SAMJ Vol 107, No 6 (2017)

JUNE 2017

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EDITORIAL SA statistics not suitable for monitoring injury and violence SDGs IN PRACTICE Lessons from history – the vulnerable in research TB among medical undergraduates in Cape Town Perils of the femoral haemodialysis catheter REVIEW Timing and safety of sentinel lymph node biopsy and neoadjuvant chemotherapy RESEARCH Improving ICD coding through training and support Clinical management of cytomegalovirus retinitis Gunshot-acquired spinal cord injury in SA

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JUNE 2017 PRINT EDITION

FROM THE EDITOR 3

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

Surplus people Bridget Farham

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

EDITOR’S CHOICE CORRESPONDENCE

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The World Health Organization excludes Mycobacterium tuberculosis from the 2017 priority pathogens list N Padayatchi, S Mahomed, M O’Donnell, F Conradie, K Naidoo

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Bridging non-communicable disease burden research to clinical care: A rising tide or a tidal wave?

I Golovaty, A van Heerden, Z Essack, H van Rooyen, R Barnabas

IZINDABA 11

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CEO AND PUBLISHER Hannah Kikaya Email: hannahk@hmpg.co.za

TECHNICAL EDITORS Emma Buchanan Kirsten Morreira Naadia van der Bergh Paula van der Bijl

OBITUARY Cecil John Tainton Craig South Africa’s vital statistics are currently not suitable for monitoring progress towards injury and violence Sustainable Development Goals M Prinsloo, D Bradshaw, J Joubert, R Matzopoulos, P Groenewald

PRODUCTION MANAGER Emma Jane Couzens

IN PRACTICE

DTP AND DESIGN Clinton Griffin Travis Arendse

MEDICINE AND THE LAW Exploitation of the vulnerable in research: Responses to lessons learnt in history A Dhai

CHIEF OPERATING OFFICER Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za

ISSUES IN PUBLIC HEALTH When students become patients: TB disease among medical undergraduates in Cape Town, South Africa H van der Westhuizen, A Dramowski

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CLINICAL ALERT Beware: The femoral haemodialysis catheter – a surgeon’s perspective T du Toit, D Thomson, E Muller

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ISSUES IN MEDICINE Complementary medicines: When regulation results in revolution L Fourie, F Oosthuizen, K du Toit

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CLINICAL UPDATE Establishing an academic biobank in a resource-challenged environment C C Soo, F Mukomana, S Hazelhurst, M Ramsay

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HEALTHCARE DELIVERY Audits of oncology units – an effective and pragmatic approach R P Abratt, D Eedes, B Bailey, C Salmon, Y Govender, I Oelofse, H Burger

REVIEW 41

HMPG

MANAGING EDITORS Ingrid Nye Claudia Naidu

30 days in medicine B Farham

EDITORIAL 14

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

Sentinel lymph node biopsy and neoadjuvant chemotherapy in the management of early breast cancer: Safety considerations and timing J Edge, S Nietz

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June 2017, Print edition

SALES MANAGER (CAPE TOWN) Azad Yusuf JOURNAL ADVERTISING Charles William Duke Reneé Hinze Ladine van Heerden Makhadzi Mulaudzi Charmalin Simpson Ismail Davids ONLINE SUPPORT Gertrude Fani FINANCE Tshepiso Mokoena HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Dr M J Grootboom, Mrs H Kikaya, Prof. E L Mazwai, Dr M Mbokota, Dr G Wolvaardt ISSN 0256-9574 SAMA website: www.samedical.org Journal website: www.samj.org.za

RESEARCH 46

Training and support to improve ICD coding quality: A controlled before-and-after impact evaluation R Dyers, G Ward, S du Plooy, S Fourie, J Evans, H Mahomed

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Analysis of HIV disease burden by calculating the percentages of patients with CD4 counts <100 cells/µL across 52 districts reveals hot spots for intensified commitment to programmatic support L M Coetzee, N Cassim, D K Glencross

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Cytomegalovirus retinitis in Cape Town, South Africa: Clinical management and outcomes* S R J Lapere, J C Rice

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Characteristics and outcomes of gunshot-acquired spinal cord injury in South Africa* C Joseph

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Screening for gestational diabetes mellitus in a South African population: Prevalence, comparison of diagnostic criteria and the role of risk factors* S Adam, P Rheeder

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Effects of exogenous human insulin dose adjustment on body mass index in adult patients with type 1 diabetes mellitus at Kalafong Hospital, Pretoria, South Africa, 2009 - 2014* T S A Sehloho, D G van Zyl

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The status of vaccine availability and associated factors in Tshwane government clinics* N J Ngcobo, M G Kamupira

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Report on the first government-funded opioid substitution programme for heroin users in the Western Cape Province, South Africa* G Michie, S Hoosain, M Macharia, L Weich

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JUNE 2017

Background photo: Dr Thabo Matsaseng | Damien Schumann / Faculty of Medicine and Health Sciences, Stellenbosch University

PRINT EDITION

EDITORIAL SA statistics not suitable for monitoring injury and violence SDGs IN PRACTICE Lessons from history – the vulnerable in research TB among medical undergraduates in Cape Town Perils of the femoral haemodialysis catheter

Box photos: Medical statistics | hvostik; Catheter | ivan68; Fractured spine | wildpixel

REVIEW Timing and safety of sentinel lymph node biopsy and neoadjuvant chemotherapy RESEARCH Improving ICD coding through training and support Clinical management of cytomegalovirus retinitis Gunshot-acquired spinal cord injury in SA

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June 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

FROM THE EDITOR

Surplus people Figures for the year 2015 from the UN Refugee Agency (UNHCR) showed that there were 65.3 million forcibly displaced people worldwide, 21.3 million refugees, 10 million stateless people and 107 100 refugees re-settled. Of these, 53% came from three countries – Somalia, Afghanistan and Syria. The top hosting countries are Turkey, Pakistan, Lebanon, Islamic Republic of Iran, Ethiopia and Jordan. Europe takes in just 6%, the Americas 12% and Asia and the Pacific (which includes Australia) 14%. There is a stark figure in the UNHCR 2015 report – 33 972 people a day flee their homes because of conflict and persecution. Experts say that figures such as this have not been seen since World War II. The term ‘refugee’ is misleading – most of these people are what are called internally displaced people (IDP). These are people who are forced from their homes but have not left their countries, and in most cases cannot do so. Refugees and asylum seekers are people who have been forced from their homes and their countries. IDP cannot simply ‘go home’– their homes are no longer available and they can no longer live normal lives, often landing up in vast camps for displaced people.

Syria is the country that springs to mind when we think about forcibly displaced people generally. But Syrians make up only onethird of the world’s refugees. Closer to home there are three major humanitarian crises unfolding – South Sudan, Somalia and northern Nigeria. There are at least 1.9 million IDP in each of South Sudan and northern Nigeria. In Somalia there are 6 million people facing starvation. Across the Horn of Africa there are around 40 million people at risk.

The proximal cause of the suffering in Africa is famine. This is largely man made, even though below-average rainfall has made local food production difficult. The crisis in northern Nigeria is due to 8 years of violent conflict, leading to widespread displacement and a desperate shortage of essential healthcare. This is part of the Chad Basin crisis, which affects some 17 million people. Likewise, in South Sudan and Somalia, it is military conflict that disrupts food production and prevents the delivery of any humanitarian assistance that is available.

According to John Campbell, writing in The Conversation,[1] the situation is similar to the events that took place in Ethiopia in the early 1980s. Western governments failed to monitor and intervene in time to prevent or mitigate the famine. It was the global media event –

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Band Aid in 1984 – that focused the attention of Western governments, and the humanitarian assistance, when it arrived, was too little, too late. The causes of famine are complex, but include poor governance, inadequate planning, limited investment in development, ongoing violence and large-scale population displacement – and development assistance to Africa has declined since 1990, and is likely to decline further as the West focuses more on its own concerns.

The extent of Western interest in Africa is focused on the flow of oil and other commodities. Along with this are determined efforts to stop illegal migrants and refugees from entering the West. If you think that re-settling and aiding people is too expensive for Western countries, look at what they are spending on keeping people out – USD21 billion for Trump’s wall between the USA and Mexico, and the European Union (EU)’s EUR2.5 billion to bottle up migrants in Africa to prevent them from reaching Europe. The current cost of humanitarian assistance for Africa is insignificant in comparison.

What happened in 1980 is nothing in comparison to the scale of the current crisis, affecting an estimated 40 million people.

Humanitarian assistance has come far too late and is too little – the EU pledged only EUR760 million to the Horn of Africa late last year, and smaller pledges were made by European states in February this year. The USA has not yet said what it will pledge in food aid. In the words of Desmond Tutu, ‘we live in a moral universe’ where what happens to others affects us all.

Let’s not forget these ‘surplus people’.

Bridget Farham Editor ugqirha@iafrica.com 1. Campbell JR. Famine creeps in on Africa while the world’s media look elsewhere. The Conversation. https:// theconversation.com/famine-creeps-in-on-africa-while-the-worlds-media-looks-elsewhere76340?utm_medium=email&utm_campaign=Latest%20from%20The%20Conversation%20 for%20April%2025%202017%20-%2072585516&utm_content=Latest%20from%20The%20 Conversation%20for%20April%2025%202017%20-%2072585516+CID_2344e614d350e5011e79371e e445919a&utm_source=campaign_monitor_africa&utm_term=Famine%20creeps%20in%20on%20 Africa%20while%20the%20worlds%20media%20looks%20elsewhere (accessed 5 May 2017).

S Afr Med J 2017;107(6):465. DOI:10.7196/SAMJ.2017.v107i6.12558

June 2017, Print edition

EDITOR’S CHOICE

When students become patients: Tuberculosis among medical undergraduates in Cape Town, South Africa

Medical students in South Africa (SA) complete undergraduate training in communities with extremely high tuberculosis (TB) incidence rates (834 per 100 000 population in 2015). SA healthcare workers (HCWs) are at high risk of developing TB, with a three times increased risk for drug-sensitive TB (DS-TB) and an up to 6.7 times increased risk for drug-resistant TB (DR-TB) compared with the general population. Poor implementation of TB infection control measures (TB-IC) is reported from SA healthcare facilites, contributing to TB exposure and development of occupational TB disease among SA HCWs and health science students.

Latent TB incidence among SA medical students was measured by tuberculin skin test (TST) conversion at 23 cases per 100 personyears (95% confidence interval (CI) 12 - 43).[1] While this rate was lower than that of SA HCWs, it is three times higher than the average annual risk of TST conversion in HCWs from five other countries with a high TB burden (8.4/100; 95% CI 2.7 - 14). Knowledge about TB-IC has been shown to reduce the odds of a positive TST in medical students by >70% (adjusted odds ratio (OR) 0.29, 95% CI 0.09 - 0.98), indicating the importance of TB-IC training at undergraduate level. However, even if TB-IC knowledge can be improved at undergraduate level, the lack of clinician role models may impact on TB-IC practices negatively.

In a study reporting SA doctors’ experiences with occupational TB disease,[2] significant diagnostic delays and high rates of invasive procedures were documented. In addition to high mortality, morbidity and treatment side-effects, DR-TB has been demonstrated to have profound psychosocial impact among SA HCWs. Although data on the incidence and impact of occupational TB in SA HCWs is sparse, even less is known about the experiences of SA medical students with occupational TB. Van der Westhuizen and Dramowski, authors of the descriptive cross-sectional study in the current issue of SAMJ,[1] aimed to: (i) investigate the clinical presentation, diagnostic investigations and treatment of TB in medical students; (ii) describe students’ experiences of developing occupational TB; and (iii) evaluate the support systems utilised following TB diagnosis.

A questionnaire was completed by students at two medical schools in the Western Cape Province who had developed TB during their undergraduate medical training between 2010 and 2015. A sub-set of the respondents to the questionnaire participated in semi-structured interviews.

Twelve students reported a diagnosis of TB during their undergraduate training years. What was worrying was the delay reported in diagnosis – the mean delay between developing symptoms and seeking help was 3.2 weeks, and the mean diagnostic delay after consultation was 8.1 weeks. The main reason for this was fear of missing academic teaching and clinical duties. Health system delays were the biggest contributing factor to diagnostic delays, including difficulty accessing services during holidays, long waiting times at public hospitals and a low index of suspicion among private healthcare providers. Only 41.7% of initial diagnoses were correct. One participant was started empirically on a DS-TB regimen without pleural fluid being sent for TB culture, which delayed the diagnosis of DR-TB. Participants collected their medication from government clinics (n=7), private pharmacies (n=7) and training hospitals (n=2), and also reported switching between the above options. Half of the participants received directly observed treatment, but found it inconvenient owing to high transport costs and missed academic time.

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The study highlights the vulnerability of medical students at two of the eight SA medical schools, documenting substantial TB exposure and risk of progression to occupational TB. In comparison with the data from Naidoo et al.[2] reporting TB disease in medical doctors in KwaZulu-Natal, medical students had a greater incidence of extra-pulmonary TB (50% v. 20%) and a higher incidence of DR-TB (16.7% v. 10%). Fewer students than doctors (25% v. 75%) reported having easy access to specialised diagnostic procedures. Students (41.7%) had a lower percentage of initial correct diagnoses than doctors (52.5%), and experienced longer diagnostic delays. This may reflect the lack of student occupational health services and the perceived lower risk for occupational TB among students. Students consistently indicated that they struggled to access diagnostics and treatment, with prominent opportunity costs (lost academic time during treatment collection) and direct costs for transport.

The lack of national guidance and policies has led to an unjust situation where SA health science students train in a hazardous working environment with no recourse to assistance with diagnostic and treatment costs for an occupational disease. There is an urgent need for SA medical training institutions and the National Department of Health to develop policies for the provision and funding of health services for students with occupationally acquired TB disease.

Sentinel lymph node biopsy and neoadjuvant chemotherapy in the management of early breast cancer: Safety considerations and timing

Traditionally, operable breast cancer has been treated by primary surgery followed by adjuvant chemotherapy, radiotherapy, endocrine therapy and targeted therapy as indicated.[3] Primary systemic chemotherapy, more commonly known as neoadjuvant chemotherapy (NACT), was reserved for large inoperable tumours or for inflammatory breast cancer. Our current decisions on local therapy remain based on historical data, where surgery was the primary treatment modality.

The extent of surgery in the treatment of breast cancer has decreased dramatically following a surgical paradigm shift from maximum tolerated therapy towards minimum required therapy.

These shifts include the transition from routine axillary lymph node dissection (ALND) to sentinel lymph node biopsy (SLNB) in node-negative patients, and the transition from routine mastectomy to breast-conserving therapy. Conversely, the use of NACT in early breast cancer has increased dramatically over the past decade. This trend poses new challenges in the management of patients with early breast cancer, specifically with regard to decision-making on the management of the axilla and adjuvant radiation.

NACT in early breast cancer has no proven survival benefit, but has other potential advantages: • It allows assessment of the success of systemic therapy by monitoring the clinical and radiological responses • Tumour size and node involvement are reduced • Breast conservation rates increase by 10 - 30% • A pathological complete response (pCR) is a significant prognostic factor • A large proportion of patients in Europe and the USA are enrolled in clinical trials, which enables evaluation of response to therapy • It allows more axilla-preserving surgery.

The use of systemic therapy as the primary treatment modality also fits into the modern perception of breast cancer as a systemic disease.

June 2017, Print edition

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EDITOR’S CHOICE

Besides the prognostic implications of evaluating response, the use of NACT has the attractive potential to increase axilla-preserving surgical therapy by reducing the need for ALND in patients who are node-negative after NACT. NACT has major potential to decrease the extent of surgery performed in the axilla.

If the nodal status is negative prior to starting NACT, it is safe to do an SLNB after NACT. If a node-positive patient has evidence of axillary disease after NACT, they should have ALND. Patients who convert from node-positive to node-negative can have an SLNB, but: • At least three nodes should be removed • Both patent blue and 99mTc-nanocolloid should be used to identify the nodes • Any size of lymph node metastasis should be considered nodepositive and should prompt ALND.

Characteristics and outcomes of gunshot-acquired spinal cord injury in SA

Spinal cord injuries (SCIs) caused by assault present a unique challenge facing the healthcare system, in that very little is known about how these injuries manifest compared with other causes of injury. Understanding the nuances of gunshot SCIs could contribute towards better care provision.

This study by Joseph[4] sought to determine the characteristics of gunshot SCIs and compare both injury characteristics and outcomes between gunshot SCI and all other traumatic causes taken together.

The gunshot SCI sub-cohort was derived from a 1-year prospective, population-based study, including both tertiary-level hospitals providing SCI care in the Cape Metropolitan area of SA. All 145 consenting survivors, after a window period of 7 days, were included, and their demographic and injury characteristics were captured according to the International SCI Core Basic Data Set. Further, selected secondary medical complications (outcomes) were prospectively and routinely assessed throughout acute care.

Both descriptive and inferential statistics were used to describe and compare characteristics and outcomes, respectively.

Of the 145 survivors of traumatic SCIs, 45 (31%) had injuries caused by gunshots. The gunshot SCI group consisted mainly of males (n=43/45, 96%), and the average age of injury was 26 years.

Most survivors of the gunshot SCI group were paraplegic (69%), had complete lesions (69%) and vertebral injuries (96%), and presented with significant associated injuries (84%). When comparing gunshot SCI with all other traumatic causes, significant differences were found in relation to demographic and injury characteristics and adverse outcomes, indicating that those survivors with gunshot SCI

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were typically younger males with complete paraplegia, and had more frequent secondary medical complications and a longer hospital stay.

This study contributes to the knowledge base of survivors with gunshot SCIs in a region of SA. Efforts should be made to reduce the occurrence of all gunshot SCIs, since these injuries impact survivors negatively in terms of injury characteristics and adverse outcomes.

Cytomegalovirus retinitis in Cape Town: Clinical management and outcomes

Cytomegalovirus (CMV) retinitis is a vision-threatening opportunistic infection that occurs mainly in immunocompromised individuals. Limited data on treatment protocols and management outcomes are available in SA. Lapere and Rice[5] reviewed the clinical presentation, management and outcome of patients who were diagnosed and treated for CMV retinitis at Groote Schuur Hospital, Cape Town, over the 10-year period 2003 - 2013, and compared treatment protocols of 13 public hospitals in SA that treat patients for CMV retinitis.

A total of 141 eyes in 91 patients were polymerase chain reactionpositive for CMV. Of these patients, 98.6% were HIV-positive and 72.5% were on highly active antiretroviral therapy (HAART) at the time of presentation. Patients who were on HAART at presentation had better mean final visual acuity (VA) than those who were not on HAART (p<0.001). There was a significant association between the number of retinal quadrants involved and final visual outcome (p=0.009). Macular (central vision) involvement had a significant adverse effect on visual outcome compared with cases in which the macula was uninvolved (p=0.005).

Independent risk factors that predict final visual outcome include presenting VA, number of retinal quadrants involved, macular involvement and being on HAART at presentation. The diagnosis and management of CMV retinitis differs among treatment centres in SA. BF 1. Van der Westhuizen H, Dramowski A. When students become patients: TB disease among medical undergraduates in Cape Town, South Africa. S Afr Med J 2017;107(6):475-479. http://dx.doi. org/10.7196/SAMJ.2017.v107i6.12260 2. Naidoo A, Naidoo S, Gathiram P, Lalloo U. Tuberculosis in medical doctors – a study of personal experiences and attitudes. S Afr Med J 2013;103(3):176-180. https://doi.org/10.7196/SAMJ.6266 3. Edge J, Nietz S. Sentinel lymph node biopsy and neoadjuvant chemotherapy in the management of early breast cancer: Safety considerations and timing. S Afr Med J 2017;107(6):497-500. http://dx.doi. org/10.7196/SAMJ.2017.v107i6.12239 4. Joseph C. Characteristics and outcomes of gunshot-acquired spinal cord injury in South Africa. S Afr Med J 2017;107(6):518-522. http://dx.doi.org/10.7196/SAMJ.2017.v107i6.12296 5. Lapere SRJ, Rice JC. Cytomegalovirus retinitis in Cape Town, South Africa: Clinical management and outcomes. S Afr Med J 2017;107(6):514-517. http://dx.doi.org/10.7196/SAMJ.2017.v107i6.12250

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CORRESPONDENCE

The World Health Organization excludes Mycobacterium tuberculosis from the 2017 priority pathogens list

To the Editor: On 27 February 2017 the World Health Organization (WHO) published the first priority pathogens list (PPL) for research and development of new antibiotics, which according to the WHO identifies ‘the most important resistant bacteria at a global level for which there is an urgent need for new treatments’. Selection criteria for prioritisation included: all-cause mortality, healthcare and community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in hospital and community settings, and treatability and current pipeline, thereby making the exclusion of Mycobacterium tuberculosis from the PPL inconceivable, justifiably provoking the international medical and scientific fraternity. Drug-resistant tuberculosis (DR-TB) is a major global epidemic, with 0.5 million cases occurring each year.[1] Extensively DR-TB (XDR-TB), in particular, is of major concern, with poor treatment success rates of <40% in most patient populations, and mortality rates of 50 - 80%.[2-6] The exclusion of M. tuberculosis from the PPL creates the impression that DR-TB is not a public health threat, undoubtedly preventing prioritisiation of TB research by policy-makers. This is not negotiable. It is noteworthy that the WHO finally dedicated resources to identify a PPL. However, central to the integrity of the report is surely the inclusion of M. tuberculosis as a key priority pathogen.

The drug development pipeline for anti-TB drugs is narrow. Existing drugs are associated with serious adverse effects, such as irreversible ototoxicity, nephrotoxicity, debilitating nausea and psychosis. After five decades, two new anti-TB drugs, bedaquiline and delamanid, were developed, with an accelerated approval of bedaquiline.

DR-TB remains an ongoing global health threat, with high levels of mortality and persistent limited treatment options. Other new options include pretomanid, and older repurposed drugs such as clofazimine. The combination of bedaquiline, pretomanid and linezolid was recently shown to be very effective in the NIX-TB clinical trial, reinforcing the positive impact of research. Seventy-two patients were recruited from April 2015; 65% of these patients had XDR-TB, while the remaining patients had multidrug-resistant TB (MDR-TB) and were either not responding to treatment or could not tolerate the side-effects. Just over half were HIV-positive. Forty patients have completed the 6-month trial and 31 have had their 6-monthly follow-up examination. Of these 31 patients, only one relapsed.[7] The release of the WHO PPL coincides with the report ‘Mortality and causes of death in South Africa, 2015: Findings from death notification’, which highlights that ‘tuberculosis was the leading cause of death in both males and females in 2015, in South Africa’.[8]

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Exclusion of TB in the WHO PPL negates acceleration of research and development efforts in DR-TB treatment. This is a violation of fundamental human rights, and will likely impede access to effective drugs for this deadly disease.

By adopting the decision to exclude TB in the PPL, the WHO runs the risk of being viewed as purveyors of ill-informed science. We therefore urgently call on the WHO to facilitate a timely review of the impact of M. tuberculosis resistance globally, which certainly warrants its inclusion in the global PPL. N Padayatchi Centre for the AIDS Programme of Research in South Africa (CAPRISA), and CAPRISA-MRC TB-HIV Pathogenesis Unit, Durban, South Africa

S Mahomed Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa sharana.mahomed@caprisa.org

M O’Donnell Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa; and Allergy and Critical Care Medicine, and Department of Epidemiology, Mailman School of Public Health, Columbia University Medical Center, NY, USA

F Conradie South African HIV Clinicians Society, Johannesburg, South Africa

K Naidoo Centre for the AIDS Programme of Research in South Africa (CAPRISA), and CAPRISA-MRC TB-HIV Pathogenesis Unit, Durban, South Africa 1. World Health Organization. Global Tuberculosis Report. Geneva: WHO, 2015.

2. O’Donnell MR, Padayatchi N, Kvasnovsky C, et al. Treatment outcomes for extensively drug-resistant tuberculosis and HIV co-infection. Emerg Infect Dis 2013;19(3):416-424. http://dx.doi.org/10.3201/ eid1903.120998 3. Pietersen E, Ignatius E, Streicher EM, et al. Long-term outcomes of patients with extensively drug resistant tuberculosis in South Africa: A cohort study. Lancet 2014;383(9924):1230-1239. http://dx.doi. org/10.1016/S0140-6736(13)62675-6 4. Falzon D, Gandhi N, Migliori GB, et al. Resistance to fluoroquinolones and second-line injectable drugs: Impact on multidrug-resistant TB outcomes. Eur Respir J 2013;42(1):156-168. http://dx.doi. org/10.1183/09031936.00134712 5. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006;368(9547):1575-1578. http://dx.doi.org/10.1016/S0140-6736(06)69573-1 6. Shah NS, Auld SC, Brust JCM, et al. Transmission of extensively drug-resistant tuberculosis in South Africa. N Engl J Med 2017;376(3):243-253. http://dx.doi.org/10.1056/NEJMoa1604544 7. Conradie F, Diacon H, Everitt D, et al.The NIX-TB trial of pretomanid, bedaquiline and linezolid to treat XDR-TB. Abstract, Conference on Retroviruses and Opportunistic Infections.

Seattle, USA, 13 - 16 February 2017. http://www.croiconference.org/sessions/nix-tb-trial-pretomanidbedaquiline-and-linezolid-treat-xdr-tb (accessed 25 April 2017).

8. Statistics South Africa. Mortality and causes of death in South Africa, 2015: Findings from death notification. Pretoria: Stats SA, 2017. www.statssa.gov.za (accessed 20 April 2017).

S Afr Med J 2017;107(6):466. DOI:10.7196/SAMJ.2017.v107i6.12474

June 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

CORRESPONDENCE

Bridging non-communicable disease burden research to clinical care: A rising tide or a tidal wave?

To the Editor: There is an increased focus on non-communicable diseases (NCDs) in low- and middle-income countries.[1] South Africa (SA)â&#x20AC;&#x2122;s National Strategic Plan on HIV looks to leverage the successes of community-based HIV programmes to build an effective NCD continuum of care.[2,3] In early 2015, our research team added evidence of the colliding burden of non-infectious and infectious diseases in rural KwaZulu-Natal, SA through an integrated homebased NCD and HIV testing and counselling (HTC) programme.[4] As parallels and differences between HIV and NCD programmes are being investigated, significant questions arise: (i) What is our ethical obligation in HIV- and NCD-integrated screening projects to followup testing and care?; and (ii) Where will the large number of at-risk patients go and how will it affect the current HIV programmes?

The benefits of early, integrated screening are clear.[5] Early case identification maximises the benefits of lifestyle and pharmacological interventions. At the community level, integrated programmes may destigmatise HIV and promote a culture of preventive health.

Furthermore, disease burden research helps policy-makers to set priorities and allocate resources.

We are reminded of the criteria for a justifiable screening programme,[6,7] specifically that (i) the costs of the programme must justify the benefits; and (ii) resources to run the programme must be available. Primum non nocere (first, do no harm) is the basis of the ethical principle of non-maleficence. In our study, numerous pitfalls arose as we reviewed the timing of the NCD testing and counselling relative to HTC. How did the health worker set priorities during counselling? What would the impact of NCD counselling be if emphasised before HIV counselling in the case of a high-risk patient? At what threshold is there diminishing return in broadening our counselling? At a systems level, we are challenged in our pursuit of distributive justice. Screening to identify high-volume, low-acuity NCD cases threatens to overburden an already challenged system.

In isolation, linkage to care data is unlikely to capture the potential harms. Once enrolled, do NCD patients continue through the cascade of care? Does the influx of NCD patients draw resources and human capital away from higher-acuity HIV or tuberculosis (TB) cases? Is it ethical to focus on community-based NCD counselling and delay clinic referral that may potentially harm the system?

We propose the following principles to preserve the responsibility of guaranteeing benefit to the community: (i) a capacity assessment

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of the NCD care cascade should be conducted, aligned to the stability of coexisting HIV and TB programmes; (ii) the screening programme should be coupled with interventions to minimise the overburdening of clinics, including community-based strategies for lifestyle modifications and support groups, and potentially to initiate therapy with medications, which raises the question of funding, as US federal funds restrict ancillary care or capacity building (outside the scope of this letter);[8] (iii) integrated screening programmes should support a steady rise rather than a flood of new patients; and (iv) the need to strengthen impact evaluations to provide feedback and ensure that integration brings more benefit than harm to the systems on which we build.

I Golovaty Department of Medicine, University of Washington, Seattle, WA, USA ilyamg@uw.edu

A van Heerden, Z Essack, H van Rooyen Human Sciences Research Council, Pretoria, South Africa

R Barnabas Department of Medicine, and Departments of Global Health and Epidemiology, University of Washington, Seattle, WA; and Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

1. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990 - 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380(9859):2224-2260. http://dx.doi.org/ 10.1016/S0140-6736(12)61766-8 2. United Nations Programme on HIV/AIDS. Global AIDS response progress report. 2012. http://www. unaids.org/sites/default/files/country/documents//ce_ZA_Narrative_Report.pdf (accessed 20 April 2017).

3. Ministry of Health. Strategic plan for the prevention and control of non-communicable diseases 2013 - 17. 2013. http://www.hsrc.ac.za/uploads/pageContent/3893/NCDs%20STRAT%20PLAN%20%20CONTENT%20 8%20april%20proof.pdf (accessed 26 April 2017).

4. Van Heerden A, Barnabas R, Norris S, Micklesfield L. Integrating non-communicable disease (NCD) screening and referral to care into home HIV testing and counseling in rural KwaZulu-Natal, South Africa: Burden of disease. International AIDS Conference, 18 - 22 July 2016, Durban, South Africa. http://repository.hsrc.ac.za/handle/20.500.11910/10129 (accessed 28 April 2017).

5. Checkley W, Ghannem H, Irazola V, et al. Management of NCD in low- and middle-income countries.

Glob Heart 2014;9(4):431-443. http://dx.doi.org/10.1016/j.gheart.2014.11.003 6. Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical Epidemiology: A Basic Science for Clinical Medicine. 2nd ed. Boston: Little, Brown, 1991:154-170.

7. Ewart R. Primum non nocere and the quality of evidence: Rethinking the ethics of screening. J Am Board Fam Pract 2000;13(3):188-196.

8. Philpott S, Slevin K, Shapiro K, Lori H. Impact of donor-imposed requirements and restrictions on standards of prevention and access to care and treatment in HIV prevention trials. Public Health Ethics 2010;3:220-228. http://dx.doi.org/10.1093/phe/phq027

S Afr Med J 2017;107(6):467. DOI:10.7196/SAMJ.2017.v107i6.12495

June 2017, Print edition

These open-access articles are distributed under Creative Commons licence CC-BY-NC 4.0.

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30 days in medicine Trans-fat restrictions linked to fall in cardiovascular events

Counties in the state of New York, USA, that have introduced restrictions on trans-fatty acids in restaurants and takeaway outlets have seen significantly fewer admissions for cardiovascular events than counties with no restrictions, according to a study published in JAMA Cardiology recently.

Partially hydrogenated oils used in baked goods, yeast breads, fried foods, chips, biscuits and margarines are the main source of trans-fatty acids in the diet. In 2007, New York City restricted transfatty acids in all public eating places. However, trans-fatty acids are still found in some packaged foods, and from 2018, the US Food and Drug Administration will prohibit the unrestricted use of partially hydrogenated oils in all food without prior approval.

In the study, researchers compared the number of admissions for myocardial infarction (MI) or stroke in 11 counties that restricted trans-fatty acids with 25 counties with no restrictions from 2002 to 2013. Although these events were already declining throughout New York state before the first restrictions were brought in, after 2006, populations with restrictions experienced significant additional declines in rates of admission for MI or stroke compared with populations with none. The significant decline in MI and strokes came at least 3 years after the restrictions were implemented.

Other public health measures that coincided with the restrictions on trans-fatty acids, such as bans on smoking in parks, beaches and pedestrian walkways, could also have affected rates of cardiovascular events, but the researchers remain convinced that trans-fatty acid restriction is an important factor.

Brandt E, Myerson R, Perraillon M, et al. Hospital admissions for myocardial infarction and stroke before and after the trans-fatty acid restrictions in New York. JAMA Cardiol 2017 (epub 12 April). http://dx.doi. org/10.1001/jamacardio.2017.0491

‘Extreme’ comorbidity common in patients with chronic heart failure

A primary care study in the UK has found that patients with chronic heart failure (CHF) often have seven or more conditions – ‘extreme’ comorbidity – and take multiple medicines. This is the first study of heart failure in the community, which is where most patients receive care. The researchers analysed data from the Primary Care Clinical Informatics Unit at the University of Aberdeen on 1 424 378 patients aged >18 years, registered with 314 practices in Scotland. The team identified 17 285 patients (1.2%) with a diagnosis of CHF due to left ventricular systolic dysfunction. The results, reported in the British Journal of General Practice, showed that patients with DHF had much higher levels of comorbidity than patients without, after standardising for age, sex and social deprivation.

Confidence Through Clinical and Real World Experience1-3 #1 NOAC prescribed by Cardiologists* Millions of Patients Treated Across Multiple Indications4 REFERENCES: 1. Patel M.R., Mahaffey K.W., Garg J. et al. Rivaroxaban versus warfarin in non-valvular atrial fi brillation. N Engl J Med. 2011;365(10):883–91. 2. Tamayo S., Peacock W.F., Patel M.R., et al. Characterizing major bleeding in patients with nonvalvular atrial fi brillation: A pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol. 2015;38(2):63–8. 3. Camm A.J., Amarenco P., Haas S. et al. XANTUS: A Real-World, Prospective, Observational Study. 4. Calculation based on IMS Health MIDAS, Database: Monthly Sales December 2015.

S4 XARELTO ® 15: Each film-coated tablet contains rivaroxaban 15 mg. Reg. No: 46/8.2/0111; Namibia S2 : 12/8.2/0006; Botswana S2 : BOT1302296 S4 XARELTO ® 20: Each film-coated tablet contains rivaroxaban 20 mg. Reg. No: 46/8.2/0112; Namibia S2 : 12/8.2/0007; Botswana S2 : BOT1302297 PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATIONS: (1) Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF); (2) Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE); (3) Treatment of pulmonary embolism (PE) and for the prevention of recurrent pulmonary embolism (PE) and deep vein thrombosis (DVT). HCR: Bayer (Pty) Ltd, Co. Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: +27 (0) 11 921 5044 Fax: +27 (0) 11 921 5041. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC).

L.ZA.MKT.GM.01.2016.1265 © Bayer January 2016 *Impact RX Data Oct - Dec 2015 NOAC: Non Vitamin K Oral Anticoagulant

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The most striking difference was in the proportion of patients with seven or more conditions, as the odds of this ‘extreme’ comorbidity were four times higher in patients with chronic heart failure than in those without (13.9% v. 1.1%; odds ratio (OR) 4.10, 95% confidence interval (CI) 3.90 - 4.32). Patients with chronic heart failure had nearly eight times the odds of coronary heart disease compared with controls (OR 7.98, 95% CI 7.72 - 8.25), in addition to a higher prevalence of atrial fibrillation and chronic kidney disease. They also had considerably higher rates of anxiety and stress-related conditions.

Polypharmacy, defined as taking five or more repeat drugs, was substantially higher in patients with chronic heart failure. However, much of the additional prescribing was accounted for by comorbidity.

Researchers recommended that clinical guidelines and health services should put much greater emphasis on managing this complexity, as this is clearly ‘the norm’.

Baron-Franco B, McLean G, Mair FS, et al. Comorbidity and polypharmacy in chronic heart failure: A large cross-sectional study in primary care. Br J Gen Pract 2017;67(658):e314-e320. http://dx.doi.org/10.3399/ bjgp17X690533

Sugary drinks tax in California cut sales by 10%

Sales of sugar-sweetened drinks in Berkley, Calif., fell by almost 10% after an excise tax was introduced, according to research published in PLoS Medicine. The tax – of one US cent per fluid ounce on drinks with added caloric sweeteners, adding an average of 68 cents to a USD2 bottle of cooldrink and 12 cents to a USD1 can – was introduced in 2014. In the first full year of the tax, the city raised USD1 416 973 (about USD12 per capita), and the money is being used for child nutrition and community health programmes.

One year after the tax was implemented, sales of sugar-sweetened drinks had fallen by 9.6% in Berkeley, while sales of untaxed beverages had risen by 3.5%. Sales of water rose by 15.6%, and sales of untaxed fruit, vegetable and tea drinks by 4.4%. Sales of sugarsweetened beverages in surrounding areas with no tax rose by 6.9%. The researchers found no evidence of higher grocery bills for consumers or loss of store revenue after the tax.

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Berkley residents are relatively affluent and are low consumers of sugary drinks, consuming 34% of the US average, but buying patterns changed in spite of this, which the authors say is promising.

Silver L, Ng S, Ryan-Ibarra S, et al. Changes in prices, sales, consumer spending, and beverage consumption one year after a tax on sugar-sweetened beverages in Berkeley, California, US: A before-and-after study. PLoS Med 2017 (epub 12 April). http://dx.doi.org/10.1371/journal.pmed.1002283

Waist measurement a stronger prediction of death risk than BMI

For some time, researchers have thought that waist measurement is a better predictor of risk of all-cause mortality than body mass index (BMI), and now a large study published in the Annals of Internal Medicine backs this up. The study included 42 702 participants from 10 years of the Health Survey for England and the Scottish Health Survey. The participants’ mean age was 57.7 years, and 46.8% were men. Of the participants 43.7% were overweight (BMI 25 - <30) and 25% were obese (BMI ≥30).

The overall prevalence of central obesity, defined as a waistto-hip ratio of ≥0.85 in women and ≥0.90 in men, was 53%. The prevalence of central obesity among normal-weight, overweight and obese participants was 28.7%, 60.2% and 72.7%, respectively.

A total of 5 355 people died over 383 542 person-years of followup. Compared with the normal-weight participants without central obesity, only normal-weight and obese people with central obesity were at increased risk of all-cause mortality. Compared with normalweight participants without central obesity, all those with central obesity were at increased risk for death from cardiovascular disease, and there was no difference between men and women.

Hamer M, O’Donovan G, Stensel D, Stamatakis E. Normal weight central obesity and risk for mortality. Ann Intern Med 2017 (epub 25 April). http://dx.doi.org/10.7326/L17-0022

B Farham Editor ugqirha@iafrica.com

June 2017, Print edition

IZINDABA

OBITUARY Cecil John Tainton Craig (4 September 1927 2 August 2016)

Cecil Craig was born in the UK during his father’s 6-month sabbatical leave. The family returned to Cape Town, where his father, Arthur Douglas Knott-Craig, was a senior administrative official at the University of Cape Town (UCT).

Cecil completed his scholastic education at Rondebosch Boys’ High School and was very proud of his alma mater. For many years he continued serving on various committees of the school, such as the school and old boys’ committees. His devoted service included chair positions for many years.

In 1950 he obtained the MB ChB degree at UCT and completed his internship at Groote Schuur Hospital. From 1953 to 1955, he practised as a general practitioner in Klerksdorp and for a short period in Port Shepstone.

In 1955 he enrolled as a postgraduate student in obstetrics and gynaecology at Groote Schuur Hospital. He obtained the MRCOG in 1958 and worked for 2 years in the UK at Nottingham Women’s Hospital and also at Kingston Hospital in London.

During his tenure in the UK, he met Mary Elizabeth (Mai) Reid, an Irish nursing sister, at Nottingham Women’s Hospital; they married in 1960. His charming wife returned with him to Cape Town – the ship voyage to Cape Town constituted their honeymoon.

From 1960 to 1963 he was a lecturer and a consultant in obstetrics and gynaecology at UCT and Groote Schuur Hospital, respectively, under his beloved Prof. James T Louw.

During his tenure as consultant, he was also involved in research on hypertension in pregnancy, and in 1962 obtained an MD on ‘Avertin in the treatment of eclampsia’.

In 1963 he entered private practice in Cape Town and soon established the largest practice in town, with six partners at one stage.

Cecil maintained a close academic relationship with the Department of Obstetrics and Gynaecology at UCT and later as senior lecturer and senior consultant. He also acted as head of firm in both obstetrics and gynaecology for many years.

In 1970 he received the honorary Fellowship of the Royal College of Obstetricians and Gynaecologists for distinguished service to the specialty.

He was highly respected by under- and postgraduate students for his teaching ability.

He taught the subject in a practical manner, and his ward rounds were keenly attended by both these groups of students. He spent many hours with the registrars in his firm, teaching a practical approach towards problems a patient might be presented with. Surgery was taught by demonstrating the operation or assisting the registrars, giving them practical guidance.

Cecil was a highly respected examiner for under- and postgraduate students. He was an examiner at the Colleges of Medicine of South Africa (SA), and an external examiner at the universities of Stellenbosch, the Witwatersrand, the Free State and Pretoria.

He was invited as visiting lecturer to the University of Oxford, Mount Sinai Hospital in New York, the University of South Wales in Sydney, University of Auckland

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in New Zealand, and the universities of Stellenbosch, the Free State, KwaZulu-Natal, the Witwatersrand and Pretoria.

He published 22 articles in peer-reviewed journals, three editorials, and three chapters in textbooks. He was the co-author of Medico-Legal Experience in Obstetrics and Gynaecology and Avoiding Medico-Legal Experiences in Obstetrics and Gynaecology.

As a result of his capabilities, he was frequently elected as a member of various committees, serving his colleagues as chairman of the SA Society of Obstetricians and Gynaecologists, the Colleges of Medicine of SA and the SA Council of the Royal College of Obstetricians and Gynaecologists.

His love of sport was well known and bowls was his passion. He would eagerly teach those who showed some interest in bowls.

He played a good game of tennis and squash and enjoyed watching rugby and soccer on occasion.

Cecil lost his beloved wife in 2008 and moved to Pinewood Retirement Village, Cape Town, where he resided until his passing.

He was a great family man and devoted father. He will be sadly missed by his sons, Peter, Mark and Terence, their wives, and his six grandchildren.

The medical fraternity has lost a highly respected and beloved colleague, friend and mentor.

Cecil and I were medical practice partners and friends.

G W E Rösemann Cape Town, South Africa rosemann@3i.co.za

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

EDITORIAL

South Africa’s vital statistics are currently not suitable for monitoring progress towards injury and violence Sustainable Development Goals Two of the most important targets to achieving the United Nation’s Sustainable Development Goals (SDGs) for reducing violence and other injuries are Target 3.6: to ‘halve the number of global deaths and injuries from road traffic accidents’ by 2020; and Target 16.1: the significant reduction of ‘all forms of violence and related death rates everywhere’.[1] Police statistics on homicide, and transport deaths from the Road Traffic Management Corporation, are considered to be under-reported[2] and are not a reliable source for monitoring SDGs. In South Africa (SA), vital statistics data are the only routine source that captures unnatural and natural deaths through death registration. Since the early 1990s, focused initiatives have identified and addressed deficiencies in the completeness of death registration[3-5] and recent estimates indicate that completeness for persons aged ≥2 years is >90%.[6] However, there are still concerns about the quality of data relating to the cause of death, i.e. underreporting of HIV/AIDS deaths owing to misclassification to other causes,[7-10] a large proportion of deaths with ill-defined causes,[11] and the validity of single-cause data.[12] The misclassification of injury deaths is another major limitation.[2,13] The Inquest Act of 1959[14] precludes forensic pathologists from reporting the manner of death, i.e. whether it is due to homicide, suicide, transport or other unintentional injuries, on the basis that it may prejudice the findings of the inquest. In many cases, only the nature of injury, e.g. penetrating wound, and whether the death is natural or unnatural, is reported on the death notification form. As the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10)[15] coding convention demands that injury deaths with unknown intent default to unintentional, the reported gunshot injuries without stated intent are all coded to unintentional gunshot injuries.[16] Strict application of the ICD-10 coding rules has resulted in 89 99% of gunshot deaths being reported as unintentional from 2007 onward.[17] Homicides are therefore grossly under-represented in official vital statistics.

The misclassification of injury deaths was clearly demonstrated in a nationally representative study of injury deaths presenting

to state forensic mortuaries in 2009.[18] Statistics SA (Stats SA) classified nearly two-thirds (63.9%) of injury deaths as being due to ‘other external causes of accidental injury’ (Fig. 1), with 10.3% due to homicide and 11.5% caused by transport injuries.[16] In contrast, the mortuary study demonstrated that homicide accounted for 36.2% of all unnatural deaths and transport for 33.8%. Moreover, the total number of injury deaths estimated from our study (N=52 493) is higher than the number reported

by Stats SA (N=49 456), possibly because a number of deaths are registered before the completion of the investigation (to enable burial). Cases that are reported to be under investigation at the time of registration are coded to natural causes. Once the inquest into an unnatural death is complete, the civil registration system does not provide a mechanism for Stats SA to update the manner of death.

In the 2014 Stats SA cause-of-death data, despite a slight decrease in other unintentional injury deaths to 58.1%,[19] the problem of misclassification of homicide and transport deaths to other unintentional injuries remains. Vital statistics cause-ofdeath data for injuries in SA are inaccurate and misleading and cannot be used to monitor progress on achieving the SDGs by 2030. The absence of information on the manner of injury death in the official statistics needs to be addressed urgently. A review and possible amendment of the Inquest Act would possibly take years. We strongly recommend that the death notification form (DHA-1663) be amended in line with the updated World Health Organization’s recommendation,[15] to include a stand-alone field for information about the manner of injury death for unnatural causes. We suggest that forensic pathologists record the alleged manner of death when they are uncertain, which can include a proviso stating that such information is for statistical purposes only. This matter is currently being discussed with stakeholders, including the National Forensic Pathology Committee, legal advisers to the departments of Home Affairs and Health, and Stats SA – holding a promise for injury data to conform to international standards, which will go a long way towards monitoring violence and injury indicators for the SDGs.

Undetermined Suicide, Undeterminedintent, Suicide, 0.8% intent, 13.6% 0.8% Homicide, 13.6% Homicide, 10.3% 10.3% Transport, Transport, 11.5% 11.5%

Undetermined Undeterminedintent, intent, 4.0% 4.0%

Other Otherunintentional, unintentional,63.9% 63.9%

A

B

Other Otherunintentional, unintentional,13.6% 13.6%

Homicide, Homicide, 36.2% Suicide, 36.2% Suicide, 12.3% 12.3%

Transport, Transport, 33.8% 33.8%

Fig. 1. Manner of injury death. (A) Stats SA, 2009 (N=49 456);[16] and (B) IMS, 2009 (N=52 493).[18] Stats SA categories are grouped according to IMS. (Stats SA = Statistics SA; IMS = Injury Mortality Survey.)

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EDITORIAL

M Prinsloo, D Bradshaw, J Joubert South African Medical Research Council, Burden of Disease Research Unit, Cape Town, South Africa megan.prinsloo@mrc.ac.za R Matzopoulos South African Medical Research Council, Burden of Disease Research Unit, Cape Town; and School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa P Groenewald South African Medical Research Council, Burden of Disease Research Unit, Cape Town, South Africa

1. United Nations. Transforming our world: The 2030 agenda for sustainable development. 2015. http:// www.un.org/ga/search/view_doc.asp?symbol=A/RES/70/1&Lang=E (accessed 4 March 2017).

2. Matzopoulos R, Prinsloo M, Pillay-van Wyk V, et al. Injury-related mortality in South Africa: A retrospective descriptive study of post-mortem investigations. Bull World Health Organ 2015;93:303-313. http://dx.doi.org/10.2471/BLT.14.145771 3. Dorrington RE, Moultrie TA, Timæus IM. Estimation of Mortality Using the South African Census 2001 Data. Cape Town: Centre for Actuarial Research, University of Cape Town, 2004. http://www. commerce.uct.ac.za/Research_Units/CARE/Monographs/Monographs/Mono11.pdf (accessed 21 April 2017).

4. Dorrington RE, Bourne D, Bradshaw D, Laubscher R, Timæus IM. The Impact of HIV/AIDS on Adult Mortality in South Africa. Cape Town: South African Medical Research Council, 2001. http://www. mrc.ac.za/bod/complete.pdf (accessed 21 April 2017).

5. Bradshaw D, Kielkowski D, Sitas F. New birth and death registration forms – A foundation for the future, a challenge for health workers? S Afr Med J 1998;88(8):971-974.

6. Dorrington RE, Bradshaw D, Laubcsher R, Nannan N. Rapid Mortality Surveillance Report, 2014. Cape Town: South African Medical Research Council, 2015. http://www.mrc.ac.za/bod/ RapidMortalitySurveillanceReport2014.pdf (accessed 21 April 2017).

7. Bradshaw D, Groenewald P, Laubscher R, et al. Initial burden of disease estimates for South Africa, 2000. S Afr Med J 2003;93(9):682-688.

8. Yudkin PL, Burger EH, Bradshaw D, Groenewald P, Ward AM, Volmink J. Deaths caused by HIV disease under-reported in South Africa. AIDS 2009;23(12):1600-1602. http://dx.doi.org/10.1097/ QAD.0b013e32832d4719 9. Burger EH, Groenewald P, Bradshaw D, Ward AM, Yudkin PL, Volmink J. Validation study of cause of death statistics in Cape Town, South Africa, found poor agreement. J Clin Epidemiol 2012;65(3):309-316. http://dx.doi.org/10.1016/j.jclinepi.2011.08.007 10. Westwood AT. Childhood deaths due to HIV – the role of the new death certificate. S Afr Med J 2000;90(9):877.

11. Pillay-van Wyk V, Bradshaw D, Groenewald P, Laubscher R. Improving the quality of medical certification of cause of death: The time is now! S Afr Med J 2011;101(9):626.

12. Joubert J, Rao C, Bradshaw D, Vos T, Lopez AD. Evaluating the quality of national mortality statistics from civil registration in South Africa, 1997 - 2007. PLoS ONE 2013;8(5):e64592. http://dx.doi.org/10.1371/ journal.pone.0064592 13. Groenewald P, Bradshaw D, Neethling I, et al. Linking mortuary data improves vital statistics on cause of death of children under five years in the Western Cape Province of South Africa. Trop Med Int Health 2016;21(1):114-121. http://dx.doi.org/10.1111/tmi.12624 14. South Africa. Inquest Act No. 58 of 1959.

15. World Health Organization. International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Version for 2016. Geneva: WHO, 2016. http://apps.who.int/classifications/ icd10/browse/2016/en (accessed 9 March 2017).

16. Statistics South Africa. Mortality and Causes of Death in South Africa, 2009: Findings from Death Notification. Pretoria: Stats SA, 2011.

17. Matzopoulos R, Groenewald P, Abrahams N, et al. Where have all the gun deaths gone? S Afr Med J 2016;106(6):589-591. http://dx.doi.org/10.7196/SAMJ.2016.v106i6.10379 18. Matzopoulos R, Prinsloo M, Bradshaw D, et al. The Injury Mortality Survey: A National Study of Injury Mortality Levels and Causes in South Africa in 2009. Cape Town: Medical Research Council, 2013.

19. Statistics South Africa. Mortality and Causes of Death in South Africa, 2014: Findings from Death Notification. Pretoria: Stats SA, 2015.

S Afr Med J 2017;107(6):470-471. DOI:10.7196/SAMJ.2017.v107i6.12464

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This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

IN PRACTICE

MEDICINE AND THE LAW

Exploitation of the vulnerable in research: Responses to lessons learnt in history A Dhai, PhD, MB ChB, FCOG, LLM, PG Dip (Int Res Ethics) Steve Biko Centre for Bioethics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: A Dhai (ames.dhai@wits.ac.za)

The Nuremberg Trials raised insightful issues on how and why doctors who were trained in the Hippocratic tradition were able to commit such egregious and heinous medical crimes. The vulnerable were considered to be subhuman, of decreased intelligence, of no moral status and lacking human dignity. The reputation of the medical profession had been undermined, professionalism questioned and the doctorpatient relationship damaged as a result of the Nazi medical experiments. The World Medical Association’s Declaration of Helsinki has been hailed as one of the most successful efforts in rescuing medical research from the darkness of the scandals and tragedies in health research.

The first Research Ethics Committee in South Africa was established in 1966 at the University of the Witwatersrand. From the mid-1970s other institutions followed suit. The promulgation of the National Health Act No. 61 of 2003, in 2004, resulted in strong protectionism for research participants in the country.

S Afr Med J 2017;107(6):472-474. DOI:10.7196/SAMJ.2017.v107i6.12437

Notwithstanding the examples of Lind, Jenner and self-experimentation, which were discussed in the previous issue,[1] examples of experimental research where people with vulnerabilities have been harmed have surfaced since medieval times. While not typical of experiments of that era, in the thirteenth century, Frederick II of Germany is said to have experimented with neonates so he could obtain knowledge about the development of language in humans.[2] Avicenna, an Arabian physician and philosopher, tested interventions directly on people because he felt that testing these on animals would not have any relevance for their use on humans.[2] Briggle and Mitcham[3] claim that in the main, the first studies of experimentations on humans took place on slaves and the poor, and that this coincided with the development of the new science of anthropology that Europeans used to study non-European peoples.[3] Generally speaking, human experimentation was initially undertaken on those who were considered to be uncivilised and often less than human, with diminished or no moral status. Even colonial and imperial rule was often justified by anthropological research that described the native peoples of Africa, the Americas and Asia as being of inferior intelligence and ability, and hence in need of paternalistic rule by European powers or immigrants. Their anthropological findings were based on the category of race.[3] In this article, the Nuremberg Trials and their implications are briefly discussed. The emergence of international norms and standards for protection of participants in research is considered, together with South Africa (SA)’s response to the global scandals and tragedies in health research.

The proceedings of the Nuremberg Trials

Among the greatest tragedies in human research experimentation, the heinous studies conducted during World War II by Nazi doctors on ‘racially inferior’ Jews and other ‘deficient’ groups,[4-8] and by Japanese doctors on people, in the main Chinese, that they determined to be less than human[3,9,10] take centre stage as the most notorious.

In the aftermath of World War II, the horrors of experimentations on concentration camp inmates were publicised during the

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Nuremberg Trials in Germany, which lasted from December 1946 to August 1947.[3,5,7,11] The trial specific to the medical atrocities is the case of the United States of America v Karl Brandt et al. – also referred to as the Nuremberg Doctors’ Trial.[12] Evidence given at the trial underscored the robust and relentless exploitation and wrongs prevalent in medical studies at that time. The vulnerable were considered to be subhuman, of low intelligence, of no moral status and lacking human dignity. The Nuremberg Doctors’ Trial raised insightful issues on how and why doctors who were trained in the Hippocratic tradition were able to commit such egregious and heinous medical crimes. As medicine was supposed to be one of the ‘world’s most advanced scientific cultures’,[11] questions on whether these doctors actually understood that they were committing crimes were raised. The defendants’ lawyers during the Nuremberg Doctors’ Trial, using a utilitarian approach, highlighted that the Allies had also engaged in medical experiments in servicing the war effort,[5,11] that the type of medical experimentation performed in the concentration camps during the war was commonplace even before the war[11] and that there were no legal restrictions on such experiments.[6] As the prosecution’s attempts at demonstrating that there were clear international rules governing medical experimentation wavered, the judges attempted to create their own set of rules, and two medical advisors to the judges, Drs Andrew Ivy and Leo Alexander, were tasked to do this.[4-6] They drafted a ten-point memorandum entitled Permissible Medical Experimentation,[7] which then became known as the Nuremberg Code, the aim of which was to obtain a way forward on one of human experimentation’s most fundamental conflicts: that of balancing the need for advancing medical science for the benefit of society with the rights of individuals to ‘personal inviolability, autonomy and self-determination’.[11] The trial, however, was based on international law as outlined in the London Agreement on the Punishment of the Major War Criminals of the European Axis (London Charter) in 1945.[12,13] Although international law had previously not codified specific war crimes, the crimes specified in the London Charter included those contained in the Hague Regulation of Warfare (1907),[14] which Germany

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had signed.[12] Germany had also signed the Kellogg-Briand Pact of 1928,[15] which condemned aggressive wars, and the Geneva Convention[16] in 1929, which specified in its rules how prisoners of war should be protected.[12] Therefore, both the judgment and the Code were de jure international in character. The Nuremberg Code is hence undoubtedly the first international medical ethics code.

It is interesting to note that besides Germany being signatory to international instruments for protection of prisoners of war, by the end of the 19th century it had started to develop some of the world’s most stringent and clearly defined medical ethics regulations,[2] and in March 1931, the Reich Health Council (Reichsgesundheitstrat) issued the Regulations Concerning New Therapy and Human Experimentation.[17] The far-reaching directives in these regulations were ‘among the most comprehensive research rules by any standard at the time’.[2] Some aspects that involved contentious issues such as voluntary informed consent, therapeutic research, non-therapeutic research and benefits were much more structured and detailed compared with the principles in the Nuremberg Code. It was stressed that the rights and dignity of subjects had to be protected at all times, and on the issue of non-therapeutic research it underscored the prohibition of experimentation in all cases where consent had not been given. Unfortunately, despite the strong protectionism in the regulations, respect for moral status, upholding dignity and according special protections for subjects enrolled in research – fundamental values highlighted in the Reich Health Council’s regulations – were ignored.

The international medical community had no option but to reflect on its conduct in the aftermath of World War II and the Nuremberg Doctors’ Trial. There were now great uncertainties regarding the role that the medical profession had to play in a post-war society. This was of huge concern to national medical associations as well.[18] The reputation of the medical profession had been undermined, professionalism questioned and the doctor-patient relationship damaged as a result of the Nazi medical experiments. Doctors all over the world were anxious that the profession as a whole could be affected negatively by the sweeping condemnation of the Nazi physicians. Therefore, it is not surprising that the revelations at the Trial were also a major factor leading to the foundation of the World Medical Association (WMA).[19]

The role of the WMA

At the first meeting to discuss an international association of doctors and national medical societies held in London in 1946, there were 32 national medical organisations present. The objective of such an international association would be to promote international medical relations, and the advancement of medicine and its social and cultural aspects. The first meeting of the newly formed WMA in 1947 was held 1 month after judgments had been delivered in the Nuremberg Doctors’ Trial.[20] The Declaration of Geneva,[21] a statement on the physician’s dedication to the medical profession, was among the first acts of the WMA and was endorsed at the 1948 General Assembly. The importance of this declaration is that when adopted, considerations of nationality, race, party politics and social class would not interfere with the physician’s responsibility for the patient’s welfare. This applied to both situations of clinical care and research.

Already in its very first declaration, the WMA had started the process of protectionism for those patients involved in research.

The Declaration of Helsinki (DoH) of 1964 was among the first international guidelines for human experimentation and it ‘reflected the longstanding interest of the WMA in issues of medical ethics and the enduring shadow of the Nazi medical war crimes.’[20] The journey of the first DoH was long and turbulent. It involved more than a

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decade of active discussion and debate among the WMA members before the final document, which was also strongly influenced by the principles of deontology and virtue ethics, could be presented to the WMA’s General Assembly for adoption in Helsinki in 1964.[20] The DoH has been hailed as one of the most successful efforts in rescuing medical research from the darkness of the tragedies resulting from the heinous atrocities in the name of medical research in Nazi Germany.[20] It has undergone several revisions, with the latest being in October 2013.

Protectionism in SA[22]

Henry Knowles Beecher, [23] a professor in research into anaesthesia, published a landmark article in the New England Journal of Medicine in 1966, entitled ‘Ethics and clinical research’. This article was the catalyst for the establishment of protectionism for research participants in SA. Beecher detailed 22 cases of research conducted by leading researchers at leading research centres that he claimed violated the basic standards of ethical research. These studies had been published in highly acclaimed and reputable reviewed journals.

He had submitted 50 cases in his original list but the number had to be reduced due to the space constraints of the journal.[6] The history of protectionism from a regulatory perspective in SA is quite meagre, and only emerged over the past 2 decades. This is understandable, as prior to 1994, citizens in the country were oppressed and subjected to the repressive apartheid regime in which people who were not white were considered to be subhuman, lacking human dignity and of decreased or no moral status, similar to the European anthropological viewpoint described above. However, the apartheid regime and philosophy were not successful in removing moral agency from the virtuous physician-researcher in the country, and in the late sixties, after Beecher’s seminal paper was published,[23] steps were set in motion at the level of individual institutions where research was conducted to introduce protections for all, and in particular the vulnerable, who were involved in research.

Cleaton-Jones[24] states that the Beecher paper was considered such a milestone in research ethics that 4 months after its publication, at the suggestion of Prof. John Hansen of the Department of Paediatrics at the then Baragwanath Hospital, which was situated in a racially demarcated township, Soweto, the University of the Witwatersrand formed the Committee for Research on Human Subjects (Medical).

Hence, this could be described as the birth of protectionism for research participants in SA. The committee was the first research ethics committee (REC) in the country, and probably one of the first in the world. The committee underwent a name change in 2003 to the Human Research Ethics Committee (Medical)[24] and is still functional today, and is probably one of the leading RECs in the country. From the mid-1970s, other institutions followed suit, and currently there are over 30 RECs registered with the National Health Research Ethics Council in the country.[25] In the beginning, guidelines for the protection of participants in research were lacking in the country. However, in 1978, Prof. de V Lochner, then vice-president of the SA Medical Research Council (SAMRC), visited the World Health Organization in Geneva, and upon his return, set to work producing a set of guidelines for the SAMRC. In 1979, the first set of guidelines, entitled Guidelines on Ethics for Medical Research, was produced by the SAMRC. These guidelines have undergone several revisions since.[24] The National Department of Health in 2000 produced Guidelines for Good Clinical Practice in Research.[24] This was updated in 2006.[26] The promulgation of the National Health Act (NHA) No. 61 of 2003,[27] in 2004, resulted in strong protectionism for research participants in the country. Chapter 9 of the NHA focuses on health research and health

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research ethics. As a result of the stipulations of chapter 9, Ethics in Health Research: Principles, Structures and Processes[28] was launched in 2004. It was a response to the NHA and, while written as guidelines, had the authority of rules. It has undergone amendment, with the second edition being issued in 2015.[29]

Conclusion[22]

Exploitation in health research of the vulnerable who were considered to be subhuman, lacking in intelligence, moral status and human dignity goes back several centuries. Germany was both signatory to international instruments for protections of prisoners of war and also had a stringent set of guidelines for protection of participants in medical research. Despite this, evidence given during the Nuremberg Trials highlighted the robust and relentless abuse, mistreatment and wrongs prevalent in medical studies at that time. The WMA’s DoH provides international norms and standards for protections. In SA, individual institutions responded to the global position by setting up RECs to provide ethical oversight in health research, which have existed since the 1960s. This became a statutory requirement in the early 2000s. In the next issue of the SAMJ, I will describe the development of the ethicoregulatory protections in health research in the country.

1. Dhai A. Health research and safeguards: The South African journey. S Afr Med J 2017;107(5):379-380. https://doi.org/10.7196/SAMJ.2017.v107i5.12345 2. Von Engelhardt D. The historical and philosophical background of ethics in clinical research. In: Schmidt U, Frewer A, eds. History and Theory of Human Experimentation. Germany: Franz Steiner Verlag, 2007:55-70.

3. Briggle A, Mitcham C. Research ethics 11: Science involving humans. In: Briggle A, Mitcham C, eds.

Ethics and Science. Cambridge: Cambridge University Press, 2012:125-155.

4. Emanuel EJ, Crouch RA, Arras JD, Moreno JD, Grady C. Scandals and tragedies of research with human participants. In: Emanuel EJ, Crouch RA, Arras JD, Moreno JD, Grady C, eds. Ethical and Regulatory Aspects of Clinical Research. Baltimore: John Hopkins University Press, 2003:1-5.

5. Moreno JD. Protectionism in Research Involving Human Subjects (Research Involving Human Subjects V2). Online Ethics Centre for Engineering, 2006. http://www.onlineethics.org/Topics/ ResResearch/ResResources/nbachindex/hmoreno.aspx (accessed 20 July 2012).

6. Emanuel EJ, Crouch RA, Arras JD, Moreno JD, Grady C. Preface xv-xviii. In: Emanuel EJ, Crouch RA, Arras JD, Moreno JD, Grady C, eds. Ethical and Regulatory Aspects of Clinical Research. Baltimore: John Hopkins University Press, 2003.

7. Levine C, Faden R, Grady C, Hammerschmidt D, Eckenwiler L, Sugarman J. The limitations of vulnerability as a protection for human research participants. Am J Bio 2004;4(3):44-49. http://doi. org/10.1080/15265160490497083

8. Iltis AS. Introduction: Vulnerability in biomedical research. J Law Med Ethics 2009;37(1): 6-11. http:// doi.org/10.1111/j.1748-720X.2009.00345.x 9. McDermott W. Opening Comments on the Changing Mores of Biomedical Research. Ann Intern Med 1967;67(7):39-42.

10. Wikipedia, the free Encyclopaedia. Unit 731. https://en.wikipedia.org/wiki/Unit_731 (accessed 27 June 2013).

11. Bärninghausen T. Communicating ‘Tainted science’: The Japanese biological warfare experiments on human subjects in China. In: Schmidt U, Frewer A, eds. Germany: Franz Steiner Verlag, 2007:117-142.

12. Schmidt U. The Nuremberg Doctors’ Trial and the Nuremberg Code. In: Schmidt U, Frewer A, eds.

History and Theory of Human Experimentation. Germany: Franz Steiner Verlag, 2007:71-116.

13. Taylor T. Opening statement of the prosecution, December 9, 1946. In: Annas GJ, Grodin MA, eds. The Nazi Doctors and the Nuremberg Code. New York: Oxford University Press, 1992:67-93.

14. International Committee of the Red Cross. Convention (IV) Respecting the laws and customs of war on land and its annex: Regulations respecting the laws and customs of war on land. The Hague, 18 October 1907. http://www.icrc.org/applic/ihl/ihl.nsf/52d68d14de6160e0c12563da005fdb1b/1d172642 5f6955aec125641e0038bfd6 (accessed 16 July 2014).

15. Office of the Historian. The Kellogg-Briand Pact of 1928. https://history.state.gov/milestones/1921-1936/ kellogg (accessed 16 July 2014).

16. International Committee of the Red Cross. Convention relative to the treatment of prisoners of war.

Geneva, 1929. http://www.icrc.org/ihl/INTRO/305 (accessed 16 July 2014).

17. Sass HM. Reichsgesundheitstrat 1931: Pre-Nuremberg German regulations concerning new therapy and human experimentation. J Med Philos 1983;8(2):99-111.

18. Weindling PJ. Human guinea pigs and experimental ethics: The BMJ’s foreign correspondent at the Nuremberg Medical Trial. BMJ 1996;313:1467-1470. https://doi.org/10.1136/bmj.313.7070.1467 19. Faden RR, Lederer SE, Moreno JD. US medical researchers, the Nuremberg Doctors’ Trial, and the Nuremberg Code: A review of findings of the Advisory Committee on Human Radiation Experiments.

JAMA 1996;276(20):1667-1671.

20. Lederer SE. Research without borders: The origins of the Declaration of Helsinki. In: Schmidt U, Frewer A, eds. History and Theory of Human Experimentation. Germany: Franz Steiner Verlag, 2007:145-164.

21. World Medical Assembly. Declaration of Geneva. http://www.wma.net/en/30publications/10policies/ g1/ (accessed 17 July 2014).

22. Dhai A. A study of vulnerability in health research. PhD thesis. Johannesburg: University of the Witwatersrand, 2015.

23. Beecher HK. Ethics and clinical research. N Engl J Med 1966;274(24); 1354-1360. https://doi. org/10.1056/NEJM196606162742405 24. Cleaton-Jones PC. Research ethics in South Africa: Putting the Mpumalanga case into context. In: Lavery J, Grady C, Wahl ER, Emanuel EJ, eds. Ethical Issues in International Biomedical Research.

Oxford: Oxford University Press, 2007:240-245.

25. The National Health Research Ethics Council. List of Registered RECs 2013. http://www.nhrec.org.za/ wp-content/uploads/2013/registerd_recs.pd (accessed 28 June 2013).

26. South African National Department of Health. The South African Good Clinical Practice Guidelines 2006. http://www.nhrec.org.za/wp-content/uploads/2008/09/gcp.pdf (accessed 28 June 2013).

27. South Africa. National Health Act No. 61 of 2003.

28. South African National Department of Health. Ethics in Health Research: Principles, Structures and Processes 2004. http://www.nhrec.org.za/wp-content/uploads/2008/09/ethics.pdf (accessed 28 June 2013).

29. South African National Department of Health. Ethics in Health Research. Principles, Processes and Structures 2015. http://www.nhrec.org.za/docs/Documents/EthicsHealthResearchFinalAused.pdf (accessed 20 December 2015).

Accepted 17 March 2017.

ISSUES IN PUBLIC HEALTH

This open-access article is distributed under CC-BY-NC 4.0.

When students become patients: TB disease among medical undergraduates in Cape Town, South Africa

H van der Westhuizen,1,2 MB ChB; A Dramowski,2,3 MB ChB, PhD, FCPaed, MMed (Paed), Cert Paed ID, DCH Department of Global Health, Division of Health Systems and Public Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 2 TB Proof, Cape Town, South Africa 3 Department of Paediatrics and Child Health, Division of Paediatric Infectious Diseases, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 1

Corresponding author: H van der Westhuizen (helene1mari@gmail.com) Background. Medical students acquire latent tuberculosis (TB) infection at a rate of 23 cases/100 person-years. The frequency and impact of occupational TB disease in this population are unknown.

Methods. A self-administered questionnaire was distributed via email and social media to current medical students and recently graduated doctors (2010 - 2015) at two medical schools in Cape Town. Individuals who had developed TB disease as undergraduate students were

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eligible to participate. Quantitative and qualitative data collected from the questionnaire and semi-structured interviews were analysed with descriptive statistics and a framework approach to identify emerging themes.

Results. Twelve individuals (10 female) reported a diagnosis of TB: pulmonary TB (n=6), pleural TB (n=3), TB lymphadenitis (n=2) and TB spine (n=1); 2/12 (17%) had drug-resistant disease (DR-TB). Mean diagnostic delay post consultation was 8.1 weeks, with only 42% of initial diagnoses being correct. Most consulted private healthcare providers (general practitioners (n=7); pulmonologists (n=4)), and nine underwent invasive procedures (bronchoscopy, pleural fluid aspiration and tissue biopsy). Substantial healthcare costs were incurred (mean ZAR25 000 for drug-sensitive TB, up to ZAR104 000 for DR-TB). Students struggled to obtain treatment, incurred high transport costs and missed academic time. Students with DR-TB interrupted their studies and experienced severe side-effects (hepatotoxicity, depression and permanent ototoxicity). Most participants cited poor TB infection-control practices at their training hospitals as a major risk factor for occupational TB. Conclusions. Undergraduate medical students in Cape Town are at high risk of occupationally acquired TB, with an unmet need for comprehensive occupational health services and support.

S Afr Med J 2017;107(6):475-479. DOI:10.7196/SAMJ.2017.v107i6.12260

Medical students in South Africa (SA) complete undergraduate training in communities with extremely high tuberculosis (TB) incidence rates (834 per 100 000 population in 2015).[1] SA healthcare workers (HCWs) are at high risk of developing TB: three times increased risk for drug-sensitive TB (DS-TB) and up to 6.7 times increased risk for drug-resistant TB (DR-TB) when compared with the general population.[2-4] Poor implementation of TB-infection control measures (TB-IC) is reported from SA healthcare facilites, contributing to TB exposure and development of occupational TB disease among SA HCWs and health science students.[5,6] Latent TB incidence among SA medical students was measured

by Tuberculin Skin Test (TST) conversion at 23 cases/100 personyears (95% confidence interval (CI) 12 - 43).[7] While this was lower than that of SA HCWs, this rate is three times higher than the average annual risk of TST conversion in HCWs from five other high-TB-burden countries (8.4/100; 95% CI 2.7 - 14).[8] Knowledge about TB-IC has been shown to reduce the odds of a positive TST in medical students by >70% (adjusted odds ratio (OR) 0.29; 95% CI 0.09 - 0.98), indicating the importance of TB-IC training at undergraduate level.[9] However, even if TB-IC knowledge can be improved at undergraduate level, the lack of clinician role models may impact TB-IC practices negatively.[10] In a study reporting SA doctors’ experiences with occupational TB disease, significant diagnostic delays and high rates of invasive procedures were documented.[11] In addition to high mortality, morbidity and treatment side-effects, DR-TB has been demonstrated to have profound psychosocial impact among SA HCWs.[12,13] Although data on the incidence and impact of occupational TB in SA HCWs are sparse, even less is known about the experiences of SA medical students with occupational TB. We aimed to: (i) investigate the clinical presentation, diagnostic investigations and treatment of TB in medical students; (ii) describe students’ experiences of developing occupational TB; and (iii) evaluate the support systems utilised following TB diagnosis.

Methods

This descriptive cross-sectional study was conducted in 2015. Medical students at two medical training universities in the Western Cape Province, SA, who had developed TB during their undergraduate medical training between 2010 and 2015, were eligible to complete an online questionnaire. Those who developed TB after graduation or prior to the commencement of their studies were not eligible for inclusion. A total of 3 500 individuals was approached to participate in the study: 2 028 (58%) were current medical students in their

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clinical training years at Stellenbosch University and the University of Cape Town who received notification of the study via university mailing lists, and 1 472 (42%) were recent medical graduates from the two universities (2010 - 2015) who were notified via email and social media (Facebook groups and the TB Proof Facebook page). A lucky-draw cash prize was offered as an incentive for participation.

All students who met the inclusion criteria were eligible to complete a self-administered electronic questionnaire that contained 15 quantitative and 14 qualitative questions. The questionnaire was developed in consultation with occupational health and infection control experts, and was piloted and reviewed to ensure it contained no stigmatising language.

A subset of the questionnaire respondents was approached to participate in 30-minute semi-structured individual interviews (two participants from each university were selected based on their ability to attend the interview). Interviews were transcribed by a trained senior researcher and coded by both investigators using a master code list. Differences in coding were resolved through discussion between the two coders. A framework approach was used to identify emerging themes. Both quantitative and qualitative responses were grouped into four domains: (i) utilisation of healthcare services; (ii) impact of disease; (iii) support structures; and (iv) TB infection control in training hospitals. Qualitative data describing the impact of stigma will be reported in a separate article. Participant number (P) is indicated before the selected quotations. Quantitative data were analysed using frequencies and percentages and reported using mean with standard deviation (SD).

Ethical approval was obtained from the Health Research Ethics Committees of Stellenbosch University (ref. no. S15/02/025) and the University of Cape Town (ref. no. 331/2015). Institutional permission was obtained from both universities.

Results

Demographics and disease presentation

Twelve individuals (mean age 24 years) self-reported a diagnosis of TB disease during their undergraduate training years. Table 1 illustrates demographic information and summarises TB disease presentation.

Utilisation of healthcare services

The majority of participants utilised private healthcare providers, specifically general practitioners (n=7) and pulmonologists (n=4).

Despite some students visiting the universities’ campus health services (n=3), diagnostic investigations were not available, and students were referred to private practitioners or public tertiary training hospitals. Participants experienced significant delays in TB

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‘Medical school trains you to believe that school is more important and that health comes second. There is no time to go to a doctor and I stayed with that lymph node for 2 weeks and it got bigger and more painful. [It is ironic that] our problem is we don’t have time to go to the clinic and doctors are roaming our corridors.’ (P2)

Table 1. Demographic information (N=12) n (%) Gender Female Male Age (years) 21 - 23 24 - 26 Year of study at TB diagnosis 2nd 3rd 4th 5th 6th Period during which TB diagnosis was made 2010 - 2012 2013 - 2015 Training institution Stellenbosch University University of Cape Town Site of TB Pulmonary TB Pleural TB TB lymphadenitis TB spine Drug sensitivity Drug-sensitive TB (DS-TB) Drug-resistant TB (DR-TB) Baseline presenting symptoms* Malaise Cough Weight loss Night sweats Fever Chest pain Lymphadenopathy Other: haemoptysis, erythema nodosum, ganglion, hoarseness and back pain Diagnostic investigations* Chest X-ray Computed tomography scan of chest Sputum culture and sensitivity testing Polymerase chain reaction-based test, e.g.

GeneXpert Sputum microscopy Tissue biopsy (e.g. pleura, lymph node) Bronchoscopy Pleural fluid aspiration Fine-needle aspiration biopsy Computed tomography abdomen Magnetic resonance imaging: spine Interferon gamma release assays

10 (83.3) 2 (16.7) 4 (33.3) 8 (66.6)

Health-system delays were the biggest contributing factor to diagnostic delays, including difficulty accessing services during holidays, long waiting times at public hospitals and a low index of suspicion among private healthcare providers. Only 41.7% of initial diagnoses were correct, with misdiagnoses ranging from pneumonia (n=3) to uncontrolled asthma (n=1), influenza (n=1), and fibromyalgia (n=1). One participant was started empirically on a DS-TB regimen without sending pleural fluid for TB culture, which delayed the diagnosis of DR-TB. Participants collected their medication from government clinics (n=7), private pharmacies (n=7) and training hospitals (n=2) and also reported switching between the above options. Half of the participants received directly observed treatment, but found it inconvenient due to high transport costs and missed academic time: ‘I got to campus health and asked, “I want to get my medication here,” and they told me, “No we don’t do that.” I asked where students get their medication and the sister said, “You have to go to a registered TB clinic”. I said, “Sister but I don’t have a car. When am I going to go? I have classes.” … Then I went to occupational health and [the sister working there] said “I can’t do anything for you. The university can’t follow you up and we give you medication.” It was just such a grey area, it was such a struggle …

Eventually sister said, “You know what, this is nonsense, I’m going to take you,” and she started giving me the medication. It should never have been that hard to get medication.’ (P1)

2 (16.7) 1 (8.3) 6 (50.0) 1 (8.3) 2 (16.7) 5 (41.7) 7 (58.3) 7 (58.3) 5 (41.7) 6 (50.0) 3 (25.0) 2 (16.7) 1 (8.3) 10 (83.3) 2 (16.7) 7 (58.3) 7 (58.3) 5 (41.7) 4 (33.3) 3 (25.0) 3 (25.0) 3 (25.0) 1 (8.3) each

Several participants highlighted the need for comprehensive student occupational health services: ‘We need someone responsible for occupational health for students.

You have students in the hospital doing the same things that the doctors are doing and the doctors have occupational health – why wouldn’t the students have that as well? There is a huge disconnect [and] misunderstanding.’ (P11)

Impact of disease

10 (83.3) 6 (50.0) 5 (41.7) 5 (41.7) 5 (41.7) 5 (41.7) 3 (25.0) 3 (25.0) 1 (8.3) 1 (8.3) 1 (8.3) 0 (0)

*Multiple answers could be selected, hence total >100%.

diagnosis: the mean delay between developing symptoms and seeking help was 3.2 weeks (range 0 - 16 weeks, SD 4.6); the mean diagnostic delay post consultation was 8.1 weeks (range 0 - 32 weeks, SD 12.3).

Fear of missing academic teaching and clinical duties influenced students’ health-seeking behaviour and delayed TB diagnosis:

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Eight participants experienced side-effects of treatment, most commonly gastrointestinal side-effects (n=8), difficulty concentrating (n=3), as well as more serious adverse events including hepatotoxicity (n=2), peripheral neuropathy (n=2) and depression (n=2).

Participants with DR-TB experienced an increased number and severity of side-effects and found treatment very difficult to endure, with one participant strongly considering discontinuing treatment: ‘Taking the pills literally takes a few minutes, but for me, the whole day I think about taking the pills then every hour I’ll be counting down till I take the pills and then the minutes and seconds. Then I sit there with my pills and then I take my pills and then I sit there in fear of the side-effects. I feel nauseous, I have diarrhoea, not able to sleep, still thinking, “Oh my gosh, I have to do this again tomorrow.” The pain from the injection consumes your whole day.’ (P2) Three participants had side-effects that resulted in long-term disability including hearing loss, depression and decreased visual acuity: ‘My hearing loss has been a very difficult adjustment and I am often seen as not paying attention or not knowing answers, when in fact [the problem is] I cannot hear normally.’ (P3)

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Participants missed academic time due to the initial 2-week isolation period, clinic visits to collect treatment and follow-up appointments. Three students had to interrupt their studies, while others were under severe pressure to catch up missed clinical time in order for them to graduate with their year group. Participants reported substantial expenses, including specialist appointments, investigations, treatment costs (DS-TB: ZAR1 060 for 6 months) and transport costs to the clinics (ZAR700 for 6 months). Participants also incurred costs as a result of treatment complications (hearing aids) and complications due to TB disease (laparoscopic repair of inguinal hernia after chronic cough). Few students had comprehensive medical aid cover. Other costs included paying the tuition fees and accommodation of the additional years of studying.

Participants’ average estimated personal expenses for DS-TB were ZAR25 000 (to a maximum of ZAR80 000) and for DR-TB up to ZAR104 000.

Three participants mentioned that their experience with TB had made them realise how difficult it can be to undergo treatment. Most participants felt that TB had increased their empathy toward patients and motivated them to provide patient-centred care: ‘There’s a certain understanding that comes with an experience like this that can’t be taught. I understand now how important it is to treat the whole patient and not just the disease because illness is far reaching and infiltrates every aspect of a person’s life.’ (P11) For some participants, their personal experience created a desire to help to make a difference to the TB burden. Several participants noted that their experience made them realise what risks their occupation poses: ‘I didn’t realise that when I went into medicine that I was exposing myself to people’s diseases – in fact all the diseases came running towards us. Being a doctor and having the profession is not worth me being so close to death.’ (P2) Two participants, both of whom had DR-TB, wanted to leave medical school: ‘I came back at the insistence of my family because I had completed so much of my degree. I had to receive psychological counselling to help me cope with the adjustment and post-traumatic stress. I do not see myself being a doctor involved in the clinical care of patients. Once I complete my degree and internship I don’t think I will continue a career in medicine.’ (P3)

Support

Two participants struggled to access any family support, as their families lived in other provinces; some relied heavily on support from friends at university. The majority of participants (n=7) strongly expressed their disappointment with the support that they received from their universities:

‘My university protocol was dismal to be honest. I wasn’t sure what to do or where to go. It was just another stressor I didn’t need when I was trying to get better.’ (P11) ‘I think faculties really need to know this is their problem, whether they want to admit it or not. They need to do more about it.’ (P2)

TB infection control in training hospitals

Most participants (n=10) cited poor TB-IC at training hospitals as their major risk factor for occupational TB. The administrative controls (fast-tracking patients with TB symptoms and isolating smear-positive patients) were poorly implemented and environmental controls (opening windows, mechanical ventilation) were infrequently used.

‘Some windows are bolted shut. Others are never opened because nobody [wants to] get cold in winter.’ (P2) Often the only TB-IC method available to students was the N95 respirator (the lowest tier of protection on the Centers for Disease Control and Prevention hierarchy of TB-IC). Both universities instituted N95 fit-testing programmes in 2013, and supply respirators to students annually, although problems with access to respirators persist: ‘Respirators are tough: they are not nice to wear, they are hot and stuffy, and the patients can’t understand you, especially if there is a language barrier. So you often have to take it off and repeat yourself for them to hear you, which actually defeats the point.’ (P10) There is also a lack of an institutional safety culture, with poor TB-IC implementation and few positive senior clinician role models: ‘We had our masks, we take them out and put them on and sometimes the doctors go, “Oh look at the third years!” [It made us wonder] are they not aware, do they know something that we don’t? It is very confusing.’ (P11) Participants felt the high-risk zones for TB exposure were areas where undifferentiated patients were seen: medical, surgical and trauma emergency units and peripheral training hospitals and clinics: ‘F1 [the medical emergency unit] is a mess; it is scary. It really is scary.’ (P11) Returning to this clinical environment after developing occupational TB disease left most participants feeling scared and concerned about TB reinfection: ‘I saw the first patient coughing and they told me the patient had TB; I felt like I was having an anxiety attack. I just had to leave the room, I didn’t want to see a patient, I didn’t want to be around a patient, I just wanted to leave.’ (P10) Participants made several recommendations to improve diagnosis, treatment and psychosocial support for students diagnosed with TB (Table 2).

Table 2. Recommendations by participants to address TB in medical students 1. Strengthen TB-IC in all healthcare facilities, from clinics, district hospitals to tertiary hospitals.

2. Develop and implement TB-prevention policies at all healthcare training institutions.

3. Ensure availability of fit-tested N95 respirators at all times, free of charge to students.

4. Provide comprehensive student occupational health services, including screening, diagnostic investigations and campus-based collection of treatment, free of charge.

5. Provide support structures for students who develop TB, including: alternative accommodation arrangements for students during the isolation period, campus-based support groups of students who have developed TB, monthly check-ups to provide treatment support and additional academic support.

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Discussion

This study highlights the vulnerability of medical students at two of the eight SA medical schools, documenting substantial TB exposure and risk of progression to occupational TB. In comparison with data from Naidoo et al.[11] reporting TB disease in medical doctors in KwaZulu-Natal, medical students had a greater incidence of extrapulmonary TB (50% v. 20%) and higher incidence of DR-TB (16.7% v. 10%). Fewer students than doctors (25% v. 75%) reported having easy access to specialised diagnostic procedures. Students (41.7%) had a lower percentage of initial correct diagnosis compared with doctors (52.5%), and experienced longer diagnostic delays. This may reflect the lack of student occupational health services and the perceived lower risk for occupational TB among students. Students consistently indicated that they struggled to access diagnostics and treatment, with prominent opportunity costs (lost academic time during treatment collection) and direct costs for transport.

Participants with DR-TB suffered long-term disability due to treatment side effects that impacted their ability to continue with clinical medicine, highlighting the urgent need for less toxic DR-TB treatment regimens. This correlated with themes identified by Padayatchi et al.[12] (prolonged morbidity, attrition from the field, psychological impact, weak support structures and poor infection control). Despite severe psychosocial impacts, most participants showed astounding resilience, drawing parallels between their experiences of TB and those of the patients they care for. The majority indicated that their TB diagnosis had given them new insight into the impact of disease and treatment in their patients’ lives, corroborating Woolf ’s findings.[14] Working in a healthcare system where TB-IC is poorly implemented, participants perceived their risk of TB reinfection to be very high. Negative clinician role modelling was found to play an important role in discouraging respirator usage, as reported in previous studies in this setting.[6] As stipulated under the Regulations for Biological Hazardous Agents and the Occupational Health and Safety Act No. 85 of 1993, healthcare workers are legally entitled to reasonable protection from TB exposure through TB-IC measures, annual TB screening and access to diagnostic and treatment services.[15] For health science students, however, there is uncertainty as to who should offer these services (the universities or the hospitals where clinical training is based), and whether students are protected by the Compensation for Occupational Injuries and Diseases Act No. 130 of 1993.

The lack of national guidance and policies has led to an unjust situation where SA health science students train in a hazardous working environment with no recourse to assistance with diagnostic and treatment costs for an occupational disease. There is an urgent need for SA medical training institutions and the National Department of Health to develop policies for the provision and funding of health services for students with occupationally acquired TB disease.

The findings of this study could likely be extrapolated to medical students at other SA universities and other high-TB-burden countries.

Other vulnerable groups highly exposed to TB disease due to poor TB-IC in healthcare settings include nursing students, allied health students, and non-clinical staff, for example porters, working in clinical areas. Further research is needed to quantify the burden of occupational TB in these subpopulations with tailored occupational health policies offering comprehensive support.

are not routinely collected. This study did not include participants who developed latent TB during their training and developed TB disease after graduation. TB is highly stigmatised, which also impacts willingness to disclose it. Given these factors, it is likely that this study underrepresents the true burden of TB disease in medical students at the two universities.

Conclusion

Medical students training in TB-endemic settings are at high risk of occupationally acquired TB. Students experienced significant diagnostic delays and barriers to accessing TB care. Participants with DR-TB interrupted their studies, incurred large expenses and experienced severe side-effects. Although the experience of TB disease increased students’ empathy with patients, they reported feeling greater vulnerability upon returning to the clinical environment. Students reported poor implementation of TB-IC in their training institutions as their major risk factor for occupational disease. Comprehensive occupational health services and institutional policies for TB prevention among health science students are urgently needed. Further research to quantify the burden of occupational TB in medical students and other neglected subpopulations should be prioritised.

Acknowledgements. We thank all participants for sharing their stories and are grateful for the assistance and insight provided by Zolelwa Sifumba.

We thank Dr Donald Skinner for advice on qualitative data analysis and Dr Moleen Zunza for assistance with the statistical analysis. We thank Capital for Good (Geneva Global) for proving funding for interview transcriptions and the lucky-draw prize through the non-governmental organisation TB Proof.

1. World Health Organization. Global Tuberculosis Report 2016. Geneva: WHO Press, 2016. http://www. who.int/tb/publications/global_report/en/ (accessed 27 February 2017).

2. Menzies D, Joshi R, Pai M. Risk of tuberculosis infection and disease associated with work in healthcare settings. Int J Tuberc Lung Dis 2007;11(6):593-605.

3. Joshi R, Reingold AL, Menzies D, Pai M. Tuberculosis among healthcare workers in low- and middleincome countries: A systematic review. PLoS Med 2006;3(12):e494. https://doi.org/10.1371/journal. pmed.0030494 4. O’Donnell MR, Jarand J, Loveday M, et al. High incidence of hospital admissions with multidrugresistant and extensively drug-resistant tuberculosis among South African healthcare workers. Ann Intern Med 2010;153(8):516-522. https://doi.org/10.1059/0003-4819-153-8-201010190-00008 5. Health Systems Trust. The National Healthcare Facilities Baseline Audit, 2012. https://www.health-e. org.za/wp-content/uploads/2013/09/National-Health-Facilities-Audit.pdf (accessed 27 February 2017).

6. Van der Westhuizen H, Kotze J, Narotam H, von Delft A, Willems B, Dramowski A. Knowledge, attitudes and practices regarding TB infection among health science students in a TB-endemic setting. Int J Infect Control 2015;11(1):1-7. https://doi.org/10.3396/IJIC.v11i4.030.15 7. McCarthy KM, Scott LE, Gous N, et al. High incidence of latent tuberculous infection among South African health workers: An urgent call for action. Int J Tuberc Lung Dis 2015;19(6):647653. https://doi.org/10.5588/ijtld.14.0759 8. Baussano I, Nunn P, Williams B, Pivetta E, Bugiani M, Scano F. Tuberculosis among healthcare workers. Emerg Infect Dis 2011;17(3):488-494. https://doi.org/10.3201/eid1703.100947 9. Van Rie A, McCarthy K, Scott L, Dow A, Venter WDF, Stevens WS. Prevalence, risk factors and risk perception of tuberculosis infection among medical students and healthcare workers in Johannesburg, South Africa. S Afr Med J 2013;103(11):853-857. https://doi.org/10.7196/ SAMJ.7092 10. Dramowski A, Marais F, Willems B, Mehtar S. Does undergraduate teaching of Infection Prevention and Control (IPC) adequately equip medical graduates for clinical practice? Afr J Health Professions Educ 2015;7(1Suppl1):S105-S110. https://doi.org/10.7196/AJHPE.500 11. Naidoo A, Naidoo S, Gathiram P, Lalloo U. Tuberculosis in medical doctors – a study of personal experiences and attitudes. S Afr Med J 2013;103(3):176-180. https://doi.org/10.7196/SAMJ.6266 12. Padayatchi N, Daftary A, Moodley T, Madansein R, Ramjee A. Case series of the long-term psychosocial impact of drug-resistant tuberculosis in HIV-negative medical doctors. Int J Tuberc Lung Dis 2010;14(8):960-966.

13. Von Delft A, Dramowski A, Sifumba Z, et al. Exposed, but not protected: More is needed to prevent drug-resistant tuberculosis in healthcare workers and students. Clin Infect Dis 2016;62(Suppl3):S275-S280. https://doi.org/10.1093/cid/ciw037 14. Woolf K, Cave J, McManus IC, Dacre JE. ‘It gives you an understanding you can’t get from any book.’ The relationship between medical students’ and doctors’ personal illness experiences and their performance: A qualitative and quantitative study. BMC Med Educ 2007;7:50. https://doi. org/10.1186/1472-6920-7-50 15. Zungu M, Malotle M. Do we know enough to prevent occupationally acquired tuberculosis in healthcare workers ? Occup Health South Africa 2011;7(5):17-21.

Study limitations

This study utilised self-reporting to identify eligible participants, as institutional data on occupational TB disease in medical students

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Accepted 27 February 2017.

June 2017, Print edition

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This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

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CLINICAL ALERT

Beware: The femoral haemodialysis catheter â&#x20AC;&#x201C; a surgeonâ&#x20AC;&#x2122;s perspective T du Toit, MB ChB, FCS, MMed, FEBS; D Thomson, MB ChB, FCS, MMed, Cert Crit Care; E Muller, MB ChB, FCS, MMed Transplant Unit, Division of General Surgery, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: T du Toit (dutoitjm@yahoo.com)

The ability to identify and address factors that threaten the optimal utilisation of donor organs is quintessential in obtaining satisfactory transplant outcomes. We share our concerns regarding the prolonged use of femoral haemodialysis catheters and its potential to jeopardise successful renal transplantation. Despite a paucity of literature on the topic, we review relevant aspects related to this pernicious form of vascular access and clarify its limited role in the modern haemodialysis unit, particularly in patients who are still considered for transplantation.

S Afr Med J 2017;107(6):480-482. DOI:10.7196/SAMJ.2017.v107i6.12391

In South Africa, access to renal replacement therapy (RRT) and transplantation is limited, mainly owing to resource constraints. In the Western Cape Province, approximately half of the public sector patients with stage 5 chronic kidney disease are denied RRT. [1] Those who are accepted are typically good transplant candidates with favourable outcomes when transplanted (5-year patient and graft survival rates of 83.5% and 77.9%, respectively). Low national organ donation (1.4 per million population (pmp)) and renal transplantation rates (4.7 pmp)[1] demand optimal utilisation of this precious resource.

This article is based on recent adverse events encountered during renal transplantation at our institution, possibly associated with the prolonged use of femoral haemodialysis catheters (FHCs). Cumbersome dissection of target vasculature, prolonged anastomosis time and unpredictable venous outflow were some of the difficulties experienced, resulting in unsalvageable early graft thrombosis on two occasions.

Despite the anecdotal nature of these findings, we believe that the association with FHCs was not incidental. In the absence of prospective data, with glaring ethical concerns prohibiting further investigation by a randomised control trial, we attempt to answer three relevant questions by applying clinical experience and the best evidence at hand.

proliferation of smooth-muscle cells and focal catheter attachment to the vein wall are consequences of prolonged catheter use.[3] A comparable interplay of mechanical forces applies to FHCs. Although dynamic mediastinal structures do not contribute to mechanical forces in the lower-limb setting, the mechanical implications of a relatively rigid intraluminal device positioned in an anatomically dynamic region have to be considered.

Areas of natural anatomical narrowing have been described and render the vessel wall vulnerable to direct mechanical trauma. In the upper extremities, these areas include the subclavian vein at the costoclavicular junction and the left brachiocephalic vein as it crosses a relatively fixed, pulsatile fulcrum of brachiocephalic artery and aorta.[4,5] Comparable areas in the lower-extremity venous system include both (but especially the left) common iliac veins where they are crossed by the right common iliac artery (Fig. 1).

Reports specifically evaluating the impact of FHCs on the surrounding vasculature are limited.[6,7] A retrospective study, including

1. Are venous complications associated with upper-extremity haemodialysis catheters applicable to FHCs?

Prolonged catheterisation of the upper-extremity venous system may induce structural damage and (in its most extreme form) lead to central vein stenosis (CVS). Owing to its crippling effect on future vascular access, CVS has been extensively studied. In our opinion, in the absence of literature evaluating aetiopathological factors specific to lower-extremity venous stenosis, valuable parallels may be drawn from the substantial pool of data on CVS. However, one should recognise unique anatomical differences and how these may affect the development of venous complications.

The development of haemodialysis catheter-associated CVS is based on an interplay of mechanical forces, generated by dynamic mediastinal structures and turbulent flow.[2] Vein-wall thickening,

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Fig. 1. Potential areas of natural anatomical narrowing in the iliac veins.

(R = right; L = left; 1 = proximal (L) common iliac vein compressed by (R) Â common iliac artery; 2 = proximal (R) common iliac vein compressed by (R) common iliac artery; 3 = distal (L) common iliac vein compressed by (L) internal iliac artery; 4 = distal (R) common iliac vein compressed by (R) internal iliac artery.)

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24 patients receiving haemodialysis by way of a temporary FHC, investigated the frequency of post-catheterisation common femoral/ external iliac vein stenosis.[6] Magnetic resonance (MR) venography (comparable to conventional venography)[8] confirmed venous stenoses in 4 of the 14 patients (29%) with >14 catheter days. All stenoses observed were in the subgroup of patients with >30 catheter days. Comparatively, the reported stenosis rates with internal jugular and subclavian vein catheters are 10%[9] and 20 - 50%,[9-11] respectively.

In another study, 7 of 27 patients (26%) with tunnelled FHCs presented with ipsilateral lower-extremity swelling within 10 days of insertion. Deep-vein thromboses were ultrasonographically confirmed in all 7 cases.[12]

2. What are the implications of prolonged FHC use, with specific reference to renal transplantation?

Several imaging modalities (including duplex ultrasound,[13,14] computed tomography venography and (3-D) MR venography[15]) have been validated in the diagnosis and exclusion of postcatheterisation venous stenosis. However, exclusion of significant stenosis (accepted as ≥50%) does not necessarily predict successful transplantation. Once reperfused, the renal allograft will receive approximately 10 - 12% of the recipient’s cardiac output. This equates to an increase in iliac vein outflow of approximately 550 mL/min in a 70 kg adult male.[16] In the presence of unrecognised upstream perivascular fibrosis and reduced venous compliance, a functional stenosis may only be unmasked upon reperfusion, potentially leading to allograft congestion and early renal vein thrombosis.

Successful transplantation contralateral to the side of suspected venous pathology has been described.[6] However, an important consideration is the physical length of the catheter and its position relative to the common iliac vein confluence (Fig. 2). Long-term (tunnelled) FHCs are often longer than their temporary (nontunnelled) counterparts, therefore potentially compromising contralateral external iliac vein outflow should stenosis develop.

In patients with venous pathology precluding heterotopic renal transplantation, an orthotopic site may be considered. In the largest orthotopic renal transplant series to date (223 transplants over a 31-year period) excellent 1-, 10- and 20-year overall patient (92%, 78% and 63%) and graft (88%, 59% and 35%) survival were reported, with no difference in 20-year patient or graft survival compared with

heterotopic transplants.[17] However, the procedure is technically demanding and associated with high surgical complication rates (66.7%) when performed infrequently.[18]

3. How should one approach the chronic haemodialysis patient in need of an FHC?

Preserving the likelihood of successful transplantation is key.

FHCs should be reserved for cases where internal jugular vein catheterisation is unsuccessful or contraindicated, with catheter days restricted to a minimum. Early referral to an access surgeon allows sufficient time for preoperative planning and usually results in prompt creation of alternative access in the majority of patients.

Patients with bilateral CVS not amenable to endovenous intervention present a unique challenge. The optimal long-term solution is expedited renal transplantation, and this should be motivated for by the treating physician on the basis of precarious vascular access. Reassessment for peritoneal dialysis is often overlooked, and relative contraindications should not apply in the face of dwindling vascular access. Owing to generally uninspiring outcomes, lower-extremity arteriovenous (AV) fistulas/grafts should not be viewed as sustainable access, but rather as a ‘bridge’ to transplantation.[19] In our opinion, all the above options should be explored prior to insertion of a long-term FHC as definitive access.

Conclusion

The correlation between early graft thrombosis and prolonged FHC use cannot be scientifically proven at this time. However, retrospective reports suggest that the iliac veins are not exempt from the venous complications associated with upper-extremity haemodialysis catheters. Although successful transplantation is still likely, prolonged FHC use may result in avoidable surgical complexities that cannot be reliably predicted preoperatively. Early graft thrombosis, despite occurring rarely, is not only devastating to the recipient and surgeon involved, but may also impact on the patient awaiting a chronic dialysis slot.

We therefore strongly believe that FHC placement should be reserved for patients in whom internal jugular vein catheterisation was unsuccessful or is contraindicated. A proactive approach to establishing alternative dialysis access is required in an effort to limit femoral catheter days, especially in patients who are still considered for transplantation. Where upper-limb access options are not viable, expedited renal transplantation, peritoneal dialysis and lower-extremity AV fistulas/graft creation should all be considered prior to insertion of a long-term FHC as definitive access.

Transplant surgeons should be informed of all patients on the waiting list with current or previous catheters beyond the common iliac vein confluence (or within both external iliac veins) for more than 30 cumulative days, as difficult transplantation should be anticipated.

Acknowledgements. None.

Author contributions. All authors contributed to the conceptualisation process, with EM and DT involved with the proofreading of the manuscript.

Funding. None.

Conflicts of interest. None.

Fig. 2. Computed tomography venogram image (coronal view) indicating the position of a long-term femoral haemodialysis catheter relative to the common iliac vein confluence. (1 = aorta; 2 = inferior vena cava; 3 = longterm haemodialysis catheter tip within distal inferior vena cava.)

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1. Moosa MR, Kidd M. The dangers of rationing dialysis treatment: The dilemma facing a developing country. Kidney Int 2006;70(6):1107-1114. http://dx.doi.org/10.1038/sj.ki.5001750 2. Hernández D, Díaz F, Rufino M, et al. Subclavian vascular access stenosis in dialysis patients: Natural history and risk factors. J Am Soc Nephrol 1998;9(8):1507-1510.

3. Forauer AR, Theoharis C. Histologic changes in the human vein wall adjacent to indwelling central venous catheters. J Vasc Interv Radiol 2003;14(9):1163-1168. http://dx.doi.org/10.1097/01.

RVI.0000086531.86489.4C

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4. Yevzlin AS. Hemodialysis catheter-associated central venous stenosis. Semin Dial 2008;21(6):522-527. http://dx.doi.org/10.1111/j.1525-139X.2008.00496.x 5. Salik E, Daftary A, Tal MG. Three-dimensional anatomy of the left central veins: Implications for dialysis catheter placement. J Vasc Interv Radiol 2007;18(3):361-364. http://dx.doi.org/10.1016/j. jvir.2006.12.721 6. Weyde W, Badowski R, Krajewska M, et al. Femoral and iliac vein stenoses after prolonged femoral vein catheter insertion. Nephrol Dial Transplant 2004;19(6):1618-1621. http://dx.doi.org/10.1093/ndt/ gfh192 7. Hegarty J, Picton M, Chandlers N, et al. Iliac vein stenosis secondary to femoral catheter placement.

Nephrol Dial Transplant 2001;16(7):1520-1521. https://doi.org/10.1093/ndt/16.7.1520 8. Yoshizako T, Kazuro K, Kawumitsu H, Yoshikawa K. Two-dimensional time-of-flight MR venography: Assessment with detection of chronic deep venous thrombosis in combination with magnetization transfer contrast. J Comput Assist Tomogr 1996;20(6):957-964.

9. Barret N, Spencer S, McIvor J, Brown EA. Subclavian stenosis: A major complication of subclavian dialysis catheters. Nephrol Dial Transplant 1988;3(4):423-425.

10. Clark DD, Albina JE, Chazan JA. Subclavian vein stenosis and thrombosis: A potential serious complication in chronic hemodialysis patients. Am J Kidney Dis 1990;15(3):265-268. https://doi. org/10.1016/S0272-6386(12)80772-4 11. Schillinger F, Schillinger D, Montagnac R, Milcent T. Post-catheterisation vein stenosis in haemodialysis: Comparative angiographic study of 50 subclavian and 50 internal jugular accesses.

Nephrol Dial Transplant 1991;6(10):722-724. https://doi.org/10.1093/ndt/6.10.722 12. Maya ID, Allon M. Outcomes of tunneled femoral hemodialysis catheters: Comparison with internal jugular vein catheters. Kidney Int 2005;68(6):2886-2889. http://dx.doi.org/10.1111/j.15231755.2005.00762.x

13. Rose SC, Kinney TB, Bundens WP, et al. Importance of Doppler analysis of transmitted atrial waveforms prior to placement of central venous access catheters. J Vasc Interv Radiol 1998;9(6):927934. https://doi.org/10.1016/S1051-0443(98)70424-5 14. Patel MC, Berman LH, Moss HA, McPherson SJ. Subclavian and internal jugular veins at Doppler US: Abnormal cardiac pulsatility and respiratory phasicity as a predictor of complete central occlusion.

Radiology 1999;211(2):579-583. http://dx.doi.org/10.1148/radiology.211.2.r99ma08579 15. Paksoy Y, Gormus N, Tercan MA. Three-dimensional contrast-enhanced magnetic resonance angiography (3-D CE-MRA) in the evaluation of hemodialysis access complications, and the condition of central veins in patients who are candidates for hemodialysis access. J Nephrol 2004;17(1):57-65.

16. Carlström M, Wilcox CS, Arendshorst WJ. Physiol Rev 2015;95(2):405-511. http://dx.doi.org/10.1152/ physrev.00042.2012 17. Musquera M. Orthotopic kidney transplantation: An alternative surgical technique in selected patients. Eur Urol 2010;58(6):927-933. http://dx.doi.org/10.1016/j.eururo.2010.09.023 18. Hevia V, Gómez V, Álvarez S, Díez-Nicolás V, Fernández A, Burgos FJ. Orthotopic kidney transplant: A valid surgical alternative for complex patients. Curr Urol Rep 2015;16(1):470. http://dx.doi. org/10.1007/s11934-014-0470-x 19. Aitken E, Jackson AJ, Kasthuri R, Kingsmore DB. Bilateral central vein stenosis: Options for dialysis access and renal replacement therapy when all upper extremity access possibilities have been lost. J Vasc Access 2014;15(6):466-473. http://dx.doi.org/10.5301/jva.5000268

Accepted 15 March 2017.

ISSUES IN MEDICINE

This open-access article is distributed under CC-BY-NC 4.0.

Complementary medicines: When regulation results in revolution L Fourie, BPharm, MSc; F Oosthuizen, BPharm, MSc, PhD; K du Toit, BPharm, MSc, PhD, LLB

Discipline of Pharmaceutical Sciences, Faculty of Health Sciences, University of KwaZulu-Natal, Durban, South Africa Corresponding author: L Fourie (liezl.fourie14@gmail.com)

Medicines have evolved over time and so has the realisation of the importance of quality control and regulatory processes. The regulatory practices include all the steps from the development and manufacture of the active ingredients until the medicines reach the consumer.

The Medicines Control Council (MCC) is mandated to regulate medicines in South Africa. Complementary medicines were previously perceived to be unregulated, although the Medicines Act does not distinguish between allopathic and complementary medicine. As the era of unregulated complementary medicine ended, the requirements in terms of dossier content left many role-players at odds. However, the MCC has a mandate to ensure that the registration of a medicine is in the interest of the public and that complementary medicine is manufactured in a facility adhering to good manufacturing practice, according to which efficacy and safety are supported by reliable data with a known shelf-life.

S Afr Med J 2017;107(6):483-485. DOI:10.7196/SAMJ.2017.v107i6.12055

Medicines have evolved over time and so has the realisation of the importance of quality control and regulatory processes.

Catastrophes such as the thalidomide disaster in the late 1950s highlighted the importance of regulating medicines on the grounds of safety, quality and efficacy, which has since been widely accepted and implemented.[1] The most important objective of medicine regulation is to ensure the safety of consumers. As medicine as such is not safe, the choice between the risk and benefit associated with its use needs to be made on the consumer’s behalf by means of regulations. The regulatory practices include all the steps from the development and manufacture of the active ingredients, to packaging and distribution, until the medicines reach the consumer. [2] In South Africa (SA), as in other countries, the public has the right to expect that only safe and effective medicines of good quality are allowed on the market, aligned with section 12 of the Constitution of SA.[3]

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The establishment of the Medicines Control Council (MCC), mandated to regulate medicines in SA, was provided for by the Medicines and Related Substances Act 101 of 1965 (Medicines Act).[2] The Medicines Act provides in section 14(2)(a) that the MCC may from time to time by resolution approved by the minister of health determine that a medicine or class or category of medicines or part of any class or category of medicines mentioned in the resolution shall be subject to registration in terms of the Medicines Act. Medicines were called up for registration according to this section and if a medicine became subject to registration and was not subsequently registered, its sale was prohibited according to section 14(1).[4]

Regulation of complementary medicines

Complementary medicines were previously perceived to be unregulated, although the Medicines Act does not distinguish

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IN PRACTICE

between allopathic and complementary medicine. In 2002, the MCC published a notice, ‘Call up notice for medicines frequently referred to as complementary medicines in terms of the Medicines and Related Substances Act, 1965 (Act No. 101 of 1965)’.[5] The Notice also indicated that the data compiled from this call-up will enable Council to audit all products currently available on the market.

Council will review the claims of safety, quality and efficacy for all identified products and will determine whether any such claims constitute a public health hazard and act accordingly. The MCC requested manufacturers to submit a document providing limited information on the medicines. The shortened application form included administrative information, a copy of the label and package insert, a breakdown of the unit formulation, and a list of other countries in which the product is sold. These application forms did not contain sufficient information for evaluation of safety, quality and efficacy and were intended as an audit process only. MBR20.8 documents were issued by the MCC as confirmation of receipt of the abbreviated application and did not indicate product registration.[6] Even though the audit period, as indicated in the Notice, expired on 22 August 2002, submissions from manufacturers continued, to some extent to obtain a National Pharmaceutical Product/Pricing Index (NAPPI) code.[7] In the case between the Treatment Action Campaign v Rath and Others (12156/05 (2008) ZAWCHC 34), Rath was found guilty of selling and distributing medicines that were not registered and that contained scheduled substances.[8] He was also found guilty of making false and unauthorised statements about the efficacy of medicines. In the High Court judgment Judge Zonde ruled against Rath and others on the grounds of the main purpose of the 2002 call-up by the MCC. He further mentioned that the MCC has failed to determine the correctness of the claims made for products that have been submitted. Furthermore, the MCC did not carry out an independent assessment of quality of these products; therefore, the products must be considered to be potentially unsafe. Any claims made about these medicines would therefore be considered to be misleading. The regulation of complementary medicines did not entail an amendment to the Act, as sections 14 and 15 imply that they have already been ‘called up for registration’. This cannot be repealed by the 2002 call-up.

However, Government Notice R870, published in the Government Gazette 37032 of 15 November 2013, incorporated new General Regulations to the Medicines Act, which finally called up complementary medicines.[9] This amendment provides that all complementary medicines will be subject to the same legislative control as allopathic medicines. Complementary medicines will be evaluated for safety, efficacy and quality and claims made will have to be substantiated. Furthermore, manufacturers, distributors, importers and exporters of complementary medicines will have to be licenced.

The amended Regulations defined complementary medicines as any substance or mixture of substance that (i) originates from plants, minerals or animals; (ii) is used or intended to be used for, or manufactured or sold for use in assisting the innate healing power of a human being or animal to mitigate, modify, alleviate or prevent illness or the symptoms thereof or abnormal physical or mental state; and (iii) is used in accordance with the practice of the professions regulated under the Allied Health Professions Act, 1982 (Act No. 63 of 1982).[9] The disciplines or practices mentioned in part (iii) of the definition include homeopathy, western herbal medicine, traditional Chinese medicine, Ayurveda, Unani medicine (Unani-Tibb) and aromatherapy.[10] Each discipline has different requirements governed

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by its own references and pharmacopoeia subject to the current science and knowledge of the particular discipline.

The definition proved problematic, as it does not provide for the origin, claims and/or uses of all perceived complementary medicines such as certain vitamin products and probiotics, which are not discipline specific and have not been used in accordance with the practice of the professions regulated under the Allied Health Professions Act as indicated in the abovementioned definition.[9,10] An amended definition of complementary medicines has been published for comment, which defines these medicines as any substance or mixture of substances that (i) originates from plants, fungi, algae, seaweeds, lichens, minerals, animals or other substance as determined by Council; and (ii) is used or purports to be suitable for use or is manufactured or sold for use in maintaining, complementing, or assisting the innate healing power or physical or mental state; or to diagnose, treat, mitigate, modify, alleviate or prevent disease or illness or the symptoms or signs thereof or abnormal physical or mental state of a human being or animal; and (iii) is used as a health supplement; or in accordance with those disciplines as determined by Council; or (iv) is declared by the Minister, on recommendation by the Council, by notice in the Government Gazette to be a complementary medicine.[11] The proposed amendments to the complementary medicine definition provide additional origins, widen the claims and added a subcategory, i.e. health supplements, to the initial definition. They also provide for a medicine that does not meet the requirements to be declared a complementary medicine by the Minister on recommendation by the MCC. Combination products, such as products comprised of more than one discipline-specific substance or discipline-specific substance(s) and health supplements, are also classified as a category of complementary medicines.

If a medicine does not meet any of the abovementioned requirements to be defined as a complementary medicine, selling will have to be discontinued and application will have to be made for registration as an allopathic medicine.

The claims of complementary medicines create pharmacological classifications, and medicines have to be submitted on designated dates, depending on their classification, e.g. antiviral complementary medicines had to be submitted by May 2014. The initial submission process will be completed by November 2019. The requirement for only submitting on a designated date in future was that the medicines must have been available for sale in SA on the date of Notice R870. In the meantime, the status quo is maintained and the medicine may be sold unless it contains banned or scheduled substances.[12] Interestingly, the Medicines and Related Substances Amendment Act 2015[13] provides for the establishment of the SA Health Products Regulatory Authority, which will replace the current MCC, but this Act will only become operational after the commencement of the Medicines and Related Substances Amendment Act 2008.[14] It will not have an effect on the call-up or definitions of complementary medicines.

Quality, safety and efficacy of complementary medicines

The labels of all complementary medicines must comply with the provisions of section 8 of the General Regulations to Medicines and Related Substances Act, 1965. According to these provisions, the labels must be written in English and at least one other official language and must indicate the category, pharmacological classification and discipline of medicine. Furthermore, the words ‘This medicine has not been evaluated by the Medicines Control Council. This medicine

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IN PRACTICE

is not intended to diagnose, treat, cure or prevent any disease’ must be added to the label.[15] Any additional information to the regulations has to be authorised by the MCC. The quality of complementary medicines is measured in terms of factors such as Good Manufacturing Practice (GMP), Good Laboratory Practice and Good Agricultural and Collection Practices specifications, identification of impurities, analytical validations and stability (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines), ensuring attributes such as identity, strength and purity of a medicine that have to be met consistently.[16,17] When evaluating the efficacy of complementary medicines, established traditional use, preclinical data and evidence from clinical trials in animals and humans are used. Literature, such as acceptable monographs and pharmacopoeial references, also needs to be taken into account to the extent depending on the risk level of the claim made. The data must support efficacy aligned with the proposed indications and claims on the label and package insert.

Safety may be established by detailed reference to the published literature and/or the submission of original study data. If a complementary medicine has been traditionally used without demonstrating harm, a review of the relevant literature should be provided. Reference should also be made to official monographs supporting safety and toxicological studies, if available. Safety is the ability of the medicine not to cause serious side-effects when assessed against its risk-benefit profile.

Conclusion

The General Regulations of 2013[9] ended an era of unregulated commercialisation of complementary medicine. Unfortunately, the requirements in terms of dossier content left many role-players at odds. Without the much needed pharmacological and scientific knowledge, the compilation of dossiers becomes an insurmountable task. Furthermore, the cost of merely applying, especially for those companies currently selling many products, is daunting.[18] Overcoming these hurdles is extremely expensive and time-consuming. Conflict between reputable trademarks and allowed proprietary names and acceptable levels of proof of efficacy, among other issues, may also cause disputes between the industry and the MCC. The majority of complementary medicines that were on the market before the General Regulations came into effect, are now under threat and the nature of the industry will change once the new laws are fully implemented.

However, the MCC has a mandate to ensure that the registration of a medicine is in the interest of the public. It will surely not be in

28

the public interest to register a complementary or any other medicine that is manufactured in a facility not adhering to GMP, according to which efficacy and safety are not supported by trustworthy data, and the shelf-life is not known. As stated above, medicine as such is not safe and the choice between the risk and benefit associated with the use of medicine needs to be made on the consumer’s behalf, by means of regulations.

Acknowledgements. None.

Author contributions. LF conceptualised and wrote the article. FO helped to edit and evaluate the manuscript. KdT supervised the work and evaluated the manuscript.

Funding. None.

Conflicts of interest. None.

1. Ridings JE. The thalidomide disaster, lessons from the past. Methods Mol Biol 2013;947:575-586. https://doi.org/10.1007/978-1-62703-131-8_36 2. Medicines Control Council. http://www.mccza.com/About (accessed 10 April 2017).

3. South Africa. Constitution of the Republic of South Africa Act No. 108 of 1996.

4. South Africa. Medicines and Related Substances Act No. 101 of 1965.

5. National Department of Health, South Africa. National Policy for Medicines and Related Substances Act, 1965 (Act No. 101 of 1965). Call up notice for medicines frequently referred to as complementary medicines. Government Gazette No. 7282:204. 2002.

6. Medicines Control Council. Registration of Medication, 2.01. General information, version 4.

2008. http://www.mccza.com/documents/1d9c57df2.01_General_information_Jul12_v8_showing_ changes.pdf (accessed 10 April 2017).

7. MediKredit. NAPPI Allocation Rules Non-Surgical Products. https://www.medikredit.co.za/index. php?option=com_content&view=article&id=92&Itemid=212 (accessed 10 April 2017).

8. Treatment Action Campaign and Another v Rath and Others (12156/05) ZAWCHC 34 2008 (4) SA 360 (C).

9. South Africa. Medicines and Related Substances Act of 1965. Regulations: Medicines and Related Substances Act. Government Gazette No. 37032, 2013. (Published under Government Notice R870.)

10. South Africa. Allied Health Professions Act No. 63 of 1982. As amended. Section 16(1A)(a).

11. South Africa. Medicines and Related Substances Act of 1965. Regulations: Medicines and Related Substances Act. Government Gazette No. 40158, 2016. Amendment. (Published under Government Notice R858.)

12. Medicines Control Council. Roadmap for registration of complementary medicines. Implementation in accordance with Government Gazette Notice R870 of 15 November 2013. http://www.mccza.com/ documents/66d8cd937.02_Roadmap_for_CAMs_Dec13_v1.pdf (accessed 10 April 2017).

13. National Department of Health, South Africa. Medicines and Related Substances Amendment Act of 1965 (Act No. 14 of 2015). Government Gazette No. 39585:607. 2016.

14. National Department of Health, South Africa. Medicines and Related Substances Amendment Act of 1965 (Act No. 72 of 2008). Government Gazette No. 32148:434. 2009.

15. South Africa. Medicines and Related Substances Act of 1965. Regulations: Medicines and Related Substances Act: Amendment. Government Gazette No. 37032, 2013. (Published under Government notice R870.)

16. Medicines Control Council. Complementary Medicines – Discipline-specific safety and efficacy. http:// www.mccza.com/documents/8b57b09c7.01_CMs_SE_DS_Jun16_v3.pdf (accessed 10 April 2017).

17. Medicines Control Council. Complementary Medicines – Quality, safety and efficacy. http://www. mccza.com/documents/035a3c0c7.01_CAMs_QSE_Dec13_v2_1.pdf (accessed 10 April 2017).

18. Medicines Control Council. Fees payable to the registrar for complementary medicines. http://www. mccza.com/documents/f7bae46017.04_Fees_CAMs_Nov13_v1.pdf (accessed 10 April 2017).

Accepted 8 February 2017.

June 2017, Print edition

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IN PRACTICE

CLINICAL UPDATE

Establishing an academic biobank in a resourcechallenged environment C C Soo,1 MSc; F Mukomana,1 BSc (Hons); S Hazelhurst,1,2 PhD; M Ramsay,1,3 PhD Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa School of Electrical and Information Engineering, Faculty of Engineering and the Built Environment, University of the Witwatersrand, Johannesburg, South Africa 3 Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1 2

Corresponding author: M Ramsay (michele.ramsay@wits.ac.za)

Past practices of informal sample collections and spreadsheets for data and sample management fall short of best-practice models for biobanking, and are neither cost effective nor efficient to adequately serve the needs of large research studies. The biobank of the Sydney Brenner Institute for Molecular Bioscience serves as a bioresource for institutional, national and international research collaborations. It provides high-quality human biospecimens from African populations, secure data and sample curation and storage, as well as monitored sample handling and management processes, to promote both non-communicable and infectious-disease research. Best-practice guidelines have been adapted to align with a low-resource setting and have been instrumental in the development of a quality-management system, including standard operating procedures and a quality-control regimen. Here, we provide a summary of 10 important considerations for initiating and establishing an academic research biobank in a low-resource setting. These include addressing ethical, legal, technical, accreditation and/or certification concerns and financial sustainability.

S Afr Med J 2017;107(6):486-492. DOI:10.7196/SAMJ.2017.v107i6.12099

The need to establish and develop formal biobanks in South Africa (SA), especially for human biological samples, is increasing.[1] Internationally funded initiatives such as Human Heredity and Health in Africa (H3Africa), and various investments into HIV, tuberculosis (TB) and malaria research, are creating awareness of the value of high-quality human biospecimen availability for health and disease research.[1] As such, academic institutions find themselves at the forefront of a drive to invest in the development of secure, affordable and convenient storage facilities for human samples. This fast-evolving scientific field brings with it many social and ethical issues that require careful consideration.[2,3] The University of the Witwatersrand, Johannesburg (Wits), has taken the lead in promoting the establishment of high-quality biobanks and biobanking practices in the region, and in addressing the legal and ethical implications for biobanking in SA.[2] The Sydney Brenner Institute for Molecular Bioscience (SBIMB) is a cross-disciplinary research institute at Wits. The institute offers postgraduate students and collaborating researchers the resources to perform high-quality and high-impact research with a focus on critical questions related to the health of African populations. The SBIMB has a growing platform of expertise in the fields of human genetics and genomics, population genetics, bioinformatics, evolutionary biology and biomedical informatics, with an extensive network of collaborators globally. Our objective, to develop capacity for genomic research in Africa, is in line with that of the H3Africa consortium, and our involvement in studies of African and SA population genetics and clinical studies in ophthalmology, rheumatology, cancers, cardiometabolic diseases and obesity is all focused on African cohorts. This article documents the challenges experienced in the establishment of the SBIMB biobank and specific considerations for biobanking in SA, as well as providing a summary

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of 10 critical issues to address before embarking on a biobanking venture in a low-resource setting.

Governance

A well-established system of governance is essential for the development of good policies, and for monitoring their implementation. Managing ethical, legal and social implications is critical for any biobank, and the attendant regulations will necessarily and desirably be burdensome. The SA legal framework currently makes no provision for the regulation or governance of biobanking.[2-4] The amendments made in 2012 to the National Health Act No. 61 of 2003 apply to tissue and stem-cell banking for clinical purposes, but not to biobanking in general.[5] They leave the regulation of biobanks in the hands of ethics regulatory bodies, rather than within a legal framework, and the regulations regarding the storage, use and re-use of DNA are vague.[2,4,6) Recommendations for regulations specific to biobanking in SA and across national African borders have been made, and an important issue that was raised was genomic sovereignty.[4,6] Developing genomic capacity in Africa, rather than exporting DNA samples for storage and analysis to higher-income countries, is essential.[6] The inherent genomic diversity of African populations is important in order to better understand disease aetiology. To prevent exploitation, special attention should be given to drafting material transfer agreements (MTAs) that specifically outline benefits to both parties, and disallow misuse or further use of samples for purposes other than those of the original agreement, unless agreed to in writing.[2,6] Through the Wits Biobanks Ethics Committee (BEC), an MTA document was drafted and approved for use for Wits research.[4,7] This document emphasises the importance of informed consent, benefit sharing and ownership of biospecimens through transfer across national boundaries.[4] It

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is available on the Wits website, and is a valuable guideline when drafting MTAs for the transfer of human biospecimens in Africa and globally.[4] Wits stipulates that approved biobanks should be registered with the SA Department of Health; however, there is currently no mechanism to do so. Regulatory bodies therefore need to develop policies and guidelines for biobanking in SA in order for the proper ethicolegal regulation of biobanking to occur.[2-4] A working group, comprising members from various academic institutions representing the interests of research and biobanking in SA, has been constituted to address these issues. The Bridging Biobanking and Biomedical Research across Europe and Africa (B3Africa) initiative is looking to align the biobanking frameworks in Africa with those already established in Europe, through the collaboration of their 11 partners.[8] The SA National Health Research Ethics Council develops guidelines for health research ethics committees, which have the responsibility to regulate research involving human subjects. The Wits Human Research Ethics Committee (HREC) (Medical), which is further advised by the Wits BEC subcommittee, regulates biobanks that store samples for research purposes at the university.[2,4] The BEC was officially constituted in 2013, as Wits took the initiative to establish regulations at an institutional level for biobanking.[2,4] The BEC stipulates their requirements under either public- or privatesector biobanks. As the SBIMB biobank is neither of these, and functions as a small-scale academic biobank, the application process was challenging. Ethics approval (ref. no. M1403107) was granted in 2015, and is valid for 5 years, with the allowance for audits or visits from members of the BEC. The SBIMB biobank is the first academic biobank to be approved by the Wits HREC, and follows the approval of two commercial service provider biobanks in Johannesburg. Future requirements for accreditation with the SA National Accreditation Body[9] strengthen the need for the involvement of the government, medical and regulatory bodies and legislation to provide SA biobanks with the means for the equivalent certification that is available elsewhere.

The SBIMB biobank has a governance structure for independent oversight through the SBIMB advisory board, which has both local and international representation. Internally, the Biobank Scientific Advisory Committee (BSAC) consists of a group of multidisciplinary individuals with a range of expertise, including clinicians, epidemiologists, geneticists, bioinformaticists and individuals with ethico-legal expertise. The BSAC manages access to both samples and associated data. Each request is assessed to ensure that ethical requirements have been met and that the research is in line with the informed consent provided by the participants, and the values and objectives of the SBIMB. The biobank management group is responsible for the daily running of the SBIMB biobank (Fig. 1). This system of governance ensures protection of the rights of research participants, regulates access to samples, and allows for future research in a manner that agrees with the ethical principles of beneficence, non-maleficence, respect for autonomy and justice, as well as being aligned with national and international guidelines and regulations which conform to the ideals of the Declaration of Taipei.

The Declaration of Taipei specifically focuses on the ethical considerations of biobanking.[10] It encompasses the collection, storage and use of human biospecimens beyond immediate healthcare and into the realm of public health.[10] This means that researchers are obliged to ensure that the rights of their participants are doubly protected.[10] Some informed-consent models are not adequate for biobanking, as they do not take into account the future use of participantsâ&#x20AC;&#x2122; samples for unrelated research studies.[2,11] Broad consent allows ethical regulation of the use of biospecimens and data

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Independent oversight SBIMB Advisory Board (SAB)

Biobank Scientific Advisory Committee (BSAC)

Management group

Ethics oversight Wits HREC (Medical) and BEC

Policies

Sample repository

Relational database

Managed access

Fig. 1. SBIMB Biobank Governance: A managed sample and data access process for the SBIMB biobank is governed through various levels of regulation including independent oversight by the SBIMB Advisory Board (SAB) and internal governance by the Biobank Scientific Advisory Committee (BSAC), all overseen by the Wits Human Research Ethics Committee (HREC (Medical)) and Biobanks Ethics Committee (BEC).

for research other than that stated in the original informed-consent document.[2-4,11] This implies that a strict governance framework is required to prevent misuse of stored samples and data, and to address the problems of exploitation and stigmatisation.[4,10,11] Community engagement and regular feedback on research outcomes are good ways to broaden understanding about research participation and its possible benefits to global health.[10,11] All SBIMB biobank personnel are required to complete the National Institutes of Health (NIH) Protection of Human Participants online course annually, and to adhere to the policies and procedures outlined by the SBIMB, Wits,[12] the H3Africa consortium[13,14] and International Society for Biological and Environmental Repositories (ISBER).[15] The SBIMB biobank has no direct contact with the research participants whose samples are stored. The principal investigator (PI) of each research project storing samples in the biobank must provide a copy of the ethics clearance certificate, templates of the original informed-consent documents stating withdrawal options, an information sheet and an undertaking that all the donors of biospecimens submitted have signed consent forms. All samples are coded with a unique identifier that can only be linked to the participant by the projectâ&#x20AC;&#x2122;s PI, meaning that the SBIMB biobank has no access to personal identifying information. The minimum data accompanying each sample do not permit identification of participants, and related phenotypic, demographic and genomic data are not stored within the biobank, nor can they be accessed by unauthorised individuals. Details of consent are documented per study, and provision is made for specifying the use and sharing of samples and related data. The SBIMB biobank respects the rights of participants to withdraw from research projects. This is done following written instruction from the project PI for withdrawal and disposal of biological samples and data.

Infrastructure, sample management and storage

Location is an important factor to consider in academic research; researchers are more likely to make use of services if the biobank is easy to find and nearby, to limit the use of expensive couriers.

Environment- and resource-specific factors may limit the feasibility of establishing a biobank, so it is advisable to consider the strengths and weaknesses of such a project.

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IN PRACTICE

In the case of the SBIMB biobank, potential modifications to the building were limited owing to the fact that the SBIMB is based on a national heritage site. The biobank itself is 70 m2 in size; therefore, only DNA and buffy coat samples are stored onsite, at –80°C. The size of the main laboratory, along with restrictions from the heritage council, prevents the installation of onsite CO2 backup cylinders, which presented a challenge due to the unstable power supply experienced in SA. To mitigate against the occasional loss of electricity, the SBIMB biobank runs on redundant power supply.

In addition to the municipal supply, it has an uninterrupted power supply (UPS) with an extra battery, and a diesel generator capable of maintaining electricity levels for up to 48 hours per tank of diesel, and which can be topped up while running. It was necessary to consider site-specific modifications or risk preventive measures.

For example, thunderstorms are common in Johannesburg in the summer and can cause power surges and outages, which necessitated the installation of earth mats and isolators. A biobank must have a back-up facility in close proximity that is capable of storing all samples in an emergency situation. The ambient temperature of the main laboratory and the temperatures of the fridges and freezers are monitored daily. The COMET temperature data monitoring system probes, which take temperature readings every 10 minutes, are linked to a modem that sends out text notifications at predetermined alarm-triggering temperatures, which for the ultralow temperature freezers is –70°C. Biobank personnel are trained to extract DNA from various sample types (whole blood, buffy coat, saliva, buccal swabs and stool samples). At least two aliquots of DNA are stored per participant. One aliquot is frozen at –80°C, while the other is refrigerated as a working aliquot. The working aliquot prevents multiple freeze-thaw cycle degradation of DNA. Ensuring high-quality DNA samples does not just rely on adequate storage, but may be affected by pre-analytical handling of samples (e.g. whole blood) from collection through to processing. A strict internal quality control (IQC) regimen is essential. An initial assessment of the quality of the samples received should be considered as part of the quality control (QC) process.

Generally, whole blood and buffy coat samples that are clotted, or that have been stored inappropriately, perform poorly during automated extraction, because the tips or needles are unable to take up the sample. Their DNA yields are therefore much lower than the average expected yield for manual extractions in these cases (below 80 µg). DNA concentration and purity (260/280 ratio indicating protein contamination) should be assessed using spectrophotometry (Nanodrop, Thermo Fisher Scientific, USA), although fluorometric (Qubit, Life Technologies, Singapore) methods provide a more accurate measure of double-stranded DNA in a sample. Agarose gel electrophoresis should also be a standard requirement in QC to check DNA integrity. Running single nucleotide polymorphism (SNP) identification panels for each sample is recommended, but costly; therefore, in lower-resource settings a multiplex polymerase chain reaction assay for a small set of SNPs may be advised as a compromise. QC results are recorded in the laboratory information management system (LIMS), and monthly reports and other supporting documentation are stored electronically, in accordance with the quality management standards regarding document control outlined in the international standard for document storage (ISO 9001:2015).[16] According to ISO 15489-1:2001, records should be created, stored, maintained and protected such that their accuracy, legibility and availability are ensured.[17] Along with secure access and user verification, audit trails through electronic logs should be available to comply with best practice guidelines, ethics regulations and international standards.[17]

Laboratory information management system (LIMS)

Sample tracking and storage location management are key aspects of biobanking. The efficient management and tracking of samples as they are received, processed, aliquotted and shipped are best performed by the implementation of LIMS software. Data security is integral to the reliable and efficient management of samples and data in a biobank.

The software should be secure, and access to data should only be granted to authorised users according to user-defined roles.

There are many commercial applications that offer comprehensive and fully auditable information and sample management, e.g.

STARLIMS, Nautilus (ThermoScientific), CloudLIMS, LDMS and Gemini Matrix, to name a few. There are also software applications that only manage sample tracking, such as TD-Biobank and Freezerworks. Although these applications are fully integrated and supported, the costs may be prohibitive in a low-resource setting, as they may include annual licence fees, initial setup and customisation costs, and training by international companies. Choosing a LIMS depends on specific requirements, affordability and personnel. Opensource software (OSS) may be preferable if resources are not available to dedicate to a LIMS. Software such as Bika LIMS and the Ark Informatics can be customised to suit the needs of any biobank, provided that a dedicated developer can be employed for customisation, support and implementation. The cost-effectiveness of using an OSS package is balanced against the cost of the developer, the regular updating of the software by its creators, the customisability of the software to one’s requirements, and the ease of implementation.

The Ark Informatics is a secure open-source LIMS software application developed within the Centre for Genetic Epidemiology and Biostatistics at the University of Western Australia in 2009.[18] It is module-based software that allows one to store minimum participant data, including data specific to consent and a full sample-location management system. It has the capacity to produce records upon request, allowing for a full audit trail. Samples received may be logged manually or according to bulk upload features. Depending on the project, the Ark Informatics can incorporate data from a database or from spreadsheets to organise all data specific to sample storage (Fig. 2). The SBIMB’s version of the Ark was modified to suit our requirements, and allows automatic uploads from REDCap[19] or any other database in a seamless workflow. Despite initial Databases

REDCap Input data

Spreadsheets

Shipping manifests

The Ark informatics • Study information • Minimum participant data • Biospecimen data • Storage data

Output data

Reports • Study summary • Study-level consent • Biospecimen summary • Biospecimen details • Nucleic acid summary

Fig. 2. Data management: Diagram depicting the various types of input data that may be imported into the Ark informatics LIMS, the type of data stored 2014 - 2015 in its modules and examples of output data in the format of reports.

Ark development

2014 Wits HREC/BEC Application

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2015 Wits HREC ethics approval

June 2017, Print edition

2012 Capital outlay for infrastructure Expansion

IN PRACTICE

implementation challenges, it is easy to use and has the relevant features that commercial systems offer.

The eB3Kit Biobank in a Box (Bibbox) (Austria), available through B3Africa, provides an integrated biobanking and bioinformatics platform.[8,20] This system consists of seven integrated work packages that monitor all aspects of biobanking, from the ethical and regulatory requirements, hardware and software requirements, a LIMS and bioinformatics platform, relevant training and dissemination and searchable datasets linked with biospecimens.[20] Once the eBiokit is purchased, the software is free and tools are available in the Bibbox ecosystem for personal customisation.[8,20] Currently Bika is being implemented, but support will also

be available for Open Specimen.[8,20] Other LIMS can be hooked up to the eBiokit for bioinformatics analysis (Galaxy/Pulsar), experiment management, Open Data Kit (ODK) for data collection with mobile phones and ethics compliance support.[8,20] Had it been available when we started the SBIMB biobank, it would have been evaluated and considered before making a decision on the most suitable LIMS option.

Discussion

The SBIMB biobank houses a valuable and constantly growing resource for multidisciplinary research in SA, and aims to be sustainable in the long term. Our main objective is to provide a high-quality bioresource, as well as expertise to support

analysis of data and samples from African populations, so that we can better characterise, understand and apply our research findings to improve the health of Africans. The establishment of a national biobank in SA has been under discussion since 2013.[1,2] Lack of adequate financial resources and insufficient current local investment in national research infrastructure, as well as misconceptions regarding ownership of biospecimens, have to date confounded the development of a feasible model for a national biobank in SA. Developing sustainability models for biobanks in low-resource settings is essential, as the funds required to run a biobank on an annual basis are significant (Table 1).

In accordance with best-practice guidelines, contingency plans should be considered in

Table 1. Cost considerations for setting up a biobank in a low-resource setting Category A. Infrastructure 1. Building and power supply

Item Physical building with demarcated areas specific to purpose Air conditioning Ventilation system (positive/negative pressure per requirements) Redundant power supply, circuitry and installation (UPS, generators) Surge/lightning protection Access control systems Security cameras and alarms Storage equipment (freezers, fridges, liquid nitrogen tanks, cupboards) Computer equipment (hardware and software) Equipment for sample processing

2. Equipment

Gel Doc (QC) and Thermal cycler (QC and PCR) Sample quantitation equipment (NanoDrop/Qubit) Gas monitors (if required) Autoclave Water purification system Temperature monitors Barcode printers and scanners Commercial or open-source (with their associated costs)

3. LIMS B. Personnel 1. Staff

Manager Scientists Data and IT manager Good clinical and laboratory practice International Air Transport Association* (IATA) certification Occupational health, safety and environment First aid External quality assurance and accreditation

2. Training

C. Maintenance 1. Calibration or accreditation 2. Temperature monitoring

Equipment SMS service Recalibration and servicing Associated infrastructural costs Annual services and recalibration

3. Building 4. Equipment

Continued ....

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Table 1. (continued) Cost considerations for setting up a biobank in a low-resource setting Category D. Consumables 1. Storage

Item

Databases

REDCap

Plates/tubes/vials Input data Boxes/racks Spreadsheets Electrophoresis consumables Shipping manifests Quantitation consumables or assays Other consumables including basic stationery Reagents andThe consumables Ark informatics

2. QC 3. General 4. Processing

• Study information • Minimum participant data

E. Overheads

Telephone and internet access • Biospecimen data Cleaning services • Storage data Security Fire extinguishers Emergency signage Building maintenance Biohazard waste removal

Reports • Study summary • Study-level consent • Biospecimen summary Costs related to shipping samples: on dry ice, refrigerated, Output data frozen • Biospecimen details • Nucleic acid summary or at ambient shipping

F. Shipping *For regulations regarding transport of dangerous goods.

the event of possible closure precipitated by a lack of sustained funding.[2,3] To mitigate such risk, support from large institutions (e.g. universities or the government), and the introduction of a ‘pay-for-services’ culture between collaborators and biobank users, would support sustainability. The SBIMB biobank has implemented a business model where researchers using the services pay according to their required needs, including the costs for the reagents and consumables used for their projects, personnel time and an annual storage fee.

Academic researchers from various universities in SA have initiated research into the feasibility of institution-based biobanks operating with a standard set of guidelines and an agreed-upon set of standard operating procedures regarding sample and data sharing, sample handling and QC. Perhaps the most feasible outcome for SA is the implementation of a virtual national network of collaborating biobanks, working according to harmonised standards and procedures. Developing a website listing the biobanks in SA, and cataloguing their respective studies and samples, will promote further collaboration, and will identify synergies to bolster national research efforts.

Establishing the SBIMB biobank has provided insight into important considerations that should be addressed in the planning stages of setting up an academic biobank. These include: necessity and feasibility (do you need to start your own biobank or can you use existing facilities?); ethical, legal and social considerations of setting up a biobank (governance, legislation

2014 - 2015 Ark development 2014 Wits HREC/BEC Application

2015 Wits HREC ethics approval

2012 Capital outlay for infrastructure Expansion

2012

2013

2014

2013 Renovations complete

2015

2016 ESBB conference 2015

2015 Additional personnel training

2014 Risk assessment

2017

2016 UCT biobanking conference

Fig. 3. SBIMB Biobank timeline: Depicting the timeline for achieving milestones required for the biobank to become a high-quality, sustainable bioresource. These include the time taken for ethics approval and customisation and development of the Ark Informatics.

and regulation); location; infrastructure (fit for purpose with suitable back-up strategies); storage (what sample types are being stored and at what temperature?); LIMS (commercial v. open source packages); accreditation or approval; and sustainability (have you developed a sustainable funding model?). Each of these considerations has been addressed in this article not only in terms of biobanking in general, but in an SA context, specifically in an academic setting. In Table 2 we provide ten broad areas for consideration when planning to set up a biobank. We suggest key questions that should be addressed, and outline minimum requirements for a successful biobanking endeavour.

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June 2017, Print edition

Setting up a biobank requires commitment, funding, institutional support, a team of dedicated researchers and considerable time.

It took 3 years for the SBIMB biobank to be ready to process, store and provide highquality DNA samples for academic research, and to obtain approval from the Wits HREC (Medical) (Fig. 3). We have plans to expand the SBIMB biobank in order to increase our research and storage capacity, and to promote further cross-institutional and cross-disciplinary biomedical research.

Acknowledgements. Research reported in this publication was supported by the National Human Genome Research Institute of the

IN PRACTICE

Table 2. Ten important broad issues to consider when planning a biobank from scratch in a low-resource environment Point 1 Need and feasibility

Considerations and key questions Do you need to build your own biobank or can you use an existing institutional or external biobank?

How long do you plan to store samples? May samples be used for future research?

Is there a favourable cost-benefit analysis?

Does your biobank need to be close to your research site?

Do you have the capital to fund a biobank?

Desired outcomes Once you have established the need to develop a biobank, perform a detailed cost analysis and ensure that you have the necessary support from your institution.

2 Ethical, legal and social considerations

What is required by your ethics committee for approval of your biobank for the storage of samples?

What consent models would you require for the research sample collections to be used for future studies?

What is an appropriate governance framework?

How are members selected?

Could your policies and processes cause harm (to individuals, communities)?

Do you have templates for MTAs? Do you have policies for sample and data withdrawal and disposal?

Is there a clear procedure in case of biobank closure?

Ensure that you have a feasible governance process, certification or approval if required, and guidelines for researchers who plan to store their samples.

Legal and institutional compliance in terms of MTAs and import/export permits.

Constitute a governing body consisting of independent oversight, regulation through ethics committees and internal governance structures. Members should be selected in order to represent all stakeholders, and to be representative of different expertise required.

3 Location

Is it appropriate in terms of proximity to study sites?

Once you have found a location that suits all of your requirements ensure that it is well-serviced and easy to Is there enough space?

Do you have access to water, power, and good transport routes? get to.

How does location affect cost?

4 Infrastructure

Is your building fit-for-purpose?

Is it secure and access-controlled?

Is the building large enough to house major equipment (and in terms of storage capacity)?

Has a risk assessment been performed?

Are there measures to ensure that there will always be water and electricity?

What are the maintenance costs for both the building and equipment?

A secure, access-controlled biobank that is securitymonitored.

Backup systems in place for utility failures.

Budget set aside for maintenance of the building and equipment.

5 Storage

What are the biospecimen types and volumes?

How long will samples be stored? Is the storage temperature appropriate?

Is the temperature of storage equipment and ambient temperature in the laboratory being monitored?

How are your biospecimens identified?

Increased capacity by using vials appropriate to volume of samples.

Ambient, refrigerated, frozen short-term, or frozen longterm at temperatures fit for sample type.

24/7 temperature monitoring systems with alarms and SMS or phone call notifications.

Barcodes (human readable, linear, 2D matrix)

6 LIMS

How are you keeping track of your samples?

Can your budget accommodate a commercial LIMS? Is opensource development of an available package more affordable?

A secure functional LIMS which allows for appropriate and efficient sample tracking and management.

7 Staff

Do you have the available funds to support dedicated staff?

Is there training in good laboratory practice?

Will your staff require any other training or certification?

Qualified, trained biobank personnel that are on mediumto long-term contracts or are permanent staff.

8 Accreditation and quality

Is there national accreditation for biobanks in your country?

Can you afford to do external quality control?

Can you afford international accreditation and certification?

An accredited biobank offering high-quality services.

Continued ....

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June 2017, Print edition

IN PRACTICE

Table 2. (continued) Ten important broad issues to consider when planning a biobank from scratch in a low-resource environment Point 9 Sustainability

Considerations and key questions Do you have funds to sustain your biobank in the long term?

Have you developed a business model for sustainability?

Desired outcomes A sustainability model for the biobank should be developed and implemented.

Funds from services rendered could contribute to sustainability.

10 Time

How long will it take to establish a biobank?

Are investors or funders aware of the time involved?

It can take years to set up a biobank; therefore, considerations of time investment should be taken into account.

National Institutes of Health under Award Number U54HG006938, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Office of the Director, National Institutes of Health.

MR is an SA Research Chair in Genomics and Bioinformatics of African populations hosted by Wits, funded by the Department of Science and Technology and administered by the National Research Foundation of SA. Wits provided infrastructure support for the Biobank. We thank the repository team from Clinical Laboratory Services, especially Dr Ute Jentsch for her invaluable advice and for assisting us in preparing our documents during the ethics application process. We thank Wits for providing us with infrastructure and general services, and the Wits BEC for their guidance and approval. A special thanks to Dr Zané Lombard and Dr Nadia Carstens for their contributions at the initial planning stages, and to Dr Carmen Swanepoel and Dr Micheline Sanderson for their expert advice. Lastly, thank you to the SBIMB biobank personnel (Natalie Smyth and Sebentile Hleli Mthimkulu) for their continuing hard work.

1. Abayomi A, Christoffels A, Grewal R, et al. Challenges of biobanking in South Africa to facilitate indigenous research in an environment burdened with human immunodeficiency virus, tuberculosis, and emerging noncommunicable diseases. Biopreserv Biobank 2013;11(6):347-354. https://doi. org/10.1089/bio.2013.0049 2. Dhai A. Establishing national biobanks in South Africa: The urgent need for an ethicoregulatory framework. S Afr J Bioeth Law 2013;6(2):38-39. https://doi.org/10.7196/SAJBL.296 3. Dhai A, Mohamed, S. Biobank research: Time for discussion and debate. S Afr Med J 2013;103(4):225227. https://doi.org/10.7196/SAMJ.6813 4. Mahomed S, Behrens K, Slabbert M, Sanne I. Managing human tissue transfer across national boundaries – an approach from an institution in South Africa. Dev World Bioeth 2016;16(1):29-35. https://doi.org/10.1111/dewb.12080 5. South Africa. National Health Act No. 61 of 2003. Regulations: General control of human bodies, tissue, blood, blood products and gametes. Government Gazette No. 35099, 2012. (Published under Government Notice R180.)

6. De Vries J, Pepper M. Genomic sovereignty and the African promise: Mining the African genome for the benefit of Africa. J Med Ethics 2012;38(8):474-478. https://doi.org/10.1136/medethics-2011-100448

7. University of the Witwatersrand: Steve Biko Centre for Bioethics. Material Transfer Agreement for Human Biological Materials. Johannesburg: Wits, 2015. http://www.wits.ac.za/research/about-ourresearch/ethics-and-research-integrity/biobanks-ethics-committee (accessed 17 August 2015).

8. Bridging biobanking and biomedical research across Europe and Africa. Bridging Biobanking and Biomedical Research across Europe and Africa Newsletter. B3A, 2016: 1. http://www.b3africa.org (accessed 11 May 2016).

9. South African National Accreditation System. South Africa: SANAS, 2015. http://www.home.sanas. co.za (accessed 24 May 2016).

10. World Medical Association Inc. WMA Declaration of Taipei on Ethical Considerations regarding Health Databases and Biobanks. France: WMA, 2016. http://www.wma.net/en/30publications/10policies/d1/ (accessed 12 January 2017).

11. Tindana P, de Vries J. Broad consent for genomic research and biobanking: Perspectives from low- and middle-income countries. Annu Rev Genomics Hum Genet 2016;17:375-393. https://doi.org/10.1146/ annurev-genom-083115-022456 12. University of the Witwatersrand: Steve Biko Centre for Bioethics. Biobanks Ethics Committee of the University of the Witwatersrand’s HREC (Medical). The Human Research Ethics Committee Medical (HREC) Principles and Policy on Biobanks. Johannesburg: Wits, 2015. http://www.wits. ac.za/research/about-our-research/ethics-and-research-integrity/biobanks-ethics-committee (accessed 17 August 2015).

13. H3Africa Consortium. H3Africa Working Group on Ethics and Regulatory Issues for Human Heredity and Health in Africa Consortium. H3Africa Guidelines for Informed Consent, Second Edition. H3A, 2014. http://www.h3africa.org/ images/GuidelinesPolicyDocs/CE%20Guidelines_Final.pdf (accessed 30 May 2016).

14. H3Africa Consortium. H3Africa Working Group on Data Sharing, Access and Release for the Human Heredity and Health in Africa Consortium. H3Africa Consortium Data Sharing, Access and Release Policy. H3A, 2014. http://www.h3africa.org/images/DataSARWG_folders/FinalDocsDSAR/ H3Africa%20Consortium%20Data%20Access%20%20Release%20Policy%20Aug%202014.pdf (accessed 30 May 2016).

15. Astrin J, Baker S, Barr TJ, et al. Best practices for repositories collection, storage, retrieval, and distribution of biological materials for research. Biopreserv Biobank 2012;10(2):79-161. https://doi. org/10.1089/bio.2012.1022 16. South African Bureau of Standards. SANS 9001:2015 ISO 9001:2015, 5th ed. South African National Standard – Quality Management Systems Requirements. SABS: Pretoria, 2015.

17. South African Bureau of Standards. SANS 15489-1:2004 ISO 15489-1:2001, 1st ed. South African National Standard – Information and Documentation Records management. SABS: Pretoria, 2004 18. Nectar. Australia: National Research Infrastructure for Australia, 2016. https://www.nectar.org.au (accessed 10 November 2015).

19. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) – a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42(2):377-381. https://doi.org/10.1016/j.jbi.2008.08.010 20. Klingström T, Mendy M, Meunier D, et al. Supporting the Development of Biobanks in Low and Medium Income Countries. IST-Africa 2016 Conference Proceedings, 2016. https://doi.org/10.1109/ ISTAFRICA.2016.7530672

Accepted 20 February 2017.

HEALTHCARE DELIVERY This open-access article is distributed under CC-BY-NC 4.0.

Audits of oncology units – an effective and pragmatic approach

R P Abratt,1,.2 FC Rad Onc; D Eedes,2 FC Rad Onc; B Bailey,2 BTech; C Salmon,3 BPhysT Hons, MBA; Y Govender,4 MTech; I Oelofse,4 BSc Hons; H Burger,5 FC Rad Onc Division of Radiation Oncology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Independent Clinical Oncology Network, Cape Town, South Africa 3 ISIMO Health, Cape Town, South Africa 4 Equra Health SA, Durban, South Africa 5 Division of Radiation Oncology, Tygerberg Hospital and Stellenbosch University, and Division of Radiation Oncology, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: R Abratt (Raymond.Abratt@uct.ac.za)

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June 2017, Print edition

IN PRACTICE

Background. Audits of oncology units are part of all quality-assurance programmes. However, they do not always come across as pragmatic and helpful to staff.

Objective. To report on the results of an online survey on the usefulness and impact of an audit process for oncology units.

Methods. Staff in oncology units who were part of the audit process completed the audit self-assessment form for the unit. This was followed by a visit to each unit by an assessor, and then subsequent personal contact, usually via telephone. The audit self-assessment document listed quality-assurance measures or items in the physical and functional areas of the oncology unit. There were a total of 153 items included in the audit. The online survey took place in October 2016. The invitation to participate was sent to 59 oncology units at which staff members had completed the audit process.

Results. The online survey was completed by 54 (41%) of the 132 potential respondents. The online survey found that the audit was very or extremely useful in maintaining personal professional standards in 89% of responses. The audit process and feedback was rated as very or extremely satisfactory in 80% and 81%, respectively. The self-assessment audit document was scored by survey respondents as very or extremely practical in 63% of responses. The feedback on the audit was that it was very or extremely helpful in formulating improvement plans in oncology units in 82% of responses. Major and minor changes that occurred as a result of the audit process were reported as 8% and 88%, respectively.

Conclusion. The survey findings show that the audit process and its self-assessment document meet the aims of being helpful and pragmatic.

S Afr Med J 2017;107(6):493-496. DOI:10.7196/SAMJ.2017.v107i6.12356

Audits of oncology units are an integral part of their qualityassurance programmes.[1,2] The aim is to maintain standards and accountability and to support continuous quality-improvement programmes.

While all healthcare workers support these aims, audits do not always have positive associations. They may be understood as being antagonistic rather than helpful, and as being bureaucratic rather than pragmatic.

An approach to audits of oncology facilities was developed that aimed to be pragmatic, user-friendly and of a high standard. The aim of this report is to report on a survey of the experience of staff in the various oncology units with this audit process.

Methods

The audit process for oncology facilities

The audit process consisted of three parts. A self-assessment audit document was first completed by staff at the oncology unit. This was followed by a visit by an independent auditor to each unit to review the data in the self-assessment document. Subsequent phone calls and correspondence were used to cross-check the implementation of necessary improvement measures and to help the units to meet these requirements.

The self-assessment audit document was developed by an accountable care organisation (Independent Clinical Oncology Network (ICON)). It was informed by the South African (SA) Department of Health National Core Standards (NCS)[3] and internationally used radiation oncology quality parameters.[4,5] The audit self-assessment document dealt with four sections in oncology units, each headed by a responsible person. These persons are the practice manager, the oncologist/nurse manager, the pharmacist/chemotherapy nurse manager and the radiation therapist (RTT)/medical physicist. Each section was further divided into functional and physical areas for purposes of the audit.

A multidisciplinary group, which included representatives of all the sections, compiled the quality-assurance items for each section.

Items in each area were listed and could be scored as either compliant (C), non-compliant (NC), work-in-progress (WIP) or not assessable (NA). There were 153 quality-assurance items in the audit document.

The self-assessment audit document was endorsed by the SA Society of Clinical and Radiation Oncology in 2015. It is available for use by all oncology units in both the private and public sector. It can be found on the SA Society of Clinical and Radiation Oncology website at

37

http://www.sascro.co.za/downloads/Oncology-Dept-Standard-AuditChecklist%20-29-Feb-2016.docx (accessed 30 January 2017).

The survey

The questions in the online survey were developed to determine the perception of the staff about the audit process, as well as the practical impact of the audit on the unit. The survey was compiled in a series of meetings by a multidisciplinary team that included oncologists, practice managers, chemotherapy nursing sisters and RTTs. To be eligible for the survey, respondents were required to have previously been part of the current audit process and to have completed the audit self-assessment form. All respondents could only complete one survey questionnaire, even if they had completed the self-assessment form for more than one section in an oncology unit or had responsibility in more than one oncology unit.

The following ethical criteria were observed in the survey: the anonymity and confidentiality of the participants in the survey were strictly maintained; all potential participants were informed that the results may be published; and those who completed the survey were given a full summary of the findings as soon as they became available. No patients were included. These criteria are acceptable for publication of survey results in Britain (C Blaine, Deputy Head of Content, British Medical Journal (personal communication)).

The first author acknowledges that for such studies in SA, â&#x20AC;&#x2DC;it is prudent to obtain ethics approval before the study begins.â&#x20AC;&#x2122;[6] The findings are published for the public good, as they will be constructive for quality-improvement programmes.

The survey was undertaken in October 2016 using an online commercial service (Survey Monkey (https://www.surveymonkey. com)). Invitations were sent to the staff of 59 oncology units in the private sector. The clinical services provided by these 59 units were as follows: 14 of these units provided a combination of radiotherapy and chemotherapy, 34 units offered only chemotherapy and 11 offered only radiotherapy.

The target number of survey responders was 132. The respondents were blinded to the investigators.

Results

The number of responders to the survey was 54 (41% of the total).

The responder rate according to professional groups is shown in Table 1.

June 2017, Print edition

IN PRACTICE

The findings of the survey focusing on the domains for the staff in oncology units, the audit process, the self-assessment document and the impact of the audit are described in Tables 2 - 5. Running totals are given for the sum of the highest two answers for responses with a five-point scale.

Discussion

The NCS tool meets a broad mandate and evaluates health services across seven domains. These are: safety, clinical care, governance, patient experience of care, access to care, infrastructure and environment and public health.

The revised ICON audit was developed using specific productivity principles.[7] This process highlights the principle that the items being measured should be assigned within their physical and functional Table 1. The proportion of responders to the audit survey (N=54) Professional group

n, %

Practice managers

24 (25)

Oncologists

37 (27)

Chemotherapy sisters

42 (57)

RTTs

25 (40)

Other

4, not assessable

Total

132 (41)

Running Responses, % totals,* % Practice manager

11

Oncologist

19

Chemotherapy sister

44

RTT

19

Other

7 27

Oncologist

15

Chemotherapy sister

31

RTT

15

Not co-ordinated by a single person

35

Responses, %

Do you appreciate the need for the audit process for qualityimprovement and regulatory purposes?

Overall, how would you rate the ICON audit process – that is, unit self-assessment, visits to the units and feedback to the units?

Extremely satisfactory

12

Very satisfactory

68

Somewhat satisfactory

20

Not so satisfactory

0

Not at all satisfactory

0

80

Was the feedback from ICON by email or telephone on your audit results satisfactory?

Extremely satisfactory

8

Very satisfactory

73

Somewhat satisfactory

19

Not so satisfactory

0

Not at all satisfactory

0

81

Responses, Running % totals, % Overall, how practical is the ICON self-assessment document?

Extremely practical

19

Very practical

44

Somewhat practical

37

Not so practical

0

Not at all practical

0

Strongly agree

22

Agree

70

Neutral/Neither agree nor disagree

7

Disagree

0

Strongly disagree

0

96

I have no opinion on the need

4

Extremely easy

27

I do not think there is a need

0

Very easy

69

Somewhat easy

4

Not so easy

0

Not at all easy

0

Do you regard the audit as a useful tool to help you maintain your personal professional standards?

30

Very useful

59

Somewhat useful

11

Not so useful

0

Not at all useful

0

89

*Running totals are the sum of the highest two answers for responses with a 5-point scale.

38

63

92

How easy to use was the response classification of compliant (C), non-compliant (NC), work in progress (WIP) and not assessable (NA)?

I appreciate the need

Extremely useful

Running totals, %

Did the instructions on the self-assessment document prepare you to complete the document?

Who co-ordinates your unit’s quality-assurance system?

Practice manager

Table 3. The audit process and the audit survey

Table 4. The self-assessment document and the audit survey

Table 2. The staff in oncology units and the audit survey

Please indicate your role in the unit

context rather than according to abstract concepts that apply to multiple different service areas. For example, the section for the pharmacist/chemotherapy nurse manager was divided in the current

96

Do you think the self-assessment document is: Overly detailed

11

About right amount of detail

85

Insufficiently detailed

June 2017, Print edition

4

96

Congress Programme at-a-glance THURSDAY 7 SEPTEMBER 2017 Pre-Congress Workshops & Meeting

7-9

September

2017

CSIR Convention Centre www.ogupdate2017.co.za

Fetal & Maternal Medicine Workshop: Placenta Gynaecologic Oncology Workshop Urogynaecology Workshop Obstetric Ultrasound Workshop: Case Discussions Infertility Workshop Contraception Workshop South African Society of Gynaecologic Oncology Meeting

FRIDAY 8 SEPTEMBER 2017 Session 1: Obstetrics Session 2: Gynaecology Session 3: Medicolegal and Ethics Session 4: Gynaecologic Oncology Session 5: Reproductive Medicine

SATURDAY 9 SEPTEMBER 2017 Session 6: Urogynecology Session 7: Maternal Medicine Session 8: Fetal Medicine Session 9: Endoscopy Session 10: A Look into the Future

Invited International Faculty Prof Phillip Bennett | United Kingdom Dr Mark Slack | United Kingdom Prof Frederic Amant | Belgium CONGRESS ORGANISERS | Londocor Event Management | Yvonne Dias Fernandes | +27 11 954 5753 | yvonne@londocor.co.za

IN PRACTICE

The audit process, including the document, follow-up visit and the feedback by email or telephone was rated by respondents as very or extremely satisfactory by 80% and 81% of respondents, respectively.

The self-assessment document was scored by respondents as very or extremely practical by 67%, and as containing the right amount of detail by 85%.

The impact of the audit was highly rated. The feedback from the survey was that the audit was very helpful or extremely helpful in formulating improvement plans (82% of respondents). Major and minor changes in oncology units occurred in 8% and 88%, respectively.

Table 5. Impact on oncology units and the audit survey Responses, %

Running totals, %

Was the feedback helpful in formulating a continuous improvement plan in your unit?

Extremely helpful

15

Very helpful

67

Somewhat helpful

15

Not so helpful

4

Not at all helpful

0

82

Limitations

Did the audit result in any changes in your unit or service delivery?

Some major changes

8

Some minor changes

88

No changes

4

96

Do you think that displaying an accreditation certificate in your unit based on the audit would reassure patients about their quality of care?

Significant reassurance to patients

52

Modest reassurance to patients

44

No reassurance to patients

4

Conclusion

96

audit into areas for pharmacy administration, pharmacy equipment and storage, chemotherapy administration area, chemotherapy treatment and the patient’s chemotherapy administration records.

The planned follow-up and feedback in order to assist with qualityimprovement programmes exceeds the usual practice in auditing facilities.

The online survey was done to assess the perceptions of the staff of the various units about the audit process, the practicality of the audit process and the impact of the audit on unit processes.

The questions were completed by 54 (41%) of 132 potential respondents. This is a high responder rate for online surveys. The highest rates were from the pharmacy/chemotherapy administration and the radiotherapy administration areas at 57% and 40%, respectively.

This may be because staff in these sections usually received personal feedback on the audits, although written feedback was given to all sections within the oncology units. A further reason could be that staff within these sections may well have a high level of responsibility for the maintenance of facility standards within oncology units.

It was noted that there was no single person coordinating the survey in 35% of units. It would be advantageous to clearly identify such a person within each unit, who would then work with a centralised quality-assurance committee within the units to facilitate the audit process and to formulate improvement strategies.

The respondents in the survey were very positively disposed to the components of the audit and its practical impact. The need for an audit was appreciated by 96% of respondents. Eighty-nine percent of the oncology unit staff reported that it was very useful or extremely useful in maintaining personal professional standards.

40

A caveat to the findings is that those respondents who felt most positive may have been more likely to complete the survey than those who felt indifferent to the survey. The respondent rate was 41%, which is relatively high for an online survey. A study of physicians has found that respondents and non-respondents had similar characteristics.[8] The findings in this survey were consistent across professional groups. Further investigation would require extensive individual interviews.

The survey findings show that the respondents have found that this audit process and its self-assessment document meet the aims of being helpful and pragmatic, and they can be useful in the maintenance of standards, accountability and establishing continuous quality-improvement programmes in oncology units.

Acknowledgements. The authors thank Dr E Marias, Dr L Jones, Ms B Wyrley Birch and Ms N Coetzee for their support and help during the course of this study.

Author contributions. All authors have contributed to the design of the study and have reviewed the manuscript.

Funding. None.

Conflicts of interest. R Abratt, D Eedes and B Bailey are employees of the Independent Clinical Oncology Network.

1. Quality Assurance Team For Radiation Oncology (QUATRO) International Atomic Energy Agency.

Comprehensive Audits of Radiotherapy Practices: A Tool for Quality Improvement. Vienna, 2007. http://www-pub.iaea.org/MTCD/publications/PDF/Pub1297_web.pdf. (accessed 30 January 2017).

2. Thwaites DI, Scalliet P, Leer JW, Overgaard J. Quality assurance in radiotherapy. Radiother Oncol 1995;35(1):61-73. https://doi.org/10.1016/0167-8140(95)01549-V 3. National Department of Health, South Africa. National Core Standards for Health Establishments in South Africa. 2011.

4. The Royal Australian and New Zealand College of Radiologists (RANZCR), The Faculty of Radiation Oncology (FRO), Australian Institute of Radiography (AIR), The Australian College of Physical Scientists and Engineers in Medicine (ACPSEM). Tripartite Radiation Oncology Practice Standards. 2011. http://www.radiationoncology.com.au/supporting-docs/ranzcr-standards.pdf (accessed 30 January 2017).

5. Cottera WG, Dobelbower Jr. RR. Radiation oncology practice accreditation: The American College of Radiation Oncology, Practice Accreditation Program, guidelines and standards. Crit Rev Oncol Hematol 2005;55(2):93-102. https://doi.org/10.1016/j.critrevonc.2005.03.002 6. National Department of Health, South Africa. Ethics in Health Research Principles, Processes and Structures.

2015. http://www.nhrec.org.za/docs/Documents/OperationalGuidelinesMinisterialConsentFinalFeb2015. pdf (accessed 30 January 2017).

7. Allen D. Getting Things Done: The Art of Stress-Free Productivity. USA: Penguin Books, 2001.

8. Kellerman SE, Herold J. Physician response to surveys. Am J Prev Med 2001;20(1):61-67. https://doi. org/10.1016/S0749-3797(00)00258-0

Accepted 21 February 2017.

June 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

REVIEW

Sentinel lymph node biopsy and neoadjuvant chemotherapy in the management of early breast cancer: Safety considerations and timing J Edge,1 MMed (Surg); S Nietz,2 FCS (SA) 1 2

Christiaan Barnard Memorial Hospital, Cape Town, South Africa Department of Surgery, Charlotte Maxeke Johannesburg Academic Hospital and University of the Witwatersrand, Johannesburg, South Africa

Corresponding author: J Edge (dr@jennyedge.co.za)

Over the last decades, breast cancer treatment has become more personalised. Treatment plans are based on the biology of the tumour rather than the stage. Consequently, neoadjuvant chemotherapy (NACT) is commonly the primary therapy for early breast cancer as well as locally advanced disease. Sentinel lymph node biopsy (SLNB) is standard axillary management for women with node-negative disease. This review looks at the relevant literature and gives guidance on the timing of SLNB when NACT is planned and evaluates the safety of performing an SLNB rather than an axillary clearance.

S Afr Med J 2017;107(6):497-500. DOI:10.7196/SAMJ.2017.v107i6.12239

Traditionally, operable breast cancer has been treated by primary surgery followed by adjuvant chemotherapy, radiotherapy, endocrine and targeted therapy as indicated. Primary systemic chemotherapy, more commonly known as neoadjuvant chemotherapy (NACT), was reserved for large inoperable tumours or for inflammatory breast cancer. Our current decisions on local therapy remain based on historical data, where surgery was the primary treatment modality.

The extent of surgery in the treatment of breast cancer has dramatically decreased following a surgical paradigm shift from maximum tolerated therapy towards minimum required therapy.[1] These shifts include the transition from routine axillary lymph node dissection (ALND) to sentinel lymph node biopsy (SLNB) in node-negative patients, and the transition from routine mastectomy to breast-conserving therapy. Conversely, the use of NACT in early breast cancer has increased dramatically over the past decade. This trend poses new challenges in the management of patients with early breast cancer, specifically with regard to decision-making on the management of the axilla and adjuvant radiation.

Although endocrine therapy has a well-established role in the neoadjuvant setting, this review is confined to the use of NACT. NACT in early breast cancer has no proven survival benefit,[2] but has other potential advantages: • It allows assessment of the success of systemic therapy by monitoring the clinical and radiological responses.

• Tumour size and node involvement are reduced.[3] • Breast conservation rates increase by 10 - 30%.[3-6] • A pathological complete response (pCR) is a significant prognostic factor.[7] • A large proportion of patients in Europe and the USA are enrolled in clinical trials, which allows an evaluation of response to therapy.

• It allows more axilla-preserving surgery.

The use of systemic therapy as the primary treatment modality also fits into the modern perception of breast cancer as a systemic disease.[8,9] It is well recognised that tumour behaviour is different in each patient and tumour biology has superseded the traditional approach of

41

anatomical staging in treatment decisions. Furthermore, the primary tumour has a different biological behaviour compared with the more indolent lymph nodes. Lymph nodes are better thought of as being ‘indicators but not governors of survival’.[10]

Response of axillary nodes to NACT

Nodal response to NACT is an important prognostic marker and patients who achieve a pCR have improved overall survival and disease-free survival.[7,11] Several studies have evaluated the response of positive axillary nodes to NACT (Table 1).

Response rates vary according to tumour biology. Hormone receptor-positive patients are less likely to achieve pCR than those with triple-negative or human epidermal growth factor receptor 2 (HER2)-positive breast cancer, highlighting the importance of patient selection.[15,16] With the addition of targeted therapy in HER2-positive patients, the conversion rates have increased to >70%.[18] Besides the prognostic implications of evaluating response, the use of NACT has the attractive potential to increase axilla-preserving surgical therapy by reducing the need for ALND in patients who are node-negative after NACT. Although removal of the lymph nodes may have little impact on survival, it adds to local control. In early breast cancer, lymph node status remains one of the most important prognostic factors and it is imperative to accurately stage all patients prior to starting any Table 1. Summation of principal studies on nodal response to NACT Nodal pCR, n (%)

Study Koolen et al.[12]

80 (40.0)

Park et al.

178 (41.0)

[13]

Hieken et al.[14]

272 (38.5)

[15]

Boughey et al.

649 (41.0)

Mamtani et al.[16]

195 (49.0)

Alvarado et al.

150 (42.0)

[17]

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REVIEW

therapy, including NACT. Therefore, all patients require a clinical and sonographic assessment of the axilla.

After assessment, patients fall into two groups: • Clinically node-negative (cN0) patients, with no sign of regional metastases on clinical examination and imaging.

• Clinically node-positive (N1) patients, with signs of regional metastases on clinical examination and/or imaging, which must be proven by fine needle aspiration (FNA) or core biopsy of the nodes.

The first group all require SLNB (ALND for node-negative patients has become obsolete in contemporary breast cancer surgery). The considerations are: • the timing of the procedure – should it be performed before or after NACT? • whether a patient who had a positive SLNB prior to NACT could have a repeat SLNB after NACT to increase the rate of axillary preservation?

The second group of patients may continue to be node-positive after NACT or may convert to node-negative. Patients who present with nodal involvement and have persistent nodal involvement after NACT should all have ALND; there is no role for SLNB. However, if patients convert to a clinically node-negative state, can one safely perform an SLNB and preserve the axilla?

Clinically node-negative patients prior to NACT Accuracy of SLNB after NACT

Data on accuracy and safety of SLNB were based on patients who had surgery first. Therefore, there were initial major concerns about the false-negative rate (FNR) and the feasibility and reliability of SLNB after NACT. However, Hunt et al.[19] compared the accuracy of SLNB in 575 patients after NACT with 3 746 patients undergoing primary SLNB, which showed comparable results. The safety of the procedure after NACT was confirmed by various other studies and two metaanalyses.[20,21] The National Comprehensive Cancer Network (NCCN) guidelines allow SLNB both before and after NACT.[22]

Timing of SLNB

SLNB before NACT – the ‘up-front’ procedure SLNB prior to NACT reflects the ‘true’ stage of the patient and allows accurate prognostication. Proponents for the up-front procedure have argued that a positive node may indicate the use of NACT; in the authors’ experience this is uncommon and the indication for NACT is made most often by consideration of tumour biology. The ratio of the primary lesion to the breast size may also be an indication for primary systemic therapy. In some cases, though, a single positive node will indicate the use of radiotherapy after a mastectomy.

This can be extremely important information in the planning of reconstructive approaches.

If the sentinel node is free of disease, no further surgical management of the axilla is required. If the node is involved, should the patient have an ALND at the time of definitive surgery or a second SLNB? This question was answered by the SENTinel NeoAdjuvant (SENTINA) trial.[23] Clinically node-negative patients with a positive SLNB prior to NACT underwent a second SLNB after chemotherapy.

The identification rate (IR) was 61.0% and the FNR 51.6%. The trial showed clearly that a second SLNB after NACT is not plausible.

From a clinical perspective this is important; when we decide on an up-front SLNB, we deny more patients the opportunity of NACT converting them to node-negative status and preserving the axilla.

When the SLNB is positive, we are committed to an ALND. In

42

general, a patient who has an up-front SLNB will always require a second operation, regardless of nodal status.

SLNB after NACT This approach allows a greater rate of minimal axillary surgery, given that many patients will convert to node-negative (Table 2).[19] If the sentinel node is negative, no further surgical management is required and the patient is spared the morbidity of an ALND. Furthermore, the patient is spared a second operation with an up-front SLNB. However, a negative SLNB after NACT can create uncertainty regarding the need of adjuvant radiation.

If the nodes are found to be involved, the patient should undergo ALND. Table 2. Identification rate, false-negative rate and local regional recurrence rate following SLNB before and after NACT[19]

IR

Primary SLNB, % (n=3 746)

SLNB after NACT, % (n=575)

98.0

97.0

FNR

4.0

9.0

LRR

0.9

1.2

IR = identification rate; FNR = false-negative rate; LLR = local regional recurrence rate.

Clinically node-positive patients prior to NACT

The traditional approach has been that anyone with treatable breast cancer and a positive axillary node should have an ALND. This approach is undoubtedly correct if the patient remains clinically node-positive after NACT. Given the high rates of pCR following NACT, is ALND still necessary in patients who convert to nodenegative?

Restaging the axilla with ultrasound scanning, magnetic resonance imaging (MRI) or positron emission tomography (PET) remains inadequate in predicting pathological response; histology is then mandatory. The data from retrospective studies attempting SLNB in patients who converted to clinically node-negative after NACT showed unacceptably high FNRs.[17,24,25] However, the results from three multicentre prospective trials suggest that SLNB in this subgroup of patients may be acceptable.

The SENTINA trial[23] divided 2 234 patients who received NACT into four groups. One of these groups comprised clinically nodepositive patients who became clinically node-negative after NACT. They had an SLNB and completion ALND; the IR was 80.0% and the FNR 14.2%, exceeding the acceptable FNR of 10.0%. A very important finding was that the FNR reduced to ˂10% if ≥3 nodes were removed.

The results also highlighted the benefit of a dual-tracer technique (patent blue and technetium-99m (99mTc)-nanocolloid) in this setting.

The American College of Surgeons Oncology Group (ACOSOG) Z-1071 trial investigated 649 patients who underwent SLNB and ALND after NACT, regardless of their clinical node status.[15] The FNR was 12.6% but the FNR again decreased to 9.1%, with dualtracer technique and removal of ≥3 nodes. However, the trial was considered to have failed as the threshold of acceptable FNR (<10%) was not achieved. A major shortcoming of the trial was the inclusion of patients without a complete clinical and radiological response.

In the Sentinel Node Biopsy Following NeoAdjuvant Chemotherapy in Biopsy Proven Node Positive Breast Cancer (SN-FNAC) trial,[26] a dual tracer technique was used to locate sentinel lymph nodes in 153 patients who were node-negative after NACT. Metastases

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REVIEW

Breast cancer patients for NACT Node-positive*

Node-negative* SLNB Node-negative

NACT Node-negative

Node-positive

SLNB: Dual tracer ≥3 nodes

ALND

Positive ALND

Negative ALND

No ALND

SLNB

Positive ALND

Negative ALND

Fig. 1. Summary of recommendations with regard to the timing of SLNB when NACT is given. (*Clinical and radiological node assessment and confirmed by fine-needle aspiration cytology.)

of any size were considered to be relevant and achieved an identification rate of 87.6%.

The FNR was 4.9% with ≥2 sentinel nodes.

In this trial the importance of using a dual tracer was emphasised. Use of immunohistochemistry to identify micrometastases and isolated tumour cells also reduced the FNR; the size of all metastases should be considered significant after NACT. Although these trials pointed out the potential to reduce ALND in node-positive patients, there were still major concerns regarding the number of patients in whom this would be applicable.[27] Importantly, the removed nodes must be true sentinel nodes, i.e. hot and/or blue nodes, and must not be randomly sampled. Mamtani et al.[16] investigated patients with histologically proven node-positive disease who underwent NACT; 68.0% turned clinically node-negative and were eligible for SLNB. Of 128 SLNB attempts, ≥3 sentinels were identified in 86.0%, and 48.0% were histologically node-negative and spared an ALND. This study and a recent meta-analysis[28] emphasise the major role of NACT to reduce ALND in patients with initial nodal disease and the feasibility of the procedure.

It must be pointed out that we lack longterm data on locoregional recurrence and survival in patients who had an SLNB only after converting from node-positive to nodenegative with NACT. Despite this, the current NCCN guidelines now allow for both ALND and SLNB in this patient group.[22] In a further attempt to decrease the FNR, clipping of involved nodes to guide removal after NACT has been proposed.[29,30] Given the increased cost and complexity of this

approach, the clinical application in our setting is questionable.

In Fig. 1 the recommendations are summarised with regard to the timing of SLNB when NACT is given.

Conclusion

NACT has major potential to decrease the extent of surgery performed in the axilla.

If the nodal status is negative prior to starting NACT, it is safe to do an SLNB after NACT. If a node-positive patient has evidence of axillary disease after NACT, they should have an ALND. Patients who convert from node-positive to node-negative can have an SLNB, but: • at least three nodes should be removed • both patent blue and 99mTc-nanocolloid should be used to identify the nodes • any size of lymph node metastasis should be considered to be node-positive and should prompt ALND. Acknowledgements. None.

Author contributions. JE and SN were equally involved in the production of the article. Both have read the final manuscript.

Funding. None.

Conflicts of interest. None.

1. Veronesi U, Stafyla V. Grand challenges in surgical oncology. Front Oncol 2012;2:127. https://doi.org/10.3389/ fonc.2012.00127 2. Mauri D, Pavlidis N, Ioannidis JPA. Neoadjuvant versus adjuvant systemic treatment in breast cancer: A meta-analysis.

J Natl Cancer Inst 2005;97(3):188-194. https://doi.org/10.1093/ jnci/dji021 3. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997;15(7):2483-2493.

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4. Van Nes JGH, Putter H, Julien J-P, et al.; Cooperating Investigators of the EORTC. Preoperative chemotherapy is safe in early breast cancer, even after 10 years of follow-up; clinical and translational results from the EORTC trial 10902. Breast Cancer Res Treat 2009;115(1):101-113. https://doi.org/10.1007/s10549-008-0050-1 5. Von Minckwitz G. Preoperative therapy: What, when and for whom? Ann Oncol 2008;1(19)(Suppl 5):v113-v116. https://doi. org/10.1093/annonc/mdn323 6. Von Minckwitz G, Untch M, Nüesch E, et al. Impact of treatment characteristics on response of different breast cancer phenotypes: Pooled analysis of the German neo-adjuvant chemotherapy trials. Breast Cancer Res Treat 2011;125(1):145156. https://doi.org/10.1007/s10549-010-1228-x 7. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 2014;384(9938):164-172. https://doi.org/10.1016/S0140-6736(13)62422-8 8. Fisher B. Laboratory and clinical research in breast cancer – a personal adventure: The David A Karnofsky Memorial Lecture.

Cancer Res 1980;40(11):3863-3874.

9. Fisher B, Anderson SJ. The breast cancer alternative hypothesis: Is there evidence to justify replacing it? J Clin Oncol 2010;28(3):366-374. https://doi.org/10.1200/JCO.2009.26.8292 10. Cady B. Lymph node metastases: Indicators, but not governors of survival. Arch Surg 1984;119(9):1067-1072.

11. Mougalian SS, Hernandez M, Lei X, et al. Ten-year outcomes of patients with breast cancer with cytologically confirmed axillary lymph node metastases and pathologic complete response after primary systemic chemotherapy. JAMA Oncol 2016;2(4):508516. https://doi.org/10.1001/jamaoncol.2015.4935.

12. Koolen BB, Valdés Olmos RA, Wesseling J, et al. Early assessment of axillary response with 18F-FDG PET/CT during neoadjuvant chemotherapy in stage II - III breast cancer: Implications for surgical management of the axilla. Ann Surg Oncol 2013;20(7):2227-2235. https://doi.org/10.1245/s10434-013-2902-0 13. Park S, Park JM, Cho JH, Park HS, Kim SI, Park B-W. Sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with cytologically proven node-positive breast cancer at diagnosis. Ann Surg Oncol 2013;20(9):2858-2865. https://doi. org/10.1245/s10434-013-2992-8 14. Hieken TJ, Boughey JC, Jones KN, Shah SS, Glazebrook KN. Imaging response and residual metastatic axillary lymph node disease after neoadjuvant chemotherapy for primary breast cancer. Ann Surg Oncol 2013;20(10):3199-3204. https://doi. org/10.1245/s10434-013-3118-z 15. Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with nodepositive breast cancer: The ACOSOG Z1071 (Alliance) Clinical Trial. JAMA 2013;310(14):1455-1461. https://doi.org/10.1001/ jama.2013.278932 16. Mamtani A, Barrio AV, King TA, et al. How often does neoadjuvant chemotherapy avoid axillary dissection in patients with histologically confirmed nodal metastases? Results of a prospective study. Ann Surg Oncol 2016;23(11):3467-3474. https://doi.org/10.1245/s10434-016-5246-8 17. Alvarado R, Yi M, le-Petross H, et al. The role for sentinel lymph node dissection after neoadjuvant chemotherapy in patients who present with node-positive breast cancer. Ann Surg Oncol 2012;19(10):31773184. https://doi.org/10.1245/s10434-012-2484-2 18. Dominici LS, Negron Gonzalez VM, Buzdar AU, et al.

Cytologically proven axillary lymph node metastases are eradicated in patients receiving preoperative chemotherapy with concurrent trastuzumab for HER2-positive breast cancer. Cancer 2010;116(12):2884-2889. https://doi.org/10.1002/cncr.25152 19. Hunt KK, Yi M, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients. Trans Meet Am Surg Assoc 2009;127:189-197. https://doi.org/10.1097/ SLA.0b013e3181b8fd5e 20. Xing Y, Foy M, Cox DD, Kuerer HM, Hunt KK, Cormier JN. Meta-analysis of sentinel lymph node biopsy after preoperative chemotherapy in patients with breast cancer. Br J Surg 2006;93(5):539-546. https://doi.org/10.1002/bjs.5209 21. Van Deurzen CHM, Vriens BEPJ, Tjan-Heijnen VCG, et al.

Accuracy of sentinel node biopsy after neoadjuvant chemotherapy in breast cancer patients: A systematic review. Eur J Cancer 2009;45(18):3124-3130. https://doi.org/10.1016/j.ejca.2009.08.001 22. National Comprehensive Cancer Network. Breast Cancer (version 2.2016). https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (accessed 2 May 2017).

23. Kuehn T, Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): A prospective, multicentre cohort study. Lancet Oncol 2013;14(7):609-618. https://doi.org/10.1016/ S1470-2045(13)70166-9 24. Shen J, Gilcrease MZ, Babiera GV, et al. Feasibility and accuracy of sentinel lymph node biopsy after preoperative chemotherapy in breast cancer patients with documented axillary metastases. Cancer 2007;109(7):1255-1263. https://doi.org/10.1002/cncr.22540 25. Takahashi M, Jinno H, Hayashida T, et al. Correlation between clinical nodal status and sentinel lymph node biopsy false negative rate after neoadjuvant chemotherapy. World J Surg 2012;36(12):2847-2852. https://doi.org/10.1007/s00268-012-1704-z

REVIEW

26. Boileau J-F, Poirier B, Basik M, et al. Sentinel node biopsy after neoadjuvant chemotherapy in biopsyproven node-positive breast cancer: The SN FNAC study. J Clin Oncol 2015;33(3):258-264. https://doi. org/10.1200/JCO.2014.55.7827 27. King TA, Morrow M. Surgical issues in patients with breast cancer receiving neoadjuvant chemotherapy. Nat Rev Clin Oncol 2015;12(6):335-343. https://doi.org/10.1038/nrclinonc.2015.63 28. El Hage Chehade H, Headon H, El Tokhy O, et al. Is sentinel lymph node biopsy a viable alternative to complete axillary dissection following neoadjuvant chemotherapy in women with node-positive breast cancer at diagnosis? An updated meta-analysis involving 3 398 patients. Am J Surg 2016;212(5):969981. https://doi.org/10.1016/j.amjsurg.2016.07.018

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29. Caudle AS, Yang WT, Krishnamurthy S, et al. Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer using selective evaluation of clipped nodes: Implementation of targeted axillary dissection. J Clin Oncol 2016;34(10):1072-1078. https://doi.org/10.1200/JCO.2015.64.009 30. Boughey JC, Ballman KV, le-Petross HT, et al. Identification and resection of clipped node decreases the false-negative rate of sentinel lymph node surgery in patients presenting with node-positive breast cancer (T0 - T4, N1 - N2) who receive neoadjuvant chemotherapy: Results from ACOSOG Z1071 (Alliance).

Ann Surg 2016;263(4):802-807. https://doi.org/10.1097/SLA.0000000000001375

Accepted 6 February 2017.

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RESEARCH

Training and support to improve ICD coding quality: A controlled before-and-after impact evaluation R Dyers,1,2 MB ChB, MSc, MMed, FCPHM (SA); G Ward,2,3 MB ChB; S du Plooy;2 S Fourie,2 MB ChB, MBA; J Evans,2 PhD; H Mahomed,1,2 MB ChB, MMed, PhD Division of Health Systems and Public Health, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 2 Western Cape Government: Health, Cape Town, South Africa 3 School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 1

Corresponding author: R Dyers (robindyers@me.com) Background. The proposed National Health Insurance policy for South Africa (SA) requires hospitals to maintain high-quality International Statistical Classification of Diseases (ICD) codes for patient records. While considerable strides had been made to improve ICD coding coverage by digitising the discharge process in the Western Cape Province, further intervention was required to improve data quality. The aim of this controlled before-and-after study was to evaluate the impact of a clinician training and support initiative to improve ICD coding quality.

Objective. To compare ICD coding quality between two central hospitals in the Western Cape before and after the implementation of a training and support initiative for clinicians at one of the sites.

Methods. The difference in differences in data quality between the intervention site and the control site was calculated. Multiple logistic regression was also used to determine the odds of data quality improvement after the intervention and to adjust for potential differences between the groups.

Results. The intervention had a positive impact of 38.0% on ICD coding completeness over and above changes that occurred at the control site. Relative to the baseline, patient records at the intervention site had a 6.6 (95% confidence interval 3.5 - 16.2) adjusted odds ratio of having a complete set of ICD codes for an admission episode after the introduction of the training and support package. The findings on impact on ICD coding accuracy were not significant.

Conclusion. There is sufficient pragmatic evidence that a training and support package will have a considerable positive impact on ICD coding completeness in the SA setting.

S Afr Med J 2017;107(6):501-506. DOI:10.7196/SAMJ.2017.v107i6.12075

The health sector in South Africa (SA) uses the World Health Organization (WHO)’s International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) codes for epidemiological surveillance as well as patient billing.

The proposed National Health Insurance (NHI) policy states that diagnosis-related groups (DRGs) will be the mechanism through which provincial and national hospitals purchase services from the national health authority.[1] The formulation of DRGs, which can roughly be summarised as average cost for similar health conditions, is dependent on accurate and complete ICD coding.

Comorbidity and complications increase the costs of managing health conditions at hospital level. The omission of ICD codes from patient records would therefore result in under-costing DRGs and under-resourcing of hospitals. Also, morbidity profiles of hospitals would be incomplete, rendering hospital admission data a poor proxy for the burden of disease for communities in the hospital’s drainage area.

While private hospitals have dedicated coders to produce comprehensive sets of ICD codes for patient encounters, clinicians at public hospitals are required to code diagnoses of all inpatients themselves. However, review of the first 18 months of the NHI pilot described the implementation of the ICD system in the public sector as unsatisfactory and in need of strengthening.[1] In response to this challenge, the Western Cape Government: Health (WCGH) department commissioned a software application for discharge

46

summaries, the electronic Continuity of Care Record (eCCR), to assist clinicians with ICD coding by integrating ICD code browsers, notes and basic coding rules.

However, as another SA study pointed out, the mere introduction of an electronic system may not produce the desired results without engaging and supporting the intended users of the system.[2] A review of the eCCR pilot showed that while ICD coding coverage was far better than in previous years, the data quality was still inadequate for billing and surveillance purposes.[3] While 74% of the patient discharge records’ primary ICD codes were accurate, only 45% of records had complete sets of the required codes during a pilot at a central hospital in 2013. This study followed on the recommendations from that study for additional training, oversight of junior clinicians and co-ordination of competing processes.

Increasing demands on clinicians make it difficult for them to commit to costly, time-consuming accredited ICD coding courses, although such programmes have been shown to have a positive impact on data quality.[4,5] Independently of this research, the WCGH introduced a package of support interventions at one of two central hospitals where the eCCR was implemented. The package included orientation to the eCCR, on-site training in the fundamentals of ICD coding, senior review of discharge summaries prepared by junior staff, access to an in-house-developed online ICD coding training course, and on-site support of a case manager designated to support eCCR users in ICD coding.

June 2017, Print edition

RESEARCH

There is little literature on the impact of training and support on ICD coding quality. Previous research used inter-observer reliability as the standard for quality, but did not appraise codes against the original patient record.[6,7] In general, research into ICD coding targets dedicated coders and focuses on efficiency and productivity. [7]

Before and after sample sizes were weighted according to the total number of patients discharged with the eCCR in each of the study periods so that folders had an equal chance of being randomly selected at each site.

Objective

Data were extracted from the eCCR database, original patient records and the human resource management information system.

The ICD codes from the eCCR were checked by one investigator (RD) against original patient records at both the intervention and the control sites to maximise the consistency with which the outcome variables were generated. Data quality checks were performed on a 10% random sample of the data to the satisfaction of a co-author (GW). Similar to a method described by Chute et al.,[8] and as used in the pilot eCCR study,[3] the primary ICD code for each patient record was reviewed and classified as one of the following: • Match. The primary diagnosis in the patient record was coded to the highest level of detail available in the ICD-10 Master Industry Table, SA version – June 2013 (SA MIT).

• Partial match. The primary diagnosis in the patient record was within the scope of the medical concept of the chosen primary ICD code descriptor, but not to the highest level of detail available in the ICD-10 SA MIT. • No match. The primary diagnosis in the patient record was not within the scope of the medical concept(s) of the chosen primary ICD code.

A retrospective evaluation of the impact of the ICD coding support package by comparing data quality before and after the introduction of the package at the intervention site and a control site, each at tertiary level hospitals in the Western Cape Province of SA. The study formed part of a larger evaluation of the eCCR and ICD coding in the Western Cape.

Methods

Study design

This was a quasi-experimental study in which the quality of ICD-10 data in the eCCR was assessed before and after the implementation of training and support at the intervention site. ICD-10 data quality was also assessed at a control site to determine the change in data quality over and above changes that may have occurred naturally without the intervention.

Study setting and population

The study was conducted in the internal medicine departments of two central hospitals in the Western Cape. Patient records and data from the eCCR were reviewed for patients who were discharged over periods of 2 months: baseline 1 August - 30 September 2014, and post-intervention 1 November - 31 December 2014. During these periods, it was required that all patients admitted to general internal medicine wards at both hospitals receive discharge summaries prepared using the eCCR.

Sample size

The two-sided Fisher’s exact test statistic was used to calculate the sample size for this study. The significance level of the test was targeted at p<0.05. It was hypothesised that ICD quality in the intervention group might improve by 15%, while the control group might change by 5%. Group sample sizes of 160 each were required to achieve 80% power to detect a difference in differences (DID) in group proportions of 0.10 from baseline to post-intervention. Each group sample size was increased by 10% to account for the possibility that original patient records might be missing, bringing the group sample size to 176.

After the eCCR database had been cleaned, 352 records were randomly selected from the intervention and control sites in proportion to the total discharges at baseline and post-intervention.

Data collection

The accuracy of primary ICD codes alone was reported in this study because this is the dominant cost driver in the formulation and selection of DRGs. The narratives in the discharge summary from the original patient record were used to determine the relevant clinical concepts of the admission episode. This assumed that clinicians summarised the most relevant clinical information in the patient episode. The eCCR discharge summaries were checked for any clinical information that should have been coded as primary or secondary diagnoses. The ordering of the codes was not used to determine coding quality, except where it influenced the primary ICD code. The technical terms relating to ICD coding in the context of this study are defined in Table 1.

Data from the patient records and eCCR were entered onto predesigned data collection forms and then entered directly into a piloted, preformatted Excel 2013 spreadsheet (Microsoft, USA) by the principal investigator (RD). A 10% sample of randomly selected folders was checked by a co-investigator, an expert in ICD coding (GW), to ensure consistency in the application of the rules used by the investigator to derive the outcome data.

Table 1. Definitions of terms often used by ICD coding specialists for the context of this study Term Primary diagnosis

Secondary diagnosis

Clinical concept Diagnostic codes

Definition for this study ‘The main condition is defined as the condition, diagnosed at the end of the episode of healthcare, primarily responsible for the patient’s need for treatment or investigation. It is the “main condition treated”. If there is more than one “main condition treated”, then the most clinically severe or life-threatening condition should be selected. There can only be one primary discharge diagnosis per patient admission.’[3] ‘Additional conditions that affect patient care or may co-exist with the primary diagnosis in terms of requiring: clinical evaluation; or therapeutic treatment; or diagnostic procedures; or extended length of hospital stay; or increased nursing care and/or monitoring. This includes any comorbidity that the patient may have. There may be multiple secondary diagnoses per patient.’[3] ‘A clinical concept is any diagnosis, procedure, risk factor, modifier, morphological reference or contextual circumstance that can be represented as an ICD code. ICD codes are therefore not restricted to diagnoses.’[3] ‘All coded clinical concepts that were coded as primary, secondary and complication ICD codes.’[3]

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Inclusion criteria

Records of inpatients who were discharged, using the eCCR, from the general internal medicine departments at two central hospitals between 1 August 2014 and 30 September 2014 for the baseline period, and between 1 November 2014 and 31 December 2014 for the post-intervention period, were included.

Exclusion criteria

Records of patients who died in hospital prior to discharge, and records of patients for whom the original paper or scanned electronic patient record could not be found after three requests on separate dates, were excluded.

Measurement tools

The International Statistical Classification of Diseases and Related Health Problems, 10th revision (SA version, January 2014), derived from and licensed to SA by the WHO, was used as a reference for checking the accuracy and completeness of ICD codes.[9] The instructional notes from the Centers for Disease Control, USA, as well as additional notes specific to SA, were used to assist in the appraisal of ICD coding quality. These resources were integrated into the eCCR and were therefore available to clinicians at the intervention site during the study period. Patient data were collected from folders and clinician characteristics from human resources records. The investigators were not blind to the study site or pre-/ post-intervention period when assessing the outcomes in this study.

Statistical analysis

The record of a patient admission was the unit of analysis. If a primary ICD code was classified as a match, as described above, it was regarded as accurate. If all the relevant clinical concepts were represented by at least partially matching ICD codes, a record was regarded as complete. The term ICD coding quality was used to refer collectively to primary ICD code accuracy and coding completeness in order to reduce repetitive statements concerning these two outcome variables.

Data were imported from Excel into Stata version 13.1 (StataCorp, USA) for analysis. Categorical variables were described with proportions and 95% confidence intervals (CIs). Means and 95% CIs and medians and interquartile ranges were calculated for continuous and count variables, respectively. The before and after groups and the intervention and control groups were treated as four independent groups in the analysis. To test for statistically significant differences in patient characteristics between the groups, the Ď&#x2021;2 statistic was used for categorical data, one-way analysis of variance for normally distributed continuous data, and the Kruskal-Wallis test for nonparametric data.

The impact of the intervention support package was determined by calculating the difference between ICD coding quality pre- and post-intervention at the control site, and then subtracting this answer from the difference between ICD coding quality pre- and postintervention at the intervention site, i.e. the DID.[10,11] Other than the inspection for CI overlap, significance testing could not be performed on the DID calculation as the outcome measurements were on the overall performance of independent groups as four distinct units rather than the individual patient records. As further recommended

by Rohrer et al.,[10] the odds of the outcome variables in the postintervention group were determined using firstly logistic regression which produced crude odds ratios (ORs), and secondly multiple logistic regression which produced adjusted ORs to account for group differences and patient and clinician characteristics.[10]

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The associations between ICD coding quality and characteristics of both the patient and the discharging clinician have been demonstrated in previous research.[3] Based on those findings and the assumption that these factors would modify likely ICD code quality, we adjusted the regression model using the patientâ&#x20AC;&#x2122;s age, gender, comorbidity and length of stay in hospital, the clinicianâ&#x20AC;&#x2122;s rank, time period relative to the intervention, and study site. The 95% CIs and p-values for the ORs were also reported, p<0.05 being regarded as statistically significant. Clinicians prepared varying numbers of summaries. This introduced a cluster design effect that was adjusted for in the analysis.

Ethics approval

The study was approved by the Health Research Ethics Committee at Stellenbosch University (ref. no. S13/08/137) and was conducted according to accepted and applicable national and international ethical guidelines and principles, including those of the international Declaration of Helsinki, October 2008. Ethics approval included a waiver of patient consent for the patient record review. Permission was obtained from the Provincial Health Research Committee to proceed with the research and to access data from routine systems (ref. no. 2013/RP/140). Patient identifiers were removed prior to analysis and reporting.

Results

Included records

None of the 352 records requested from the intervention and control sites had missing folders. None of the patients had died prior to discharge, and therefore all records were included in the analysis.

There were no missing data.

Patient and clinician characteristics and associations with ICD coding quality

Descriptive characteristics of patients and clinicians are shown in Tables 2 - 3. Although there appeared to be a greater proportion of females at the intervention site than at the control site, this was not statistically significant (p=0.52). There were no statistically significant differences between the groups for the patient characteristics of age (p=0.31), length of stay (p=0.41) and comorbidity (p=0.30). There Table 2. Baseline characteristics of patients and clinicians Control site Patient characteristics n=74 (N=159) Female patients, % 50.0 (38.5 - 61.5) (95% CI) Age (yrs), median (IQR) 50.5 (36 - 63) Length of stay (d), median (IQR) Comorbidity (n conditions), median (IQR) Clinician characteristics (N=41), n (%) Intern

Intervention site n=85 55.3 (44.4 - 65.7) 47 (32 - 60)

7 (5 - 11)

9 (5 - 15)

4 (3 - 5)

4 (3 - 5)

n=30

n=21

21 (70.0)

16 (76.2)

Medical officer

4 (13.3)

0 (0)

Registrar

5 (17.6)

4 (19.0)

Specialist

0 (0)

1 (4.8)

CI = confidence interval; IQR = interquartile range.

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While the percentage of records with complete codes at the control site improved only slightly from 22.5% (95% CI 14.5 - 34.2) to 25.5% (95% CI 17.9 - 35.0), the intervention site percentages improved

100 Records with accurate codes,ICD % codes, % Records withprimary accurateICD primary

were, however, statistically significant differences between the groups in terms of the rank of the discharging clinicians (p<0.01). These differences are also apparent in Tables 2 - 3. None of the associations between patient characteristics and ICD code accuracy were statistically significant in the crude and adjusted analyses. While the association with the clinician rank of ‘specialist’ appeared significant (Table 4), this is likely to be a spurious finding as only one specialist’s discharge summaries were sampled for this study (Tables 2 - 3). The odds of a record being encoded completely decreased by 33% for every additional comorbid condition in the patient (Table 5).

Impact of training and support on ICD coding quality

DID results The number of records with accurate primary ICD codes improved slightly from 71.1% (95% CI 61.1 - 80.4) at baseline to 79.1% (95% CI 69.4 - 86.4) after the intervention at the intervention site, while the accuracy of records at the control site remained essentially unchanged. The DID in primary ICD code accuracy between the intervention and control sites was only 6.6% (Fig. 1).

Intervention site n=91

56.9 (46.9 - 66.3)

61.5 (51.0 - 71.1)

51.5 (33 - 68)

7 (4 - 16)

3 (2 - 5)

4 (3 - 5)

n=27

n=16

14 (51.9)

13 (81.3)

Medical officer

1 (3.7)

1 (6.3)

Registrar

12 (44.4)

1 (6.3)

Specialist

0 (0)

1 (6.3)

71.8% 69.6%

68.9%

40 60 20 40 200

Before 0

After Time period relative to training and support intervention Intervention site

After

Control site

Time period relative to training and support intervention

43 (30 - 57)

8 (5 - 14)

69.6% 79.1%

68.9%

60 80

Before

Records with accurate codes,ICD % codes, % Records withprimary accurateICD primary

Length of stay (d), median (IQR) Comorbidity (n conditions), median (IQR) Clinician characteristics (N=43), n (%) Intern

Control site n=102

71.8%

site Fig. 1. Percentages of recordsIntervention with accurate primary ICDControl codessite at the intervention site compared with the control site before and after the training and support 100intervention.

Table 3. Post-intervention characteristics of patients and clinicians Patient characteristics (N=193) Female patients, % (95% CI) Age (yrs), median (IQR)

79.1%

80 100

80 100

68.1%

60 80 68.1% 40 60

27.1%

20 40 200

22.5% 27.1%

25.5%

22.5% Before

25.5%

0

After Time period relative to training and support intervention

Before

Intervention site

Control site

After

Time period relative to training and support intervention Intervention site

Control site

Fig. 2. Percentages of records with complete sets of ICD codes at the intervention site compared with the control site before and after the training and support intervention.

CI = confidence interval; IQR = interquartile range.

Table 4. Crude and adjusted ORs (also adjusted for clustering) between patient/clinician characteristics and accuracy of primary ICD codes Crude OR

95% CI

p-value

Adjusted OR

95% CI

p-value

Female

0.92

0.57 - 1.48

0.73

0.92

0.56 - 1.50

0.73

Age

1.00

0.99 - 1.01

0.92

1.00

0.99 - 1.02

0.63

Length of stay

1.00

0.98 - 1.02

0.88

1.00

0.98 - 1.02

0.98

Comorbidity

0.92

0.80 - 1.05

0.20

0.90

0.78 - 1.04

0.17

Patient characteristics

Clinician characteristics Medical officer (relative to interns)

1.00

Registrar (relative to interns)

0.69

0.37 - 1.32

0.27

1.00 0.80

0.46 - 1.36

0.41

Specialist (relative to interns)

2.71

2.09 - 3.51

<0.01*

0.56

0.38 - 0.39

<0.01*

OR = odds ratio; CI = confidence interval. *Statistically significant.

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Table 5. Crude and adjusted ORs between patient/clinician characteristics and completeness of ICD codes Crude OR 95% CI

p-value

Adjusted OR 95% CI

p-value

Female

1.11

0.71 - 1.71

0.66

1.09

0.66 - 1.82

0.72

Age

0.99

0.97 - 1.00

0.03

1.01

0.99 - 1.02

0.71

Length of stay

1.02

1.00 - 1.03

0.10

1.02

1.00 - 1.03

0.04*

Comorbidity

0.75

0.65 - 0.86

<0.01

0.67

0.55 - 0.82

<0.01*

Medical officer (relative to interns)

0.27

0.03 - 2.30

0.23

0.38

0.28 - 5.18

0.47

Registrar (relative to interns)

0.65

0.33 - 1.27

0.21

1.07

0.50 - 2.27

0.86

Specialist (relative to interns)

3.3

0.29 - 36.59

0.34

1.9

1.31 - 2.77

<0.01*

Patient characteristics

Clinician characteristics

OR = odds ratio; CI = confidence interval. *Statistically significant.

considerably from 27.1% (95% CI 18.5 - 37.7) to 68.1% (95% CI 57.8 - 77.0), which translates into a DID of 38.0% (Fig. 2).

Multiple regression results Relative to the baseline period, patient records at the intervention site had a 6.6 (95% CI 3.5 - 16.2) adjusted OR of having a complete set of ICD codes for an admission episode after the introduction of the training and support package for ICD coding. This includes adjustment for patient characteristics, clinician characteristics, time period relative to the intervention and study site. However, for the same scenario, the adjusted OR of 1.9 (95% CI 0.97 - 3.6) for accuracy of the primary ICD codes was not statistically significant.

Discussion

The results of this study describe the impact of a training and support intervention on the completeness and accuracy of discharge ICD codes generated in an electronic discharge summary application for clinicians. Potential confounding factors that could influence the impact of the intervention were also taken into account.

Despite use of the same criteria and measurement tools, the ICD code quality at both sites during the baseline period of this study was notably lower than that found in research conducted 1 year previously, in which accuracy and completeness were reported as 74% and 45%, respectively.[3] This may be because the novelty of using an electronic application for discharges had worn off, or because the researchers in the previous study had under-estimated the Hawthorne effect. Surprisingly, the relationships described between ICD coding quality and patient and clinician characteristics in the previous research were not evident in this study. Besides strength of association being very weak and non-significant, there was little change between the ORs in the crude and adjusted analyses of these characteristics (Tables 4 - 5). The significant association with the rank of specialist should be interpreted cautiously, as there was only one specialist at the intervention site whose discharge summaries were sampled for this study. The significant associations move from strongly positive to strongly negative between the crude and adjusted analysis, suggesting instability in this finding.

Indeed, exposure to the training and support intervention had the strongest association with ICD coding completeness. However, the intervention package did not make much difference to the accuracy of primary ICD codes. Given the inherent limitations of the ICD system described by Chute et al.,[12] accuracy in the region of 75% may be as good as it gets for a clinical setting where discharges

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are mostly prepared by the most junior clinicians who, besides not having been trained to expert level in ICD coding, are still learning to diagnose and manage complex cases in a tertiary hospital. Other research has suggested that it may be impossible ever to achieve 100% accuracy and completeness in ICD coding owing to the design of the ICD system.[6,12,13] None of the disease classification systems are able to capture all clinical concepts that are of interest to clinicians. [8,13] Differences between descriptors of the ICD coding system and everyday clinical terminology also contribute to inaccurate and incomplete coding.[12,14] As has been the case in previous research, this study showed that increasing comorbidity had a negative association with the quality of ICD codes, possibly owing to the challenge of finding correct terminology for the ICD descriptors in the look-up browser for each additional clinical concept that required encoding.[3] The addition of SA synonyms for the American terminology used in the ICD code descriptors and help notes to the eCCR since the 2013 study did not seem to have a significant effect on the data quality, though there were reports of improved user experience in the qualitative component of the larger eCCR evaluation study (Dyers et al., unpublished data).

While these results are encouraging in terms of a systemstrengthening intervention to improve ICD coding quality, this may still not be of an acceptable standard for the purposes of revenue retrieval and compliance with financial prescripts. Twenty percent of inaccurately coded patient records may negatively impact on DRG costing, resulting in underfunding of services purchased by hospitals from the national health authority as proposed in the NHI policy. Despite the notable impact of the intervention of 38% on the completeness of ICD coding, there is still room for improvement by 32% to ensure that all the required clinical concepts are encoded.

For the purpose of initial DRG formulation, this may require the use of expert encoders. Repeated training interventions may also progressively improve coding quality.

Study limitations

There may have been patient, clinician and service confounding variables that were not adjusted for. Although there was a risk of measurement bias in this study due to the investigators not being blinded to the retrospective ‘assignment’ of patients to the intervention and control groups, efforts were made to apply the same coding rules to all groups consistently by a single observer, i.e. the principal investigator (RD), who had no particular interest in the performance of the intervention package.

June 2017, Print edition

RESEARCH

The order of ICD codes was not considered for this study. The observed improvement in performance may therefore still not have been according to international coding standards. The use of only one clinical discipline at two central hospitals limits the generalisability of these results. However, this retrospective quasi-experimental evaluation forms part of a province-wide quality improvement cycle from which local policy-makers can draw lessons and be mindful of the caveats to the findings.

While there were imbalances in clinician numbers and characteristics between the groups over the study periods due to clinician rotations and varying team numbers, addressing these by intervening in the work environment or randomising patient and clinician assignment to balance the number of discharges per clinician would have created an artificial scenario and produced results that could never be achieved in the real working world. This research made use of a pragmatic approach to assessing the impact of a systemstrengthening intervention where the complexity of the actual healthcare delivery setting was deliberately retained. This resulted in meaningful findings for translation into policy. However, it is acknowledged that the two central hospitals have different histories, university links and cultures, the potential role of which in the findings cannot be completely excluded.

Recommendations

It may not be affordable for managers to introduce the entire training and support package in all clinical departments in all hospitals, the most expensive component of the package being the case manager.

However, policy-makers should consider scaling up the less costly components, such as the orientation programme, senior review of discharge summaries prepared by junior staff and access to the online ICD course.

In addition, it may be worthwhile to explore the affordability and cost-effectiveness of incrementally introducing onsite support by designated case managers to clinical areas that treat complex patients and where in-hospital costs are high, e.g. secondary, tertiary and high-care units for obstetrics, paediatrics, general surgery and internal medicine. This may have short-term cost benefits in these areas that could also spill over into other clinical areas in the medium term as clinicians rotate through the various disciplines in their training. As the more stable members of clinical teams, i.e. the senior clinicians, become more comfortable with ICD coding, the improvement in data quality may be sustained and possibly improved in the long term.

Hospital managers are advised to pursue the use of ‘checklists, alerts, and predictive tools; embedded clinical guidelines that promote standardized, evidence-based practices; electronic prescribing and test-ordering that reduces errors and redundancy; and discrete data fields that foster use of performance dashboards and compliance reports’.[15] This should form part of ongoing quality improvement processes for hospital data in general and not just for ICD coding, so that there is coherence and efficiency in the generation of all health service data.

Additional research and innovative monitoring mechanisms that include larger samples of patient records and health facilities over

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longer periods of time are recommended to get a more reliable picture of ICD coding quality.

Conclusion

Despite the inherent limitations of this non-randomised study design, this research provides sufficient pragmatic evidence that training and support had a substantial positive impact on ICD coding quality in an SA hospital setting. Additional research is required to explore the long-term impact, sustainability and cost-effectiveness of this intervention package to support clinicians in generating goodquality data for hospital inpatients.

Acknowledgements. We thank the following people at WCGH for providing us with data for this research: Ian de Vega, Lesley Shand, Nadine Ross, and Noel Weeder and team. Our thanks also go to Frans Vorster, Peter Raubenheimer, Tracey Naledi and Krish Vallabhjee for providing technical support, and to Tonya Esterhuizen for statistical support.

Author contributions. All the authors were involved with the design of the study. RD, GW and SdP were involved with the data collection. SdP developed the eCCR prototype software tool. RD wrote the first draft of the manuscript with the assistance of HM, and SF and JE commented on subsequent drafts.

Funding. None.

Conflicts of interest. None.

1. Matsoso MP, Fryatt R. National Health Insurance: The first 18 months. S Afr Med J 2013;103(3):156158. http://dx.doi.org/10.7196/SAMJ.6601 2. Littlejohns P, Wyatt JC, Garvican L. Evaluating computerised health information systems: Hard lessons still to be learnt. BMJ 2003;326(7394):860-863. http://dx.doi.org/10.1136/bmj.326.7394.860 3. Dyers RE, Evans J, Ward GA, Mahomed H. Are central hospitals ready for National Health Insurance? ICD coding quality from an electronic patient discharge tool for clinicians. S Afr Med J 2016;106(2):181-185. http://dx.doi.org/10.7196/SAMJ.2016.v106i2.10079 4. Lorenzoni L, da Cas R, Aparo UL. The quality of abstracting medical information from the medical record: The impact of training programmes. Int J Qual Health Care 1999;11(3):209-213. http://dx.doi. org/10.1093/intqhc/11.3.209 5. Groom A. Congratulations! You’ve passed the coding course. Paper presented at the International Federation of Health Records Organizations Congress, Melbourne, Victoria, 2 - 6 October 2000. Reprinted in ICD Coding Newsletter (November 2000). Melbourne: Victorian ICD Coding Committee and Victorian Department of Human Services, 2000.

6. Watzlaf VJ, Garvin JH, Moeini S, Anania-Firouzan P. The effectiveness of ICD-10-CM in capturing public health diseases. Perspect Health Inf Manag 2007;4:6.

7. Stanfill MH, Hsieh KL, Beal K, Fenton SH. Preparing for ICD-10-CM/PCS implementation: Impact on productivity and quality. Perspect Health Inf Manag 2014;11(Summer):1f.

8. Chute CG, Cohn SP, Campbell KE, Oliver DE, Campbell JR, for the Computer-Based Patient Record Institute’s Work Group on Codes & Structures. The content coverage of clinical classifications. J Am Med Inform Assoc 1996;3(3):224-233. http://dx.doi.org/10.1136/jamia.1996.96310636 9. World Health Organization. International Classification of Diseases. Geneva: WHO, 2012. http://www. who.int/classifications/icd/en/ (accessed 2 June 2012).

10. Rohrer JE. Nonrandomized impact evaluation studies: Errors and tips. J Prim Care Community Health 2010;1(2):70-72. http://dx.doi.org/10.1177/2150131910374718 11. Rohrer JE. Quasi-experimental evaluation without regression analysis. J Public Health Manag Pract 2009;15(2):109-111. http://dx.doi.org/10.1097/01.PHH.0000346006.59275.1e 12. Chute CG, Huff SM, Ferguson JA, Walker JM, Halamka JD. There are important reasons for delaying implementation of the new ICD-10 coding system. Health Aff (Millwood) 2012;31(4):836-842. http:// dx.doi.org/10.1377/hlthaff.2011.1258 13. Chute CG. Clinical classification and terminology: Some history and current observations. J Am Med Inform Assoc 2000;7(3):298-303. http://dx.doi.org/10.1136/jamia.2000.0070298 14. Jiang G, Pathak J, Chute CG. Formalizing ICD coding rules using Formal Concept Analysis. J Biomed Inform 2009;42(3):504-517. http://dx.doi.org/10.1016/j.jbi.2009.02.005 15. Silow-Carroll S, Edwards JN, Rodin D. Using electronic health records to improve quality and efficiency: The experiences of leading hospitals. Issue Brief (Commonw Fund) 2012;17(Jul):1-40.

Accepted 15 March 2017.

June 2017, Print edition

These open-access articles are distributed under Creative Commons licence CC-BY-NC 4.0.

RESEARCH

Analysis of HIV disease burden by calculating the percentages of patients with CD4 counts <100 cells/µL across 52 districts reveals hot spots for intensified commitment to programmatic support L M Coetzee, PhD; N Cassim, MPH; D K Glencross, MB BCh, MMed National Priority Programme, National Health Laboratory Service, Johannesburg, South Africa; and Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: D K Glencross (debbie.glencross@nhls.ac.za) Background. South Africa (SA)’s Comprehensive HIV and AIDS Care, Management and Treatment (CCMT) programme has reduced new HIV infections and HIV-related deaths. In spite of progress made, 11.2% of South Africans (4.02 million) were living with HIV in 2015.

Objective. The National Health Laboratory Service (NHLS) in SA performs CD4 testing in support of the CCMT programme and collates data through the NHLS Corporate Data Warehouse. The objective of this study was to assess the distribution of CD4 counts <100 cells/µL (defining severely immunosuppressed HIV-positive patients) and >500 cells/µL (as an HIV-positive ‘wellness’ indicator).

Methods. CD4 data were extracted for the financial years 2010/11 and 2014/15, according to the district where the test was ordered, for predefined CD4 ranges. National and provincial averages of CD4 counts <100 and >500 cells/µL were calculated. Data were analysed using Stata 12 and mapping was done with ArcGIS software, reporting percentages of CD4 counts <100 and >500 cells/µL by district.

Results. The national average percentage of patients with CD4 counts <100 cells/µL showed a marked decrease (by 22%) over the 5-year study period, with a concurrent increase in CD4 counts >500 cells/µL (by 57%). District-by-district analysis showed that in 2010/11, 44/52 districts had >10% of CD4 samples with counts <100 cells/µL, decreasing to only 17/52 districts by 2014/15. Overall, districts in the Western Cape and KwaZulu-Natal had the lowest percentages of CD4 counts <100 cells/µL, as well as the highest percentages of counts >500 cells/µL. In contrast, in 2014/15, the highest percentages of CD4 counts <100 cells/µL were noted in the West Rand (Gauteng), Vhembe (Limpopo) and Nelson Mandela Bay (Eastern Cape) districts, where the lowest percentages of counts >500 cells/µL were also noted.

Conclusions. The percentages of CD4 counts <100 cells/µL highlighted here reveal districts with positive change suggestive of programmatic improvements, and also highlight districts requiring local interventions to achieve the UNAIDS/SA National Department of Health 90-90-90 HIV treatment goals. The study further underscores the value of using NHLS laboratory data, an underutilised national resource, to leverage laboratory test data to enable a more comprehensive understanding of programme-specific health indicators.

S Afr Med J 2017;107(6):507-513. DOI:10.7196/SAMJ.2017.v107i6.11311

In 2004, the National Department of Health (NDoH) rolled out South Africa (SA)’s first Comprehensive HIV and AIDS Care, Management and Treatment (CCMT) programme.[1] The initial CCMT was later extended in the HIV, AIDS and sexually transmitted diseases national strategic plan (NSP) to reduce HIV incidence by 50% during the period 2007 - 2011.[2] Later, NSP goals for 2012 - 2016 aimed to expand access to treatment, care and support further to 80% of eligible patients, while reducing the rate of new HIV infections and HIV-associated maternal mortality by 50% and new HIV infections in children by 90%.[3] The CCMT programme has grown considerably since 2004, with declines in new HIV infections reported.[3-5] However, recent data reveal that despite these advances, SA still has a considerable burden of HIV disease and other challenges to overcome.

Since the inception of the CCMT programme, absolute CD4 T-lymphocyte counts have been used to establish baseline levels of immunosuppression in HIV-positive patients and identify those eligible for initiation onto antiretroviral therapy (ART), as well as for laboratory monitoring of patients on ART.[6] In SA, a network of ~60 CD4 testing facilities in the National Health Laboratory Service (NHLS) have provided ~3.6 million CD4 tests per annum to >3 000 NDoH health facilities (hospitals and clinics). These data sets are

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collated nationally through the NHLS Corporate Data Warehouse (CDW).

During the period 2004 - 2015, the NHLS provided >32 million CD4 tests in support of the CCMT programme. Cumulative and annualised CD4 laboratory test volume data linked to the districts/ provinces where the tests were ordered (but not necessarily where patients live) provide important insights into and information about the relative HIV disease burden. Marked immunosuppression can be characterised by CD4 counts <100 cells/μL, and HIV-positive patient ‘wellness’ by the distribution of CD4 counts >500 cells/μL.

Objective

To document the distribution and percentages of severely immunosuppressed HIV-positive patients, as well as the percentages of recovering and treated patients with CD4 counts >500 cells/µL, overall across SA’s nine provinces and in the context of the country’s 52 districts.

Methods

CD4 data were extracted from the NHLS CDW to establish a baseline (2010/11) with which 2014/15 outcomes could be compared. Data were analysed using Microsoft Excel and Stata 12. National averages

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were established for CD4 ranges <100 cells/µL, 100 - 200, 201 - 350 and 351 - 500 cells/µL and >500 cells/µL, after which the percentages of results with reported CD4 counts <100 and >500 cells/µL, categorised by province and district for the the years 2010/11 and 2014/15, were assessed. District boundaries data were downloaded from the demarcation board web page (http://www.demarcation.org. za) and uploaded to ArcGIS software (version 10.2, Esri, USA) to enable district boundaries to be defined, including the highlighting of prioritised National Health Insurance (NHI) pilot districts.

Health district percentages for CD4 counts <100 and >500 cells/µL were captured in ArcGIS and subsequently mapped using quintile graduated colour function in ArcGIS to define bins by district. Bins defined included seven for CD4 <100 cells/µL (2010/11) with a range of 7.7 - 19.9% in increments of 2%. For 2014/15 data, similar bins were created for a range of 6.3 - 13.9%, also in increments of 2%. For CD4 counts >500 cells/µL (2014/15), only four bins were created for a range of 30.5 - 50% with increments of ~5%.

Results

National, provincial and district averages were compiled from 3.5 million data points in 2010/11 and 3.9 million data points in 2014/15.

Analysis of percentages of patients within specified CD4 ranges, overall and across provinces

The percentages of patients with CD4 counts in the ranges of <100, 101 - 200, 201 - 350, 351 - 500 and >500 cells/μL in the financial years 2010/11 and 2014/15 are set out in Table 1, according to province.

Percentages of patients with higher CD4 counts increased across the country from 2010/11 to 2014/15, with higher percentages of patients with CD4 counts >350 or >500 cells/μL noted across all provinces.

Overall there was less evidence of immunosuppression (CD4 count <100 cells/µL) by 2014/15; in 2010/11 the national average was noted to be 12.47% v. an average of 9.69% by 2014/15 (a 22% decrease over 4 years). In this latter group, the percentage of patients with CD4 counts between 100 and 200 cells/μL decreased by 50% between 2010/11 and 2014/15, while a 25% reduction was noted in the percentage of patients whose CD4 counts fell into the ‘severely immunosuppressed’ group, i.e. <100 cells/μL (Table 1). The national percentage of patients with a CD4 count >500 cells/µL increased dramatically by 57% from an average of 23.19% in 2010/11 to 36.47% in 2014/15. Further details on the changes at provincial level can be seen in Table 1.

Analysis of percentages of patients with CD4 counts <100 cells/μL, by district

The percentages of immunosuppressed patients (CD4 count <100 cells/µL) are shown in the context of 52 districts for the years 2010/11 and 2014/15 in Figs 1 and 2 (A and B).

Fig. 1 shows the distribution of percentages of CD4 counts <100 cells/µL, per district grouped by province for 2010/11. These data sets indicate that almost half the districts (24/52) were above the national average of 12.3%. Twenty-nine of 52 districts had a figure of >12% in the same time frame, with the highest district percentage noted (Greater Sekhukune in Limpopo Province (LP)) at 18.9%.

Although the national average percentage of CD4 counts <100 cells/ µL fell to 9.7% in 2014/15, only 26 of 52 districts managed to reduce the percentage of immunosuppressed patients. This leaves 17 districts with a percentage higher than the national average. The highest percentage noted in 2014/15 in a district was 13.0% (West Rand, Gauteng Province (GP)). A better appreciation of the decrease in the district average percentages of CD4 counts <100 cells/µL over time can be seen in Fig. 2 (A and B), where colour-graded bins are used.

In 2010/11, the majority of districts (44/52) had individual average percentages of CD4 counts <100 cells/µL that exceeded 10%. Greater Sekhukune district had the highest percentage of CD4 counts <100 cells/µL, exceeding 18%, while three districts had a percentage of >16% (West Rand in GP, Capricorn and Waterberg in LP). Ten more districts had percentages of CD4 counts <100 cells/ µL between 14% and 16% (these were Chris Hani and Joe Gqabi districts in the Eastern Cape (EC), Lejweleputswa in the Free State (FS), City of Johannesburg Metro, Tshwane Metro, Ekurhuleni Metro and Sedibeng districts in GP, Vhembe in LP and Gert Sibande and Nkangala in Mpumalanga Province (MP)). Higher percentages of CD4 counts <100 cells/µL were not limited to rural areas, but were noted in urban areas as well, with figures of 12 - 14% and 10 - 12% being noted in 15 districts each (Fig. 1 (insert) and Fig. 2 (A)). The districts with the lowest percentages of CD4 counts <100 cells/µL in 2010/11 were Eden and Overberg in the Western Cape (WC) at 7.7% and 7.9%, respectively. Six districts had an average percentage of <10%; these included districts from WC (Cape Winelands, Cape Town Metro, West Coast), KZN (Ilembe and Uthukela) and FS (Motheo).

A marked overall positive shift was noted by 2014/15, when no district had a >14% average percentage of CD4 counts <100 cells/µL (Figs 1 and 2 (B)). Overall, districts with a percentage of CD4 counts

Table 1. Summary of distribution of the percentages of patients with reported CD4 ranges (cells/µL) for the financial years 2010/11 and 2014/15 Average percentage of CD4 counts for 2010/11 (2014/15) Province Eastern Cape

<100 13.02 (9.55)

101 - 200 16.52 (10.86)

201 - 350 27.52 (20.99)

351 - 500 19.91 (22.16)

>500 23.03 (36.44)

Free State

11.97 (9.60)

16.61 (10.81)

28.42 (21.19)

20.15 (22.15)

22.85 (36.25)

Gauteng

14.99 (11.55)

17.14 (11.38)

28.28 (20.91)

19.02 (21.51)

20.57 (34.66)

KwaZulu-Natal

11.15 (7.33)

15.00 (9.06)

27.21 (20.19)

20.74 (23.30)

25.90 (40.12)

Limpopo

15.62 (11.82)

17.34 (11.58)

27.08 (21.08)

18.57 (20.94)

21.38 (34.58)

Mpumalanga

13.22 (10.15)

16.26 (11.36)

27.54 (22.07)

19.57 (22.29)

23.40 (34.13)

North West

11.51 (10.36)

16.23 (11.12)

28.51 (20.62)

20.65 (21.52)

23.10 (36.39)

Northern Cape

11.85 (9.10)

16.56 (11.3)

28.10 (21.02)

20.40 (21.54)

23.08 (37.03)

Western Cape

8.87 (7.82)

14.67 (10.38)

29.05 (20.45)

22.04 (22.76)

25.37 (38.60)

National average

12.47 (9.69)

16.26 (10.87)

27.97 (20.95)

20.12 (22.02)

23.19 (36.47)

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20

CD4 counts <100 cells/μL, %

18 16 14

CD4 proportion (%) of annual samples tested with a CD4 count <100 cells/µL for the 2010/11 and 2014/15 financial years <10%

10 - 12%

12 - 14%

14 - 16%

16 - 18% 18 - 20%

Number of districts, 2010/11

8

15

15

10

3

1

Number of districts, 2015/16

35

13

4

-

-

-

2010/11 2014/15

12.4%

12

9.69%

10 8 6 4

0

Alfred Nzo Amathole Buffalo City Metro Cacadu Chris Hani Joe Gqabi Nelson Mandela Bay Metro O R Tambo Fezile Dabi Lejweleputswa Motheo Thabo Mofutsanyana Xhariep City of Johannesburg Metro City of Tshwane Metro Ekurhuleni Metro Sedibeng West Rand Amajuba Ethekwini Metro Ilembe Sisonke Ugu Umgungundlovu Umkhanyakude Umzinyathi Uthukela Uthungulu Zululand Capricorn Greater Sekhukhune Mopani Vhembe Waterberg Ehlanzeni Gert Sibande Nkangala Bojanala Dr Kenneth Kaunda Dr Ruth Segomotsi Mompati Ngaka Modiri Molema Frances Baard John Taolo Gaetsewe Namakwa Pixley Ka Seme Siyanda Cape Winelands Central Karoo City of Cape Town Metro Eden Overberg West Coast

2

EC

FS

GP

KZN

LP

MP

NW

NC

WC

Fig. 1. Graphical summary of the average percentage of samples with CD4 counts <100 cells/μL, per district, grouped by province, for 2010/11 and 2014/15.

Darker blue bars represent the 2010/11 data and lighter blue bars the 2014/15 data. The national average percentage of CD4 counts <100 cells/μL is indicated for 2010/11 at 12.3% (solid green line) and for 2014/15 at 9.4% (solid red line). The insert summarises the number of districts with a percentage of CD4 counts <100 μL per category, for 2010/11 and 2014/15. (EC = Eastern Cape; FS = Free State; GP = Gauteng Province; KZN = KwaZulu-Natal; LP = Limpopo Province; MP = Mpumalanga Province; NW = North West; NC = Northern Cape; WC = Western Cape.)

<100 cells/µL >10% had reduced substantially, declining four-fold over 5 years from 44/52 (84.6%) in 2010/11 to 17/52 (33%) by 2014/15 (Fig. 2 (B)). There was a dramatic increase in the number of districts with a lower percentage of CD4 counts <100 cells/µL (<10%), from 8 in 2010/11 to 35 in 2014/15. Only four districts had percentages of CD4 counts <100 cells/µL between 12% and 14% in 2014/15, including West Rand, City of Johannesburg, Nelson Mandela Bay (EC) and Vhembe (Table 1 and Fig. 2 (B)). Thirteen districts had an average percentage of CD4 counts <100 cells/µL between 10% and 12% in 2014/15, including four districts in LP (Capricorn, Greather Sekhukhune, Mopani, Waterberg), three in GP (Bojanala, Tshwane Metro, Ekurhuleni), two each in MP (Ehlanzeni, Nkangala) and North West (NW) (Dr Kenneth Kaunda and Fezile Dabi) and one each in FS (Lejweleputswa) and EC (Chris Hani). By 2014/15, KZN had the lowest recorded percentage of CD4 counts <100 cells/µL, noted in Umkhanyakude district (5.4%). The majority of KZN districts (9/11) showed a remarkable decrease in percentages of CD4 counts <100 cells/µL, with a mean of 7.3% in 2014/15.

Although there is evidence that some districts had a marked reduction in the percentage of immunosuppressed patients over the 5 years since 2010, 32/52 districts showed only modest change over the same period, reducing by 1 - 4 percentage points (see Fig. 1 for details). By 2014/15, the largest reduction in the percentage of CD4 counts <100 cells/µL was noted in Greater Sekhukhune district in LP, where a 7 percentage points reduction occurred, from 18.9% to 11.8%. Other districts that showed reductions of >5 percentage points included five in KZN (Ethekwini Metro, Umkhanyakude, Ugu, Nkangala, Zululand), two in EC (Joe Gqabi and OR Tambo), GP (Sedibeng and Ekurhuleni) and LP (Waterberg and Capricorn),

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and one in MP (Gert Sibande). Five districts showed no change in the percentage of CD4 counts <100 cells/µL over time, i.e. Nelson Mandela Bay in EC, Motheo in FS, Dr Kenneth Kaunda in NW and Eden and Overberg in WC. A negative trend was documented for a single district, Mopani, in LP (minus 1 percentage point).

NHI pilot districts (n=11) are highlighted in Fig. 2 (A and B).

In 2010/11, the majority of NHI districts had a percentage of CD4 counts <100 cells/µL exceeding 14%. By 2014/15, only Vhembe district showed an average percentage of CD4 counts <100 cells/µL >12%, with the rest reporting percentages <10%. A sub-analysis of NHI v. non-NHI districts showed similar responses over time.

Analysis of percentages of patients with CD4 counts >500 cells/μL, by district

Fig. 3 shows the percentages of patients with CD4 counts >500 cells/ μL, by district. Generally, districts with lower percentages of CD4 counts <100 cells/µL matched with districts with higher percentages of counts >500 cells/µL, both for 2010/11 and 2014/15 (Figs 3 and 4), i.e. an inverse relationship was noted. Correlation of regression analysis confirmed a strong significant relationship overall between CD4 counts <100 and >500 cells/µL (Spearman non-parametric r=–0.82; p<0.0001). As with the CD4 <100 cells/µL data, there is evidence of changes in the percentages of CD4 counts >500 cells/μL over the 5-year study period, with the highest proportions of counts >500 cells/µL noted in KZN and WC during 2014/15. However, not all districts showed the same inverse relationship between a decline in CD4 counts <100 cells/μL and an increase in counts >500 cells/ μL. Fig. 4 incorporates this information in the context of the percentage of severely immunosuppressed patients (CD4 <100 cells/µL) to

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36.5%), Mopani (11.6% and 33.6%) and Waterberg (11.3% and 36.2%) (Fig. 4). This quadrant Q4 represents districts where the percentage of CD4 counts <100 cells/μL was below the national average, but the percentage of counts >500 cells/μL was also below the national average (not in keeping with the national trend). Q2 and Q4 therefore represent districts where the inverse relationship between CD4 <100 and CD4 >500 cells/µL does not follow overall national trends, indicating a higher percentage of immunosuppression and/or a lower percentage of CD4 values exceeding the 500 cells/μL level (considered to imply wellness).

CD4 counts <100 cells/µL, 2010/11, %

Discussion

A CD4 counts <100 cells/µL, 2014/15, %

B Fig. 2. Maps reflecting HIV disease burden as percentages of samples with CD4 counts <100 cells/μL in the context of 52 districts in South Africa, in 2010/11 (A) and 2014/15 (B). National Health Insurance districts are highlighted with blue borders.

reveal the relationship between the percentage of CD4 counts >500 cells/µL (y-axis) and the percentage of counts <100 cells/µL (x-axis), highlighting districts that are currently below the national average reported for 2014/15.

Fig. 4 illustrates the relationship between the percentage of CD4 counts <100 cells/μL and that of counts >500 cells/μL in quadrants.

The best-case scenario (Q1) represents districts where the percentage of CD4 counts >500 cells/μL was highest and the percentage of counts <100 cells/μL lowest. Districts that fulfil these criteria are nine in KZN, five in WC, two in FS, three in EC, two in NC and one in NW. Q2 represents districts where the percentage of CD4 counts <100 cells/

μL was above the national average, but in contrast the percentage of counts >500 was also above the national average, including Buffalo City Metro (EC), Sedibeng (GP), Mangaung (FS), Frances Baard (NC) and Dr Kenneth Kaunda (NW). Q3 represents districts with the highest percentage of CD4 counts <100 cells/μL and the lowest percentage of counts >500 cells/µL and includes 19 districts in seven provinces.

These are LP (n=5 districts), GP (n=4), MP (n=3), NW (n=2), FS (n=2), EC (n=2) and NC (n=1). Most of the Q3 districts were in LP, including Vhembe (CD4 count <100 cells/μL 12.8% and >500 cells/μL 30.5%), Greater Sekhukhune (11.8% and 36.2%, respectively), Capricorn (11.6% and

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Travis et al.[7] explain that in the attempt to overcome health systems constraints necessary to achieve the Millennium Development Goals, focus on disease priority in the health context has left key areas such as workforce, drug supply, health financing and information systems under-resourced. They further describe the lack of generation and use of information for monitoring systems as a major barrier to solving priority health problems.[7] SA is unique in having the CDW held by the NHLS, which enables both collection and use of vital laboratory-related health data.

SA is one of the first countries in Africa to adopt universal test and treat (UTT) in accordance with the 2016 World Health Organization guidelines[8] and the UNAIDS 90-90-90 targets.[9] In a recent NDoH circular[10] (September 2016), eligibility criteria for UTT clearly state that baseline monitoring of the CD4 count is the ‘key factor in determining fast-tracking and prioritization of patients with CD4 <350 and CD4 <200 cells/µl into care’, and eligibility for opportunistic infection prophylaxis is defined as a CD4 count of <200 cells/µL and that for cryptococcal disease screening at <100 cells/µL.[6,10] The NHLS CDW is an invaluable health data repository that can be unlocked to provide information to address gaps and guide interventions in local health services. The data presented in this article specifically focus on the group of HIV-positive patients with CD4 counts of <100 cells/µL, mapped by district to indicate severe immunosuppression.

Since 2004, the NDoH has achieved progress in the CCMT programme. Initial reports revealed an average CD4 count of individuals presenting for HIV counselling and treatment (HCT) of <200 cells/μL,[4] but counts have risen steadily since com-

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mencement of the programme, increasing to 271 cells/µL in 2014.[11] In line with these trends, data reported here confirm an overall decrease in the proportion of patients with a CD4 count <100 cells/µL of 2.8 percentage points (effective as a 22% improvement) over 5 years. However, despite this progress, ~11% of all patients nationally still had CD4 counts <200 cells/µL in 2014/15 (Table 1). This is in line with other published data indicating that a significant number of patients continue to initiate ART late,[11] despite changes in threshold guidelines and scaling up of national HIV programmes. Additional data reported here further confirm a significant increase in the percentage of patients with CD4 counts >500 cells/µL (13% increase), with an overall inverse relationship to the decline in counts <100 cells/µL. CD4 group intervals in the <200, <350 and <500 cells/µL showed a similar trend, i.e. an increase in the percentages of patients with higher CD4

CD4 counts >500 cells/µL, 2015, %

Fig. 3. Map reflecting the proportion of samples with CD4 counts >500 cells/μL, as percentages of the annual total CD4 volumes shown per district for 2014/15. NHI districts are highlighted with blue borders.

50

Umkhanyakude

National average (9.4%)

CD4 counts >500 cells/μL, %

45 Umgungundlovu

Ugu

Uthukela

40 Q2

Q3

35

West Coast Ethekwini Metro Cape Winelands Thabo Mofutsanyana City of Cape Town Metro Dr Ruth Segomotsi Mompati Ilembe Overberg Buffalo City Metro Uthungulu Siyanda Sedibeng Alfred Nzo Dr Kenneth Kaunda Frances Baard Namakwa Sisonke Cacadu Umzinyathi Xhariep Eden Motheo O R Tambo Joe Gqabi City of Tshwane Metro Capricorn Ngaka Modiri Molema Amathole Waterberg Pixley Ka Seme Greater Sekhukhune John Taolo Gaetsewe Zululand Amajuba Ekurhuleni Metro Central Karoo Ehlanzeni Gert Sibande Fezile Dabi Nkangala Mopani Chris Hani

Q1

National average (37.0%) Q4

Lejweleputswa Bojanala Nelson Mandela Bay Metro City of Johannesburg Metro

West Rand

Vhembe

30 14

12

10

8

6

4

CD4 counts <100 cells/μL, % Fig. 4. The relationship of percentages of samples with CD4 counts <100 cells/μL v. >500 cells/μL for 2014/15 by district. Quadrants 1 - 4 (Q1 - Q4) rank districts according to CD4 <100 cells/μL (x-axis) v. >500 cells/μL (y-axis). The national averages of these two categories are indicated in red and green, respectively.

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counts, from 2010/11 to 2014/15 (Table 1 and Fig. 1). This may reflect better uptake, earlier enrolment into care and patients responding better to treatment, although it was out of the scope of this study to report on programmatic parameters.

Analysing data at a district level (Figs 1 - 4) added important information that was masked by national or provincial averages reported. Firstly, district-by-district performance was not consistent during the 5-year study period, but this could perhaps be expected, considering that the same performance cannot be expected across all districts or provinces. This approach allows for localised response and customisation of HIV programmes[7] and maintaining focus by targeting local needs while still taking into consideration the broader health system context. In some districts there was a dramatic reduction in the percentage of patients with CD4 counts <100 cells/µL, i.e.

5 - 7 percentage point reductions were noted in 8/52 districts (including Greater Sekhukhune at 7.1%). Gert Sibande and Ethekwini also showed a 5 - 6 percentage point reduction in CD4 counts <100 cells/ µL. Three districts (Eden, Dr Kenneth Kaunda and Mopani), however, showed an increase in the percentage of counts <100 cells/μL during the 5-year period. Although most districts matched the CD4 <100 cell/µL average of the parent province, in others a marked contrast to provincial percentages was noted, emphasising the importance of contextual interpretation of local HCT and CCMT initiatives (Figs 1 - 4) in any given district. This highlights the importance of the inclusion of district and sub-district data to successfully identify target problem areas. Underlying reasons/ root causes can then be identified and addressed (Figs 1 and 4), including HCT, earlier enrolment into care and long-term therapy compliance. Fig. 4 shows the areas where focused attention is urgently required (Q3), in which the burden of severely immunosuppressed patients (CD4 <100 cells/µL) is highest. Districts that reported no change in the percentage of immunosuppressed patients (CD4 <100 cells/µL) over the 5-year period were Dr Kenneth Kaunda (NW), Eden (WC), Mangaung (FS), Nelson Mandela Bay Metro (EC) and Overberg (WC). In the Alfred Nzo district, the percentage of immunosuppressed patients (CD4 <100 cells/µL) increased from 10.8 to 11.6% across the 5-year period. In contrast, the dramatic changes seen in the remote district of Umkhanyakude in KZN (where the percentage of patients with CD4 counts <100 cells/µL was only 5.4% and the percentage of patients with counts >500 cells/µL >50% in 2014/15) should serve as a beacon of hope and testimony to the success of local/provincial CCMT initiatives.[12,13] While district and provincial NDoH activities have played a significant role, SA health and related statistics for 2016 may offer insights into other factors that could have contributed to the dramatic improvement noted in districts across KZN, such as that in Umkhanyakude.[13] This 2016 report reveals that, although KZN has the highest antenatal prevalence of HIV infection in SA, the province also has the highest number of hospital beds and medical personnel as well as the highest spend on laboratory servicing.[13] Furthermore, KZN is one of two provinces with the highest HIV testing coverage, KZN and LP reporting that 39.0% and 40.8%, respectively, of adults aged 15 - 49 years were tested for HIV in 2013/14.[13] The data reported in our article correspond to those of Day et al.[13] in the South African Health Review in that KZN districts had the lowest percentages of CD4 counts <100 cells/µL. Day et al.[13] also reported that the two provinces with the poorest HIV testing coverage were FS and GP, at 26.2% and 23.3%, respectively; our findings are consistent with these figures in that GP had two of three districts with the highest percentages of immunosuppressed patients (CD4 <100 cells/ µL) and the lowest percentages of patients with CD4 counts >500 cells/ µL nationwide. A platform for sharing lessons learned and systems

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used in districts that have shown improvement over time could offer help and insights to assist translation of best practices into other districts where little improvement has been noted. Such an approach could improve outcomes in districts where a marked burden of disease still exists, and facilitate their alignment with the NSP and the UNAIDS/NDoH 90-90-90 strategy.[3,9] Finally, the data presented here and outcomes noted at district level, highlighting those areas across SA where the percentage of patients with CD4 counts <100 cells/µL is high, should be considered in the light of CD4 categories[10] currently used by the NDoH to prioritise or fast-track patients into care. HIV patients with CD4 counts <100 cells/µL are severely immunosuppressed, urgently requiring enrolment into care. Through the national NHLS CD4 service, this group is currently automatically screened for the presence of cryptococcal antigen (CrAg)[6,10] to identify HIVpositive immunosuppressed patients with early cryptococcal disease before they progress to meningitis. The CrAg results are reported to health facilities via the NHLS HIV dashboard on a weekly basis as ‘results for action’ (RFA),[14] to enable prompt patient follow-up and antifungal treatment; immediate enrolment onto ART should also be a priority. The NHLS RFA system also enables health facilities to be notified about HIV-positive patients with CD4 counts <100 cells/ µL, who in our opinion should be considered as medical emergencies requiring urgent enrolment onto ART. Formal acknowledgement of this specific category of patients by the NDoH is required to enable action at clinic level and ultrafast tracking of this group of patients into care.

Study limitations

The CD4 laboratory data used in this study do not distinguish between first-ever and follow-up CD4 tests, and may include both ART-naive patients and those already on ART, or patients with higher CD4 counts not yet enrolled onto ART. The study did not investigate underlying factors that could contribute to higher percentages of CD4 counts <100 cells/µL (and lower percentages of counts >500 cells/µL), such as CD4 recovery over time, adherence or retention in HIV care. The study merely aimed to report the distribution of immunosuppressed individuals across 52 districts in an effort to identify hot spots for programmatic intervention, and it was not in its scope to assess cohorts.

Conclusions

The collation of NHLS CDW CD4 data provided important insights into HIV disease burden, i.e. immunosuppression (CD4 <100 cells/ µL) and patients with CD4 counts >500 cells/µL. The latter could indicate baseline results for patients not yet on treatment (see ‘Study limitations’) or response to ART. Analysis of CD4 counts <100 cells/ µL overall, together with a review of the percentages of patients with counts >500 cells/µL, by province and by district, showed a positive shift over time (a decrease in the percentage of CD4 counts <100 cells/ µL and an increase in counts >500 cells/µL) and identified districts that may require urgent interventions to lower their percentage of counts <100 cells/µL. The study underscores the value of using laboratory data for identifying areas with higher priority needs for programmatic intervention.

Acknowledgements. The authors thank the NHLS CDW staff for help and support in extracting data. DKG thanks the NRF for Incentive Funding for Rated Researchers.

Author contributions. LMC: co-developed and executed research, reviewed the first draft, data analysis assistance and editorial input; NC: co-

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developed and executed research, reviewed the first draft, data analysis assistance and editorial input; DKG: conceptualised idea for research, editorial input and project leader/budget owner, final submitted draft.

Funding. None.

Conflicts of interest. None.

1. National Department of Health, South Africa. Operational Plan for Comprehensive HIV and AIDS Care, Management and Treatment for South Africa. Pretoria: NDoH, 2003.

2. National Department of Health, South Africa. HIV & AIDS and STI Strategic Plan for South Africa: 2007-2011. Pretoria: NDoH, 2007.

3. National Department of Health, South Africa. National Strategic Plan for HIV, TB and STI's 2012-2016.

Pretoria: Joint Committee on HIV and AIDS, NDoH, 2012.

4. National Department of Health, South Africa. Progress Update on the National Strategic Plan for HIV, TB and STIs 2012-2016. Pretoria: Joint Committee on HIV and AIDS, NDoH, 2013.

5. Rehle TM, Hallett TB, Shisana O, et al. A decline in new HIV infections in South Africa: Estimating HIV incidence from three national HIV surveys in 2002, 2005 and 2008. PLoS One 2010;5(6):e11094. http:// dx.doi.org/10.1371/journal.pone.0011094 6. National Department of Health, South Africa. 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: NDoH, 2015.

7. Travis P, Bennett S, Haines A, et al. Overcoming health-systems constraints to achieve the Millennium Development Goals. Lancet 2004;364(9437):900-906. http://dx.doi.org/10.1016/S0140-6736(04)16987-0 8. World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Geneva: WHO, 2016.

9. Joint United Nations Programme on HIV/AIDS (UNAIDS). 90-90-90 – an Ambitious Treatment Target to Help End the AIDS Epidemic. Geneva: UNAIDS, 2014.

10. National Department of Health, South Africa. Implementation of the Universal Test and Treat Strategy for HIV Positive Patients and Differentiated Care for Stable Patients. Pretoria: Joint Committee on HIV and AIDS, NDoH, 2016.

11. Kufa T. Evaluation of programmes to support adherence during all stages of the HIV care cascade in South Africa: Determinants of CD4 immune recovery among individuals on antiretroviral therapy in South Africa: A national analysis. 2016. https://doi.org/10.13140/RG.2.2.14702.41287 (accessed 3 May 2017).

12. National Department of Health, South Africa. Health Indicators Update: Antiretroviral Indicators.

Pretoria: Directorate: Monitoring and Evaluation, NDoH, 2013:35.

13. Day C, Gray A. South African Health Review 2016: Health and Related Indicators. Annual Report.

Durban: Health Systems Trust, 2016.

14. Carmona S. Groundbreaking data system set to accelerate HIV/Aids elimination in SA [press release].

Johannesburg: Right to Care, 2016. http://www.righttocare.org/press-releases/groundbreaking-datasystem-set-to-accelerate-hivaids-elimination-in-sa/

Accepted 8 March 2017.

Cytomegalovirus retinitis in Cape Town, South Africa: Clinical management and outcomes S R J Lapere, MB ChB, FCOphth (SA), MMed (Ophth); J C Rice, MB BCh, FCOphth (SA), MRC Ophth, MPH (Clinical Research) Department of Ophthalmology, Groote Schuur Hospital, Cape Town, South Africa Corresponding author: S R J Lapere (steven.lapere@gmail.com) Background. Cytomegalovirus (CMV) retinitis is a vision-threatening opportunistic infection that occurs mainly in immunocompromised individuals. Limited data on treatment protocols and management outcomes are available in South Africa (SA).

Objectives. To review the clinical presentation, management and outcomes of patients who were diagnosed and treated for CMV retinitis at Groote Schuur Hospital, Cape Town, SA, over a 10-year period, and to compare treatment protocols of 13 public hospitals in SA that treat patients for CMV retinitis.

Methods. A retrospective case review was performed of all patients treated for CMV retinitis at Groote Schuur Hospital between 2003 and 2013. In addition, a questionnaire was sent to 13 public hospitals in SA that treat patients with CMV retinitis.

Results. A total of 141 eyes in 91 patients were polymerase chain reaction-positive for CMV. Of these patients, 98.6% were HIV-positive and 72.5% were on highly active antiretroviral therapy (HAART) at the time of presentation. Patients who were on HAART at presentation had better mean final visual acuity (VA) than those who were not on HAART (p<0.001). There was a significant association between the number of retinal quadrants involved and final visual outcome (p=0.009). Macular (central vision) involvement had a significant adverse effect on visual outcome compared with cases in which the macula was uninvolved (p=0.005).

Conclusions. Independent risk factors that predict final visual outcome include presenting VA, number of retinal quadrants involved, macular involvement and being on HAART at presentation. The diagnosis and management of CMV retinitis differ among treatment centres in SA. S Afr Med J 2017;107(6):514-517. DOI:10.7196/SAMJ.2017.v107i6.12250

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i6.12250

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These open-access articles are distributed under Creative Commons licence CC-BY-NC 4.0.

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Characteristics and outcomes of gunshot-acquired spinal cord injury in South Africa C Joseph, RPT, PhD Physiotherapy Department, Community and Health Sciences Faculty, University of the Western Cape, Cape Town, South Africa; and Physiotherapy Division, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden Corresponding author: C Joseph (conran.joseph@gmail.com) Background. Spinal cord injuries (SCIs) caused by assault present a unique challenge facing the healthcare system, in that very little is known about how these injuries manifest compared with other causes of injury. Understanding the nuances of gunshot SCIs could contribute towards better care provision.

Objective. To determine the characteristics of gunshot SCI and compare both injury characteristics and outcomes between gunshot SCI and all other traumatic causes taken together.

Methods. The gunshot SCI sub-cohort was derived from a 1-year prospective, population-based study, including both tertiary-level hospitals providing SCI care in the Cape Metropolitan area of South Africa (SA). All consenting 145 survivors, after a window period of 7 days, were included, and their demographic and injury characteristics were captured according to the International SCI Core Basic Data Set. Further, selected secondary medical complications (outcomes) were prospectively and routinely assessed throughout acute care. Both descriptive and inferential statistics were used to describe and compare characteristics and outcomes, respectively.

Results. Of the 145 survivors of traumatic SCIs, 45 (31%) injuries were caused by gunshots. The gunshot SCI group consisted mainly of males (n=43; 96%), and the average age of injury onset was 26 years. Most survivors of the gunshot SCI group were paraplegic (69%), had complete lesions (69%) and vertebral injuries (96%), and presented with significant associated injuries (84%). When comparing gunshot SCI with all other traumatic causes, significant differences were found in relation to demographic and injury characteristics and adverse outcomes, indicating that those survivors with gunshot SCI were typically younger males with complete paraplegia, had more frequent secondary medical complications, and a longer hospital stay.

Conclusion. This study contributes to the knowledge base of survivors with gunshot SCIs in a region of SA. Efforts should be made to reduce the occurrence of all gunshot SCIs, since those injuries impact survivors negatively in terms of injury characteristics and adverse outcomes.

S Afr Med J 2017;107(6):518-522. DOI:10.7196/SAMJ.2017.v107i6.12296

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i6.12296

Screening for gestational diabetes mellitus in a South African population: Prevalence, comparison of diagnostic criteria and the role of risk factors S Adam,1 MB ChB, FCOG (SA), MMed (O&G), Cert Maternal Fetal Medicine (SA); P Rheeder, MB ChB, MMed (Int Med), FCP (SA), MSc (Clin Epidemiol), PhD 1 2

Department of Obstetrics and Gynaecology, School of Medicine, Faculty of Health Sciences, University of Pretoria, South Africa Department of Internal Medicine, School of Medicine, Faculty of Health Sciences, University of Pretoria, South Africa

Corresponding author: S Adam (sumaiya.adam@up.ac.za) Background. The prevalence of gestational diabetes mellitus (GDM) is increasing. Most major world organisations now recommend universal screening for GDM based on the International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria. Currently there is a lack of consensus on the diagnostic criteria for GDM used in South Africa (SA). The Society for Endocrinology, Metabolism and Diabetes of South Africa’s revised guidelines recommend the use of the IADPSG criteria for the diagnosis of GDM. Objectives. To determine the prevalence of GDM in an SA population. We compared the prevalence of GDM using the various diagnostic criteria and evaluated the risk factors associated with GDM. Methods. This was a prospective cohort observational study carried out at a level 1 clinic in Johannesburg, SA. All pregnant women at <26 weeks’ gestation were recruited. Patients known to have GDM were excluded. At recruitment, a data questionnaire was completed and

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RESEARCH

bloods were drawn for a random glucose test and measurement of the glycated haemoglobin level. A 75 g 2-hour oral glucose tolerance test (OGTT) was scheduled before 28 weeks’ gestation.

Results. Five hundred and fifty-four patients (55.4%) completed the OGTT. The prevalence of GDM was 25.8% if universal screening and the IADPSG criteria were used. If universal screening and the National Institute for Health and Care Excellence (NICE) criteria were used, the prevalence was 17.0%. If selective risk factor-based screening was used, only 254 (45.8%) of the women would have had an OGTT. The prevalence of GDM in this instance would have been 15.2% with the IADPSG criteria and 3.6% with the NICE criteria. Two hundred and fifty-four patients (45.8%) had at least one risk factor for GDM. The presence of one or more risk factors had a poor sensitivity (58.7%) and specificity (58.6%) for the detection of GDM in our study population.

Conclusions. The prevalence of GDM would be substantially increased if universal screening with the IADPSG criteria were to be employed. Risk factors are a poor screening test for GDM. S Afr Med J 2017;107(6):523-527. DOI:10.7196/SAMJ.2017.v107i6.12043

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i6.12043

Effects of exogenous human insulin dose adjustment on body mass index in adult patients with type 1 diabetes mellitus at Kalafong Hospital, Pretoria, South Africa, 2009 - 2014 T S A Sehloho,1,3 BPharm, CAHM, MSc (Epi); D G van Zyl,2,3 MMed (Int Med), FCP (SA), MSc (Clin Epi), PhD (Int Med) National Department of Health, Pretoria, South Africa Department of Internal Medicine, School of Medicine, Faculty of Health Sciences, University of Pretoria, South Africa 3 School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, South Africa 1 2

Corresponding author: T S A Sehloho (tohlang.sehloho@health.gov.za) Background. To maintain fasting blood glucose levels within near to the normal range in type 1 diabetes mellitus (DM), frequent insulin dose adjustments may be required with short-, intermediate- and long-acting insulin formulations. Patients on human insulin generally experience weight gain over time, regardless of the level of glycaemic control achieved.

Objectives. To determine the effects of human insulin, adjusted quarterly to achieve glycaemic control, on body mass index (BMI), and establish dose regimens that achieve optimal glycaemic control without increasing BMI in patients with type 1 DM at the Kalafong Diabetes Clinic in Pretoria, South Africa.

Methods. The sample size (N=211, 48.8% male) was obtained by non-probability convenience sampling of all available records of patients with type 1 DM aged ≥18 years at baseline at the clinic. The longitudinal relationships of covariates with time-varying BMI, as well as with time-varying glycated haemoglobin (HbA1c) levels, were explored using multilevel mixed-effects linear regression modelling.

Results. The majority of the patients (84.8%) received the twice-daily biphasic human insulin regimen and the remainder received the basal neutral protamine Hagedorn (NPH) plus prandial regular human insulin regimen. The multivariable multilevel mixed-effects linear regression model indicated that time-varying BMI was significantly positively related to time-varying twice-daily biphasic insulin dosage (β (standard error) 0.464 (0.190), p=0.015), baseline HbA1c (0.092 (0.026), p<0.001) and baseline BMI (0.976 (0.016), p<0.001). There were significant inverse associations with the number of years spent in the study (–0.108 (0.052), p=0.038), time-varying HbA1c (–0.154 (0.031), p<0.001) and male sex (–0.783 (0.163), p<0.001). There were non-significant negative longitudinal associations of age (–0.005 (0.006), p=0.427) and current smoking status (–0.231 (0.218), p=0.290) with BMI outcomes.

Conclusions. There was no evidence that optimal quarterly-prescribed daily dosage adjustments of insulin improved and maintained blood glucose control without increasing body weight. When compared with the basal NPH plus prandial insulin regimen, twice-daily biphasic insulin was associated with a statistically significant increase in subsequent BMI. Baseline HbA1c and BMI were also significantly positively associated with time-varying BMI. However, males appeared to be at a lower risk than females of an increase in BMI during insulin therapy.

A question for further research is whether the analogue insulins will be associated with the same increase in BMI, as well as the same modest improvements in HbA1c, seen in this sample.

S Afr Med J 2017;107(6):528-534. DOI:10.7196/SAMJ.2017.v107i6.12098

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i6.12098

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These open-access articles are distributed under Creative Commons licence CC-BY-NC 4.0.

RESEARCH

The status of vaccine availability and associated factors in Tshwane government clinics N J Ngcobo,1 MB ChB, MSc Med (Bioethics and Health Law), MBA, DOH, DTM&H, DCH; M G Kamupira,2 MB ChB, PhD (Public Health), MPH 1 2

Independent consultant, Pretoria, South Africa World Health Organization, Country Office, Pretoria, South Africa

Corresponding author: N J Ngcobo (ntombenhle1m@gmail.com) Background. Vaccines have greatly contributed to the control of vaccine-preventable diseases and to human development. Efforts by many countries to introduce new vaccines are a significant move towards achieving the sustainable development goal for health. However, effective vaccine supply chains that ensure an uninterrupted supply of vaccines are pivotal to attaining universal access to life-saving vaccines and sustainable development. The introduction of new vaccines puts a strain on supply chains; South Africa is no exception, as there are indications of vaccine stock-outs in clinics.

Objective. To establish the status of vaccine availability and associated factors in government health facilities of Tshwane Health District in Gauteng Province.

Methods. A cross-sectional study was conducted in a sample of randomly selected government clinics in the Tshwane health district of Gauteng Province. Data were collected using a structured measurement instrument in participating clinics. Data were analysed using Excelbased software (Microsoft, USA).

Results. A total of 31 clinics participated. In the preceding 12 months, clinics had experienced vaccine stock-outs, especially of the three newer vaccines: pneumococcal conjugate vaccine, rotavirus and Pentaxim. These were also out of stock for a long duration; for over 2 weeks in a majority of clinics. The causes of vaccine stock-outs were: poor management of stock, district depot out of stock, unreliable deliveries, lack of pharmacy assistants and limited fridge capacity. Further burdening the situation is the ineffective emergency-ordering system.

Conclusion. Significant shortages of vaccines, which are essential drugs, occur in Tshwane government clinics. Vaccine supply chain issues and vaccine shortages should be treated as a priority at all levels of the healthcare system; therefore, a similar study should be conducted at national level. It is recommended that the vaccine supply chain should be restructured and overhauled with the use of advances in technology and could be linked with current initiatives such as MomConnect.

S Afr Med J 2017;107(6):535-538. DOI:10.7196/SAMJ.2017.v107i6.12149

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i6.12149

Report on the first government-funded opioid substitution programme for heroin users in the Western Cape Province, South Africa G Michie,1 BSc Hons, MB ChB, DA (SA), FCPsych (SA); S Hoosain,2 BPsych, PGDip (Addictions Care); M Macharia,1 PhD; L Weich,1 MB ChB, MRCPsych, FCPsych (SA) 1 2

Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Sultan Bahu Treatment Centre, Mitchellâ&#x20AC;&#x2122;s Plain, Cape Town, South Africa

Corresponding author: L Weich (lizew@sun.ac.za) Background. Although pharmacological opioid substitution treatment (OST) is a well-established treatment modality for heroin addiction, it is a relatively recent introduction in low- and middle-income countries.

Objective. To report on a pilot OST programme initiated in 2013 that was the only public-funded programme in South Africa (SA) at the time. Participants were offered standard care only (n=68) or, for the OST group (n=67), standard care plus Suboxone (Reckitt Benckiser), a synthetic partial opioid agonist, in a 12-week clinician-monitored programme.

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Methods. Clinical records of 135 participants in the rehabilitation programme at Sultan Bahu Rehabilitation Centre in Mitchellâ&#x20AC;&#x2122;s Plain, Cape Town, SA, from 1 January to 31 December 2014 were reviewed. Data collected included demographics and duration in treatment (retention) as well as number of urine samples provided, positive tests or self-reported use events and dates of first positive/negative tests.

Results. Significantly more participants in the OST group (65.7%) than controls (44.1%) completed the treatment (p=0.019). Among the non-completers, retention was higher in the OST group than in the standard care group (48.2 v. 30.1 days; p=0.001). The groups did not differ in respect of number of missed appointments and time to first positive test. However, the proportion of participants testing positive was higher in the OST group (80.6%) than in the standard care group (61.8%), although the former were tested nearly three times (18.3 v.

6.6 times) more. Consequently, the positive rate (proportion of positive tests) was substantially lower in the OST group (16.8%) than in the standard care group (23.3%).

Conclusions. The results demonstrate modest success of this pilot OST programme in terms of completion and retention and should argue for a move to increase availability of and accessibility to OSTs for the management of opioid use disorder.

S Afr Med J 2017;107(6):539-542. DOI:10.7196/SAMJ.2017.v107i6.12140

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i6.12140

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True (A) or false (B): Exploitation of the vulnerable in research: Responses to lessons learnt in history 1. Examples of experimental research where people with vulnerabilities have been harmed have surfaced since medieval times.

2. In the main, the first studies of experimentations on humans took place on slaves and the poor, and this coincided with the development of the new science of anthropology that Europeans used to study non-European peoples.

When students become patients: TB disease among medical undergraduates in Cape Town, South Africa (SA) 3. In SA, medical students complete their undergraduate training in communities with a very high incidence of TB (834/100Â 000 population in 2015).

4. Latent TB incidence among SA medical students was measured by tuberculin skin test conversion at 23 cases/100 person-years.

Sentinel lymph node biopsy and neoadjuvant chemotherapy in the management of early breast cancer: Safety considerations and timing 5. Neoadjuvant chemotherapy has proven survival benefit in early breast cancer.

6. In breast cancer, tumour biology has superseded the traditional approach of anatomical staging in treatment decisions.

7. Nodal response to neoadjuvant chemotherapy is an important prognostic marker.

8. In early breast cancer, lymph node status remains one of the most important prognostic factors, and it is imperative to stage all patients accurately prior to starting any therapy.

Training and support to improve ICD coding quality: A controlled before-and-after impact evaluation 9. The formulation of diagnosis-related groups (DRGs), which can roughly be summarised as average cost for similar health conditions, is dependent on accurate and complete ICD coding.

10. The omission of ICD codes from patient records would result in under-costing DRGs and under-resourcing of hospitals.

Cytomegalovirus (CMV) retinitis in Cape Town, SA: Clinical management and outcomes 11. CMV is continually suppressed by cell-mediated immunity, so infection is usually asymptomatic in immunocompetent hosts.

12. CMV retinitis is a relentless vision-threatening infection that can cause irreversible vision loss within weeks to months.

13. CMV retinitis is the most common cause of vision loss in patients with AIDS. Characteristics and outcomes of gunshot-acquired spinal cord injury in SA 14. Costly prevention campaigns and programmes have led to a decline in the occurrence of traumatic spinal cord injuries (TSCIs) globally.

15. It was only recently established that assault, i.e. gunshots, stab wounds and use of non-penetrating objects, was the leading cause of TSCI, causing ~60% of casualties in the Cape Metropolitan region of SA. Screening for gestational diabetes mellitus in an SA population: Prevalence, comparison of diagnostic criteria and the role of risk factors 16. SA is now regarded as one of the worldâ&#x20AC;&#x2122;s most obese nations.

17. The prevalence of gestational diabetes mellitus (GDM) in SA is estimated to be 1.6 - 8.8% based on scant data and selective risk factor-based screening.

18. The significant increase in the prevalence of GDM reported in this study compared with previous SA studies can be attributed to the lower diagnostic threshold and the use of universal screening.

Effects of exogenous human insulin dose adjustment on body mass index in adult patients with type 1 diabetes mellitus at Kalafong Hospital, Pretoria, SA, 2009 - 2014 19. Patients on intensive insulin therapy have been observed to experience weight gain over time, regardless of the level of glycaemic control achieved.

20. In this study, there was no evidence that optimal quarterly prescribed daily dosage adjustments of insulin improved and maintained blood glucose control without increasing body weight.

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