015). 5. Letraset Limited v Helios Limited 1972 (3) SA 245 (A). 6. Stauffer Chemical Co and another v Sasfan Marketing and Distribution Co 1987 (2) SA 331 (A). 7. ICH Harmonized Tripartite Guideline (Q6A). Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, 1999. http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q6A/Step4/Q6Astep4.pdf (accessed 15 June 2015). 8. Gorog S. Drug safety, drug quality, drug analysis. J Pharm Biomed Anal 2008;48(2):247-253. 9. ICH Harmonized Tripartite Guideline (E3). Structure and Content of Clinical Study Reports, 1996. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guideline. pdf (accessed 15 June 2015). 10. Fefer E. Pharmaceutical Legislation and Regulation. In: MDS-3:Managing Access to Medicines and Health Technologies, 3rd ed. WHO Publication, 2012. http://apps.who.int/medicinedocs/documents/ s19577en/s19577en.pdf (accessed 15 June 2015). 11. ICH Harmonized Tripartite Guideline (S7A). Safety Pharmacology Studies for Human Pharmaceuticals, 2000. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/ Safety/S7A/Step4/S7A_Guideline.pdf (accessed 15 June 2015).

S Afr Med J 2015;105(11):905-906. DOI:10.7196/SAMJ.2015.v105i11.10185

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Pre-exposure prophylaxis for South African adolescents: What evidence? L-G Bekker, MB ChB, DTMH, DCH, FCP (SA), PhD; K Gill, MB ChB, DA, Dip Pall Med; M Wallace, BSocSci Hons, MSc, PhD Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa Corresponding author: L-G Bekker (linda-gail.bekker@hiv-research.org.za)

Adolescents and young women, particularly in South Africa, are at increased risk of HIV acquisition. To date, we have had limited primary prevention options to offer. Oral pre-exposure prophylaxis (PrEP) is an additional prevention modality that has now been proven to reduce HIV acquisition in those who take it consistently during periods of HIV infection exposure. We review the PrEP evidence in adolescents and highlight some of the research gaps. Our recommendation is to increase the number of demonstration projects and other scale-up opportunities to offer oral PrEP to at-risk adolescents, and monitor carefully to answer the outstanding questions. S Afr Med J 2015;105(11):907-911. DOI:10.7196/SAMJ.2015.v105i11.10222

Adolescents and youth constitute one-third of popu lations in sub-Saharan Africa, and despite having some of the highest HIV incidence and prevalence rates in the world, we have very few prevention interventions to offer this key population.[1] Since the first realisation that much HIV transmission was occurring via heterosexual and homosexual sex, the primary prevention options have consisted only of sexual abstinence, including sexual debut delay, monogamous sex with an individual of known HIV-negative status, or consistent condom use. While female condoms are available, most reliance has been on male condoms.

Adolescents and HIV

Adolescence is a period of transition from childhood to adulthood, spanning the years 10 - 19, although neurodevelopmental specialists argue that brain and therefore psychological modelling continues until at least 25 years of age.[2] It is a period of immense physical, psychological, social and emotional growth and is characterised by many opportunities for experimentation, new experiences and consequent vulnerabilities.[3] Yet it is a time also characterised by limited access to information and appropriate health and prevention services, leading to an increased risk of acquisition of HIV and other infections.[4,5] Navigating this transition successfully is highly dependent on individual efficacy and resilience, as well as input and support from family, friends, schools and communities.[6] Given these vulnerabilities, both sexual abstinence and monogamy have limited application throughout the period of adolescence and are impractical as exclusive HIV prevention interventions for youth. In generalised epidemics, females experience much higher levels of HIV infection than their male counterparts in late adolescence and throughout the early reproductive years.[1] While behaviour is an important driver of infection, the risk behaviours of South African (SA) adolescents are not necessarily greater than those of adolescents elsewhere.[7] Biological differences partly explain this apparent contradiction, but social and structural factors also instigate and maintain the risk behaviours that ultimately drive the adolescent epidemic in SA.[8,9] Much has been written about the high levels of sexual coercion and violence in SA.[10,11] Power inequality and intimate partner

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violence decrease condom use and increase the risk of HIV infection in adolescent females and young women.[11,12] Inequality in sexual relationships is further amplified when there is a significant age difference between the two parties. Older men are more likely to be infected with HIV than adolescents, and this may be contributing to sudden increases in HIV acquisition in adolescent females as they commence relationships with older men. In 1990, Stein[13] advocated user-dependent prevention methods, particularly female-initiated and managed ones. It was thought that vaginal microbicides could fill this prevention gap. In 2015, we do not yet have a licensable vaginal microbicide, but oral pre-exposure prophylaxis (PrEP) is certainly a viable alternative. Oral PrEP involves the administration of a single antiretroviral (ARV) agent, or dual agents, to HIV-negative individuals prophylactically, to protect them from infection should they be exposed to an infective source. Following the first study of PrEP efficacy, among men who have sex with men (MSM) and transgendered women (TGW) and reported in 2010, the concept of a daily pill (emtricitabine (FTC) and tenofovir (TDF), sold as Truvada) to prevent HIV infection has become increasingly evident as a useful additional biomedical intervention to offer to individuals in conjunction with regular testing, counselling, condoms and safe lubricants.[14]

PrEP evidence

To date there have been ten randomised controlled trials (RCTs) of TDF-based PrEP reporting HIV outcomes.[15] PrEP was effective for both men and women. The studies have involved more than 17 000 people and have demonstrated an overall reduction in HIV acquisition risk of 51% (women relative risk (RR) 0.57; 95% confidence interval (CI) 0.34 - 0.94, and men RR 0.38; 95% CI 0.2 0.6). Three studies in which there was high adherence to the study product (>70% of drug detection) showed that PrEP was most efficacious and also that HIV infection was significantly reduced in those studies in which drug detection levels were moderate (41 - 70% detection). Unfortunately in the two studies with lowest adherence (<40% detection), involving heterosexual women in southern and East Africa, PrEP had no effect.[15-17] The reasons for the particularly low uptake and use of oral PrEP in these two studies have been speculated on elsewhere and a range of potential reasons have been suggested,

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structural, behavioural and/or psychological. [18] Unfortunately this has led to some controversy around the effectiveness of oral PrEP in black African women. It is important to note, however, that two of the three studies considered by the US Food and Drug Administration (FDA) prior to licensure of PrEP as a prevention modality included women from Uganda, Kenya and Botswana.[15] As a consequence, in 2012 the FDA approved TDF/FTC PrEP for men and women at risk of sexual acquisition of HIV. The South African Medicines Control Council is currently considering this ARV combination for a similar indication. The critical component of PrEP’s success is that people actually take it. The current recommendation in all guidelines is to aim for a daily dose of the single combination tablet during periods when sexual HIV exposure is possible.[15,19] The scientific rationale is that systemic drug levels will influence tissue drug levels at the site where HIV contact may occur. This applies to vaginal, penile and rectal mucosa. As a result of this extensive evidence base, the World Health Organization (WHO) has just included oral PrEP as an additional prevention choice as part of combination prevention for people at substantive risk in its 2015 comprehensive treatment and care

guidelines.[15] Table 1 lists all ten randomised controlled trials to date and highlights those in which age was delineated. In addition, for some time the WHO has recommended demon stration projects in various populations and settings to try to delineate the best distribution platforms in both high- and lowerincome settings.

Adolescents and PrEP

There is a dearth of literature examining attitudes to oral PrEP use among adolescents globally. This scarcity is even more pronounced in sub-Saharan Africa. Most of the research on attitudes among youth and adolescents has been done in the USA, with young men who have sex with men (YMSM). Table 2 describes some of the cited literature. Generally, knowledge of PrEP was limited, 27 - 38% of study participants having heard of PrEP and 1 - 1.5% having used it,[20,21] with many expressing a desire for more information.[22,23] Knowledge was found to be associated with higher education, recent HIV testing and gay identity,[21] as well as increased age, having had a sexually transmitted infection and having health insurance.[20] In all studies, there was generally a positive attitude towards PrEP and a willingness

Table 1. Randomised controlled trials comparing oral PrEP with placebo Trial name and location

No. enrolled

Age (years), median (range)

Study population

No. aged <25 years

Efficacy outcome

FEM-PrEP Daily

2 120

23 (18 - 35)

WSM

1 213

Stopped for futility

iPrEx Daily

2 499

27 (18 - 67)

MSM/TGW

1 153, no significant difference in ages

44%

Partners PrEP Daily

4 758

33 W, 34 M (18 - 65)

Serodiscordant couples

583, no significant difference between women <25 and >25 years

75%

TDF2 Daily

1 219

25 (18 - 39)

Heterosexual men and women

<21 yrs: 25

62%

West African study

536

Unknown

Women

Unknown

65% efficacy Stopped early for structural reasons

Voice, MTN-003 Daily gel v. oral

5 029

25 (18 - 45)

WSM

Unknown

Stopped for futility

US safety study, CDC 4323 Daily

400

39 (18 - 60)

MSM

Unknown

TVD detected in 50% of people who seroconverted and in 81% of those who did not

Ipergay Pericoital

414

35 (29 - 43)

MSM

Bangkok, IDU study Daily

2 413

31 (20 - 60)

PWID

1 033 <30

49%

IAVI, Kenya Pericoital v. daily

26 (18 - 46)

MWSM

Unknown

MEMS cap adherence 83% in daily arm

86% efficacy Placebo arm stopped early owing to positive results

IDU = intravenous drug users; IAVI = International AIDS Vaccine Initiative; WSM = women who have sex with men; PWID = people who inject drugs; MWSM = men who have sex with women and men; MEMS cap = medication event monitoring system caps.

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Table 2. PrEP-related research Reference

Type of research

Population studied

Bauermeister et al.[20]

Quantitative

YMSM (18 - 24 years)

Kubicek et al.[22]

Qualitative

YMSM (18 - 25 years)

Pérez-Figueroa et al.[23]

Qualitative

YMSM (18 - 21 years)

Rucinski et al.

Quantitative

YMSM (18 - 40 years)

Smith et al.[24]

Qualitative

YMWSM (18 - 24 years)

Quantitative

MSM (16 - 20 years)

[21]

Mustanski et al.

[25]

YMWSM = young men who have sex with women and men.

to use it. Nonetheless, barriers to use were raised. One of the most significant concerns was possible side-effects of the drug,[22,24] with 36% of participants in one study reporting that they would not use PrEP for this reason.[20] Other barriers included the regimen burden and uncertainty regarding ability to adhere to a daily pill and regular check-ups,[23-25] the partial efficacy of PrEP,[24,25] access and cost issues[22,23] and low perceived risk of HIV infection.[24] In addition, stigma was identified as a potential barrier in terms of being seen taking HIV treatment medication, as well as the association of taking PrEP with high-risk sexual behaviour and groups.[23,24] In contrast, others reported that they would be proud to take PrEP[24] and that it was well suited to certain situations and people (serodiscordant couples, people who found it difficult to adhere to condom use, those in casual sexual relationships).[22,23,25] Given the differences in social context between YMSM in the USA and adolescents in SA, these data are not necessarily applicable to SA. Very little research has examined these issues in SA adolescents so far. Acceptability, interest, concerns and preferences regarding ARV-based prevention in pill, gel and injectable format have been explored in young women in SA and female sex workers and serodiscordant couples in Kenya.[26] With an overall sample of 36, two focus groups with adolescent girls (14 - 17 years) and two with young women (18 - 24 years) were conducted in SA. All groups expressed strong interest in PrEP use. Interestingly, adolescent girls felt that PrEP would be obtainable with privacy more easily than condoms, enhancing its appeal. Young women were enthusiastic, but concerned about the interactions with drugs and alcohol and also the challenges of adherence while under the influence of substances (often preceding sex). In addition, they speculated that ultimately products would not be used with trusted partners (much like condoms), thus making them no more effective. In terms of formulation preference, adolescents noted that all formulations presented adherence challenges. They felt that daily pills could be taken or used more easily than vaginal gel (coitally dependent), as sex was difficult to predict, but had concerns around swallowing pills and the impact on urine smell. Some preferred the coitally dependent gel as a less burdensome regimen, although they felt that it would be unpleasant to insert and might smell, while injections if given in depot form were viewed as painful. Among young women, those who preferred pills felt that they were safer than injections and more private than gel use, but others had concerns about daily pill adherence. Some preferred the injection owing to familiarity with the injectable contraceptive, and felt it was safer, longer lasting, private and difficult to forget about. One other study examined willingness to use PrEP among young women in SA as part of a global survey of 1 790 participants from seven countries;[27] 124 young women (18 24 years) from SA participated. In contrast to most other subgroups, side-effects, cost and the need for regular HIV testing posed higher barriers to use in this subgroup. With regard to the relative

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importance of key PrEP attributes, young SA women rated route of administration most highly, followed by frequency of HIV testing, time spent obtaining PrEP, dispensing site and frequency of pick up. A bimonthly injection in the buttocks was most preferred, with HIV testing 6-monthly. These studies are limited by their hypothetical nature, but highlight the importance of choice and convenience in meeting the needs of different young women in SA. All ten randomised controlled PrEP studies exclusively included people aged >18 years, and only three stratified trial populations into younger (<25 years) and older.[15] In those studies, sexual and other behaviours were riskier in the younger group, but adherence and subsequently PrEP effectiveness were reduced. One of the studies in this group is the Global iPrEx study performed in MSM.[14] A subanalysis of the younger participants (18 - 24 years), who made up almost half of the overall cohort, demonstrated that those aged <25 years were 3.74 times (95% CI 2.40 - 5.82) less likely to show drug detection in the blood (p<0.001) compared with those aged >25 years. The incidence of HIV per 100 person-years among young MSM was 3.06 in the TDF/FTC group and 4.24 in the placebo group.[28] The US-based Adolescent Trials Network (ATN) has reported on feasibility, safety and adherence in PrEP studies in the young MSM population (18 - 22 years) in the USA as part of Project PrEPare. ATN 082 enrolled 68 individuals (mean age 19.9 years) in a placebocontrolled study in which 58 individuals were randomised to a behavioural intervention alone or the behavioural intervention either with TDF/FTC or placebo.[29] Self-reported medication adherence averaged 62% (range 43 - 83%), while rates of detectable plasma tenofovir ranged from 63.2% to 20% (weeks 4 - 24). The most commonly reported reasons for missing doses included being away from home (60%), forgetting (50%) and being too busy (47%).[29] ATN 110 enrolled 200 MSM aged 18 - 22 years who were offered the same behavioural intervention with oral PrEP but in an openlabel manner. PrEP was well tolerated with minimal side-effects. While PrEP drug levels commensurate with a prevention-efficacious dose of >4 pills per week were seen in >50% of blood samples at week 4, this had reduced by week 48, with marked differences in consistent adherence by ethnicity. Participants who reported condomless sex were more likely to be adherent.[30] This study has an ongoing ‘brother’ study in 15 - 19-year-olds, and adherence and feasibility data from this adolescent cohort are eagerly awaited in 2016 (ATN 113). An optimistic picture is emerging from the open-label extensions of the randomised trials and the demonstration studies now in the field, the most promising of these being the recent PROUD (MSM) and Partners PrEP open-label extensions and demonstration studies (discordant black African couples).[31-33] A recent study known as ADAPT HPTN 067, conducted in Cape Town, SA, randomised 179 heterosexual women into three arms of self-administered daily, event-driven and intermittent TDF/FTC PrEP over a 24-week period.[34] The ‘coverage’ of sexual events with PrEP taking was measured along with actual PrEP blood levels. The coverage of sexual events, reported adherence and blood drug levels of the women in the daily arm were better than those in the other intermittent arms. In addition, overall adherence in the daily arm was good at 10 and 30 weeks of follow-up, and similar between younger and older participants.[34] PrEP is feasible in younger individuals. These recent open-label studies suggest that if individuals are told that an intervention such as PrEP works, not only are they more likely to take it, but also those most at risk self-identify. TDF and FTC are two ARV agents with a relatively clean safety profile. With many patient-years of exposure worldwide, both are regarded as a safe combination in people on HIV treatment, and they form part of the triple, single-pill antiviral agent currently

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being dispensed to millions of HIV-positive South Africans. Of note, all the above PrEP studies in normal healthy individuals also had an unremarkable safety profile. Adverse events were mild and minimal, occurring in the minority and mostly in the first month of exposure. These self-limiting adverse events included headaches, bloating, nausea and mild diarrhoea. Some of the studies noted non-progressive, subclinical declines in renal functioning and bone mineral density, none of which caused clinical events.[14] Another theoretical risk is that of HIV-resistance mutations occurring when breakthrough HIV infection occurs in the face of inadequate PrEP drug levels. This phenomenon has not occurred in the RCTs to date. [15] As PrEP scale-up starts in earnest, adverse events, safety and the threat of resistance will need to be closely monitored. If a pill a day in the form of oral PrEP is an intervention that can be used by young women and men discreetly and independently, and can significantly reduce HIV acquisition, we urgently need to find out how to make this available to the young SA individuals who would benefit most, and in such a way that would derive the greatest impact.[35,36]

Recommendations

One of the quickest ways to get oral PrEP into the adolescent community safely and effectively would be to initiate a number of projects in a number of settings and from a variety of distribution Table 3. Knowledge gaps in PrEP provision for adolescents Questions in provision of oral PrEP to adolescents Behavioural Acceptability of PrEP Willingness to use daily PrEP dherence to/persistence with programme (monitoring, testing, A counselling) Adherence to daily pills Stigma Sexual disinhibition with condom migration Biomedical Tolerability Toxicities – impact on bone mineralisation More STIs? – mucosal activation More frequent sex, sex partners

platforms involving SA adolescent users. Unfortunately, of the many demonstration projects around the world that are currently underway or imminently planned, very few involve adolescent populations.[37] One open-label study called Pluspills is part of the broader CHAMPS-SA project of the Desmond Tutu HIV Foundation and is currently enrolling 150 young men and women aged 15 - 19 years in Cape Town and Soweto. Data on acceptability, use and adherence will be available in October 2016. Another HPTN-sponsored study is also undergoing regulatory review and will involve 400 young black African women aged 15 - 24 years. It is expected to launch by 2016. In addition, a number of agencies are considering combination prevention projects among adolescent girls and young women that could inform scale-up of PrEP in southern and eastern Africa. These include a multi-institutional project funded by USAID and the very exciting DREAMS project spearheaded by PEPFAR and various private funders in PEPFAR-sponsored African countries.[38,39] There are a number of gaps in our knowledge of how best to utilise this intervention among adolescents, and these could be answered by well-constructed and monitored field projects. Table 3 lists some of these outstanding questions.

Future directions

Oral PrEP is available and has a growing evidence base for its wider deployment. Unlike ARV treatment, oral PrEP is an intervention that individuals would need and use only during periods of HIV risk. The analogy is malaria prophylaxis, where antimalarial prophylactic agents are only taken during periods of exposure to potentially infected mosquitoes. In the case of adolescents this may cover the periods of sexual experimentation and when permanent sexual partners have not yet been established and partner status is unknown, which it is hoped would also align with the highest incidence rates. In addition, other longer-acting modalities are in clinical develop ment that may assist with daily adherence, something that has been identified as difficult in adolescent populations. Some of these modalities include a vaginal ring that needs only monthly admini stration, and long-acting injectable agents that may be dispensed every 2 months. Table 4 lists some of these PrEP modalities and when efficacy data to support their use may be available. The analogy is that of contraception, where both choice of modality and options for prolonged dosing intervals have been shown to increase adherence and effectiveness.

Less frequent sex? Loading dose

Table 4. Some of the newer alternative modalities in the pipeline

Size and smell of pills

Modality

Study

Results expected

Increased unwanted pregnancy and STIs

Dapivirine vaginal ring

ASPIRE MTN 020 Phase 3

Q4 2015/Q1 2016

The Ring Study IPM 027 Phase 3

Q4 2016

Cabotegravir LA PrEP 8-week injectable PrEP

HPTN 077 Phase 2a

Q3 2017

TMC278 (rilpivirine) LA PrEP 8-week injectable PrEP

HPTN 076 Phase 2a

Q4 2017

Cabotegravir LA PrEP v. oral PrEP v. placebo

HPTN 083 Phase 2b

To be commenced

Structural Which health platform? SRH, ANC, FP, PHC Regular testing Adolescent-friendly services Confidentiality/privacy Social Enablers to assist with daily adherence, e.g. SMS messaging nablers to assist with integration into programme, e.g. social E media/networks STIs = sexually transmitted infections; SRH = sexual and reproductive health; ANC = antenatal clinic; FP = family planning; PHC = primary healthcare; SMS = text message.

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LA = long acting; Q = quarter of year.

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Conclusions

Apart from sexual abstinence, to date we have been able to offer young women only the male latex condom as protection against HIV infection. Given some of the difficulties described above, it is less than surprising that in 2015 we see incidence rates among young SA women that are the highest in the world. Young people, and especially young women, need more prevention options to protect themselves.[36] Oral PrEP certainly is one such modality that has great promise. Offering this intervention to our adolescent and young adult population has the potential to make a significant dent in our epidemic. References 1. Dellar RC, Dlamini S, Abdool Karim Q. Adolescent girls and young women: Key populations for HIV epidemic control. J Int AIDS Soc 2015;18(Suppl 1):19408. [http://dx.doi.org/10.7448/IAS.18.2.19408] 2. World Health Organization. Health for the World’s Adolescents: A Second Chance in the Second Decade. Geneva: WHO, 2014. http://apps.who.int/adolescent/second-decade/files/1612_MNCAH_ HWA_Executive_Summary.pdf (accessed 15 July 2014). 3. Bekker L-G, Johnson L, Wallace M, Hosek S. Building our youth for the future. J Int AIDS Soc 2015;18(Suppl 1):20027. [http://doi.org/10.7448/IAS.18.2.20027] 4. Gulliver A, Griffiths KM, Christensen H. Perceived barriers and facilitators to mental health helpseeking in young people: A systematic review. BMC Psychiatry 2010;10(1):113. [http://dx.doi. org/10.1186/1471-244X-10-113] 5. Delany-Moretlwe S, Cowan F, Busza J, Bolton-Moore C, Kelley K, Fairlie L. Providing comprehensive health services for young key populations: Needs, barriers and gaps. J Int AIDS Soc 2015;18(Suppl 1):19833. [http://dx.doi.org/10.7448/IAS.18.2.19833] 6. DiClemente RJ, Salazar LF, Crosby RA, Rosenthal SL. Prevention and control of sexually transmitted infections among adolescents: The importance of a socio-ecological perspective – a commentary. Public Health 2005;119(9):825-883. [http://dx.doi.org/10.1016/j.puhe.2004.10.015] 7. Pettifor AE, Levandowski BA, Macphail C, et al. A tale of two countries: Rethinking sexual risk for HIV among young people in South Africa and the United States. J Adolesc Health 2011;49(3):237-243. [http://dx.doi.org/10.1093/ije/dyn131] 8. Eaton L, Flisher AJ, Aarø LE. Unsafe sexual behaviour in South African youth. Soc Sci Med 2003;56(1):149-165. [http://dx.doi.org/10.1016/S0277-9536(02)00017-5] 9. Jaspan HB, Berwick JR, Myer L, et al. Adolescent HIV prevalence, sexual risk, and willingness to participate in HIV vaccine trials. J Adolesc Health 2006;39(5):642–648. [http://dx.doi.org/10.1016/j. jadohealth.2006.05.016] 10. Wood K, Maforah F, Jewkes R. ‘He forced me to love him’: Putting violence on adolescent sexual health agendas. Soc Sci Med 1998;47(2):233-242. [http://dx.doi.org/10.1016/S0277-9536(98)00057-4] 11. Jewkes RK, Dunkle K, Nduna M, Shai N. Intimate partner violence, relationship power inequity, and incidence of HIV infection in young women in South Africa: A cohort study. Lancet 2010;376(9734):4148. [http://dx.doi.org/10.1016/S0140-6736(10)60548-X] 12. Pettifor AE, Measham DM, Rees HV, Padian NS. Sexual power and HIV risk, South Africa. Emerg Infect Dis 2004;10(11). [http://dx.doi.org/10.3201/eid1011.040252] 13. Stein Z. HIV prevention: The need for methods women can use. Am J Public Health 1990;80(4):460462. [http://dx.doi.org/10.2105/AJPH.80.4.460] 14. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363(27):2587-2599. [http://dx.doi.org/10.1056/ NEJMoa1011205] 15. World Health Organization.Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. 2015. WWW.who.int (accessed 1 October 2015). 16. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med 2012;367(5):411-422. [http://dx.doi.org/10.1056/NEJMoa1202614] 17. Marrazzo JM, Ramjee G, Richardson B, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med 2015;372:509-518. [http://dx.doi.org/10.1056/ NEJMoa1402269] 18. Heffron R, Baeten J. Tenofovir-based oral PrEP prevents HIV infection among women. Curr Opin HIV AIDS (in press).

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19. Smith DK, Koenig LJ, Martin M. Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – 2014 Clinical Practice Guideline. US Public Health Service CDC, 2014:67. 20. Bauermeister JA, Meanley S, Pingel E, et al. PrEP awareness and perceived barriers among single young men who have sex with men in the United States. Curr HIV Res 2013;11(7):520-527. [http:// dx.doi.org/10.2174/1570162X12666140129100411] 21. Rucinski KB, Mensah MP, Sepkowitz KA, et al. Knowledge and use of pre-exposure prophylaxis among an online sample of young men who have sex with men in New York City. AIDS Behav 2013;17(6):2180-2184. [http://dx.doi.org/10.1007/s10461-013-0443-y] 22. Kubicek K, Arauz-Cuadra C, Kipke MD. Attitudes and perceptions of biomedical HIV prevention methods: Voices from young men who have sex with men. Arch Sex Behav 2015;44(2):487-497. [http:// dx.doi.org/10.1007/s10508-014-0398-8] 23. Pérez-Figueroa RE, Kapadia F, Barton S, et al. Acceptability of PrEP uptake among racially/ethnically diverse young men who have sex with men: The P18 Study. AIDS Educ Prev 2015;27(2):112-125. [http://dx.doi.org/10.1521/aeap.2015.27.2.112] 24. Smith DK, Toledo L, Smith D-F, et al. Attitudes and program preferences of African-American urban young adults about pre-exposure prophylaxis (PrEP). AIDS Educ Prev 2012;24(5):408-421. [http:// dx.doi.org/10.1521/aeap.2012.24.5.408] 25. Mustanski B, Johnson AK, Garafalo R, et al. Perceived likelihood of using HIV pre-exposure prophylaxis medications among young men who have sex with men. AIDS Behav 2013;17(6):21732179. [http://dx.doi.org/10.1007/s10461-012-0359-y] 26. Mack N, Evens E, Tolley EE, et al. The importance of choice in the rollout of ARV-based prevention to user groups in Kenya and South Africa: A qualitative study. J Int AIDS Soc 2014;17(Suppl 2):19157. [http://dx.doi.org/10.7448/IAS.17.3.19157] 27. Eisingerich AB, Wheelock A, Gomez G, et al. Attitudes and acceptance of oral and parenteral HIV preexposure prophylaxis among potential user groups: A multinational study. PLoS One 2012;7(1):e28238. [http://dx.doi.org/10.1371/journal.pone.0028238] 28. Bekker L-G, Glidden DV, Hosek S, et al. PrEP in young MSM: Needs and challenges. Presented at the 20th Conference on Retroviruses and Opportunistic Infections (CROI), 3 - 6 March 2013, Atlanta, USA. http://retroconference.org (accessed 17 October 2015). 29. Hosek S, Siberry G, Bell M, et al. Project PrEPare (ATN082): The acceptability and feasibility of an HIV pre-exposure prophylaxis (PrEP) trial with young men who have sex with men (YMSM). J Acquir Immune Defic Syndr 2013;62(4):447-456. [http://dx.doi.org/10.1097/QAI.0b013e3182801081] 30. Hosek S, Rudy B, Landovitz R, et al. An HIV pre-exposure prophylaxis demonstration project and safety study for young men who have sex with men in the United States (ATN 110). J Int AIDS Soc 2015;18. 31. Grant R, Anderson PL, MacMahan V, et al. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: A cohort study. Lancet Infect Dis 2014;14(9):820-829. [http://dx.doi.org/10.1016/S1473-3099(14)70847] 32. Baeten J, Heffron R, Kidoguchi L. Near elimination of HIV transmission in a demonstration project of PrEP and ART. Presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2015), Seattle, USA, 23-26 February 2015. 33. McCormack S, Dunn DT, Desai M, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): Effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet 2015. Published online September 10, 2015. [http://dx.doi.org/10.1016/ S0140-6736(15)00056-2] 34. Bekker LG, Hughes J, Amico R, et al. HPTN 067/ADAPT Cape Town: A comparison of daily and nondaily PrEP dosing in African women. Presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2015), Seattle, USA, 23-26 February 2015, Poster No. 978LB. 35. Baeten JM, Haberer JE, Liu AY, Sista N. Preexposure prophylaxis for HIV prevention: Where have we been and where are we going? J Acquir Immune Defic Syndr 2013;63(Suppl 2):S122-S129. [http:// dx.doi.org/10.1097/QAI.0b013e3182986f69] 36. Pettifor A, Nguyen N, Celum C, et al. Tailored combination prevention packages and PrEP for young key populations. J AIDS Soc 2015;18(Suppl 1):19434. [http://dx.doi.org/10.7448/IAS.18.2.19434] 37. AVAC, Global Advocacy for HIV Prevention, New York City, USA. Combination prevention. http:// www.avac.org/infographic/defining-combination-prevention-ongoing-trials-sub-saharan-africa (accessed 10 October 2015). 38. USAID. USAID announces microbicide awards. 6 August 2015. https://www.usaid.gov/what-we-do/ global-health/hiv-and-aids/technical-areas/microbicides-providing-hiv-prevention-option/2015microbicide-awards (accessed 18 October 2015). 39. PEPFAR: The US President’s Emergency Plan for AIDS Relief, the Bill & Melinda Gates Foundation, and the Nike Foundation partner on $210 million initiative to reduce new HIV infections in adolescent girls and young women. 1 December 2014. http://www.pepfar.gov/press/releases/2014/234531.htm (accessed 18 October 2015).

Accepted 19 October 2015.

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School-based human papillomavirus vaccination: An opportunity to increase knowledge about cervical cancer and improve uptake of screening G Dreyer,1 MB ChB, MMed (O&G), MCOG (SA), PhD; F H van der Merwe,2 MB ChB, MMed (O&G), FCOG; M H Botha,2 MB ChB, MMed (O&G), FCOG (SA), PhD; L C Snyman,1 MB ChB, MPraxMed, MMed (O&G), FCOG (SA); D Constant,3 MSc, MPH; C Visser,1 BSc Hons, MSc; J Harvey,4 MCom, PhD Department of Obstetrics and Gynaecology and Gynaecological Oncology Unit, Faculty of Health Sciences, University of Pretoria, South Africa Department of Obstetrics and Gynaecology and Unit for Gynaecological Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa 3 Women’s Health Research Unit, School of Public Health, Faculty of Health Sciences, University of Cape Town, South Africa 4 Centre for Statistical Consultation, Stellenbosch University, Western Cape, South Africa 1 2

Corresponding author: G Dreyer (gretadreyer@mweb.co.za)

Background. Poor knowledge about cervical cancer plays a role in limiting screening uptake. HPV vaccination provides an untested platform to distribute information that could possibly improve knowledge and screening coverage. Objective. To measure changes in knowledge and screening uptake when information and screening opportunities were provided to mothers of adolescent HPV vaccine recipients. Methods. During an HPV vaccine implementation project in the Western Cape (WC) and Gauteng Province (GP), South Africa, information about cervical cancer was provided to parents during a lecture, written information was distributed, and mothers were then invited to either screen at their clinic (WC) or use a self-screening kit (GP). A structured questionnaire was used to test cervical cancer knowledge and screening practices, comparing these before and after the project and between the two screening groups. Results. Complete data for both questionnaires were available for 777 of 906 recruited women. Initial knowledge was poor, but on retesting 6 months later, knowledge about symptoms (p<0.005), screening (p<0.005) and vaccination (p<0.05) improved significantly after the information session and school-based HPV vaccination. In the second questionnaire, women reported significantly more screening and the last reported screening test was more recent. This improvement was more favourable in GP than in the WC (41% v. 26% reporting screening in the past 12 months). Conclusion. These results demonstrate how adolescent HPV vaccine programmes can help to control cervical cancer among mothers by offering information and screening. It is important not to lose this opportunity to educate mothers and their daughters and offer effective methods to prevent cervical cancer in both generations. S Afr Med J 2015;105(11):912-916. DOI:10.7196/SAMJ.2015.v105i11.9814

Cervical cancer in South Africa (SA), as in most developing countries, remains an unchecked epi demic.[1-3] Although reasons for the high prevalence and late presentation are complex, poor uptake of screening plays a major role. Together with health systems factors, educational level and knowledge determine healthseeking behaviour and therefore screening coverage. Many authors have investigated knowledge about cervical cancer among SA women, and have generally reported this to be lacking.[4-7] It is expected that improved knowledge of cervical cancer will translate into an improvement in screening uptake. If knowledge can be improved by verbal or written communication, parents of human papillomavirus (HPV) vaccine recipients would be an appropriate target for such an educational drive. These mothers are not realistic targets for primary prevention, but should be in the appropriate age group for screening. In addition, information about the two modalities of prevention seems to combine well. Linking various health interventions to school-based HPV vaccination is a popular idea because preadolescents generally do not present for health information or care.[8-10] Potential disadvantages include a diluted message, increased cost and the possibility that connecting this vaccine to sexual health may decrease uptake. It is

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therefore essential that any planned health intervention be evalua ted and motivated thoroughly before implementation. The main aim of this project was to investigate whether an edu cational drive to improve knowledge and screening of mothers can be successful when linked to school-based HPV vaccination. In order to answer this question, knowledge and screening behaviour were tested before and after an educational intervention, followed by an invitation to participate in screening.

Methods

The Vaccine and Cervical Cancer Screen (VACCS) project aimed to vaccinate 2 000 primary schoolgirls in Gauteng Province (GP) and the Western Cape (WC) during 2011 and 2012, after approval from the national and provincial departments of health and basic education. The study was also approved by the institutional research ethics review committees of the universities of Pretoria (219/2009) and Stellenbosch (N11/01/008). Schools were selected on the basis of geographical distribution and consent from headmasters and school governing bodies. Printed information, consent and invitation material was distributed to all girls in grades 4 - 7. These pamphlets invited parents to consent to vaccination of their daughters and to attend information events at schools where they would receive more detailed information.

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After receiving information about the project, parents and female guardians were invited to participate in a questionnaire study and had to provide written consent. The questionnaire (Q1) contained both open-ended and closed questions on demographics and aspects of cervical cancer and its prevention, and was administered by medical students who asked the questions and recorded answers. The educational intervention followed, consisting of a 15-minute PowerPoint presentation by a medical doctor and information leaflets covering most of the information assessed in the questionnaire. Parents and daughters were invited to sign consent and assent for the girl child to be vaccinated, and all mothers were invited to partake in cervical cancer screening. Two different types of screening were employed in the two study sites to evaluate and compare impact on screening behaviour. In the WC, where cervical screening services are better developed, mothers were encouraged to visit their nearest clinic and undergo conventional cytology-based screening. In GP, female parents and guardians were offered a tampon collection kit for HPV determination with written information on how to self-collect the sample. These specimens were collected from the school during the following month and tested for high-risk HPV, and women who screened positive received results and an invitation to further investigation and treatment if necessary. [11] All women received results via cell phone messaging (texting). During the following months, vaccination took place at the school and telephonic interviews were conducted with the mothers after 6 months, repeating the same questions (Q2). Data from the two questionnaires were analysed to determine levels of knowledge and self-reported screening behaviour before and after the study. Differences between the answers were determined for each participant and analysed. Outcomes of the vaccination programme and the main results of the self-screening study have been reported elsewhere.[12]

Data management

Questionnaire data consisted of basic demographic data, information about access to and use of healthcare facilities, knowledge of cervical cancer and previous cervical cancer screening. Questions were asked to test basic knowledge about cervical cancer and protection against the disease, followed by questions on previous cervical cancer screening tests and their results. Using these data, knowledge scores were calculated by awarding points for correct answers to a maximum score of 5 marks each for knowledge about cervical cancer symptoms, screening options and vaccination (the scoring system is shown in Appendix 1, available in the online version of this article). For each of these three, a critical minimum score was determined based on information supplied at the lecture. It was then calculated in terms of how many women’s knowledge improved to this critical minimum between the first and second questionnaires. Because two different methods were employed to impact on screening behaviour at the two study sites, data on changes in screening uptake were analysed separately for these two groups. For screening behaviour, a score was calculated (behaviour score) according to the time of the last reported screening test. After completing the questionnaire at the start and end of the study, all participants who improved their ‘time of last screening test’ to <1 year ago were considered study screen participants.

Results

Demographic data

We invited all attending parents to participate in the study, of whom only two were excluded (male parents were ineligible). Questionnaire data were available for 906 women, and 777 also completed the second questionnaire. Loss to follow-up was due to inability to make telephonic contact or refusal to answer Q2. Demographics of this

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group were not different to the total group. The median age of the participants was 38.0 years and the level of education varied between very little formal schooling (up to grade 7 in 10.1% of women) and tertiary education (23.3% of women). Half of all participants received a salary and another 6.8% were self-employed. Differences between the provinces were significant, with parents at the GP schools being slightly younger and better educated.[13]

Knowledge about cervical cancer and its symptoms before and after health education

Before the educational intervention, knowledge about cervical cancer and its symptoms was similarly poor among participants in both sites, with 31.7% of the total group (n=906) saying that they knew nothing about cervical cancer or did not know what it was. Among those who answered questions about the symptoms of cervical cancer, pain was mentioned most commonly as an important symptom (30.0%), followed by discharge (20.9%). Significantly more women in the WC cohort than in GP knew that unusual bleeding was a symptom (24.0% v. 18.3%; p=0.04). In the second interview, only 11.9% of respondents said that they knew nothing about cervical cancer. Knowledge about the important symptoms of the disease improved, and 46.8% respondents mentioned pain, 42.1% unusual bleeding and 32.0% discharge. These answers are shown in Appendices 2 and 3 (available in the online version of this article).

Knowledge about cervical cancer prevention before and after health education

With regard to cervical cancer prevention, 53.1% of respondents initially said that they knew how a woman can protect herself against the disease; 86.1% of these women (24.6% of the total) mentioned a Pap smear as protective. Other answers included some form of medical care, protective sexual practices such as condoms, vaccines, or not having sex (only 2.4%). After the health education intervention, 83.3% of respondents thought that they knew how to protect against cervical cancer. In the total group, 66.5% now mentioned ‘Pap smear’ as protective. The biggest change was seen in knowledge that the vaccine exists, which increased from 4.2% to 26.3%. These data were also elicited by an open-ended question, and some answers are shown in Appendix 4 (available in the online version of this article). When asked whether they had ever heard of a vaccine against cervical cancer, 17.2% answered ‘yes’ before the project, and 84.1% at the end of the project. Only 15.9% of participants attempted to answer the question on preferred recipients of HPV vaccines, mostly correctly. However, attitude towards and trust in vaccines were very positive, with 90.6% of respondents saying that the vaccine will be good to have, and 89.8% saying that they would advise primary schoolgirls to have it. Responses to these last two questions at the end of the study were even better (97.4% and 98.1%).

Knowledge scores and changes after intervention

Using the method described above, knowledge scores were calculated both before and after the information event and compared per participant for those women who completed both questionnaires. Data for the complete group are set out in Table 1, showing a trend of improvement in knowledge scores (graphically illustrated in Diagrams 1 - 3, available in the online version of this article). According to the critical or essential level of knowledge, participants were divided into three groups: those whose knowledge scores improved to adequate levels, those who remained at the same level of adequacy, and those who demonstrated poorer knowledge at the second interview.

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Initially, 30.8% of participants (239/777) attained a knowledge score of 0/5 for cervical cancer and its symptoms, considered to be inadequate, while only 9.1% remained at a knowledge score of 0 after attending the health education event. In 21.6% of women knowledge scores improved to a level of adequacy. The improvement was statistically significant (p<0.005) and the data are shown in Table 2 (A). Similarly, for cervical cancer screening any knowledge score above 0/5 was considered adequate for the purposes of this analysis. After education, 62.9% had confirmed adequate knowledge, v. 30.6% before. Improvement per person was also statistically significant (p<0.005) (Table 2, B). Scoring for vaccine knowledge included two questions that actually tested attitude towards vaccines, requiring a ‘yes’ or ‘no’ answer. In

view of the positive attitudes towards vaccines in general, vaccine knowledge scores were generally good. A minimum score of 3/5 was considered adequate and was attained by 17.6% at the start of the study and 80.8% at the end of this study (p=0.045) (Table 2, C).

Screening behaviour scores and changes after the intervention

Women were asked whether they ever had a cervical cancer test and how long ago the last test had been. Answers were used to calculate a screening behaviour score, and scores of 0/5 were awarded for ‘never’ or ‘unsure if ever’, 1/5 for ‘more than 10 years ago’ and so on, with a score of 5/5 for a test ‘less than a year ago’. Changes in screening behaviour for the whole group are shown for ‘ever’ v. ‘never’ and for

Table 1. Knowledge scores before and after health education for all women who completed Q1 and Q2 (N=777) Knowledge of symptoms Score

Before health education

Knowledge of screening

After health education

Before health education

Knowledge of vaccination

After health education

Before health education

After health education

239

115

539

288

215

199

150

254

135

152

135

552

109

163

131

537

= considered adequate knowledge score;

= considered inadequate knowledge score.

Table 2. Changes in knowledge scores Questionnaire 1

Questionnaire 2

Questionnaire 1 totals

A. Changes in knowledge scores about cervical cancer and its symptoms (p<0.005) Inadequate knowledge Score 0

Adequate knowledge Score 1 - 5

Inadequate knowledge Score 0

168

239

Adequate knowledge Score 1 - 5

494

538

Questionnaire 2 totals

115

662

777

B. Changes in knowledge scores about protection by screening (p<0.005) Inadequate knowledge Score 0

Adequate knowledge Score 1 - 5

Inadequate knowledge Score 0

235

304

539

Adequate knowledge Score 1 - 5

185

238

Questionnaire 2 totals

288

489

777

C. Changes in knowledge scores about cervical cancer protection by vaccination (p<0.05) Inadequate knowledge Score 0 - 2

Adequate knowledge Score 3 - 5

Inadequate knowledge Score 0 - 2

133

507

640

Adequate knowledge Score 3 - 5

121

137

149

628

777

Questionnaire 2 totals = improvement in score;

= score unchanged;

= decrease in score.

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Table 3. Self-reported screening behaviour Questionnaire 1

Questionnaire 2

Questionnaire 1 totals

A. Self-reported screening behaviour: never v. any cervical screening history (p<0.005) Never screened Score 0

Ever screened Score 1 - 5

Never screened Score 0

194

144

338

Ever screened Score 1 - 5

358

391

Questionnaire 2 totals

227

502

729

Screened >1 year ago Score 0 - 4

Screened ≤1 year ago Score 5

Screened >1 year ago Score 0 - 4

421

134

555

Screened ≤1 year ago Score 5

130

174

465

264

729

B. Screening before v. during the past year (p<0.005)

Questionnaire 2 totals = improvement in score;

= score unchanged;

= decrease in score.

Discussion

Participants, %

50 40 30 Before

After

10 0

Never >1 year ago

<1 year ago

Western Cape Province

<1 year ago

Gauteng Province

Fig. 1. Self-reported screening behaviour before and after health intervention for the two sites.

‘less than 1 year ago’ v. ‘more than a year ago’ in Table 3. Using both cut-offs, a significant improvement was demonstrated over the study period (p<0.005).

Screening behaviour in the two sites

The initial self-reported screening behaviour for the two provincial sites showed no significant differences. Changes in screening behaviour reflected significantly more recent screening after the health education at both sites. In GP, where self-screening was also offered, changes in screening behaviour were more favourable (Fig. 1). The improvement in screening behaviour as reported by women themselves under estimated the impact of this health inter

vention in the GP site, when compared with the self-screening data. It was confirmed that 253 of the 558 women (45.3%) who completed Q1 handed in a self-collected screening test, while only 51 women moved to the ‘less than 1 year ago’ category in Q2. Among participants in the WC, the num ber of women reporting ‘never’ screening decreased and those who reported ‘more than 1 year ago’ increased, suggesting that the health information motivated women to improve screening behaviour. However, a search through the data system of the National Health Laboratory Service could not confirm recent screening at this laboratory (which services all public health care facilities) in more than a very limited number of participants.

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This study showed that simple health edu cation during a vaccine implementation project can have a measurable effect on the knowledge of mothers of primary schoolchildren and that significant improvements in knowledge about symptoms, screening and vaccination could be demonstrated. Importantly, we also demonstrated that increased knowledge scores can be linked to improved screening behaviour when opportunities for screening were easy to access.[11] Lack of knowledge about disease detection and prevention has often been linked to high prevalence and late diagnosis of cervical cancer, but evidence about interventions to address this problem effectively is limited.[4] Consistent with previous reports, the present study confirmed that many SA women at risk for cervical cancer lack even the most basic knowledge about the disease and how they can protect themselves.[5,6] These results support HPV vaccination campaigns as a potential platform to supply health information about cervical cancer that can influence screening decisions. Mothers and other female guardians of primary schoolchildren are at the ideal age for cervical screening and are socially and economically critically important. During this study the educational intervention consisted of a combination of an oral presentation and written material, which will probably not be possible on a nationwide scale. Although alternative educational initiatives should preferably be tested before wide implementation, a minimum of written

RESEARCH

educational material should be offered addressing the risk of nonvaccinated women and offering alternative cancer prevention via screening.[8] Answers to questions that tested attitude toward vaccination in general were overwhelmingly positive, with parents showing healthseeking behaviour where their children were involved. The positive attitude towards vaccines may also reflect previous good experiences with the childhood vaccine programme. We trust that these positive results will contribute to widespread acceptance and successful introduction of the new and essential HPV vaccines in SA and similar developing countries. Women offered on-site self-screening had a larger improvement in self-reported screening behaviour than those invited to use existing facilities.[11] The uptake of the test was calculated and the results support this finding. Observed uptake of self-screening was higher than what was reported by the respondents, cautioning that women did not understand that this test was indeed a new type of cancer screening test. Improvements in self-reported screening data among participants who were invited to screen at existing clinics were not supported by other data sources available to us and should be interpreted with caution.

Study limitations

Limitations of our study include the inherent limitations of administered questionnaires, difficulties in assessing knowledge and attitudes accurately using a questionnaire, and the potential inaccuracy of self-reported data on the use of health services. Inconsistent data on screening behaviour between the two questionnaires and between women’s reports and other data sources demonstrate this inaccuracy. Women may not recall the time since their last screening test accurately, and the results of these questions may also be influenced by social desirability bias.

Conclusion

The results of this questionnaire study demonstrate that knowledge about cervical cancer among SA women at risk for the disease is lacking, but can be improved significantly by simple educational interventions. School-based HPV vaccination programmes provide an opportunity for successful education that can include information about vaccination and screening. Additionally, this project showed that HPV vaccine programmes can be used to improve cervical cancer screening coverage. Selfcollected molecular tests that were provided at the information events achieved higher uptake than a reminder to use the existing clinic-based service, and all women received results using schoolbased logistics. It is hoped that the overwhelmingly positive attitude towards vaccination found during this study predicts a high uptake of pre adolescent HPV vaccine outside the research setting. Acknowledgements. We gratefully acknowledge the assistance of the following groups and persons that enabled the successful completion of this project.

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The VACCS study was supported financially by the Cancer Research Initiative of South Africa, a national collaborative research programme supported by the South African Medical Research Council and the Cancer Association of South Africa. Vaccine manufacturing companies (GlaxoSmithKline Biologicals SA and Merck) approved the protocol and supported this investigator-initiated study by generously donating all vaccines used in this project. The screening programme as well as treatment of screen-positive women was funded by the 1st for Women Foundation. We wish to acknowledge the efforts and inputs of Prof. Gerhard Lindeque, who provided valuable advice; Ms Bertha Grond, who managed the finances; study co-ordinator Ms Riekie Burden and her team of registered nurses, who handled all study and vaccine processes seamlessly; Dr Karin Richter, who managed the laboratory screening tests; consultants and registrars of the Department of Obstetrics and Gynaecology, University of Pretoria, who presented lectures at the information events; and the undergraduate medical students who administered the questionnaires and gave us valuable feedback. The funders were given the opportunity to review a preliminary version of this manuscript for factual accuracy, but the authors are solely responsible for final content and interpretation. References 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61(2):69-90. [http://dx.doi.org/10.3322/caac.20107] 2. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer, 2013. http://globocan.iarc.fr (accessed 10 March 2014). 3. Bruni L, Barrionuevo-Rosas L, Albero G, et al. ICO Information Centre on HPV and Cancer (HPV Information Centre). Human Papillomavirus and Related Diseases in the World. Summary Report 2015-04-08. http://www.hpvcentre.net/statistics/reports/XWX.pdf (accessed 27 March 2015). 4. Francis SA, Nelson J, Liverpool J, et al. Examining attitudes and knowledge about HPV and cervical cancer risk among female clinic attendees in Johannesburg, South Africa. Vaccine 2010;28(50):80268032. [http://dx.doi.org/10.1016/j.vaccine.2010.08.090] 5. Van Schalkwyk SL, Maree JE, Wright SC. Cervical cancer: the route from signs and symptoms to treatment in South Africa. Reprod Health Matters 2008;16(32):9-17. [http://dx.doi.org/10.1016/S09688080(08)32399-4] 6. Hoque M. Awareness of cervical cancer, Papanicolau’s smear and its utilization among female, final year undergraduates in Durban, South Africa. J Cancer Res Ther 2013;9(1):25-28. [http://dx.doi. org/10.4103/0973-1482.110350] 7. Francis SA, Battle-Fisher M, Liverpool J, et al. A qualitative analysis of South African women’s knowledge, attitudes, and beliefs about HPV and cervical cancer prevention, vaccine awareness and acceptance, and maternal-child communication about sexual health. Vaccine 2011;29(47):8760-8765. [http://dx.doi.org/10.1016/j.vaccine.2011.07.116] 8. MacPhail C, Venables E, Rees H, et al. Using HPV vaccination for promotion of an adolescent package of care: Opportunity and perspectives. BMC Public Health 2013;13:493. [http://dx.doi. org/10.1186/1471-2458-13-493] 9. Ropero-Álvarez AM, Kurtis HJ, Danovaro-Holliday MC, et al. Vaccination week in the Americas: An opportunity to integrate other health services with immunization. J Infect Dis 2012;205(suppl 1):S120-S125. [http://dx.doi.org/10.1093/infdis/jir773] 10. Kharbanda EO, Stockwell MS, Fox H, et al. The role of human papillomavirus vaccination in promoting delivery of other preventive and medical services. Acad Pediatr 2011;11(4):326-332. [http:// dx.doi.org/10.1016/j.acap.2010.12.013] 11. Snyman LC, Dreyer G, Botha MH, van der Merwe FH, Becker PJ. The Vaccine and Cervical Cancer Screen (VACCS) project: Linking cervical cancer screening to HPV vaccination in the South West District of Tshwane, Gauteng, South Africa. S Afr Med J 2015;105(2):115-120. [http://dx.doi. org/10.7196/SAMJ.8418] 12. Botha MH, van der Merwe FH, Snyman LC, Dreyer G. The Vaccine and Cervical Cancer Screen (VACCS) project: Acceptance of human papillomavirus vaccination in a school based program in two provinces of South Africa. S Afr Med J 2015;105(1):40-43. [http://dx.doi.org/10.7196/SAMJ.8419] 13. Van der Merwe FH, Botha MH, Snyman LC, Dreyer G. The vaccine and cervical cancer screen (VACCS) project: Screening behaviour of adult women – a story of missed opportunities. Poster session presented at the 15th biennial meeting of the International Gynecologic Cancer Society, 8 - 11 November 2014, Melbourne, Australia.

Accepted 28 September 2015.

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300

Participants, n

250 200 150

Before health education

100

After health education

50 0

Score Diagram 1. Knowledge of cervical cancer symptoms.

600

Participants, n

500 400 300

Before health education

200

After health education

100 0

Score Diagram 2. Knowledge of cervical cancer screening.

600

Participants, n

500 400 300

Before health education

200

After health education

100 0

Score Diagram 3. Knowledge of cervical cancer vaccination.

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Appendix 1. Calculation of knowledge scores from responses in questionnaires 1 and 2 Score calculation: ‘Knowledge about cervical cancer symptoms’ Question

Response

Points awarded (maximum of 5)

301 & 601. Can you explain what you understand about cervical cancer – that is cancer of the mouth of the womb?

Do not know

Any correct or nearly correct answer

303 & 603. What changes in your body would make you think that you had cervical cancer?

Pain Discharge from vagina Odour from vagina Unusual bleeding

1 point each

Score calculation: ‘Knowledge about protection against cervical cancer’ Points awarded (maximum of 5)

Question

Response

304 & 604. How can a woman protect herself against developing cervical cancer?

Regular pap smear Regular examination of womb Not having sex Using condoms Vaccine/injection Other screening tests

1 point each

Score calculation: ‘Knowledge about cervical cancer protection by vaccination’ Question

Response

Points awarded (maximum of 5)

501 & 801. Have you ever heard of a vaccine or injection to prevent cervical cancer?

Yes

502 & 802. IF YES: Who is the vaccine or injection for?

Women/girls only Men and women/girls Women/girls under a certain age Women/girls who have not had sexual intercourse yet

2 points each

503 & 803. Do you think a vaccine to prevent cervical cancer would be good to have?

Yes

505 & 805. Would you advise primary school girls to have this vaccine?

Yes

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Appendix 2. Answers to open-ended question: ‘What do you understand about cervical cancer?’

Response

Q1, question 301 (N=750) n (%)

Q2, question 601 (N=714) n (%)

Don’t know/nothing

308 (41.0)

112 (15.7)

Cancer of the mouth of the womb or cervix

69 (9.2)

175 (24.5)

Cancer, illness, growth, sores or bleeding of the womb

192 (25.6)

278 (38.9)

Must have Pap smears

33 (4.4)

10 (1.4)

Cancer of private parts/affects only women

27 (3.6)

53 (7.4)

STD/can get from unsafe sex

31 (4.1)

34 (4.8)

HPV/virus

5 (0.7)

12 (1.7)

Self, friend, family member has it

6 (0.8)

2 (0.3)

Type of cancer

12 (1.6)

3 (0.4)

Abnormal cells, growth, lump, mass, cyst

9 (1.2)

1 (0.1)

Dangerous, fatal, incurable disease

19 (2.5)

6 (0.8)

Affects vagina

13 (1.7)

15 (2.1)

Appendix 3. Answers to open-ended question: ‘What changes in the body would make you think that you had cervical cancer?’

Response

Q1, question 302 (N=906) n (%)

Q2, question 602 (N=777) n (%)

Pain

272 (30.0)

359 (46.2)

Discharge

189 (20.9)

249 (32.0)

Odour

92 (10.1)

137 (17.6)

Ulcers/sores

64 (7.1)

140 (18.0)

Unusual bleeding

185 (20.4)

327 (42.1)

There are no signs

11 (1.2)

8 (1.0)

Don’t know

71 (7.8)

90 (11.6)

Appendix 4. Answers to open-ended question: ‘How can a woman protect herself against cervical cancer?’ Q1, question 304 (N=906) n (%)

Q2, question 604 (N=777) n (%)

Pap smear

223 (24.6)

419 (53.9)

Regular examination of womb

74 (8.2)

126 (16.2)

Seeing a special doctor

38 (4.2)

124 (16.0)

Regular visit to general practitioner

30 (3.3)

43 (5.5)

Not having sex

22 (2.4)

18 (2.3)

Using condoms

61 (6.7)

113 (14.5)

Vaccine/injection

38 (4.2)

205 (26.4)

Other screening tests

21 (2.3)

28 (3.6)

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Missed opportunities for immunisation in health facilities in Cape Town, South Africa N Jacob, MB ChB; D Coetzee, FCPHM Western Cape Government: Health, and School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: N Jacob (nasj11@yahoo.com)

Background. Childhood immunisations are a cost-effective public health intervention for prevention of infectious diseases. Immunisation coverage is still suboptimal, however, which may result in disease outbreaks. Immunisation at every contact with a health facility is a strategy developed by the World Health Organization in order to improve immunisation coverage. Objectives. To estimate the prevalence of missed opportunities for immunisation at different levels of healthcare in the Western Cape Province, South Africa, and assess factors associated with missed opportunities. Methods. The study included a health facility-based cross-sectional exit survey of caregivers with children up to 5 years of age, followed by a qualitative exploration of staff attitudes towards immunisation. Results. The overall prevalence of missed opportunities for immunisation was 4.6%; 81.3% of caregivers brought Road-toHealth booklets (RTHBs) to consultations; and 56.0% of health workers asked to see the RTHBs during consultations. Children attending primary level facilities were significantly more likely to have their RTHBs requested than children attending a tertiary level facility. Lack of training and resources and heavy workloads were the main challenges reported at secondary/tertiary level facilities. Conclusion. Missed opportunities for immunisation at health facilities in Cape Town were low, probably reflecting good immunisation coverage among children accessing health facilities. Increased health worker support, particularly at secondary/tertiary levels of care, is needed to improve the use of RTHBs to provide immunisation. S Afr Med J 2015;105(11):917-921. DOI:10.7196/SAMJ.2015.v105i11.10194

The Expanded Program on Immunization (EPI) initiated by the World Health Organization (WHO) in 1974 aimed to provide vaccines to children world wide.[1] Despite advances in expanding immuni sation services, coverage remains suboptimal in many areas. Where accessibility and utilisation of health services are low, every contact with a health facility provides an opportunity to immunise, particularly as these children are likely to be at an increased risk of vaccine-preventable diseases.[2,3] The EPI Global Advisory Group[2] defines a missed opportunity as ‘any contact with a health service that did not result in an eligible child or woman receiving the needed vaccines’.[1,2] The elimination of missed opportunities can significantly improve immunisation coverage, thus reducing the risk of vaccine-preventable disease.[2] The current immunisation schedule for the EPI in South Africa (EPI-SA) is in the Road-to-Health booklet (RTHB) issued to a child’s mother at birth or to a subsequent caregiver. Despite health facility immunisation coverage figures that exceed 95%, the Western Cape Province (WC) of SA experienced a major measles outbreak in 2009/2010. Herd immunity of 95% is required to prevent ongoing measles virus transmission.[4,5] Low coverage, lower efficacy of some vaccines (e.g. measles vaccine at 9 months), incorrect vaccine administration and host response factors are the main causes of outbreaks of vaccine-preventable illness in areas with a functional immunisation programme. The 2009/2010 epidemic raised concerns regarding the validity of immunisation coverage data. Since coverage indicators are very sensitive to data inaccuracies such as incorrect population estimates, reported data may not be a true reflection of coverage in the population. In addition to improving the quality of coverage data, it is imperative that strategies to improve coverage

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are strengthened. The missed-opportunity survey was developed in 1984 to evaluate immunisation practices and improve immunisation coverage.[1,3] In 1991, the EPI reviewed all missed-opportunity studies published worldwide or reported to the WHO.[3] Missed opportunities were found in all studies except one, with an overall median of 32% of children and women of childbearing age having had missed immunisation opportunities.[3] Reasons for missed opportunities included false contraindications, health worker practices and vaccine shortages. A more recent systematic review by Rainey et al.[6] evalua ted reasons for under-vaccination of children in low- and middleincome countries. Immunisation system issues including missed opportunities, distance to services and low health worker knowledge were the most frequently observed reasons for under-vaccination. Missed-opportunity surveys conducted in the WC in the 1990s revealed a prevalence of 60 - 95%. Category of consulting health worker, age of child and type of service (i.e. curative, preventive or integrated service) impacted on whether RTHBs were requested and immunisations given appropriately.[7-9] A 2005 household survey among children aged 12 - 23 months in the WC revealed immunisation coverage rates of 76.8% for vaccines due by 9 months and 53.2% for vaccines due by 18 months. The main reasons for not being immunised were clinic-related factors, including missed opportunities (34%).[10] Studies conducted in developed countries have highlighted poor knowledge of EPI-SA, insufficient time, and staff not viewing immunisations as a priority or within their scope of practice.[11-13] These factors have yet to be explored in developing countries. Few missed-opportunity studies have been conducted in the past decade, worldwide and in SA.

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Methods

A cross-sectional study design comprising two components was used: 1. A health facility-based cross-sectional survey to determine the prevalence of missed opportunities for immunisation and associated factors. 2. Qualitative exploration of staff atti tudes towards immunisation using a semistructured questionnaire. The study population was children 0 - 5 years of age attending healthcare facilities with a caregiver from 08h00 to 16h00 on weekdays in the Cape Town metro. Purposeful sampling was employed to select study sites. Five sites representative of primary, secondary and tertiary levels of care were selected, including a local clinic (clinic A – primary level), a community health centre (CHC B – primary level), one district hospital (hospital A –secondary level), one regional hospital (hospital B – secondary level) and one central hospital (hospital C – tertiary level). A sample size of 96 per facility was calcu lated, estimating that 50% of opportunities would be missed, with an alpha error of 0.05 and absolute precision of 0.1. A recruiter identified caregiver/child pairs exiting the health facility, including both inpatients and outpatients. Only caregivers aged >13 years were included in the study. All caregivers were interviewed by a trained fieldworker. A request for an RTHB during the consultation was used as a proxy indicator that the immunisation status of a child was checked by the health worker. Logistic regression was used to explore associations between outcomes (immunisa tion status, request for RTHB and presence of RTHB) and explanatory variables with adjustment for potential confounding vari ables. A forward selection procedure was applied for model building. The final model was selected by comparison of models using the likelihood ratio test and Akaike’s infor mation criterion. In order to elicit themes regarding staff attitudes towards immunisation, a purpose ful sample of two to three staff members at participating health facilities were interviewed by the primary researcher (NJ) using a semistructured questionnaire. Data were analysed manually by NJ. The research protocol was approved by the University of Cape Town Human Research Ethics Committee (HREC: 321/2014). The research followed the ethical standards outlined in the Helsinki Declara tion[14] and the National Health Act. [15] The risks to study participants were minimal.

Table 1. Descriptive characteristics of caregiver, child and visit to facility* Variable

Overall

Age of child (months), median (range)

11 (0 - 60)

Age of caregiver (years) median (range)

29 (16 - 70)

Day of week, % (95% CI) Monday

23.0 (19.2 - 26.8)

Tuesday

19.1 (15.6 - 22.6)

Wednesday

17.6 (14.2 - 21.1)

Thursday

18.7 (15.2 - 22.2)

Friday

21.6 (17.9 - 25.3)

Time of day, % (95% CI) 09h00 - 11h59

41.8 (37.4 - 46.3)

12h00 - 13h59

32.3 (28.0 - 36.5)

14h00 - 16h00

25.9 (21.9 - 29.9)

Primary caregiver, %

100.0

Specific illness reported by caregiver, % (95% CI)

21.6 (17.9 - 25.3)

HIV

1.7 (0.5 - 2.8)

1.5 (0.4 - 2.5)

Malnutrition

0.4 (–0.2 - 1.0)†

Health worker consulted, % (95% CI) Doctor only

39.2 (34.8 - 43.7)

Nurse only

51.3 (46.8 - 55.8)

Doctor and nurse

5.7 (3.6 - 7.8)

Allied health staff only

3.8 (2.1 - 5.5)

RTHB asked for by health worker, % (95% CI)

64.9 (60.7 - 69.2)

RTHB present, % (95% CI)

81.3 (77.8 - 84.8)

Vaccines given today, % (95% CI) Yes – all pending vaccines given

17.3 (13.9 - 20.6)

Yes – some pending vaccines given

2.1 (0.8 - 3.4)

80.7 (77.1 - 84.2)

Vaccine pending but contraindication to immunisation, % (95% CI) No

4.6 (2.7 - 6.4)

Yes

0.2 (–0.2 - 0.6%)†

Not applicable (complete immunisations)

95.2 (93.3 - 97.1)

Immunisation status – complete by RTHB (N=392), % (95% CI)

94.6 (92.4 - 96.9)

Immunisation status – complete by caregiver report (N=90), % (95% CI)

86.7 (79.5 - 93.8)

Overall immunisation status, % (95% CI) Complete by caregiver

16.2 (12.9 - 19.5)

Uncertain by caregiver

2.1 (0.8 - 3.4)

Complete by RTHB

77.0 (73.2 - 80.7)

Missed opportunities by RTHB (N=21), % (95% CI) Incomplete RTHB and checked by health worker

61.9 (39.3 - 84.6)

Combined overall immunisation status, % (95% CI) Complete (RTHB + caregiver)

93.2 (90.9 - 95.4)

Uncertain (caregiver)

2.1 (0.8 - 3.4)

Incomplete (RTHB + caregiver)

4.6 (2.6 - 6.4)

Incomplete with contraindication

0.2 (–0.2 - 0.6)†

CI = confidence interval. *N=482 unless specified. † CIs overlapping 0.

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Results

Four hundred and eighty-two participants were recruited, with an overall respondent rate of 81.1%. Respondent rates varied, ranging from 67.2% at hospital C to 86.4% at clinic A. Descriptive characteristics are summarised in Table 1. The majority of children who participated in the study attended the facility for a consultation due to illness or for a follow-up consultation (Fig. 1). Discharged newborn infants exiting the facility were included, but no children discharged following inpatient admission participated in the study. Of the caregivers, 81.3% had RTHBs present at the consultation. During children’s consultations, 64.9% of health workers requested the RTHB. This decreased to 56.0% when excluding children who presented specifically for immunisation. There were notable differences between facilities. Only 11.6% of health workers requested to see RTHBs at hospital C, while >70% of health workers at all other facilities requested the RTHB (Fig. 2). Of patients attending primary level facilities (clinic A and CHC B), 90.0% brought RTHBs to the facility. However, only 64.0% of patients attending hospital C did so. Of the 392 children who had an RTHB present, 5.4% had incomplete immunisations. Of caregivers of the 90 children who did not have an RTHB present, 13.3% reported that immunisation status was incomplete or uncertain. Overall, 77.0% of children had complete immunisations according to the RTHB, 16.2% had complete immunisations according to the caregiver’s report, and the remaining 6.9% had incomplete immunisation status by RTHB or caregiver report or uncertain immunisation status by caregiver report. Of the 21 children with incomplete immuni sations by RTHB, 61.9% had their RTHBs checked on the day, and 61.5% of these children received some, but not all, due immunisations on the same day. No facilities experienced vaccine stock-outs during the study period, and one child was erroneously identified by the health worker as too sick for immunisation. Only one child had a true contraindication to immunisation. The overall prevalence of missed opportunities for immunisation according to both RTHB

accompanying a sick caregiver had RTHBs requested, and were also excluded from the model. Those with an RTHB present at consultation were 34.8 times more likely to have their RTHB requested by the health worker than those without RTHBs. A child presenting with an acute illness was 3.5 times more likely to have the RTHB requested compared with a child presenting for followup. Children presenting to health facilities from Monday to Thursday were more likely to have RTHBs requested than those presenting on Friday. Children presenting to hospital C were least likely to have RTHBs requested. Those seen at clinic A were 17.2 times more likely to have their RTHBs requested than those seen at hospital C. Although exploratory

and caregiver reports was 4.6%. This figure increased to 6.6% when uncertain immunisation status was included. At all facilities, among children with RTHBs, >90% of children exiting the facilities had complete immunisations required for age. When excluding children presenting spe cifically for immunisation, 68.7% of children seen by nurses only had their RTHB requested, compared with 49.2% seen by doctors only. The logistic regression revealed no stati stically significant determinants of complete immunisation status. A number of factors associated with health worker requests for RTHB were identified (Table 2). The model excluded those attending for immunisations and newborns who had been discharged. Similarly, none of the children

Newborn discharges

8% Child sick 25%

Immunisation 20%

Accompanying another child 11%

Child’s follow-up 32%

Caregiver’s follow-up 2% Caregiver sick 2% Fig. 1. Reason for attending health facility. 100 90 80 70 Proportion, %

Participation in the study was voluntary, and all participants provided written informed consent. All children found to be eligible for immunisation were immunised on site in the designated clinical area. Verbal consent for immunisation was obtained from caregivers.

60 50

RTHB present RTHB requested

40 30 20 10 0

Clinic A

CHC B

Hospital A

Hospital B acute

Fig. 2. RTHB requested by health worker, by facility.

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Hospital B OPD

Hospital C OPD

Total

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Table 2. Factors associated with health worker requests for RTHB Variable

p-value*

95% CI

RTHB present

34.80

0.0000

7.32 - 165.43

Age (months)

0.97

0.0220

0.95 - 1.00

Reason for attending (reference: child’s follow-up)

Accompanying another child

0.06

0.0000

0.01 - 0.26

Caregiver follow-up

0.09

0.1070

0.00 - 1.69

Child sick

3.49

0.0130

1.30 - 9.34

Monday

1.66

0.4030

0.51 - 5.39

Tuesday

4.03

0.0790

0.85 - 19.05

Wednesday

15.44

0.0030

2.50 - 95.27

Thursday

11.10

0.0030

2.27 - 54.33

Day (reference: Friday)

Site (reference: hospital C) Hospital A

3.26

0.1950

0.54 - 19.55

CHC B

7.31

0.0190

1.39 - 38.52

Clinic A

17.21

0.0000

4.52 - 65.42

Hospital B acute

1.46

0.7360

0.16 - 13.07

Hospital B OPD

5.34

0.1690

0.49 - 57.97

OR = odds ratio; CI = confidence interval. *p-values <0.05 indicated in bold.

Table 3. Factors associated with RTHB present at health facility visit Variable

p-value*

95% CI

Accompanying another child

0.08

0.0000

0.03 - 0.20

Caregiver follow-up

0.04

0.0010

0.00 - 0.26

Caregiver sick

0.01

0.0000

0.00 - 0.12

Child sick

3.21

0.0330

1.10 - 9.37

0.96

0.0000

0.95 - 0.98

Reason for attending (reference: child’s follow-up)

Age (months) Site (reference: hospital C) Hospital A

5.52

0.0560

0.96 - 31.87

CHC B

2.94

0.2140

0.54 - 16.14

Clinic A

2.00

0.2120

0.67 - 5.95

Hospital B acute

1.29

0.8090

0.16 - 10.43

Monday

1.25

0.5890

0.56 - 2.78

Tuesday

1.74

0.4310

0.44 - 6.92

Wednesday

1.23

0.8250

0.20 - 7.54

Thursday

1.21

0.8230

0.22 - 6.60

Day (reference: Friday)

OR = odds ratio; CI = confidence interval. *p-values <0.05 indicated in bold.

analysis revealed that nurses were more likely than doctors to request RTHBs, this factor did not influence the model significantly, probably due to collinearity with site. Younger children and those who were sick were significantly more likely to present with an RTHB, as shown in Table 3.

Staff attitudes towards immunisation

The majority of the 17 staff members interviewed 2 weeks after the quantitative component of the study said that they checked the RTHB and viewed it as an important and useful clinical tool. Doctors at tertiary level noted that RTHBs were

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less likely to be checked among follow-up patients, as they are well known to the hospital and assumed to be up to date with immunisations. Many felt that a dedicated, well-trained immunisation nurse should be appointed at secondary/tertiary health facilities to prescribe and administer immunisations. The majority of those interviewed identified challenges that often led to missed immunisations at health facilities (Table 4).

Discussion

This study revealed that the prevalence of missed opportunities for immunisation at selected health facilities in Cape Town was low. The majority of children who presented specifically for immunisations received those immunisations on the day of the study, suggesting good local immunisation cover age among children accessing health facili ties. However, children who do not access routine immunisation services are more likely to become ill, and to present particularly at secondary and tertiary services. The low percentage of health workers who requested RTHBs at these higher-level services indicates that vulnerable children could be missed. Furthermore, while a request for an RTHB was a proxy indicator for checking immunisation status, the health worker may have requested the RTHB to check other information. A large proportion of children whose immunisations were incomplete had their RTHBs requested on the day and received some, but not all, of their immunisations. Although no vaccine stock-outs occurred during the study period and only one correct contraindication to immunisation was elicited, missed opportunities for immunisation may also be influenced by health worker knowledge regarding sched ules and contraindications to immunisation. It appears that false contraindications to immunisation or concerns regarding simultaneous administration of immuni sations contributed to the missed oppor tunities, as seen in similar studies.[3] A number of factors were associated with requests for RTHBs by health workers dur ing consultation. Having the RTHB present at the consultation had the largest effect. This may indicate that mothers were aware of the need to bring the RTHB at every visit, or that health workers were more likely to request the RTHB if it was visible to them at the consultation. The lower proportions of children with an RTHB present, as well as requests for an RTHB at hospital C, suggests that caregivers were aware that

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Table 4. Immunisation-related challenges Vaccine stock-outs Hospital pharmacies do not stock certain vaccines Unavailability of vaccines after hours at all levels of care Staff shortages and high workloads, particularly among nursing staff Uncertainties among doctors regarding dosages and prescription format for immunisations Pervasive nursing perspective that immunisations are only for primary level facilities Poor staff training on immunisations, management of adverse events and cold-chain management Staff conflict on appropriate hospital area where immunisations should be allocated Lack of resources, e.g. EPI fridge

RTHBs were less likely to be utilised at facilities such as hospital C. Hospital C has more diverse patients attending follow-up services compared with the other facilities, and unmeasured contributory factors such as socioeconomic status and level of education may also have played a role. The main differences observed across health facilities were due to the nature of the visit. Secondary/tertiary level outpatient services typically see older children for follow-up purposes. At primary level facilities, younger children present for preventive care such as immunisation and management of acute illness. The markedly lower percentage of RTHBs requested in the hospital C outpatient department is probably due to the fact that these children are known to the doctors. Nevertheless, it reveals that routine documentation of health visits in the RTHB is practised infrequently. It also suggests that the RTHB is viewed as a tool for primary level only, with little relevance to tertiary facilities, and that it is not used to ensure good continuity of care across all levels. Compared with other days, RTHBs were least likely to be requested on Mondays and Fridays, after adjustment for site, age of child and reason for attending the health facility. An increased patient load and health worker fatigue may have contributed to this finding. Children accompanying other children for consultations and those accompanying caregivers for follow-up visits were markedly less likely than other children to have their RTHB requested. Nevertheless, some accompanying children had an RTHB with them. The presence of a child at any health facility is an opportunity for immunisation and health promotion, particularly where access to and utilisation of healthcare is poor.

A clear difference was seen in staff atti足 tudes towards immunisation at secondary/ terti足 ary level facilities. Heavy workload, pharmacy stock practice, lack of training and uncertainty regarding immunisation guidelines and practices were cited as reasons for the avoidance of immunisation at hospitals. Clinicians preferred to refer to primary level facilities, creating a missed opportunity. Clinicians in secondary/tertiary facilities identified the need for a dedicated immunisation nurse who could administer immunisations appropriately and train other clinicians on guidelines and practices.

Study limitations

The poor response rate at hospital C may have introduced selection bias. Nonresponders were generally in a hurry and their children may have been less likely to be immunised. Only senior management at facilities was informed about the study, so that practices were not influenced by the study; however, awareness of the study over the study period may have influenced health worker practices. Furthermore, a number of questions in the questionnaire relied on caregiver recall. Social desirability bias may have influenced results, particularly when the RTHB was not presented. Extending the study after working hours would also have explored the prevalence of missed opportunities after hours, when resources, including time and staff, are often limited further. A household survey to identify missed opportunities would have been more representative, but also far more costly.

Conclusion

This study revealed a low prevalence of missed opportunities for immunisation at

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selected health facilities in Cape Town, reflecting good local immunisation coverage among children accessing the facilities. The lower proportion of health workers assessing RTHBs during consultations indicates that missed opportunities may occur if immunisation coverage is poor. Increased health worker support regarding immunisations is needed to ensure that opportunities for immunisation are not missed and immunisation coverage is improved still further. Funding. We gratefully acknowledge the Western Cape Government: Health and the School of Public Health and Family Medicine, University of Cape Town, for their support in funding this study. References 1. World Health Organization. Systematic review of missed opportunities for vaccination: Request for proposals. http://www.who.int/immunization/rfp_review_missed_ opportunities_vaccination/en/ (accessed 12 February 2014). 2. United Nations. Millennium Development Goals. http://www. un.org/millenniumgoals/ (accessed 12 February 2014). 3. Hutchins SS, Jansen H, Robertson SE, Evans P, Kim-Farley RJ. Studies of missed opportunities for immunization in developing and industrialized countries. Bull World Health Organ 1993;71(5):549-560. 4. Nelson KE, Williams CM. Infectious Disease Epidemiology, Theory and Practice. Sudbury, MA: Jones & Bartlett, 2006. 5. Bernhardt GL, Cameron NA, Willems B, Boulle A, Coetzee D. Evaluating measles vaccination coverage in high-incidence areas of the Western Cape Province, following the mass vaccination campaign. S Afr Med J 2013;301(3):181-186. [http://dx.doi. org/10.7196/SAMJ.6196] 6. Rainey JJ, Watkins M, Ryman TK, Sandhu P, Bo A, Banerjee K. Reasons related to non-vaccination and under-vaccination of children in low and middle income countries: Findings from a systematic review of the published literature, 1999-2009. Vaccine 2011;29(46):8215-8221. [http://dx.doi.org/http://dx.doi. org/10.1016/j.vaccine.2011.08.096] 7. Yach D, Metcalf C, Lachman P, et al. Missed opportunities for measles immunisation in selected Western Cape hospitals. S Afr Med J 1991;79(8):437-439. 8. Harrison D, Barron P, Glass B, Sonday S, van der Heyde Y. Far fewer missed opportunities for immunisation in an integrated child health service. S Afr Med J 1993;83(8):575-576. 9. Bachmann MO, Barron P. Missed opportunities for immunisation in curative and preventive services in a community health centre. S Afr Med J 1996;86(8):947-949. 10. Corrigall J, Coetzee D, Cameron N. Is the Western Cape at risk for an outbreak of preventable childhood diseases? Lessons from an evaluation of routine immunisation coverage. S Afr Med J 2008;98(1):41-45. 11. Prislin R, Sawyer MH, De Guire M, Brennan J, Holcomb K, Nader PR. Missed opportunities to immunize: Psychosocial and practice correlates. Am J Prev Med 2002;22(3):165-169. [http:// dx.doi.org/10.1016/s0749-3797(01)00429-9] 12. Prislin R, Sawyer MH, Nader PR, Goerlitz M, de Guire M, Ho S. Provider-staff discrepancies in reported immunization knowledge and practices. Prev Med 2002;34(5):554-561. [http:// dx.doi.org/10.1006/pmed.2002.1019] 13. Szilagyi PG, Rodewald LE, Humiston SG, et al. Immunization practices of pediatricians and family physicians in the United States. Pediatrics 1994;94(4):517-523. 14. World Health Organization. Declaration of Helsinki. http:// www.who.int/bulletin/archives/79(4)373.pdf (accessed 5 March 2014). 15. South African Government. National Health Act 61 of 2003. http://www.gov.za/documents/download.php?f=68039 (accessed 5 March 2014).

Accepted 10 October 2015.

RESEARCH

A profile of anti-vaccination lobbying on the South African internet, 2011 - 2013 R J Burnett,1 MPH, PhD; L J von Gogh,1 BA; M H Moloi,2 MPH; G François,3 MSc, PhD S outh African Vaccination and Immunisation Centre, Department of Virology, Sefako Makgatho Health Sciences University, Pretoria, South Africa 2 Department of Public Health, Sefako Makgatho Health Sciences University, Pretoria, South Africa 3 Department of Epidemiology and Social Medicine, University of Antwerp, Belgium 1

Corresponding author: R J Burnett (rose.burnett@smu.ac.za)

Background. The South African Vaccination and Immunisation Centre receives many requests to explain the validity of internet-based anti-vaccination claims. Previous global studies on internet-based anti-vaccination lobbying had not identified anti-vaccination web pages originating in South Africa (SA). Objective. To characterise SA internet-based anti-vaccination lobbying. Methods. In 2011, searches for anti-vaccination content were performed using Google, Yahoo and MSN-Bing, limited to English-language SA web pages. Content analysis was performed on web pages expressing anti-vaccination sentiment about infant vaccination. This was repeated in 2012 and 2013 using Google, with the first 700 web pages per search being analysed. Results. Blogs/forums, articles and e-shops constituted 40.3%, 55.2% and 4.5% of web pages, respectively. Authors were lay people (63.5%), complementary/alternative medicine (CAM) practitioners (23.1%), medical professionals practising CAM (7.7%) and medical professionals practising only allopathic medicine (5.8%). Advertisements appeared on 55.2% of web pages. Of these, 67.6% were sponsored by or linked to organisations with financial interests in discrediting vaccines, with 80.0% and 24.0% of web pages sponsored by these organisations claiming respectively that vaccines are ineffective and that vaccination is profit driven. The vast majority of web pages (92.5%) claimed that vaccines are not safe, and 77.6% of anti-vaccination claims originated from the USA. Conclusion. South Africans are creating web pages or blogs for local anti-vaccination lobbying. Research is needed to understand what influence internet-based anti-vaccination lobbying has on the uptake of infant vaccination in SA. S Afr Med J 2015;105(11):922-926. DOI:10.7196/SAMJ.2015.v105i11.9654

The South African Expanded Programme on Immunisation (EPI-SA) provides free universal infant vaccination against ten diseases, using an accelerated schedule for a programme that is unique in sub-Saharan Africa.[1] Despite high EPI-SA administrative vaccination coverage figures (i.e. official District Health Information System data), reports of pockets of suboptimal vaccination coverage[2-4] and sporadic measles outbreaks[2,3,5,6] have prompted research into reasons why some SA children are not fully vaccinated. While an earlier survey of caregivers reported reasons such as missed vaccination opportunities, incorrect information given by clinic staff, unavailability of vaccines and lack of access to clinics,[4] a more recent survey of EPI-SA managers reported that resistance from parents because of anti-vaccination rumours also plays a role.[3] Anecdotal reports of parental refusal from SA healthcare workers support this finding.[2,6] In addition, the South African Vaccination and Immunisation Centre (SAVIC) at the Sefako Makgatho Health Sciences Uni versity has received many requests from concerned parents to explain the validity of anti-vaccination claims found on the internet. These claims originated mainly from the USA, and previous global studies on internet-based anti-vaccination lobbying[7-12] had not identified any anti-vaccination web pages originating in SA. This seemed to suggest that while some SA parents are concerned about vaccination, this concern had not resulted in the creation of websites for local anti-vaccination lobbying. The aim of this study was therefore to characterise SA internet-based anti-vaccination lobbying.

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Methods

During 2010, a pilot study identified search terms most likely to find SA anti-vaccination sentiment; these search terms were used for the first study in April 2011. Three search engines were used (Google, Yahoo and MSN-Bing), with searches limited to Englishlanguage (of the 11 official languages, this is the ‘language of science’ in SA,[7] and all the researchers were proficient in English, with one being proficient in some of the other ten languages) SA web pages, and results with content referring to childhood vaccination being analysed for anti-vaccination sentiment. Web pages with medical advice about contraindications for specific vaccines were excluded. Duplicate web pages were discarded, and the remaining web pages were categorised as articles, blogs/forums or online shopping sites (e-shops). Detailed content analysis (anti-vaccination claims, author’s profession, advertising content, country of origin of claim) was performed independently by two researchers, with consensus being reached for any discrepant findings. Data were captured in Microsoft Excel 2010 (Microsoft Office, USA) and imported into Epi Info version 3.5.3 (Centers for Disease Control and Prevention, USA) for quantitative analysis. In December 2012 and October 2013, the search was repeated using Google and the search term ‘do not vaccinate’, limited to English-language SA web pages. The exact phrase ‘do not vaccinate’ (identified in 2011 as returning the most hits) was tried as a search term in 2012, but fewer than 300 web pages were found, with very few being anti-vaccination. Google’s ‘advanced search’ (discontinued during 2014) allowed for searches to include all words in a search string, and this identified a far greater number of anti-vaccination web pages. The later searches were therefore limited

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to web pages containing all words. The first 700 web pages of results were analysed independently by two researchers, with a third resolving any discrepant findings, and analyses were performed as in 2011. Web pages identified in 2011 and 2012 that were not among the first 700 hits in October 2013 and were still active were added to those found in October 2013 for the final analysis.

Results

Anti-vaccination internet profile in April 2011

The search terms identified by the pilot study (Table 1) found 238 web pages. Of these, 11.8% (28/238) contained anti-vaccination sentiment related to childhood vaccines. After discarding duplicates, 15 web pages remained for detailed content analysis. Of these, Google found 80.0% (12/15) (Yahoo found 5 of these, 2 of which MSN-Bing also found; 7 were found by Google only), while Yahoo found 3 that were not found by Google or MSN-Bing. Blogs/forums, articles and e-shops const ituted 40.0% (6/15), 46.7% (7/15) and 13.3% (2/15) of web pages, respectively. Of the blogs/ forums and articles, 50.0% (3/6) and 14.3% (1/7), respectively, advertised products/ services provided by the author/sponsor promoting anti-vaccination claims, bringing the proportion of commercial web pages to 42.9% (6/15). Advertisements promoted natural health products (16.7%, 1/6), a book about the dangers of mercury-containing dental fillings and a dental practice where mercury-containing fillings could be safely removed and replaced (16.7%, 1/6) (antivaccination content on these web pages were related to the anti-vaccination claim that thimerosal, a mercury-based preservative used in multidose vaccines, results in idiopathic illnesses including autism), and products unrelated to anti-vaccination claims (66.7%, 4/6). Lay people constituted 66.7% (10/15) of the authors (7 parents, 2 journalists and 1 natural health product salesperson), 20.0% (3/15) were complementary/alterna tive medicine (CAM) professionals (an acupuncturist, a homeopath and an osteopath), and 13.3% (2/15) were medical professionals (a dentist and a doctor). Antivaccination claims included that vaccines are not safe (93.3%, 14/15), that the risk of adverse events following immunisation (AEFIs) is higher than the risk of the disease (73.3%, 11/15), that vaccination poses ethical/religious concerns (40.0%, 6/15), that vaccines are ineffective (33.3%, 5/15), that those promoting vaccination have financial motives (33.3%, 5/15), and that

vaccines were not responsible for the decline of infectious diseases (26.7%, 4/15). The majority (80.0%, 12/15) of the claims had links to web pages originating from the USA.

Anti-vaccination internet profile in December 2012

Of the first 700 web pages found using the term ‘do not vaccinate’, 37 contained antivaccination sentiment related to childhood vaccines. Blogs/forums, articles and e-shops constituted 40.5% (15/37), 54.1% (20/37) and 5.4% (2/37) of the web pages, respectively. Of the blogs/forums and articles, 33.3% (5/15) and 60.0% (12/20), respectively, advertised products or services provided by the author/ sponsor promoting anti-vaccination claims, bringing the proportion of commercial web pages to 51.4% (19/37). Advertisements promoted natural health products (63.2%, 12/19), products unrelated to anti-vaccination claims (21.1%, 4/19), a dental practice where mercury-containing fillings are ‘safely’ removed and replaced (5.3%, 1/19), chelation products claiming to cure ‘mercury toxicity’ (5.3%, 1/19), and a course on integrative

medicine and a compact disc (CD) on the spiritual aspects of medicine (5.3%, 1/19). Table 1. List of search terms used for the 2011 study Search terms (limited to the exact phrases) Do not immunise Do not immunize Do not vaccinate Don’t immunise Don’t immunize Don’t vaccinate Immunisation is harmful Not immunising Not immunizing Reasons for not vaccinating Should not vaccinate Vaccination is harmful Vaccine injured Vaccine scare Vaccines are toxic

Table 2. Occupations of authors (N=52) and advertising Author category

n (%)

Adverts present* n (%)

Lay people†

33 (63.5)

18 (54.5)

Parent‡

24 (72.7)

11 (45.8)

Journalist

4 (12.1)

2 (50.0)

Attorney§

2 (6.1)

2 (100.0)

Business person

2 (6.1)

2 (100.0)

‘Traditional Council’¶

1 (3.0)

1 (100.0)

CAM professionals

12 (23.1)

10 (83.3)

Homeopath

3 (25.0)

2 (66.7)

Naturopath

5 (41.7)

5 (100.0)

Nutrition expert

2 (16.7)

2 (100.0)

Craniosacral therapist

1 (8.3)

Osteopath

1 (8.3)

1 (100.0)

4 (7.7)

2 (50.0)

Medical doctor (unspecified) practising homeopathy

2 (50.0)

1 (50.0)

General medical practitioner practising homeopathy

1 (25.0)

1 (100.0)

Medical doctor (unspecified) practising chiropracty

1 (25.0)

3 (5.8)

Medical doctor (unspecified)

1 (33.3)

Gastroenterologist

1 (33.3)

Nurse

1 (33.3)

Medical professionals practising CAM

Medical professionals

*There were 37 web pages with advertising, but for 7 of these the authors could not be identified. † For the purposes of this study the term ‘lay’ refers to people who have not qualified as either medical (i.e. allopathic medicine) or CAM practitioners. ‡ Parents who were also alternative medicine (1) or medical (1) professionals are not included here. § The same attorney wrote for both websites which were advertising the same dental practice. This dental practice advertised the safe removal of dental fillings. ¶ The KwaNgcolosi Traditional Council is a group of farmers/producers of Umlingo WamaNgcolosi, a juice that is claimed to cure all diseases, including AIDS, although the group deny the existence of HIV/AIDS.

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Of the authors who could be identified, 67.9% (19/28) were lay people (12 parents, 3 journalists, 2 natural health product salespeople, an attorney and a ‘Traditional Council’), 21.4% (6/28) were CAM practitioners (2 homeopaths, a homeopath practising as a natural birth expert, a craniosacral therapist, an osteopath and a nutrition expert), 7.1% (2/28) were medical doctors practising CAM (a chiropractor and a homeopath), and 3.6% (1/28) was a medical doctor practising only allopathic medicine. Anti-vaccination claims were made about vaccine safety (97.3%, 36/37), the risk of AEFIs (83.8%, 31/37), vaccine effectiveness (70.3%, 26/37), profit motives (48.6%, 18/37), the decline of infectious diseases (45.9%, 17/37), and ethical/religious concerns (37.8%, 14/37). The claims had links to web pages originating from the USA (81.1%, 30/37), the UK (10.8%, 4/37) and India (2.7%, 1/37).

Anti-vaccination internet profile in October 2013

Of the first 700 web pages found using the term ‘do not vaccinate’, 45 were identified as containing anti-vaccination sentiment related to childhood vaccines. Blogs/forums, articles and e-shops constituted 33.3% (15/45), 64.4% (29/45) and 2.2% (1/45) of the webpages, respectively. Of the blogs/ forums and articles, 26.7% (4/15) and 62.1% (18/29), respectively, advertised products or services provided by the author/sponsor promoting anti-vaccination claims, bringing the proportion of commercial web pages to 51.1% (23/45). Advertisements promoted natural health products (65.2%, 15/23), products unrelated to anti-vaccination claims (13.0%, 3/23), dental practices where mercury-containing fillings are ‘safely’ removed and replaced (8.7%, 2/23), books about anti-vaccination (8.7%, 2/23), and professional services related to autism (4.3%, 1/23). Of the authors who could be identified, 55.6% (20/36) were lay people (15 parents, 2 journalists, 2 attorneys and ‘Traditional Council’), 27.8% (10/36) were CAM practitioners (5 naturopaths, 2 nutrition experts, a homeopath, a homeopath practising as a natural birth expert and a craniosacral therapist), 8.3% (3/36) were medical doctors practising CAM (2 homeopaths and a chiropractor), and 8.3% (3/36) were medical professionals (a doctor (unspecified), a nurse and a gastroenterologist). Anti-vaccination claims were made about vaccine safety (93.3%, 42/45), the risk of AEFIs (71.1%, 32/45), vaccine effectiveness (66.7%, 30/45), the decline of infectious diseases (51.1%,

Table 3. Products/services advertised on web pages* (N=37) and authors of antivaccination content Product/service

n (%)

Authors of anti-vaccination content

Natural immune boosters

22 (59.5)

7 unidentified, 5 naturopaths, 2 salespersons, 2 nutrition experts, 2 mothers, 1 each homeopath, osteopath, ‘Traditional Council’, journalist

Unrelated to anti-vaccination

8 (21.6)

7 mothers, 1 journalist

Anti-vaccination books

2 (5.4)

Parents

Dental filling replacement

2 (5.4)

The same attorney wrote content on two different websites

Chelation products

1 (2.7)

Homeopath

Course and CD†

1 (2.7)

Medical doctor practising as a homeopath

Autism treatment

1 (2.7)

General medical practitioner practising as a homeopath

*Adverts in parenting forums and newspapers were excluded from this analysis. † Course on integrative medicine, CD on the spiritual aspect of medicine.

Table 4. Frequency of anti-vaccination claims on 67 SA web pages Anti-vaccination claim

n (%)

Vaccines are not safe

62 (92.5)

Risk of AEFIs greater than risk of disease

49 (73.1)

Vaccines are ineffective

44 (65.7)

Vaccines not responsible for decline in diseases

32 (47.8)

Vaccination poses ethical or religious concerns

29 (43.3)

Vaccination is profit driven

27 (40.3)

23/45), ethical/religious concerns (46.7%, 21/45), and profit motives (35.6%, 16/45). The claims had links to web pages originating from the USA (73.3%, 33/45), the UK (11.1%, 5/45) and India (2.2%, 1/45).

Final analysis

Twenty-two web pages identified in 2011 and 2012 were not among the first 700 hits in October 2013 but were still active, giving a total of 67 web pages for the final analysis. Blogs/forums, articles and e-shops constituted 40.3% (27/67), 55.2% (37/67) and 4.5% (3/67) of the web pages, respectively. The occupation of 77.6% (52/67) of the authors could be identified (Table 2). Advertisements for products/ services provided by the author/sponsor promoting anti-vaccination claims were found on 55.2% (37/67) of the web pages (Table 3). Of these, 67.6% (25/37) were sponsored by or linked to organisations with financial interests in discrediting vaccines (selling products/services to build the immune system naturally (88.0%) and to remove metals (12.0%)), with 80.0% (20/25) and 24.0% (6/25) of web pages sponsored by these organisations claiming respectively that vaccines are ineffective and vaccination is profit driven. Of all

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Table 5. Countries of origin of antivaccination claims (N=67) Country

n (%)

USA only

48 (71.6)

UK only

1 (1.5)

USA and UK

4 (6.0)

India

2 (3.0)

South Africa*

12 (17.9)

*No links to source provided.

commercial web pages, 32.4% (12/37) claimed that vaccination is profit driven. The vast majority of web pages claimed that vaccines are not safe (Table 4), with the majority of anti-vaccination claims originating from the USA (Table 5).

Discussion

The profit motive behind antivaccination lobbying

This study investigated anti-vaccination lobbying on SA web pages over 3 years. During piloting many anti-vaccination web pages contained advertisements for so-called natural alternatives to vaccines, or to treat the so-called ‘vaccine-injured’ child. Professions of authors, whether they or their

RESEARCH

sponsors advertised products/services, and web page type used as the platform for anti-vaccination lobbying, were therefore investigated. Website articles and blogs/forums constituted the two largest platforms throughout the 3 years, while e-shops constituted the smallest platform. However, the proportion of commercial web pages increased every year, making up 55.2% in the final analysis. More importantly, 67.6% of commercial web pages were sponsored by organisations with financial interests in discrediting vaccines. Ironically, 80.0% of these web pages claimed that vaccines are ineffective, while selling products/services with no evidence of preventing vaccine-preventable diseases or curing the ‘harms caused by vaccines’. Another irony is that 24.0% claimed that vaccination is profit driven, while their sponsors work in an industry that in 2009 had a global retail market worth EUR 45 - 50 billion (USD 61 - 68 billion),[13] compared with the global vaccine market, which was worth only USD 24 billion in 2013.[14] Lay people (mostly parents) constituted the largest proportion of authors, with just over half of their web pages containing advertisements. CAM practitioners were the next largest group, with over 80% of their web pages in the final analysis being commercial. Medical practitioners were the smallest group, with the web pages of those practising only allopathic medicine containing no advertisements, while half the web pages of medical doctors practising CAM contained advertising. Overall, CAM practitioners therefore advertised products/services more frequently than other groups. Previous studies have reported on products being sold by those engaging in internet-based anti-vaccination lobbying, with 44% containing advertising,[15] between 33%[11] and 40%[9] selling antivaccination books, tapes and CDs, and between 13%[12] and 16%[11] selling natural products. While these figures are lower than those reported here, this does not imply that SA anti-vaccination lobbyists are profiting more from discrediting vaccines than those in other countries. No internet-based study can possibly identify all web pages containing anti-vaccination sentiment, and none of these studies attempted to do so. A probable explanation for commercial web pages being so well represented in all studies is that codes written in html (called meta tags, which are not visible in the web page text) are added to more sophisticated web pages to ensure that they are among the first ‘hits’ when searching using specific terms corresponding with the meta tags.[16] Those who make a living out of selling products/services clearly benefit from increased visibility, and would be more likely to use meta tags than those who are not selling products/services. Also, anti-vaccination lobbying in countries such as the USA is very well orchestrated by a number of sophisticated organisations with websites that often appear official and authoritative.[10,12,15] Because of their apparent credibility, links to these websites abound on anti-vaccination web pages from all around the globe, and the more incoming links to a website, the higher this website is ranked when searching with Google.[16] This phenomenon together with the use of meta tagging is probably the reason behind why these websites appear so frequently in global studies. Anti-vaccination organisations of this type do not seem to exist in SA, so it follows that commercial anti-vaccination web pages have a greater opportunity to rise to the top of the list of web pages found when searches are limited to SA web pages.

Anti-vaccination claims and origins

The original impetus for doing this study was that a number of SA parents had become concerned about vaccinating their children after reading anti-vaccination claims on the internet. At that time

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nothing was known about anti-vaccination lobbying on SA web pages, and most of the original claims brought to SAVIC originated from the USA. This study found that this is still the case, with most anti-vaccination claims in the final analysis originating from the USA, and not differing substantially from other global studies. For example, the finding in each year of the study that more than 90% of anti-vaccination web pages claimed that vaccines are not safe concurs with the 91 - 100% reported globally,[8-12] with a more recent study reporting 80%.[15] Similarly, the finding that over 70% of anti-vaccination web pages in all years claimed that the risk of AEFIs is high is supported by the 76 - 100% reported globally.[8-12,15] Interestingly, the claim that vaccines are ineffective was found on 33.3% of the 2011 SA web pages, and this finding is supported by the 32% found in a 2010 global study.[15] However, by 2012 this had risen to 70%, and in the final analysis 65.7% of SA anti-vaccination web pages made this claim, which is closer to earlier global reports of 79 83%.[9-11] This gives support to the notion that SA anti-vaccination lobbyists are still in the process of catching up with global trends,[2] and in future we may see this claim occurring more frequently. Other claims made on SA anti-vaccination web pages that did not appear as frequently as reported globally include that vaccination is profit driven (40.3% v. 52 - 91% globally[9,10,12,15]) and poses ethical/ religious concerns (43.3% v. 70 - 79% globally,[9-12] with one study reporting 44%[15]). A possible explanation for the profit-motive claim being less frequent on SA web pages may be that so many of the anti-vaccination authors were themselves motivated by profit. While the irony of claiming that vaccination is profit driven while profiting from selling alternative products has already been pointed out, only 24% of those benefiting financially from discrediting vaccines made this claim. It is therefore possible that the other 76% recognised the hypocrisy of making this claim, and therefore avoided doing so. The lower frequency of ethical/religious concerns on SA web pages is perhaps easier to explain, since in SA vaccination is not mandatory, while in the USA it is. Violation of civil liberties is therefore irrelevant for South Africans who choose to not have their children vaccinated.

Study limitations

The 2011 study was limited by specific search terms identified in a pilot study as most likely to find anti-vaccination sentiment, and found that 11.8% of identified web pages had anti-vaccination content. In contrast, the 2012 and 2013 studies used a broader search term identifying greater numbers of web pages, the totals of which were not recorded, the first 700 web pages being analysed each year. However, the same search conducted in July 2014 found 7 990 results, so these two samples conceivably represent about 10% of all web pages found each year. Because of the differing search terms, the 2011 findings may not be a valid baseline for those from 2012 and 2013. Also, because only the top 700 web pages were analysed, the 2012 and 2013 samples are not representative of antivaccination lobbying on the SA internet. However, this was not the intention of this study, which focused on the profile of those who are so interested in discrediting vaccines that they spend time and money on creating websites or blogs to do so. Finally, the study was limited to English-language web pages. There may therefore be SA anti-vaccination web pages in any of the other ten official languages, which may express different anti-vaccination concerns from those reported here. However, in September 2014 searches on words for vaccinate (or words used for vaccinate in languages with no word for vaccinate) found no relevant web pages. These words included ukugoma (isiZulu), kugoma (SiSwati), go thlabela (Sepedi), ukugonya/ ukutofa (isiXhosa), inent (Afrikaans), ho kgahla/ho enta (Sesotho) and go enta (Setswana).

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Conclusions

References

The latest SA census (October 2011) found that 35.2% of inhabitants have access to the internet,[17] a substantial increase from the 15% reported in 2007.[18] In the USA, where 81% of adults use the internet, 72% of internet users search for health information online.[19] Of these, 77% start their search using a search engine (Google, Yahoo or Bing), 13% use a health information specialist website such as WebMD, 2% use a general site such as Wikipedia, and only 1% use social media such as Facebook. [19] Web pages sourced through search engines are therefore an important source of health information for most internet users in the USA. There are no data from SA on online health information-seeking behaviour. However, this study found that some South Africans have created web pages for local anti-vaccination lobbying, with many having financial interests in discrediting vaccines, and that they have taken their misinformation from web pages largely originating in the USA. Many of these anti-vaccination lobbyists are parents, so it is possible that a growing number of young SA parents are using a search engine such as Google to find information about vaccination, and are encountering misinformation instead. Now that the existence of SA internet-based anti-vaccination lobbying has been established, research is needed to understand what influence this has on the uptake of infant vaccination in SA. Acknowledgements. The authors thank E A Tshatsinde and N G Burnett for validating the data. Conflicts of interest. The salaries of SAVIC staff are funded by the Sefako Makgatho Health Sciences University. SAVIC also receives unrestricted educational grants from the vaccine industry for community projects.

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1. South African Department of Health. Expanded Programme on Immunisation – EPI (SA) Revised Childhood Immunisation Schedule from April 2009. http://www.kznhealth.gov.za/vaccinations.pdf (accessed 26 March 2015). 2. Burnett RJ, Larson HJ, Moloi MH, et al. Addressing public questioning and concerns about vaccination in South Africa: A guide for healthcare workers. Vaccine 2012;30(Suppl 3):C72-C78. [http://dx.doi. org/10.1016/j.vaccine.2012.03.037] 3. Wiysonge CS, Ngcobo NJ, Jeena PM, et al. Advances in childhood immunisation in South Africa: Where to now? Programme managers’ views and evidence from systematic reviews. BMC Public Health 2012;12:578. [http://dx.doi.org/10.1186/1471-2458-12-578] 4. Corrigall J, Coetzee D, Cameron N. Is the Western Cape at risk of an outbreak of preventable childhood diseases? Lessons from an evaluation of routine immunisation coverage. S Afr Med J 2008;98(1):41-45. 5. Le Roux DM, le Roux SM, Nuttall JJ, Eley BS. South African measles outbreak 2009 - 2010 as experienced by a paediatric hospital. S Afr Med J 2012;102(9):760-764. [PMID: 22958701]. 6. Siegfried N, Wiysonge CS, Pienaar D. Too little, too late: Measles epidemic in South Africa. Lancet 2010;376(9736):160. [http://dx.doi.org/10.1016/S0140-6736(10)61100-2] 7. Webb P. Science education and literacy: Imperatives for the developed and developing world. Science 2010;328(5977):448-450. [http://dx.doi.org/10.1126/science.1182596] 8. Nasir L. Reconnoitering the antivaccination web sites: News from the front. J Fam Pract 2000;49(8):731-733. 9. Wolfe RM, Sharp LK, Lipsky MS. Content and design attributes of antivaccination web sites. JAMA 2002;287(24):3245-3248. 10. Davies P, Chapman S, Leask J. Antivaccination activists on the World Wide Web. Arch Dis Child 2002;87(1):22-25. 11. Zimmerman RK, Wolfe RM, Fox DE, et al. Vaccine criticism on the World Wide Web. J Med Internet Res 2005;7(2):e17. 12. Kata A. A postmodern Pandora’s box: Anti-vaccination misinformation on the Internet. Vaccine 2010;28(7):1709-1716. [http://dx.doi.org/10.1016/j.vaccine.2009.12.022] 13. Brookes G. Economic Impact Assessment of the European Union (EU)’s Nutrition & Health Claims Regulation on the EU food supplement sector and market. 2010. http://www.pgeconomics.co.uk/pdf/ Impact-Assessment-health-claims.pdf (accessed 26 March 2015). 14. World Health Organization. Prequalification to make high-quality, safe and affordable vaccines. 2013. http://www.who.int/features/2013/vaccine_prequalification/en/ (accessed 26 March 2015). 15. Bean SJ. Emerging and continuing trends in vaccine opposition website content. Vaccine 2011;29(10):1874-1880. [http://dx.doi.org/10.1016/j.vaccine.2011.01.003] 16. Wolfe RM, Sharp LK. Vaccination or immunization? The impact of search terms on the internet. J Health Commun 2005;10(6):537-551. 17. Statistics South Africa. Census 2011. https://www.statssa.gov.za/Census2011/Products/Census_2011_ Key_results.pdf (accessed 26 March 2015). 18. Gillwald A, Moyo M, Stork C. Understanding what is happening in ICT in South Africa. Evidence for ICT Policy Action. Policy Paper 7, 2012. http://www.researchictafrica.net/docs/Policy%20Paper%20 7%20-%20Understanding%20what%20is%20happening%20in%20ICT%20in%20South%20Africa. pdf (accessed 26 March 2015). 19. Pew Research Center’s Internet & American Life Project. Health Online 2013. http://www.pewinternet. org/files/old-media//Files/Reports/PIP_HealthOnline.pdf (accessed 26 March 2015).

Accepted 4 August 2015.

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Age of diagnosis of congenital hearing loss: Private v. public healthcare sector I R T Butler,1 MB ChB, MMed (ORL); D Ceronio,2 BLog; T Swart,2 MCommPath (SLP & Aud); G Joubert,3 BA, MSc epartment of Otorhinolaryngology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa D Audiologist in private practice, Bloemfontein, South Africa 3 Department of Biostatistics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 1 2

Corresponding author: I Butler (butlerirt@ufs.ac.za)

Background. The age of diagnosis of congenital hearing loss is one of the most important determinants of communication outcome. A previous study by the lead author had evaluated the performance of the public health services in Bloemfontein, South Africa (SA), in this regard. This study aimed to examine whether the private health services in the same city were any better. Objective. To determine whether the age of diagnosis of congenital hearing loss (CHL) in children seen in the private healthcare sector in Bloemfontein, Free State Province, SA, was lower than that in the public healthcare system in the same city. Methods. A comparative study design was utilised and a retrospective database review conducted. Data obtained from this study in the private healthcare sector were compared with data from a previous study in the public healthcare sector using the same study design. Results. Forty-eight children aged <6 years with disabling hearing impairment (DHI) were identified in the private healthcare sector during the study period; 33/47 (70.2%) did not undergo hearing screening at birth. The median age of diagnosis of DHI in the private healthcare sector was 2.24 years, and this was statistically significantly lower than the median age of diagnosis of 3.71 years in the public healthcare sector (p<0.0001; 95% confidence interval (CI) 0.99 - 2.0). The median age of diagnosis of CHL in the private healthcare sector was 3.01 years in children who were not screened at birth, and 1.25 years in those who were screened at birth. This difference was statistically significant (p<0.01; 95% CI 0.72 - 2.47). We also compared the median age of diagnosis of CHL in children from the private healthcare sector who were not screened at birth (median 3.01 years) with that in children in the public healthcare sector (median 3.71 years). This difference was statistically significant (p<0.01; 95% CI 0.41 - 1.56). Conclusions. Children in the Free State are diagnosed with CHL at a younger age in the private healthcare sector than in the public healthcare sector. With the social and economic benefits of early intervention in cases of DHI well established internationally, SA healthcare providers in both the public and private sectors need to develop screening, diagnostic and (re)habilitation services for children with hearing impairment. S Afr Med J 2015;105(11):927-929. DOI:10.7196/SAMJ.2015.v105i11.9576

A recent study by Butler et al.[1] found that the median age of diagnosis of congenital hearing loss (CHL) in a public sector tertiary referral hospital was 3.71 years. This is in sharp contrast to the Health Professions Council of South Africa (HPCSA) recommendation[2] that diagnosis of hearing loss be achieved by 4 months of age (for clinic-based hearing screening programmes) and the international standard recommendation of 3 months of age (for hospital-based hearing screening programmes). One of the main reasons identified for this late age of diagnosis was the lack of newborn hearing screening programmes in the public health sector in South Africa (SA). Universal newborn hearing screening (UNHS) is now a wellestablished practice in developed countries[2] and has resulted in a significant lowering of the age of diagnosis of CHL, with consequent earlier intervention in managing the hearing impairment. The benefits of early intervention in cases of CHL are well established and include normalisation of communication skills and reduction of learning difficulties, cognitive developmental delays and the behavioural and emotional issues associated with untreated CHL.[3-11] It has been estimated that 90% of SA children have no access to hearing screening services.[5] This is mainly because UNHS is virtually non-existent in the public health service, which covers approximately 85% of the SA population; only 7.5% of public hospitals with birthing

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units provide some sort of hearing screening.[12] Where hearing screening is available in the public sector, it is usually selectively applied to high-risk infants (such as those in neonatal intensive care units) or achieves screening in only a small percentage of the target population. The situation in the private healthcare sector is only marginally better. A 2011 publication found that only 53% of private hospitals offered some form of newborn hearing screening, and only 15% offered UNHS. UNHS is not covered by medical aid schemes as part of the â&#x20AC;&#x2DC;birthing packageâ&#x20AC;&#x2122;. As a result, hearing screening in the private healthcare setting represents an additional financial cost to parents, which many are unwilling to bear in view of their perceived low risk of CHL.[12] Newborn hearing screening has been offered at the two major private hospitals in Bloemfontein, Free State Province, SA, since 2007. It is performed by audiologists from a single audiology practice and includes diagnostic tests on those children who do not pass the screening test. This provides an excellent opportunity to determine the age of diagnosis of CHL in the private healthcare setting and to compare this with the situation in the public healthcare setting.

Objectives

The primary aim of our study was to determine whether the age of diagnosis of CHL in children seen in the Deon Ceronio audiology practice in Bloemfontein (private healthcare sector) was lower than

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that in the public healthcare system in the same city. The hypothesis was that the age of diagnosis of CHL in the private healthcare setting would prove to be significantly lower than in the public healthcare setting. Our secondary aims were to determine the age of first visit to the practice, and the time delay between first visit and diagnosis of hearing loss; to determine how many children underwent newborn hearing screening and what the influence of hearing screening was on the age of diagnosis of CHL; and to document any subsequent interventions.

Methods

A comparative study design was utilised and a retrospective database review conducted. Ethical approval was granted by the Ethics Committee of the Faculty of Health Sciences of the University of the Free State (ECUFS 140/2014), and written permission was obtained from the Deon Ceronio audiology practice to access the database. Data were compared with those generated from our previous study in the state healthcare sector, published in 2013.[1] The inclusion criteria were as follows: • Diagnosis of disabling hearing impairment (DHI) using the World Health Organization definition of DHI in children aged <15 years, i.e. pure-tone average in the better-hearing ear <30 dB • Children aged <6 years at time of diagnosis • Diagnosis during the period 1 January 2004 - 31 December 2013 • No history or findings on examination consistent with an acquired form of hearing loss. Data were analysed and results summarised by frequencies and percentages (categorical variables) and means, standard deviations or percentiles (numerical variables). The private and public sector results were compared using 95% confidence intervals (CIs) for differences in means, medians or percentages.

Results

In the private sector, records were available for diagnostic hearing tests on 179 children aged <6 years at the time of testing during the 10-year study period. Forty-eight children fulfilled the inclusion criteria of suffering from DHI. Twenty-six (54.2%) were female and 22 (45.8%) male. All had been referred to the practice with the suspicion of bilateral hearing loss. Data pertaining to hearing screening at birth were available for 47 children. Thirty-three (70.2%) of these 47 children did not undergo hearing screening at birth. When the data were analysed (Table 1) our original hypothesis was proved correct, with a statistically significantly lower age of diagnosis of CHL in the private sector than in the public sector (p<0.0001, 95% CI 0.99 - 2.0). The data from the private healthcare sector were further analysed according to different time periods (Table 2). This was performed in order to evaluate the influence of a newborn hearing screening programme (NHSP) on the age of diagnosis of CHL. The audiology practice initiated an NHSP in 2007 at both private hospitals in Bloemfontein. However, UNHS in these facilities was only widely accepted in 2009. The period 2004 - 2008 (‘pre-screening’) was compared with the period 2009 - 2013 (‘post-screening’). The difference in age of diagnosis was not found to be statistically significant (p=0.399, 95% CI –0.56 - 1.28). This appears to be due to the small number of cases in each of the periods. The median age of diagnosis of CHL in the private healthcare sector was found to be 3.01 years in children who were not screened

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at birth, and 1.25 years in those children who were screened at birth (Table 3). This difference was statistically significant (p<0.01; 95% CI 0.72 - 2.47). We also compared the median age of diagnosis of CHL in children from the private healthcare sector who were not screened at birth (median 3.01 years) with that in children in the public healthcare sector (median 3.71 years). This difference was statistically significant (p<0.01; 95% CI 0.41 - 1.56). The median age at first visit to the audiological practice was 2.13 years. The time delay between the first visit to the audiological practice and the diagnosis of CHL was a median of 13 days. In terms of interventions, 15 children (31.3%) eventually received cochlear implants and 21 (43.8%) received conventional hearing aids with auditory-verbal/auditory-oral speech and language therapy. Ten children (20.8%) received hearing aids but followed a total communication rehabilitation framework, and two (4.2%) were referred for sign language-based rehabilitation.

Discussion

Many articles on hearing screening in SA have been published. [1,2,5,7,12] All have dealt with the complexities of establishing NHSPs in our dichotomous healthcare system, and have emphasised the importance of early identification and intervention in cases of CHL. To the best of our knowledge, this is the first SA study that has demonstrated a significant reduction in the age of diagnosis of CHL following implementation of an NHSP. The data (Table 3) showed a statistically significant difference in the age of diagnosis of DHI in children who underwent hearing screening at birth compared with children who did not. While the numbers were too small to demonstrate a statistical difference in the age of diagnosis when comparing the ‘pre-screening period’ (2004 - 2008) with the ‘postscreening period’ (2009 - 2013), the trend was clear, with median ages of 2.48 years and 1.57 years for each period, respectively. While the age of diagnosis of CHL in children in the public sector (3.71 years) appeared comparable to that in children in the private sector who had not undergone hearing screening (3.01 years), this difference was statistically significant. This suggests that the implementation of UNHS is not the only factor determining the age of diagnosis of DHI in our population. Access to screening and Table 1. Median age of diagnosis of CHL in the public and private healthcare sectors Sector

Median age at diagnosis, years

Public (n=260)

3.71

Private (n=48)

2.24

Table 2. Median age of diagnosis of CHL when analysed according to time periods Period

Children identified with DHI, n

Median age at diagnosis, years

2004 - 2008

2.48

2009 - 2013

1.57

Table 3. Effect of newborn hearing screening in the private sector Screened at birth? (private)

Median age at diagnosis, years

3.01

Yes

1.25

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diagnostic audiology services once there is parental suspicion of hearing loss is of paramount importance, and delays in performance of the appropriate diagnostic testing are identified as being of great significance. The median delay between the first visit to the audiology practice and the diagnosis of CHL in this study was 13 days. We did not compare this with the median delay between the first visit to the ENT clinic and the age of diagnosis in our study in the public sector (49 days),[1] as our intention when examining this variable in the previous study had been to determine whether delays in our own hospital were responsible for the late age of diagnosis. However, since many of the children identified in the current study were referred by other audiologists for confirmation of the DHI, use of the ‘age at first visit to the audiology practice’ to calculate the delay to DHI was imprecise. In terms of the interventions that took place, only two children (4.2%) in the current study were referred for sign language-based intervention, while in the public sector 46 (26%) children followed this path. This is a significant difference and confirms our contention that children are being identified too late in the public sector for spoken language-based interventions (hearing aids or cochlear implants). Fifteen children (31.3%) in the current study received cochlear implants as part of their intervention. National guidelines for early detection of hearing loss were published by the HPCSA in 2007.[2] These guidelines proposed that CHL be diagnosed by 4 months of age, and that appropriate interventions be implemented by 8 months of age at the maximum. While the median age of diagnosis in the private healthcare sector (2.24 years) was found to be statistically significantly lower than the age of diagnosis in the public healthcare sector (3.71 years), this falls well short of the national guideline of 4 months. The implementation of the NHSP in the private healthcare sector resulted in a reduction of the age of DHI from 2.48 years to 1.57 years. However, 70.2% of the children with DHI in the current study did not undergo newborn hearing screening. The major reasons for the low percentage of screened infants are the novelty of the screening service during the early part of the study period, and the fact that the cost of this service is not covered by the ‘birthing package’ of the hospital and represents an additional cost that parents are unwilling to accept. More work needs to be done in sensitising parents to the importance of UNHS and advocating that medical aid schemes cover this cost. This study has provided scientific evidence that newborn hearing screening is essential to lower the age of diagnosis of CHL and facilitate early intervention, the benefits of which have been shown

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internationally.[6,8-11,13] Children who are identified and managed appropriately are likely to be able to join the mainstream school system. It is hoped that health administrators in the private and public sectors, medical insurance companies and practitioners will respond to this evidence. This is particularly important in our local context, given the dearth of schools that cater for children with hearing impairments.

Conclusion

This is the first SA study to demonstrate that implementation of UNHS reduces the age of diagnosis of CHL. There is a need to advocate for greater support from SA healthcare providers (both public and private) regarding development of screening, diagnostic and (re)habilitation services for children who are born with, or develop, hearing impairments. References 1. Butler I, Basson S, Britz E, et al. Age of diagnosis of congenital hearing loss at Universitas Hospital, Bloemfontein. S Afr Med J 2013;103(7):474-475. [http://dx.doi.org/10.7196/SAMJ.6395] 2. Professional Board for Speech, Language and Hearing Professions, Health Professions Council of South Africa. Early Hearing Detection and Intervention Programmes in South Africa: Position Statement. Pretoria: HPCSA, 2007. www.hpcsa.co.za/Uploads/.../early_hearing_detection_statement. pdf (accessed 6 February 2012). 3. World Health Organization. Report of the Informal Working Group on Prevention of Deafness and Hearing Impairment Programme Planning. Geneva: WHO, 1991 (with adaptations from the Report of the First Informal Consultation on Future Programme Developments for the Prevention of Deafness and Hearing Impairment, WHO, Geneva, 23-24 January 1997, WHO/PDH/97.3). 4. Olusanya B. Highlights of the new WHO report on newborn and infant hearing screening and implications for developing countries. Int J Pediatr Otorhinolaryngol 2011;75(6):745-748. [http:// dx.doi.org/10.1016/j.ijporl.2011.01.036] 5. Swanepoel D, Storbeck C, Friedland P. Early hearing detection and intervention in South Africa. Int J Pediatr Otorhinolaryngol 2009;73(6):783-786. [http://dx.doi.org/10.1016/j.ijporl.2009.01.007] 6. Yoshinaga-Itano C, Coulter D, Thomson V. Developmental outcomes of children with hearing loss born in Colorado hospitals with and without universal newborn hearing screening programs. Semin Neonatol 2001;6(6):521-529. [http://dx.doi.org/10.1053/siny.2001.0075] 7. Swanepoel D, Almec N. Maternal views on infant hearing loss and early intervention in a South African community. Int J Audiol 2008;47(Suppl. 1):S44-S48. [http://dx.doi.org/10.1080/14992020802252279] 8. Niparko J, Tobey E, Thal D, et al. Spoken language development in children following cochlear implantation. JAMA 2010;303(15):1498-1506. [http://dx.doi.org/10.1001/jama.2010.451] 9. Moog J, Geers A. Early educational placement and later language outcomes for children with cochlear implants. Otol Neurotol 2010;31(8):1315-1319. [http://dx.doi.org/10.1097/MAO.0b013e3181eb3226] 10. Geers A, Moog J, Biedenstein J, et al. Spoken language scores of children using cochlear implants compared to hearing age-mates at school entry. J Deaf Stud Deaf Educ 2009;14(3):371-385. [http:// dx.doi.org/10.1093/deafed/enn046] 11. Govaerts P, de Beukelaer C, Daemers K, et al. Outcome of cochlear implantation at different ages from 0 to 6 years. Otol Neurotol 2002;23(6):885-890. [http://dx.doi.org/10.1097/00129492-20021100000013] 12. Meyer M, Swanepoel D. Newborn hearing screening in the private healthcare sector: A national study. S Afr Med J 2011;101(9):665-667. 13. Colletti L, Mandala M, Shannon R, et al. Estimated net saving to society from cochlear implantation in infants: A preliminary analysis. Laryngoscope 2011;121(11):2455-2460. [http://dx.doi.org/10.1002/ lary.22131]

Accepted 5 October 2015.

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Evaluation of fetal MRI in a South African referral centre A Daire,1 MBBS, MMed (Diag Rad), FCRad(D) (SA); S Andronikou,2,3 MB BCh, FCRad(D) (SA), FRCR (Lond), PhD; A Boutall,4 MB ChB, DA(SA); S Constantatos,4 MB ChB, Dip Obst (SA); C Stewart,4 MB ChB, FCOG, MMed (O&G); S E Candy,1 BSc HED, MB ChB, FCRad(D) (SA) epartment of Radiology, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa D Departments of Radiology and Paediatrics, Faculty of Health Sciences, University of Cape Town, South Africa 3 Department of Radiology, University of Bristol and Bristol Royal Hospital for Children, UK 4 Department of Obstetrics and Gynaecology, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: A Daire (arthurdaire@gmail.com)

Background. The Department of Radiology at Groote Schuur Hospital, Cape Town, South Africa, has been performing fetal magnetic resonance imaging (MRI) since 2007. Fetal MRI findings have not previously been analysed to correlate them with antenatal and postnatal findings. Objectives. To determine the most common indication for fetal MRI, and to correlate antenatal MRI with antenatal ultrasound (US), postnatal imaging and postmortem findings. Methods. This was a retrospective study of imaging carried out between January 2006 and December 2011. Seventy fetal MRI cases with complete antenatal and postnatal medical records were included. Antenatal US and antenatal MRI were compared, and also compared with the postnatal imaging findings. Stata 12 was used to analyse the data, and Spearman’s test to test the agreement between the results. Results. Intracranial pathology was the most common indication for fetal MRI, with ventriculomegaly being the commonest indication determined from prenatal US. There was 72% agreement between antenatal US and fetal MRI. Postnatal findings showed 28% agreement with antenatal US and 39% agreement with fetal MRI. Conclusions. Intracranial pathology was the major indication for fetal MRI. There was good agreement between prenatal US and fetal MRI but poor agreement between antenatal and postnatal findings, largely as a result of resolution of ventriculomegaly. S Afr Med J 2015;105(11):930-933. DOI:10.7196/SAMJ.2015.v105i11.9415

A number of studies have shown the supremacy of magnetic resonance imaging (MRI) over ultrasound (US) in fetal imaging.[1-3] Use of this technique has yet to be reported from developing countries, where prenatal care and resources may be limited. Locally the accuracy of prenatal US has yet to be determined against MRI, and the success of limited-sequence fetal MRI in predicting fetal pathology has not yet been reported from a South African (SA) or sub-Saharan African institution. No substantial fetal MRI series has been reported from Africa, and only a few cases[4] have been reported from other institutions in SA. This study reviews prenatal and postnatal MRI performed at Groote Schuur Hospital (GSH), Cape Town, SA, over the 6-year period 2006 - 2011.

Objective

To determine the current indications for fetal MRI, and the degree of agreement between antenatal MRI and antenatal US, postnatal imaging and postmortem findings in one SA referral centre.

Methods

This was a longitudinal retrospective observational study of fetal MRI performed at GSH. All fetal MRI scans done from 1 January 2006 to 31 December 2011 were included. Those without prenatal US or postnatal information pertinent to the imaging findings and final diagnosis were excluded. Patient records were accessed after approval from the Human Research Ethics Committee of the University of Cape (approval number: 507/2009). Records included patient clinical notes, antenatal US reports, fetal and postnatal MRI images and reports and, where applicable, postmortem reports.

930

All prenatal fetal MRI scans were performed on a Siemens Symphony 1.5 Tesla MRI scanner with a ‘short protocol’ using the fast imaging with steady-state precession (FISP) sequence (TR = 4.3 and TE = 2.2). Where there was a neurological indication, scans were obtained routinely in three planes centred on the fetal head and/or spinal column. In the event of a non-neurological indication, imaging was centred in three planes over the relevant anatomical region. Maternal demographic data, including HIV and VDRL status, were obtained from the clinical records. Antenatal US reports accessed from the fetal and maternal unit database formed the basis for referral for MRI, which may have resulted in positive or negative bias in fetal MRI reporting. Any diagnostic discrepancies between the US and MRI reports prompted review of the MRI scans, in particular with regard to measurement of the ventricles in cases of suspected hydrocephalus. Abnormalities were broadly categorised into neurological and nonneurological. Ventriculomegaly was defined as a lateral atrial (trigonal) diameter of ≥10 mm and was categorised as mild (10 - 12 mm), moderate (13 - 15 mm) and severe (>16 mm). Spearman’s correlation test was used to test the agreement between the antenatal US and fetal MRI, and the postnatal findings (clinical, imaging (CT or MRI) or postmortem).

Results

Seventy-three patients who had undergone fetal MRI were identified. Documentation was not available in three patients, and these were excluded from the study. A total of 70 patients met the inclusion and exclusion criteria. The mean maternal age of the study population was 27.6 years (range 17 - 43), and the mean gestational age was 29.3 weeks (range 16 - 38) at the time of first antenatal US examination.

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The mean gestational age at time of fetal MRI was 34 weeks (range 31 - 37). The mean interval between antenatal US and MRI was 4.7 weeks. One patient had cytomegalovirus (CMV) infection, and two patients were VDRLpositive. Two fetuses had chromosomal abnormalities confirmed on genetic karyo typing, one Klinefelter syndrome and the other Patau syndrome. There were 12 (17.1%) fetal/neonatal deaths, including three (4.2%) in which the pregnancy was terminated. In five (7.1%) of these cases, a postmortem examination was conducted.

1.1% 1.1% 1.1%

Hydrocephalus/ventriculomegaly

3.4%

Chiari malformation

1.1% 1.1% 1.1%

Dandy-Walker malformation 10.14%

Holoprosencephaly

2.3%

Intracranial masses

2.3%

Cysts Microcephaly

6.9% 25.36%

1.1%

Corpus callosum agenesis Nonspecific

3.4%

Prenatal ultrasound findings

The majority of referrals (54/70, 77.1%) for fetal MRI were for intracranial pathology detected at US. Of these, 32/54 (59.2%) were for hydrocephalus/ventriculomegaly and 9/54 (16.6%) for suspected DandyWalker malformation. Other neurological indications included ‘cysts’, ‘corpus callosal agenesis’ and ‘holoprosencephaly’.

Normal

1.1%

Soft-tissue masses 2.3%

Hemivertebra 5.7%

3.4%

Diaphragmatic hernia Cardiac rhabdomyoma Pulmonary sequestration

Fig. 1. Fetal MRI findings overall.

Fetal MRI findings (n=70)

Ten (14.3) of the antenatal MRI scans were normal. Hydrocephalus/ventriculomegaly was confirmed on fetal MRI in 25 cases. This represents 35.7% of the total number of fetal MRI scans and 78.1% of those referred for suspected ventriculomegaly on antenatal US. The fetal MRI findings are summarised in Fig. 1.

Additional information on fetal MRI

Of the 70 cases reviewed, seven (10.0%) had additional findings on MRI (Fig. 2). Six of these (8.6%) were found to have corpus callosum agenesis (Fig. 3), and one had a Chiari II malformation associated with a myelomeningocele. All seven had been referred for MRI with ventriculomegaly diagnosed on US.

Fig. 2, a and b. FFE T2-weighted fetal MRI scans in (a) axial and (b) sagittal planes, demonstrating severe ventriculomegaly at 26 weeks’ gestation. Corpus callosum agenesis was difficult to identify in this case, but was diagnosed on postnatal imaging.

Ventriculomegaly

Of the 32 cases referred with an US diagnosis of ventriculomegaly, 25 were con firmed on MRI. Twenty-two (68.7%) involved both lateral ventricles, nine (28.1%) were unilateral and one involved the third ventricle and both lateral ventricles. Seven cases of ventriculomegaly (21.8%) had resolved spontaneously at follow-up antenatal US. In these patients the mean gestational age at antenatal US was 31 weeks (range 20 - 33). The mean ventricular size was 11 mm (mild ventriculomegaly). Six cases had a ventricular size of 11 mm and one 12 mm. None of the cases that resolved spontaneously had associated fetal anomalies.

Fig. 3, a and b. FFE T2-weighted fetal MRI scan of corpus callosum agenesis (arrows) at 32 weeks’’ gestation, referred due to ventriculomegaly at antenatal US.

Of the twenty-two cases (68.7%) with persistent antenatal ventriculomegaly, 25.0% (8/32) had unexplained ventri culomegaly, 18.7% (6/32) had corpus callosum agenesis and 9.3% (3/32) had Chiari malformations. Two of these were

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of the Chiari II variety with lumbosacral cutaneous defect, meningo cele, ventri culomegaly and small posterior fossa with vermian descent. One had a Chiari III malformation with an occipital encephalo cele, a small crowded posterior fossa and

RESEARCH

left sided). Two cases had soft-tissue masses, of which one had Klippel-Trenaunay-Weber syndrome and the other a facial teratoma, both diagnosed antenatally. Other abnormalities were pulmonary sequestrations (n=2), hemivertebra (n=2), bronchogenic cyst (n=1), haemangioma (n=1), duodenal atresia (n=1) and ventricular rhabdomyoma (n=1).

Fig. 4, a - c. Chiari malformations demonstrated with fetal MRI. (a) FFE T2-weighted fetal MRI (sagittal images) demonstrating a Chiari III malformation with occipital encephalocele (arrow) at 24 weeks’ gestation. (b and c) FFE T2-weighted fetal MRI scan at 23 weeks’ gestation – sagittal images demonstrating Chiari II malformation (note spinal defect, arrow) and crowding of the posterior fossa structures.

Postnatal findings: Clinical, imaging and postmortem

Hydrocephalus/ventriculomegaly was the most common finding on postnatal CT or MRI. The neurological postnatal imaging findings are graphically presented in Fig. 6. Postmortem examinations demonstrated an arachnoid cyst, corpus callosum agenesis and left diaphragmatic hernia. No post mortem confirmation was possible in two fetuses that died in utero. One of these had a severe Dandy-Walker malformation, and the pregnancy was terminated medically.

Maternal diagnosis and imaging findings

Fig. 5, a and b. FFE T2-weighted fetal MRI scan at 32 weeks’ gestation demonstrating semilobar holoprosencephaly in a patient with Patau syndrome. (a) coronal image demonstrates that the thalami are partially fused and a monoventricle (arrows). The anterior horns of both lateral ventricles are absent. There is absence of the rostrum and genu of the corpus callosum, with only the posterior aspect of body and splenium present. (b) Sagittal scan demonstrates a characteristic large posterior cyst (curved arrow). 1.2% 1.2% Normal 4.9%

Ventriculomegaly/hydrocephalus

13.30%

Chiari malformation Dandy-Walker malformation

5.12%

Holoprosencephaly Masses

1.3% 9.21%

Cysts

2.5%

Corpus callosum agenesis 4.9%

Nonspecific findings 3.7%

Hypoxic ischaemic injury

Fig. 6. Neurological postnatal findings.

ventriculomegaly (Fig. 4). This abnormality had not been detected on antenatal US. Two cases of semilobar holoprosencephaly (Fig. 5) were confirmed among those with ventriculomegaly.

Non-neurological fetal MRI indications and findings

Non-neurological indications for MRI were identified in 16 cases. Four fetuses had congenital diaphragmatic hernias (one right sided and three

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Two mothers had positive serological tests for syphilis. The fetal anomalies found in these cases were Chiari II malformation and Klippel-Trenaunay-Weber syndrome. Fetal chromosome testing confirmed trisomy 13 (Patau syndrome) in one of the cases of holoprosencephaly and a 47,XXY karyotype (Klinefelter’s syndrome) in one of the cases referred for ventriculomegaly.

Statistical analysis

Our study demonstrated significant agree ment between antenatal US and fetal MRI, with a Spearman’s correlation coefficient of 0.7246 (p<0.0001). However, correlation between antenatal US and postnatal findings was lower, with a ratio of 0.2817 (p=0.02) and a correlation coefficient of 0.3879 (p<0.001) between the fetal MRI and postnatal findings. These findings are summarised in Table 1.

Discussion

GSH is fortunate in having a team of dedicated and experienced fetal ultra sonographers. Maternal size, the presence of polyhydramnios and fetal position may reduce the reliability of US examination. Furthermore, limited access to MRI in our resource-restricted environment may have resulted in delay between antenatal US and MRI, which could have affected correlation either positively or negatively.

Agreement between fetal MRI and antenatal US

Our results demonstrate a reasonably high agreement (72%; Spearman’s rho=0.7246)

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Table 1. Statistical correlation between antenatal imaging findings and postnatal findings Agreement categories

Spearman’s correlation coefficient

Antenatal ultrasound/fetal MRI

0.7246; p<0.0001

Antenatal ultrasound/postnatal findings

0.2817; p<0.02

Fetal MRI/postnatal findings

0.3879; p<001

between fetal MRI and antenatal US, although this is lower than the agreement of 83% reported by Griffiths et al.[5] MRI revealed additional brain anomalies not seen on US more commonly in our study than did the Griffiths study (29% v. 17%). We speculate that these discrepancies may be attributable to reduced US sensitivity associated with late antenatal booking in our setting, the mean gestational age at first US being 29.3 weeks. Resolution of mild ventriculomegaly without associated major anatomical brain abnormality, a well-described phenomenon,[6] occurred in just under a third of cases in our study. Gaglioti et al.[7] demonstrated a posi tive correlation between degree of ventri culomegaly and rate of morbidity and mortality. These authors recommended fetal MRI on all suspected cases of ventriculomegaly to exclude other anomalies, especially in those with moderate to severe ventriculomegaly.

Agreement between antenatal imaging and postnatal findings

There was a low agreement of 28% (Spear man’s rho=0.2817) between antenatal US and postnatal findings, with 14% of studies reported as normal postnatally. A somewhat higher agreement of 39% (Spearman’s rho=0.3879) was found between fetal antenatal MRI and postnatal findings. In a study of 100 patients, Dhouib et al.[8] showed an 85% agreement when they compared antenatal and postnatal MRI brain findings. Objective measures of the degree of hydrocephalus necessitate close follow-up with trigonal measurements in the identical plane. Late gestation, maternal obesity and technical challenges may pose challenges to attaining good diagnostic imaging and could explain our lack of correlation. Few centres in Africa, even where MRI is available, appear to perform fetal MRI. The reasons for this may reflect lack of

skills and resources. They may also include a fatalistic attitude on the parts of both patient and clinician, combined with the belief that late termination is not possible even in the setting of a very severe/lethal fetal condition. One patient in our population with ventriculomegaly was diagnosed with CMV infection postnatally. The typical findings of periventricular calcification, migrational disorder, cerebral volume loss and white matter abnormalities seen in congenital CMV infection[9] may be impossible to diagnose on the fast T2 images acquired in antenatal MRI. Chiari II malformation and KlippelTrenaunay-Weber syndrome, found in the fetuses of two VDRL-positive patients, are not known to be associated with congenital syphilis and were therefore considered unrelated. Ventriculomegaly found in a fetus with Klinefelter syndrome (47,XXY) was also considered to be coincidental. Holoprosencephaly was an expected finding in the fetus diagnosed with Patau syndrome (trisomy 13), although the other associated anomalies (such as polydactyly, flexion of the fingers, heart defects, facial clefting and neural tube defects[10]) were not identified.

Conclusions

The most common indications for fetal MRI in this SA referral centre were for intracranial pathology. In the majority of cases, these scans followed detection of ventriculomegaly at prenatal US. Our study confirms the value of antenatal US as a screening tool for the assessment of ventricular size. It further confirms the complementary role of fetal MRI in assessing callosal integrity and size and anatomical detail of the contents of the posterior fossa, particularly in the setting of more readily diagnosable ventriculomegaly. Confirmation of these abnormalities allows

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refinement of genetic counselling with respect to fetal outcome. Agreement between antenatal US and fetal MRI in our setting is comparable to that reported in other centres. The poor correlation between the prenatal and postnatal findings largely results from resolution of ventriculomegaly. However, issues such as achieving earlier booking of patients and capacitation of US services to permit routine scans for all pregnant women need to be addressed. We recommend interdisciplinary review of all imaging with discussion in every case. Further prospective research with neurological and developmental follow-up of these cases would be helpful in determining the implications of the antenatal findings, particularly in the setting of late gestational presentation. 3 Tesla MRI and double reading may also improve sensitivity and specificity of future interpretation of both antenatal modalities. References 1. Hubbard AM, Adzick NS, Crombleholme TM, et al. Congenital chest lesions: Diagnosis and characterisation with prenatal MR imaging. Radiology 1999;212(1):43-48. [http://dx.doi. org/10.1148/radiology.212.1.r99jl3143] 2. Danzer E, Hubbart AM, Hedrick HL, et al. Diagnosis and characterisation of the fetal sacrococcygeal teratoma with prenatal MRI. AJR Am J Roengenol 2006;187(4):W350-W356. [http://dx.doi.org/10.2214/AJR.05.0152] 3. Mirza F, Bauer S, van der Veer A, Laifer-Narin S, Simpson LL. Agenesis of the corpus callosum: A comparison of prenatal ultrasound and magnetic resonance imaging. Am J Obstet Gynecol 2008;199(6, Suppl. A):S195. [http://dx.doi. org/10.1016/j.ajog.2008.09.716] 4. Ranchod AI, Andronikou S, Modi M. Fetal MRI for charac terising a variety of posterior fossa anomalies suspected at 3rd trimester ultrasound examination: A short series of 4 cases. South African Journal of Radiology 2012;16(1):27-29. 5. Griffiths PD, Reeves MJ, Morris JE, et al. Prospective study of fetuses with isolated ventriculomegaly investigated by antenatal sonography and in utero MR imaging. AJNR Am J Neuroradiol 2010;31(1):106-111. [http://dx.doi.org/10.3174/ ajnr.A1767] 6. Levine D, Barnes PD, Robertson RR, Wong G, Mehta TS. Fast MR imaging of fetal central nervous system abnormalities. Radiology 2003;229(1):51-61. [http://dx.doi.org/10.1148/radiol.2291020770] 7. Gaglioti P, Danelon D, Bontempo S, Mombro M, Cardaropoli S, Todros T. Fetal cerebral ventriculomegaly: Outcome in 176 cases. Ultrasound Obstet Gynecol 2005;25(4):372-377. [http:// dx.doi.org/10.1002/uog.1857] 8. Dhouib A, Blondiaux E, Moutard ML, et al. Correlation between pre- and postnatal cerebral magnetic resonance imaging. Ultrasound Obstet Gynecol 2011;38(2):170-178. [http://dx.doi. org/10.1002/uog.8937] 9. Fink KR, Thapa MM, Ishak GE, Pruthi S. Neuroimaging of pediatric central nervous system cytomegalovirus infection. Radiographics 2010;30(7):1779-1796. [http://dx.doi.org/10.1148/ rg.307105043] 10. Medscape. Patau syndrome. http://emedicine.medscape.com/ article/947706-overview (accessed 14 October 2012).

Accepted 5 October 2015.

RESEARCH

Depressive and post-traumatic stress symptoms following termination of pregnancy in South African women: A longitudinal study measuring the effects of chronic burden, crisis support and resilience U Subramaney,1 PhD; G E Wyatt,2 PhD; J K Williams,2 PhD; M Zhang,2 MS; H H Liu,3 PhD; D Chin,2 PhD Department of Psychiatry, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Department of Biobehavioural Sciences, Semel Institute, University of California, Los Angeles (UCLA), USA 3 Division of Public Health, Department of Medicine and Department of Biostatistics, University of California, Los Angeles (UCLA), USA 1 2

Corresponding author: U Subramaney (ugasvaree.subramaney@wits.ac.za)

Background. Termination of pregnancy (TOP) remains a controversial issue, regardless of legislation. Access to services as well as psychological effects may vary across the world. Objectives and methods. To better understand the psychological effects of TOP, this study describes the circumstances of 102 women who underwent a TOP from two socioeconomic sites in Johannesburg, South Africa, one serving women with few economic resources and the other serving women with adequate resources. The relationship between demographic characteristics, resilience and symptoms of posttraumatic stress disorder (PTSD) and depression before, 1 month after and 3 months after the procedure was also examined. Results. Time since TOP, age, chronic burden, resilience and the interaction of site with religion and site with chronic burden were significant. In addition, site differences were found for religion and chronic burden in predicting depression scores. Women from both sites had significant decreases in depression scores over time. The interaction of time with site was not significant. Higher chronic burden scores correlated with higher depression scores. No variables were significant in the bivariate analysis for PTSD. Conclusion. Resilience, religion and chronic burden emerge as significant variables in women undergoing a first-trimester TOP, and warrant further assessment in studies of this nature. S Afr Med J 2015;105(11):934-938. DOI:10.7196/SAMJ.2015.v105i11.9394

Termination of pregnancy (TOP), the first-trimester outpatient procedure of evacuating the uterus a few hours after administering prostaglandin, is steeped in the context of political, moral and religious controversy. Decisions about TOP are sometimes difficult, and it is likely that many women initially experience symptoms of depression and post-traumatic stress disorder (PTSD) when they choose to terminate a pregnancy.[1] Research regarding the effects of TOP on women’s mental health, however, is complex. Symptoms of depression, anxiety and PTSD among adolescents and young women aged 15 - 25 years have been documented. [2,3] Associations between TOP and an increased risk of depression, anxiety, suicidal behaviours and substance abuse have also been reported. Reardon et al.[4] studied psychiatric admissions of lowincome women aged 13 - 49 years following TOP and childbirth, and found that TOP was associated with a significantly higher relative risk of psychiatric admission than delivery of a baby, for every time period examined. In another study the degree of adjustment before the pregnancy was found to be a factor contributing to a positive or negative response to TOP, factors associated with a negative emotional adjustment including a history of psychosocial instability, poor or no family ties, few friends and a poor working pattern.[5] While the literature initially supported the notion that TOP has few long-term negative sequelae,[5-7] findings have been mixed.[2-7] Most studies that reported negative mental health sequelae have had methodological limitations. It is important to gain a better understanding of the circumstances and mental health effects of TOP in countries where opportunities to terminate pregnancies have only recently become available.

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South African (SA) reproductive health policy and the laws that underwrite it are among the most progressive and comprehensive in the world.[8] Before implementation of the Choice on Termination of Pregnancy (CTOP) Act,[9] only 800 - 1 000 legal TOPs were performed each year, and many women resorted to illegal and dangerous methods.[8] Within 2 years of the new legislation, over 40 000 women accessed abortion services annually. However, gaps in the implementation of reproductive health policies and in service delivery remain and need to be addressed in order to achieve meaningful improvements in women’s reproductive health status.[10] Studies have found that women still do not access services owing to lack of information about abortion rights, perceived poor quality of care, and fear of being stigmatised.[8,10,11] For example, in one study, 32% of sexually active women did not know that TOP could be conducted legally; this is especially true of women from rural v. urban areas of the country.[10] Consequently, while the CTOP Act[9] that replaced the very stringent Abortion and Sterilization Act of 1973[12] appears to have had a marked impact on abortion-related mortality, there are few studies that describe the circumstances of TOP. Trueman and Magwentshu[13] emphasise that 16 years after the CTOP Act, negative attitudes and hostility towards abortion have not been eradicated in SA, and the interplay between morals, ethics and legal duties remains controversial.[13] For various reasons, there is lack of enforcement of the law to ensure that the approximately 260 facilities (including private and non-governmental facilities) designated to provide abortion services do so effectively.[8] In addition, women may still be concerned about being judged when they seek an abortion.

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In order to understand the effects of TOP, studies of risk and resilience in the context of TOP in SA, as well as the inclusion of factors such as the impact of socioeconomic status and social support, are needed. One such study reported that pre-abortion depression and low self-efficacy predicted postabortion depression.[14] In addition to service provision, there is a dearth of literature on the psychological impact of abortion. The research reported in this article examines the following multiple distal and proximal factors that may affect the sequelae of TOP: (i) the characteristics and circumstances of women with differing economic profiles who terminate a pregnancy in the first trimester; and (ii) the relationship between demographic factors, resilience, ecosystem and macrosystem factors, and symptoms of depression before TOP (T1) as well as depression and PTSD symptoms 1 month (T2) and 3 months (T3) after TOP.

•

Methods Procedure

The study employed a descriptive, analytical approach to a short-term longitudinal study. TOP clinics in SA are available at designated centres in public or private healthcare settings, and by 1997, 292 facilities had been designated nationally.[8] The clinics participating in this study were selected from two different socioeconomic regions in Johannesburg, SA. Site 1 is in an urban area and serves a population of relatively low socioeconomic status. Site 2 is in an affluent suburb of Johannesburg. Women were recruited by responding to flyers at the two clinics. After telephonic screening, those who were eligible consented to take part in the study. At any point in the study, participants who were at high risk in terms of clinical depression and/or suicidality were referred to a community mental health clinic, or to a private mental healthcare practitioner (psychiatrist/psychologist).

Measures

Participants were personally interviewed at baseline, as well as 1 and 3 months after the procedure. The following demographic information was obtained: age, employment, marital status, language spoken, income and religious affiliation. In addition, the following measures were administered: • The Chronic Burden Scale, a 21-item selfrating scale measuring difficulties experienced in the past month from a number of stressors (e.g. economic, employment, crime, legal problems). Responses range from 1 (not a problem) to 4 (a major problem). The measure yielded a reliable sum score in a sample of African American,

•

Latino and Caucasian women (Cronbach’s alpha = 0.83), with a higher score indicating greater stress burden.[15] The Crisis Support Scale, measuring social support after a crisis had occurred and rated on a 4-point scale ranging from 0 (never) to 4 (always).[16] The Connor Davis Risk and Resilience Scale (CD-RISC), a 25-item scale rating items on a 5-point scale (0 - 4), with high[17] er scores reflecting greater resili ence. The CD-RISC demonstrated good internal consistency and test-retest reliability (Cronbach’s alpha = 0.89). There are five subscales: personal competence, social competence, family coherence, social support and personal structure. The Beck Depression Inventory (BDI), a 21-item self-rating scale also using a Likert format, assessing depression in mood and thought.[18] As a screening tool for depression, recommended cut-off points are 0 - 9 non-depressed, 10 - 15 mild dep ression, 16 - 23 moderate depression, and ≥24 severe depression. The Impact of Event Scale, revised version (IES-R), a useful tool that assesses the subjective experience of 22 traumatic events in the past week, including intrusive thoughts, re-experiencing and avoidance reactions, each on a severity rating of 0 5.[19] This was administered to monitor symptom changes between T2 and T3 together with the BDI.

Statistical analysis

Statistical analysis was done using SAS version 9.3 (SAS, USA). The two groups were compared on primary outcome measures (BDI for depression, IES-R for PTSD), in addition to clinical and other

demographic variables using χ2 tests (for dichotomised variables) and Student’s t-tests (for continuous measures). Two steps were then undertaken: bivariate analysis between predictors and outcomes for each time point, and a bivariate analysis across the three time points for the depression outcome. Variables that were significant in step 2 were put in a final model, as were variables that were significant for at least two time points in step 1. For all analyses, statistical significance was set at p<0.05 and all tests were two-tailed.

Results

Demographic profile

In total, 124 women were screened, 64 from site 1 and 60 from site 2. The data from 102 women (51 from each site) who completed all three visits were analysed. Twenty-two women (13 from site 1 and 9 from site 2) were lost to follow-up. A comparative analysis of the two sites showed that site 1 had more black women and fewer women who were employed outside the home. Those who were employed earned a lower income and were less educated than those at site 2. Also, more women listed an African language as their home language (isiZulu, isiXhosa, Sesotho, Setswana or other) compared with their site 2 counterparts. There were no site differences in terms of marital status and age (Table 1).

Chronic burden, crisis support and CD-RISC scores

There were no site differences for scores on the chronic burden scale or the crisis support questionnaire scale. Site 2 women had a significantly higher CD-RISC scores (mean 64.9) than site 1 (mean 50.3) (p=0.0003).

Table 1. Demographic profile of the two sites Age (years), mean (SD)

Site 1 (N=51)

Site 2 (N=51)

p-value

29.2 (6.5)

27.0 (5.2)

t=1.88, p=0.0628

Race, n (%)

χ2 <0.0001

Black

50 (98.0)

35 (68.6)

Other

1 (2.0)

16 (31.4)

Single

44 (86.3)

Married

Marital status, n (%)

1.0000 7 (13.7)

7 (13.7)

Level of education ≥ matric, n (%)

26 (51.0)

45 (88.2)

χ2 <0.0001

Employed, n (%)

31/50 (62.0)

42/50 (84.0)

χ2 p=0.0132, Fisher’s exact p=0.0233

Income <ZAR5 000/month, n (%)

31/31 (100.0)

20/42 (47.6)

χ2 <0.0001

Religion Christian, n (%)

16/47 (34.0)

29/50 (58.0)

χ2 0.0181

Black language, n (%)

50 (98.0)

33/50 (66.0)

χ2 <0.0001

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Reason for TOP

(95% CI 5.82 - 12.25), p<0.0001); for site 2, T1 v. T2 mean 3.6 (9.4) (95% CI 0.92 - 6.27); T2 v. T3 mean 3.3 (7.65) (95% CI 6.4 - 9.51); T1 v. T3 mean 7 (11.04) (95% CI 9.22 13.76), p<0.0001.

Only 22 women (21.6%) responded to this question. Of these, 13 (25.5%) were from site 1 and 9 (17.7%) from site 2. There were no significant differences in BDI scores between those who answered this question and those who did not.

IES-R scores (Tables 2 and 3)

Scores were low for both groups at both visits (T2 and T3). The mean score for the IES-R for site 1 was 16 at the initial assessment and 9 at T3. For site 2 the initial mean IES-R score was 19, and at T3 it was 10. There were significant decreases in scores between T2 and T3 for both sites (site 1: T2 v. T3 mean (SD) 7.7 (9.98) (95% CI 4.97 - 10.93), p<0.0001); site 2: T2 v. T3 mean 9.7 (12.11) (95% CI 10.14 - 15.06), p<0.0001).

Previous TOPs

For site 1, 14 women reported that this was not their first TOP. Twelve had undergone one other TOP and two had undergone two previous TOPs. For site 2, 12 women reported having undergone previous TOPs. Of these only one had undergone two previous TOPs. There were no significant differences between the BDI scores of women who were having a TOP for the first time v. those who were not.

p=0.0378). Nothing significant was found for site 1 women. Table 5 illustrates the bivariate analysis for depression across three time points. Chronic burden as well as resilience (CD-RISC) scores were significantly related to depression across the three time points (p=0.0003 and p=0.0255, respectively). None of the predictors was related to PTSD.

Repeated measures analysis (Table 6)

Religion, chronic burden and CD-RISC as well as time, site and their interaction term were put in the final model. Time, site and

Bivariate analysis: Effect of demographic variables, chronic burden, crisis support and CDRISC on depression and PTSD

BDI scores (Tables 2 and 3)

At baseline, BDI scores were low for both groups. At T2 and T3, scores decreased significantly for both groups: for site 1, T1 v. T2 mean (standard deviation (SD)) 6.6 (1.03) (95% confidence interval (CI) 3.22 - 9.99); T2 v. T3 mean 2.43 (3.08) (95% CI 1.56 3.29), p<0.0001; T1 v. T3 mean 9.03 (11.43)

Table 2. BDI and IES-R scores over time Site 1

Site 2

11.56

13.02

4.96

9.23

2.52

5.90

16.64

19.43

8.86

9.72

BDI scores

For site 2 women, religion (belonging to the Christian faith) had a significant impact on depression scores at visits 2 and 3 (p=0.0171 and p=0.0342, respectively), as did chronic burden (visit 1 p=0.0079, visit 2 p=0.0167 and visit 3 p=0.0002) and CD-RISC (visit 1

IES-R scores

Table 3. BDI and IES-R scores over time by site Site 1 T1 v. T2

Site 1 T2 v. T3

Site 1 T1 v. T3

Site 2 T1 v. T2

Site 2 T2 v. T3

Site 2 T1 v. T3

BDI Mean (SD)

6.60 (1.03)

2.43 (3.08)

9.03 (11.43)

3.6 0 (9.40)

3.33 (7.66)

7 .00 (11.04)

95% CI

3.22 - 9.99

1.56 - 3.29

5.82 - 12.25

0.92 - 6.27

1.18 - 5.49

3.86 - 10.14

p-value

0.0003

<0.0001

0.0093

0.0031

<0.0001

IES-R Mean (SD)

7.78 (9.99)

9.71 (12.12)

95% CI

4.97 - 10.93

6.30 - 13.11

p-value

<0.0001

Table 4. Bivariate analysis at each time point Age

Income

Employed

Religion

Chronic burden

Crisis support

CD-RISC

First TOP

BDI 1 (S1)

0.1594

0.0796

0.0323

0.0571

0.2630

–0.0393

–0.2091

0.0533

BDI 1 (S2)

0.1114

0.4434

0.7510

0.5804

0.0079

0.6961

0.0378

0.5968

BDI 2 (S1)

0.1127

0.0772

0.1648

0.2417

0.2366

0.0083

–0.1191

0.0126

BDI 2 (S2)

0.2595

0.4546

0.1013

0.0171

0.0167

0.9342

0.2378

0.9003

BDI 3 (S1)

0.0779

0.0668

0.0518

0.2153

0.3593

0.0774

–0.1904

–0.0530

BDI 3 (S2)

0.4363

0.5176

0.6087

0.0342

0.0002

0.4392

0.0578

0.5967

IES 2 (S1)

0.1748

0.0412

0.0440

0.3600

0.1359

0.2349

–0.1145

–0.4280

IES 2 (S2)

0.0789

0.6904

0.6636

0.9721

0.8922

0.8147

0.2568

0.9660

IES 3 (S1)

0.1788

0.0836

0.0652

0.1261

0.1084

0.0757

–0.0970

–0.0888

IES 3 (S2)

0.0722

0.4178

0.5194

0.2184

0.2780

0.9398

0.3369

0.3749

S1 = site 1; S2 = site 2. Correlation coefficients: Prob. >r under H0: Rho=0.

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Table 6. Final model for depression (repeat measures analysis)

Table 5. Bivariate analysis for depression across visits

Effect

Num. DF

Den. DF

f-value

p-value

Estimate

p-value

Time

185

33.92

<0.0001

Age

–0.18

0.1217

Site

12.44

0.0007

Income

–1.44

0.3796

Time*site

185

1.13

0.3263

Employment

–1.56

0.3296

Religion

0.05

0.8320

Religion

1.93

0.1861

Chronic burden

15.49

0.0002

Chronic burden

0.23

0.0003

CD-RISC

6.00

0.0162

Crisis support

0.01

0.9504

Resilience

–0.08

0.0255

Num. DF = numerator degrees of freedom; Den. DF = denominator degrees of freedom; Time*site = interaction between time and site.

First TOP

0.26

0.8699

chronic burden were significantly related to depression. Site 2 had a higher rate of depression reported than site 1 (p=0.0007). Both sites showed significant decreases in depression over time (p<0.0001). The higher the chronic burden, the higher the depression (p=0002). The interaction of time by site was not significant (p=0.3263). As no variables were significant in the bivariate analysis for PTSD, a model for PTSD was not run.

Discussion

This study examined the initial and shortand moderate-term adjustment of 102 mainly black women who had undergone TOP at one of two clinics, one serving mainly women with low economic resources and the other women of higher socioeconomic status. In contrast to some findings in the literature, which showed that poor women are more likely to experience negative sequelae after TOP than their financially more secure counterparts,[4] our study found that after a TOP in women with higher income, the higher the levels of chronic burden, the higher the scores were for depressive symptoms, and, not surprisingly, that the higher the resilience, the lower the depression. The availability of support in times of crisis seemed to have no effect on depressive symptoms. This did not hold true for women of lower income. With regard to interventions to ensure that women adjust to the procedure and do not have residual effects that could exacerbate the symptoms of depression, pre- and post-abortion counselling must consider factors such as resilience, social support and economic measures. While not directly examined in this research study, the issue of stigma in obtaining a TOP could have been the reason why only 21.6% of the women responded to the question ‘Reasons for the TOP’. The value of this study is that it has undertaken careful assessment, via face-to-

face interview, of the demographics in two distinct socioeconomic groups with a focus on race and income. Interesting findings were that across socioeconomic status, scores were generally low for depression. This may reflect transient mood and stress associated with the predicament and decision-making. The findings show that what a woman brings to the experience of abortion can influence how she copes with it. It is also possible that depressive symptoms may have been a result of the procedure itself, i.e. the process of evacuating the uterus in the awake state by manual vacuum aspiration, or the entire experience of terminating a pregnancy, may have led to feelings of depression. Health professionals need to identify some of the economic and life challenges that women report prior to TOP in order better to understand the symptoms, or lack thereof, after the procedure is complete. Service providers may need to ask in-depth questions about previous depressive symptoms to minimise further effects.

Study limitations

Limitations of the study include the relatively small sample, preclu ding generalisation to all women in SA. While language (African v. non-African language) was examined, most women spoke English. Ethnicity, cultural differences and rural areas await further study. Religion may play a role in conferring protection against depressive symptoms in women of lower socioeconomic status. However, we did not examine in depth how religious women were, but rather whether they belonged to the Christian faith or not (34% of women at site 1 and 58% at site 2 reported themselves to be Christian, with various other religions making up the rest). The interaction between religious belief and socioeconomic burden needs to be studied further. Finally, while depressive symptoms were selfreported, an objective measure of depression may have been useful to fully understand these findings. The fact that only 22 out of 102 women gave reasons for the TOP limits analysis of this variable as a potential cause for depressive symptoms at baseline. Qualitative measures

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November 2015, Vol. 105, No. 11

may provide a richer understanding of decisionmaking in TOP. One such study, reported in 1997, assessed women’s experiences of induced abortion under the previous Act. Although limited by small sample size, findings supported the multidimensional nature of the abortion experience, with participants indicating some degree of ambivalence about their experience. The manner in which women responded to the procedure was found to be a joint function of their psychological state and of the social environment in which the abortion occurred.[20] A final limitation is that as the follow-up period in this study was only 3 months, any effects of delayed-onset PTSD symptoms would not have been captured.

Conclusions

The findings from both clinics suggest that women may not necessarily become depressed or experience trauma in the short or medium term following TOP. Enquiry about social support and resilience factors may assist clinics in improving the experience of women obtaining a TOP. It may be helpful to follow up women later than 3 months after TOP and counsel or refer appropriately. It is suggested that using the ACASI (Audio Interviewer Assisted Computerized Interview, where the questions are read to women to avoid literacy bias) in a larger study would be preferred, so that women would not have to report their reasons to an interviewer. The goal of the changes in legislature regarding TOP was to offer services that were not available to all SA women, and studies like this may aid in understanding how to expand services and ensure that women are more comfortable in seeking them. Acknowledgements. The authors thank the management and staff of the Boiphaballo women’s clinic and the DISA clinic in Johannesburg. The research was supported by the PHODISO training programme in traumatic stress studies (NIH number5 D43 TW007278-04).

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References 1. Coleman PK, Reardon DC, Strahan T, Cougle JR. The psychology of abortion: A review and suggestions for future research. Psychology and Health 2005;20(2):237-271. [http://dx.doi.org/10.10 80/0887044042000272921] 2. Pope LM, Adler NE, Tschann JM. Postabortion psychological adjustment: Are minors at increased risk? J Adolesc Health 2001;29(1):2-11. [http://dx.doi.org/10.1016/S1054-139X(01)00212-9] 3. Fergusson DM, Horwood LJ, Ridder EM. Abortion in young women and subsequent mental health. J Child Psychol Psychiatry 2006;47(1):16-24. [http://dx.doi.org/10.1111/j.1469-7610.2005.01538.x] 4. Reardon DC, Cougle JR, Rue VM, Shuping MW, Coleman PK, Ney PG. Psychiatric admissions of lowincome women following abortion and childbirth. CMAJ 2003;168(10):1253-1256. 5. Belsey EM. Predictive factors in the emotional response to abortion: King’s Termination Study-IV. Soc Sci Med 1977;11(2):71-82. [http://dx.doi.org/10.1016/0037-7856(77)90002-6] 6. Adler NE, David HP, Major BN, Roth SH, Russo NF, Wyatt GE. Psychological responses after abortion. Science 1990;248(4951):41-44. [http://dx.doi.org/10.1126/science.2181664] 7. Cohen L, Roth S. Coping with abortion. J Human Stress 1984;10(3):140-145. [http://dx.doi.org/10.10 80/0097840X.1984.9934968] 8. Jewkes R, Rees H. Dramatic decline in abortion related mortality due to the Choice on Termination of Pregnancy Act. S Afr Med J 2005;95(4):250. 9. South African Government. Choice on Termination of Pregnancy Act, 1996 (Act No. 92 of 1996). http://www.acts.co.za/choice-on-termination-of-pregnancy-act-1996/ (accessed 10 October 2015). 10. Morroni C, Myer L, Tibarzawa K. Knowledge of the abortion legislation among South African women: A cross sectional study. Journal of Reproductive Health 2006;3:7. [http://dx.doi.org/10.1186/17424755-3-7] 11. Engelbrecht MC, Pelser AJ, Ngwena C, van Rensburg HC. The implementation of the Choice on Termination of Pregnancy Act: Some empirical findings. Curationis 2000;23(2):4-14. [http://dx.doi. org/10.4102/curationis.v23i2.624]

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12. South African Government. The Abortion and Sterilization Act 2 of 1975. 13. Trueman KA, Magwentshu M. Abortion in a progressive legal environment: The need for vigilance in protecting and promoting access to safe abortion services in South Africa. Am J Public Health 2013;103(3):397-399. [http://dx.doi.org/10.2105/AJPH.2012.301194] 14. Faure S, Loxton H. Anxiety, depression and self efficacy levels of women undergoing first trimester abortions. S Afr J Psychol 2003;33(1):28-38. [http://dx.doi.org/10.1177/008124630303300104] 15. Gurung RA, Taylor SE, Kemeny M, Meyers H. ‘HIV is not my biggest problem’: The impact of HIV and chronic burden on depression in women at risk for AIDS. J Soc Clin Psychol 2004;23(4):490-511. [http://dx.doi.org/10.1521/jscp.23.4.490.40305] 16. Joseph S, Andrews B, Williams R, Yule W. Crisis support and psychiatric symptomatology in adult survivors in adult survivors of the Jupiter cruise ship disaster. Br J Clin Psychol 1992;31(1):63-73. [http://dx.doi.org/10.1111/j.2044-8260.1992.tb00968.x] 17. Connor KM, Davidson JR. Development of a new resilience scale: The Connor-Davidson Resilience Scale (CD-RISC). Depress Anxiety 2003;18(2):76-82. [http://dx.doi.org/10.1002/da.10113] 18. Beck AT, Beamesderfer A. Assessment of depression: The depression inventory. In: Pichot P, OlivierMartin R, eds. Psychological Measurements in Psychopharmacology. Oxford: S Karger, 1974. [http:// dx.doi.org/10.1159/000395074] 19. Weiss DS, Marmar CL. The Impact of Event Scale – revised. In: Keane JPWTM, ed. Assessing Psychological Trauma and PTSD. New York: Guilford Press, 1996:339-411. 20. Sufla S. Experiences of induced abortion among a group of South African women. S Afr J Psychol 1997;27(4):214-222. [http://dx.doi.org/10.1177/008124639702700403]

Accepted 3 October 2015.

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Childhood cancer incidence in South Africa, 1987 - 2007 D C Stefan,1,2 MD, PhD; D K Stones,3 MB ChB, DCH, MMed (Paed), FCP (SA); R D Wainwright,4 MB ChB, FCP; M Kruger,1 MB ChB, MMed (Paed), FCP, M Phil, PhD; A Davidson,5 MB ChB, DCH (SA), FCPaed (SA), Cert Med Onc (Paed) (SA), M Phil; J Poole,6 MB BCh, FCP (SA) Paed; G P Hadley,7 MB ChB FRCS (Edin), FCS (SA); D Forman,8 BA, PhD, FFPHM; M Colombet,8 MSc; E Steliarova-Foucher,8 PhD, RNDr, MSc epartment of Paediatrics and Child Health, Tygerberg Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University, D Tygerberg, Cape Town, South Africa 2 South African Medical Research Council, Cape Town, South Africa 3 Department of Paediatrics and Child Health, Universitas Academic Hospital Complex and Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 4 Paediatric Haematology and Oncology Unit, Department of Paediatrics, Chris Hani Baragwanath Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 5 Haematology-Oncology Service, Red Cross War Memorial Children’s Hospital, and Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa 6 Paediatric Haematology/Oncology, Department of Paediatrics, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa 7 Department of Paediatric Surgery, Inkosi Albert Luthuli Central Hospital, Durban, South Africa 8 I nternational Agency for Research on Cancer, Lyon, France 1

Corresponding author: D C Stefan (cristina.stefan@mrc.ac.za)

Background. Childhood cancer is an emerging problem in Africa. Its extent is hazy because data are scarce, but it should be addressed. This is the first report from the South African Children’s Tumour Registry (SACTR), which covers the whole of South Africa (SA). It provides minimal estimates of cancer incidence and discusses the challenges of cancer surveillance and control in a child population in a middleincome country. Only about 2% of the African population is covered by cancer registries producing comparable incidence data. Objective. To present and interpret incidence patterns and trends of childhood cancer over a 21-year period. The results should raise awareness of the problem of childhood cancer in an African population and provide sensible data for taking this problem in hand. Methods. All eligible and validated cancer cases registered in the SACTR over the period 1987 - 2007 and classified according to the International Classification of Childhood Cancer were included. Population data were retrieved from official sources and estimated for the population subcategories. Incidence rates were standardised to the world standard and time trends were evaluated using joinpoint models, adjusting for sex and age. Results. Based on the 11 699 cases, the overall age-standardised average annual incidence rate was 45 per million. Threefold differences in the overall incidence rates were observed between the ethnic groups, ranging from 116 for whites to 37 for black Africans, and they differed by diagnostic group. Differences between the nine provinces of SA relate to the ethnic composition and prevailing socioeconomic status. The overall incidence rate declined by 1.2% per year for the whole country (p<0.01). However, the decline was mainly observed during the first few years of the study period, after which rates stabilised or increased. Conclusions. Diagnosis and notification of childhood cancer should improve. The differences in incidence between ethnic groups suggest the priorities for cancer control. S Afr Med J 2015;105(11):939-947. DOI:10.7196/SAMJ.2015.v105i11.9780

South Africa (SA), located at the southern tip of Africa, is divided into nine provinces (Fig. 1). The Western Cape and Gauteng provinces are the most densely populated regions and, together with KwaZulu-Natal Province, contribute two-thirds of the economy of the country.[1] Of the total SA population of 52 million, 49% are males. About 79% are black African, 9% white, 2.5% Asian or Indian and 9% coloured. The population is young: 73% are aged under 40 years, 30% under 15 and 11% under 5. The birth rate is 19/1 000, with an infant mortality rate of 42/1 000 live births; the under-5 mortality rate is 60/1 000 live births. The most common causes of death in children under 5 years of age are diseases of infectious origin and malnutrition.[1] Over 80% of South Africans have no health insurance, and 15% pay for private insurance.[2] In public hospitals treatment is free for all children below the age of 6 years, while modest income-based contributions are required for older children. A new National

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Health Insurance scheme to provide basic health cover for all will be implemented shortly, according to the policy Green Paper of the National Department of Health published in 2011. The Health System Trust assessed in 2012 that there are 3 880 primary public healthcare facilities. These may refer patients with a diagnosis of cancer to a secondary hospital. If the diagnosis is confirmed, paediatric patients are referred to the relevant paediatric oncology unit (POU) for treatment. Africa has 1 billion inhabitants, of whom 41% are younger than 15 years of age.[3] Over 36 000 children are diagnosed with cancer annually, and their number is increasing with improving control of infectious diseases. In any given year, the ratio of children who die from cancer represents 60% of those diagnosed; the equivalent figure is 20% or less in developed countries of Europe and North America.[4] Data on which the above figures are based are extremely scarce. Only about 2% of the total population of Africa is covered by populationbased cancer registries producing comparable incidence figures.[5]

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RESEARCH

for Oncology, 3rd edition (ICD-O-3).[6] The cases originally coded to the ICD-O-2[7] were recoded to the ICD-O-3 in agreement with the original medical records. The registry respects confidentiality principles at all times. Identifying information is used for data input, quality control and follow-up. In all reports only grouped data are presented.

Cancer cases

Fig. 1. Map of SA showing the nine provinces and the location of the nine POUs. (Adapted from Htonl/ CC-BY-SA-3.0 of 25 January 2010, available from http://commons.wikimedia.org/wiki/File:Map_of_ South_Africa_with_English_labels.svg. 1 = Tygerberg Hospital (referral for the Western Cape); 2 = Red Cross War Memorial Children’s Hospital (referral for the Western Cape and Eastern Cape); 3 = Universitas/Pelonomi Academic Hospital Complex (referral for the Free State, Northern Cape and parts of the Eastern Cape and North West); 4 = Kalafong Hospital (referral for Northern Gauteng and Mpumalanga); 5 = H F Verwoerd Hospital (referral for Northern Gauteng and Mpumalanga); 6 = Ga-Rankuwa/George Mukhari hospitals (referral for Limpopo); 7 = Chris Hani Baragwanath Hospital (referral for southern Gauteng and North West); 8 = Charlotte Maxeke Hospital (referral for southern Gauteng and North West); 9 = King Edward/Inkosi Albert Luthuli Central Hospital (referral for KwaZulu-Natal and parts of the Eastern Cape.)

Collection of data on childhood cancers throughout the country was started in 1987 by the South African Children’s Cancer Study Group (SACCSG) as a collaboration between the nine referral POUs shown in Fig. 1. The objective of the South African Child ren’s Tumour Registry (SACTR) is to describe the cancer burden in the national childhood population. In this first report from the SACTR, we aimed to present and interpret incidence patterns and trends of childhood cancer over a 21-year period (1987 - 2007) in this ethnically diverse population. The results should raise awareness of the problem of childhood cancer in an African population and provide sensible data for dealing with this problem.

Methods

The South African Children’s Tumour Registry

During 1987 - 2007, the nine POUs (Fig. 1) treated children with cancer and provid-

ed data to the SACTR. More recently, the SACTR data sources have included two new satellite units in the Eastern Cape Province and one in KwaZulu-Natal. Each POU sends its data to the central SACTR office as electronic files or as physical records by registered post. In addition to the POU sites, data also come from several oncologists treating children with cancer in private healthcare institutions and from some private paediatricians. In the central registry, the relevant information is recorded into the electronic database of a customised CanReg 4 computer program, adapted for childhood cancer by the International Agency for Research on Cancer (IARC). Data are validated in collaboration with the data originators. Duplicate registration is prevented by manual matching of new cases. Relapses are matched with earlier registration of the same patient and flagged. Since 2002, information on tumour site, morphology and behaviour has been coded according to the International Classification of Diseases

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The SACTR records all malignant tumours, as well as non-malignant central nervous system (CNS) tumours, occurring in chil dren aged under 15 years of age who are resident in SA. Children are considered resident if their parents have been resident for >12 months or if they themselves have lived in SA for at least 6 months, according to the identity documents examined by designated administrative personnel. Records of all patients registered during the period 1987 - 2007 included identi fication number, province of residence, gender, age in years, ethnic group, dates of birth and diagnosis, tumour site, histological classification, behaviour and most valid basis of diagnosis. The extracted data were verified in collaboration with the IARC and converted to the International Classification of Childhood Cancer, 3rd edition (ICCC-3).[8]

Population data

Population data were obtained from the United Nations[9] and from Statistics South Africa,[1] although these sources did not provide figures for all cross-categories of gender, age, ethnic group and province in each calendar year. We were able to extract 1 201 data cells within the study period and a further 122 from the preceding or succeeding years. We have estimated the missing population figures by linear interpolation or extrapolation of available data, using the relevant gender, age, ethnic and province categories. The derived population estimates are based on the assumptions of linear population growth within the population subcategories over the periods with unavailable data. The estimated population data used for calculating the incidence rates in this study are shown in Table 1.

Analysis of incidence rates

Incidence rates are expressed as an average annual number of cases per million personyears.[10] The age-standardised average annual incidence rate (ASR) for the age range 0 - 14 years is the weighted average of the age-specific incidence rates using the weights of the world standard population for the age groups 0 - 4, 5 - 9 and 10 - 14 years.

RESEARCH

Table 1. Estimated average annual child population of SA in years 1987 - 2007, used for calculation of incidence rates Age groups (years), n

0-4

5-9

10 - 14

Total, N

Total

4 274 603

4 314 149

4 292 439

12 881 191

Gender Boys

2 142 583

2 162 443

2 145 146

6 450 172

Girls

2 132 020

2 151 706

2 147 293

6 431 019

Ethnic group Black

3 560 614

3 577 436

3 514 557

10 652 607

White

238 403

261 288

295 470

795 161

Coloured

370 882

368 748

370 591

1 110 221

Asian, Indian, Pakistani

77 068

82 929

90 287

250 284

Unknown

27 636

23 748

21 534

72 918

Province Limpopo

571 368

607 058

595 942

1 774 368

North West

290 603

288 152

281 377

860 132

Mpumalanga

352 128

361 048

357 870

1 071 046

Gauteng

706 054

633 142

605 502

1 944 698

Free State

239 321

255 150

261 922

756 393

KwaZulu-Natal

945 778

953 332

963 744

2 862 854

Northern Cape

106 282

106 617

108 427

321 326

Western Cape

372 527

359 440

359 916

1 091 883

Eastern Cape

690 542

750 210

757 739

2 198 491

The parameters of the incidence trends were estimated using software for analysis of trends using Jointpoint Regression Program 3.5.4 of 2012 developed at the National Cancer Institute, Bethesda, USA. These analyses were based on the crude rate, assuming Poisson variance of counts. The joinpoints were identified using the Hudson method and their optimal number was determined by the permutation test.

Results

During the period 1987 - 2007, there were 11 712 cancer cases reported to the registry. Thirteen of these were non-malignant tumours in sites other than the CNS and were excluded from the analyses. No second primary tumours were recorded. Overall, 93.7% of cases were microscopically verified and in 0.7% of cases (n=77) the basis of the diagnosis was unknown. There were no cases identified from a death certificate only. The date of birth was imprecise in approximately 13% of all cases (day and month missing). There were 301 cases (2.6%) in which the patient was considered too young or too old for the given cancer type. One case of mixed carcinoma of major salivary gland in an infant was checked and confirmed. Less than 4% of cases (n=452)

were classified into unspecified diagnostic categories. Of the tumours that occurred in the brain, 6.7% (n=90 cases) were nonmalignant. Information on laterality was available for 61.2% of retinoblastomas, 56.9% of nephroblastomas and 64.3% of gonadal tumours. Information on ethnicity was unavailable in 12 cases (0.1%). Of all cases, 67.9% occurred in black African, 15.0% in white, 13.8% in coloured and 3.2% in Asian/Indian children. The overall male/female ratio was 1.3, and varied by ethnic group (Table 3). Based on the 11 699 cases included in the analyses, the overall ASR was 45.2 per million (Table 2). ASRs differed between the individual diagnostic groups and the ethnic groups (Table 3). The incidence rates were highest among white children in almost all diagnostic groups examined, except retinoblastoma and hepatic tumours (highest in coloured children), germ cell tumours (highest in Asian/Indian children) and Kaposi’s sarcoma (highest in black Africans). The incidence rates differed between the provinces fivefold (data not shown); the highest ASRs per million were seen in the Western Cape (88.4) and Gauteng (81.0). The Western Cape was the province with the

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lowest proportion of black African (33%) and the largest proportion of coloured (49%) and white (16%) ethnicity. Gauteng also had a lower proportion of black African (77%) and a larger proportion of white (9%) populations compared with the other provinces. The lowest incidence rates were observed in the Eastern Cape (21.8) and Limpopo provinces (18.4). The overall ASRs were intermediate in the Northern Cape (52.9), Free State (64.3), KwaZulu-Natal (39.0), Mpumalanga (26.0) and North West (26.4) provinces. A set of graphs (Fig. 2) shows the incidence trends for selected tumour groups. Over the 21-year study period, the overall incidence rate (adjusted for age group and gender) was seen to decline by 1.2% per year for the whole country (p<0.01). However, the decline was not homogeneous during the study period. Overall rates decreased markedly between 1987 and 1994 by 8.1% per year (p<0.001), and increased thereafter by 1.9% per year (p=0.002). Leukaemia dropped by 7.8% per year (p<0.001) to 1995 and increased by 1.7% per year (p=0.082) thereafter. The incidence of lymphomas decreased by 7% per year (p<0.004) until 1995 and then increased by 2.7% per year (p=0.03). The dramatic decline in the incidence of CNS tumours (–28.3; p=0.037) was reversed from 1990, with a sustained increase of 4.7% per year (p<0.001).

Discussion

This is the first report of the SACTR, a member of the African Network of Cancer Registries (http://afcrn.org/) since its creation in January 2011. Compared with Globocan 2012,[4] where the estimated incidence of all paediatric cancers (0 - 14 years) in Africa is 96 and 73 per million for boys and girls, respectively, the rates we observed are much lower. It should, however, be noted that the Globocan estimates are largely based on data from regional cancer registries, most of them urban, and they may therefore overestimate the national cancer incidence. The rural areas show lower rates.[11] The observed overall ASR of 36.3 per million for black Africans is nevertheless low in comparison with the rates reported from Malawi (220 per million for males), Uganda (140 per million for females) or Zimbabwe[10] (Table 4). The lack of cases pertains predominantly to lymphomas, CNS tumours, retinoblastomas, bone tumours, carcinomas and possibly Kaposi’s sarcomas. Burkitt’s lymphoma is the most common childhood cancer in holoendemic malaria regions in Africa, with a strong association with both intense malaria infection and

RESEARCH Table 2. Numbers of cases and incidence rates by gender in the child population (0 - 14 years) for SA, 1987 - 2007 Age-specific rate

ASR

Diagnostic group

0-4

5-9

10 - 14

Crude rate

ASR

M/F

Boys

Girls

Cum. rate

MV, %

Leukaemia

3 113

15.5

11.3

7.7

11.5

11.9

1.3

13.5

10.3

173

100.0

Lymphoid leukaemias

2 081

11.1

7.7

4.4

7.7

8.0

1.4

9.4

6.7

115

100.0

Acute myeloid leukaemias

862

3.8

3.1

2.7

3.2

1.2

3.5

3.0

100.0

Chronic myeloproliferative diseases

119

0.4

0.5

0.4

1.0

0.4

100.0

MDS and other diseases

0.2

0.0

0.1

1.6

0.1

100.0

Unspecified leukaemias

0.2

0.0

0.1

2.0

0.2

0.1

100,0

Lymphomas and related neoplasms

1 595

4.9

7.4

5.4

5.9

5.8

2.2

8.0

3.6

99.9

IIa

Hodgkin’s lymphomas

612

1.0

3.2

2.6

2.3

2.2

2.9

3.2

1.1

99.8

IIb

Non-Hodgkin’s lymphomas (except Burkitt’s lymphoma)

563

1.6

2.5

2.1

2.0

1.7

2.6

1.5

99.8

IIc

Burkitt’s lymphoma

378

2.0

1.6

0.6

1.4

1.5

2.4

2.1

0.9

100.0

IId

Miscellaneous lymphoreticular neoplasms

0.3

0.0

0.1

0.9

0.1

100.0

IIe

Unspecified lymphomas

0.0

0.1

0.0

3.3

0.1

0.0

100.0

III

CNS neoplasms

1 334

5.9

6.0

3.0

4.9

5.1

1.1

5.4

4.8

73.8

IIIa

Ependymomas and choroid plexus tumours

110

0.7

0.4

0.2

0.4

1.2

0.5

0.4

100.0

IIIb

Astrocytomas

352

1.5

1.6

0.9

1.3

1.1

1.4

1.3

99.1

IIIc

CNS embryonal tumours

323

1.7

1.1

0.7

1.2

1.4

1.1

100.0

IIId

Other gliomas

272

1.1

1.5

0.4

1.0

0.9

1.0

1.1

51.8

IIIe

Other specified CNS neoplasms

0.1

0.3

0.2

0.8

0.2

0.3

98.4

IIIf

Unspecified CNS neoplasms

215

0.8

1.0

0.5

0.8

1.3

0.9

0.7

0.0

Neuroblastoma

748

6.3

1.3

0.6

2.8

3.1

1.3

3.4

2.7

94.3

IVa

Neuroblastoma and ganglioneuroblastoma

740

6.3

1.3

0.6

2.7

3.0

1.3

3.4

2.7

94.2

IVb

Other peripheral nervous cell tumours

0.0

0.1

0.0

1.7

0.0

100.0

Retinoblastoma

779

7.8

0.8

0.1

2.9

3.3

1.2

3.5

3.1

84.5

Renal tumours

1 568

12.6

3.9

1.0

5.8

6.4

1.0

6.5

6.3

96.0

VIa

Nephroblastoma and other tumours

1 557

12.5

3.8

0.9

5.8

6.4

1.0

6.4

6.3

96.0

VIb

Renal carcinomas

0.0

0.1

0.0

0.6

0.0

100.0

VIc

Unspecified malignant renal tumours

VII

Hepatic tumours

240

1.6

0.4

0.6

0.9

1.5

1.1

0.8

92.9

VIIa

Hepatoblastoma

152

1.5

0.1

0.6

1.5

0.8

0.5

100.0

VIIb

Hepatic carcinomas

0.1

0.3

0.5

0.3

1.5

0.3

0.2

93.3 Continued ...

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RESEARCH Table 2. (continued) Numbers of cases and incidence rates by gender in the child population (0 - 14 years) for SA, 1987 - 2007 Age-specific rate

ASR

Diagnostic group

0-4

5-9

10 - 14

Crude rate

ASR

M/F

Boys

Girls

Cum. rate

MV, %

VIIc

Unspecified malignant hepatic tumours

0.0

0.1

0.0

0.9

0.0

0.1

7.7

VIII

Malignant bone tumours

473

0.5

1.5

3.2

1.7

1.6

1.1

1.7

1.6

99.2

VIIIa

Osteosarcomas

359

0.3

1.1

2.7

1.3

1.2

1.0

1.2

100.0

VIIIb

Chondrosarcomas

0.0

100.0

VIIIc

Ewing tumour and sarcomas of bone

100

0.3

0.4

1.2

0.4

0.3

100.0

VIIId

Other specified bone tumours

0.0

2.0

0.0

100.0

VIIIe

Unspecified malignant bone tumours

0.0

0.1

0.0

1.7

0.0

50.0

Soft-tissue sarcomas

1 087

5.7

3.7

2.7

4.0

4.2

1.5

4.9

3.4

96.7

IXa

Rhabdomyosarcomas

711

4.1

2.3

1.4

2.6

2.8

1.4

3.2

2.4

100.0

IXb

Fibrosarcomas

0.4

0.1

0.2

0.3

1.3

0.3

0.2

100.0

IXc

Kaposiâ&#x20AC;&#x2122;s sarcoma

147

0.6

0.8

0.2

0.5

0.6

2.1

0.8

0.4

76.2

IXd

Other specified softtissue sarcomas

102

0.3

0.5

0.4

1.2

0.4

0.3

100.0

IXe

Unspecified softtissue sarcomas

0.2

1.7

0.3

0.2

98.2

Germ cell tumours

436

2.8

1.0

1.1

1.6

1.7

0.5

1.1

2.3

99.1

CNS germ cell tumours

0.0

0.1

0.0

1.6

0.1

0.0

100.0

Other extragonadal germ cell tumours

297

2.3

0.6

0.5

1.1

1.2

0.4

0.7

1.7

100.0

Malignant gonadal germ cell tumours

111

0.4

0.5

0.3

0.5

99.1

Gonadal carcinomas

0.0

1.0

0.0

100.0

Other, unspecified gonadal tumours

0.1

0.0

0.1

0.0

0.1

72.7

Carcinomas and melanomas

223

0.6

1.3

0.8

1.0

0.8

97.3

XIa

Adrenocortical carcinomas

0.2

0.0

0.1

0.8

0.1

94.4

XIb

Thyroid carcinomas

0.0

0.1

0.8

0.1

100.0

XIc

Nasopharyngeal carcinomas

0.0

0.1

0.4

0.2

1.3

0.2

100.0

XId

Malignant melanomas

0.1

0.6

0.1

86.2

XIe

Skin carcinomas

0.1

2.0

0.1

96.3

XIf

Other and unspecified carcinomas

0.1

0.2

0.5

0.3

0.9

0.3

100.0

XII

Other and unspecified neoplasms

103

0.6

0.3

0.2

0.4

0.9

0.4

12.6

XIIa

Other specified malignant tumours

0.1

0.0

0.5

0.0

0.1

100.0

XIIb

Other unspecified malignant tumours

0.5

0.3

0.2

0.3

0.4

1.0

0.4

0.3

1.1

11 699

64.8

38.1

26.9

43.2

45.2

1.3

50.4

40.0

649

93.7

Total

ASR = age-standardised rate (all rates are expressed per million); M/F = male/female ratio; Cum. rate = cumulative rate; MV = microscopic verification.

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Table 3. Cancer incidence in the childhood population (age 0 - 14 years) for SA, 1987 - 2007, according to ethnic group Ethnic group Black

White

Coloured

Asian

Diagnostic group

ASR

M/F

ASR

M/F

ASR

M/F

ASR

M/F

1 820

8.2

1.4

643

43.4

1.2

493

22.1

1.2

153

33.1

1.6

1 072

4.9

1.5

520

35.3

1.2

357

16.1

1.4

128

27.8

1.5

623

2.8

1.3

6.5

0.9

117

5.1

0.8

5.0

2.4

1 095

4.9

2.3

231

13.5

2.0

225

9.5

2.5

8.3

1.5

IIa

426

1.8

3.5

4.1

1.7

3.7

2.6

3.9

1.3

IIb, d, e

240

1.1

2.3

3.6

2.5

3.2

2.9

1.5

2.5

IIc

429

1.9

1.6

5.8

1.9

2.6

2.0

2.9

1.5

III

786

3.6

1.1

251

16.1

1.4

266

11.6

1.2

6.2

0.6

IIIa

0.3

1.1

1.7

1.5

0.9

1.5

0.5

0.0

IIIb

182

0.8

1.0

5.0

1.3

3.5

1.2

1.9

0.8

IIIc

170

0.8

1.5

4.7

1.7

3.2

0.9

1.5

0.3

IIId

178

0.8

2.9

1.3

1.9

1.3

1.2

0.5

IIIe

0.2

0.7

0.5

0.6

0.3

1.7

0.5

IIIf

150

0.7

1.3

1.4

1.7

1.4

0.6

2.0

IVa

444

2.2

1.3

156

11.3

1.3

112

5.4

1.3

5.9

1.2

664

3.4

1.2

2.8

1.1

3.3

0.7

2.6

1.2

VIa

1 256

6.2

1.1

126

9.2

0.7

143

6.8

0.9

6.8

1.1

VII

160

0.7

1.6

1.7

1.1

2.3

1.4

1.2

1.5

VIIa

0.4

1.4

1.2

2.2

2.0

1.9

1.2

1.5

VIIb

0.2

2.0

0.3

0.5

0.4

0.5

VIII

310

1.3

1.1

4.8

1.1

2.2

0.8

2.9

0.9

VIIIa

260

1.1

2.5

1.1

1.7

0.8

1.3

0.3

VIIIc

0.2

1.4

2.3

1.1

0.4

0.8

1.4

1.7

861

4.0

1.4

6.5

1.5

4.3

1.3

6.6

3.3

IXa

560

2.6

1.3

4.4

1.8

2.7

1.4

5.4

3.0

IXb

0.2

1.4

0.7

0.4

3.0

IXc

140

0.6

2.2

0.1

0.2

0.7

0.2

IXd

0.3

1.1

0.8

1.5

0.6

0.8

1.0

4.0

IXe

0.2

2.2

0.4

1.0

0.4

1.0

298

1.4

0.4

3.6

0.8

2.7

0.4

5.1

1.9

219

1.1

0.4

1.9

0.5

1.8

0.3

3.0

1.6

0.3

0.4

1.2

1.0

0.7

0.3

1.7

3.0

152

0.6

1.1

2.2

0.6

1.1

1.5

0.8

0.3

XIc

0.2

1.9

0.3

0.6

XIf

0.3

0.9

0.4

0.3

6.0

0.4

0.0

XII

0.4

1.1

0.4

0.2

0.6

Total

7 942

36.9

1.3

1 758

115.8 1.2

1 614

72.2

1.2

373

79.5

1.4

ASR = age-standardised rate per million; M/F = male/female ratio.

Epstein-Barr virus.[12,13] In SA, malaria is present only in very small areas and Burkitt’s lymphoma is sporadic. In sub-Saharan Africa, with a high prevalence of HIV, the incidence of Kaposi’s sarcoma in children has increased considerably over the past 30 years. However, even if the prevalence of HIV in SA (17.9%)[14] is higher than in Uganda (7.2%)[10] or Zambia (12.7%),[15] the incidence rates of Kaposi’s sarcoma in SA are much lower than in other southern

944

African countries.[11] This may be explained by the comparatively low rates of endemic Kaposi’s sarcoma in SA[16] and the lower prevalence of human herpesvirus infection in SA than, for example, in Uganda.[17] The overall incidence rates for the white population (ASR 116.2 per million) are rather low, but comparable with rates observed in the 1980s in some populations of South America (ASR 118 - 136

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200 180

All cancers

160

140

All

120

Black

100

White

Coloured

ASR per million

Leukaemias

Asian

All

Black

White

Coloured

Asian

20 0

0 1987 1989 1991 19931995 1997 1999 20012003 2005 2007

1987 1989 1991 1993 1995 1997 1999 20012003 2005 2007

Year

CNS tumours

All

Black White

Coloured

Asian

ASR per million

Lymphomas

All

Black

White

Coloured

Asian

5 0

0 1987 1989 1991 19931995 1997 1999 2001 2003 2005 2007

1987 1989 1991 199319951997 199920012003 2005 2007

Year

Fig. 2. Time trends of childhood cancer incidence (age 0 - 14 years) in SA.

per million) and Eastern Europe (ASR ~125 per million).[10] The higher incidence rates in the white compared with the black African population may be explained by a better rate of diagnosis and access to tertiary healthcare treatment in a POU. The cultural background and genetic factors may also be relevant, as the higher incidence rates in the white population, compared with the black, are also observed in the USA.[10] Our rates for the Asian/Indian ethnic group (ASR 79 per million) are at the lower end of the ASR range observed in India and the developing countries of South-East Asia in the 1980s or early 1990s (74 - 110 per million).[10] As black African children constitute two-thirds of the total dataset, their very low registration rates impact heavily on the national incidence estimates. The low incidence rates may be partly explained by underdiagnosing, misdiagnosing or under-reporting. The diagnosis of many tumours, in particular those of the CNS, may be delayed as the appropriate technology required to confirm the diagnosis is not always available.[18] In many rural areas there is also cultural pressure that traditional healers should be consulted before modern medical services are accessed. All these obstacles lead to children dying without a proper diagnosis, referral and treatment. For the majority of SA citizens, the public health system is the only means to access the POUs. Once the diagnosis has been suspected or confirmed, patients are likely to be referred to and registered by a POU. It is possible that some cases are diagnosed but not registered. The lack of medical services in some provinces impacts on both access to care and the likelihood of being diagnosed and registered. Although under-registration should not differ between the ethnic groups, reporting may be more difficult in more deprived areas where the proportion of black African population is larger. Limpopo and the Eastern Cape have the highest proportion of population (55%) with

945

no income, while in the two provinces with the highest incidence rates, Gauteng and Western Cape, this proportion is lower (41%).[1] Table 4 shows the impact of exclusion of the provinces with lowest rates. There are a number of smaller centres and individual practices that are able to diagnose and treat children with cancer but do not necessarily send data to the SACTR. Although the SACCSG encourages reporting to the SACTR, the registration process remains challenging. As a consequence, the rates reported here should be considered minimal estimates of the true status. Deaths are certified in SA, and there is a central collection of death certificates. The SACTR did not attempt to link these records with the registry database, as the quality of their information has been assessed as low.[19] In countries where death data are available to cancer registries, these may help to achieve higher registration completeness, provided the causes of death are correctly assessed and coded. The correct incidence estimates depend on the registration quality as much as on the population data. We had to estimate figures for a large number of categories under many assumptions, which may have influenced the incidence rates in some ethnic groups and provinces more than others. There could also have been a mismatch of the classification of ethnic group or province between the official data and the SACTR, which would have affected the calculated rates in subgroups. Internationally, ASRs for childhood cancers have tended to increase in recent decades, while our data show a decrease in incidence rates over the study period. The overall decline was caused by the high rates observed at the beginning of the period. In particular, the dramatic decline in the rates of the CNS tumours in whites between

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Table 4. Comparison of the reported age-standardised (world) incidence rates in selected populations in Africa Country

Mali

Namibia

Nigeria

Uganda

Zimbabwe

Region

Bamako

National

Ibadan

Kampala

Harare, black Africans

SACTR

Selected regions*

Black Africans

Reporting period

1987 - 1995

1983 - 1992

1985 - 1992

1992 - 1995

1990 - 1994

1987 - 2007

Source

IICC-2

Current data

Cases, N

226

241

383

340

219

11 699

9 640

7 942

Diagnostic group, ASR I

Leukaemia

3.1

6.2

8.3

10.6

23.1

11.9

15.2

8.2

Lymphoid leukaemia

0.7

4.5

2.6

3.3

11.6

8.0

10.4

4.9

Lymphomas

17.2

5.8

27.1

52.9

12.5

5.8

7.9

4.9

IIa

Hodgkin’s lymphoma

6.6

2.0

3.3

2.2

3.5

2.2

3.0

1.8

IIc

Burkitt’s lymphoma

1.7

1.9

18.0

36.1

2.4

1.5

2.0

1.9

III

CNS tumours

1.4

7.3

11.1

2.3

12.0

5.1

7.2

3.6

Symp. nervous system tumours

0.0

3.6

0.2

1.0

4.0

3.1

4.1

2.2

Retinoblastoma

24.5

4.5

7.4

11.1

10.5

3.3

4.0

3.4

Renal tumours

12.2

6.4

4.9

8.0

16.5

6.4

8.0

6.2

VIa

Nephroblastoma

4.8

6.0

4.7

8.0

16.5

6.4

7.9

6.2

VII

Hepatic tumours

3.7

0.2

1.1

2.7

2.1

0.9

1.2

0.7

VIII

Bone tumours

2.7

3.4

2.1

5.6

4.3

1.6

2.2

1.3

Soft-tissue sarcomas

2.7

4.6

5.4

73.4

19.7

4.2

5.5

4.0

IXc

Kaposi’s sarcoma

0.0

0.7

0.0

67.5

10.6

0.6

0.8

0.6

Germ cell and gonadal tumours

2.7

1.1

0.4

1.7

2.5

1.7

2.4

1.4

Epithelial and melanoma

5.5

2.4

1.7

7.3

2.7

0.8

1.1

0.6

XII

Other and unspecified neoplasms

2.0

0.4

0.8

6.2

1.6

0.4

0.6

0.4

77.7

45.9

70.5

182.7

111.6

45.2

59.3

36.9

Total

[10]

IICC-2 = International Incidence of Childhood Cancer, vol. 2; *Excluding Limpopo, Eastern Cape and North West.

ASR = age-standardised rate per million.

1987 and 1989 may suggest a break in links between the registry and the neurosurgical departments. This pattern could also reflect inclusion of prevalent cases in the first years of registration, typical of new cancer registries. The annual rates stabilised for several tumour types from 1995, and further close monitoring of the trends is required. National cancer registration for all ages was launched in SA in 1986 under the auspices of the National Health Laboratory Service. However, this initially relied on voluntary reporting, which mostly came from pathological laboratories and isolated physicians. Clinically diagnosed cases (6% in the present series) were therefore not registered. The National Cancer Registry (NCR) was revitalised on the initiative of the Department of Health on 26 April 2011 with Government Notice No. R.380, stipulating compulsory reporting of all cancers to the NCR based in Johannesburg. Since 2011, POUs have submitted the same dataset to both the NCR and the SACTR every 3 months. The databases of both cancer registries should therefore be equally complete and include the same

946

registered tumours. However, from a recently published report[20] based on data from the NCR for 2000 - 2006 it became evident that further efforts are required to unify the registration procedures and strengthen collaboration between the two cancer registries. Although the overall rate they reported (45.7 per million) was very similar to ours (45.2/million), there are differences in the incidence rates of several diagnostic groups. These differences may be caused by the use of additional data sources by the NCR, which would explain the higher incidence rates of lymphomas, epithelial neoplasms, soft-tissue sarcomas and bone tumours. The SACTR may be more efficient in excluding unconfirmed diagnoses, metastatic extension of primary tumours, duplicate registrations of such tumours, etc. On the other hand, the SACTR reports higher incidence rates of leukaemia and solid tumours characteristic of the paediatric age range, such as retinoblastoma, neuroblastoma or renal tumours. The continued work of the SACTR is required for multiple reasons. First, the data on childhood cancers are collected through the network of the POUs that ensures a link to detailed clinical

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RESEARCH

information on each patient, which is not mandated by the NCR. Supporting the SACTR enables the SACCSG to have the feedback required for deciding on new treatment protocols, improving data quality and describing outcome results in terms of survival. The POUs also strive to acquire data on some patients from private practice through the paediatrician links, which would not necessarily be possible through the general cancer registry with an at least 20-fold higher volume of cases. Specific focus on childhood cancer helps to improve registration in this age range. The NCR continues to present itself as a pathology cancer registry,[21] and no report on cancer incidence for all ages has been produced to date. It is likely that only the childhood cancer data are of sufficient quality, to a large extent attributable to the work of the SACTR and SACCSG.

Conclusions

The SACTR is the first paediatric population-based cancer registry established in Africa, and it has national coverage. Despite uncertainties inherent in the presented data, the SACTR constitutes an invaluable resource of information for policy planning and research. This report challenges us to improve the diagnosis and notification of childhood cancer to both the NCR and the SACTR, and to tackle the ethnic inequalities in access to appropriate care. Continuous collection of data is indispensable for evaluation of demographic, geographical and temporal variations. Ultimately this will lead to earlier diagnosis, better management, and improved outcomes for children with cancer in SA. Acknowledgments. The following colleagues played a prominent role in establishing and supporting the SACTR: Ruellyn Cockcroft, founder of the SACCSG tumour registry in 1987 – H F Verwoerd Hospital 1987 - 1990, Ga-Rankuwa Hospital 1990 – 1996; Paddy Hartley and Cyril Karabus – Red Cross War Memorial Children’s Hospital; Richard Cohn – Johannesburg (until 1997); Lourens de Jager – H F Verwoerd Hospital 1993 - 2000, and his private patients since 2006; East London – Sydney Smith and Mark Painter; Tygerberg Hospital – Peter Hesseling and Glyn Wessels; Polokwane as satellite till 2009, thereafter independent – Oloko Wedi; Durban – Joan

947

Naidoo until 1993 and R Thejpal from 1993; Bloemfontein – Sydney Smith until 1990, and all consultants and medical officers in the department from 1987 to 2007; Rina Nortje – secretary, SACTR. References 1. Statistics South Africa. www.statssa.gov.za/publications/P0302/P03022014.pdf (accessed 3 March 2015). 2. World Health Organization. Bridging the gap in South Africa. Bull World Health Organ 2010;88(11):803-804. [http://dx.doi.org/10.2471/BLT.10.021110] 3. United Nations, Department of Economic and Social Affairs, Population Division. World Population Prospects: The 2012 Revision, DVD Edition. New York: United Nations, 2013. 4. International Agency for Research on Cancer. Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Default.aspx (accessed 2 October 2012). 5. Forman D, Bray F, Brewster D, et al. Cancer Incidence in Five Continents. Vol. X. Lyon: International Agency for Research on Cancer, 2014. 6. Fritz A, Percy C, Jack A, et al. International Classification of Diseases for Oncology. 3rd ed. Geneva: World Health Organization, 2000. 7. Percy C, van Holten V, Muir C. International Classification of Diseases for Oncology. 2nd ed. Geneva: World Health Organization, 1992. 8. Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P. International Classification of Childhood Cancer, third edition. Cancer 2005;103(7):1457-1467. [http://dx.doi.org/10.1002/cncr.20910] 9. United Nations Department of Economic and Social Affairs. Population Division. http://www.un.org/ en/development/desa/population/ (accessed 2 October 2015). 10. Parkin DM, Kramarova E, Draper GJ, et al. International Incidence of Childhood Cancer. Lyon: International Agency for Research on Cancer, 1998. 11. Somdyala NI, Bradshaw D, Gelderblom WC, Parkin DM. Cancer incidence in a rural population of South Africa, 1998-2002. Int J Cancer 2010;127(10):2420-2429. [http://dx.doi.org/10.1002/ijc.25246] 12. Van den Bosch CA. Is endemic Burkitt’s lymphoma an alliance between three infections and a tumour promoter? Lancet Oncol 2004;5(12):738-746. [http://dx.doi.org/10.1016/S1470-2045(04)01650-X] 13. Geser A, Brubaker G, Draper CC. Effect of a malaria suppression program on the incidence of African Burkitt’s lymphoma. Am J Epidemiol 1989;129(4):740-752. 14. Minhas V, Crabtree KL, Chao A, et al. The Zambia Children’s KS-HHV8 Study: Rationale, study design, and study methods. Am J Epidemiol 2011;173(9):1085-1092. [http://dx.doi.org/10.1093/aje/kwq465] 15. AVERT. HIV and AIDS in Sub-Saharan Africa. http://www.avert.org/hiv-aids-sub-saharan-africa.htm (accessed 2 October 2015). 16. Cook-Mozaffari P, Newton R, Beral V, Burkitt DP. The geographical distribution of Kaposi’s sarcoma and of lymphomas in Africa before the AIDS epidemic. Br J Cancer 1998;78(11):1521-1528. [http:// dx.doi.org/10.1038/bjc.1998.717] 17. Dollard SC, Butler LM, Jones AM, et al. Substantial regional differences in human herpesvirus 8 seroprevalence in sub-Saharan Africa: Insights on the origin of the ‘Kaposi’s sarcoma belt’. Int J Cancer 2010;127(10):2395-2401. [http://dx.doi.org/10.1002/ijc.25235] 18. Stefan DC, Siemonsma F. Delay and causes of delay in the diagnosis of childhood cancer in Africa. Pediatr Blood Cancer 2011;56(1):80-85. [http://dx.doi.org/10.1002/pbc.22714] 19. Mathers CD, Fat DM, Inoue M, Rao C, Lopez AD. Counting the dead and what they died from: An assessment of the global status of cause of death data. Bull World Health Organ 2005;83(3):171-177. 20. Erdmann F, Kielkowski D, Schonfeld SJ, et al. Childhood cancer incidence patterns by race, sex and age for 2000-2006: A report from the South African National Cancer Registry. Int J Cancer 2015;136(11):2628-2639. [http://dx.doi.org/10.1002/ijc.29308] 21. Babb C, Urban M, Kielkowski D, Kellett P. Prostate cancer in South Africa: Pathology based national cancer registry data (1986-2006) and mortality rates (1997-2009). Prostate Cancer 2014;2014:419801. [http://dx.doi.org/10.1155/2014/419801, http://dx.doi.org/10.1155/2014/391257]

Accepted 29 June 2015.

November 2015, Vol. 105, No. 11

GUEST EDITORIAL

Adolescent health The period of adolescence is associated with complex psychological, physical and cognitive changes as children transition to adulthood. In more recent times this transition has taken on added complexities, particularly in developing countries undergoing social and political changes, in an era of increasing globalisation and access to information through new technologies. While adolescents comprise about 25% of the global population, they constitute up to 40% of the population in sub-Saharan Africa, creating what is also referred to as the â&#x20AC;&#x2DC;youth bulgeâ&#x20AC;&#x2122; in the population pyramid. This demographic shift in sub-Saharan Africa is also associated with poorer health outcomes in adolescents as a result of a convergence of communicable and non-communicable diseases. Notably, the gender gaps in infant and childhood survival are being reversed, with secondary sexual development resulting in increasing vulnerability of young women, which perpetuates vicious cycles of intergenerational poverty, low levels of schooling, and ill health that undermine social and economic transformation in these settings. Given the importance of this topic, the SAMJ has dedicated two special CME issues to it. In this first part, the focus is on sexual and reproductive health, including HIV and AIDS. The contribution by Baxter and Moodley[1] highlights the negative outcomes of teenage pregnancies and the impact on maternal mortality rates and indirect impact on infant mortality rates and overall increase in disease burden of HIV and tuberculosis. The article by Dellar et al.[2] links and contextualises HIV service provision with other sexual reproductive health needs of young women and provides specific guidance to clinicians on opportunities and specific action that clinicians can take in providing health services to adolescents. While there have been huge reductions in vertical transmission of HIV and a decline in AIDS-related deaths in infants with early antiretroviral (ARV) treatment initiation, these infants and children are now transitioning to adolescence. In addition to the usual challenges faced

by adolescents, HIV-infected children often have to face for the first time that they have AIDS and need to be on lifelong ARV treatment. The articles by Naidoo et al.[3] and Dawood[4] underscore some of the challenges in treating adolescent AIDS patients and issues that need to be considered, such as drug choices, treatment adherence, disclosure of HIV status, fear of stigma and discrimination and its implications with regard to secondary sexual development, and risks associated with horizontal transmission of HIV. Waning immunity from childhood immunisation and the development of new vaccines requiring delivery during adolescence introduce new challenges relating to vaccine delivery beyond childhood. The article by Tathiah et al.[5] shares experiences in the introduction of the human papillomavirus vaccine, which provides a strong foundation for the introduction of vaccines that target adolescents but are still being developed. Quarraisha Abdool Karim Guest editor quarraisha.abdoolkarim@caprisa.org 1. Baxter C, Moodley D. Improving adolescent maternal health. S Afr Med J 2015;105(11):948-952. [http://dx.doi.org/10.7196/SAMJ.2015.v105i11.10126] 2. Dellar R, Waxman A, Abdool Karim Q. Understanding and responding to HIV risk in young South African women: Clinical perspectives. S Afr Med J 2015;105(11):952. [http://dx.doi.org/10.7196/ SAMJ.2015.v105i11.10099] 3. Naidoo K, Munsami A, Archary M. Adolescent antiretroviral management: Understanding the complexity of non-adherence. S Afr Med J 2015;105(11):953. [http://dx.doi.org/10.7196/SAMJ.2015.v105i11.10150] 4. Dawood H. Adolescent HIV treatment issues in South Africa. S Afr Med J 2015;105(11):953. [http:// dx.doi.org/10.7196/SAMJ.2015.v105i11.10130] 5. Tathiah H, Naidoo M, Moodley I. Human papillomavirus (HPV) vaccination of adolescents in the South African private health sector: Lessons from the HPV demonstration project in KwaZulu-Natal. S Afr Med J 2015;105(11):954. [http://dx.doi.org/10.7196/SAMJ.2015.v105i11.10135]

S Afr Med J 2015;105(11):948. DOI:10.7196/SAMJ.2015.v105i11.10195

REVIEW

Improving adolescent maternal health C Baxter,1 PhD; D Moodley,1,2 PhD Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa Department of Obstetrics and Gynaecology, Faculty of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa

Corresponding author: C Baxter (cheryl.baxter@caprisa.org)

Each year thousands of adolescent girls and young women in South Africa (SA) become pregnant and many die from complications related to pregnancy and childbirth. Although women of all ages are susceptible, girls <15 years of age are five times as likely, and those aged 15 - 19 years twice as likely, to die from complications related to childbirth than women in their 20s. In SA, non-pregnancy-related infections (e.g. HIV), obstetric haemorrhage and hypertension contributed to almost 70% of avoidable maternal deaths. In addition to the implementation of standardised preventive interventions to reduce obstetric haemorrhage and hypertension, better reproductive health services for adolescents, access to HIV care and treatment for women infected with HIV, and improved access to and uptake of long-acting reversible contraception are important ingredients for reducing maternal mortality among adolescents. S Afr Med J 2105;105(11):948-952. DOI:10.7196/SAMJ.2015.v105i11.10126

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Each year, >200 million women worldwide become pregnant, with almost 90% of the pregnancies occurring in developing countries. The World Health Organization (WHO) estimates that about 16 million young women aged 15 - 19 years and 1 million girls <15 years of age give birth each year, accounting for about 11% of all births worldwide. Although the number of adolescent girls aged 15 - 19 giving birth has declined globally between 1990 and 2011, the decrease in sub-Saharan Africa is marginal – decreasing from 123 births/1 000 girls in 1990 to 117 births/1 000 girls in 2011.[1] The majority of young women become sexually active during early adolescence and many before marriage. In sub-Saharan Africa, about 60% of young women are sexually active by the age of 18 years and many women living in developing countries give birth to their first child before that age. In South Africa (SA), >30% of 19-year-olds report having given birth at least once and many of these young women have not yet completed their secondary education when they become pregnant.[2]

Global estimates and causes of maternal mortality

Although the number of women dying from complications related to pregnancy and child bearing has declined by 45% between 1990 and 2013,[1] maternal mortality remains unacceptably high. In 2013, an estimated 289 000 women died globally during and after pregnancy and childbirth. Almost all of the maternal deaths (99%) occurred in developing countries – over two-thirds in sub-Saharan Africa.[1] A systematic analysis of the causes of maternal mortality between 2003 and 2009 shows that the majority of maternal deaths are due to severe bleeding (27.1%), hypertensive disorders (14%), sepsis (10.7%) and unsafe abortions (7.9%).

Maternal mortality among adolescents

Although complications related to pregnancy and childbirth may occur in women of all ages, adolescent girls <15 years face a particularly high risk of maternal mortality. According to the United Nations Population Fund (UNFPA), girls <15 years are five times as likely, and those aged 15 - 19 twice as likely, to die from complications related to childbirth than women in their 20s. A study of 854 377 Latin American women shows that young girls <15 years had a higher risk of maternal death, early neonatal death and anaemia compared with women aged 20 - 24 years.[3] In SA, adolescents are at a significantly increased risk of dying owing to complications of hypertension in pregnancy.[4] Compared with women aged 20 - 24 years, adolescents also

experience an increased risk of premature labour and giving birth to low-birth-weight infants. A systematic analysis of population health data shows complications in pregnancy and childbirth to be leading causes of death among adolescent girls in developing countries.[5] The incomplete physical development of a young girl’s body, high rates of unintended pregnancy among young girls, and their lack of information concerning their bodies and preparation with regard to pregnancy and childbirth all contribute to an increased risk of maternal mortality. Unmarried pregnant teenagers often encounter societal disapproval and report stress and instability in their relationships with their families and partners. Young adolescents are sometimes discouraged from seeking appropriate care during pregnancy because of negative health service provider attitudes, or face other obstacles in accessing services (e.g. inconvenient locations or operating hours and/or insufficient funds to pay for services or transport). For these and other reasons, young women are less likely to access care during pregnancy than older women and more likely to seek abortions, particularly if the pregnancy is unintended. In 2008, there were an estimated 86 million unintended preg nancies worldwide,[6] 48% of which were terminated through abortions, often under unsafe conditions. Young women aged 15 - 19 years accounted for about 3.2 million (15%) of unsafe abortions performed worldwide. Unsafe abortions are estimated to cause 70 000 maternal deaths each year, and result in serious complications that require medical treatment in a further 8 million women.[7] Although abortion has been legal in SA since 1997, and can be obtained by any woman of any age if she is <13 weeks pregnant, many women still obtain abortions unsafely. In addition to the health risks to the young mother and her child, pregnancy during adolescence can negatively impact on a young woman’s opportunities for education. Young women who become pregnant while at school often drop out and only a few return after childbirth. One study in KwaZulu-Natal shows that only about 30% of adolescents aged 14 - 19 and half of young women aged 20 - 24 who had dropped out of school because of pregnancy returned to school.[8] Although SA law allows pregnant girls to remain in school and return to school after childbirth, those with family support and/or financial support are more likely to return to school after childbirth.

Adolescent pregnancy and antenatal care

Most maternal deaths are considered prevent able because the management and prevention of complications that lead to such deaths are well known. A report on confidential enquiries

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into maternal deaths in SA shows that nonpregnancy-related infections (e.g. HIV), obstetric haemorrhage and hypertension contri buted to 67% of avoidable deaths during 2011 - 2012.[4] In SA, maternity care is a vital component of primary healthcare and standardised guidelines have been developed for the management of preg nancies.[9] Antenatal care for adolescents in SA is not particularly different from that available to older women. While antenatal attendance may be substandard for all women, adolescents are more likely to access antenatal services late in pregnancy or not at all. The lack of antenatal care contributes to pregnancy complications and adverse birth outcomes associated with adolescent pregnancies. In addition to the implementation of recommended preventive interventions to reduce obstetric haemorrhage (e.g. community education, prevention of prolonged labour, prevention of anaemia, use of safe methods for induction of labour and active management of the third stage of labour)[9] and hypertension (e.g. calcium supplementation during antenatal care, and detection, early referral and timely delivery of women with hypertension),[9] many other clinical and sociobehavioural challenges faced by adolescents in pregnancy can be addressed at a primary healthcare level (Table 1).

Screening for HIV and linkage to appropriate care, treatment and prevention

In sub-Saharan Africa, young women are dis proportionately affected and acquire HIV infection about 5 years earlier than men.[10] A national survey conducted in SA in 2012 shows that HIV prevalence among 15 - 19-year-old women was 5.6% compared with 0.7% in young men of the same age. In the same year, the SA Department of Health estimated that HIV prevalence among pregnant 15 - 19-year-olds was 12.4%. Therefore, adolescents and young women in SA who engage in unprotected sex leading to pregnancy are at a particularly high risk of acquiring HIV. Reducing HIV infection among this vulnerable population is critical, and the strengthening of HIV services for pregnant women is an urgent priority. All maternity health facilities should encourage young women to know their HIV status by offering counselling and testing. Testing adolescents for HIV is an important opportunity to engage with and link them to essential HIV treatment, care and prevention interventions. HIV prevention tools, including repeated counselling and testing (every 6 months), provision of condoms, and post-exposure prophylaxis should be made available for all HIV-negative women. An SA study examining barriers to HIV testing uptake and participation in prevention of mother-tochild transmission (PMTCT) among adolescent mothers revealed that healthcare worker-client interactions, early premarital pregnancy stigma,

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Table 1. Adolescent pregnancies and sociobehavioural and clinical risks Sociobehavioural risks

Clinical risks

Risk

Prevention and management

More likely to smoke throughout pregnancy

Risk-reduction counselling

Less likely to breastfeed

Infant feeding counselling

Increased risk of inadequate diet during pregnancy

Dietary assessments and advice

More likely to develop postnatal depression

Screening and psychological support

More likely to experience mental health problems

Mental health assessments and psychological support

Increased risk of experiencing isolation and breakdown of the relationship with the child’s father

Engage family support

Increased risk of losing financial support from the child’s father

Referral to social welfare and engage family support

Less likely to access antenatal care

Adolescent-friendly, easily accessible antenatal clinics

Seek to conceal their pregnancy for as long as possible

Sexuality education at schools School reproductive health programme Non-judgemental school guidance counsellor/nurse Facilitate referral to nearest antenatal clinic

Risk of repeat pregnancies

Increase access to contraceptive

Increased risk of maternal anaemia, postpartum haemorrhage, pre-eclampsia

Maintain regular antenatal visits, treat adolescent pregnancies as being high-risk

Increased risk of preterm delivery and low-birth-weight baby

Maintain regular antenatal visits, treat adolescent pregnancies as being high-risk

Adapted from: Department for Children, Schools and Families, Department of Health, Royal College of Midwives. Getting maternity services right for pregnant teenagers and young fathers. A practical guide for midwives, doctors, maternity support workers and receptionists. 2008. www.teachernet.gov.uk/publications (accessed 1 October 2015).

lack of confidentiality and poor treatment by healthcare workers strongly influenced adherence to the PMTCT protocol.[11] An increasing number of children who were infected with HIV perinatally are surviving into adolescence. Therefore, some of the adolescents who are HIV-positive may have acquired HIV vertically through MTCT, while others would have acquired HIV horizontally through sex or drug use. Young women who acquired HIV perinatally and are already on antiretroviral treatment (ART) should be monitored for longterm ART toxicities and virological failure, and managed according to national guidelines.[12] Young women who are not yet on ART should be linked to and provided with treatment according to current ART guidelines, with appropriate dose and regimen adjustments for adolescents. The current SA national guidelines recommend immediate initiation with lifelong ART in pregnant women.[12] Pregnant women who are HIV-positive should also be screened for tuberculosis and

offered information on the availability of PMTCT interventions, including counselling on safe infant feeding choices. Young women should be counselled about disclosing their HIV status to others and be empowered and supported to determine if, when, how and to whom to disclose.[12] Adolescents require much support from healthcare providers, peers and their community to disclose safely and confidently, and to be able to cope with any negative reactions from their family, friends and community. National guidelines for the management of HIV recommend that adolescents should be allowed and encouraged to invite an adult or a friend to be present to support them.[12] One of the major challenges that HIV-positive adolescents face is adherence to treatment. One SA study showed that adolescents were significantly less likely to adhere to ART and had lower rates of virological suppression than adults. There fore, healthcare providers need to support adolescents in finding strategies to overcome adherence challenges.

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Postnatal care and support for adolescents

Given that most SA women return to the clinic postnatally and bring their infants for sche duled immunisation visits, these encounters are important for reducing morbidity and mortality among adolescents and their newborns. These opportunities are important for preventing, diagnosing and treating medical complications in the first few weeks after delivery and promo ting HIV prevention and contraceptive services to prevent further unwanted or unplanned pregnancies. The postpartum visits should also focus on counselling on baby care, promotion and support of breastfeeding, nutritional advice, and immunisation.

Prevention of unintended and unwanted pregnancies

Provision of contraception is an important tool for the prevention of unwanted and/or unplanned pregnancies and ultimately the prevention of maternal deaths. All women, including adolescents, need access to contraception and safe abortion services, if that is their choice. Although the worldwide use of contra ception has increased significantly between 1990 and 2012, the unmet need for family planning is still high, estimated to be 25% in sub-Saharan Africa.[13] Although making contraception more accessible would reduce the rate of unintended pregnancies, it is also essential that contraception be used consistently, correctly and effectively. A number of safe and effective contraceptive options are available. Long-acting reversible contraception options that are recommended for adolescents include: • Intrauterine devices, which can last up to 5 years. • Progestogen-only injectables such as Depot medroxyprogesterone acetate (DMPA) (Depot-Provera), which is administered once every 12 weeks, and norethisterone enanthate (NET-EN), which is administered once every 8 weeks. Although controversial, a meta-analysis of observational studies in sub-Saharan Africa has suggested that DMPA may be associated with increased HIV risk, particularly in younger women.[14] Although more evidence is needed to empirically confirm this association, women who may be at risk for HIV should be counselled to also use condoms if they insist on using DMPA for contraception. • Subdermal progestogen implants that provide protection for 3 - 5 years. Long-acting reversible methods are preferred for adolescents because these are less reliant on compliance or correct and consistent use. Other options that could be considered for adolescents but are dependent on compliance include:

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Table 2. Global standards for improving the quality of healthcare services for adolescents Standard 1: Adolescents’ health literacy The health facility implements systems to ensure that adolescents are knowledgeable about their own health and know where and when to obtain health services Standard 2: Community support The health facility implements systems to ensure that parents, guardians, and other community members and community organisations recognise the value of providing health services to adolescents and support such provision and the utilisation of services by adolescents Standard 3: Appropriate package of services The health facility provides a package of information, counselling, diagnostic, treatment, and care services that fulfil the needs of all adolescents. Services are provided in the facility and through referral linkages and outreach Standard 4: Providers’ competencies Healthcare providers demonstrate the technical competence required to provide effective healthcare services to adolescents. Healthcare providers and support staff respect, protect and fulfil adolescents’ rights to information, privacy, confidentiality, non-discrimination, non-judgemental attitude and respect Standard 5: Facility characteristics The health facility has convenient operating hours, a welcoming and clean environment, and maintains privacy and confidentiality. It has the equipment, medicines, supplies and technology needed to ensure effective service provision to adolescents Standard 6: Equity and non-discrimination The health facility provides quality services to all adolescents irrespective of their ability to pay, their age, gender, marital status, education level, ethnic origin, sexual orientation, or other characteristics Standard 7: Data and quality improvement The health facility collects, analyses and uses data on service utilisation and quality of care, disaggregated by age and gender to support quality improvement. Health facility staff are supported to participate in continuous quality improvement Standard 8: Adolescents’ participation Adolescents are involved in the planning, monitoring and evaluation of health services and decisions regarding their own care, as well as in certain appropriate aspects of service provision From WHO/UNAIDS, with permission: Global Standards for Quality Health Care Services for Adolescents. A Guide to Implement a Standards-driven Approach to Improve the Quality of Health Care Services for Adolescents. Vol. 1: Standards and Criteria. Geneva: WHO, 2015. http://www.who.int/maternal_child_adolescent/documents/global-standards-adolescent-care/en (accessed 1 October 2015).

• Oral contraceptive (OC) pills. If taken consistently and correctly, contraceptive pills, such as low-dose combined oral contraceptive (COC) pills and progestogen-only pills (POPs), are highly effective. Oral contraceptives that contain cyproterone acetate or drospirenone also provide the added benefit of treating acne, making them an attractive option for some adolescents. However, non-adherence and ‘pill failure’ are common among OC users. • Emergency contraception. Two types of safe and effective emergency contraceptive methods are currently available in SA: (i) hormonal emergency contraceptive pills, particularly POPs, taken within 5 days of unprotected intercourse; and (ii) the insertion of a copper intrauterine device by a health professional up to 5 days after unprotected inter course. When emergency contraception is requested, it is an important opportunity to provide counselling about the future use of regular contraception and the prevention of unintended pregnancies. • Male and female condoms, when used correctly and consistently, are highly effective in preventing both pregnancy and sexually transmitted infections, including HIV. However, correct and consistent use is difficult to achieve and many men and women have a negative attitude towards condoms. Regardless of the challenges, use of condoms should always be promoted, with an emphasis on consistent and proper use.

Improvement in health systems to reduce maternal morbidity and mortality among adolescents

To overcome barriers to care among adolescents, services for them could be made more ‘youth friendly’. Healthcare providers need to use a counselling approach that is non-judgemental and develop skills and techniques that welcome adolescent clients to their clinics

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and encourage them to seek care. Health facilities management are encouraged to maintain the eight standards, developed by the WHO, to improve quality of healthcare services for adolescents[15] – services that are equitable, accessible, acceptable, appropriate and effective (Table 2). References 1. United Nations (UN). The Millennium Development Goals Report 2014. New York: UN, 2014. 2. Kaufman CE, de Wet T, Stadler J. Adolescent pregnancy and parenthood in South Africa. Studies in Family Planning 2001;32(2):147-160. http://dx.doi.org/10.1111/j.1728-4465.2001.00147.x] 3. Conde-Agudelo A, Belizán JM, Lammers C. Maternal-perinatal morbidity and mortality associated with adolescent pregnancy in Latin America: Cross-sectional study. Am J Obstet Gynecol 2005;192(2):342-349. [http://dx.doi.org/10.1016/j.ajog.2004.10.593] 4. Pattinson R, Fawcus S, Moodley J, National Committee for Confidential Enquiries into Maternal Deaths. Saving Mothers 2011 - 2012: Tenth Interim Report on Confidential Enquiries into Maternal Deaths in South Africa. Pretoria: National Department of Health, 2014. 5. Patton GC, Coffey C, Sawyer SM, et al. Global patterns of mortality in young people: A systematic analysis of population health data. Lancet 2009;374(9693):881-892. [http://dx.doi.org/10.1016/S0140-6736(09)60741-8] 6. Singh S, Sedgh G, Hussain R. Unintended pregnancy: Worldwide levels, trends, and outcomes. Studies in Family Planning 2010;41(4):241-250. [http://dx.doi.org/10.1111/j.1728-4465.2010.00250.x] 7. Singh S, Wulf R, Hussain R, Bankole A, Sedgh G. Abortion Worldwide: A Decade of Uneven Progress. New York: The Guttmacher Institute, 2009. 8. Grant MJ, Hallman KK. Pregnancy-related school dropout and prior school performance in KwaZuluNatal, South Africa. Studies in Family Planning 2008;39(4):369-382. [http://dx.doi.org/10.1111/j.17284465.2008.00181.x] 9. Department of Health. Guidelines for maternity care in South Africa: A manual for clinics, community health centres and district hospitals. http://www.rmchsa.org/wp-content/uploads/2013/05/MaternalCare-Guidelines-2015_FINAL-15.6.15.pdf (accessed 26 August 2015). 10. UNAIDS. The Gap Report. 2014. http://www.unaids.org/en/resources/documents/2014/20140716_ UNAIDS_gap_report (accessed 29 September 2015). 11. Varga C, Brookes H. Factors influencing teen mothers’ enrollment and participation in prevention of mother-to-child HIV transmission services in Limpopo Province, South Africa. Qual Health Res 2008;18(6):786-802. [http://dx.doi.org/10.1177/1049732308318449] 12. Department of Health. National Consolidated Guidelines for the Prevention of Mother-to-Child Transmission of HIV (PMTCT) and the Management of HIV in Children, Adolescents and Adults. Pretoria: National Department of Health, 2014. 13. Sedgh G, Hussain R, Bankole A, Singh S. Women with an Unmet Need for Contraception in Developing Countries and Their Reasons for Not Using a Method. New York: The Guttmacher Institute, 2007. 14. Morrison CS, Chen PL, Kwok C, et al. Hormonal contraception and the risk of HIV acquisition: An individual participant data meta-analysis. PLoS Med 2015;12(1):e1001778. [http://dx.doi.org/10.1371/journal.pmed.1001778] 15. Nair M, Baltag V, Bose K, Boschi-Pinto C, Lambrechts T, Mathai M. Improving the quality of health care services for adolescents, globally: A standards-driven approach. J Adolesc Health 2015;57(3):288298. [http://dx.doi.org/10.1016/j.jadohealth.2015.05.011]

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ARTICLE

Understanding and responding to HIV risk in young South African women: Clinical perspectives R Dellar,1,2 MBiochem Molecular and Cellular Biochemistry (Oxon); A Waxman,1 MSc Public Health in Developing Countries; Q Abdool Karim,1,3 PhD (Medicine) entre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa C Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa 3 Mailman School of Public Health, Columbia University, New York, USA 1

Corresponding author: R Dellar (rachael.dellar@gmail.com)

Young women (15 - 24 years) contribute a disproportionate 24% to all new HIV infections in South Africa – more than four times that of their male peers. HIV risk in young women is driven by amplifying cycles of social, behavioural and biological vulnerability. Those most likely to acquire infection are typically from socioeconomically deprived households in high HIV-prevalence communities, have limited or no schooling, engage in transactional sex or other high-risk coping behaviours, and have a history of sexually transmitted infections (STIs) and/or pregnancy. Despite the imperative to prevent HIV acquisition in young women, there is a dearth of evidence-based interventions to do so. However, there are several steps that healthcare workers can take to improve outcomes for this key population at the individual level. These include being able to identify high HIV-risk young women, ensuring that they receive the maximum social support they are eligible for, providing reliable and non-judgemental counselling on sexual and reproductive health and relationships, delivering contraceptives and screening and treating STIs in the context of accessible, youth-friendly services. S Afr Med J 2015;105(11):952. DOI:10.7196/SAMJ.2015.v105i11.10099

Despite huge improvements in access to antiretroviral therapy (ART) and an overall decline in HIV incidence in South Africa (SA), young women (15 - 24 years) remain uniquely vulnerable to infection. They contribute about a quarter of all new HIV infections occurring in SA and are thus key to epidemic control. Understanding and responding to the risk they face is a public health imperative. Many studies have sought to characterise factors associated with higher vulnerability to HIV in young women. Together, these studies paint a picture of an amplifying cycle of risk for many young South Africans. Typically, this cycle is founded in poor socioeconomic backgrounds that drive engagement in high-risk sexual behaviours and expose young women to risks of sexual abuse, sexually transmitted infections (STIs) and pregnancy. Directly and indirectly, all these experiences have substantial implications for the odds of young women acquiring HIV. Those at greatest risk can be identified and prioritised by healthcare workers as being from unstable or child-headed households, not being in school, engaging in transactional sex, being victims of gender-based violence and/or having a history of pregnancy or STIs. Despite the current lack of biological technologies available to reduce HIV acquisition risk in young women, healthcare workers may have a substantive impact on young women’s lives at the individual level by helping them to break out of the cycles of vulnerability they face. Ensuring that young people receive the full available social and financial support they are eligible for via governmental and non-governmental organisations is an important first step, especially considering the many structural factors that drive high-risk behaviours in this key population. Healthcare workers can also provide reliable information on sexual and reproductive health. Importantly, such counselling should be tailored to the individual recipient and aim to include discussions about healthy relationships

and female genital cleaning practices in addition to the more standard risk-reduction curriculum. Providing access to STI screening, STI treatment, and family planning services is key. Critical to all these healthcare worker-initiated strategies is an environment in which young people feel comfortable: a nonjudgemental, non-stigmatising, confidential service. Clinics in high HIV-prevalence areas might consider developing specially trained youth-friendly teams that serve clinics at specific hours suited to young people. Furthermore, in rural communities, mobile treatment and education services could reach more isolated young women. Healthcare worker cognizance of the real-life context of the lives of young women is vital to assisting them in reducing their HIV risk and supporting the public health goals of epidemic control.

Why is it important to address HIV risk in SA’s young women?

Preventing new HIV infections in adolescent girls and young SA women is a public health imperative. This key population has an unprecedentedly high risk of acquiring HIV. In 2012, it was estimated that 1 young SA woman (15 - 24 years) was infected every 5 minutes.[1] Further, given that a quarter of all new infections in SA occur in young women, the goals of an ‘AIDS-free generation’ will not be achieved without reducing their risk of HIV acquisition.[1]

What do we know about what contributes to HIV risk in young people?

A large number of studies have sought to characterise social, behavioural and biological factors associated with HIV risk in young women (Box 1). The factors fall into several broad categories that describe a network of inter-related risk (Fig. 1). At a structural level, young women at greatest risk of HIV acquisition are those from socioeconomically deprived communities

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School drop-out Adult death(s) in household In a child-headed household

Poverty

Transactional sex

Engagement in high-risk behaviours

Stigmatisation Limited or no schooling

Sex with an older partner

Food insecurity

Early sexual debut

Poor knowledge of and access to SRH services

Poor SRH outcomes

Risk of gender-based violence Pressure to not use a condom

Risk of pregnancy Risk of HIV exposure

HIV risk

Risk of STI exposure Invasive vaginal cleaning practices

Genital inflammation

Fig. 1. Network of amplifying risk for young South African women (SRH = sexual and reproductive health).

Box 1. Factors associated with being HIV-positive and/or with HIV acquisition Factors associated with HIV risk in young people from southern Africa have previously been reviewed [2] and include: living in a high HIV-prevalence area with low ART coverage; being from a household with poor socioeconomic indicators, including food insecurity and adult death; not being in school or having few years of schooling; a relatively early sexual debut; more than the average number of lifetime sexual partners; sex with an older partner, potentially in a transactional relationship (sex for gifts or favours); inconsistent condom use; a history of sexually transmitted infections; and a history of pregnancy. Most of these factors have been identified via cross-sectional studies and thus show associations with being HIV-positive. Only a few factors have been tested and confirmed in longitudinal studies that follow a cohort over time as being associated with higher HIV acquisition risk. with high levels of unemployment, high background HIV prevalence, and poor access to ART programmes.[1,3] In these communities, the most vulnerable households include those with histories of premature adult deaths (often AIDS related), typically with a degree of food insecurity. Young women from child-headed households are at particular risk (Box 2: Lihle’s story).[4] Young women from poor socioeconomic backgrounds are more likely to have few years of schooling, leading to poor knowledge of sexual and reproductive processes and services available to them (Box 2: Thembe’s story).[4] Furthermore, young women living in such settings may also engage in high-risk behaviours to either relieve immediate survival challenges or because of a limited sense of a potential better future. [5,6] These behaviours may include early sexual debut and engagement in transactional sex (sex for gifts or favours, rather than formal prostitution), often with older partners with higher HIV prevalence than their peers (Box 2: Sarah’s story).[7,8] Young women experiencing gender-based violence are also at high risk of HIV acquisition, as negotiating condom use in such relationships is especially difficult.[9] If engagement in high-risk behaviours does not directly result in HIV infection, it often leads to other poor sexual and reproductive

Box 2. Case studies of HIV risk from rural KwaZulu-Natal Three stories compiled from a qualitative study on the lives of young women in a particularly high HIV-prevalence rural district of KwaZulu-Natal highlight the real-life context of HIV risk in SA:[12] • Lihle’s story. Lihle is 17 years old and, following the death of her mother from AIDS, is living in a child-headed home. She does not attend school because she is looking after the home and her younger siblings. Because of her family’s state of poverty, she engages in transactional sex with older men. She says that ‘men give you something because they want to have sex with you … I think they use your financial situation to their benefit, to satisfy their need’. She is worried about getting HIV and about her personal safety, ‘sometimes I have sex expecting nothing in return, sometimes I am coerced and expect any outcome’. • Thembe’s story. Thembe is a 19-year-old girl from the local rural area. Her boyfriend lives in another town. She has unprotected sex with him once or twice a month when she visits him. Although she wants to use a condom, he repeatedly refuses. He says that he wants to have children with her, even though he is currently expecting a child with another young woman. She doesn’t want to have children and is worried about contracting HIV, but he tells her that ‘having unprotected sex makes your partner love you more’. She considered using the contraceptive medroxyprogesterone (Depo-Provera) to prevent pregnancy, but she has heard that ‘at some point your womb is closed [if you don’t conceive when you are young]’ and she is concerned because she ‘doesn’t know where your blood goes when you don’t menstruate’. • Sarah’s story. Sarah is 16 years old and is already HIVpositive. She dropped out of school earlier in the year following an unplanned pregnancy. She says she was tricked into pregnancy by her abusive boyfriend, who once ‘sweet and innocent’ is now ‘too clever’. She would like him to ‘stop hitting and cheating with other girls’. As a result of her pregnancy and school drop-out, Sarah became stigmatised by her community. She has defaulted on her HIV treatment because she doesn’t like to leave the house, and there is no one available to ensure that she takes it regularly. She has recently been diagnosed with TB.

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health outcomes that compound risk. Herpes simplex virus 2 (HSV-2), human papillomavirus (HPV) and other STIs can all leave women biologically more susceptible to HIV for every exposure they have.[10] Certain female genital cleansing practices (including douching and insertion of foreign substances) may also mediate risk via inflammation.[11] Moreover, engaging in unprotected sex carries a risk of pregnancy, which can lead to stigmatisation and school drop-out, and may amplify the risks of gender-based violence or engagement in transactional sex owing to vulnerability and material need, respectively (Box 2: Sarah’s story).

What tools do healthcare workers have to reduce the risk of young people becoming infected with HIV?

Given the current lack of availability of effective biomedical HIV prevention technologies[2,12] and the importance of structural factors in driving HIV in young SA women, it might seem that there is not much healthcare workers can do to support the former in reducing their odds of acquiring HIV, except advocate for broader economic and scientific development (Box 3). However, a closer look at the case studies in Box 2 reveals a number of ways in which healthcare workers might intervene to break young women out of the cycles of amplifying risk they face. The first action in helping to reduce the vulnerability of their young female patients is confirming that those in severe financial need, or from child-headed households, receive the full governmental support (both financial and social) available to them. In some cases, referral to local non-governmental organisations for additional aid may also be an option. Ensuring that young women such as Lihle receive adequate support is essential in preventing them feeling forced into engaging in transactional sex or other high-risk behaviours for immediate survival. A second action that healthcare workers can take is to provide reliable and non-judgemental counselling on sexual and reproductive health. Although such counselling is usually available, lack of healthcare worker expertise or time often means Box 3. Future tools for HIV prevention in young SA women Despite the risk faced by young SA women, there is a dearth of evidence-based HIV prevention interventions available to them.[2,12] No biomedical technologies to prevent HIV are yet available, and although school- and community-based education programmes are common, few have been evaluated for efficacy. Two promising future tools in HIV prevention in young women are pre-exposure prophylaxis (PrEP) and conditional cash transfers. • PrEP: PrEP is the administration of antiretrovirals in HIVnegative individuals for the prevention of HIV infection. Many variations of PrEP have been or are being developed, including oral, topical, barrier and injectable formulations. Despite early trials demonstrating the effectiveness of PrEP for HIV prevention, implementation has been slowed by problems with adherence highlighted in more recent studies.[15] • Conditional cash transfers: Cash transfers that incentivise beha viours thought to reduce HIV risk (including promoting remaining in school) have recently emerged as a promising new strategy to reduce young people’s vulnerability to HIV.[2,16] Two randomised controlled trials undertaken in SA (HPTN 068 and CAPRISA 007) were unable to demonstrate any impact on HIV acquisition as a result of lower than anticipated HIV incidence rates.

that key risk factors are not adequately addressed. For example, if Thembe was given complete information on fertility control, she might have chosen to initiate hormonal contraceptives, thereby reducing her pregnancy risk, avoiding dropping out of school, and ultimately reducing her HIV risk. Counselling with regard to condom use should be included, but healthcare workers should be aware that young women often have limited say in this decision. If couple counselling or engaging with a male partner is not possible, counselling should extend to relationships and negotiating advice on safer sexual matters. Another important extension of counselling that is currently rarely performed is the discussion of inappropriate vaginal cleaning practices that may increase susceptibility to HIV. A third intervention point in the cycles of HIV risk faced by young women is the treatment of STIs other than HIV. Treating HSV-2 and other STIs is critical to ensure that young people’s HIV exposure risk is reduced. Therefore, all young people attending clinics should be screened for STIs, even if this is not the primary purpose of their visit. Prerequisites to all of these interventions is the provision of accessible services prioritised for the most HIV-vulnerable young women. All healthcare workers should be able to identify young people at highest HIV risk (using the above associations as guiding points) and have an obligation to ensure that they are providing non-stigmatising and completely confidential services. Furthermore, clinics in high-risk areas might consider the additional provision of mobile youth-friendly sexual and reproductive health education programmes and services to reach those without access to or not utilising fixed healthcare facilities.[14]

Conclusions

Understanding and responding to the unprecedented levels of HIV risk in young SA women is a public health imperative for continued progress towards control of the HIV epidemic. Healthcare workers have a vital role to play in reducing this risk, as they have the opportunity to make substantial changes to young women’s lives at the individual level. Maximising this benefit requires healthcare workers to be able to understand the complexity of what drives vulnerability to HIV in young women so that they can identify women who require special attention, such as those from childheaded households, those not in school, and those engaging in transactional sex. Understanding the drivers of HIV is also critical in developing appropriate intervention strategies to break down cycles of risk. At the core of these healthcare worker-initiated intervention strategies is ensuring that vulnerable young people have access to the social support available to them, receive reliable, extensive and non-judgemental counselling, and are regularly screened for STIs. Developing youth-friendly services tailored to meet the unique sexual and reproductive health needs of young people is also critical. Acknowledgements. Rachael Dellar was previously supported by the CAPRISA Fellowship Training Programme and is currently funded by an MRC Flagship Grant (MRC-RFA-UFSP-01-2013/UKZN HIVEPI). Aliza Waxman was a CAPRISA trainee supported by a Fogarty Fullbright Scholarship. The case studies in Box 2 were compiled from a series of interviews with young women, undertaken as part of a larger qualitative research study (approved by the University of KwaZulu-Natal (UKZN) Humanities and Social Sciences Research Ethics Committee (HSS REC/0019/014)).

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References 1. Shisana O, Rehle T, Simbayi LC. South African National HIV Prevalence Incidence and Behaviour Survey 2012. Cape Town: HSRC Press, 2014. 2. Dellar RC, Dlamini S, Karim QA. Adolescent girls and young women: Key populations for HIV epidemic control. J Int AIDS Soc 2015;18(2 Suppl 1):19408. [http://dx.doi.org/10.7448/ ias.18.2.19408] 3. Pettifor AE, Rees HV, Kleinschmidt I, et al. Young people’s sexual health in South Africa: HIV prevalence and sexual behaviors from a nationally representative household survey. AIDS 2005;19(14):1525-1534. 4. Hallman K. Gendered socioeconomic conditions and HIV risk behaviours among young people in South Africa. Afr J AIDS Res 2005;4:37-50. [http://dx.doi.org/10.2989/16085900509490340] 5. Chatterji M, Murray N, London D, Anglewicz P. The factors influencing transactional sex among young men and women in 12 sub-Saharan African countries. Soc Biol 2005;52(1-2):56-72. http:// dx.doi.org/10.1080/19485565.2002.9989099] 6. Weiser SD, Leiter K, Bangsberg DR, et al. Food insufficiency is associated with high-risk sexual behavior among women in Botswana and Swaziland. PLoS Med 2007;4(10):1589-1597; discussion 1598. [http://dx.doi.org/10.1371/journal.pmed.0040260] 7. Dunkle KL, Jewkes RK, Brown HC, Gray GE, McIntryre JA, Harlow SD. Transactional sex among women in Soweto South Africa: Prevalence risk factors and association with HIV infection. Soc Sci Med 2004;59(8):1581-1592. [http://dx.doi.org/10.1016/j.socscimed.2004.02.003] 8. Stoebenau K, Nixon SA, Rubincam C, et al. More than just talk: The framing of transactional sex and its implications for vulnerability to HIV in Lesotho, Madagascar and South Africa. Global Health 2011;7:34. [http://dx.doi.org/10.1186/1744-8603-7-34] 9. Pettifor AE, Measham DM, Rees HV, Padian NS. Sexual power and HIV risk South Africa. Emerg Infect Dis 2004;10(11):1996-2004. [http://dx.doi.org/10.3201/eid1011.040252] 10. Cohen MS. HIV and sexually transmitted diseases: Lethal synergy. Top HIV Med 2004;12(4):104-107.

11. McClelland RS, Lavreys L, Hassan WM, Mandaliya K, Ndinya-Achola JO, Baeten JM. Vaginal washing and increased risk of HIV-1 acquisition among African women: A 10-year prospective study. AIDS 2006;20(2):269-273. [http://dx.doi.org/10.1097/01.aids.0000196165.48518.7b] 12. Waxman A, Humphries H, Frohlich J, et al. Young women’s life experiences and perceptions of sexual and reproductive health in rural KwaZulu-Natal South Africa (in preparation). 13. Mavedzenge SN, Luecke E, Ross DA. Effectiveness of HIV Prevention Treatment and Care Interventions Among Adolescents: A Systematic Review of Systematic Reviews. UNICEF Technical Brief. New York: UNICEF, 2013. 14. Denno DM, Chandra-Mouli V, Osman M. Reaching youth with out-of-facility HIV and reproductive health services: A systematic review. J Adolesc Health 2012;51(2):106-121. [http://dx.doi.org/10.1016/j. jadohealth.2012.01.004] 15. Bekker L-G, Gill K, Wallace M. Pre-exposure prophylaxis for South African adolescents: What evidence? S Afr Med J 2015;105(11):907-911. [http://dx.doi.org/10.7196/SAMJ.2015.v105i11.10222] 16. Pettifor A, MacPhail C, Nguyen N, Rosenberg M. Can money prevent the spread of HIV? A review of cash payments for HIV prevention. AIDS Behav 2012;16(7):1729-1738. http://dx.doi.org/10.1007/ s10461-012-0240-z]

Continuing medical education resources Dellar RC, Dlamini S, Abdool Karim Q. Adolescent girls and young women: Key populations for HIV epidemic control. J Int AIDS Soc 2015;8(2 Suppl 1):19408. Shisana O, Rehle T, Simbayi LC, et al. South African National HIV Prevalence, Incidence and Behaviour Survey, 2012. Cape Town: HSRC Press, 2014. http://www.hsrc.ac.za/uploads/pageContent/4565/ SABSSM%20IV%20LEO%20final.pdf (accessed 23 September 2015). UNICEF Technical Brief. Effectiveness of HIV Prevention, Treatment and Care Interventions Among Adolescents: A Systematic Review of Systematic Reviews. UNICEF: New York, 2013.

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ARTICLE

Adolescent antiretroviral management: Understanding the complexity of non-adherence K Naidoo,1,2 MB ChB; A Munsami,1 MSSC; M Archary,3 MB ChB entre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa C MRC-CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa 3 Paediatric Infectious Disease Unit, King Edward VIII Hospital, University of KwaZulu-Natal, Durban, South Africa 1 2

Corresponding author: K Naidoo (kogie.naidoo@caprisa.org)

This case-based discussion highlights challenges in adolescent antiretroviral management, focusing on non-disclosure of status and the subsequent impact of suboptimal treatment adherence. Despite the scale-up of antiretroviral therapy (ART) and recommendations made by the World Health Organization (WHO) for ART for all human immunodeficiency virus (HIV)-infected paediatric patients, ART coverage in adolescents lags behind that in adults. Challenges of sustaining lifelong ART in children and adolescents require consideration of specific behavioural, physiological and psychosocial complexities associated with this special group. To preserve future drug options and sustain lifelong access to therapy, addressing non-adherence to treatment is critical to minimising acquisition of ART drug resistance and treatment failure. We review the psychosocial and developmental components that influence the course of the disease in adolescents and consider the complexities arising from perinatal exposure to ART and the growing risk of transmitted ART drug resistance in high-burden resourcelimited settings. S Afr Med J 2015;105(11):953. DOI:10.7196/SAMJ.2015.v105i11.10150

Case report

A 13-year-old male adolescent with severe respiratory distress presented to a medical outpatient department. He was admitted to the adult ward with suspected Pneumocyctis jirovecii pneumonia. He was known to be HIV-infected and on antiretroviral therapy (ART) for approximately 10 years, with a CD4 count of 10 cells/µL (0.1%) and a viral load of 1.5 million copies/mL (Fig. 1). On further enquiry, it was noted that his mother had died from an HIV-related illness when he was 3 years old; he was subsequently adopted by his maternal aunt. History of nevirapine exposure for prevention of mother-to-child transmission (PMTCT) was not known. During a routine clinic visit, at age 3, he was diagnosed as HIV-positive and was commenced on ART (stavudine, lamivudine and efavirenz). The patient’s ART regimen was changed at his local clinic to second-line therapy (zidovudine, didanosine, lopinavir) when he was 5 years old. The reason for the change was not documented; however, during that time his aunt commenced shift work at night, and a neighbour was given the responsibility of administering medication to the patient for almost a year. After adherence counselling, his aunt resumed normal working hours and took responsibility for administering ART, after which the patient maintained HIV viro logical suppression to undetectable levels with reasonable CD4 count recovery, until 2 years ago. As is common in our setting, the carer had not yet disclosed the HIV status to the patient. Here, the patient believed that his daily medication comprised antituberculosis drugs to prevent him from becoming ‘sick’. A school friend pointed out that the medication was ART. His aunt had noticed initial subtle behavioural change, which progressed to overt aggression, violent tendencies towards his co-learners at school and substance abuse. He stopped taking ART and left his aunt’s home.

During the course of the latest admission for P. jirovecii pneu monia, the patient and his aunt underwent extensive counselling and the former agreed to recommence ART (zidovudine, lamivudine, lopinavir/ritonavir), under supervision of his aunt. Six weeks later his viral load was 700 000 copies/mL and an HIV drug-resistance genotype test showed mutations to protease inhibitors (M46I, I54V, V82A), nucleoside reverse-transcriptase inhibitors (NRTIs) (M41L, D67N, K70T, T215Y, K219Q) and non-nucleoside reverse-transcriptase inhibitors (NNRTIs) (K103N). During the course of infancy, childhood and adolescence, he had accumulated extensive mutations to all available classes of antiretroviral medications, limiting current and future treatment options. Based on the patient’s resistance testing, he was commenced on tenofovir/emtricitabine (Truvada), daurinavir/ ritonavir and raltegravir. He currently remains virologically suppressed. We present a case that highlights the complexity of managing long-term adolescent survivors of HIV acquired through vertical transmission. We describe the impact of non-disclosure of HIV status on medication adherence, and the impact of non-adherence on acquisition of ART drug resistance. Urgent unmet needs in adolescent HIV care include the challenge of lifelong ART, limited safe, effective and robust drug options, and lack of co-formulated antiretroviral drugs appropriate for oncedaily dosing.[1] While the development of a single-pill treatment regimen has resulted in high ART adherence and acceptability, with substantial improvements in quality of care in HIV-infected adults, this option is not yet available to children and adolescents.[2]

What is the burden of disease in adolescents and children?

Globally, adolescence is defined as the period of development between the ages of 10 and 19 years, represents the fastest growing age group of HIV-infected people, and accounts for 5.9% of the burden of HIV.[1] Approximately 2 500 of the 6 300 new HIV infections that

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1 600 000

35 VL

1 400 000

1 200 000

Status disclosure/non-adherence

Treatment intiation

CD4, %

1 000 000 800 000 600 000 400 000

5 0

Viral load (copies/mL)

CD4, %

200 000

Age (years)

Treatment regimen

D4t/3TC/EFV AZT/ddi/LPV/RTV AZT, 3TC, LPV/RTV

Fig. 1. CD4 count and viral load responses to ART during 13 years of follow-up of a child with vertically acquired HIV (VL = viral load; D4t = stavudine; 3TC = lamivudine; EFV = efavirenz; AZT = zidovudine; ddi = didanosine; LPV = lopinavir; RTV = ritonavir).

occur daily worldwide, are in adolescents and youth 15 - 24 years of age, while a third of these are in children <15 years owing largely to vertical transmission.[1] Temporal trends analysis of adolescent HIV prevalence conducted between 2006 and 2012 in South Africa (SA), while showing decreases from 22.4% to 19.3% (15 - 24 age group), 13.7% to 14.4% (15 - 19 age group) and 28.0% to 24.2% (20 - 24 age group),[3] still remains alarmingly high. The expanding disease burden among adolescents underscores the need for a greater understanding and suitable adaptation of HIV care and treatment services to adequately meet the needs of this patient population. Notwithstanding unprecedented investments in ART scale-up and delivery in the past decade, published literature shows that adolescents are less likely to access HIV care and remain in care or achieve virological suppression.[4] Despite guidance in the management of adolescent ART issued by the WHO in 2013 there have, however, been serious impediments to reducing delays in the initiation of appropriate ART, in supporting adherence to treatment and in retention of adolescents in care.[1] Currently, approximately 90% of the estimated 3 million children living with HIV globally[1] reside in sub-Saharan Africa[5] â&#x20AC;&#x201C; only 27% of those who require ART receive it.[1] Furthermore, in SA only 45% of the 369 000 HIV-infected children aged 10 - 14 years, and 14.3% of the 720Â 000 aged 15 - 24 years, currently receive ART.[6] This may be due to HIV-exposed children often not receiving conclusive HIV test results, poor linkage to appropriate paediatric care, and lack of facilities that specifically cater for children.[1] As in adults, the benefits of ART in HIV-positive children and adolescents include a decreased risk of death, improved growth, better immune function, and a marked reduction in infectious complications.[7] The benefits and risks need to be considered in the context of safe and sustainable therapeutic options for lifelong ART. In 2013, WHO HIV guidelines recommended that adult ART regimens and dosing schedules be applied to adolescents >35 kg. These recommendations did not take into consideration the pubertal changes and growth delays that affect ART metabolism, a lack of clarity guiding the timing of transition from weight-based to age-

based dosing, and a lack of efficacy and safety data on co-formulated agents.[8] HIV resistance in children occurs as transmitted drug resistance (TDR), which is either vertical (from mother to child) or horizontal (through a sexual partner), or has been acquired, and results from poor ART adherence. The US Reaching for Excellence in Adolescent Care and Health (REACH) study evaluating disease progression, which was conducted in HIV-positive adolescents infected through sexual behaviour or injection drug use, found that only 41% of adolescents aged 12 19 years reported >95% adherence to ART. [9] Factors associated with poor adherence included depression, pill burden, advanced HIV status, alcohol use, and dropping out of school.[10] In addition, Murphy et al.[9] reported that only 28.3% of adolescents reported >95% adherence in the previous month. Barriers to adherence included ART toxicity and complications with regard to integrating pill-taking with day-to-day routines.[7,9] In another US study, the Pediatric AIDS Clinical Trial Group (PACTG) 381, of 120 adolescents (aged 11 - 22 years) infected via high-risk behaviour and receiving triple ART therapy, only 44 (37%) stayed on study treatment for the 3 years of observation. Twenty-nine (24%) reached and maintained viral suppression, and poor adherence was the main predictor of virological failure.[11] With increases in the number of adolescents on ART, sustaining optimal ART adherence has emerged as a major challenge to maintaining ongoing AIDS-free survival and prevention of sexual transmission for this group. Antiretroviral regimens are often complex, require good adherence for efficacy, and may lead to the development of viral resistance due to treatment non-adherence (defined as <95% of medication taken, or >1 missed dose per week) or suboptimal levels of antiretroviral agents. Furthermore, in many HIV-endemic resource-limited settings, the future impact of perinatal HIV transmission strategies, including nevirapine or zidovudine mono- or dual therapy on acquisition of resistance to non-nucleoside-based first-line ART regimens, has not been fully quantified. Our case highlights themes that have already emerged from the literature in developed countries. A meta-analysis

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on ART adherence among children, adolescents and young adults living with HIV found variable and suboptimal adherence rates. This was especially the case among adolescents, where adherence was highly dependent on complex relationships between individuals, their families, society and other treatment regimen-related factors.[10] A recently published systematic review of 15 studies assessing correlates of ART adherence among adolescents in low- and middle-income countries, highlights several factors associated with challenges in ART adherence and potential areas for intervention. Emerging themes for suboptimal adherence across all studies include gender and knowledge of serostatus, influence of family structure, impact of onerous ART regimens – including route of administration – and attitudes about medication, healthcare and environmental factors, such as rural versus urban and missed appointments.[12] Other studies cite the following psychosocial risk factors for poor ART adherence: being orphaned, mental health problems, changes of guardianship, and absence of parental and social support.[5] As seen with the case presented, major hindrances to adolescent adherence are the lack of autonomy and reliance on adult caregivers to access care, complying with clinic visits, collecting medication and adhering to the dosage schedule.[11] These are further confounded by issues surrounding status disclosure, autonomy and maturity. Decisions around HIV status disclosure differ in those with horizontally acquired infection compared with vertical infection. However, evidence suggests that non-disclosure is associated with various negative outcomes.[5] Often, status disclosure is deferred until children approach cognitive maturity and puberty, but the decision to disclose is dependent on the family and caregivers, especially as adolescent status disclosure simultaneously discloses the status of the biological mother.[5,11] Non-adherence to ART is further complicated by behavioural experimentation typical of this phase of development. The ability of HIV-infected adolescents to successfully transition from reliance on adults towards autonomy in taking responsibility for their illness, managing adherence to drugs and visiting clinics is further complicated during this stage of development by the display of behavioural patterns that deviate from expected or prescribed patterns,[5] making close observation and interventions for non-adherence necessary.[11] The recently revised 2015 SA Paediatric ART treatment guidelines advocate an abacavir-based regimen for first-line ART in children <15 years or <40 kg, which may then be changed to tenofovir disoproxil fumarate at 15 years of age and weight ≥40 kg in those with an undetectable viral load. The use of abacavir-based regimens in paediatric populations is thought to aid in slowing down acquired drug resistance, especially in children who require extended periods of ART owing to the high genetic barrier to resistance[11] and favourable cross-resistance pattern. Conversely, a multicohort analysis of early virological response in 9 453 SA children <16 years of age showed lower virological suppression rates at 6 months in those receiving an abacavir-based lopinavir/ritonavircontaining regimen compared with those receiving a stavudine-based lopinavir/ritonavir-containing regimen (54% v. 70%, p<0.0001).[13] Furthermore, alternative agents such as tenofovir disoproxil fumarate, while recommended for use in children >2 years of age by the US Food and Drug Administration, are currently registered in SA for use in patients >12 years of age owing to safety concerns and lack of available paediatric formulations.[14] The WHO has, however, highlighted the risk of tenofovir-related renal and bone toxic effects, and recommends specific monitoring of children and prepubertal adolescents receiving tenofovir.[5] Tenofovir alafenamide, a novel tenofovir prodrug currently being evaluated in Phase 2b and 3 trials in adolescents, achieves a 90% reduction in plasma tenofovir concentrations. This drug has also shown improved renal and bone safety profiles, while maintaining equivalent virologial suppression rates in adults compared with tenofovir disoproxil fumarate-containing regimens.[2]

Recent ART scale-up in SA has allowed more people to access care, but may inevitably engender HIV drug resistance, thereby limiting the benefits of treatment. Increases in paediatric HIV drug resistance in resource-limited settings have been driven by limited access to routine viral load monitoring, limited availability of paediatric drugs for second-line therapy and complexities related to PMTCT, paediatric care and ART adherence, as seen in the presented case.[1] A recently published review of drug-resistant mutation prevalence rates after first-line ART failure among children in resource-limited settings, showed mutation rates of 80% for NRTIs, 88% for NNRTIs and 54% for boosted protease inhibitors.[15] A survey conducted in 18 African countries reported an increase in TDR, primarily driven by NNRTI resistance, with moderate levels of TDR (5 - 15%) being documented in KwaZulu-Natal.[15] This is of concern, as this drug class forms the backbone of first-line ART regimens and prophylaxis for PMTCT.[15]

What are the research gaps in understanding ART resistance in children?

HIV-infected children and adolescents remain at high risk of disease progression and death. Insufficient attention has been directed towards the creation of specialised centres offering HIV testing and care. Evaluating the impact of services that prioritise the needs of children and adolescents in care on long-term ART adherence and retention is warranted. SA has recently celebrated tremendous success in improving PMTCT, offering all HIV-infected pregnant women immediate ART access. This implies that most children who were exposed to HIV during the perinatal period have also been exposed to maternal ART. The magnitude of HIV prevalence in the sexually active age group and the growing risk of transmitted ART resistance emphasise the need for research into the use of pre-ART resistance testing in children and adolescents initiating or changing ART. Observation of acquisition rates of ART resistance is especially important to inform future drug sequencing, especially in high-burden settings offering a programmatic approach. References 1. World Health Organization (WHO). HIV and Adolescents: Guidance for HIV Testing and Counselling and Care for Adolescents Living with HIV: Recommendations. Geneva: WHO, 2013. 2. Jarcho JA, Gandhi M, Gandhi RT. Single-pill combination regimens for treatment of HIV-1 infection. N Engl J Med 2014;371(3):248-259. [http://dx.doi.org/10.1056/NEJMct1215532] 3. National Department of Health (NDOH). The National Antenatal Sentinel HIV and Syphilis Prevalence Survey, South Africa. 2005-2012. Pretoria: NDOH, 2013. 4. Lindsey JC, Bosch RJ, Rudy BJ, Flynn PM. Early patterns of adherence in adolescents initiating highly active antiretrovial therapy predict long-term adherence, virologic, and immunologic control. AIDS Patient Care STDs 2009;23(10):799. [http://dx.doi.org/10.1089/apc.2009.0081] 5. Lowenthal ED, Bakeera-Kitaka S, Marukutira T, Chapman J, Goldrath K, Ferrand RA. Perinatally acquired HIV infection in adolescents from sub-Saharan Africa: A review of emerging challenges. Lancet Infect Dis 2014;14(7):627-639. [http://dx.doi.org/10.1016/S1473-3099(13)70363-3] 6. Shisana OR, Simbayi LC, Zuma K, et al. South African National HIV Prevalence, Incidence and Behaviour Survey, 2012. Pretoria: HSRC Press, 2014. 7. Nachman SA, Stanley K, Yogev R, et al. Nucleoside analogs plus ritonavir in stable antiretroviral therapy – experienced HIV-infected children: A randomized controlled trial. JAMA 2000;283(4):492498. [http://dx.doi.org/10.1001/jama.283.4.492] 8. Nachman S, Zheng N, Acosta EP, et al. Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years. Clin Infect Dis 2014;58(3):413-422. [http://dx.doi. org/10.1093/cid/cit696] 9. Murphy DA, Wilson C, Durako S, Muenz L, Belzer M. Antiretroviral medication adherence among the REACH HIV-infected adolescent cohort in the USA. AIDS Care 2001;13(1):27-40. [http://dx.doi. org/10.1080/09540120020018161] 10. Kahana SY, Rohan J, Allison S, Frazier TW, Drotar D. A meta-analysis of adherence to antiretroviral therapy and virologic responses in HIV-infected children, adolescents, and young adults. AIDS Behav 2013;17(1):41-60. [http://dx.doi.org/10.1007/s10461-012-0159-4] 11. Levin L. Abacavir in children: Abacavir. S Afr J HIV Med 2002;3(3):19-22. 12. Hudelson C, Cluver L. Factors associated with adherence to antiretroviral therapy among adolescents living with HIV/AIDS in low-and middle-income countries: A systematic review. AIDS Care 2015;27(7):805-816. [http://dx.doi.org/10.1080/09540121.2015.1011073] 13. Technau K-G, Schomaker M, Kuhn L, et al. Virologic response in children treated with abacavircompared with stavudine-based antiretroviral treatment: A South African multi-cohort analysis. Pediatr Infect Dis J 2014;33(6):617-622. [http://dx.doi.org/10.1097/INF.0000000000000222] 14. Food and Drug Administration. Antiretroviral drugs used in the treatment of HIV infection. http:// www.fda.gov/ForPatients/Illness/HIVAIDS/Treatment (accessed 2 October 2015). 15. Hamers RL, Sigaloff KC, Wensing AM, et al. Patterns of HIV-1 drug resistance after first-line antiretroviral therapy (ART) failure in 6 sub-Saharan African countries: Implications for second-line ART strategies. Clin Infect Dis 2012;54(11):1660-1669. [http://dx.doi.org/10.1093/cid/cis254]

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ARTICLE

Adolescent HIV treatment issues in South Africa H Dawood, MB ChB, FCP (SA), MSc (Epi), LLM Infectious Diseases Unit, Department of Medicine, Grey’s Hospital, Pietermaritzburg, and Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa Corresponding author: H Dawood (dawoodh@ukzn.ac.za)

Following the discovery of the human immunodeficiency virus (HIV), our knowledge of HIV infection and management has increased rapidly, but implementation of interventions has been slow in resource-limited settings. In particular, interventions such as antiretroviral treatment (ART) and prevention of mother-to-child transmission were hindered owing to lack of access to antiretroviral drugs. This resulted in ongoing HIV transmission, morbidity and mortality associated with opportunistic infections. Notwithstanding the current progress in HIV prevention and treatment, challenges remain in preventing new infections in adolescents and supporting and treating HIV-infected adolescents. Barriers to successful treatment of infection in adolescents include denial of diagnosis, poor understanding or perception of future benefits of treatment and current-orientated thinking that may contribute to non-adherence to ART. Side-effects that lead to stigmatisation, such as lipoatrophy (stavudine, zidovudine), diarrhoea and flatulence (lopinavir/ritonavir) and gynaecomastia (efavirenz), may be intolerable and prevent adherence to treatment. This article highlights common treatment issues in HIV adolescent care and provides guidance on their management in the South African setting. S Afr Med J 2015;105(11):953. DOI:10.7196/SAMJ.2015.v105i11.10130

Adolescents as a group undergo rapid biological and social role changes.[1] The World Health Organization (WHO) defines adolescents as individuals in the age group 10 - 24 years.[1] The South African (SA) Department of Health’s definition of adolescence is in line with those of the United Nations (UN) and the WHO – an adolescent is described as a young person aged between 10 and 19 years.[2] In 2013, of the estimated 35 million people living with HIV, there were approximately 210 000 new HIV infections among children in sub-Saharan Africa.[3] In SA, women aged 15 - 24 years are the group with the highest rate of new HIV infections and should therefore be considered to be most at risk.[2] Among this age group, heterosexual transmission of HIV infection is the predominant risk factor.[2] With the implementation of the SA HIV antiretroviral drug treatment guidelines in 2004, there was increased access to anti retroviral treatment (ART) for adults and children.[4] The number of children with HIV infection requiring long-term treatment is increasing in SA owing to improved survival of those initiated on ART, an increase in the number of long-term HIV disease nonprogressors and an increase in behavioural HIV transmission among adolescents. While addressing the needs of HIV-infected adolescents is a national priority, the optimal treatment regimen for children and adolescents remains a challenge in SA and internationally. There is a lack of information with regard to pharmacokinetics and safety and efficacy data in children and adolescents. While the current guidelines are helpful and based on expert opinion, evidence-based management of adolescent HIV is urgently required.[5]

Adolescence and HIV infection

Adolescence is a unique period of rapid physical, biological, intellectual, behavioural and emotional growth.[6] This heterogeneous group of pubertal children and young adults are more vulnerable and at an increased risk of HIV acquisition.[7] Furthermore, adolescents are less likely to present for testing or be tested for HIV infection.[8]

Young women are often diagnosed with HIV after the diagnosis of an unplanned pregnancy, leading to the dual impact of a new diagnosis and an unplanned pregnancy. Biological factors such as the presence of a sexually transmitted infection (STI), exposure to partners with acute HIV infection, and sharing partners within sexual networks may increase the likelihood of HIV exposure to a recently infected partner. In young women, the immature cervix is lined with columnar epithelium instead of squamous epithelium; this may increase the susceptibility to HIV infection.[9] Moreover, larger thymic volume and activity in adolescents may slow natural progression to acquired immune-deficiency syndrome (AIDS) compared with older adults.[10] Sexual practices among adolescents play an important role in HIV transmission. They do not consider oral or anal sex as ‘real sex’. Oral sex is viewed as less risky and often this is not explored in the sexual history.[11] Physicians usually communicate ineffectively and are unclear when obtaining a sexual history; hence, risky behaviours are often missed. Sexual reproductive healthcare is central to medical care of adolescents and should include screening for STIs, risk-reduction counselling and contraception counselling. Human papillomavirus vaccination and screening are important elements of this care.[12]

HIV counselling, testing and disclosure

After testing for HIV infection adolescents are less likely to link to services for prevention (barrier and hormonal contraception access, circumcision) and treatment interventions. The following groups of adolescents (key populations) are considered to be most at risk for HIV and STIs: adolescent males who have sex with men, adolescents who are sexually exploited or engage in sex work, adolescents who abuse substances, transgender adolescents (male and female), adolescents affected by AIDS (orphans, children of chronically ill caregivers), and adolescent clients of sex workers and the partners of these clients.[2] It should be noted that the

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Children’s Act 38 of 2005 enables a child of ≥12 years with sufficient emotional and mental maturity to comprehend the risks and benefits of treatment to consent to HIV testing and treatment without parental consent.[13] HIV testing and counselling (HTC), with linkages to prevention, treatment and care, should be offered to all adolescents as a priority, especially those in the designated high-risk groups. Counselling, with an emphasis on the potential benefits and risks of HIV disclosure, should be offered before and after testing. This group should be empowered and supported to disclose their HIV status. Underutilisation of HTC services results in late diagnosis and complications associated with HIV infection.[12] The support during disclosure may include healthcare providers, parents, peers and the community. Privacy, confidentiality and support to cope with negative reactions such as discrimination and alienation from family, friends and community are essential to successful HIV testing and disclosure, access to treatment, linkage and retention in care. Disclosure of HIV status is a continuous process that occurs throughout adolescence and ranges from informing young people of their HIV status (either at diagnosis or later, depending on their age) to adolescents independently sharing their HIV status with others when they are ready to do so. Adolescents need support from healthcare providers, peers and the community to disclose safely and confidentially, and to be able to cope with any negative reactions from family, friends and their community. Key adolescent populations are particularly sensitive to confidentiality issues as they are often at risk of legal consequences and abuse linked to their high-risk practices and lifestyles.

Adolescent HIV treatment in SA

Current evidence suggests that survival of HIV-infected adolescents is associated with effective ART. The current SA ART guideline (2015) recommends ART for all children 10 - 15 years of age with WHO clinical stage 3 or 4 disease or a CD4 count ≤500 cells/μL.[2] Those with a CD4 count of ≤200 cells/μL, WHO stage 4 disease, multidrug- or extreme drug-resistant tuberculosis (MDR/XDRTB) should initiate ART within 7 days of establishing eligibility to commence treatment. Pregnant adolescent women should be commenced on ART, irrespective of the CD4 count or WHO clinical stage. The guidelines make a distinction in the recommended nucleoside reverse-transcriptase inhibitor (NRTI) choice for treatment of adolescents based on age and weight. Adolescents <40 kg or <15 years should be commenced on abacavir and lamivudine or emtricitabine together with efavirenz. Those with an undetectable viral load (VL) (<50 copies/mL) and no adverse events may remain on this regimen until eligible for transition to the fixeddose combination pill (tenofovir, emtricitabine and efavirenz) at 15 years and if their weight is >40 kg. Prior to this transition, a creatinine clearance (CrCl) and urine dipstick examination should be performed to exclude renal disease. If the CrCl is <80 mL/min or >1+ proteinuria is observed on urine dipstick examination the patient should be referred for expert advice before transition to the fixed-dose combination pill. Adolescents who fail first-line ART, defined by two consecutive VL measurements >1 000 copies/mL more than 1 month apart in spite of good adherence, should be changed to a second-line regimen of zidovudine and lamivudine together with lopinavir/ritonavir. Before changing this regimen, the hepatitis B status should be checked. If the patient is hepatitis B surface antibody positive, tenofovir should be added.

Adolescents who fail second-line therapy should be referred to a specialist for planning and motivation of third-line ART. The choice of regimen is based on HIV genotype resistance testing, previous drug exposure, potential mutations and expert opinion.

Case vignette

A 13-year-old boy was commenced on ART (stavudine, lamivudine and efavirenz) in June 2009. His baseline CD4 count was 168 cells/µL and VL 86 342 copies/mL. His VL was undetectable at 6 months and 1 year after commencing ART. The first VL suppression was only recorded in August 2010. Throughout this time he was counselled on the importance of using his medication as prescribed. In July 2011, the treatment regimen was changed to tenofovir, lamivudine and efavirenz. The VL was detectable in February 2012 (10 983 copies/mL), although he always reported taking his medi cation. The regimen was then changed to second-line treatment of tenofovir, lamivudine and lopinavir/ritonavir (Aluvia). In July 2012, despite the change in regimen, his VL remained detectable (12 589 copies/mL). Genotype resistance tests indicated resistance to non-NRTIs only. The patient remained on second-line treatment. In early 2013, the VL was 20 000 copies/mL. At that stage his grandmother reported that the HIV diagnosis was disclosed to him and he was non-adherent with his medication. He received extensive counselling with regard to risk reduction and adherence to ART. Learning points: There are several barriers that challenge success ful treatment in HIV-infected adolescents. Denial of diagnosis and poor understanding of the need for treatment are common, especially among those recently infected.[14] An adolescent’s perception of the future benefits of treatment is limited by concrete and currentorientated thinking. Side-effects that lead to stigmatisation, such as lipoatrophy (stavudine, zidovudine), diarrhoea and flatulence (lopinavir/ritonavir) and gynaecomastia (efavirenz), may be intole rable.[12] Failure or fear of disclosure may result in mistrust of parents and medical treatment providers. Rebellion against parents and other authority could lead to poor adherence after long periods of compliance.[12] Misinformation, lack of family support and stigmatisation from peers may further influence adherence. Mental health issues, such as depression, low self-esteem and hopelessness, and substance abuse could further influence medi cation compliance.[12] Different strategies to improve adherence include pill boxes, reminder systems (cellular telephone alarms, short messaging services (SMS)) to maintain daily schedules, peer-to-peer adherence messages and counselling together with healthcare provider and parent support.[12] Low pill burden and once-daily treatment regimens with minimal side-effects also impact on long-term compliance.[7] Attention to monitoring adherence and providing ongoing support are key to effective ART.

Conclusion

There remain barriers to the development and sustainability of comprehensive multidisciplinary care for adolescents, such as fragmented, vertical healthcare systems, transportation, distance, timing and access to services. Ideally, there should be specialised services at accessible sites such as mobile or outreach clinics together with consultation with HIV and other experts.[15] Transition to adult services may pose a challenge to the young adult and consideration should be given to a stepwise transition plan to a multidisciplinary team, e.g. gynaecology services, general primary care providers and adult HIV specialists. Adolescents require access to appropriate, comprehensive healthcare services to benefit from effective HIV prevention and treatment strategies.

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References 1. Sawyer SM, Afifi RA, Bearinger LH, et al. Adolescence: A foundation for future health. Lancet 2012;379:1630-1640. [http://dx.doi.org/10.1016/S0140-6736(12)60072-5] 2. National Department of Health, South Africa. National Consolidated Guidelines for PMTC and Management of HIV in Children, Adolescents and Adults, April 2015. Pretoria: Department of Health, 2015. 3. UNAIDS. Fact Sheet. Global statistics. http://www.unaids.org/en/resources/campaigns/2014/2014gapreport/ factsheet (accessed 27 August2015). 4. Ferrand RA, Bandason T, Musvaire P, et al. Causes of acute hospitalization in adolescence: Burden and spectrum of HIV-related morbidity in a country with an early-onset and severe HIV epidemic: A prospective survey. PLoS Med 2010;7(2):e1000178. [http://dx.doi.org/10.1371/journal.pmed.1000178] 5. Anderson EJ, Yogev R. The glory of guidelines and the twilight of reality. Controversies and challenges in the prevention and treatment of HIV in children. Expert Rev Anti Infect TherÂ 2012;10(7):761-774. [http://dx.doi.org/ 10.1586/eri.12.60] 6. Pettifor A, Bekker L-G, Hosek S, et al. Preventing HIV among young people: Research priorities for the future. J AIDS 2013;63(2):S155-S160. [http://dx.doi.org/10.1097/QAI.0b013e31829871fb] 7. Rakhmanina NY, Capparelli EV, van der Anher JN. Personalized therapeutics: HIV treatment in adolescents. Clin Pharmacol Ther 2008;84(6):734-740.

8. Lowenthal ED, Bakeera-Kitaka S, Marukutira T, Chapman J, Goldrath K, Ferrand RA. Perinatally acquired HIV infection in adolescents from sub-Saharan Africa: A review of emerging challenges. Lancet Infect Dis 2014;14(7):627-639. [http://dx.doi.org/10.1016/S1473-3099(13)70363-3] 9. Moscicki AB, Ma Y, Holland C,Vermund SH. Cervical ectopy in adolescent girls with and without human immunodeficiency virus infection. J Infect Dis 2001;183(6):865-870. [http://dx.doi.org/10.1086/319261] 10. Rosenburg PS, Goedert JJ, Biggar RJ. Effect of age at seroconversion on natural AIDS incubation distribution. AIDS 1994;8:803-810. 11. Halpern-Felsher BL, Cornell JL, Kropp RY, Tschann JM. Oral versus vaginal sex among adolescents: Perceptions, attitudes and behavior. Paediatrics 2005;115:845-851. 12. Agwu AL, Fairlie L. Antiretroviral treatment, management challenges and outcomes in perinatally HIV-infected adolescents. J Int AIDS Soc 2013;16:18579. [http://dx.doi.org/10.7448/IAS.16:118579] 13. Childrenâ&#x20AC;&#x2122;s Act No. 38 of 2015, Section 29. 14. Agwu AL, Siberry GK, Ellen J, et al. Predictors of highly active antiretroviral therapy utilization for behaviorally HIV-1-infected youth: Impact of adult versus pediatric clinical care site. J Adolesc Health 2012;50(5):471-477. [http://dx.doi.org/10.1016/j.jadohealth.2011.09.001] 15. Napierala Mavedzenge SM, Doyle AM, Ross DA. HIV prevention in young people in sub-Saharan Africa: A systematic review. J Adolesc Health 2011;49(6):568-586. [http://dx.doi.org/10.1016/j. jadohealth.2011.02.007]

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ARTICLE

Human papillomavirus (HPV) vaccination of adolescents in the South African private health sector: Lessons from the HPV demonstration project in KwaZulu-Natal N Tathiah,1 BSc (Hons), MB ChB, Dip HIV Man, MS (Epi), MMed (PHM), FCPHM; M Naidoo,2 MB ChB, MFamMed, FCFP, MSc (Sports Medicine), Dip HIV Man, DipPEC, PhD; I Moodley,3 PhD Inkosi Albert Luthuli Central Hospital and Discipline of Public Health Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa 2 Discipline of Family Medicine, School of Nursing and Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa 3 Discipline of Public Health Medicine, School of Nursing and Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa 1

Corresponding author: N Tathiah (tathiah@ukzn.ac.za)

In South Africa (SA), >4 000 women die annually of cervical cancer, a disease caused by the human papillomavirus (HPV). Infections caused by certain genotypes of HPV increase the risk of cervical cancer. HIV-infected women in particular are more likely to have persistent HPV infection, with higher-risk genotypes. In SA, two vaccines (HPV quadrivalent (types 6, 11, 16, and 18) vaccine, recombinant (Gardasil) and HPV bivalent (types 16 and 18) vaccine, recombinant (Cervarix)) are currently registered for the prevention of HPV-related disease. In the past, there have been significant challenges to achieving high coverage and uptake of vaccination – contributory factors include cost and lack of awareness. An HPV demonstration project among schoolgirls in rural KwaZulu-Natal showed that high vaccine uptake is achievable. In 2014, the National Department of Health launched the national HPV vaccination programme among female learners attending public schools. Awareness of HPV vaccination among healthcare providers, education of parents, teachers and learners, and avoidance of missed opportunities for vaccination are vital to the success of the programme. Primary healthcare practitioners may play an important role in cervical cancer prevention by identifying and offering vaccination to girls who miss the opportunity to be vaccinated at school. HPV vaccination should be considered as one arm of a comprehensive programme of cervical cancer prevention and control. S Afr Med J 2015;105(11):954. DOI:10.7196/SAMJ.2015.v105i11.10135

In South Africa (SA), cervical cancer is diagnosed in >7 700 women each year, with >4 000 women dying annually of the disease.[1] Cervical cancer is caused by human papillomavirus (HPV) infection, the most common viral infection of the reproductive tract.[2] More than 190 types of HPV have been identified; these are classified as high- or low-risk groups, depending on their potential to cause cancerous lesions.[2] HPV infection results in a number of conditions in males and females, ranging from precancerous lesions to those that become cancerous.[2] While the majority of HPV infections may result in spontaneous resolution without symptoms or disease, persistent infection with high-risk types may result in disease.[2] In women, persistent infection with HPV high-risk types 16 and 18 may lead to precancerous lesions, which if left untreated may progress to cervical cancer. For males and females, 90% of all cases of anogenital warts are caused by HPV high-risk types 6 and 11.[2] HIV-positive women have a higher prevalence and persistence of HPV infections, with an increased progression to cervical cancer.[2] Cervical HPV infection is diagnosed using tests based on HPVDNA performed on cervical or vaginal swabs. Routine screening is done by cytology or visual inspection of the cervix by staining with acetic acid. HPV-induced changes in cervical epithelium are detected by the Papanicolaou (Pap) test. Precancerous lesions are treated by cryotherapy or surgical excision of the affected areas.[2] In SA, there are currently two vaccines registered for the prevention of HPV-related disease: a quadrivalent vaccine (against HPV types 6,

11, 16 and 18 (Gardasil)) and a bivalent vaccine (against HPV types 16 and 18 (Cervarix)).[2] Both vaccines are intended for prophylactic use – before the onset of sexual activity and exposure to HPV.[2] The quadrivalent vaccine is indicated for use in females and males ≥9 years of age.[2] It can be administered according to a 3-dose (0, 2, 6 months) or 2-dose (0 and 6 months) schedule. The second dose should be given a minimum of 1 month after the first dose, and the third dose a minimum of 3 months after the second dose.[2] The bivalent vaccine is indicated for use in males and females ≥9 years of age. The recommended dosing schedule is 0 and 6 months. The second dose can be given between 5 and 7 months after the first dose.[2] The need for booster doses for either the quadrivalent or bivalent vaccines has not been established. Both vaccines should be administered intramuscularly (0.5 mL) in the deltoid region.[2] The vaccines should be stored in a refrigerator (2 - 8oC) and should not be frozen.[2] Neither vaccine contains live biological products and are non-infectious; they also do not contain any preservative agents.[2] Studies have shown that both vaccines are safe and highly immunogenic after administration. Current evidence indicates that the 2-dose schedule in females (9 - 14 years) is non-inferior to the 3-dose schedule.[2] The vaccines have been shown to be safe and immunogenic – also in HIV-positive individuals.[2] Countries such as the USA, Australia, the UK, Canada and France offer HPV vaccination as part of a national immunisation programme.[3] In SA, historically, there has been a limited uptake of the HPV vaccine in the private sector, where estimates indicate that

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approximately 50 000 individuals may have been vaccinated with the HPV vaccine between 2009 and 2014.[4] Contributory factors may have been the high cost of the vaccines (approximately ZAR650 per dose of vaccine), and a paucity of knowledge and awareness around cervical cancer and HPV, and vaccine availability among healthcare workers and patients.[4]

HPV demonstration project in KwaZulu-Natal

An HPV demonstration project was conducted among 963 female learners (9 - 12 years) in rural KwaZulu-Natal (KZN) and showed a high uptake of the vaccine, using the delivery model of school health teams. The uptake of the vaccine was 99.7%, 97.9% and 97.8% for the first, second and third doses, respectively.[5] The high level of HPV vaccine delivery and uptake seen in this demonstration project is most likely owing to a combination of factors. Firstly, there was intensive communication with and education of all stakeholders, including the Department of Health (DOH) and the Department of Education (DOE) at national, provincial and district level, school governing bodies, parents, learners, educators, healthcare workers, community leaders and the media prior to initiating vaccination. Community engagement and mobilisation was an integral part of this process, as was the role of the media in promoting awareness. Secondly, there was emphasis on obtaining informed consent from parents or guardians in a timely manner so that questions and concerns with regard to the safety and other long-term effects could be satisfactorily addressed. The third factor involved the optimisation of aspects of the healthcare system considered crucial to the success of the vaccination project. These included the leadership of members of the DOH and DOE, the project team, management of the human resource capacity (including training of the existing school health teams), and partnerships that existed between different government departments and the community, and between public and the private sectors. Other key aspects of the healthcare system included information management, which was important in terms of monitoring delivery, uptake and adverse events, and management of the cold chain and infrastructure.[5] The high vaccine uptake observed in this HPV demonstration project is comparable to findings from other studies.[6-8] A schoolbased HPV vaccination programme in Brazil also found high rates of vaccine uptake – 87.5%, 86.3% and 85.0% for the three doses, respectively.[6] A multicountry study of vaccination programmes in Peru, Uganda, Vietnam and India showed a high coverage in schoolbased programmes in the first 3 countries (>80%).[7] In India, where a set of mixed strategies were used (school-based healthcare centres and community campaigns), coverage varied between 68.4% and 87.8%, depending on the populations targeted.[7] A study of the vaccination of 87 000 girls (9 - 18 years) in 7 lowincome countries (Bhutan, Bolivia, Cambodia, Cameroon, Haiti, Lesotho and Nepal) using school-based strategies, health facility approaches, and combination school and facility models found a range of coverage rates depending on the delivery model.[8] Overall, for all the countries, the model using the health facility alone had a coverage of 77%, while the school-based and combination strategies had a coverage >90%.[8] While school-based programmes have generally exhibited high uptake or coverage rates, the opposite has been shown in non-school-based programmes. In the USA, which uses a non-school-based model, coverage has been reported as 35% for all 3 doses.[9] HPV vaccination was introduced into the routine immunisation schedule in 2006 for girls 11 or 12 years old, with a recommendation for catch-up doses in females aged 13 - 26 years.[10] In 2011, routine vaccination of

males in the same age groups as the female target population was recommended. The vaccine type HPV prevalence decreased by >50% (from 11.5% to 5.1%).[10] The US Centers for Disease Control and Prevention (CDC) highlighted three areas to be addressed to improve the HPV vaccination coverage: the education of parents, as many do not understand the need for the vaccine or have concerns over its safety; healthcare providers who will be involved in recommending the vaccine – some are less likely to recommend the HPV vaccine than they would other vaccines; and the need to reduce missed opportunities for vaccination during healthcare visits.[9] Experiences from HPV vaccine demonstration projects in other countries have shown that public messaging around cervical cancer, HPV, and the HPV vaccine has an important impact on the acceptability and effectiveness of vaccination programmes.[6-8] The success of the vaccination programme in Brazil is attributed to the school-based advertising strategy and the role of the media.[6] The information disseminated in schools played a significant role in the parents consenting to vaccinate their children. Also, the learners had an important part in actively conveying information from schools to their homes.[6-8] A report of a school-based HPV vaccination programme in Peru highlighted the feasibility of using the existing resources in the healthcare system.[11] Key elements related to the preparedness of the healthcare system were human resources, training, cold chain and infrastructure, and the recording and reporting of vaccinations.[11] The facilitating factors were planning, co-ordination between education and health, facilitation between levels of the healthcare system, training, and comprehensive community awareness strategies.[11]

DOH roll-out of HPV vaccines in schools

In April 2014, the SA DOH launched the national school-based HPV vaccination programme for Grade 4 (≥9 years old) female learners attending public schools, with a target population of an estimated 500 000 learners.[12] A 2-dose strategy was adopted, using the bivalent vaccine (Cervarix).[12] The vaccination programme has been included in the Extended Programme on Immunisation (EPI).[12] Prior to the commencement of the vaccination process, the Department of Basic Education (DBE) released a Guide for Educators, and made available vaccination consent forms, letters to parents and caregivers, and promotional material.[12] Unpublished preliminary data indicate that the coverage is >90% for both the first and second rounds of vaccination.[4]

Implications for the primary healthcare provider

Despite the HPV vaccine being rolled out through the school health teams to female learners in Grade 4 (≥9 years), it is anticipated that some learners may miss the opportunity to be vaccinated because the vaccine is offered to public school learners only. Other learners may miss vaccination owing to absenteeism or no access to school health teams.[13] This affords the primary healthcare practitioner the opportunity to contribute towards primary prevention of cervical cancer. Essential to this is the ability to identify girls who are eligible for the HPV vaccination school programme but have missed the opportunity, and to provide appropriate counselling to their parents. A clinical algorithm (Fig. 1) is outlined, which may be of use to the practising general practitioner or primary healthcare provider. The Children’s Act 38 of 2005 provides for a child ≥12 years of age with sufficient emotional and mental maturity, who is able to comprehend the risks and benefits of treatment, and can consent to medical treatment without consent from a parent or guardian.[14] The

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Recommendations for private healthcare providers to increase awareness and improve uptake of HPV vaccination among adolescents

Identify girl/woman eligible for the HPV vaccine (9 - 26 years of age). If yes:

Is the client in Grade 4, and ≥9 years? Does the client qualify for vaccination by the school health team?

If yes to both questions, ask the parent to discuss HPV vaccination roll-out at the local school with the school secretary

If the client is not eligible for the school health vaccination programme consider the following: Does the client have a medical aid that will pay for the vaccine? Can the client/parents afford to pay for the vaccine?

If yes to either of the questions: Obtain informed consent from parent or client >12 years who is able to comprehend the implications of the vaccination

Perform the vaccination at 0 and 6+ months Fig. 1. Clinical algorithm for healthcare providers.

implication is that a child ≥12 years meeting these criteria can independently consent to HPV vaccination. However, children <12 years require parental consent; the DBE provides information and forms for parents to sign before the visit by school health teams.

Case vignette

A 9-year-old girl is asked to get her parents to sign consent forms for the administration of the HPV vaccine. The forms are signed by the mother and the child is administered the vaccine 2 days later when the school health team visits the school. Subsequently, the child develops a fever for a few days, which resolves spontaneously. The parents are upset and approach the school for an explanation. The parents state that they were not informed of this possible side-effect of the vaccine.

Learning point: It is important to note that signing the consent form may not necessarily imply informed consent; therefore, it is important that members of the public are given the opportunity to ask questions about the intervention. The Health Professions Council of South Africa (HPCSA) states that the legal requirements for proper informed consent in SA should include the following: • ‘Knowledge of the nature or extent of the harm or risk; • Appreciated and understood the nature of the harm or risk; • Consented to the harm or assumed the risk; and • The consent must have been comprehensive (i.e. extended to the entire transaction, inclusive of its consequences).’[15]

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In view of the demonstrated success of vaccinating learners in a school-based HPV vaccination delivery model, it is recommended that the private sector increase knowledge and awareness around cervical cancer, HPV and the need for HPV vaccination, especially in adolescents. This strategy should be viewed as part of a country-wide comprehensive programme for cervical cancer prevention and control that targets girls and women across each stage of their life course. References 1. Bruni L, Barrionuevo-Rosas L, Serrano B, et al. Institut Català d’Oncologia (ICO) Information Centre on HPV and Cancer (HPV Information Centre). Human papillomavirus and related diseases in South Africa. Summary Report. 2014. www. hpvcentre.net (accessed 26 March 2014). 2. World Health Organization. Human papillomavirus vaccines: WHO position paper. Weekly Epidemiological Record 2014;43(89):465-492. 3. Boyce T, Holmes A. Addressing health inequalities in the delivery of the human papillomavirus vaccination programme: Examining the role of the school nurse. PLoS One 2012;7(9):e3416. [http:// dx.doi.org/10.1371/journal.pone.0043416] 4. Richter K. Implementation of HPV Vaccination in South Africa. Pretoria: Public Health Association of South Africa, 2015. 5. Moodley I, Tathiah N, Mubaiwa V, et al. High uptake of Gardasil vaccine among 9 - 12-year-old schoolgirls participating in an HPV vaccination demonstration project in KwaZulu-Natal, South Africa. S Afr Med J 2013;103(5):318-321. [http://dx.doi. org/10.7196/samj.6414] 6. Fregnani JHTG, Carvalho AL, Eluf-Neto J, et al. A school-based human papillomavirus vaccination program in Barretos, Brazil: Final results of a demonstrative study. PloS One 2013;8(4):e62647. [http://dx.doi.org/10.1371/journal.pone.0062647] 7. LaMontagne DS, Barge S, Nga TL, et al. Human papilloma virus vaccine delivery strategies that achieved high coverage in low- and middle-income countries. Bull World Health Organ 2011;89:821-830B. [http://dx.doi.org/10.2471/ BLT.11.08986] 8. Ladner J, Besson M, Hampshire R, et al. Assessment of eight HPV vaccination programs implemented in lowest income countries. BMC Public Health 2012;12:370. [http://dx.doi. org/10.1186/1471-2458-12-370] 9. Centers for Disease Control and Prevention (CDC). Human papillomavirus vaccination coverage among adolescent girls, 2007-2012, and post licensure vaccine safety monitoring, 20062013. MMWR Morb Mortal Wkly Rep 2013:591. 10. Markowitz LE, Hariri S, Lin C, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010. J Infect Dis 2013;208(3):385-393. [http://dx.doi.org/10.1093/ infdis/jit192] 11. Penny M, Bartolini R, Mosqueira NR, et al. Strategies to vaccinate against cancer of the cervix: Feasibility of a school-based HPV vaccination program in Peru. Vaccine 2011;29(31):5022-5030. [http://dx.doi.org/10.1016/j.vaccine.2011.04.078] 12. National Department of Health. Human papilloma virus (HPV) vaccination campaign. 2014. http://www.health.gov.za/ (accessed 26 March 2014). 13. Botha M, Richter K. Cervical cancer prevention in South Africa: HPV vaccination and screening both essential to achieve and maintain a reduction in incidence. S Afr Med J 2015;105(1):3335. [http://dx.doi.org/10.7196/samj.9233] 14. McQuoid-Mason DJ. Can children aged 12 years or more refuse life-saving treatment without consent or assistance from anyone else? S Afr Med J 2014;104(7):466-467. [http://dx.doi. org/10.7196/samj.8417] 15. Health Professions Council of South Africa (HPCSA). HPCSA Guidelines for Good Practice in the Health Care Professions: Seeking Patients’ Informed Consent: The Ethical Considerations. Booklet 9. Pretoria: HPCSA, 2008:1-13.

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NOVEMBER 2015

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True (A) or false (B): SAMJ Appropriate indications for positron emission tomography/com puted tomography (PET/CT) 1. P ET imaging permits physicians to avoid costly, often high-risk biopsy surgery in cancer cases, resulting in significant cost savings. Antenatal care in SA 2. Offered routinely to healthy pregnant women, antenatal care is a unique preventive public health intervention. 3. Early antenatal booking represents an opportunity to determine gestational age, treat infections such as syphilis, offer dietary supplementation and institute antiretroviral therapy. 4. Uncertain gestational age is an important cause of pregnancy morbidity linked to missed diagnosis of fetal growth impairment, iatrogenic preterm delivery and unnecessary labour induction for suspected post-dates pregnancy, leading to increased use of caesarean section. School-based human papillomavirus (HPV) vaccination 5. Poor uptake of screening plays a major role in the high prevalence of cervical cancer in SA. 6. School-based HPV vaccination programmes provide an oppor tunity for successful education about vaccination and screening. Evaluation of fetal magnetic resonance imaging (MRI) in one SA referral centre 7. The most common indication for fetal MRI is suspicion of con genital cardiac defects. Childhood cancer incidence in South Africa (SA), 1987 - 2007 8. Cancer deaths represent 60% of new annual cases in childhood populations of Africa, while the equivalent figure is 20% or less in developed countries of Europe and North America. 9. Retinoblastoma and hepatic tumours are highest in coloured children, germ cell tumours highest in Asian/Indian children and Kaposi’s sarcoma highest in black Africans. 10. In sub-Saharan Africa, the incidence of Kaposi’s sarcoma in children has increased with a high prevalence of HIV, but the incidence rates of Kaposi’s sarcoma in SA are much lower than in other southern African countries.

CME Improving adolescent maternal health 11. The most common causes of maternal mortality globally are obstetric haemorrhage, hypertension and infections. 12. Adolescent girls <15 years of age are five times more likely to die from complications related to childbirth than women in their twenties. Understanding and responding to HIV risk in young SA women: Clinical perspectives 13. Young women are a key population in the HIV epidemic. 14. Young women in school are more at risk of acquiring HIV than young women out of school. Adolescent antiretroviral management: Understanding the com plexity of non-adherence 15. Current guidelines have made recommendations for adult ART regimens and dosing schedules to be applied to adolescents weighing >35 kg. 16. Psychosocial factors associated with treatment are a major hin drance to ART adherence. Adolescent HIV treatment issues in SA 17. Heterosexual HIV transmission accounts for the majority of HIV infections among women aged 15 - 24 years. 18. HIV treatment should only be initiated in adolescents when the CD4 count is <200 cells/µL. Human papillomavirus (HPV) vaccination of adolescents in the SA private health sector: Lessons from the HPV demonstration project in KwaZulu-Natal 19. There are 190 genotypes of HPV, each of which has a similar risk of causing cervical cancer. 20. HPV vaccines are indicated for use in females only.

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November 2015, Vol. 105, No. 11

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