SAMJ Vol 104, No 3 (2014) by HMPG

MARCH 2014

VOL. 104 NO. 3

Cardiovascular prevention: Lifestyle and statins

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The cons of INH TB prophylaxis â&#x20AC;&#x201C; pros to follow

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Research ethics evolution: Nuremberg to Helsinki

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New imaging for the diagnosis of childhood TB

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Markers to identify cardiovascular disease risk in HIV

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CME: Spina bifida

212-221

Progress towards the Millennium Development Goals

222-251

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MARCH 2014

FROM THE EDITOR

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Patient autonomy or patient confusion? B Farham

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EDITOR’S CHOICE

VOL. 104 NO. 3

EDITOR Janet Seggie, BSc (Hons), MD (Birm), FRCP (Lond), FCP (SA) EDITOR EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG MD (Hon), FCM (Hon)

CORRESPONDENCE 154

African mass circumcision programmes: A dangerous distraction G J Boyle, G Hill

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Reducing the surgical complications of smoking by cotinine testing D J Potgieter, G dos Passos, C E Price, A D Rogers

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A path to full-service contracting with general practitioners under National Health Insurance S Moosa

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Primary prevention of rheumatic fever in children: Key factors to consider A Steer, M Danchin; response from J H Irlam, B M Mayosi, M E Engel, T A Gaziano, A C Whitelaw

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A balanced approach to interpreting the WHIRCDMT P B Wilson

DEPUTY EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB EDITORIAL SYSTEMS MANAGER Melissa Raemaekers, BSc (Hons), PhD SCIENTIFIC EDITOR Kerry Gordon, MSc, PhD TECHNICAL EDITORS Paula van der Bijl, BA, HDipLib Emma Buchanan, BA NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za HEAD OF PUBLISHING Robert Arendse

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From coal-face clinicians to change agents – igniting healthcare innovation Annually, 1% of gold miners die – 4% sent home sick

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CLINICAL PRACTICE Clinical Access to Bedaquiline Programme for the treatment of drug-resistant tuberculosis F Conradie, G Meintjes, J Hughes, G Maartens, H Ferreira, S Siwendu, I Master, N Ndjeka

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DRUG ALERT Recommendations pertaining to the use of viral vaccines: Influenza 2014 S Walaza

PRODUCTION ASSISTANT Neesha Hassan ART DIRECTOR Brent Meder DTP & DESIGN Anelia du Plessis | Carl Sampson ONLINE MANAGER Gertrude Fani

REVIEW 168 Cardiovascular prevention: Lifestyle and statins – competitors or companions? L H Opie, A J Dalby 174 Isoniazid preventive therapy for tuberculosis in South Africa: An assessment of the local evidence base R Wood, L-G Bekker 178

MEDICINE AND THE LAW The research ethics evolution: From Nuremberg to Helsinki A Dhai

EDITORIAL

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New imaging approaches for improving diagnosis of childhood tuberculosis S Bélard, S Andronikou, T Pillay, M P Grobusch, H J Zar

RESEARCH

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CONSULTING EDITOR JP de V van Niekerk, MD, FRCR

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Systematic review of the evidence for rational dosing of colistin E Visser Kift, G Maartens, C Bamford

187 Determinants, outcomes and costs of ceftriaxone v. amoxicillin-clavulanate in the treatment of community- acquired pneumonia at Witbank Hospital S N Xaba, O Greeff, P Becker

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The impact of chronic pseudomonal infection on pulmonary function testing in individuals with cystic fibrosis in Pretoria, South Africa A Pentz, P Becker, R Masekela, O Coetzee, R J Green

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Cardiometabolic markers to identify cardiovascular disease risk in HIV-infected black South Africans J M van Rooyen, C M T Fourie, H S Steyn, G Koekemoer, H W Huisman, R Schutte, L Malan, M Glyn, W Smith, C Mels, A E Schutte

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High pleural fluid adenosine deaminase levels: A valuable tool for rapid diagnosis of pleural TB in a middle-income country with a high TB/HIV burden C P Onyenekwu, A E Zemlin, R T Erasmus

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Integration of TB and ART services fails to improve TB treatment outcomes: Comparison of ART/TB primary healthcare services in Cape Town, South Africa R Kaplan, J Caldwell, L-G Bekker, K Jennings, C Lombard, D A Enarson, R Wood, N Beyers

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Tuberculosis incidence in Cameroonian prisons: A 1-year prospective study J Noeske, N Ndi, G Amougou Elo, S Mbondi Mfondih

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GUEST EDITORIAL Spina bifida: A few simple facts about a complex condition G Fieggen

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REVIEW Spina bifida: A multidisciplinary perspective on a many-faceted condition G Fieggen, K Fieggen, C Stewart, L Padayachy, J Lazarus, K Donald, S Dix-Peek, Z Toefy, A Figaji

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

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ARTICLES Aetiology and antenatal diagnosis of spina bifida K Fieggen, C Stewart

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Perinatal management of spina bifida L Padayachy, D Ochieng’

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The paediatric neuropathic bladder J Lazarus

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© Copyright: Health and Medical Publishing Group (Pty) Ltd, a subsidiary of SAMA Use of editorial material is subject to Creative Commons Attribution – Noncommercial Works License 3.0. http://creativecommons. org/licenses/by-nc/3.0

An approach to the developmental and cognitive profile of the child with spina bifida N Ramsundhar, K Donald

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Starry sky over the Southern African Large Telescope (SALT) at the South African Astronomical Observatory in Sutherland, Northen Cape Province, South Africa. Photo and text: Eric Nathan Email: eric@ericnathan.com

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CONTENTS LISTED IN Index Medicus (Medline) Excerpta Medica (EMBASE) Web of Knowledge Biological Abstracts (BIOSIS) Science Citation Index (SciSearch) Current Contents/Clinical Medicine

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FIRST PUBLISHED IN 1884

Patient autonomy or patient confusion? A couple of weekends ago a friend, Richard, popped in for a cup of tea – a very fit, active septuagenarian who rides the Cape Argus Pick n Pay Cycle Tour every year and has recently started running. A few years ago he had a triple bypass. At the time, his cardiologist told him that, ‘From today, you become a vegetarian ... ’. According to Richard, the cardiologist told him to cut out eggs, butter, red meat and any source of saturated fats from his diet; standard advice that we have all given at some stage in our careers. Richard’s problem, though, was this: ‘Now’ he says, ‘I am told that margarine is actually bad for me, eggs are fine and there are even people saying that it is OK to eat saturated fats – who is right? What do I do?’ Scanning the popular medical press over the past few months would only have added to Richard’s confusion – with headlines such as: ‘New analysis suggests whole diet approach to lower cardiovascular risk has more evidence than low-fat diets’;[1] ‘Butter is bad – a myth we’ve been fed by the “healthy eating” industry’.[2] I would imagine that many doctors are confused – just think how your patients must be feeling. Along with the furore about possibly modifying ‘healthy eating’ guidelines (never mind the heated debate over fats v. carbohydrates), we have conflicting advice on the globally popular, bestselling cholesterol drugs – the statins – from: ‘Taking statins to lower cholesterol? New guidelines provide opportunity to discuss options with your doctor’ – Mayo Clinic;[3] ‘Low-dose statins good option for some heart patients, study finds’ – Medical Xpress;[4] to the confusing alternative: ‘Cholesterol drug statins should be given to millions more, [National Health Service (NHS)] guidance says’ – The Guardian.[5] We live in an era of patient autonomy; the idea being to involve our patients more in their care. All well and good, and certainly better than the paternalistic attitude that was prevalent a few decades ago, but what is it that we are expecting patients to do? The Mayo Clinic,[3] based on a commentary by three of their physicians published recently in JAMA[6] on the 2013 American College of Cardiology and American Medical Association cardiovascular guidelines,[7] informs the the reader – assumed to be a layperson – that ‘clinicians and patients should use shared decision-making to select individualised treatments based on the new guidelines to prevent cardiovascular disease’. They add, ‘Shared decision-making is a collaborative process that allows patients and their clinicians to make health care decisions together, taking into account the best scientific evidence available, as well as the patient’s values and preferences.’ The new guidelines recommend that anyone with a ‘10-year cardiovascular risk of 7.5% or higher’ is offered statins. But, the article goes on to say, ‘[commentator] Dr Montori cautions that the risk threshold established by the guideline panel is somewhat arbitrary. Instead he recommends that patients and their clinicians use a decision-making tool to discuss the risks and benefits of treatment with statins’. This same learned gentleman adds that rather than routinely prescribing statins to the millions of adults who have at least a 7.5% risk of having a heart attack or stroke within 10 years, clinicians and

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patients should discuss the potential harms and burdens of statins to arrive at a decision that ‘reflects the existing research and the values and context of each patient’. He goes on to say – very tellingly in my opinion – ‘ ... we move the decision-making from the scientist to the patient ... ’. Conversely, the article in The Guardian,[5] arguably read by fairly well-educated people, explains that new NHS guidance says that everyone who has only a low risk of heart disease or stroke should be offered statins, already taken by some 7 million people in England. The National Institute for Health and Care Excellence (NICE), itself rather a paternalistic outfit, is now telling British GPs that they should prescribe – not offer – statins to all those with a 10% risk of heart disease and stroke, dropped from the previous threshold of 20%, and different again from the US threshold of 7.5%.[8] Many doctors find it difficult to interpret guidelines – all based on relatively complex statistical analyses derived from drug trials, many of which used different methods of analysis and all of which talk about percentage risk, relative risk, confidence limits, number needed to treat, hazard ratios, etc. – which, with the best will in the world, most of us cannot interpret easily. Yet, we are asking our patients to make decisions ‘in consultation’ based on tools developed using these statistics? In my opinion, we need to think again about exactly what patient autonomy means and make sure that we don’t simply offer confusion. Bridget Farham

Deputy Editor ugqirha@iafrica.com 1. Elsevier Press Release. New analysis suggests whole diet approach to lower cardiovascular risk has more evidence than low-fat diets. Philadelphia, PA. 5 February 2014. http://www.elsevier.com/about/pressreleases/research-and-journals/new-analysis-suggests-whole-diet-approach-to-lower-cardiovascularrisk-has-more-evidence-than-low-fat-diets#sthash.KRXvrqN3.dpuf (accessed 12 February 2014). 2. Blythman J. Butter is bad – a myth we've been fed by the ‘healthy eating’ industry. The Guardian. 23 October 2013. http://www.theguardian.com/commentisfree/2013/oct/23/butter-bad-saturated-fathealthy-eating-industry (accessed 12 February 2014). 3. Plutowski S. Taking statins to lower cholesterol? New guidelines provide opportunity to discuss options with your doctor. Mayo Clinic News Network. 4 February 2014. http://newsnetwork.mayoclinic. org/discussion/taking-statins-to-lower-cholesterol-new-guidelines-provide-opportunity-to-discussoptions-with-your- (accessed 12 February 2014). 4. Brophy Marcus M, HealthDay. Low-dose statins good option for some heart patients, study finds. Medical Xpress. 10 February 2014. http://medicalxpress.com/news/2014-02-low-dose-statins-goodoption-heart.html (accessed 12 February 2014). 5. Boseley S. Cholesterol drug statins should be given to millions more, NHS guidance says. The Guardian. 12 February 2014. http://www.theguardian.com/society/2014/feb/12/cholesterol-drugstatins-offered-millions-more-nhs-guidance (accessed 12 February 2014). 6. Montori VM, Brito JP, Murad MH. The optimal practice of evidence-based medicine: Incorporating patient preferences in practice guidelines. JAMA 2013;310(23):2503-2504. [http://dx.doi.org/10.1001/ jama.2013.281422] 7. Stone NJ, Robinson J, Lichtenstein AH. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014 (in press). [http://dx.doi.org/10.1161/01.cir.0000437738.63853.7a] 8. NICE. Lipid modification: Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. http://guidance.nice.org.uk/CG/ WaveR/123 (accessed 12 February 2014).

S Afr Med J 2014;104(3):152. DOI:10.7196/SAMJ.8060

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2014/02/25 2:00 PM

EDITOR’S CHOICE

CME: Spina bifida

This month’s education component (and that of the April issue) deals with the problem of spina bifida, which is the most common permanently disabling birth defect. In South Africa (SA), it affects an estimated 0.77 - 6.1/1 000 live births, with higher incidences in rural areas. Genetic and environmental factors act together to cause the condition, which ranges in severity from occult spinal dysraphism, signalled by a dimple (or red marks, hyperpigmented patches, tufts of hair or small lumps) in an infant’s lower back to meningomyelocele (complicated by hydrocephalus in ~80 - 90% of cases). The latter requires surgery within 2 - 3 days of birth to prevent infection and preserve neurological function. We include a review[1] and summaries of full articles (available online).

Adopting a beneficial lifestyle for cardiovascular protection

Opie and Dalby offer us a review[2] of how we might, and encourage our patients to, adopt favourable lifestyles to promote protection from cardiovascular disease (CVD). Their focus is on those studies with ‘hard’ endpoints, namely cardiovascular events and/or mortality. Beneficial lifestyle factors are: non-smoking; exercise for ≥30 min 3 - 5 times per week at moderate walking pace, which notably, is as good as an intensive walking pace; maintaining an ideal body weight on an ideal diet; and a modest alcohol intake. The Mediterranean diet – the beneficial components being high intake of vegetables, legumes, fruits and nuts, cereal, fish, and monounsaturated fats with small amounts of meat, poultry, and high-fat dairy products – reduces mortality by 25%, coronary heart disease deaths by 33%, and cancer by 24%.

Markers for CVD risk in HIV

HIV-related CVD is under-recognised and the clinical assessment thereof is a critical challenge for practitioners, especially in SA. Besides the traditional risk factors for CVD, in people living with HIV there are specific factors that potentially increase the risk for developing CVD: chronic inflammation; metabolic changes associated with the infection; therapy; and lipodystrophy. Van Rooyen et al.[3] offer us cardiometabolic markers to identify CVD risk in HIV-infected black South Africans. Despite the limitations and the relatively small size of this study, these authors propose that by employing lipid ratios and high-density lipoprotein cholesterol (HDL-C) levels for screening, early identification of South Africans living with HIV and at risk for CVD may be achieved. A triglyceride (TG):HDL-C ratio ≥1.49, total cholesterol (TC):HDL-C ratio ≥5.4 and an HDL-C level ≤0.76 mmol/l was indicative of CVD risk.

Rational dosing of colistin

Globally, multidrug-resistant (MDR) Gram-negative bacilli causing nosocomial infections (notably in Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter spp. and Acinetobacter baumannii) have become an important emerging threat. In SA, carbapenem resistance is emerging in K. pneumoniae and Enterobacter spp., while high levels of resistance to all antimicrobial classes are observed among P. aeruginosa and A. baumannii, the latter having emerged as a common pathogen in intensive care units. There are good theoretical grounds to suggest that colistin should be used in combination with other effective antibacterials to treat such infections, especially in patients with normal renal function and when treating bacteria with minimum inhibitory concentrations >1 mg/l. Visser Kift et al.[4] used information gleaned from their systematic review to develop simple recommendations for rational dosing (refer to Table 1 on pg. 185). It is imperative that colistin is

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dosed appropriately to minimise the risk of resistance as it is a lastline agent against MDR Gram-negative bacteria and the pipeline of new drugs in development for these organisms is limited. Access to colistin needs to be made easier in SA, especially in the public sector where carbapenem resistance is increasing.

Improved imaging for diagnosis of childhood TB

An Editorial from Belard et al.[5] alerts us to the value of focused assessment with sonography for HIV/TB (FASH) in children. FASH is a bedside ultrasound that has been developed to improve detection of extrapulmonary tuberculosis (EPTB) in HIV-infected adults, becoming one of the most applied modules in adult emergency rooms in SA. Being well tolerated and non-invasive, it is especially promising and, because of the relatively high frequency of EPTB in young children, its yield in identifying abdominal nodes, hepatic or splenic hypoechoic lesions as well as pericardial, pleural or ascitic effusions – all indications of EPTB – is high. Windows for mediastinal ultrasound include the suprasternal notch and parasternal intercostal spaces, which allow for detection of enlarged lymph nodes in the superior and anterior mediastinum.

Research ethics evolution

Since its original formulation, the Declaration of Helsinki (DOH) [6] has undergone seven revisions and two clarifications, with the most recent revision recently adopted during the World Medical Association Assembly by an overwhelming majority (>75%) of member associations. Some of the main changes include a more readable structure, revised paragraphs on vulnerable groups, Research Ethics Committees, post-study provisions and the introduction of compensation for research-related injuries and a specific reference to biobanks. As it reaches its 50th anniversary in 2014, the DOH remains one of the most authoritative statements on ethical standards for human research in the world. It is a set of principles that has kept up with advances in science and technology.

SA’s progress towards the MDGs

This month’s supplement reveals SA’s progress towards the Millennium Development Goals (MDGs).[7] MDGs 4, 5 and 6 are directly related to health and the functioning of the healthcare system. MDG 4 relates to reducing child mortality, MDG 5 speaks to improving maternal health and MDG 6 to combating HIV/AIDS, malaria and other diseases, such as TB. Targets were set for countries to reach by 31 December 2015, using the year 1990 as a baseline. This supplement has a number of papers that describe the progress that SA has made in reaching some of these targets and some of the continuing challenges that need to be overcome to meet, or at least get as close to reaching, the targets as possible. JS 1. Fieggen G, Fieggen K, Stewart C, et al. Spina bifida: A multidisciplinary perspective on a many-faceted condition. S Afr Med J 2014(3):213-217. [http://dx.doi.org/10.7196/SAMJ.8079] 2. Opie LH, Dalby AJ. Cardiovascular prevention: Lifestyle and statins – competitors or companions? S Afr Med J 2014;104(3):168-173. [http://dx.doi.org/10.7196/SAMJ.7942] 3. Van Rooyen JM, Fourie CMT, Steyn HS, et al. Cardiometabolic markers to identify cardiovascular disease risk in HIV-infected black South Africans. S Afr Med J 2014;104(3):195-199. [http://dx.doi. org/10.7196/SAMJ.7739] 4. Visser Kift E, Maartens G, Bamford C. Systematic review of the evidence for rational dosing of colistin. S Afr Med J 2014;104(3):183-186. [http://dx.doi.org/10.7196/SAMJ.7011] 5. Bélard S, Andronikou S, Pillay T, Grobusch MP, Zar HJ. New imaging approaches for improving diagnosis of childhood tuberculosis. S Afr Med J 2014;104(3):181-182. [http://dx.doi.org/10.7196/SAMJ.7984] 6. Dhai A. The research ethics evolution: From Nuremberg to Helsinki. S Afr Med J 2014;104(3):178-180. [http://dx.doi.org/10.7196/SAMJ.7864] 7. Pillay Y, Barron B. Progress towards the Millennium Development Goals in SA. S Afr Med J 2014;104(3 Suppl 1):223. [http://dx.doi.org/10.7196/SAMJ.7924] 8. Pentz A, Becker P, Masekela R, Coetzee O, Green RJ. The impact of chronic pseudomonal infection on pulmonary function testing in individuals with cystic fibrosis in Pretoria, South Africa. S Afr Med J 2014;104(3):191-194. [http://dx.doi.org/10.7196/SAMJ.7222]

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CORRESPONDENCE

African mass circumcision programmes: A dangerous distraction

To the Editor: Evidence of the futility of mass circumcision campaigns to reduce HIV sexual transmission in sub-Saharan Africa (SSA) has been outlined in the SAMJ by former Editor-in-Chief, Prof. Ncayiyana.[1] The claim is based on three randomised controlled trials (RCTs) in South Africa, Uganda, and Kenya that circumcision reduces men’s risk for HIV by ~60%.[2,3] Numerous flaws in these RCTs included: inadequate equipoise; researcher and participant expectation bias; selection bias; inadequate blinding; problematic randomisation; lead-time bias; attrition bias/ participants lost to follow-up; early termination; and failure to investigate non-sexual transmission – all of which exaggerated treatment effects.[4,5] Overlooked data from at least one of these trials suggest that circumcision provided no protection at all. In the Ugandan femaleto-male trial, HIV incidence among genitally intact men who waited 10 min after coitus to clean their penis (0.39/100 person years (PYs)) was less than that among all circumcised men (0.66/100 PYs).[6,7] When results from the other two trials are adjusted for the known sources of error bias, the estimated relative reduction in HIV risk in these trials is also considerably less than the reported 60% (and the absolute risk reduction falls commensurately) (personal communication – R S van Howe, 12 March 2011).[4,5] The World Health Organization (WHO)/Joint United Nations Programme on HIV/AIDS (UNAIDS) accepted the claims of the three RCTs just weeks after publication of two RCTs in the Lancet in 2007.[8] These organisations continue to promote circumcision[9] despite evidence that intact men who wipe their penis following sex have a lower risk for HIV infection than circumcised men,[7] and the results of an Ugandan RCT,[10] which reported a 61% relative increase (6% absolute increase) in male-to-female HIV sexual transmission from circumcised men v. genitally intact men.[4] There are serious weaknesses in the management of the three RCTs – not asking, not reporting, not tracing and unethical practices.[11,12] Based on evidence reported by the study teams, up to half of the incident HIV infections observed in the three trials appear to be non-sexually transmitted, and may have been acquired through skin-piercing procedures (including healthcare procedures and cosmetic services).[11,12] Moreover, epidemiological data reveal a higher prevalence of HIV infection among circumcised men than genitally intact men in at least seven SSA countries, including Cameroon, Rwanda, Lesotho, Malawi, Tanzania, Ghana, and Swaziland.[4,11] To ascertain what is driving the HIV epidemic, infections must be traced to their sources. The RCTs’ failure to trace infections is a common omission among many studies of HIV in Africa.[11,12] These persistent failures raise questions: why have experts not looked for and stopped nosocomial transmission; why do medical organisations not warn Africans about healthcare dangers, but seem willing to stigmatise Africans as a group, and HIV-positive African adults individually, for alleged sexual promiscuity?[11,12] To date, no one can explain how sexual transmission could produce such horrible rates of HIV infection in SSA countries, where surveys find that heterosexual behaviour is similar to or even less risky than in Europe or the UK.[11] Decades ago we could have moved beyond speculation to explain Africa’s HIV epidemics, if researchers had simply traced infections to their sources.[11,12] Instead of reducing the sexual transmission of HIV, as claimed by WHO/UNAIDS, male circumcision programmes may actually risk increasing HIV infections owing to the use of inadequately sterilised skin-piercing instruments, premature resumption of sexual intercourse as early as 3 weeks following circumcision[13] (‘ … 30% of men

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undergoing circumcision had sex within the healing period, then more new HIV infections in women would be generated than averted.’[14]) We concur with Prof. Ncayiyana’s review of the evidence.[15] In our opinion, mass circumcision programmes in SSA are a dangerous distraction and WHO/UNAIDS should abandon their efforts to promote male circumcision. Gregory J Boyle

Independent research consultant, Queensland, Australia gregb_322@hotmail.com

George Hill

Vice-President of Bioethics and Medical Science, Doctors Opposing Circumcision, Seattle, USA 1. Ncayiyana DJ. The illusive promise of circumcision to prevent female-to-male HIV infection – not the way for South Africa. S Afr Med J 2011;101(11):775-777. 2. Kesinger M, Millard PS. Voluntary male medical circumcision. S Afr Med J 2012;102(3):123-124. 3. Venter F, Rees H, Pillay Y, et al. The medical proof doesn’t get much better than VMMC. S Afr Med J 2012;102(3):124-125. 4. Boyle GJ, Hill G. Sub-Saharan African randomised clinical trials into male circumcision and HIV transmission: Methodological, ethical and legal concerns. J Law Med 2011;19(2):316-334. 5. Van Howe RS, Storms MR. How the circumcision solution in Africa will increase HIV infections. J Pub Health Afr 2011;2:e4. [http://dx.doi.org/10.4081/jphia.2011.e4] 6. Gray RH, Kigozi G, Serwadda D, et al. Male circumcision for HIV prevention in men in Rakai Uganda: A randomised trial. Lancet 2007;369(9562):657-666. [http://dx.doi.org/10.1016/S01406736(07)60313-4] 7. Makumbi FE, Gray RH, Wawer M, et al. Male post-coital penile cleansing and the risk of HIVacquisition in rural Rakai district, Uganda. Paper presented at the 4th International AIDS Society Conference, Sydney, Australia, 22 - 25 July 2007. http://www.ias2007.org/pag/Abstracts. aspx?SID=55&AID=5536 (accessed 6 March 2012). 8. World Health Organization. WHO and UNAIDS Announce Recommendations from Expert Consultation on Male Circumcision for HIV Prevention. 28 March 2007. http://www.who.int/hiv/ mediacentre/news68/en/index.html (accessed 6 May 2012). 9. WHO/UNAIDS. Joint Strategic Action Framework to Accelerate the Scale-Up of Voluntary Medical Male Circumcision for HIV Prevention in Eastern and Southern Africa 2012-2016. 1 November 2011. http://www.who.int/hiv/pub/strategic_action2012_2016/en/index.html (accessed 6 May 2012). 10. Wawer MJ, Makumbi F, Kigozi G, et al. Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: A randomised controlled trial. Lancet 2009;374(9685):229-237. [http://dx.doi.org/10.1016/S0140-6736(09)60998-3] 11. Gisselquist D. Points to consider: Responses to HIV/AIDS in Africa, Asia, and the Caribbean. London: Adonis & Abbey, 2007. 12. Gisselquist D, Potterat JJ, St Lawrence JS, et al. How to contain generalized HIV epidemics? A plea for better evidence to displace speculation. Int J STD AIDS 2009;20(7):443-446. [http://dx.doi. org/10.1258/ijsa.2009.009003] 13. KENYA: Male Circumcision Programme Suffers Setback. IRIN News, 2 March 2012. http://www. plusnews.org/report.aspx?reportid=94992 (accessed 5 March 2012). 14. Hewett PC, Hallett TB, Mensch BS, et al. Sex with stitches: Assessing the resumption of sexual activity during the postcircumcision wound-healing period. . AIDS 2012;26(6):749-756. [http://dx.doi. org/10.1097/QAD.0b013e32835097ff] 15. Ncayiyana DJ. Voluntary male medical circumcision – Dan Ncayiyana responds. S Af Med J 2012;102(3):125-126.

S Afr Med J 2014;104(3):154. DOI:10.7196/SAMJ.5978

Reducing the surgical complications of smoking by cotinine testing

To the Editor: We read with interest the edition of SAMJ (November 2013) dedicated to smoking, arguably the most significant modifiable cause of death and disease. One of the areas not addressed relates to the impact of smoking in the context of surgery. It is well recognised that smoking increases the risk of overall complications, arrhythmias, thrombotic episodes, pneumonia, infection, wound healing complications and prolonged hospital stays, as well as the need for further surgery.[1-3] As surgeons we are frequently held responsible for these complications, and yet the decision to undertake the procedure at all should often be scrutinised, especially in the elective setting, rather than just the technical execution thereof. Use of cotinine, a metabolite of nicotine, has been proposed to detect active smokers who claim not to smoke. This group may comprise as many as 34% of current smokers, which is not surprising considering the deceptive behaviour of people with addictions in general – in other words, up to a third of active smokers may lie about their smoking status. It has been demonstrated that smokers who

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developed wound healing complications had higher levels of cotinine than those who did not when tested peri-operatively.[1-3] A study by Coon et al.[1] demonstrated that patients who claimed to have quit smoking were particularly likely to be deceitful, and a cost saving strategy may be employed whereby only this group is tested. In their cohort of plastic surgery patients, the test would detect 1 out of 10 ‘former’ smokers, as opposed to 1 in 66 of all patients in a selfreported non-smoking population. We believe that routine or selective serum or urine cotinine testing will enable us to stratify risk in both elective and reconstructive scenarios. Many procedures will therefore be cancelled, or at least delayed pending smoking cessation, which may have remarkable cost benefits for health systems, especially one as stretched as ours. Theatre time has been reduced in recent years despite increasing demand, and funding has inexplicably been diverted away from specialist surgical services. The onus is on surgeons to be far stricter when applying absolute and relative contraindications, such as smoking, to elective surgery. Denying a patient a procedure s/he requires may also provide just the incentive needed to stop smoking. D J Potgieter G dos Passos C E Price A D Rogers

Division of Plastic, Reconstructive and Maxillofacial Surgery, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa rogersadr@gmail.com 1. Coon D, Tiffaha S, Christensen J, Bonawitz SC. Plastic surgery and smoking: A prospective analysis of incidence, compliance, and complications. Plast Reconstr Surg 2013;131(2):385-393. [http://dx.doi. org/10.1097/PRS.0b013e318277886a] 2. Marin VP, Ptynia KB, Langstein HN, et al. Serum cotinine concentration and wound complication in head and neck reconstruction. Plast Reconstr Surg 2008;121(2):451-457. [http://dx.doi.org/10.1097/01. prs.0000297833.53794.27] 3. Rohrich RJ, Coberly DM, Krueger JK, Brown SA. Planning elective operations on patients who smoke: Survey of North American plastic surgeons. Plast Reconstr Surg 2002;109(1):350-355. [http://dx.doi. org/10.1097/00006534-200201000-00057]

S Afr Med J 2014;104(3):154-155. DOI:10.7196/SAMJ.7740

A path to full-service contracting with general practitioners under National Health Insurance

To the Editor: National Health Insurance (NHI) is important in South Africa (SA). On 27 November 2013, during a lecture at the University of the Witwatersrand, the National Minister of Health spoke about the ‘Americanisation’ of healthcare. In discussing service contracts for general practitioners (GPs), he was open but cautious: ‘How will we monitor them?’ There is a perception that GPs are poorly equipped and badly trained, and will limit patient access when they are faced with high volumes. There is also concern that the current public service will be ‘destroyed’ by competition with GPs. ‘Americanisation’ is indeed evident in SA, with hospital specialist claims having increased from 35.3% in 1992 to 60% in 2012. The GP’s share declined from 11.5% in 1992 to 6.3% in 2012.[1,2] The population is also becoming ‘Americanised’ in terms of their expectations for specialist care. The benefits of a strong primary care service have been abundantly evident for a while. Primary care physicians reduce mortality compared with other specialists. Family physicians offer more easily accessed services at a lower cost, with fewer visits and fewer prescriptions.[3] Many criticise the UK’s National Health Service (NHS) for perceived poorer quality compared with services offered in the USA, but fail to see the social injustices of the latter. This is the

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challenge in SA: to achieve the best society-wide outcome for health spend. I support the Minister in his crusade to achieve that. What counts in strong primary care is a combination of universal financial coverage, low or no co-payment, an equitable distribution of resources (or attempts at equitable distribution), and comprehensiveness of service. These produce greater first-contact access/use, better person-focused care over time, an expanded range of services, and better co-ordination of care.[3] This is the missing element in SA’s present primary care system, as nurses ‘push queues’.[4] Patients either bypass ‘nurse-driven’ clinics to go to hospitals, or visit GPs. Almost half of the out-of-pocket expenditure of R30 billion by South Africans in 2009 was for private GPs.[5] Health professionals do not want to work in public clinics because of poor working conditions and poor career paths.[6] The Green Paper on NHI[7] has usefully spoken of a capitated primary care system where GPs are included as providers, yet the National Department of Health seems equivocal about them, with GPs facing mistrust and misrepresentation. GPs in SA appear willing to provide services at almost the same prices as the Johannesburg Health District, the largest metropolitan health district in SA.[8] The Minister should consider starting implementation of NHI with re-assembling the primary healthcare (PHC) service – both public and private – into one robust ‘public’ service with strong regulatory oversight. NHI funds appear to be unspent, and government could start contracting with GPs in pilots on this basis. GPs could be asked to take on a defined population of say 10 000 people in pilot districts and to service patients from this population in their own premises. They would, of course, add nurses to their teams. GPs could implement the PHC outreach programme with community health workers and task shifting, overseen by GPs themselves, and would respond to utilisation risk with strong preventive-promotive efforts and better practice management, rather than limiting access. [8] As part of the public sector, these GPs should be subsidised for laboratory tests according to National Health Laboratory Service prices, and permitted to buy drugs according to a state-determined extended PHC formulary, or directly from contracted companies or wholesalers in line with on the State tenders. Grants for facilities and information technology should receive consideration. A broad-based black economic empowerment process could guide all contracting and procurement. The NHS in the UK was implemented in a similar simple manner in the late 1940s, with just one contract signed per GP upon entering practice, before the Labour government implemented performance management in the 1990s. How would GPs be monitored? This could be done in the same way as in the current public service. Accountability can be made stronger with a contract that can be terminated on non-performance, and especially in the case of fraudulent use of drugs/laboratory tests. Strong performance management is needed, but what is not necessary is a slew of worthless indicators. The focus should rather be on outcomes. A third of the capitation should be at risk, based simply on one to four indicators in each of the following categories: Millennium Development Goals; clinical disease progression; patient behaviour change; and patient satisfaction (especially in relation to waiting times). Professionalism and peer review (as part of practice-based mandatory postgraduate training in family medicine) need to be built in as part of the regulatory approach in the contracting process. The two big risks to capitation are utilisation and referrals. Pilots should test these and other important parameters such as demographic disease profiles, costs of medicines and materials, optimal staff mix, training, group practice, performance management and out-of-pocket expenditure. There are enough GPs in SA: 5 000 (of the 10 000 practising) could cover the country’s needs.

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Blood pressure elevator. What the doctor ordered.

As a member of the South African Medical Association you can expect to receive special treatment. Simply inform your nearest Mercedes-Benz dealer of your SAMA status to take advantage of an exclusive opportunity that includes As a memberservice of the bookings, South African Medical Association, you couldplan, qualify offers*, a guaranteed preferential a 6 year/100000km maintenance andfor of exclusive course, guaranteed discounts* and other 3-day service booking as well as PremiumDrive, our 6 year/100 000km maintenance plan. To take advantage special offers. of this outstanding opportunity, inform your nearest dealer of your SAMA status. *Not in conjunction with other Mercedes-Benz Fleet Programmes/Offers. Excludes AMG and Limited Edition models. Vehicle specifications may varyMercedes-Benz for the South African market. *Not in conjunction with other Fleet Programmes/Offers. Excludes AMG and Limited Edition models. Vehicle specifications may vary for the South African market.

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The government should reward early adopters of this suggested re-engineering of PHC and incentivise GPs to later manage the overall cost spiral of specialist-hospital referrals. Government needs to move quickly to remove the referee-player conflict by setting up roles separately in pilot districts. Current facilities need to be strengthened to function as decentralised, independent providers (perhaps as community health centre-clinic complexes) and respond to patient needs, as they compete with GP providers. Competition will prove healthy. The current district health management should focus on public health strategy, programmes and outcomes, while the Office for Standards Compliance checks on quality and outcomes. There is even a role for current medical administrators, who might be subcontracted by the NHI to manage provider contracts and fee-for-service care at district level and account to the District Health Authority. With an election coming up, these are the kind of debates we should be having. Shabir Moosa

Department of Family Medicine, Johannesburg Health District, and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa shabir@drmoosa.co.za 1. Council of Medical Schemes. CMS Annual Report 1992-1993. Pretoria: CMS, 1993. 2. Council of Medical Schemes. CMS Annual Report 2012-2013. Pretoria: CMS, 2013. 3. Starfield B. Primary care: An increasingly important contributor to effectiveness, equity, and eﬃciency of health services. SESPAS report 2012. Gac Sanit 2012;26(5):25-31. [http://dx.doi.org/10.1016/j. gaceta.2011.10.009] 4. Moosa S, Gibbs A. A focus group study of primary health care in Johannesburg Health District, South Africa: ‘We are just pushing numbers’. S Afr Fam Pract 2014 (in press). 5. McIntyre D. Private sector involvement in funding and providing health services in South Africa: Implications for equity and access to health care. Harare: Equinet, 2010. 6. Moosa S, Wojczewski S, Hoffman K, et al. Why there is an inverse primary-care law in Africa. Lancet Global Health 2013;1(6):e332-e333. [http://dx.doi.org/10.1016/S2214-109X(13)70119-0] 7. National Department of Health. National Health Insurance in South Africa. Pretoria: NDoH, 2011. 8. Moosa S, Luiz J, Carmichael T. Introducing a national health insurance system in South Africa: A general practitioner’s bottom-up approach to costing. S Afr Med J 2012;102(10):794-797. [http:// dx.doi.org/10.7196/SAMJ.6072]

S Afr Med J 2014;104(3):155-156. DOI:10.7196/SAMJ.7719

Primary prevention of rheumatic fever in children: Key factors to consider

To the Editor: We applaud the efforts by Irlam et al.[1,2] to conduct a cost-effectiveness analysis of primary prevention of rheumatic fever (RF) in children. The authors used a Markov decision analysis cohort model to assess seven different treatment strategies for children presenting with sore throat. A particular strength of the study was the inclusion of costs relating to secondary prevention and development of chronic rheumatic heart disease (RHD). The authors concluded that using clinical criteria for the diagnosis of pharyngitis without culturing for group A streptococci is the most cost-effective intervention for the prevention of RF and RHD in settings where these diseases are endemic.[1] However, we believe that they have not fully considered several important issues. The authors chose to use a clinical decision rule to diagnose group A streptococcal pharyngitis in children presenting with sore throat that requires only two of three features to be present for treatment to be initiated: enlarged cervical nodes; absence of rash; and absence of rhinitis.[3] This clinical decision rule is highly sensitive (92%), but is poorly specific (38%), which means that while only 8/100 children would be missed, 62/100 children with sore throat would receive antibiotic treatment unnecessarily. While this strategy may be better than treating all, we believe that the authors have underappreciated the importance of the unintended consequences resulting from overuse of antibiotics, particularly antibiotic resistance. The authors

correctly point out that resistance to penicillin in group A streptococci has never been reported; however, they did not consider the impact of widespread use of penicillin on drug resistance developing in other bacteria. A key example is the promotion of penicillin-resistant Streptococcus pneumoniae, a worldwide health problem that was originally described in South Africa (SA), where it is has been strongly associated with injudicious use of antibiotics in patients with viral infections.[4-6] Some of the probability assumptions used in the model may not be applicable to most settings. A key issue in this study was the incidence of sore throat used (8.7/1 000 child years, 0.87%). This figure, derived from an RF registry in the Vanguard community, is extremely low compared with published data, which suggest that sore throat occurs in at least 33% of children/year.[7-9] The study used a figure of 15% for the prevalence of group A streptococci in the pharynx; this means that only 1 - 2 of every 1 000 children/ year experience a group A streptococcal sore throat (1.3/1 000 child years). Data from other RF-endemic countries suggest a far higher incidence of group A streptococcal sore throat by a factor of over 100 times: 147/1 000 child years in Fiji and up to 950/1 000 child years in India.[9,10] The very low incidence of both sore throat and group A streptococcal-positive sore throat reported by Irlam et al. suggests that many SA children do not present for care, which is a concern for a public healthcare programme that relies on treatment of sore throat. In addition, the use of such a low incidence of group A streptococcal sore throat may have underestimated the expected costs from associated complications. The study did not include rapid group A streptococcal antigen tests in the Markov model on the basis that these tests have ‘low sensitivity’. While the sensitivity of a few of these tests is low, the majority of modern tests have sensitivity >85% and nearly all have high specificity (>95%).[11] A number of immunoassay rapid tests and the majority of the newer molecular rapid tests have sensitivity >90%. These figures compare very favourably with the clinical decision rule outlined in the study, particularly because the higher specificity of rapid tests would substantially reduce overdiagnosis. Rapid tests have decreased in cost over time, with many being cheaper than culture, and potentially applicable to low-income settings. Rapid tests have clear advantages for the diagnosis of group A streptococcal pharyngitis because an on-the-spot clinical decision can be made. This is important because a considerable portion of the cost attributed to culture in the study by Irlam et al. was the cost of a return visit, which would be obviated by a rapid test. We believe that a low-cost rapid test that has high sensitivity and a fast turnaround time should be a research priority for the RF research community, particularly in low-income settings. Diagnosis and treatment of group A streptococcal pharyngitis is important in the control of RF and RHD. We agree with the authors that in resource-poor populations, the very ones that are most affected by rheumatic disease, a pragmatic approach to the diagnosis of group A streptococcal pharyngitis that minimises cost is necessary. However, factors other than cost, such as antibiotic resistance and the likelihood of the target population presenting with sore throat, should also be considered when developing clinical guidelines and public health interventions.

B p u n n

T n f t t i f a a s

U b t m f b

Andrew Steer

Centre for International Child Health, Department of Paediatrics, and Department of General Medicine, Royal Children’s Hospital, Melbourne, Australia; Group A Streptococcal Research Group, Murdoch Childrens Research Institute, Melbourne, Australia andrew.steer@rch.org.au

A S

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Margie Danchin

Department of General Medicine, Royal Children’s Hospital, Melbourne, Australia; Group A Streptococcal Research Group, and Vaccine and Immunisation Research Group, Murdoch Childrens Research Institute, Melbourne, Australia 1. Irlam JH, Mayosi BM, Engel ME, Gaziano TA. A cost-effective strategy for primary prevention of acute rheumatic fever and rheumatic heart disease in children with pharyngitis. S Afr Med J 2013;103(12):894-895. [http://dx.doi.org/10.7196/SAMJ.7244] 2. Irlam J, Mayosi BM, Engel M, Gaziano TA. Primary prevention of acute rheumatic fever and rheumatic heart disease with penicillin in South African children with pharyngitis: A costeffectiveness analysis. Circ Cardiovasc Qual Outcomes 2013;6(3):343-351. [http://dx.doi.org/10.1161/ CIRCOUTCOMES.111.000032] 3. Steinhoff MC, Walker CF, Rimoin AW, Hamza HS. A clinical decision rule for management of streptococcal pharyngitis in low-resource settings. Acta Paediatr 2005;94(8):1038-1042. [http://dx.doi. org/10.1111/j.1651-2227.2005.tb02042.x] 4. Appelbaum PC, Bhamjee A, Scragg JN, Hallett AF, Bowen AJ, Cooper RC. Streptococcus pneumoniae resistant to penicillin and chloramphenicol. Lancet 1977;2(8046):995-997. [http://dx.doi.org/10.1016/ S0140-6736(77)92892-6] 5. Jacobs MR, Koornhof HJ, Robins-Browne RM, et al. Emergence of multiply resistant pneumococci. N Engl J Med 1978;299(14):735-740. [http://dx.doi.org/10.1056/NEJM197810052991402] 6. Goldstein FW. Penicillin-resistant Streptococcus pneumoniae: Selection by both beta-lactam and nonbeta-lactam antibiotics. J Antimicrob Chemother 1999;44(2):141-144. 7. Danchin MH, Rogers S, Kelpie L, et al. Burden of acute sore throat and group A streptococcal pharyngitis in school-aged children and their families in Australia. Pediatrics 2007;120(5):950-957. [http://dx.doi.org/10.1542/peds.2006-3368] 8. El-Kholy A, Sorour AH, Houser HB, et al. A three-year prospective study of streptococcal infections in a population of rural Egyptian school children. J Med Microbiol 1973;6(1):101-110. [http://dx.doi. org/10.1099/00222615-6-1-101] 9. Nandi S, Kumar R, Ray P, Vohra H, Ganguly NK. Group A streptococcal sore throat in a periurban population of northern India: A one-year prospective study. Bull World Health Organ 2001;79(6):528533. 10. Steer AC, Jenney AWJ, Kado J, et al. Prospective surveillance of streptococcal sore throat in a tropical country. Pediatr Infect Dis J 2008;28(6):477-482. [http://dx.doi.org/10.1097/INF.0b013e318194b2af] 11. Gerber MA, Shulman ST. Rapid diagnosis of pharyngitis caused by group A streptococci. Clin Microbiol Rev 2004;17(3):571-580. [http://dx.doi.org/10.1128/CMR.17.3.571-580.2004]

Irlam et al. respond: We appreciate the interest of Steer and Danchin in our article,[1] and wish to respond to the key issues they raise. Their concern about the overuse of penicillin on the resistance of bacteria other than group A streptococci is certainly a valid one that requires close attention. SA has had one of the highest reported rates of pneumococcal penicillin resistance in the world,[2] but the full impact of resistance in S. pneumoniae in our setting needs to be properly assessed.[3] While overuse of penicillin for the treatment of suspected group A streptococcal pharyngitis may affect pneumococcal resistance rates, this needs to be weighed against the risk of a missed streptococcal throat progressing to acute rheumatic fever (ARF). The very low incidence of sore throat (8.7/1 000 child years) and prevalence of group A streptococcal-positive sore throat (15% in children presenting with sore throat, 0.13% overall) in the Vanguard Study Area population between June 2008 and June 2010 may largely be a result of under-presentation at urban primary healthcare clinics in this setting. Incidence data for this study were derived from all the clinics covering a defined local geographical area of Cape Town. While patients attending private medical facilities would have been missed, it is expected that this will be a very small number, because most people in the area use public sector healthcare facilities. As we showed in our original paper, however, the higher the incidence, the more cost-effective either the clinical decision rule or ‘Treat All’ strategies become, which makes our results even more applicable to regions with higher incidence.[4] When we used rates similar to those suggested by Steer and Danchin, the strategy of ‘Treat All’ becomes preferable. Nevertheless, in our paper we call for wider efforts to complement this opportunistic, cost-effective, passive strategy of RF and RHD prevention at primary healthcare clinics. For example, active screening for RHD using portable echocardiography and computer-assisted auscultation followed by secondary prophylaxis is currently being undertaken and evaluated in schools in the same community.[5] Our primary reason for the exclusion of rapid group A streptococcal antigen tests in the Markov model was that these tests are not currently used in public sector primary healthcare settings in SA. We agree that

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a low-cost rapid test with high sensitivity and a fast turnaround time should be a research priority that may, in the light of cost-effectiveness modelling and large-scale evaluation studies, prove to be a very useful addition to updated clinical guidelines for the management of RF and RHD in the public sector in SA. Funding is currently being sought to conduct a study on the utility of rapid streptococcal tests. We thank Steer and Danchin for their critique. We share their concern for safety and effectiveness as well as cost in developing clinical guidelines and public healthcare interventions for early prevention of ARF and RHD. James H Irlam

Primary Health Care Directorate, University of Cape Town, South Africa james.irlam@uct.ac.za

Bongani M Mayosi Mark E Engel

Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa

Thomas A Gaziano

Department of Cardiology, Brigham and Women’s Hospital, Boston, USA

Andrew C Whitelaw

Department of Microbiology, Tygerberg Hospital and National Health Laboratory Service, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa 1. Irlam JH, Mayosi BM, Engel ME, Gaziano TA. A cost-effective strategy for primary prevention of acute rheumatic fever and rheumatic heart disease in children with pharyngitis. S Afr Med J 2013;103(12):894-895. [http://dx.doi.org/10.7196/SAMJ.7244] 2. Felmingham D, Feldman C, Hryniewicz W, et al. Surveillance of resistance in bacteria causing community-acquired respiratory tract infections. Clin Microbiol Infect 2002;8(Suppl 2):12-42. [http:// dx.doi.org/10.1046/j.1469-0691.8.s.2.5.x] 3. Crowther-Gibson P, Govender N, Lewis DA, et al. Part IV. GARP: Human infections and antibiotic resistance. S Afr Med J 2011;101(8):567-578. 4. Irlam J, Mayosi BM, Engel M, Gaziano TA. Primary prevention of acute rheumatic fever and rheumatic heart disease with penicillin in South African children with pharyngitis: A cost-effectiveness analysis. Circ Cardiovasc Qual Outcomes 2013;6(3):343-351. [http://dx.doi.org/10.1161/CIRCOUTCOMES.111.000032] 5. Engel ME, Zuhlke LJ, Robertson K. Rheumatic fever and rheumatic heart disease: Where are we now in South Africa? SA Heart 2009;6(1):20-23.

S Afr Med J 2014;104(3):156-157. DOI:10.7196/SAMJ.7880

A balanced approach to interpreting the WHIRCDMT

To the Editor: I read with interest the critique of the Women’s Health Initiative Randomized Controlled Dietary Modification Trial (WHIRCDMT)[1] by Prof. Tim Noakes.[2] His critique focused on the varying incidence of cardiovascular outcomes between women with and without a history of cardiovascular disease (CVD), and justly called for more discussion and transparency with respect to these findings. The latter half of the critique, however, unfairly portrays the low-fat dietary intervention as deleterious for weight gain and the development of diabetes mellitus (DM). First, Prof. Noakes should be applauded for raising awareness around what many researchers and clinicians would characterise as the disappointing findings of the WHIRCDMT. Additionally, his discussion on the potentially negative effects of a low-fat diet in women with prior history CVD or DM is illuminating. Evidence from other studies supports the idea that reducing dietary fat without paying attention to the composition of foods substituting it can have deleterious effects.[3] Several of the criticisms of the WHIRCDMT, however, were exaggerated or misleading. Specifically, Prof. Noakes states that for women randomised to the intervention group, ‘the leanest women

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at the start of the trial gained weight on the low-fat diet’.[2] While the leanest women in the intervention group did indeed gain weight, this was also true for the leanest women in the control group.[4] In fact, women in the intervention group had significantly lower weight than those in the control group among women with a body mass index <25 kg/m2 at baseline.[4] May this result simply reflect that the leanest women were more susceptible to weight gain, regardless of assigned diet? It is important to remember that this trial was conducted at the same time that prevalence of obesity in the US increased,[5] and increases in weight for a proportion of participants would be expected due to myriad changes in the environment. A second issue with Prof. Noakes’ critique is the statement that, ‘those with the least insulin resistance at the start of the trial were at greater risk of developing type 2 DM if assigned to the low-fat diet’.[2] He is correct that there was a significant interaction between intervention assignment and glycaemic control markers (insulin and homeostasis model assessment, insulin resistance).[6] In truth, however, there were no detectable differences between individual tertiles,[6] which limits the ability to make causative statements regarding subgroups. What is more, the absolute counts in the lowest tertiles were extremely small, mostly because data on glycaemic measures were available for only 2 816/45 887 participants.[6] Moreover, the true significance of any subgroup analysis should be viewed with scepticism. In effect, these analyses remove the protection from confounding that randomisation provides, and unless subgroup analyses are done only on a few, pre-specified endpoints, they can lead to erroneous conclusions.[7] Thus, Prof. Noakes’ statement seems, at a minimum, overly confident regarding the effects of a low-fat dietary intervention for the primary prevention of DM. Prof. Noakes’ critique of the WHIRCDMT highlights several issues with the prescription of a low-fat diet, including the variability of

effectiveness for different groups in the population. In particular, individuals with pre-existing CVD and DM may experience harmful effects when attempting to follow a low-fat diet. Nevertheless, the WHIRCDMT does not provide high-quality evidence that a lowfat diet emphasising fruits, vegetables and whole grains contributes disproportionately to the development of DM and weight gain. While it can be agreed the WHIRCDMT was disappointing in many ways for researchers and clinicians alike, a more balanced approach to the interpretation of the results is warranted. Patrick B Wilson

School of Kinesiology, University of Minnesota, Minneapolis, USA wilso733@umn.edu

1. Howard BV, Van HL, Hsia J, et al. Low-fat dietary pattern and risk of cardiovascular disease: The Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006;295(6):655666. [http://dx.doi.org/10.1001/jama.295.6.655] 2. Noakes TD. The Women’s Health Initiative Randomized Controlled Dietary Modification Trial: An inconvenient finding and the diet-heart hypothesis. S Afr Med J 2013;103(11):824-825. [http://dx.doi. org/10.7196/SAMJ.7343] 3. Jakobsen MU, O’Reilly EJ, Heitmann BL, et al. Major types of dietary fat and risk of coronary heart disease: A pooled analysis of 11 cohort studies. Am J Clin Nutr 2009;89(5):1425-1432. [http://dx.doi. org/10.3945/ajcn.2008.27124] 4. Howard BV, Manson JE, Stefanick ML, et al. Low-fat dietary pattern and weight change over 7 years: The Women’s Health Initiative Dietary Modification Trial. JAMA 2006;295(1):39-49. [http://dx.doi. org/10.1001/jama.295.1.39] 5. Mokdad AH, Serdula MK, Dietz WH, et al. The spread of the obesity epidemic in the United States, 1991-1998. JAMA 1999;282(16):1519-1522. [http://dx.doi.org/10.1001/jama.282.16.1519] 6. Tinker LF, Bonds DE, Margolis KL, et al. Low-fat dietary pattern and risk of treated diabetes mellitus in postmenopausal women: The Women’s Health Initiative Randomized Controlled Dietary Modification Trial. Arch Intern Med 2008;168(14):1500-1511. [http://dx.doi.org/10.1001/archinte.168.14.1500] 7. Rothwell PM. Subgroup analysis in randomised controlled trials: Importance, indications, and interpretation. Lancet 2005;365(9454):176-186. [http://dx.doi.org/10.1016/S0140-6736(05)17709-5]

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This month in the SAMJ ... Robin Wood*,† is Professor of Medicine and Director of the Desmond Tutu HIV Centre at the Institute of Infectious Diseases and Molecular Medicine, University of Cape Town. He has authored or co-authored 10 book chapters and over 350 articles in peer-reviewed journals; served as a member of the editorial boards of many prominent national and international peer-reviewed journals. He is a visiting scientist at Harvard Medical School and member of the scientific advisory board of the US Presidents Emergency Plan for AIDS Relief and the International Partnership for Microbicides.

* Wood R, Bekker L-G. Isoniazid preventive therapy for tuberculosis in South Africa: An assessment of the local evidence base. S Afr Med J 2014;104(3):174-177. [http://dx.doi.org/10.7196/7968] † Kaplan R, Caldwell J, Bekker L-G, et al. Integration of TB and ART services fails to improve TB treatment outcomes: Comparison of ART/TB primary healthcare services in Cape Town, South Africa. S Afr Med J 2014;104(3):204-209. [http://dx.doi.org/10.7196/7696]

Linda-Gail Bekker*,† is Professor of Medicine and the Deputy Director of the Desmond Tutu HIV Centre at the Institute of Infectious Diseases and Molecular Medicine, University of Cape Town (UCT). Her doctoral studies examined the host response to tuberculosis (TB) in the presence of HIV co-infection. Her research interests span the optimisation of prevention, care and management of TB, HIV and related infections. She has (co-) authored more than 200 papers in peer-reviewed journals. She is principle investigator of the US National Institutes of Health-funded UCT Clinical Trials Unit and serves on numerous international scientific working groups and committees including the US Presidents Emergency Plan for AIDS Relief Scientific Advisory Board. She is President-Elect for the International AIDS Society for 2014. * Wood R, Bekker L-G. Isoniazid preventive therapy for tuberculosis in South Africa: An assessment of the local evidence base. S Afr Med J 2014;104(3):174-177. [http://dx.doi.org/10.7196/7968] † Kaplan R, Caldwell J, Bekker L-G, et al. Integration of TB and ART services fails to improve TB treatment outcomes: Comparison of ART/TB primary healthcare services in Cape Town, South Africa. S Afr Med J 2014;104(3):204-209. [http://dx.doi.org/10.7196/7696]

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From coal-face clinicians to change agents – igniting healthcare innovation Two young Cape Townbased doctors, evoked by the overwhelm they’ve seen at struggling public hospitals, have custom-educated themselves to facilitate pioneering, inclusive healthcare solutions, bringing local patients, healthcare workers and technicians together for the first time. Capetonian Dr Francois Bonnici, who founded the Bertha Centre for Social Innovation and Entrepreneurship (Bertha Centre) at the University of Cape Town (UCT)’s Graduate School of Business (GSB), and Pretoria-born, Dr Lindi van Niekerk, who recently joined him, have just put creative solutions – be they high-tech, low-tech or ‘no-tech’ – at the centre of South Africa (SA)’s healthcare radar. South Africans are known globally for creative, highly appropriate and effective custombuilt solutions in healthcare, ranging from wind-up Doppler ultrasound fetal heart rate monitors, home-based parental care for young tracheotomy patients, to containerbased HIV care for truckers and sex workers on our highways. However, this broad ingenuity has never been formally embraced or framed in an inclusive, philanthropic way – or given a solid platform for expression. Bonnici and Van Niekerk are doing just that – with two successful launch events held in Cape Town at the end of January; the first, a 2-day Healthcare Hackathon, at Groote Schuur Hospital (GSH). Here 60 of 100 shortlisted applicants, including healthcare workers, students, software developers, engineers, entrepreneurs and designers, collaborated and competed in teams to produce a workable prototype – matched with a sustainable business model for showcasing countrywide – with a R15 000 prize up for grabs for the most innovative, practical outcome. The second event, also in Cape Town and a few days later, was an inclusive and carefully thought out Healthcare Innovation Summit, to which a broad but select sweep of delegates, mainly local, but many from across the continent, were invited. Aimed at addressing Africa’s most pressing healthcare needs, topics included ‘collaboratively re-imagining healthcare, opportunities for healthcare innovation, better healthcare design, transforming primary care from

Healthcare game-changers Drs Francois Bonnici and Lindi van Niekerk. Picture: Chris Bateman.

the inside out, navigating the innovation ecosystem and assessing innovation impact’. The centre has also published a Health Innovators Review featuring leading health innovators in SA who have successfully implemented inclusive, effective and affordable solutions that have improved care. A quick assessment of Bonnici and Van Niekerk’s own impact after they ran headlong into major delivery challenges during their public hospital tenures makes for impressive reading and underscores the philanthropic zeal with which they’ve set about their task.

When the personal becomes pragmatic and political

Bonnici graduated top of his UCT Medical School class and his evolution includes a Rhodes scholarship (he was top of his local MBA class and completed a Public Health degree at Oxford), the Namibian public health sector, Mowbray Maternity Hospital (community service), and some paediatric specialisation at Cape Town’s Red Cross War Memorial Children’s Hospital. He left Red Cross to hone his newly acquired business management and social innovation skills in Geneva and Davos in Switzerland, working for both the Global Fund for HIV/TB and Malaria and the World Economic Forum where he says he ‘got to understand the

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top-end, 30 000 foot stuff ’. Public/private partnerships were an integral part of his overseas work sojourns. Stints at earthquake disasters in India and public child health in Mexico reaffirmed his formative SA/ Namibian experiences. ‘My time in Geneva made me think that the top-down solutions were so far removed from what I was passionate about – so I began looking at things from the bottom-up. Finding new ways of creatively overcoming challenges and constraints – whether private business modalities or public ones,’ he explained. Among his collaborative creations is the wind-up, low-cost fetal heart rate and oxygen monitor which won the global Index Design for Life award and which is now used by Médecins Sans Frontiéres in 15 countries. Bonnici ‘walked the walk’ well before Oxford; this included a 1999 stint at Windhoek’s Katutura State Hospital where he ‘lived with, and learnt everything from the nurses,’ admitting newborn infants in cardboard boxes or wrapped in newspaper and colliding headfirst with a 16% premature birth rate. He found babies stacked three to an incubator (the hospital had eight of these). ‘That year we did 45 resuscitations – 44 were unsuccessful,’ he recalls. Newborn health was ‘under-recognised’ at the time as a cause of infant mortality, says Bonnici, so he canvassed the opinion of Katutura Hospital’s initially sceptical paediatrician (one of three in Namibia at the time) and nurses, intent on introducing a Kangaroo Care (KC) programme. He sat down and wrote a KC policy, which was forwarded to Namibia’s Minister of Health. Within four months it became official Namibian health policy. Immediately after this and during his community service at Mowbray Maternity Hospital (which he called his ‘night job’), he realised he could again add more value. ‘I wrote to the province and told them about my public health degree, so my day job turned into improving newborn care at 26 secondary urban and rural hospitals.’ Mowbray Maternity has a special place in his heart; he was born there and met his wife there. The first concrete underpinning of his passion for innovation came after his return from Geneva when he approached UCT’s GSB to begin a Centre for Social Innovation and Entrepreneurship. ‘There

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was so much happening in SA, but all our top campus researchers were overseas. UCT was positive, but had no spare money and [we] were fortunate enough to find a South African family foundation in London’ (which began the Bertha Foundation). The Bertha Foundation funds activism, whether it is Corruption Watch, Equal Education, the non-governmental organisation Section 27, or documentaries on societal issues. Today the GSB’s Bertha Centre works across disciplines. Bonnici spends a significant amount of time with National Treasury applying his skills to social financing while helping build socially motivated businesses.

Converting deep frustration into helpful compassion

During Lindi van Niekerk’s internship at Victoria Hospital she saw patients dying while awaiting a place in GSH’s dialysis queue, which spurred her on to try to make a difference. ‘There were multiple cases every day of patients being turned away. The realisation dawned on me that we could still do something, even if we weren’t curing.’ So, she pioneered the Abundant Life care programme that helps the Hospice

and Palliative Care Association in the Cape Metropole to handle the overflow from its maximum caseload of 800 patients per annum. Van Niekerk adds, ‘Patients are dying of organ failure because we don’t have the resources, and one in five patients will need end-of-life care in our hospitals’. Abundant Life’s main aim is to get patients supporting one another and back home, delivering wheelchairs, bedpans and other vital equipment to make this possible. Her programme, supported by Rotary (funding for pain management), GSH and various day hospitals, has reduced admissions by about 40% and increased managed deaths at home in the Cape Metropole by between 60% and 70%. She first met Bonnici while at Victoria Hospital and decided to do public health. ‘My consultants said nobody wants to do that!’ she laughs. However, after ‘exploring different places where I could bring about change,’ she put her ambition of becoming a neurologist on hold, a 2010/2011 scholarship to study public health at the London School of Tropical Medicine, the welcome interruption. Like Bonnici, she realised how quickly a physician could become ‘detached from

the realities on the ground,’ and convinced the province to let her do palliative care work during her community service tenure. ‘I was driven by my own “failures” within the system. I wanted to make a difference and really do something for people,’ she adds. The GSB Bertha Centre is the first of its kind in SA and the Bonnici/Van Niekerk duo have crafted their own job descriptions. ‘It’s a unique opportunity. We’re extremely fortunate to be involved and it’s very different to what my friends are doing,’ says Van Niekerk. The pair believe that as clinicians, it’s ‘easy to lose the bigger picture perspective, especially where it links to other disciplines and what we can learn and bring in’. Put differently, and to quote one of the Eastern Cape’s award-winning deep rural hospital delegates to the Innovation Summit, Zithulele Hospital’s Chief Medical Officer, Dr Ben Gaunt, ‘if you don’t have a dream, how will you ever have a dream come true?’ Chris Bateman chrisb@hmpg.co.za S Afr Med J 2014;104(3):159-160. DOI:10.7196/SAMJ.7997

Annually, 1% of gold miners die – 4% sent home sick What was believed to hold high promise in bringing down the tuberculosis (TB) prevalence among highly migratory gold miners, wide-scale prophylactic drug intervention among asymptomatic (dormant) carriers has now been found to have little protective effect. This is according to Prof. Gavin Churchyard, CEO of the non-profit, gold-sector, public health benefit Aurum Institute. This has far-reaching and sobering implications for the ongoing nationwide spread of TB, of which the incidence (new cases over time) is driven by HIV. Churchyard reiterates that the moment a TB carrier (i.e. dormant) becomes HIV-positive and their immune system is progressively compromised, their risk of developing active TB increases.

The prevalence of undiagnosed TB disease is the driving force of TB transmission at a population level and has changed little at gold mines, based on two surveys a decade apart. The first Aurum Institute survey, in 2000, including some 2 000 gold miners, revealed that 2.5% of them had undiagnosed active TB. The second probe in 2011 (this time of 13 000 gold miners), done as part of Churchyard’s latest research and recently published in the New England Journal of Medicine,[1] uncovered a prevalence of 2.3% – in spite of widespread campaigning for and administration of prophylactic isoniazid preventive therapy (IPT). This is cold comfort to those revelling in nationwide HIV successes, including an antiretroviral treatment (ART) programme now reaching 2.3 million people in South Africa (SA) (up from 923 000 in 2009). HIV prevalence in the mining sector is currently

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Professor Gavin Churchyard, CEO of the Aurum Institute. Pictures: Chris Bateman.

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unclear – the last survey in 2000 put it at 30%, almost triple the national average. Churchyard takes boasts of a 10% or lower HIV prevalence from some mining houses with a pinch of salt, observing that these are often based on ‘unreliable and typically unrepresentative’ samples. He concedes that the mining sector led the way in the national ART roll-out, but says current individual mining house HIV prevalence measurements are shaky. ‘Representative HIV prevalence surveys done by independent research bodies and supported by labour are required to monitor the impact of HIV programmes on the HIV epidemic’, he emphasises. Gold miners, because of their long-term exposure to silica dust deep underground, are highly prone to developing silicosis with attendant TB (latent or active). They make up 32% of all miners in the country.

Debate on laws limiting exposure

Debate in mining medical circles currently centres on whether legislation should require mining houses to limit the number of years a worker spends underground to 10 or 15 years (Brazil has set the ceiling for certain job categories at 10 years). Churchyard said silicosis prevalence ‘jumped dramatically’ among gold miners after 15 - 20 years of underground work, but described reducing this time frame as a currently ‘un-validated intervention’. A full 41% of gold mine workers are found to have active TB upon autopsy. Meanwhile one in every 100 gold miners in SA has been dying annually for at least the past 10 years – and the mortality rate, fed by the HIV/TB epidemic, shows no sign of changing anytime soon. An additional 4% of gold miners are repatriated home (medically boarded) every year owing to ill health (mainly lung disease) – roughly 5 times the national workforce average. This is according to both Churchyard and Dr Thutula Balfour-Kaipa, the South African Chamber of Mines (COM)’s Chief Health Officer, who add that historic upheavals (like the infamous Marikana Mine protest killings on 16 August 2012) and the ongoing inter-union strife, significantly affect essential health monitoring and research. The silicosis-driven death rate on gold mines is underscored by one of SA’s most successful litigants on behalf of silicosis and asbestosisaffected current and former mineworkers, Richard Spoor. He told Izindaba that among just the 30 000 gold miner clients currently cited in what could be a seismic, landscapealtering wider class action, 300 men die annually. ‘We’re losing 300 of our clients to

silicosis-linked TB or HIV every year, which is entirely consistent with the figures you’re reporting on,’ he added.

Labour objections complicate HIV monitoring – Chamber

Balfour-Kaipa said HIV surveillance on the mines was ‘very much determined by the approach and attitude of the relevant union’. While it was understandable that many unions were uncomfortable with the idea of linking an HIV test to someone, mining houses made a strict distinction between occupational health and primary healthcare. ‘The occupational health officer who determines your fitness to work doesn’t know your HIV status, but there are still pockets where the union does not support testing’. She said the current volatile union environment, ‘doesn’t help – when unions are struggling for survival, issues like health tend to take a back seat’.

Dr Thutula Balfour-Kaipa, Health Officer for the South African Chamber of Mines.

An added complication in measuring HIV prevalence was workers who belonged to a medical aid being tested privately. In spite of this, anecdotal evidence was that HIV rates had stabilised along with those in the general population. She said mining houses with the largest numbers of migrant workers (gold and platinum) had the highest levels of HIV and were therefore above the national average. ‘You may find prevalence at 18% on a gold or platinum mine but as low as 12% in the coal sector (low migrancy).’ Balfour-Kaipa said a final tally currently being completed on 2013’s fatal mine accidents ‘looks like it’s going to be under 100 workers, making it a landmark year, given that in 2012 there were 123 deaths (excluding the 34 Marikana killings)’.

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The COM believed that health on mines had ‘improved overall – TB is a huge part of this, so even a small improvement there helps a lot. The concern now is silicosis; we’re not really happy with progress on this. Silicosis is the product of both concentrations of dust and length of exposure. We assume mines are doing everything possible to get dust levels as low as possible but the length of exposure is our biggest challenge.’ She admitted that there were no national guidelines on duration of exposure. If government, labour and the employers decided to ‘go this route, we’d have to be very clear on what happens to a person and their job’. Balfour-Kaipa said there was no active discussion on this ‘yet’. ‘We’d like to see stability at union level so that we can focus on health. With all these political battles, strikes, and membership strife, health and safety come last.’ Churchyard said no hard data existed on national medical boarding rates, but when pushed, estimated the figure at ‘around 0.1% or 0.2% of the national workforce’. The gold mining sector medical boarding rate is 1%, making it a possible 5 - 10 times higher. Meanwhile, Spoor revealed that if a class legal action (the 30 000 miners cited are onetenth of the numbers who could potentially benefit) was allowed – and succeeded – ‘outlier’ or marginally profitable mines could go out of business after paying attendant health damages. In terms of a ruling by Gauteng’s Deputy Judge President, Justice Mojapelo, in the South Gauteng High Court in November last year, SA’s gold mines have until May this year to file answering papers to a tripartite miner application to have their class action ratified. The three law firms representing the miners must then respond by the end of August. If certified, the class action that ensues (probably in early 2015), would cover all gold miners past and present who contracted silicosis as a result of their work on the gold mines; almost certainly resulting in a paroxysm of nervous coughing on the Johannesburg Stock Exchange. While Spoor concedes that SA’s gold mines have unique ventilation problems because of their unparalleled depth and shaft diameters, he says a class action win will ‘make it more expensive to let people get sick and die, and lead to rational employers investing in improved safety measures’. He says it seems the industry has recognised that a class action is more pragmatic than being inundated with thousands of different claims, ‘or suffering death by a thousand cuts’. ‘I think they’ll support the action, but drag it out as long as possible,’ he believes. Meanwhile Yale University’s Law School and its School of Public Health, have jointly

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just released a searing indictment of SA’s century-old legal compensation system for occupational lung disease. Labelling the compensation system ‘grossly underfunded, inadequate and poorly implemented,’ the review, which compares SA unfavourably with a host of other mining countries, recommends major legal reform, with shortterm overhaul of an administrative system which currently underpays a minority of legitimate claimants (in some medical incapacity cases payouts are as low as R1 000 for every year worked).

Among just the 30 000 gold miner clients currently cited in what could be a seismic, landscape-altering wider class action, 300 men die annually. Spoor, whose out of court settlements from asbestos mining houses total R1.1 billion since 2003, won a Constitutional Court battle two years ago in which the 1911-initiated Occupational Diseases in Mines and Works Act was found to trample common law rights. A 2009 collaborative study by the University of the Witwatersrand and University College, London, estimated that there are to be 288 000 cases of compensable silicosis in SA, which put unpaid liability at R10 billion in 1998 values (R27 billion in today’s values).

Phasing out of single-sex hostels a ‘huge relief ’

When both mining health executives were asked about changes in accommodation for miners (the proportion of miners in singlesex hostels was 90% in early 2000), they said this had dropped to ‘well below 50%,’ a hugely positive HIV and TB transmission risk reduction. Other positives included the sharing of HIV/TB health services between richer and poorer mines. Churchyard said one of the most dramatic changes in national health policy recently

was the introduction of continuous IPT for immunocompromised people for three years, making SA one of the first countries worldwide to add IPT to ART for longer than six months. He explained that IPT was ‘like an umbrella – it only protects you from the rain (of TB disease) for as long as you keep it up’. Adding IPT to the ART regimen meant that the national TB incidence could be kept down, thus reducing the pool of TB infectious people and having an overall population level impact. From less than 1% of all HIV-infected South Africans on IPT five years ago, which he called ‘inexcusable’ at the time, more than 370 000 of the 2.3 million people on ART were now on IPT. Churchyard revealed that the national TB rate had peaked in 2008 and has started to decline; but even with a slight drop, SA has the second highest TB rate or epidemic in the world (one in 100 people). Gold mine TB rates stand at three in 100 workers, platinum 1 - 2 in 100 workers, while coal mirrors the national rate with the diamondmining sector even lower. HIV drives not only TB, but (according to a major paper on SA miners which Churchyard contributed to in the American journal, Clinical Infectious Diseases), [2] bacterial pneumonia, cryptococcosis, enteritis, bronchitis, urinary tract infections and soft tissue infections. Cryptococcosis (a fungal infection leading to lesions or abscesses in the brain and central nervous system) caused 44% of deaths in HIVpositive patients, the study found. Balfour-Kaipa said data from the Department of Mineral Resources showed that occupational TB reported by gold mines had dropped from 4 500 in 2007 to 2 838 in 2012. Churchyard added a caveat, suggesting official underestimation; he said these figures came from routine data collection and recorded only cardiopulmonary TB in miners who had done risk work (defined as more than 200 risk shifts). Balfour-Kaipa said analysis of annual reports from the majority of SA mining

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companies showed that TB rates had declined from 1 387 cases per 100 000 workers in 2010 to 1 031 cases per 100 000 in 2012. Silica dust was responsible for TB in the gold sector being up to three times the average SA rate over ‘the past several decades’.

If certified, the class action that ensues (probably in early 2015), would cover all gold miners past and present who contracted silicosis as a result of their work on the gold mines; almost certainly resulting in a paroxysm of nervous coughing on the Johannesburg Stock Exchange. The take home message …

The Health Executives’ main take home message? Very similar to that of the National Health Minister, Dr Aaron Motsoaledi, actually: go back to basics; scale up HIV testing; speed up access to ART; initiate ART earlier (at a CD4+ cell count level of 500, not 350); rapidly scale-up the use of new TB diagnostic technology (e.g. GeneXpert); and limit miners’ exposure to dust. Taken together these measures would have a major impact on TB rates and HIV infections. Chris Bateman chrisb@hmpg.co.za 1. Churchyard GJ, Fielding KL, Lewis JJ. A trial of mass isoniazid preventive therapy for tuberculosis control. N Engl J Med 2014;370:301-310. [http://dx.doi.org/10.1056/NEJMoa1214289] 2. Corbet E, Churchyard G, Charalambos S, et al. Morbidity and mortality in South African gold miners: Impact of untreated disease due to human immunodeficiency virus. Clin Infect Dis 2002:34(9):1251-1258. [http://dx.doi.org/10.1086/339540]

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OBITUARIES Hymie Gaylis

surgical faculty in San Diego with the rank of Clinical Professor and was actively involved in the undergraduate teaching programme for many years. During my 2013 visit with him we enjoyed many laughs and reminiscences. Despite physical frailty, Hymie had remained mentally razor sharp, and drawing from his vast experience in publishing he gave me invaluable advice and suggestions for a book that I am working on. Sincere condolences are extended to Rhoda, Franklin, Brendan and their families. A giant has fallen. Norman A Blumberg Houston, Texas, USA monteflora@sbcglobal.net

Dennis James Pudifin It was with great sadness that I learned of Hymie’s death at age 92 in San Diego, in early December 2013. He and I were among the last surviving residents of Resdoc from 1951. He was a groomsman at my wedding and we remained close friends for more than 60 years. Maureen and I spent a quality week with Hymie and Rhoda in San Diego just a few months ago. There will undoubtedly be many tributes to Hymie’s surgical prowess: he was a towering figure, and a pioneer among South African surgeons. I believe that he was the father of vascular surgery in Johannesburg, if not the whole country. Hymie refined his surgical training and expertise at the Postgraduate School at Hammersmith Hospital in London in the 1950s, where he served as a surgical registrar under the late Ian Aird, then one of the world’s surgical giants, and later trained in Boston under Robert Linton. Hymie was temperamentally well suited to the merciless demands of the vascular surgical subspecialty. He was unhurried, patient and a meticulous operator. He conducted a huge and demanding private practice in addition to heading a surgical unit at Wits. A modest and humble man, Hymie never talked about his exceptional talents as a ‘do-it-yourselfer’ – he could make or repair anything. He was also an exceptional swimmer, spotted once swimming across False Bay at Muizenberg, sharks be damned. When Hymie retired he emigrated to the USA to be close to his two sons, both Wits medical graduates. It was not in his nature to be idle, and he soon joined the

Prof. Dennis Pudifin passed away on 3 December 2013. He was born on 13 May 1934. Dennis qualified from the University of Cape Town in 1957 as a medical doctor. He did his internship at Edendale Hospital in Pietermaritzburg and then trained in the same hospital under Dr John Cosnett, a well-known physician who was skilled in clinical medicine and whose obituary Dennis provided a few months ago. Dennis obtained his fellowship in internal medicine from the Colleges of Medicine of South Africa and then joined the Department of Medicine at King Edward VIII Hospital, Durban, as a consultant/lecturer. In 1980 he was appointed Professor of Medicine and Deputy Head of the Department of Medicine at the University of Natal. His

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particular interests were immunology, AIDS, clinical medicine and teaching. He spent a year at the Radcliffe Infirmary training in immunology, and published valuable research in that field with June Duursma. He was an active member of the British Society of Immunology and the South African Society of Immunology, of which he was president in 1988, and he was elected a fellow of the Royal College of Physicians of London in 1979. In 1994 he reached retiring age, but he continued working as a physician and as Emeritus Professor until just before his death. In spite of a terminal illness, he remained passionate about teaching students. Medicine consists of two components, the scientific aspect and the humane aspect. In spite of scientific and technological advances, the doctor of today does not enjoy the same respect as in the past. Before the days of antibiotics the general practitioner in many a small town made house calls. He or she had very few effective drugs, yet was a highly respected member of the community. How was this respect earned, and why is it disappearing? The doctor cared for the patient and the family. He comforted the patient, and if the patient died, he comforted the family. He applied ethical principles to his practice: do no harm to the patient (primum non nocere), practise beneficence, refrain from maleficence, and maintain patient confidentiality. Respect in life is earned, not endowed because of position. Dennis had a strong ethical code, and was devoted to the Medical School and the Department of Medicine. He cared for his patients, and enjoyed teaching students. This is a dying breed today. I am deeply indebted to him for his loyalty, friendship and advice while he served as my deputy. Dennis’s first wife died, and his son died tragically on a yacht in the Indian Ocean. His daughter Collett, from his first wife, settled in Australia. He leaves his second wife Jenny and their daughter Sarah. Like Chaucer’s ‘veray parfit gentil knight’, Dennis was a gentleman. I would like to end by quoting Mark Anthony’s tribute to the dead Brutus in Shakespeare’s Julius Caesar: ‘His life was gentle, and the elements So mixed in him that nature might stand up And say to all the world “This was a man”.’ Y K Seedat Emeritus Professor of Medicine, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa seedaty1@gmail.com

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CLINICAL PRACTICE

Clinical Access to Bedaquiline Programme for the treatment of drug-resistant tuberculosis F Conradie, G Meintjes, J Hughes, G Maartens, H Ferreira, S Siwendu, I Master, N Ndjeka Francesca Conradie is a researcher at the School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Graeme Meintjes is Associate Professor at the Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, South Africa. Jennifer Hughes is a medical officer for Médecins Sans Frontières, Khayelitsha, Cape Town, South Africa. Gary Maartens is Head of the Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa. Hannetjie Ferreira is a medical officer at the MDR/XDR TB Unit, Klerksdorp/Tshepong Complex, North West Province, South Africa. Sweetness Siwendu is a medical officer at Metro TB Hospital Complex at Brooklyn Chest Hospital, Cape Town, South Africa. Dr Iqbal Master is a clinical manager at the MDR TB Unit, King Dinuzulu Hospital Complex, Durban, South Africa. Norbert Ndjeka is Director of the Drug-Resistant TB, TB & HIV, National TB Control & Management, National Department of Health, South Africa. Corresponding author: F Conradie (fconradie@witshealth.co.za)

While clinical disease caused by drug-sensitive Mycobacterium tuberculosis (MTB) can usually be treated successfully, clinical disease caused by drug-insensitive MTB is associated with a poorer prognosis. In December 2012, a new drug, bedaquiline, was approved by the US Food and Drug Administration. This article documents the process whereby the National Department of Health, Right to Care and Médecins Sans Frontières obtained access to this medication for South Africans who might benefit from subsequent implementation of the Clinical Access to Bedaquiline Programme. S Afr Med J 2014;104(3):164-166. DOI:10.7196/SAMJ.7263

While clinical disease caused by drug-sensitive Mycobacterium tuberculosis (MTB) can usually be treated successfully, clinical disease caused by druginsensitive MTB is associated with a poorer prognosis. In December 2012, a new drug, bedaquiline, was approved by the US Food and Drug Administration (FDA) for the treatment of multidrug-resistant (MDR) tuberculosis (TB). In a review paper, the four goals of a compassionate use/early access programme for new TB drugs are outlined: to protect patients; to minimise the risk of treatment failure and emergence of resistance; to exercise fairness; and to comply with regulatory guidance.[1] This article documents the process whereby the National Department of Health (NDoH), Right to Care (a US Agency for International Development-funded non-governmental organisation) and Médecins Sans Frontières (MSF) obtained access to this medication for South Africans who might benefit from subsequent implementation of the Clinical Access to Bedaquiline Programme (CAP). Attention was paid to the regulatory framework, fairness and protection of patients while being cognisant of the need to prevent emergence of resistance to bedaquiline.

Setting

In South Africa (SA), 14 161 cases of MDR-TB were documented in 2012. The proportion of MDR-TB cases with additional resistance to a quinolone and a second-line injectable, i.e. extensively drug resistant TB (XDR-TB), is estimated at 10.9% (N=1 545)[2] with an ill-defined proportion being ‘pre-XDR-TB’, i.e. MDR with resistance to either a quinolone or a second-line injectable. While the outcomes of patients with pre-XDR-TB have not been well documented, the outcomes of XDR-TB are poor. In a retrospective cohort study at four designated XDR-TB provincial treatment facilities in SA between August 2002 and February 2008, 195 adult patients with cultureproven XDR-TB were analysed; 21 patients died before initiation of

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any treatment, 174 patients (82 with HIV infection) were treated, and 62 (36%) patients died during follow-up. Sputum culture conversion was achieved in only 33/174 (19%) patients.[3] There are several new classes of TB drugs becoming available, including bedaquiline, which is a diarylquinoline. Bedaquiline offers a new mechanism of anti-TB action by specifically inhibiting mycobacterial adenosine triphosphate synthase.[4] In December 2012, the FDA granted accelerated approval for bedaquiline based on two phase 2 studies involving 440 people with drug-resistant TB (DR-TB). The first trial was a randomised, double-blind, placebo-controlled trial with bedaquiline and an optimised background regimen. The second was an open-label trial. Bedaquiline, when given with other existing MDR-TB drugs, increased the proportion of people whose sputum cultures converted to negative after 2 and 6 months of treatment. Bedaquiline, when given with other existing MDR-TB drugs, also reduced the time to sputum culture conversion, offering the possibility of a shorter treatment duration in the future. Bedaquiline is currently only commercially available in the US and is not yet registered by the SA Medicines Control Council (MCC). In the interim, some patients with few other treatment options, and before the drug’s approval in their countries, have been offered bedaquiline through an early access programme put in place by the manufacturer, Janssen Pharmaceutica. Under controlled compassionate use programmes and early access trials, several countries including SA have made bedaquiline available for patients with XDR- or pre-XDR-TB. In an expanded access programme (EAP) model, a clinician requests a drug for a named individual patient based on a specific clinical access guidance document. In an EAP, patients can be enrolled and offered access to the medication if they meet specific eligibility criteria. Based on this model, MDR-TB patients who have limited treatment options have been allowed access to bedaquiline as part of an individually tailored treatment regimen in a CAP in SA.

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Table 1. MDR-TB patients, 2004 - 2010* Patients, n Province

2004

2005

2006

2007

2008

2009

2010

2011

2012

Total, N

Eastern Cape

379

545

836

1 092

1 501

1 858

1 782

2 178

2 205

12 376

Free State

116

151

198

179

381

253

267

412

390

2 347

Gauteng

537

676

732

986

1 028

1 307

934

1 643

1 198

9 041

KwaZulu-Natal

583

1 024

2 200

2 208

1 573

1 773

2 032

1 825

6 630

19 848

Limpopo

185

204

126

290

266

1 338

Mpumalanga

162

134

139

506

657

446

312

824

760

3 940

Northern Cape

168

155

188

199

290

631

353

427

373

2 784

North West

130

203

225

397

363

520

158

473

267

2 736

Western Cape

1 085

1 192

1 179

1 771

2 220

2 078

1 422

2 013

2 072

15 032

Total, N

3 219

4 120

5 774

7 429

8 198

9 070

7 386

10 085

14 161

69 442

MDR-TB = multidrug-resistant tuberculosis. *Laboratory diagnosis from the National Health Laboratory Service.

Key aspects of the CAP Exercise of fairness

SA has nine provinces, all having MDR-/XDR-TB treatment facilities but with differing MDR-/XDR-TB burdens (Table 1). According to the National Health Laboratory Service, in KwaZulu-Natal, 11 393 diagnoses of MDR-TB were made between 2004 and 2010 and in the same time period 782 diagnoses were made in Limpopo. To ensure equitable access to bedaquiline by selected XDR- or pre-XDR-TB patients, there should ideally be a clinical site in each province offering the programme. Initially, four sites were approved by the MCC to begin the programme, based on results of clinical research. However, this excluded other, less well-resourced provinces. Additional sites in all the remaining provinces have since been identified for expansion of the project. To prepare all future sites, good clinical practice training was provided to at least two members of staff from the selected MDR-/ XDR-TB facilities. Strict adherence to the guidance document was stressed as the newer sites were not all experienced in conducting research. Once trained, the TB directorate of the NDoH set up an official start-up meeting at each of the sites.

Protection of patients

The principle underpinning protection of participating patients is their ability and capacity to make autonomous decisions and to give informed consent. Both the CAP and the informed consent document were approved by each site’s research ethics committee prior to the start of the programme and enrolment of participants. A potential safety risk identified in the development of bedaquiline, in common with moxifloxacin and clofazimine that are included in MDR-TB treatment regimens, was the prolongation of the QTc interval on electrocardiogram (ECG) with associated risks of lifethreatening ventricular arrhythmias and sudden death. Thus, built into the CAP is rigorous ECG monitoring with only sites capable of adhering to this being permitted to enrol patients.

Regulatory guidance

Clinical research sites that were involved in the phase 2 clinical trials of bedaquiline were approached first to implement a compassionate use programme for bedaquiline. A requirement to participate was that the patients who accessed the drug were treated within the national

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TB programme, thus ensuring that the new drug is supported by other quality assured and approved second-line TB drugs. In November 2011, the compassionate use programme was presented to the MCC by the MDR-TB directorate of the NDoH. The MCC was concerned at that time that the drug was not registered by any other regulatory authorities. They requested that the protocol be amended and implemented as a clinical trial, with appropriate safety monitoring, and with the TB directorate of the NDoH being responsible for sponsorship. In collaboration with Right to Care and MSF, a CAP for SA was drafted by the NDoH based on the compassionate use framework. In December 2012, the CAP was approved by the MCC.

Minimise the risk of treatment failure

Bedaquiline is a new TB drug with a novel mode of action. The old adage of never adding a single drug to a failing regimen is important to reduce the risk of developing acquired resistance. An SA clinical advisory committee was therefore established, comprising a number of experts in the treatment of MDR-/XDR-TB. This virtual committee operates by e-mail consensus, with all new cases being discussed, and three members, other than the proposing responsible clinician, approving the use of bedaquiline as part of an appropriate regimen. Regimens for individual patients accessing bedaquiline through the programme are individualised and tailored according to the patient’s TB susceptibility pattern, treatment history and exposure to other TB drugs, and other individual factors. Key roles of the committee are to ensure that bedaquiline is used only when other TB drugs known to be effective, or are likely to be effective, are available to be used in the patient’s regimen. The committee advises on an optimal treatment regimen for each case. Once approval from the local team is obtained, the responsible physician submits a patient summary to the Janssen Global Programme Manager who then co-ordinates clinical approval by Janssen, at the hands of a panel of clinical experts, and communicates the decision back to the responsible physician for each site. In parallel, approval is obtained from the MCC on a Section 21 or named-patient basis.

Discussion

This initiative has had a number of far-reaching consequences. Firstly, patients with DR-TB that has a poor prognosis are being

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offered expedited access to a novel drug in a safe and controlled environment. Secondly, the model that has been established may prove useful in the future for other new TB agents. While much public attention has been paid to MDR-TB in the last 5 years, it remains under-researched. The programme has expanded the capacity for research that does not exist currently in most MDRTB facilities. It bears noting that evidence for the regimen used in the current national TB treatment programme is based on expert opinion and not on clinical trial data. Cohort data from Van Deun et al.[5] demonstrated the efficacy of a seven-drug combination, 9-month course of treatment for MDR-TB. This so called ‘Bangladesh’ regimen consists of high-dose isoniazid, high-dose gatifloxacin, kanamycin, prothionamide, ethambutol, pyrazinamide and clofazimine given for only 9 months and is now being compared with the standard 18 - 24-month regimen in The Evaluation of a Standardised Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MultidrugResistant Tuberculosis (STREAM), an International Union Against Tuberculosis and Lung Disease sponsored, non-inferiority clinical trial. This is the first of a number of trials aimed at establishing more effective, safer and shorter MDR-TB regimens using newly available drugs. The CAP in SA has provided the initial training and back-up for such clinical trials in the future. Finally, HIV co-infection with TB is very common in SA. National HIV guidelines mandate the expedited initiation of antiretroviral therapy in any patient with MDR-/XDR-TB. Data on concomitant

antiretroviral use with bedaquiline will emerge following imple menation of the programme.

Conclusion

There remains much work to be done to find a new effective, safe and evidence-based treatment regimen for MDR-/XDR-TB. Bedaquiline must form part of a long-term strategy aimed at combatting DR-TB. Other drugs that might include linezolid – an oxazalidinone that is also used for the treatment of resistant Gram-positive infections – and clofazimine – a drug used for the treatment of leprosy – must be added to develop regimens for the treatment of XDR- and pre-XDRTB. The CAP in SA has resulted in both access to treatment with a novel drug for patients with DR-TB and enhancement of research capacity. 1. Horsburgh CR, Haxaire-Theeuwes M, Wingfield C, et al. Compassionate use of and expanded access to new drugs for drug-resistant tuberculosis. Int J Tuberc Lung Dis 2013;17(2):146-152. [http://dx.doi. org/10.5588/ijtld.12.0017] 2. World Health Organization. Global Tuberculosis Report 2013. Geneva: WHO, 2013. http://www.who. int/tb/publications/global_report/en/ (accessed 10 July 2013). 3. Dheda K, Shean K, Zumla A, et al. Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: A retrospective cohort study. Lancet 2010;375(9728):17981807. [http://dx.doi.org/10.1016/S0140-6736(10)60492-8] 4. Diacon AH, Pym AS, Grobusch M, et al. The diarylquinolone TMC 207 for the treatment of multidrug-resistant tuberculosis. N Engl J Med 2009;369(23):2397-2405. [http://dx.doi.org/10.1056/ NEJMoa0808427] 5. Van Deun A, Maug AK, Salim MA, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2010;182(5):684-692. [http://dx.doi.org/10.1164/rccm.201001-0077OC]

Accepted 19 July 2013.

DRUG ALERT

Recommendations pertaining to the use of viral vaccines: Influenza 2014 S Walaza S Walaza is a medical epidemiologist at the Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases (NICD), Johannesburg, South Africa and has compiled this article on behalf of the Centre for Respiratory Diseases and Meningitis, NICD, Johannesburg, South Africa and the National Department of Health, Pretoria, South Africa Corresponding author: S Walaza (sibongilew@nicd.ac.za)

Here we provide recommendations for the use of viral vaccines in anticipation of the 2014 southern hemisphere influenza season. For a review of the 2013 influenza season, please refer to the National Institute for Communicable Diseases, National Health Laboratory Service website (http://www.nicd.ac.za). S Afr Med J 2014;104(3):166-167. DOI:10.7196/SAMJ.8010

Recommended vaccine formulation

The following strains have been recommended by the World Health Organization (WHO)[1] for the 2014 southern hemisphere influenza season: • A/California/7/2009 (H1N1)pdm09-like virus (A/Christchurch/ 16/2010 is an A/California/7/2009-like virus) • A/Texas/50/2012 (H3N2)-like virus (A/Texas/50/2012 is an A(H3N2) virus that, following adaptation to growth in eggs, has maintained antigenic properties similar to the majority of

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recently circulating cell-propagated A(H3N2) viruses including A/ Victoria/361/2011) • B/Massachusetts/2/2012-like virus. Vaccines should contain 15 μg of each haemagglutinin antigen in each 0.5 ml dose.

Indications

• Persons (adults or children) who are at high risk for influenza and its complications because of underlying medical conditions

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• • • • • • •

and who are receiving regular medical care for conditions such as chronic pulmonary and cardiac diseases, chronic renal diseases, diabetes mellitus and similar metabolic disorders; individuals who are immunosuppressed (including HIV-infected persons with CD4+ counts >100 cells/µl); individuals who are morbidly obese (body mass index ≥40 kg/m2) Pregnant women – irrespective of stage of pregnancy Residents of old-age homes, chronic care and rehabilitation institutions Children on long-term aspirin therapy Medical and nursing staff responsible for the care of high-risk cases Adults and children who are family contacts of high-risk cases All persons >65 years of age Any persons wishing to protect themselves from the risk of contracting influenza, especially in industrial settings where largescale absenteeism could cause significant economic losses.

Dosage

• Adults: Whole or split-product or subunit vaccine: one dose intramuscularly (IM) • Children (<12 years of age): Split-product or subunit vaccine: one dose IM • Children (<9 years of age) who have never been vaccinated: two doses, 1 month apart • Children (<3 years of age): Half the adult dose on two occasions separated 1 month apart • The influenza vaccine is not recommended for infants <6 months of age.

Contraindications

• Persons with a history of severe (anaphylactic) hypersensitivity to eggs or other components of the vaccine • Persons with acute febrile illnesses should preferably be immunised after symptoms have disappeared.

Timing

Vaccines should be given sufficiently early to provide protection for the winter. A protective antibody response takes about two weeks to develop.

Antiviral chemotherapy

At present, influenza A (H1N1) pdm09 and H3N2, and influenza B viruses remain sensitive to oseltamivir (and zanamivir). The dosages for treatment and post-contact prophylaxis (where indicated) are provided in Table 1.

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Table 1. Recommended dosage of antiviral agents for treatment Dosage* Age group

Oseltamivir

Zanamivir

Adults

75 mg td

2 × 5 mg inhalations (10 mg total) td

Premature neonates

1 mg/kg td

Infants (0 - 12 months)

3 mg/kg td

≤15

30 mg td

15 - 23

45 mg td

24 - 40

60 mg td

>40

75 mg td

2 × 5 mg inhalations (10 mg total) td (only in children aged ≥12 years)

Children, weight (kg)

td = twice daily. * Recommended duration of treatment is five days. Zanamivir is only registered for children ≥5 years of age.

Antiviral chemoprophylaxis

Antiviral chemoprophylaxis for the contacts of persons infected with influenza is currently not recommended. Recent WHO recommendations advise presumptive treatment using the treatment regimen described above for higher-risk individuals (patients with severe immunosuppression or transplant patients) exposed to influenza instead of the previously recommended long-term lowerdose chemoprophylaxis regimen. These higher-risk individuals need to be carefully monitored during the influenza season for early signs and should then be treated immediately on suspicion of infection. For a more detailed description of antiviral management and chemoprophylaxis of influenza, please refer to the National Institute for Communicable Diseases Healthcare Workers Handbook on Influenza.[2] For the full report on recommended influenza vaccines, refer to the WHO recommendations.[1] 1. World Health Organization. Recommended Composition of Influenza Virus Vaccines for use in the 2014 Southern Hemisphere Influenza Season. 26 September 2013. http://www.who.int/influenza/ vaccines/virus/recommendations/201309_recommendation.pdf?ua=1 (accessed 30 January 2014). 2. National Institute for Communicable Diseases. Healthcare Workers Handbook on Influenza. Johannesburg: NICD, 2013. http://www.nicd.ac.za/assets/files/Healthcare%20Workers%20 Handbook%20on%20Influenza%20in%20SA%20-%20Final.pdf (accessed 30 January 2014).

Accepted 30 January 2014.

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REVIEW

Cardiovascular prevention: Lifestyle and statins – competitors or companions? L H Opie, MD, DSc, FCP (SA, Hon); A J Dalby, FCP (SA), FACC, FESC Prof. Lionel Opie is Director Emeritus at the Hatter Institute for Cardiovascular Research in Africa, Faculty of Health Sciences, University of Cape Town, South Africa. Dr Anthony Dalby is a cardiologist in private practice at the Milpark Hospital, Johannesburg, South Africa. Corresponding author: L H Opie (lionel.opie@uct.ac.za)

Favourable lifestyles promote cardiovascular protection. Exercise can induce beneficial changes in the genome that decrease low-density lipoprotein cholesterol (LDL-C) and increase anti-inflammatory markers. The Mediterranean dietary pattern, fortified by nuts, while not reducing weight, reduces mortality. Lifestyle changes combined with statin therapy provide potent protection against coronary heart disease, especially when used for secondary prevention after cardiovascular events. Decisions regarding the initiation of statin therapy for primary prevention are more difficult, requiring consideration of both the LDL-C level and the degree of cardiovascular risk for dyslipidaemic patients. Combining intensive exercise and statin therapy substantially reduces the mortality risk, and thus is potentially the ideal riskreducing combination. S Afr Med J 2014;104(3):168-173. DOI:10.7196/SAMJ.7942

Lifestyle: Exercise and dietary patterns

Exercise training: What can it do?

While there are many benefits of regular exercise such as better subjective health and better sleep, a major benefit is countering cardiovascular disease (CVD). Thus, regular exercise can lower blood pressure (BP) in hypertensives by 11/8 mmHg.[6] This requires 30 - 60 min of exercise 3 - 5 times per week at a moderate walking pace, which is as good as an intensive walking pace. Greater degrees

Thorough cardiovascular assessment The ability to undertake high levels of exercise such as marathon running, does not ensure protection from myocardial infarction or death.[10] Thus, the intention to

1 000

800

600

All causes

400

Cancer

200 Cardiovascular disease

0 0

Number of risk factors, n

Fig. 1. All-cause, cardiovascular and cancer mortality over 24 years in the Women’s Health Study in relation to the number of risk factors present. Figure from Opie,[46] modified from data from Dam et al.[4]

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SAMJ 7942.indd 168

of ambulatory activity provide an incremental benefit to those at high cardiovascular risk.[7] In patients with chronic heart failure, exercise training lessens mortality.[8] Experimentally, exercise training gives protection after experimental reinfarction.[9]

Unhealthy lifestyles increase death over 24 years

Deaths per 100 000 person years

This review evaluates the beneficial effects of lifestyle (including exercise and diet) and of statins by considering the strength of data for each individually and their combination. The focus is on those studies with ‘hard’ endpoints, namely cardiovascular events and/or mortality. This approach is similar to that which formed the basis of the 2013 guidelines of the American College of Cardiology (ACC) and American Heart Association (AHA) which evaluate the relationship between statin therapy and the reduction in hard endpoints.[1] The major components of the beneficial lifestyle were first defined in two long-term studies on American health professionals – the Women’s and Men’s Health Studies (Fig. 1.)[2-4] Those lifestyle factors were nonsmoking (36% relative risk reduction in total deaths), exercise for ≥30 min daily (22%), ideal body weight (18%), an ideal diet (16%) and modest alcohol intake (9%). Mortality rose sharply as the number of risk factors increased. Lifestyle risk factors were cigarette smoking (ever), lack of physical activity (<30 min/day moderate- to vigorous-intensity activity), low diet quality (lowest three-fifths of healthy diet score), overweight (body mass index ≥25 kg/m2) and an alcohol intake of 0 or ≥15 g/day. Diet and exercise are part of an overall pattern of healthy living applicable not only to privileged professionals but to all racial groups including the less affluent and those living in large cities.[5]

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undertake intensive exercise training requires a medical history, blood lipids and an exercise electrocardiogram before starting. Exercise reduces low-density lipoprotein cholesterol (LDL-C) Taking into account data from 11 major outcome studies, intense exercise would reduce the 10-year risk of a coronary heart disease (CHD) event from 5% to just under 4%, while with statins, the greater LDL-C reduction would reduce the risk from 5% to about half that (2.5%).[11] The apparently unexplained aspect of these data is exactly how exercise reduces LDL-C. In part, the effect may be the result of other lifestyle changes often associated with intense exercise such as a better diet and weight loss, but the unexpected change specific to exercise is, surprisingly, that in the genome. Exercising the genome The explanation of why vigorous exercise promotes health independently of other lifestyle changes comes from studies on identical same-sex twins who were either persistently physically active or inactive throughout their lives.[12] Gene expression in adipose tissue and in skeletal muscle was quantified by nuclear magnetic resonance spectroscopy to yield the metabolome. The altered gene expression in the muscle of the active twins was associated with increased fatty acid oxidation, while in adipose tissue, fatty acid storage was decreased (Fig. 2).

Lifelong vigorous physical activity

Gene expression

Circulating metabolites

LDL-C

HDL-C

Superior metabolic protection Fig. 2. Eﬀects of persistent lifelong physical activity on the genomic pattern, which results in beneficial changes in circulating metabolites. For detailed proposals refer to Kujala et al.[12] Note, the beneficially decreased serum lowdensity lipoprotein cholesterol (LDL-C) and increased high-density lipoprotein cholesterol (HDL-C) levels.

The major metabolic changes between active and inactive twins were that blood glucose was lower in the physically active twins (p<0.001), serum fatty acid composition shifted towards a less saturated profile, and lipoprotein subclasses towards lower verylow-density lipoprotein (V-LDL) (p<0.001), all of which are associated with lower risks of CHD. Taken together, these data prove that intense lifelong exercise can on its own induce beneficial changes in the expression of the genome unassociated with any other lifestyle change.

Food, diet and health

Food patterns and long-term weight loss There are strong links between food patterns (as opposed to calorie-restricted diets) and cardiovascular health. In the American health professionals studies, with participants eating their normal pattern of food, and not on any diet, weight gain was associated with eating potato chips, potatoes, meats, butter, refined grains, sweets and desserts.[13] Small amounts of weight loss were associated with regular eating of vegetables, nuts, whole grains, fruit and yoghurt. Among weight-gainers, the worst offenders were sugar-sweetened beverages and 100% fruit juices. These relatively small changes in weight play a modest role in cardiovascular prevention. Diets: low-fat, high-fat, low-carbohydrate and others It is important to distinguish between ‘diet’ in the sense of patterns of eating food and the usual weight-reducing diets; it is chiefly the former that will now be evaluated. The ideal trial should have sufficient statistical power to demonstrate which dietary pattern produces a clear endpoint difference in CVD and/or mortality. The 2-year Israeli study fell short of this ideal even though adherence rates were excellent.[14] Subjects were allocated to one of three diets: a low-fat diet, the Mediterranean diet, or a low-carbohydrate diet, which has much in common with the New Atkins diet.[14] Weight loss over 2 years was greatest on the lowcarbohydrate diet (4.7 kg from an initial 90 kg), while LDL-C fell most on the Mediterranean diet. This study illustrates that even 2 years of strict dietary adherence is insufficient to impact on cardiovascular endpoints, a recurring problem when evaluating diets. The very-low-carbohydrate, high-protein, high-fat Banting diet is closely related to the Atkins diet.[15] It allows more attractive foods and has good data to show weight loss and decreased insulin sensitivity, but at the cost of increasing LDL-C.[16] However, there are no reports on major outcomes such as

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CVD and/or mortality. Indeed, as Noakes[17] points out, large, well-designed outcome trials are urgently needed to test this hypothesis. In contrast, the Japanese diet is high in carbohydrate, containing much rice and little fat, yet the Japanese live longer than others. Perhaps the accompanying fish is protective, or maybe the secret lies in eating slowly. Another new diet with beneficial metabolic changes, which include a decreased LDL-C, is the New Nordic Diet, which is high in fruit, vegetables, whole grains and fish.[18] It has the merit of reducing both body weight and BP in centrally obese individuals but so far lacks data on CVD reduction.[18] Though a wide variety of diets is proposed, most lack comparative data, do not consider what each diet can achieve in terms of weight loss (if needed), blood lipid patterns and projected cardiovascular benefits, while simultaneously ensuring good compliance. Dietary adherence is enhanced by enthusiastic input, attractive presentation and personal contact.[15] Dietary patterns that reduce mortality The Mediterranean diet reduces mortality by 25%, CHD deaths by 33%, and cancer by 24%.[19] Its beneficial components are a high intake of vegetables, legumes, fruits and nuts, cereal, fish and monounsaturated fats, with small amounts of meat, poultry and high-fat dairy products. Two studies link specific components of the Mediterranean dietary pattern to decreased mortality. In the first, in persons at high cardiovascular risk, the Mediterranean diet was supplemented with either extravirgin olive oil or nuts. This reduced the incidence of major cardiovascular events and deaths.[20] Both nuts and olive oil possess cardioprotective qualities, albeit with differing mechanisms.[21] The second study narrowed down the specific beneficial component to nuts[22] as part of a lifestyle that increased physical activity, and fruit or vegetables, and avoided smoking and dietary red meat. While the overall data favour the Mediterranean dietary pattern, it seems simpler to add more nuts to the diet especially if that specifically decreases mortality.

Diet plus exercise as part of a beneficial lifestyle

This combination accounted for 30% of the overall lifestyle benefits in the American health professionals studies (Table 1). Diet, exercise and not smoking would account for 58% of the benefit. Experimentally, the damage caused by a very high-fat diet in rodents was reduced by exercise, the

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this risk by almost half. However, the closer the untreated LDL-C gets to 2.5 mmol/l, a threshold often recommended for introducing statin therapy, the less the absolute benefit, even though the relative cardiovascular benefit, expressed as the percentage decrease in risk, remains constant.

Table 1. The lifestyle beneficial ‘big five’*,† Lifestyle big five

Protection from death, % (frequency)‡

Mechanism proposed

Non-smoking

28 (35)

Protects arteries

Exercise (≥30 min/day)

17 (22)

Slows the heart, lowers BP

Ideal weight

14 (18)

Avoids the toxic substances released from fat cells

Ideal diet

13 (16)

High unsaturated fatty acids, high fruit and vegetables, less red meat

Modest alcohol

7 (9)

Anti-stress, alcohol improves blood cholesterol patterns

All five

79 (100)

BP = blood pressure. *Note that successful coping with stress is not listed and may be estimated at 20 - 25% of the total lifestyle beneficial pattern. † Table constructed from American health professionals studies.[2,4] ‡ Deaths from all causes, including heart, stroke and cancer. Values in brackets indicate the frequency of the five lifestyle factors listed.

The LDL hypothesis: The lower, the better but the fewer are the absolute benefits

CHD event, %

Diabetes 1° prevention

CareDM-T

15 Care-T

LipidCM-T 4S-T

Lipid-P

Care-P

Lipid-T

HPS-P PROST-T HPS-T CARDS-T AFCAPS-T Ascot-T JUP-P

PROS-P

TNT-T

10 JUP-T

0 50

1.3

1.8

110

2.5

Diabetes 2° prevention

Upld DM-P

4S Care LipidDM-T DM-P

AFCAPS-P

130 mg/dl

3.0

3.5

150

4.0

4S-P

Secondary prevention

Primary prevention WPS-P

WPS-T

Ascot-P

4SDM-P (45%)

170

4.5

190

5.0

210

5.4

mmol/L LDL-C

Fig. 3. Relationship between low-density lipoprotein cholesterol (LDL-C) levels and coronary heart disease (CHD) events in major trials for primary and secondary prevention. The lower the LDL-C, the fewer the 10-year events. Note the far greater eﬀects with secondary than with primary prevention and especially marked eﬀects in diabetics. For original figure and details of trials, refer to Gotto and Opie.[47] (Based on the current European Society of Cardiology guidelines for overt CHD.)

proposed site of interaction being at the level of gastrointestinal hormones.[23]

Is it all too complex?

There are so many food and dietary choices, each with arguments in their favour, that our personal choice has been simplified to: ‘All the colours every day’, a brief but compelling message from an Italian nutritionist.

Evaluation of statin therapy

Statins: Benefits predominate

There is no doubt that statins are effective in secondary prevention, e.g. after an acute

coronary syndrome (ACS); however, a steep linear relationship exists between LDL-C levels and the 10-year CHD risk (Fig. 3). Thus, the higher the initial LDL-C, the greater the statin-induced reduction of CHD events. Under-dosing statin in this setting is a frequent error; doses should be at the upper end of the dose range to obtain maximal cardioprotection.[24] The benefit of statins is less in primary prevention. Even at very high LDL-C levels (e.g. 5 mmol/l), the 10-year risk is only close to 5% (Fig. 3). Statins affect a risk reduction of about one-fifth for every 1 mmol/l drop in LDL-C.[25] Therefore, statins can reduce

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Current ACC/AHA guideline recommendations Almost all patients with prior ACS events, and/or clinical atherosclerotic cardiovascular disease (ASCVD) or otherwise judged to be at high risk, such as those with diabetes, require a statin for secondary prevention. For primary prevention, the 2013 ACC/ AHA guideline recommendations for statin therapy cover are LDL-C in the range 1.8 - 4.8 mmol/l (Table 2).[1] Higher LDL-C levels may need exclusion of hereditary lipid problems by a lipidologist. The four major groups that have been shown to derive benefit from statins are those: • with clinical ASCVD, in patients <75 years of age • with primary elevation of LDL-C of ≥4.9 mmol/l • with diabetes, in patients aged 40 - 75 years with an LDL-C of 1.8 - 4.8 mmol/l, but without ASCVD • without clinical ASCVD or diabetes with an LDL-C of 1.8 - 4.8 mmol/l and an estimated 10-year risk of ASCVD ≥7.5% South African guidelines The South African guidelines,[26] based on those of the European Society of Cardiology (ESC), recommend the assessment of risk in primary prevention using the updated Framingham risk charts. The four categories of the Framingham risk score refer to the 10-year risk of any cardiovascular event. For the highest risk group (>30%), the LDL-C goal is 1.8 mmol/, for the 15 - 30% risk group it is 2.5 mmol/l, and for <15% risk the goal is 3 mmol/l.[26] Risk prediction is no easy matter Accurate risk prediction is difficult, whether the ACC/AHA or the ESC guidelines are used. A recent Lancet editorial pointed out that the levels of risk prediction by the new ACC/AHA guidelines are roughly double those observed in several major outcome trials, including the Women’s Health Study, the Physicians’ Health Study and the Women’s Health Initiative Observational Study (Fig. 1). Thus, up to 50% of Americans apparently targeted by their new guidelines do not actually have a risk that exceeds 7.5%.[27]

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Table 2. The major current ACC/AHA guidelines[1] for statin indications taking the level of evidence into account A. Must give Class of recommendation I, level of evidence A: • Persons <75 years of age with clinical ASCVD, give high intensity dose; if not tolerated, give moderate dose • Persons 40 - 75 years of age with DM, without ASCVD and with an LDL-C 1.8 - 4.8 mmol/l, give moderate dose (Fig. 2) • Primary prevention in adults 45 - 75 years of age, without ASCVD or DM and estimated 10-year ASCVD risk of ≥7.5% (Fig. 2) B. Reasonable to give Class of recommendation I, level of evidence B: • Primary prevention in patients ≥21 years of age with an LDL-C ≥4.9 mmol/l; high dose, or if not tolerated, moderate dose • Primary prevention in patients ≥21 years of age with an LDL-C 1.8 - 4.8 mmol/l and 10-year risk of ≥7.5% • Genetic predisposition: No clear recommendation but include genetically high LDL-C ≥4.1 mmol/l, strong family history Class of recommendation IIA, level of evidence B: • P atients ≥75 years of age with clinical ASCVD after considering the potential benefit v. potential adverse effects, drug-drug interactions and personal preference; give moderate to high dose ASCVD = atherosclerotic cardiovascular disease; DM = diabetes mellitus; LDL-C = low-density lipoprotein cholesterol.

The most recent approach, derived from the Treating to New Targets (TNT) trial (N=10 001), gives 13 easy-to-measure clinical predictors: age; sex; smoking; diabetes mellitus; total cholesterol; HDL-C; systolic BP; history of myocardial infarction; coronary artery bypass grafting; congestive heart failure or abdominal aortic aneurysm; glomerular filtration rate; and treatment status (low- (10 mg) or high-dose (80 mg) atorvastatin). [28] When applying these factors in the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial (N=8 888), the model identified a group of 11.7% whose predicted 5-year number needed to treat (NNT) was ≤25 and a group of 41.9% whose predicted NNT was ≥50.[28] Of note, however, peripheral artery disease and stroke were not included. Should low-risk CVD patients take a statin? This remains an unresolved issue, the problem being that in clinical practice the level of risk is decided largely by the levels of LDL-C and not by clear clinical criteria. The current Cochrane review supports statin use for primary prevention even in patients at risk levels <10%.[29] The review found reductions in all-cause mortality, major vascular events and revascularisations with no excess of adverse events among people without evidence of CVD treated with statins. These data make a strong case for statins in primary prevention in selected patients with risk rates that merit therapy (see section on risk prediction). Could additional tests help the decision? Supporting the current concept that vascular inflammatory changes are fundamental to the development of atherosclerosis,[24] months of

Skeletal: adverse

Statin Exercise training

Slow down to fast walking pace

Less myalgia CK rarely raised

Myalgia Intention to continue running CK raised Options Stop statin Continue running

Continue statin Switch to fast walking

Fig. 4. Suggested algorithm for runners developing myalgia. For advantages of walking fast and intensely, refer to Jukema et al.[39] (CK = creatine kinase.)

potent statin therapy reduced C-reactive protein (CRP) levels in association with decreased major adverse coronary events. [30] Thus, inflammation may be an important driver of residual cardiovascular risk in patients with coronary artery disease despite aggressive statin therapy. The advantage for South African doctors is that highsensitivity CRP and apolipoprotein a can be measured easily.[26] In exceptional cases the accuracy of risk prediction may be improved by imaging techniques such as carotid ultrasound, coronary calcium scoring or computed tomography coronary angiography, which may detect preclinical atherosclerosis and thereby support the need for treatment.[26]

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Cardiac: beneficial

Mitochondrial effects

Statin side-effect: Memory lost or improved?

An anguished patient cried out: ‘Several people I know had terrible leg cramps when they took statins. I also read in the paper that statins can cause memory loss. My doctor wants me to start taking statins, but I’m scared. How real are these concerns?’[31] According to the Cochrane review,[29] few side-effects should be anticipated. However, two that often concern patients are memory loss and, especially in exercising patients, myalgia. At least some degree of memory loss is inevitable in the age group of many persons taking statins. Data from the large randomised controlled trials assessing the development of

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Table 3. Interaction between varying degrees of exercise-induced fitness and statin treatment on mortality rates in dyslipidaemic US veterans[11]* Category

Total, N

MET† group

Deaths, %

HR unadjusted

HR fully adjusted

p-value‡

Least fit No statin

1 024

≤5.0

1.22

1.35

<0.0001

Statin

1 060

≤5.0

1.0

No statin

1 154

5.1 - 7.0

0.81

1.02

0.81§

Statin

1 573

5.1 - 7.0

0.57

0.65

<0.0001

No statin

1 335

7.1 - 9.0

0.50

0.81

0.01

Statin

1 705

7.1 - 9.0

0.28

0.41

<0.0001

Moderately fit

Fit

Highly fit No statin

1 498

>9.0

0.27

0.53

<0.0001

Statin

694

>9.0

0.16

0.30

<0.0001

MET = metabolic equivalent of task; HR = hazard ratio. *Data from Kokkinos et al.[10] (Tables 3 and 4). † Measure of energy expenditure; 1 MET is the amount of energy required to sit quietly. ‡ p-value for fully adjusted HRs. § p-value not significant.

Alzheimer’s disease and memory loss are not yet available. Though initial analyses indicate that statins do not prevent Alzheimer’s disease, they have a significant beneficial effect on the mini-mental state 30-point questionnaire test used to screen for cognitive impairment.[32] A meta-analysis of 16 studies focused on short- and long-term cognitive effects of statins found no short-term benefit with suggestion of a longterm benefit in preventing dementia.[33] The anti-inflammatory effects of statins provide a plausible mechanism for these statin effects.[34]

Statin side-effect: Myalgia

Prominent among the statin side-effects are myalgia and muscular weakness, which may be associated with a rise in circulating creatine kinase (CK).[35] In order of increasing severity and decreasing incidence, the statin-induced muscle-related conditions are myalgia, myopathy with elevated CK levels with or without symptoms, and rhabdomyolysis. Statins may increase CK levels without decreasing average muscle strength or exercise performance. In one large study, only about 2% had myalgia that could be attributed to statin use.[35] At a cellular level, statins optimise cardiac mitochondrial function but impair skeletal mitochondrial function by inducing different levels of reactive oxygen species at these two sites. The level of exercise and/or dose of statin may need reduction if the severity of the pain is limiting exercise (Fig. 4). Coenzyme Q10 has no proven benefit.[35] Myalgia should be balanced against the positive health benefits of statins beyond the cardiovascular, which include decreased adverse events in heart failure patients,[36] decreased atrial fibrillation, modest antihypertensive effects and reduced risks of malignancies.[35]

Statins and new-onset diabetes

The four major risk factors for developing diabetes are: metabolic syndrome; impaired fasting glucose; body mass index (BMI) ≥30 kg/ m2 and glycated haemoglobin A1c >6%.[37] In a 5-year trial (N=17 603) in those with one or more risk factors, the use of 20 mg rosuvastatin daily was associated with a 39% reduction in the first occurrence of a major cardiovascular event (hazard ratio (HR) 0.61; p=0.0001) and a 28% increase in diabetes (HR 1.28; 95% confidence interval (CI) 1.07 - 1.54; p=0.01).[37]

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Overall, considering all statins, in 13 trials (N=91 140) statin therapy was associated with a 9% (95% CI 1.02 - 1.17) increased risk for incident diabetes.[38] Treatment of 255 patients with statins for 4 years resulted in only one extra case of diabetes.[38] This small absolute risk for new diabetes is more than outweighed by cardiovascular benefits.[39] Thus, in 17 080 patients high-dose statin therapy over 5 years decreased ACS or death by 45% at the cost of 13.3% new-onset diabetes.[40] Most importantly, new-onset diabetes can be avoided if the patient has none or only 1/4 risk factors for new diabetes: fasting blood glucose >5.5 mmol/l; fasting triglycerides >1.7 mmol/l; BMI >30 kg/m2; and a history of hypertension. In those with 2 - 4 of these adverse factors, new-onset diabetes developed in 14%.[41] Which statins are least likely to cause new diabetes? Compared with pravastatin, which was not associated with new diabetes, the absolute risks were 26, 31 and 34 events per 1 000 years of therapy, respectively, for simvastatin, atorvastatin and rosuvastatin.[42] These are remarkably low risks.

Statins in renal disease

In patients with chronic kidney disease, including those receiving dialysis, statins reduce the risk of major cardiovascular events.[43]

Lifestyle plus statins: Do they go together?

This is an ideal combination for those with high LDL-C levels that do not respond to lifestyle changes alone or for those who have not received or are unlikely to follow advice about making lifestyle changes. For some, if not many, patients it may be easier to take one or two tablets each day than to find the time and determination to exercise regularly. Despite this, the attending medical practitioner should strongly recommend combining statins with lifestyle changes, including exercise. In an observational study, both statins and exercise individually reduced the adverse outcomes of CVD. Their combined effects were additive (Table 3). In the least physically fit, no statin group, baseline total cholesterol was 6.0 mmol/l, with baseline LDL-C being

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4 mmol/l. After statin treatment, total cholesterol was 4.1 mmol/l, and LDL-C was 2.6 mmol/l (p<0.0001). Before intense exercise, lipids levels were similar. After intense exercise training, values were: total cholesterol 5.1 mmol/l, with LDL-C being 3.6 mmol/l. The combination of high fitness (for definition, refer to Lee and Paffenbarger[45]) and statin treatment in patients yielded a substantial reduction in mortality risk than in those who were least fit and either taking statin or no statin (HR 0.30; p<0.0001). The major unresolved problem is that either exercise or statins can singly cause muscular symptoms with an elevation of serum CK.[35] There is, as yet, no clearly defined outcomes-based policy to deal with such symptoms. A reasonable practical approach is to assess the CK level, and if elevated, to reduce either the statin dose or the intensity of exercise to brisk walking (Fig. 4).[44,45]

Conclusion

Both lifestyle changes and statin therapy and their combination have well-defined positive roles in the management of the patient who needs advice on cardiovascular health. Acknowledgements. We thank Proff M Ntsekhe and P J Commerford, Department of Cardiology, Groote Schuur Hospital, Cape Town, South Africa for their helpful comments. References 1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2013. [http:// dx.doi.org/10.1161/01.cir.0000437738.63853.7a] 2. Chiuve SE, McCullough ML, Sacks FM, Rimm EB. Healthy lifestyle factors in the primary prevention of coronary heart disease among men: Benefits among users and nonusers of lipid-lowering and antihypertensive medications. Circulation 2006;114(2):160-167. [http://dx.doi.org/10.1161/ CIRCULATIONAHA.106.621417] 3. Chiuve SE, Rexrode KM, Spiegelman D, Logroscino G, Manson JE, Rimm EB. Primary prevention of stroke by healthy lifestyle. Circulation 2008;118(9):947-954. [http://dx.doi.org/10.1161/ CIRCULATIONAHA.108.781062] 4. Van Dam RM, Li T, Spiegelman D, Franco OH, Hu FB. Combined impact of lifestyle factors on mortality: Prospective cohort study in US women. BMJ 2008;337:a1440. [http://dx.doi.org/10.1136/bmj.a1440] 5. Dong C, Rundek T, Wright CB, Anwar Z, Elkind MS, Sacco RL. Ideal cardiovascular health predicts lower risks of myocardial infarction, stroke, and vascular death across whites, blacks, and hispanics: The northern Manhattan study. Circulation 2012;125(24):2975-2984. [http://dx.doi.org/10.1161/ CIRCULATIONAHA.111.081083] 6. Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med 2011;364:2392-2404. [http://dx.doi.org/10.1056/ NEJMoa1014296] 7. Yates T, Haffner SM, Schulte PJ, et al. Association between change in daily ambulatory activity and cardiovascular events in people with impaired glucose tolerance (NAVIGATOR trial): A cohort analysis. Lancet 2013. [http://dx.doi.org/10.1016/S0140-6736(13)62061-9] 8. Piepoli MF, Davos C, Francis DP, Coats AJ; ExTraMATCH Collaborative. Exercise training metaanalysis of trials in patients with chronic heart failure (ExTraMATCH). BMJ 2004;328:189-196. [http:// dx.doi.org/10.1136/bmj.37938.654220.EE] 9. Posel D, Noakes T, Kantor P, Lambert M, Opie LH. Exercise training after experimental myocardial infarction increases the ventricular fibrillation threshold before and after the onset of reinfarction in the isolated rat heart. Circulation 1989;80(1):138-145. [http://dx.doi.org/10.1161/01.CIR.80.1.138] 10. Noakes TD, Opie LH, Rose AG, Kleynhans PH, Schepers NJ, Dowdeswell R. Autopsy-proved coronary atherosclerosis in marathon runners. N Engl J Med 1979;301(2):86-89. [http://dx.doi.org/10.1056/ NEJM197907123010205] 11. Kokkinos PF, Faselis C, Myers J, Panagiotakos D, Doumas M. Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: A cohort study. Lancet 2013;381:394-399. [http://dx.doi.org/10.1016/S0140-6736(12)61426-3] 12. Kujala UM, Mäkinen VP, Heinonen I, et al. Long-term leisure-time physical activity and serum metabolome. Circulation 2013;127(3):340-348. [http://dx.doi.org/10.1161/CIRCULATIONAHA.112.105551] 13. Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med 2011;364(25):2392-2404. [http://dx.doi.org/10.1056/ NEJMoa1014296] 14. Shai I, Schwarzfuchs D, Henkin Y, et al; Dietary Intervention Randomized Controlled Trial (DIRECT) Group. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med 2008;359(3):229-241. [http://dx.doi.org/10.1056/NEJMoa070868] 15. Noakes TD, Creed S-A, Proudfoot J, Grier D. The Real Meal Revolution. Cape Town: Quivertree Publications, 2013. 16. Noakes M, Foster PR, Keogh JB, James AP, Mamo JC, Clifton PM. Comparison of isocaloric very low carbohydrate/high saturated fat and high carbohydrate/low saturated fat diets on body composition and cardiovascular risk. Nutr Metab (Lond) 2006;3:7. [http://dx.doi.org/10.1186/1743-7075-3-7] 17. Noakes TD. Low-carbohydrate and high-fat intake can manage obesity and associated conditions: Occasional survey. S Afr Med J 2013;103(11):826-830. [http://dx.doi.org/10.7196/SAMJ.7302]

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18. Poulsen SK, Due A, Jordy AB, et al. Health effect of the New Nordic Diet in adults with increased waist circumference: A 6-mo randomized controlled trial. Am J Clin Nutr 2014;99(1):35-45. [http://dx.doi. org/10.3945/ajcn.113.069393] 19. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 2003;348(26):2599-2608. [http://dx.doi.org/10.1056/ NEJMoa025039] 20. Estruch R, Ros E, Salas-Salvadó J, et al; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet N Engl J Med 2013;368:1279-1290. [http://dx.doi. org/10.1056/NEJMoa1200303] 21. Opie LH. Mediterranean diet for primary prevention of cardiovascular disease. N Engl J Med 2013;369:672-677. [http://dx.doi.org/10.1056/NEJMc1306659] 22. Bao Y, Han J, Hu FB, et al. Association of nut consumption with total and cause-specific mortality. N Engl J Med 2013;369:2001-2011. [http://dx.doi.org/10.1056/NEJMoa1307352] 23. Shaodong C, Haihong Z, Manting L, Guohui L, Zhengxiao Z, Zhang YM. Research of influence and mechanism of combining exercise with diet control on a model of lipid metabolism rat induced by high fat diet. Lipids Health Dis 2013;12:21. [http://dx.doi.org/10.1186/1476-511X-12-21] 24. Arnold SV, Spertus JA, Masoudi FA, et al. Beyond medication prescription as performance measures: Optimal secondary prevention medication dosing after acute myocardial infarction. J Am Coll Cardiol 2013;62(19):1791-1801. [http://dx.doi.org/10.1016/j.jacc.2013.04.102] 25. Baigent C, Keech A, Kearney PM, et al.; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366(9493):1267-1278. [http://dx.doi. org/10.1016/S0140-6736(05)67394-1] 26. Klug E; South African Heart Association (S A Heart); Lipid and Atherosclerosis Society of Southern Africa (LASSA). South African Dyslipidaemia Guideline Consensus Statement. S Afr Med J 2012;102(3):178-187. 27. Ridker PM, Cook NR. Statins: New American guidelines for prevention of cardiovascular disease. Lancet 2013;382(9907):1762-1765. [http://dx.doi.org/10.1016/S0140-6736(13)62388-0] 28. Dorresteijn JA, Boekholdt SM, van der Graaf Y, et al. High-dose statin therapy in patients with stable coronary artery disease: Treating the right patients based on individualized prediction of treatment effect. Circulation 2013;127(25):2485-2493. [http://dx.doi.org/10.1161/ CIRCULATIONAHA.112.000712] 29. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013;1:CD004816. [http://dx.doi.org/10.1002/14651858. CD004816.pub5] 30. Puri R, Nissen SE, Libby P, et al. C-reactive protein, but not low-density lipoprotein cholesterol levels, associate with coronary atheroma regression and cardiovascular events after maximally intensive statin therapy. Circulation 2013;128(22):2395-2403. [http://dx.doi.org/10.1161/CIRCULATIONAHA.113.004243] 31. Heart Advisor. October 2008. http://www.heart-advisor.com/issues/11_10/ (accessed 31 January 2014). 32. McGuinness B, Passmore PJ. Can statins prevent or help treat Alzheimer's disease? Alzheimers Dis 2010;20(3):925-933. [http://dx.doi.org/10.3233/JAD-2010-091570] 33. Swiger KJ, Manalac RJ, Blumenthal RS, et al. Statins and cognition: A systematic review and metaanalysis of short- and long-term cognitive effects. Mayo Clin Proc 2013;88(11):1213-1221. [http:// dx.doi.org/10.1016/j.mayocp.2013.07.013] 34. Tendolkar I, Enajat M, Zwiers MP, et al. 1-year cholesterol lowering treatment reduces medial temporal lobe atrophy and memory decline in stroke-free elderly with atrial fibrillation: Evidence from a parallel group randomized trial. Int J Geriatr Psychiatry 2012;27(1):49-58. [http://dx.doi. org/10.1002/gps.2688] 35. Opie LH. Exercise-induced myalgia may limit the cardiovascular benefits of statins. Cardiovasc Drugs Ther 2013;27(6):569-572. [http://dx.doi.org/10.1007/s10557-013-6483-8] 36. Correale M, Totaro A, Passero T, et al. Treatment with atorvastatin is associated with a better prognosis in chronic heart failure with systolic dysfunction: Results from the Daunia Heart Failure Registry. Neth Heart J 2013;21(9):408-416. [http://dx.doi.org/10.1007/s12471-013-0430-y] 37. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: An analysis from the JUPITER trial. Lancet 2012;380(9841):565571. [http://dx.doi.org/10.1016/S0140-6736(12)61190-8] 38. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: A collaborative metaanalysis of randomised statin trials. Lancet 2010;375(9716):735-742. [http://dx.doi.org/10.1016/ S0140-6736(09)61965-6] 39. Jukema JW, Cannon CP, de Craen AJ, Westendorp RG, Trompet S. The controversies of statin therapy: Weighing the evidence. J Am Coll Cardiol 2012;60(10):875-881. [http://dx.doi.org/10.1016/j. jacc.2012.07.007] 40. Ko DT, Wijeysundera HC, Jackevicius CA, et al. Diabetes mellitus and cardiovascular events in older patients with myocardial infarction prescribed intensive-dose and moderate-dose statins. Circ Cardiovasc Qual Outcomes 2013;6(3):315-322. [http://dx.doi.org/10.1161/ CIRCOUTCOMES.111.000015] 41. Waters DD, Ho JE, Boekholdt SM, et al. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: Effect of baseline risk factors for diabetes. J Am Coll Cardiol 2013;61(2):148-152. [http://dx.doi.org/10.1016/j.jacc.2012.09.042] 42. Carter AA, Gomes T, Camacho X, et al. Risk of incident diabetes among patients treated with statins: Population based study. BMJ 2013;346:f2610. [http://dx.doi.org/10.1136/bmj.f2610] 43. Hou W, Lv J, Perkovic V, Yang L, et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: A systematic review and meta-analysis. Eur Heart J 2013;34(24):1807-1817. [http://dx.doi.org/10.1093/eurheartj/eht06] 44. Schnohr P, Scharling H, Jensen JS. Intensity versus duration of walking, impact on mortality: the Copenhagen City Heart Study. Eur J Cardiovasc Prev Rehabil 2007;14(1):72-78. [http://dx.doi. org/10.1097/HJR.0b013e3280144470] 45. Lee IM, Paffenbarger RS Jr. Associations of light, moderate, and vigorous intensity physical activity with longevity: The Harvard Alumni Health Study. Am J Epidemiol 2000;151(3):293-299. [http:// dx.doi.org/10.1093/oxfordjournals.aje.a010205] 46. Opie LH. Living Longer, Living Better. Exploring the Heart-Mind Connection. Oxford: Oxford University Press, 2011:36. 47. Gotto A Jr, Opie LH. Lipid-modifying and anti-atherosclerotic drugs. In: Opie LH, Gersh BJ, eds. Drugs for the Heart. 7th ed. Philadelphia: Elsevier Saunders, 2009:353.

Accepted 16 January 2014.

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REVIEW

Isoniazid preventive therapy for tuberculosis in South Africa: An assessment of the local evidence base R Wood, FCP (SA), DSc (Med); L-G Bekker, FCP (SA), PhD Robin Wood and Linda-Gail Bekker are based at the Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, South Africa Corresponding author: L-G Bekker (linda-gail.bekker@hiv-research.org.za)

Worldwide, South Africa (SA) has the worst tuberculosis (TB) epidemic. In SA, there are >6.1 million people living with HIV (PLWH) and the country now has the largest antiretroviral treatment programme with >2 million people receiving combination therapy. While there has been a marked recent decline in HIV-associated deaths, >50% of TB cases still continue to be diagnosed in PWLH. The current TB control strategy based on passive case finding, chemotherapy of childhood TB contacts and directly observed therapy has clearly failed to control endemic TB in SA. Two recent meta-analyses have shown a >60% reduction in TB in HIV-infected adults after isoniazid preventive therapy (IPT). SA has implemented the World Health Organization policy and IPT is now recommended for HIV-positive people for up to 36 months. Originally, there was only one SA study included in the evidence base supporting this policy, but subsequently four randomised controlled trials have been conducted in SA populations. These studies, together with local observational studies, are the subject of this local, evidence-based review. S Afr Med J 2014;104(3):174-177. DOI: 10.7196/SAMJ.7968

South Africa (SA) has the worst tuberculosis (TB) epidemic of any major country in the world, with >300 000 cases notified each year.[1] There are >6.1 million people living with HIV (PLWH) in SA, and the country now has the largest antiretroviral treatment (ART) programme with >2 million people receiving combination therapy.[2] While there has been a marked recent decline in HIV-associated deaths,[2] >50% of TB cases still continue to be diagnosed in PWLH.[1] However, even HIV-uninfected individuals continue to develop active TB at rates as high as those recorded before the availability of chemotherapy.[3] The current TB control strategy based on passive case finding, chemotherapy of childhood TB contacts and directly observed therapy has clearly failed to control endemic TB in SA.[4] This critical situation has produced a body of policy makers who have proposed that TB control may be restored in part by expanding previously targeted preventive strategies to all PLWH,[1,5,6] or to whole communities.[7] Isoniazid (INH) prophylaxis of TB infection was first demonstrated in animal models in the 1950s,[8] studied in childhood contacts of TB cases in the 1960s[9] and became recommended for children <5 years of age with an adult household contact.[10] A combined analysis of randomised controlled trials (RCTs) of isoniazid preventive therapy (IPT) in (HIV-uninfected) adults performed between 1962 and 1994 demonstrated a reduction of active TB by 60% in a variety of recently TB-exposed or -infected populations.[11] A subsequent Cochrane meta-analysis of 12 RCTs of IPT in HIV-infected adults, largely without ART, showed a 62% reduction in TB, restricted to individuals with positive tuberculin skin tests (TSTs).[12] However, the World Health Organization (WHO) considered performing TSTs a stumbling block to the implementation of IPT and in 2011 revised the IPT guidelines, making a strong explicit recommendation that ‘TST was not a requirement for initiating IPT in PLWH’.[1] SA has implemented WHO policy and IPT is now recommended for all 6.1 million PLWH[2] for up to 36 months.[5,6]

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Originally, there was only one SA study included in the evidence base supporting this policy,[13] but subsequently four RCTs have been conducted in SA populations.[14-18] These, together with local observational studies, are the subject of this local data review.

Mechanisms of IPT action

IPT is based on the widely accepted theory that primary infection with Mycobacterium tuberculosis is followed by a latent phase during which dormant tubercle bacilli may reactivate to cause TB disease. [19] INH sterilises these latent organisms. However, bacteriological latency may not correlate perfectly with clinical latency and a more dynamic balance between organism and host immunity may determine progression to active disease.[20] INH may act by altering this balance in favour of the host and against the organism.

Tuberculin skin testing

The TST has remained the primary method for targeting IPT to those with known TB infection, but the TST is subject to both physiological and post-treatment reversions.[21] A positive TST in childhood generally reflects recent infection with a high risk of progression to active disease. In contrast, the majority of SA adults are latently infected and a positive TST reflects earlier TB infection, which is associated with a lowered risk of endogenous reactivation[22] and protection (79% confidence interval (CI) 70 - 86%) against TB re-infection progressing to active disease.[23] HIV-infection increases TB incidence,[24] but TST-positivity decreases as CD4+ cell counts decline.[25] While ART improves CD4+ cell counts[26] and TB immunity,[27] the changes in the TST during ART have not been well characterised.

Challenges for IPT implementation

In contrast to the implementation of the ART programme, nontargeted IPT implementation has been very poor.[28] Rationale for the reticence to implement IPT include: that short-term trial efficacy

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2.95 3.02 N/A N/A 6.9|| 2.7 39 41 years N/A 78 744 Churchyard et al.[17]

Mining workforce

16.2

N/A 0

72 52

52 36 years

34 years 216 (152 - 360)

354 (191 - 466) HIV-positive, symptomatic, TST-positive

HIV-positive, ART clinic attenders

1 580 Rangaka et al.[16]

N/A

9.3 0

N/A 96

52§ 38 years

4 months N/A

99 (24 - 269) HIV-negative, symptomatic, TST-negative

HIV-negative, exposed outpatients 804

118 Mohammed et al.[13]

15.7 N/A

RCTs = randomised controlled trials; IPT = isoniazid preventive therapy; IQR = interquartile range; ART = antiretroviral therapy; PYs = person years; TB = tuberculosis; TST = tuberculin skin test; INH = isoniazid; N/A = not applicable; HR = hazard ratio; CI = confidence interval. *INH 5 mg/kg daily or thrice weekly until age of 12 months continued in immunological impaired (CD4+ count <15%) and symptomatic HIV. † HR: 0.46 (95% CI 0.22 - 0.95). ‡ HR: 0.28 (95% CI 0.10 - 0.78). § INH 15 mg/kg twice weekly. ¶ HR: 0.63 (95% CI 0.41 - 0.94). || Intensified TB screening of 27 126 individuals randomised to the intervention cohort.

3.6

N/A 6.8 N/A

1.2

0.9

18 34.7 27.9

6.9 0.5 0.5

2.3¶

11.6

7.7

23.4 7.2

9.4 32

9 52*

96 4 months

25 months 20% (14 - 28)

28% (6 - 58) HIV-positive, hospital outpatients

HIV-positive, hospital symptomatic 263

548 Madhi et al.[15]

Zar et al.

[14]

N/A

†

8.2

Placebo

37.8

4.2 6.1

‡

IPT Placebo

Deaths/100 PYs Study population

Status N

Table 1. RCTs of IPT conducted in South Africa

CD4+ cell count, % or mean (IQR)

Age, mean

Regimen (weeks)

ART use at baseline, %

TB baseline prevalence, %

IPT

TB incidence/100 PYs

FORUM

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data preceded widespread introduction of ART and may lack current relevance; TST-positive ART-naive individuals who were the subgroup with demonstrable benefit, constitute only a minority of PLWH;[25] the TST-negative majority of PLWH may be subjected to therapy without personal benefit; any sustained benefit is considerably reduced in SA where the ongoing risk of TB re-infection is high; lack of long-term effectiveness limits potential epidemiological impact; where service delivery falls short of desired levels, the implementation of IPT may overburden the healthcare system and divert attention from more effective treatment priorities; INH is an important component of standard TB treatment, resistance is already high and clinical experience has shown that widespread use of antibiotics is inevitably followed by increasing drug resistance, a concern reinforced by a recent modelling study of the long-term impact of community-wide IPT.[29]

RCTs in SA

SA clinical scientists have performed several large and well-conducted RCTs of IPT, which have contributed significantly to the existing body of scientific evidence and are summarised in Table 1. Two RCTs have been performed in SA paediatric populations. The first; randomised 263 HIV-positive children, recruited in two Cape Town teaching hospitals, to daily or thrice-weekly IPT or placebo.[14] The children had advanced symptomatic HIV manifested by low weight-for-age and height. The study was discontinued because of an early survival benefit largely in the first 6 months in the IPT arm compared with the control arm. TB incidence was also reduced in the intervention arm by 72%. Few of the children were receiving ART at baseline because the study was conducted prior to wide access to ART. Diagnosis of TB in sick HIV-infected infants is difficult and the early mortality benefit observed in this study may have resulted from INH treatment of unrecognised primary TB.[30] A second paediatric RCT, a primary prevention with 96 weeks IPT v. placebo, was conducted in 548 HIV-infected and 804 HIV-exposed children <4 months of age, recruited from hospital clinics in Johannesburg, Cape Town and Durban.[15] The HIV-infected children in this study were less sick than in the prior study and ART use was higher, with 99% commencing ART during the study. There was no difference in TB infection, TB disease or death between the INH and control arms in either HIV-infected or HIVexposed children. INH resistance was noted in 28% of TB cases. The very different outcomes in these two paediatric studies underscore the importance of exercising great care when generalising beyond the population under study.[29] The study populations differed by age, severity of HIV disease, nutritional status and ART use, as illustrated by very different TB and mortality rates in the control arms of each study. The single SA study included in the Cochrane review[12] was an RCT of IPT given twice weekly to TST-negative, HIV-infected adults, all of whom were anergic.[13] The study, which was conducted before ART availability in a population with advanced HIV disease, showed no effect on mortality or TB incidence.[13] The majority of screened subjects were TST-negative and the 17% of subjects with a positive TST who qualified for IPT under existing guidelines had much higher CD4+ cell counts than those in the randomised study population. The statistical power of the study was reduced, as TB incidence rate in the study was considerably lower than reported previously, probably due to exclusion of TB cases treated within the previous 5 years and baseline TB screening including sputum culture. Over 2 000 patients attending an ART clinic in Cape Town were assessed for entry into an RCT with 12 months IPT.[16] Of the 1 536 otherwise consenting and eligible patients, 250 were diagnosed with prevalent active TB disease by screening, including sputum culture, at baseline. Of the finally enrolled population, 43% reported a history of prior TB, only 30% were TST-positive and the majority was already established receiving ART before initiating IPT. During a follow-up of mean 2.4 years, 37 and 58 incident cases were identified in the IPT and control arms, respectively; (hazard ratio (HR) 0.62; 95% CI 0.41 - 0.94). Drug-resistance testing

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identified INH resistance in 6/25 (24%) cases tested. All-cause mortality did not differ between intervention and control arms. In secondary analysis there was no evidence that the effect of IPT was restricted to those who were TST-positive. The authors concluded that the ‘ … modest effects described and the high rate of TB in the IPT arm, suggest ART plus IPT alone may not be adequate to control TB at the population level’. These two studies again underscore the hazard of generalising beyond any study population, as it appears that the predictive value of TST testing for IPT may be more important before ART when immunity is deteriorating than after ART when immunity is improving. TB screening in both studies had a very high yield of TB cases. A very large community-wide RCT in SA miners randomised the workforce of eight mineshafts to receive 9 months of IPT and of seven mineshafts to receive placebo. The primary endpoint was TB incidence during the following year and secondary endpoint TB prevalence at the study end.[7] The placebo clusters were screened within the normal mining healthcare service but those in the IPT arm underwent more intensive TB screening.[31] There were no differences in either primary or secondary endpoints between treatment and control arms.[17,18] A post hoc analysis of participants commencing IPT in the intervention cohort had a temporary non-sustained decrease in TB incidence compared with controls.[17,18] The positive results of the post hoc analysis were attributed to a temporary benefit of IPT. However, the differential screening procedures between the two study arms did not allow for attribution of benefit to either IPT or to intensified TB screening. A laboratory sub-study of INH resistance reported 12% resistance in first TB cases but no significant increase in the IPT arm compared with the control group.[32]

Observational studies in SA

A large observational study (N=2 778) in urban and rural SA compared TB-free survival during a mean of 1.5 years, split into time accrued receiving IPT, ART, and IPT with ART, and reported a significantly high effectiveness of IPT in combination with ART.[33] Exceptionally wide confidence limits and selection bias did not support the conclusion of significant IPT benefit.[34] A second large observational study of 3 270 workers in an occupational health setting reported a 49% reduction in mortality associated with receipt of IPT prior to or during ART.[35] The HR remained significant after adjustment for clinical parameters, CD4+ cell count, calendar year and employing company. Although the authors’ reporting of a halving of mortality by IPT was plausible among individuals initiating ART in a setting of high TB incidence,[35] no

similar mortality benefit of additional IPT with ART has been reported in any randomised adult study.

Implications of local studies

Variable study results can provoke one of two scientific responses: to look harder within our existing theory with even larger and longer studies with more meta-analyses; or alternatively, to question our basic biological and epidemiological assumptions. Much of the interstudy variability in IPT efficacy can be explained by differential baseline screening procedures, differential use of ART and different TB exposures. The two studies, which screened all participants with TB culture, reported much lower TB rates in the control arms than predicted.[13,16] The control arm of the mining study with no additional TB screening at baseline was followed by TB incidence similar to historic levels.[17] Intensified baseline TB screening in the IPT arm that identified and excluded an additional 1 705 (6.9%) prevalent TB cases was followed by a transient lowered TB incidence. [17] Additionally, the magnitude of the prevalent TB cases identified by intensified screening was two-fold higher than all the cases identified during each of these studies and far exceeded the numbers of cases prevented by IPT. Studies with ART had much lower clinical event frequencies in both paediatric and adult studies than those without ART. Furthermore, INH performed different biological roles, each with differential efficacy, in the different populations including: prophylaxis both before and after a known TB exposure; treatment of childhood primary TB; sterilisation of recent or distantly acquired ‘latent’ infection; and treatment of either pauci- or multibacillary adult disease. Table 2 outlines a conceptual framework of the different population groups in each of the studies. While in the TB-susceptible paediatric populations, stratification can be by known TB exposure (household contact) and primary disease (symptomatic), adult studies are stratified by TST status which, in an already infected population, reflects distantly acquired primary infection, but also TB re-infection and in PLWH, immune decline and recovery before and after ART, respectively. Treatment of active TB disease with INH monotherapy will occur more frequently in situations where TB diagnosis is difficult or when screening procedures are less stringent. Paediatric TB diagnosis is difficult; therefore undiagnosed primary TB would be highest in symptomatic HIV disease, lower in asymptomatic HIV disease and lowest in the asymptomatic HIV-uninfected children. All TST-negative adult subjects prior to ART were anergic, a reflection of poor immunity rather than identification of a group without prior TB infection. It is unclear how TST-positivity after

Table 2. Study populations by HIV, TST and probable TB exposure Paediatric subjects

HIV status

Pre-primary exposure*

Known primary exposure

Primary disease*

Zar et al.

Positive

Excluded

Madhi et al.[15]

Positive

+++

Excluded

[14]

Negative

+++

Excluded

Adult subjects

HIV status

TST-negative*

TST-positive: Recent*

TST-positive: Distant*

Mohammed et al.[13]

Positive

+++

Positive Rangaka et al.[16] Churchyard et al.

[17]

+++

Positive

+/-

Positive

+/-

Negative

+/-

+++

TST = tuberculin skin test; TB = tuberculosis; ARI = annual risk of TB infection. *Estimated frequencies: +/- determined by the ARI; + determined by ARI and rate of progression of primary infection to active TB; ++: 10 - 50%; +++: >50%.

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initiating ART reflects immune recovery or new TB exposures. However, TSTs appeared to identify groups with different responses to IPT pre and post ART. Extrapolation of results from the pre-ART era may now lack relevance in an era of greater access to ART. The observation that INH resistance was not increased in wellconducted IPT studies in which screening procedures ensured unrecognised active TB was minimal;[31] is not necessarily reassuring for future scenarios where IPT is given to 6.1 million PLWH without similar screening procedures.[5,6]

Conclusions

The total lack of IPT efficacy in the community-wide study, and only modest benefits in the ART clinic population, indicate that hopes that IPT would positively impact the TB epidemic in SA are optimistic. Intensified TB screening at study entry identified a large number of previously unrecognised TB cases, was associated with a decrease in subsequent TB incidence and identified many more cases than occurred during the course of the studies. Of concern, the prevalence of INH resistance was high in all those studies where it was measured. Therefore expansion of IPT to all PLWH in SA must be associated with efficient TB screening and monitoring of INH resistance. Importantly, implementation of this modestly beneficial intervention should not divert us from the priority to increase access to ART urgently and reduce the treatment gap. TB control will require a new focus on reducing ongoing transmission, which results in the majority of our population becoming TB infected before adulthood.[36] 1. WHO Department of HIV/AIDS, Stop TB Department. Guidelines for Intensified Tuberculosis Case-Finding and Isoniazid Preventive Therapy for People Living with HIV in Resource-Constrained Settings. Geneva: WHO, 2010. http://www.who.int/hiv/pub/tb/9789241500708/en/ (accessed 10 February 2014). 2. Joint United Nations Programme on HIV/AIDS. Global Report: UNAIDS Report on the Global AIDS Epidemic 2013. Geneva: UNAIDS, 2013. http://www.unaids.org/en/media/unaids/ contentassets/documents/epidemiology/2013/gr2013/UNAIDS_Global_Report_2013_en.pdf (accessed 10 February 2014). 3. Wood R, Lawn SD, Caldwell J, et al. Burden of new and recurrent tuberculosis in a major South African city stratified by age and HIV-status. PLoS One 2011;6(10):e25098. [http://dx.doi.org/10.1371/journal. pone.0025098] 4. Wood R, Lawn SD, Johnstone-Robertson S, Bekker L-G. Tuberculosis control has failed in South Africa â&#x20AC;&#x201C; time to reappraise strategy. S Afr Med J 2011;101(2):111-114. 5. National Department of Health. Guidelines for Tuberculosis Preventive Therapy Among HIV Infected Individuals in South Africa. Pretoria: NDoH, 2010. http://www.sasohn.co.za/images/TB%20 prophylaxis%20in%20South%20Africa%20final%20%2031%2003%2010.pdf (accessed 10 February 2014). 6. National Department of Health. South African Antiretroviral Treatment Guidelines 2013. Pretoria: NDoH, 2013. http://www.sahivsoc.org/upload/documents/2013%20ART%20Guidelines-Short%20Combined%20 FINAL%20draft%20guidelines%2014%20March%202013.pdf (accessed 10 February 2014). 7. Fielding KL, Grant AD, Hayes RJ, Chaisson RE, Corbett EL, Churchyard GJ. Thibela TB: Design and methods of a cluster randomised trial of the effect of community-wide isoniazid preventive therapy on tuberculosis amongst gold miners in South Africa. Contemp Clin Trials 2011;32(3):382-392. [http:// dx.doi.org/10.1016/j.cct.2010.12.008] 8. Zorini AO. Sul nuovo metodo di chemioprofilassi antitubercolare mediante isoniazide. Rivista Tuberc Malattie Appar Resp 1956;4:403-437. 9. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Adv Tuberc Res 1969;17:28-106. 10. Bass JB Jr, Farer LS, Hopewell PC, et al; American Thoracic Society, Centers for Disease Control, American Academy of Pediatrics. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994;149:1359-1374. [http://dx.doi.org/10.1164/ ajrccm.149.5.8173779]

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11. Smieja MJ, Marchelli CA, Cook DJ, Smaill FM. Isoniazid for preventing tuberculosis in nonHIV infected persons. Cochrane Database Syst Rev 2000;(2):CD001363. [http://dx.doi. org/10.1002/14651858.CD001363] 12. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2010;(1):CD000171. [http://dx.doi.org/10.1002/14651858. CD000171.pub3] 13. Mohammed A, Myer L, Ehrlich R, Wood R, Cilliers F, Maartens G. Randomised controlled trial of isoniazid preventive therapy in South African adults with advanced HIV disease. Int J Tuberc Lung Dis 2007;11(10):1114-1120. 14. Zar HJ, Cotton MF, Strauss S, et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: Randomised controlled trial. BMJ 2007;334(7585):136. [http:// dx.doi.org/10.1136/bmj.39000.486400.55] 15. Madhi SA, Nachman S, Violari A, et al. Primary isoniazid prophylaxis against tuberculosis in HIVexposed children. N Engl J Med 2011;365(1):21-31. [http://dx.doi.org/10.1056/NEJMoa1011214] 16. Rangaka MX, Wilkinson RJ, Boulle A, et al. Isoniazid plus antiretroviral therapy to prevent tuberculosis: A randomised double-blind placebo-controlled trial. Lancet (in press). 17. Churchyard GJ, Fielding KL, Lewis JJ, et al. Community-wide Isoniazid Preventive Therapy Does Not Improve Tuberculosis Control Among Gold Miners in South Africa: The Thibela TB study; Abstracts presented at the 19th Conference on Retroviruses and Opportunistic Infections, Seattle, USA. 5 - 8 March 2012. Abstract #150aLB. 18. Fielding K. Individual-level Effect of Isoniazid Preventive Therapy on Risk of TB: The Thibela TB Study. Abstract presented at the 19th Conference on Retroviruses and Opportunistic Infections, Seattle, USA. 5 - 8 March 2012. Abstract #150bLB, 2012. 19. Mazurek GH, Jereb J, Lobue P, Iademarco MF, Metchock B, Vernon A; Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention. Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR Recomm Rep 2005;54(RR-15):49-55. 20. Lin PL, Ford CB, Coleman MT, et al. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat Med 2014;20:75-79. [http://dx.doi. org/10.1038/nm.3412] 21. Menzies R. Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion. Am J Respir Crit Care Med 1999;159(1):15-21. [http://dx.doi.org/10.1164/ajrccm.159.1.9801120] 22. Horsburgh CR. Priorities for treatment of latent tuberculosis infection in the United States. N Engl J Med 2004;350(20):2060-2067. [http://dx.doi.org/10.1056/NEJMsa031667] 23. Andrews JR, Noubary F, Walensky RP, Cerda R, Losina E, Horsburgh CR. Risk of progression to active tuberculosis following reinfection with Mycobacterium tuberculosis. Clin Infect Dis 2012;54(6):784791. [http://dx.doi.org/10.1093/cid/cir951] 24. Wood R, Maartens G, Lombard CJ. Risk factors for developing tuberculosis in HIV-1 infected adults from communities with a low or very high incidence of tuberculosis. J Acquir Immune Defic Syndr 2000;23(1):75-80. [http://dx.doi.org/10.1097/00042560-200001010-00010] 25. Kerkoff AD, Kranzer K, Samandari T, et al. Systematic review of TST responses in people living with HIV in under-resourced settings: Implications for isoniazid preventive therapy. PLoS One 2012;7(11):e49928. [http://dx.doi.org/10.1371/journal.pone.0049928] 26. Lawn SD, Myer L, Bekker L-G, Wood R. CD4 cell count recovery among HIV-infected patients with very advanced immunodeficiency commencing antiretroviral treatment in sub-Saharan Africa. BMC Infect Dis 2006;6:59. [http://dx.doi.org/10.1186/1471-2334-6-59] 27. Lawn SD, Bekker L-G, Wood R. How effectively does antiretroviral treatment of HIV restore immune responses to Mycobacterium tuberculosis? Implications for tuberculosis control. AIDS 2005;19(11):1113-1124. 28. Nardell E, Churchyard G. What is thwarting tuberculosis prevention in high-burden settings? N Engl J Med 2011;365(1):79-81. [http://dx.doi.org/10.1056/NEJMe1105555] 29. Mills Hl, Cohen T, Colijn C. Community-wide isoniazid therapy drives drug-resistant tuberculosis: A modelbased analysis. Sci Transl Med 2013;5(180):180ra49. [http://dx.doi.org/10.1126/scitranslmed.3005260] 30. Madhi SA, Kim S, Mitchell C. Isoniazid prophylaxis against tuberculosis in children. N Engl J Med 2011;365(1):1543-1544. [http://dx.doi.org/10.1056/NEJMoa1011214] 31. Churchyard GJ, Fielding KL, Lewis JJ, Chihota VN, Hanifa Y, Grant AD. Symptom and chest radiographic screening for infectious tuberculosis prior to starting isoniazid preventive therapy: Yield and proportion missed at screening. AIDS 2010;24(Suppl 5):S19-S27. [http://dx.doi.org/10.1097/01. aids.0000391018.72542.46] 32. Van Halsema CL, Fielding KL, Chihota VN, et al. Tuberculosis outcomes and drug susceptibility in individuals exposed to isoniazid preventive therapy in a high HIV prevalence setting. AIDS 2010;24(7):1051-1055. [http://dx.doi.org/10.1097/QAD.0b013e32833849df] 33. Golub JE, Pronyk P, Mohapi L, et al. Isoniazid preventive therapy, HAART and tuberculosis in HIV-infected adults in South Africa: A prospective cohort. AIDS 2009;23:631-636. [http://dx.doi. org/10.1097/QAD.0b013e328327964f] 34. Wood R, Lawn SD, Bekker L-G. Are the effects of isoniazid preventive therapy and HAART additive in preventing of HIV-associated tuberculosis? AIDS 2009:23(11):1444-1446. [http://dx.doi.org/10.1097/ QAD.0b013e32832d53e7] 35. Charalambous S, Grant AD, Innes C, et al. Association of isoniazid preventive therapy with lower early mortality in individuals on antiretroviral therapy in a workplace programme. AIDS 2010;24 (Suppl 5):S5-S13. [http://dx.doi.org/10.1097/01.aids.0000391010.02774.6f] 36. Wood R, Liang H, Wu H, et al. Changing prevalence of TB infection with increasing age in high TB burden townships in South Africa. Int J Tuberc Lung Dis 2010;14(4):406-412.

Accepted 3 February 2014.

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MEDICINE AND THE LAW

The research ethics evolution: From Nuremberg to Helsinki A Dhai Ames Dhai is Director of the Steve Biko Centre for Bioethics in the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: A Dhai (amaboo.dhai@wits.ac.za)

Health research sets out to acquire not only theoretical knowledge but also benefits for many people and often society as a whole, and is therefore justified. The quandary, though, is how such an important, shared purpose can be pursued with full protection of individuals and communities, in particular those with vulnerabilities. Abuses in the field surfaced in the early 1800s, and by the 1890s, anti-vivisectionists were calling for laws to protect children because of the increasing numbers of institutionalised children being subjected to unethical research. When read together, the Nuremberg Code and the Universal Declaration of Human Rights can be interpreted as establishing a basis for underpinning the principles of free and informed consent and avoiding harms and exploitation in scientific experiments involving human participants. The Declaration of Helsinki has been recognised as one of the most authoritative statements on ethical standards for human research in the world. S Afr Med J 2014;104(3):178-180. DOI:10.7196/SAMJ.7864

Carol Levine has stated that research ethics was ‘born in scandal and reared in protectionism’.[1] Concerns about the conduct of researchers in healthcare date back to at least the end of the 19th century. [2] Because individuals and groups were being exploited and harmed, the concept of vulnerability steadily gained prominence,[3-6] with concerns over the participation of vulnerable individuals and groups appearing in national and international policy and guideline documents.[5] With this surfaced the all-too-familiar tensions between scientific progress and societal interests on the one hand and individual rights and interests on the other, regarding the goals of health research. There is no question that health research sets out to acquire not only theoretical knowledge but also benefits for individuals and society as a whole, and is therefore justified. The quandary posed is how such an important, shared purpose can be pursued with full protection of individuals and communities,[2] and those with vulnerabilities in particular.

Ethical issues in health research: A historical perspective

Even very early experiments with humans had positive outcomes. In the 1700s, James Lind, a British surgeon, studied scurvy in sailors over a 6-year period aboard the HMS Salisbury. He used an interventional study design in which some sailors were provided a diet that included fresh fruits and vegetables and others none (the control arm as in contemporary research methodologies), and in so doing was able to show that sailors in the control arm were more likely to develop scurvy than those that received fresh fruits and vegetables.[2,7] Two and a half decades later, Edward Jenner tested the cowpox vaccine on his own and other children; the vaccinated children did not get smallpox, hence the origin of the smallpox vaccine.[2,8] While these research successes were being celebrated, abuses were beginning to surface, and by the 1890s, anti-vivisectionists were calling for laws to protect children as a response to the increasing numbers of institutionalised children being subjected to vaccine experiments in Europe and the USA. The first attempt to test a polio

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vaccine was thwarted after the American Public Health Association condemned the programme.[6] In 1897, Giuseppe Sanarelli, an Italian bacteriologist injected five people with an organism that he had isolated to prove his postulate that it caused yellow fever. His action, which resulted in severe harm, was widely criticised,[2] and by the early 1900s, research rules were imposed by the Prussian state and the US Congress that contemplated the prohibition of medical experiments for particular groups such as pregnant women.[6,9] In the wake of the Sanarelli scandal, Walter Reed was commissioned by the US Surgeon General to identify the cause of yellow fever, a raging epidemic in Cuba at that time. He developed ethical guidelines to act as safeguards for the research, which was to be overseen by the US Army’s Yellow Fever Board. This Board could be described as the forerunner to what is today known as the Research Ethics Committee (REC) or Institutional Review Board. The guidelines included: self-experimentation by members on the Board; written contracts that clearly explained the risks involved in the experimentation for individuals who were not members of the Board (the precursor to written, informed consent forms); payment in gold for those who volunteered; US$100 compensation for those who became ill with yellow fever; enrolment to be restricted to adults >24 years of age; children to be excluded; and all journal publications on the research to use the phrase ‘with his full consent’.[2,10] These safeguards, utilised by the Yellow Fever Board, the contract process for obtaining explicit consent and the heroism of the Board members helped legitimise health research in the aftermath of earlier scandals.[2] It also led to medical researchers being ‘largely inoculated against regulation by the legendary status of self-experimentation by the Yellow Fever Board members’.[6] Dr Jesse Lezear died after subjecting himself to mosquito bites, confirming the hypothesis of mosquito-borne disease.[2,6] Reed’s untimely death a few years later, as a result of an error by a colleague, was mistakenly believed to be because of his involvement as a volunteer subject while on the Board. This added to the illusion that medical researchers were of such exceptionally moral character that they should be elevated to the status of martyrs.[6] Some other exemplary cases of self-

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experimentation in the 20th century include Werner Forssmann who, in 1930, practised cardiac catheterisation on himself and won a Nobel Prize in Physiology or Medicine in 1956 for his work;[11] and JBS Haldane who subjected himself to various gases in decompression chamber experiments in an attempt to find out how best to protect sailors in submarines.[11] However, it was the Reed legend that served as the primary reference point and the justification for self-regulation in medical research for many decades to follow. Notwithstanding the examples of Lind, Jenner and selfexperimentation as cited above, in the main, the first studies of experimentation on humans involved slaves and the poor.[11] Briggle and Mitcham[11] assert that this coincided with the development of the new science of anthropology, which Europeans used as a means to study non-European people. They state that, generally speaking, human experimentation was undertaken initially on those who were considered to be uncivilised, and often, less than human. Even colonial and imperial rule was often justified by anthropological research which 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.[11]

The Nuremberg Code

[12]

Among the greatest and most notorious tragedies in human research experimentation were the heinous studies conducted during World War II by Nazi doctors on ‘racially inferior’ Jews and other ‘deficient’ groups[2,3,5,6,11,13] and by Japanese doctors on those people, mainly Chinese, whom they considered to be less than human.[11,14] Lethal human experimentation – including some of the most notorious war crimes during World War II – was undertaken at Unit 731 in Northeast China, a covert biological and chemical warfare research and development unit of the Imperial Japanese Army. Up to 12 000 men, women and children, 70% of whom were Chinese, died as a result of being subjected to experimentation conducted there. Close to 30% of the subjects were Russian. Others included people from South-East Asia and the Pacific Islands. Many scientists from Unit 731 went on to acquire prominent careers after the war, in politics, academia, business and medicine. One of the probable reasons that these scientists were not tried for war crimes, akin to the trial of the Nazi scientists, is that the information and experience gained from those studies of biological warfare proved of great value for the US biological weapons development programme; it is alleged that a deal to this effect was concluded between the US and Japan in 1948.[14] The horrors of experimentation on concentration camp inmates were publicised during the Nuremberg Trials in Germany in the aftermath of World War II.[2,3,5,6,11] Nazi doctors and bureaucrats were tried by the Allies for subjecting thousands of concentration camp prisoners to egregious experiments. While 1 750 victims were identified in the indictment, they represented an extremely small proportion of those killed or injured. There were 23 defendants – a token assortment selected from the 350 candidates for prosecution. [2,6] The atrocities included anthropological studies in which hundreds of prisoners were killed so as to assemble a collection of skeletons – killed because they were considered by the Nazis to be prototypes of what they called the ‘repulsive but characteristic subhuman’.[2] The robust and relentless exploitation and harm prevalent in medical studies at that time cannot be overemphasised adequately. The vulnerable were considered to be subhuman, of decreased intelligence, of no moral status and as lacking human dignity. The defendants’ lawyers during the Nuremberg Trial highlighted the fact that the Allies had also engaged in medical experiments

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in servicing the war effort,[6] arguing that the type of medical experimentation in Nuremberg during the war was commonplace even before the war. They pointed out that there were no legal restrictions on such experiments.[11] 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 tasked two medical advisors to the judges, Drs Andrew Ivy and Leo Alexander, with this undertaking.[2,6,11] Drs Ivy and Alexander drafted a ten-point memorandum entitled ‘Permissible Medical Experimentation’,[11] which thereafter became known as the Nuremberg Code (NC).[12,15] Although the NC, consisting of ten characteristics for acceptable research involving humans, is among the most widely-known documents of ethics in research,[2] and is often cited as one of the most important documents in the history of research ethics,[16-19] it was not cited in any of the findings against the defendants and never itself became a formal part of law in Europe or North America. While it is clear that the courts believed protection was needed, it is unclear how much significance they wished to give the NC in the operations of medical research.[6] Although they were urged by Drs Ivy and Alexander to identify persons with mental disorders as in need for special protection, the courts declined to do so. In fact, the requirement that there must always be voluntary, informed consent for all participants in any form of research undermined the relevance of the NC to research designed for vulnerable people with diminished or absent competence.[6] Nevertheless, it would seem that the key contribution of the NC was to merge Hippocratic ethics and human rights into one code.[16] Principles 2 - 8 and 10 of the NC require that physician-researchers protect the best interests of their subjects. Principles 1 and 9 proclaim that subjects are able to protect themselves, with Principle 9 giving the subject as much authority as the physician-researcher to end participation before the conclusion of any research undertaking.[16] Moreover, the influence of the NC on international documents is significant and the Universal Declaration of Human Rights (UDHR),[20] adopted a year later in 1948, makes claims closely associated with the NC.[11] The Preamble of the UDHR talks to the ‘disregard and contempt of human rights that have resulted in barbarous acts which have outraged the conscience of mankind.’ Article 5 states that ‘No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment.’ and Article 27 states that ‘Everyone has the right freely ... to share in scientific advancement and its benefits.’ When read together, the NC and the UDHR can be interpreted as underpinning the principles of free and informed consent[11] and avoiding harms and exploitation in scientific experiments involving human participants. Despite the NC being given the status of an International Code for the ethical conduct of research at the end of the Nuremberg Trial, and despite it having substantial influence on international documents like the UDHR, for many years after the introduction of these documents, researchers continued with ‘business as usual’, failing to recognise that there were good reasons for protecting human research participants.[2,6,21] The Nazi transgressions were attributed to the abnormalities associated with a totalitarian regime with unquestionable brutality. The notion was that researchers working in democratic states would not succumb to atrocities and exploitation of vulnerable participants enrolled in research. The NC was therefore viewed as not applicable to those in civilised democracies – it was a document necessary to strain barbarians.[2,21] However, evidence emerged in the 1950s that vulnerable individuals and populations were being exploited and harmed in research in such democracies as the US, despite the safeguards in the NC. The World Medical

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Association (WMA), perturbed by the ongoing mistreatment of research participants and also the restrictive nature of the NC regarding mandatory, informed consent from those who lacked capacity, began discussions on the ethics of research.[22]

The WMA’s Declaration of Helsinki

The WMA was established in London in 1946 and held its first General Assembly in Paris in 1947. During this time, deliberations and resolutions focused on crimes committed in the doctor-patient relationship since 1933 by certain members of the medical profession in Germany during World War II.[22] The Declaration of Geneva,[23] an updated version of the Hippocratic Oath, and the International Code of Medical Ethics,[24] adopted by the WMA in 1948 and 1949, respectively, were guidance documents for physicians specifically in the context of clinical care. These documents, however, have had a resounding presence in the Declaration of Helsinki as evidenced by their use in the introduction of the Declaration of Helsinki through all its revisions. Physician-researchers are bound by the words: ‘The health of my patient will be my first consideration’[23] (Declaration of Geneva) and ‘Any act or advice which could weaken physical or mental resistance of a human being may be used only in his interest’[24] (International Code of Medical Ethics). The 1964 Declaration of Helsinki was the first formal declaration by the WMA for physicians doing research and served for the first time to distinguish biomedical researchers as a specific class of physicians.[11] This first version was adopted after a 12-year debate. Since its original formulation, the Declaration of Helsinki has undergone seven revisions and two clarifications, with the most recent revision being in October 2013.[25] Previously revised versions were published in 1975, 1983, 1989, 1996, 2000 and 2008. Public debate regarding the latest version has been the most intensive of any revision of the Declaration of Helsinki thus far received. Over a 2-year period, through an open and collaborative approach, input was obtained from many expert stakeholders and organisations globally and was carefully considered during the drafting process. Four expert conferences were held and about 150 comments were reviewed.[25] Some of the main changes include a more readable structure, revised paragraphs on vulnerable groups, RECs, post-study provisions, and the introduction of compensation for research-related injuries and a specific reference to biobanks. The Declaration of Helsinki was adopted during the WMA Assembly by an overwhelming majority (>75%) of member associations.[25]

Conclusion

Notwithstanding criticisms of the Declaration of Helsinki, including its current revisions, by some commentators, the Declaration of Helsinki is recognised as one of the most authoritative statements

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on ethical standards for human research in the world.[26] It remains the leader as it reaches its 50th anniversary this year. It is a set of principles that are regularly updated. Therefore, the Declaration of Helsinki has not lagged behind as science and technology has advanced and has kept pace with scientific progress. 1. Levine C. Has AIDS changed the ethics of human subjects research? Law Med Health Care 1998;16(34):163-173. [http://dx.doi.org/10.1111/j.1748-720X.1988.tb01942.x] 2. 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: Johns Hopkins University Press, 2003:1-5. 3. 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 Bioeth 2004;4(3):44-49. [http:// dx.doi.org/10.1080/15265160490497083] 4. Macklin R. Bioethics, vulnerability and protection. Bioethics 2003;17(5-6):473-486. [http://dx.doi. org/10.1111/1467-8519.00362] 5. Iltis AS. Introduction: Vulnerability in biomedical research. J Law Med Ethics 2009;37(1):6-11. [http:// dx.doi.org/10.1111/j.1748-720X.2009.00345.x] 6. Moreno JD. Protectionism in Research Involving Human Subjects (Research Involving Human Subjects V2). Online Ethics Centre for Engineering. 25 July 2006. http://www.onlineethics.org/Topics/ ResResearch/ResResources/nbachindex/hmoreno.aspx (accessed 20 July 2012). 7. Lind J. A Treatise of the Scurvy. Edinburgh: Sands, Murray and Cochran, 1753. 8. Jenner E. An Inquiry into the Causes and Effects of Variolae Vaccinae. London: Sampson Low, 1798. 9. Lederer SE, Grodin MA. Historical Overview: Paediatric Experimentation. In: Grodin MA, Glantz LH, eds. Children as Research Subjects: Science, Ethics and the Law. New York: Oxford University Press, 1994. 10. Emanuel EJ, Crouch RA, Arras JD, Moreno JD, Grady C. Preface. In: Ethical and Regulatory Aspects of Clinical Research. Baltimore: Johns Hopkins University Press, 2003:xv-xviii. 11. Briggle A, Mitcham C. Research Ethics 11: Science Involving Humans. In: Briggle A, Mitcham C, eds Ethics and Science. 1st ed Cambridge: Cambridge University Press, 2012:125-155. 12. Jewish Virtual Library. The Doctors Trial: Nuremberg Code. http://www.jewishvirtuallibrary.org/ jsource/Holocaust/Nuremberg_Code.html (accessed 26 June 2013). 13. McDermott W. The changing mores of biomedical research. II. Challenge and discussion. Opening comments. Ann Intern Med 1967;67(7):39-42. 14. Unit 731. https://en.wikipedia.org/wiki/Unit_731 (accessed 27 June 2013). 15. Taylor T. Opening Statement of the Prosecution December 9, 1946. In: Annas GJ, Grodin MA, eds. The Nazi Doctors and the Nuremberg Code: Human Rights in Human Experimentation. New York: Oxford University Press, 1992:67-93. 16. Shuster E. Fifty years later: The significance of the Nuremberg Code. N Engl J Med 1997;337(20):14361440. [http://dx.doi.org/10.1056/NEJM199711133372006] 17. Moreno JD. Reassessing the influence of the Nuremberg Code on American medical ethics. J Contemp Health Law Policy 1997;13(2):347-360. 18. Katz J. The Consent Principle of the Nuremberg Code: Its Significance Then and Now. In: Annas GJ, Grodin MA, eds. The Nazi Doctors and the Nuremberg Code: Human Rights in Human Experimentation. New York: Oxford University Press, 1992:227-239. 19. Grodin MA, Annas GJ. Legacies of Nuremberg: Medical ethics and human rights. JAMA 1996;276(20):1682-1683. [http://dx.doi.org/10.1001/jama.1996.03540200068035] 20. United Nations. The Universal Declaration of Human Rights. http://www.un.org/en/documents/udhr/ (accessed 22 June 2013). 21. 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. [http://dx.doi.org/10.1001/jama.1996.03540200053031] 22. Human D, Fluss SS. The World Medical Association’s Declaration of Helsinki: Historical and Contemporary Perspectives. Ferney-Voltaire: WMA, 2001. http://www.wma.net/en/20activities/10eth ics/10helsinki/draft_historical_contemporary_perspectives.pdf (accessed 29 June 2013). 23. World Medical Association. WMA Declaration of Geneva. http://www.wma.net/ en/30publications/10policies/g1/index.html (accessed 29 June 2013). 24. World Medical Association. WMA International Code of Medical Ethics. http://www.wma.net/ en/30publications/10policies/c8/index.html (accessed 29 June 2013). 25. World Medical Association. World Medical Journal 2013;59(5). http://www.wma.net/ en/30publications/20journal/pdf/wmj201305.pdf (accessed 17 December 2013). 26. Kimmelman J, Weijer C, Meslin EM. The Helsinki Discords: FDA, ethics and international drug trials. Lancet 2009;373(9657):13-14. [http://dx.doi.org/10.1016/S0140-6736(08)61936-4]

Accepted 6 January 2014.

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EDITORIAL

New imaging approaches for improving diagnosis of childhood tuberculosis In South Africa (SA), childhood tuberculosis (TB) still accounts for considerable morbidity and mortality. The incidence of TB disease and risk of progression to severe or disseminated forms are especially high in young children or those with HIV infection. Childhood TB presents most commonly as primary TB, often with non specific signs and symptoms; TB may also present as acute pneumonia. The clinical diagnosis can therefore be challenging. [1] Furthermore, due to difficulty in obtaining goodquality specimens and the paucibacillary nature of childhood TB, microbiological confirmation is only achieved in a minority of children, especially in settings where there is limited capacity for microbiological confirmation.[1] Imaging is a major part of the diagnostic work-up for childhood TB. Chest X-rays are relatively inexpensive and widely available. However, detection of mediastinal and hilar lymphadenopathy – cardinal signs of primary pulmonary TB – is often limited, there is wide inter-observer variability in detection of nodes and pulmonary findings may be non specific. Other imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are capable of demonstrating comprehensively the lungs and the mediastinum, but the radiation dose in CT, the need for sedation in MRI, the costs and limited availability all currently prevent their use in routine management. The merit of ultrasound for detecting features of abdominal, pleural and pericardial TB has long been acknowledged and its application in paediatrics is especially attractive as it does not involve radiation nor require sedation. Furthermore, ultrasound of the mediastinum has been shown to detect lymphadenopathy in TB patients who have a normal chest X-ray.[2] One strategy for improving the diagnosis of childhood TB is the refinement of currently available imaging tools and use of simplified protocols tailored to the detection of TB. Point-of-care ultrasound for extrapulmonary TB (EPTB), mediastinal ultrasound and limited chest MRI are all promising new imaging approaches presently being evaluated in paediatric studies. The increasing availability of digital imaging enables telemedicine, where radiological images can be transmitted anywhere in the world allowing for expert interpretation and opinion.

Point-of-care ultrasound for EPTB – focused assessment with sonography for HIV/TB

With the availability and affordability of high-quality portable ultrasound machines, point-of-care sonography has become an integral part of many medical disciplines.[3] Physician-performed ultrasound at the patient’s bedside limits the time to diagnosis and treatment decisions and reduces referrals. Abdominal nodes, hepatic or splenic hypo-echoic lesions as well as pericardial, pleural or ascitic effusions, which are likely representatives of EPTB in settings where TB is highly prevalent, are recognisable with basic ultrasound training.[4] A bedside ultrasound protocol for HIV/TB (focused assessment with sonography for HIV/TB (FASH))[5] has been developed to improve detection of EPTB in HIV-infected adults, and has now become one of the most applied modules in adult emergency rooms in SA.[6] The value of FASH in children is especially promising. It is well tolerated and non-invasive, and, because of the relatively high rate of EPTB in young children, the yield of positive ultrasound findings is high.

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Mediastinal ultrasound for intrathoracic lymphadenopathy

Mediastinal and hilar lymphadenopathy are the hallmarks of primary pulmonary TB. Sensitivity and specificity for identifying lymphadenopathy, using traditional anterior-posterior and lateral radiographs in children, is relatively poor. CT studies found lymphadenopathy in up to 60% of TB patients who had normal chest X-rays,[7] but because of the significant radiation burden, CT is not a standard imaging option in children. Mediastinal ultrasound is currently being investigated as an alternative imaging test despite the anatomically limited access. Windows for mediastinal ultrasound include the suprasternal notch and parasternal intercostal spaces, which allow detection of enlarged lymph nodes in the superior and anterior mediastinum. One paediatric imaging study showed that mediastinal ultrasound detected lymphadenopathy in 67% of children with TB who had a normal chest X-ray; the mediastinal ultrasound findings were confirmed on CT.[2] Current research, investigating mediastinal ultrasound, is now being performed in larger cohorts in Cape Town and Johannesburg by two different groups.

Limited chest MRI for intrathoracic TB

MRI in children is preferred over CT because it does not involve ionising radiation. Chest MRI is only receiving attention recently because it was believed to have disadvantages in demonstrating the lungs. MRI is expensive and routine imaging requires the child to be immobile for a prolonged period, therefore requiring anaesthesia or monitored sedation. The radiation-free imaging capacity of MRI, however, remains attractive for evaluating mediastinal lymphadenopathy in children. To demonstrate the usefulness of MRI in TB imaging, new limited protocols that do not require sedation are currently being tested in a collaborative partnership between two SA universities and a private practice. Limited sequences in the form of diffusion-weighted imaging and Short Tau Inversion Recovery (STIR) are performed within 10-min slots. Unlike lymphoma in which lymphadenopathy demonstrates high signal on T2/STIR imaging, TB lymph nodes may demonstrate characteristic low signal intensity. TB-specific signal intensity has already been demonstrated in the parenchyma of TB patients on MRI.[8]

Telemedicine

Many sub-Saharan African countries have limited radiology expertise within their borders,[9] which is considered a significant contributor to patient morbidity and mortality.[10] Digital medical images and reports or opinions on these can, however, be sent electronically from an area with no radiologist to a part of the world where expertise is available. This mechanism of radiology interpretation, known as teleradiology,[9] is being increasingly adopted to successfully assist underserved areas.[9-11] An alteration in the diagnosis following a teleradiology consultation has been recorded in up to 50% of cases.[10] Point-of-care imaging, non-invasiveness, low-risk and improved visualisation of the mediastinum are desirable goals for imaging TB in children. Although ultrasound and MRI are not new imaging modalities, refinement of protocols and novel applications may improve their diagnostic capacities for childhood TB. Bedside

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EDITORIAL

ultrasound is promising also, as a monitoring tool for response to treatment.[12] Furthermore, ultrasound imaging is especially suitable for use in remote settings where no or only X-ray imaging is available. Lack of expertise on the ground for interpreting images can be overcome through simple telereading mechanisms via email or other internet-based platforms that can provide even subspecialist expertise to assist in patient diagnosis.

Heather J Zar Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital and University of Cape Town, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa

Sabine Bélard Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital and University of Cape Town, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa; Centre of Tropical Medicine and Travel Medicine, Division of Internal Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands

1. Whittaker E, Zar HJ. Promising directions in the diagnosis of childhood tuberculosis. Expert Rev Respir Med 2012;6(4):385-395. [http://dx.doi.org/10.1586/ers.12.36] 2. Bosch-Marcet J, Serres-Créixams X, Zuasnabar-Cotro A, et al. Comparison of ultrasound with plain radiography and CT for the detection of mediastinal lymphadenopathy in children with tuberculosis. Pediatr Radiol 2004;34(11):895-900. [http://dx.doi.org/10.1007/s00247-004-1251-3] 3. Moore CL, Copel JA. Point-of-care ultrasonography. N Engl J Med 2011;364(8):749-757. [http:// dx.doi.org/10.1056/NEJMra0909487] 4. Heller T, Wallrauch C, Lessells RJ, et al. Short course for focused assessment with sonography for human immunodeficiency virus/tuberculosis: Preliminary results in a rural setting in South Africa with high prevalence of human immunodeficiency virus and tuberculosis. Am J Trop Med Hyg 2010;82(3):512-515. [http://dx.doi.org/10.4269/ajtmh.2010.09-0561] 5. Heller T, Wallrauch C, Goblirsch S, Brunetti E. Focused assessment with sonography for HIVassociated tuberculosis (FASH): A short protocol and a pictorial review. Crit Ultrasound J 2012;4(1):21. [http://dx.doi.org/10.1186/2036-7902-4-21] 6. Van Hoving DJ, Lamprecht HH, Stander M, et al. Adequacy of the emergency point-of-care ultrasound core curriculum for the local burden of disease in South Africa. Emerg Med J 2013;30(4):312-315. [http://dx.doi.org/10.1136/emermed-2012-201358] 7. Delacourt C, Mani TM, Bonnerot V. Computed tomography with normal chest radiograph in tuberculous infection. Arch Dis Child 1993;69(4):430-432. [http://dx.doi.org/10.1136/ adc.69.4.430] 8. Peprah KO, Andronikou S, Goussard P. Characteristic magnetic resonance imaging low T2 signal intensity of necrotic lung parenchyma in children with pulmonary tuberculosis. J Thorac Imaging 2012;27(3):171-174. [http://dx.doi.org/10.1097/RTI.0b013e318211abfb] 9. Coulborn RM, Panunzi I, Spijker S, et al. Feasibility of using teleradiology to improve tuberculosis screening and case management in a district hospital in Malawi. Bull World Health Organ 2012;90(9):705-711. [http://dx.doi.org/10.2471/BLT.11.099473] 10. Shiferaw F, Zolfo M. The role of information communication technology (ICT) towards universal health coverage: The first steps of a telemedicine project in Ethiopia. Glob Health Action 2012;5:1-8. [http://dx.doi.org/10.3402/gha.v5i0.15638] 11. Zanaboni P, Wootton R. Adoption of telemedicine: From pilot stage to routine delivery. BMC Med Inform Decis Mak 2012;12:1. [http://dx.doi.org/10.1186/1472-6947-12-1] 12. Bosch-Marcet J, Serres-Créixams X, Borrás-Pérez V. Value of sonography for follow-up of mediastinal lymphadenopathy in children with tuberculosis. J Clin Ultrasound 2007;35(3):118-124. [http://dx.doi. org/10.1002/jcu.20304]

Savvas Andronikou Department of Radiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Outreach Committee, World Federation of Paediatric Imaging; Schnetler, Corbett and Partners Radiology, Cape Town, South Africa Tanyia Pillay Department of Radiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Martin P Grobusch Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa; Centre of Tropical Medicine and Travel Medicine, Division of Internal Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands

Corresponding author: S Bélard (sabine.belard@uct.ac.za)

S Afr Med J 2014;104(3):181-182. DOI:10.7196/SAMJ.7984

This month in the SAMJ ...

Ames Dhai* is Director of the Steve Biko Centre for Bioethics at the Faculty of Health Sciences, University of the Witwatersrand. She established the centre in 2007. The centre, which runs Masters and PhD programmes in bioethics and health law, has local and international recognition as a leading centre in these disciplines, and was recently awarded status as a World Medical Association (WMA) Co-operating Centre and the South African Unit of the United Nations Educational, Scientific and Cultural Organization (UNESCO) International Network in Bioethics. Prof. Dhai serves on several policy-making bodies in the country and is currently the President of the South African Medical Association. She also serves regularly as a consultant/expert advisor for the World Health Organization (WHO), and is on their African Advisory Committee for Health Research, and serves on the WMA Working Group on health databases and biobanks. She participated in the WMA’s Working Group on amendments to the current Declaration of Helsinki and in activities of the US Institutes of Medicine and the US National Academies of Sciences. She is an ethicist of international standing who can be credited with entrenching bioethics as an integral aspect of health sciences in South Africa. She started off her career as a medical doctor, specialised in obstetrics and gynaecology, and then went on to graduate with a Masters in Law and Ethics. *Dhai A. The research ethics evolution: From Nuremberg to Helsinki. S Afr Med J 2014;104(3):178-180. [http://dx.doi.org/10.7196/SAMJ.7864]

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RESEARCH

Systematic review of the evidence for rational dosing of colistin E Visser Kift,1 MB ChB, BScMedSc (Hons); G Maartens,1 MB ChB, MMed (Int Med); C Bamford,2 MB ChB, MMed (Med Micro), MPhil 1

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa Division of Medical Microbiology, Department of Clinical Laboratory Sciences, University of Cape Town, and National Health Laboratory Service, Groote Schuur Hospital, South Africa

Corresponding author: G Maartens (gary.maartens@uct.ac.za) Background. There is an alarming global increase in the incidence of nosocomial infections with multidrug-resistant Gram-negative bacteria, which are often only susceptible to colistin. Colistin was developed prior to current methods of establishing dosing using pharmacokinetic-pharmacodynamic relationships. Dosing regimens differ in package inserts from different manufacturers and in different guidelines. It is imperative to avoid under-dosing with colistin in order to limit the development of resistance, as it is the last line of defence. Methods. We conducted a systematic review of the literature to develop guidelines for rational dosing of intravenous colistin, with a particular focus on critically ill patients. Results. Colistin is administered as the inactive pro-drug colistimethate sodium. Colistin demonstrates concentration-dependent bacterial killing, suggesting that higher doses should be administered less frequently to achieve higher peak concentrations. Dose-related nephrotoxicity occurs, making it impossible to safely achieve concentrations that prevent the selection of resistant mutants or the effective eradication of bacteria with higher minimum inhibitory concentrations. Theoretically, combination therapy should be used to reduce the risk of selection of resistant bacteria. In critically ill patients, a loading dose should be given to rapidly achieve therapeutic concentrations, followed by maintenance doses of 4.5 MU 12-hourly. Maintenance dose adjustment is necessary with renal impairment. Conclusion. Easier access to colistin is needed in South Africa, where it is not a registered medicine. Further research is needed to better characterise colistin’s pharmacokinetic-pharmacodynamic relationships in humans and to establish whether combinations of colistin with other antimicrobials result in improved clinical outcomes or a reduction in selection of resistant bacteria. S Afr Med J 2014;104(3):183-186. DOI:10.7196/SAMJ.7011

Since the discovery of antimicrobial agents, everevolving mechanisms of microbial resistance have been shaping the field of infectious diseases. Globally multidrug-resistant (MDR) Gram-negative bacilli causing nosocomial infections (notably in Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter sp. and Acinetobacter baumannii) have become an important emerging threat.[1] In South Africa (SA), carbapenem resistance is emerging in K. pneumoniae and Enterobacter sp. while high levels of resistance to all antimicrobial classes are observed among P. aeruginosa and A. baumannii.[2] A. baumannii is a common pathogen in intensive care units (ICUs).[3] The antimicrobial susceptibility patterns of isolates of bacteraemic A. baumannii complex isolates over time in the public and private sectors in SA are shown in Figs 1A and 1B, respectively. Particularly striking is the decline in carbapenem susceptibility from 35% in 2007 to only 17% in 2011 in the public sector. More than half the isolates in the private sector were resistant to carbapenems, but there was no clear downward trend. Inappropriate antibiotic prescription practices in ICUs in the public and private sectors in SA are common and associated with poor patient outcomes.[4] Both carbapenem resistance and inappropriate antibiotic use are associated with increased mortality in patients with Acinetobacter bacteraemia.[5-8] Many acinetobacteria and other MDR Gram-negative bacteria are only susceptible to colistin (polymyxin E). Colistin is not a registered medicine in SA, but it can be obtained via a Medicines and Related Substance Act, Section 21 application to the Medicines Control Council. The polymyxin group of antibiotics was discovered in the 1940s,[9,10] but their popularity soon faded due to reports of

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nephrotoxicity and the availability of safer antibiotics in the 1970s.[11] Important pharmacokinetic and pharmacodynamic data for colistin are lacking, which are necessary for safe and effective dosing, particularly in critically ill patients and those with impaired renal function.[12] No international consensus exists on the correct dose, and dosing units are not standardised. Package insert dosing instructions differ between manufacturers. An additional problem is that prescribing units differ between manufacturers, including mg for colistin base activity (CBA) and colistimethate sodium (CMS), and international units for CMS. This creates confusion among clinicians and complicates interpreting the available literature. The product accessed in SA (Colimycine) is labelled in international units. One million units (MU) of CMS is roughly equivalent to 80 mg of CMS and 30 mg of CBA. Under-dosing of colistin increases the risk of the development of resistance and hetero-resistance, which is important as colistin is the last line of defence against MDR Gram-negative bacteria. Colistin resistance was first reported in the Czech Republic in 1999 and worldwide reports are accumulating at an alarming rate.[13] Eighteen of 132 (13.6%) bloodstream isolates of A. baumannii complex were resistant to colistin in Groote Schuur Hospital, SA, during 2011.

Methods

We conducted a systematic review of the evidence for rational dosing of intravenous (IV) colistin, with a particular focus on patients who are critically ill or have renal impairment. English language, peerreviewed journal publications (predating April 2013) were identified by searching the PubMed database. The search terms included various combinations of the following keywords: polymyxins;

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RESEARCH

Loading doses 100% Ciprofloxacin

90%

Piperacillin-tazobactam

Ceftazidime

Imipenem

80% Susceptibilty, %

70% 60% 50% 40% 30% 20% 10%

0% 2007

100%

Tobramycin

2008

Ciprofloxacin

2009

Piperacillin-tazobactam

2010

Ceftazidime

2011

Imipenem

90% 80%

Susceptibilty, %

70% 60% 50% 40% 30% 20% 10%

0% 2007

2008

2009

2010

2011

Fig. 1. Susceptibility of A. baumannii complex blood isolates to selected antimicrobial agents at laboratory sites in South Africa, 2007 - 2011. (A) Five large public sector (2011 susceptibility data are based on provisional results);[2,43] and (B) eight private sector laboratory sites (personal communication, Colleen Bamford for the National Antibiotic Study Forum).

colistin; colistimethate sodium; intravenous; severe sepsis; critically ill; pharmacokinetics; pharmacodynamics; dosing; dosing units; dosing interval; nephrotoxicity; renal failure; renal replacement; resistance; combination therapy; MDR Gram-negative infections; Acinetobacter; Pseudomonas; and Klebsiella. After reviewing the abstracts, relevant fulltext manuscripts were retrieved. Additional articles were identified by hand searching the references of articles obtained by the electronic search strategy. Finally, based on the evidence obtained, an IV colistin dosing guideline for the treatment of MDR Gramnegative infections was developed, with a particular focus on critically ill patients.

Results

Pharmacokinetic overview

Colistin is administered intravenously as the inactive pro-drug CMS, which is hydrolysed to active colistin.[14] In critically ill patients, colistin plasma concentrations

peak seven hours after CMS administration. The half-lives of CMS and colistin are 2.3 and 14.4 hours, respectively. [15] Distribution to cerebrospinal, pleural and synovial fluid is poor.[10] Unconverted CMS is predominantly eliminated by the kidneys, partly by tubular secretion. By contrast, colistin is predominantly cleared by unknown nonrenal mechanisms and undergoes extensive renal tubular reabsorption.[16]

Dose adjustment in renal failure

In patients with renal impairment the elimination of CMS is decreased and a greater fraction of the administered dose is converted to colistin,[17-19] necessitating a dose adjustment. Both CMS and colistin are efficiently cleared by venovenous haemofiltration[20] and haemodialysis.[17,21-22] Therefore, a supplemental dose of colistin needs to be given after dialysis and higher doses are required in patients undergoing venovenous haemofiltration.

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Drugs take 4 - 5 times their half-lives to reach target steady-state plasma concentrations. A loading dose is required in serious infections to rapidly achieve therapeutic concentrations. Critically ill patients with severe sepsis have significant capillary leak,[23-24] which increases the volume of distribution of colistin 4 - 15-fold.[25-26] The loading dose in critically ill patients is therefore higher than in less-ill patients.[15,17] It is important to note that the magnitude of the loading dose is not affected by renal impairment; only subsequent maintenance doses or dose intervals should be adjusted.

Pharmacokineticpharmacodynamic relationships

Colistin has no activity against Gram-positive bacteria and anaerobes,[10] but rapidly kills Gram-negative bacteria in a concentrationdependent manner.[14,19,27] The bactericidal activity of colistin is partly due to its detergent effect on the bacterial cell membrane.[10,19,28] This disruptive effect on membrane integrity may account for the in vitro synergy observed with certain antimicrobials (e.g. rifampicin). [28] Murine studies showed that the most predictive index for antibacterial effect against P. aeruginosa and A. baumannii was the ratio of the area under the curve to the minimum inhibitory concentration (AUC/MIC).[29-30] Extrapolating from murine AUC/MIC colistin data, Garonzik et al.[17] estimated that in humans a total colistin AUC/ MIC of 60 is the average achieved using currently recommended doses. This AUC/ MIC of 60 would be expected to result in a suboptimal pharmacodynamic effect of somewhere between stasis and 1 log10 kill for most susceptible bacteria. The authors acknowledge that there are limitations to their estimates as free concentrations of colistin were measured in the murine infection models[29-30] and there are no human data on the protein binding of colistin. Peak concentrations of at least 4 mg/l (four times the MIC) were needed to eliminate P. aeruginosa in one study, but in critically ill patients this concentration was only reached with doses of 9 MU of CMS.[31] A recent in vitro study showed that the mutant prevention concentration (at which 90% of isolates tested were prevented from developing mutant strains) exceeds 128 mg/l,[32] a concentration not achievable with currently used doses. A high proportion of clinician-selected dosing regimens result in sub-therapeutic colistin concentrations. [12,15,17,26,31,33] Of particular concern is a recent study showing that it is not possible to reach the modest target

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Table 1. IV CMS dosing guideline for the treatment of MDR Gram-negative infections Dose

Patient category

Dosing suggestion

Critically ill or severe sepsis

9 - 12 MU*

Maintenance

eGFR >60 ml/min

4.5 MU 12-hourly

eGFR 30 - 60 ml/min

3 MU 12-hourly

eGFR 10 - 30 ml/min

2 MU 12-hourly

eGFR <10 ml/min

1 MU 12-hourly

Intermittent haemodialysis

1 MU 12-hourly plus supplemental dose of 1 MU after each episode of dialysis

Continuous renal replacement

4.5 MU 12-hourly†

IV = intravenous; CMS = colistimethate sodium; MDR = multidrug-resistant; eGFR = estimated glomerular filtration rate. *Loading dose is calculated according to ideal body weight: 12 MU CMS for 70 kg and 9 MU for 55 kg patients. † [17] Garonzik et al. recommend higher daily doses of 16 MU as both CMS and colistin are filtered during renal replacement therapy.

colistin AUC/MIC of 60 in patients with creatinine clearances >70 ml/ min without exceeding the upper limit daily dose of 10 MU CMS recommended in the package insert.[17]

Nephrotoxicity

The recommended dosing intervals of colistin range between 6 and 12 hours. The long half-life of colistin suggests that less frequent dosing intervals should be adequate. On theoretical grounds giving higher doses less frequently should result in higher peak concentrations and more effective bacterial eradication. However, extended dosing intervals may lead to periods of low colistin concentrations allowing for resistant subpopulations to occur within a microbial population susceptible to colistin (heteroresistance).[28-30,34] Small, uncontrolled studies report good efficacy, without significant renal toxicity, of high-dose CMS regimens given 12-hourly[35] or daily.[31] There are no randomised, controlled, clinical trials (RCTs) evaluating the efficacy and safety of once-, twice- and thrice-daily dosing of colistin.

In contrast to initial reports that colistin’s nephrotoxicity rates approached 50%, the majority of recent studies report much lower renal toxicity rates of 10 - 30%.[38] A local study found that the risk of nephrotoxicity of colistin (dosed at the relatively low total daily dose of 6 MU of CMS) was similar to that of tobramycin.[39] Colistin’s nephrotoxicity is dose-dependent and mostly mild and reversible. [25,38,40] One study showed that rates of nephrotoxicity were significantly higher in patients receiving daily maintenance doses greater than the equivalent of 12 MU of CMS in a 70 kg patient.[38] Colistin’s exact mechanism of nephrotoxicity is not established.[11,12,40,41] Patients with abnormal renal function at the start of colistin therapy have consistently been identified as being at high risk for nephrotoxic events.[28] General measures to limit colistin’s nephrotoxicity include regular monitoring of renal function with appropriate dose adjustment (especially with prolonged use), adequate hydration and limited use of concomitant nephrotoxic drugs. Therapeutic monitoring of CMS/ colistin concentrations is not commercially available.

Combination therapy

Discussion

Dosing interval

A strong theoretical basis exists for the use of colistin as part of combination antimicrobial therapy to maximise antimicrobial activity and to reduce the risk of the emergence of resistance, especially in patients with normal renal function or with bacterial MICs >1 mg/l. [10,17] As discussed above, currently used doses (9 MU CMS per day in divided doses) can neither achieve the modest target AUC/MIC of 60 in patients with normal renal function,[17] nor prevent the selection of resistant mutant subpopulations.[10,32] Many studies have proposed different colistin combination regimens. The most frequently studied are combinations of colistin with rifampicin or the carbapenems,[13] which both showed synergy in vitro.[36] Other in vitro studies report effective combinations with tigecycline, amikacin, fosfomycin, azithromycin, ceftazidime, minocycline and, surprisingly, the glycopeptides vancomycin and teicoplanin.[10,13] Combination with levofloxacin or tobramycin decreased the mutant selection window of colistin.[37] Some in vitro antibiotic combination studies demonstrated bactericidal activity even against colistin-resistant strains and others showed bactericidal activity at sub-MIC concentrations of colistin.[28] There is an urgent need for RCTs comparing the efficacy of different combinations of antimicrobial agents with colistin. One trial showed that the 30-day mortality rate of patients with serious MDR A. baumannii infections was not reduced by the addition of rifampicin to colistin, but the study was limited by the relatively low total daily dose of CMS (6 MU) used.[44]

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It is imperative that colistin is dosed appropriately to minimise the risk of resistance as it is a last-line agent against MDR Gramnegative bacteria, and the pipeline of new drugs in development for these organisms is very small.[42] There are good theoretical grounds to suggest that colistin should be used in combination with other effective antibacterials, especially in patients with normal renal function and when treating bacteria with MICs >1 mg/l.[10,17] We used the information gleaned from our systematic review to develop simple recommendations for rational dosing (Table 1). A key study that informed our recommendations was conducted by Garonzik et al.,[17] who integrated population pharmacokinetic data with pharmacodynamic data in a model to estimate dosing in critically ill patients with a wide range of renal function (including those receiving renal replacement therapy). Even though the maintenance doses we recommend are higher than in the package insert of the currently used unregistered product in SA, these will still only result in concentrations that have suboptimal bacterial killing. Higher doses are likely to result in unacceptable rates of nephrotoxicity.[38] We suggest 12-hour dosing intervals in view of the long half-life of colistin (14 hours) and because of the theoretical benefit of the resulting higher peak concentrations, but, as discussed above, 8-hourly dosing is also acceptable. CMS is unstable in aqueous solutions, therefore it should be administered shortly after reconstitution.[10] All critically ill patients with severe sepsis, regardless of their renal function, require a loading dose of 9 - 12 MU of CMS to ensure the rapid attainment of

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therapeutic concentrations. [15,17] The loading dose range in the table is based on ideal body weight. The loading dose should be administered intravenously over 1 - 2 hours, followed by the first maintenance dose after 12 hours.[15] Maintenance doses can be given as IV infusions over 15 min.[26] In patients with an estimated glomerular filtration rate <60 ml/min, CMS dose adjustment is required. Twelve-hourly dosing is appropriate in patients with renal impairment, because only CMS, the inactive pro-drug, is subjected to renal elimination (not the active drug colistin). CMS doses equal to or even higher than the daily dose in patients with normal renal function are required in patients on continuous renal replacement therapy, because both CMS and colistin are removed.[17,22] Garonzik et al.[17] recommend a daily dose of 16 MU of CMS in this setting. There is a clear need for further research on colistin, particularly to establish pharmacokinetic-pharmacodynamic relationships in humans. More RCTs need to be conducted to determine if combination therapy results in superior outcomes, and, if so, which combinations should be used. Finally, access to colistin needs to be made easier in SA, especially in the public sector where carbapenem resistance is increasing. References 1. Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against resistant Gram-negative organisms: Extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc 2011;86(3):250259. [http://dx.doi.org/10.4065/mcp.2010.0674] 2. Bamford C, Bonorchis K, Ryan A, et al. Antimicrobial susceptibility pattern of selected bacteraemia isolates from South African public sector hospitals, 2010. South Afr J Epidemiol Infect 2011;26(4):243-50. 3. Ntusi NB, Badri M, Khalfey H, et al. ICU-associated Acinetobacter baumannii colonisation/infection in a high HIV-prevalence resource-poor setting. PLoS One 2012;7(12):e52452. [http://dx.doi. org/10.1371/journal.pone.0052452] 4. Paruk F, Richards G, Scribante J, Bhagwanjee S, Mer M, Perrie H. Antibiotic prescription practices and their relationship to outcome in South Africa: Findings of the prevalence of infection in South African intensive care units (PISA) study. S Afr Med J 2012;102(7):613-616. 5. Kim YJ, Kim SI, Hong KW, Kim YR, Park YJ, Kang MW. Risk factors for mortality in patients with carbapenem-resistant Acinetobacter baumannii bacteremia: Impact of appropriate antimicrobial therapy. J Korean Med Sci 2012;27(5):471-475. [http://dx.doi.org/10.3346/jkms.2012.27.5.471] 6. Kwon KT, Oh WS, Song JH, et al. Impact of imipenem resistance on mortality in patients with Acinetobacter bacteraemia. J Antimicrob Chemother 2007;59(3):525-530. [http://dx.doi.org/10.1093/ jac/dkl499] 7. Metan G, Sariguzel F, Sumerkan B. Factors influencing survival in patients with multi-drug-resistant Acinetobacter bacteraemia. Eur J Intern Med 2009;20(5):540-544. [http://dx.doi.org/10.1016/j. ejim.2009.05.005] 8. Lee YT, Kuo SC, Yang SP, et al. Impact of appropriate antimicrobial therapy on mortality associated with Acinetobacter baumannii bacteremia: Relation to severity of infection. Clin Infect Dis 2012;55(2):209215. [http://dx.doi.org/10.1093/cid/cis385] 9. Li J, Nation R, Milne RW, Turnidge JD, Coulthard K. Evaluation of colistin as an agent against multiresistant Gram-negative bacteria. Int J Antimicrob Agents 2005;25(1):11. [http://dx.doi.org/10.1016/j. ijantimicag.2004.10.001] 10. Yahav D, Farbman L, Leibovici L, Paul M. Colistin: New lessons on an old antibiotic. Clin Microbiol Infect 2012;18(1):18-29. [http://dx.doi.org/10.1111/j.1469-0691.2011.03734.x] 11. Nation RL, Li J. Colistin in the 21st century. Current Opin Infect Dis 2009;22(6):535-543. [http:// dx.doi.org/10.1097/QCO.0b013e328332e672] 12. Li J, Nation R, Turnridge J, et al. Colistin: The re-emerging antibiotic for multidrug-resistant Gramnegative bacterial infections. Lancet Infect Dis 2006;6(9):589-601. [http://dx.doi.org/10.1016/S14733099(06)70580-1] 13. Cai Y, Chai D, Wang R, Liang B, Bai N. Colistin resistance of Acinetobacter baumannii: Clinical reports, mechanisms and antimicrobial strategies. J Antimicrob Chemother 2012;67(7):1607-1615. [http:// dx.doi.org/10.1093/jac/dks084] 14. Bergen PJ, Li J, Rayner CR, Nation RL. Colistin methanesulfonate is an inactive prodrug of colistin against Pseudomonas aeruginosa. Antimicrob Agents Chemother 2006;50(6):1953-1958. [http:// dx.doi.org/10.1128/AAC.00035-06] 15. Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by Gram-negative bacteria. Antimicrob Agents Chemother 2009;53(8):3430-3436. [http:// dx.doi.org/10.1128/AAC.01361-08] 16. Li J, Milne RW, Nation RL, Turnidge JD, Smeaton TC, Coulthard K. Use of high-performance liquid chromatography to study the pharmacokinetics of colistin sulfate in rats following intravenous administration. Antimicrob Agents Chemother 2003;47(5):1766-1770. [http://dx.doi.org/10.1128/ AAC.47.5.1766-1770.2003] 17. Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother 2011;55(7):3284-3294. [http://dx.doi. org/10.1128/AAC.01733-10]

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18. Michalopoulos AS, Karatza DC, Gregorakos L. Pharmacokinetic evaluation of colistin sodium. Expert Opin Drug Metab Toxicol 2011;7(2):245-255. [http://dx.doi.org/10.1517/17425255.2011.541439] 19. Michalopoulos AS, Falagas ME. Colistin: Recent data on pharmacodynamics properties and clinical efficacy in critically ill patients. Ann Intensive Care 2011;1(1):30. [http://dx.doi.org/10.1186/21105820-1-30] 20. Marchand S, Frat JP, Petitpas F, et al. Removal of colistin during intermittent haemodialysis in two critically ill patients. J Antimicrob Chemother 2010;65:1836-1837. [http://dx.doi.org/10.1093/jac/ dkq185] 21. Li J, Rayner CR, Nation RL, et al. Pharmacokinetics of colistin methanosulfonate and colistin in a critically ill patient receiving continuous venovenous hemodialfiltration. Antimicrob Agents Chemother 2005;49:4814-4815. [http://dx.doi.org/10.1128/AAC.49.11.4814-4815.2005] 22. Karvanen M, Plachouras D, Friberg LE, et al. Colistin methanesulfonate and colistin pharmacokinetics in critically ill patients receiving continuous venovenous hemodiafiltration. Antimicrob Agents Chemother 2013;57(1):668-671. [http://dx.doi.org/10.1128/AAC.00985-12] 23. Roberts JA, Lipman J. Antibacterial dosing in intensive care: Pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clin Pharmacokinet 2006;45(8):755-773. [http://dx.doi. org/10.2165/00003088-200645080-00001] 24. De Paepe P, Belpaire FM, Buylaert WA. Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock. Clin Pharmacokinet 2002;41(14):1135-1151. [http:// dx.doi.org/10.2165/00003088-200241140-00002] 25. Varghese JM, Roberts JA, Lipman J. Antimicrobial pharmacokinetic and pharmacodynamic issues in the critically ill with severe sepsis and septic shock. Crit Care Clin 2011;27(1):19-34. [http://dx.doi. org/10.1016/j.ccc.2010.09.006] 26. Couet W, Gregoire N, Marchand S, Mimoz O. Colistin pharmacokinetics: The fog is lifting. Clin Microbiol Infect 2012;18(1):30-39. [http://dx.doi.org/10.1111/j.1469-0691.2011.03667.x] 27. Bergen PJ, Bulitta JB, Forrest A, Tsuji BT, Li J, Nation RL. Pharmacokinetic/pharmacodynamic investigation of colistin against Pseudomonas aeruginosa using an in vitro model. Antimicrob Agents Chemother 2010 Sep;54(9):3783-3789. [http://dx.doi.org/10.1128/AAC.00903-09] 28. Landman D, Georgescu C, Martin DA, Quale J. Polymyxins revisited. Clin Microbiol Rev 2008;21(3):449-465. [http://dx.doi.org/10.1128/CMR.00006-08] 29. Dudhani RV, Turnidge JD, Coulthard K, et al. Elucidation of the pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models. Antimicrob Agents Chemother 2010;54(3):1117-1124. [http://dx.doi.org/10.1128/ AAC.01114-09] 30. Dudhani RV, Turnidge JD, Nation RL, Li J. fAUC/MIC is the most predictive pharmacokinetic/ pharmacodynamic index of colistin against Acinetobacter baumannii in murine thigh and lung infection models. J Antimicrob Chemother 2010;65(9):1984-1990. [http://dx.doi.org/10.1093/jac/ dkq226] 31. Daikos GL, Skiada A, Pavleas J, et al. Serum bactericidal activity of three different dosing regimens of colistin with implications for optimum clinical use. J Chemother 2010;22(3):175-178. 32. Cai Y, Li R, Liang B, Bai N, Liu Y, Wang R. In vitro antimicrobial activity and mutant prevention concentration of colistin against Acinetobacter baumannii. Antimicrob Agents Chemother 2010;54(9):3998-3999. [http://dx.doi.org/10.1128/AAC.00264-10] 33. Markou S, Markantonis SL, Dimitrakis E, et al. Colistin serum concentrations after intravenous administration in critically ill patients with serious multidrug-resistant, Gram-negative bacilli infections: A prospective, open-label, uncontrolled study. Clin Infect Dis 2008;30:143. [http://dx.doi. org/10.1016/j.clinthera.2008.01.015] 34. Bergen PJ, Li J, Nation RL, Turnidge JD, Coulthard K, Milne RW. Comparison of once-, twiceand thrice-daily dosing of colistin on antibacterial effect and emergence of resistance: Studies with Pseudomonas aeruginosa in an in vitro pharmacodynamic model. J Antimicrob Chemother 2008;61(3):636-642. [http://dx.doi.org/10.1093/jac/dkm511] 35. Dalfino L, Puntillo F, Mosca A, et al. High-dose, extended-interval colistin administration in critically ill patients: Is this the right dosing strategy? A preliminary study. Clin Infect Dis 2012;54(12):17201726. [http://dx.doi.org/10.1093/cid/cis286] 36. Rodriguez CH, De Ambrosio A, Bajuk M, et al. In vitro antimicrobials activity against endemic Acinetobacter baumannii multiresistant clones. J Infect Dev Ctries 2010;4(3):164-167. [http://dx.doi. org/10.3855/jidc.604] 37. Cai Y, Yang J, Kan Q, et al. Mutant prevention concentration of colistin alone and in combination with levofloxacin or tobramycin against multidrug-resistant Acinetobacter baumannii. Int J Antimicrob Agents 2012;40(5):477-478. [http://dx.doi.org/10.1016/j.ijantimicag.2012.06.018] 38. Pogue JM, Lee J, Marchaim D, et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis 2011;53(9):879-884. [http://dx.doi.org/10.1093/cid/ cir611] 39. Gounden R, Bamford C, Van Zyl-Smit R, Cohen K, Maartens G. Safety and effectiveness of colistin compared with tobramycin for multi-drug resistant Acinetobacter baumannii infections. BMC Infect Dis 2009;9(1):26. [http://dx.doi.org/10.1186/1471-2334-9-26] 40. Spapen H, Jacobs R, Van Gorp V, Troubleyn J, Honore PM. Renal and neurological side effects of colistin in critically ill patients. Ann Intensive Care 2011;1:14. [http://dx.doi.org/10.1186/21105820-1-14] 41. Hartzell JD, Neff R, Ake J, et al. Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center. Clin Infect Dis 2009;48:1724-1728. [http://dx.doi. org/10.1086/599225] 42. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 2009;48(1):1-12. [http://dx.doi. org/10.1086/595011] 43. Bamford C, Badenhorst L, Duse A, et al. Antimicrobial susceptibility patterns of selected invasive pathogens from public sector hospitals in South Africa, in 2007. South Afr J Epidemiol Infect 2009; 24(2):28-30. 44. Durante‐Mangoni E, Signoriello G, Andini R, et al. Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug‐resistant Acinetobacter baumannii. A multicentre, randomised, clinical trial. Clin Infect Dis 2013;57(3):349-358. [http://dx.doi. org/10.1093/cid/cit253]

Accepted 16 September 2013.

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Determinants, outcomes and costs of ceftriaxone v. amoxicillin-clavulanate in the treatment of communityacquired pneumonia at Witbank Hospital S N Xaba, MB BCh, Dip HIV Man (SA); O Greeff, MB ChB, MPharmMed, MD, FFRP, FCFP; P Becker, BSc, MSc, PhD Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, South Africa Corresponding author: O Greeff (oppel.greeff@up.ac.za)

Background. Community-acquired pneumonia (CAP) is a major cause of death and morbidity worldwide. Treatment is centred on antibiotics with ceftriaxone and amoxicillin-clavulanate being some of the most commonly prescribed agents. Objective. To compare treatment outcomes and costs in patients receiving either of these two antibiotics at Witbank Hospital (WH). Methods. A total of 200 randomly selected adult patient files (100 receiving ceftriaxone and 100 amoxicillin-clavulanate) recording a diagnosis of CAP were studied to determine the length of hospital stay, comorbid conditions and treatment outcomes. A descriptive and comparable analysis was performed. Results. Male gender, higher CURB-65 scores and death were associated with the use of ceftriaxone. Severity of disease and previous antibiotic exposure influenced the duration of hospital admission. Conclusion. Gender and severity of disease (based on the CURB-65 score) were the determinants of antibiotic choice at WH. Male gender increased the likelihood of being treated with ceftriaxone, as did a CURB-65 score of >2. There were no differences in the outcomes of CAP patients treated with ceftriaxone compared with those treated with amoxicillin-clavulanate. Irrespective of antibiotic used, gender and severity of disease influenced treatment outcomes. Male gender was associated with a higher mortality and longer hospital stay. The average duration of stay for both antibiotics was not significantly different. Thus, only level 1 and 2 costs need to be considered when comparing the two regimens. On this basis, ceftriaxone was cheaper than amoxicillin-clavulanate. S Afr Med J 2014;104(3):187-191. DOI:10.7196/SAMJ.7243

Community-acquired pneumonia (CAP) is the most common type of lower respiratory tract infection and can be life-threatening, especially among young children, the elderly and those with comorbid conditions.[1] The most common pathogen associated with CAP is Streptococcus pneumoniae.[2] Males generally suffer a more severe form of the disease with a higher associated mortality. [3] For those with diabetes mellitus, pneumonia is associated with more severe presentation, poor prognosis and poor outcomes.[4,5] HIV infection is also a major risk factor for pneumonia. CAP symptoms are non-specific and patients may present with both upper and lower respiratory tract symptoms. There is no rapid, simple, accurate and cost-effective method for immediate diagnosis of CAP in most patients at presentation. A chest radiograph is necessary to establish the diagnosis of CAP and to differentiate it from other respiratory illnesses.[6] The decision whether or not to admit a patient influences the extent of diagnostic testing as well as the choice of empirical antimicrobial treatment. Pharmacokinetics, efficacy, safety profile, cost, spectrum of activity and whether or not a specific pathogen is identified influence antibiotic treatment choice. Several clinical societies worldwide have authored treatment guidelines for CAP as a way of standardising chemotherapeutic treatment.[7-9]

Methods

Our research was conducted at Witbank Hospital (WH), a 350-bed secondary-level hospital in Mpumalanga Province affiliated to the University of Pretoria as a satellite facility. Clinical records of patients

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who were treated with ceftriaxone or amoxicillin-clavulanate for CAP, as diagnosed by the treating clinician, from January 2010 to January 2012 were selected and categorised according to the antibiotic selected. For each group, every fourth file was selected beginning with a random number until a total of 100 were reached. This gave a total of 200 randomly selected files with half being treated with amoxicillin-clavulanate and the other half with ceftriaxone. Patients were of any race, gender and over 13 years of age. To establish the determinants of choice of antibiotic, we examined the severity of disease, presence of comorbid conditions, previous hospital admission/antibiotic exposure, contraindications, ease of administration of either drug and its availability, or lack thereof. To determine treatment outcomes, we established the number of those who: (i) were successfully treated/discharged from hospital; (ii) had complications, which might or might not have been directly related to the choice of antibiotic; and (iii) died. Successful treatment was defined by the resolution of symptoms and by recorded resolution of pneumonic changes on chest radiograph and/or improvement of inflammatory markers (C-reactive protein and white cell count). Death was confirmed by a record in the patient file, as were complications related to the drugs. Treatment costs were determined by ascertaining the direct costs of acquisition of the antibiotics. Costs related to (i) the diagnosis and treatment of pneumonia; (ii) antibiotic administration; and (iii) hospital accommodation were determined by interviewing relevant hospital personnel. Costs related to other antibiotics used in combination with the study antibiotics were similar as the same antibiotic (erythromycin) was used.

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This study was approved by the Ethics Committee of the University of Pretoria.

Table 1. Demographic data

Statistical analysis

A descriptive and comparable analysis was performed. Continuous variables were analysed using the Mann-Whitney U test. Univariate analysis was based on the χ2 test for qualitative variables, while Student’s t-test was used for quantitative variables. Non-parametric tests were used in the absence of a normal distribution. A logistic model was used to adjust for the effect of multiple variables such as gender, HIV status and severity of disease. A p-value of <0.05 was considered significant.

Results

Results are summarised in Table 1. In addition to the comorbidities listed, five patients were receiving amoxicillin-clavulanate, and five were receiving ceftriaxone. One patient receiving ceftriaxone had unexplained hepatitis, with negative viral studies. Logistic regression was performed to ascertain whether HIV, gender, severity of illness (the CURB-65 score) and previous antibiotic exposure were determinants of antibiotic choice (Table 2). Severity of pneumonia was assessed using the CURB-65 score, which includes fives components: C – confusion; U – urea >7 mmol/l; R – respiratory rate >30 breaths/min; B – blood pressure, systolic <90 mmHg or diastolic <60 mmHg; and 65 - age >65 years.[10] HIV was not a determinant of antibiotic treatment choice (p=0.51). Male gender was significantly associated with the use of ceftriaxone (p=0.001). A higher CURB-65 score was also significantly associated with the use of ceftriaxone (moderate CURB-65 score: p=0.003; severe CURB65 score: p=0.002). Previous antibiotic exposure was associated with a slightly higher use of ceftriaxone, but this was statistically insignificant (p=0.799). From multivariate logistic regression, it was established that only gender and CURB-65 score were associated with ceftriaxone treatment (Table 3). There was also a significant interaction between gender and CURB-65 score (p=0.046). For death as an outcome, choice of antibiotic, HIV status, gender, severity of disease and previous antibiotic exposure were analysed by logistic regression. Ceftriaxone showed a significant association with death as an outcome (p=0.032). HIV showed no significant influence (p=0.459). There was a higher incidence of deaths among males. A significant association between the severity of disease and death was observed (p=0.029). Previous antibiotic exposure was not associated with death (p=0.312). Treatment with ceftriaxone was associated with a slightly longer length of hospital stay than amoxicillin-clavulanate; however, the difference was not statistically significant (mean 6.21 v. 5.22 days, respectively; p=0.093). The HIV-positive status of patients led to a slightly longer hospital stay after treatment with ceftriaxone v. amoxicillin-clavulanate; however, this was not statistically significant (mean 6.04 v. 4.49 days, respectively; rank-sum p=0.253). There was no association between gender and length of stay (rank-sum p=0.477). Severity of disease did have an influence on the length of stay, with moderate disease leading to an average of 5.04 days in hospital and severe disease leading to an average of 7.01 days in hospital (rank-sum p=0.015). Previous antibiotic exposure also led to a slightly longer hospital stay than no previous exposure (mean 6.97 v. 5.12 days, respectively; rank-sum p=0.015), which is statistically significant. From multivariate logistic regression analysis, death was associated with ceftriaxone, a high CURB-65 score and male gender. When

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Patients, N

Ceftriaxone

Amoxicillinclavulanate

100

15 - 83

14 - 89

Age (years) Range Average

45.73

41.37

Median

37.5

Male

Female

6.22

5.18

Gender, n

Length of hospital stay (days) Average

Patients with previous antibiotic exposure, n

Median

CURB-65 score, average

2.4

2.1

Comorbidities, n HIV T2DM

Epilepsy

COPD

Heart failure

Ischaemic stroke

Pneumonia-related complications, n Pleural effusion Septic shock

Deep vein thrombosis

Lung abscess

Outcomes, n Complications

Patients successfully treated (discharged)

Deaths

T2DM = type 2 diabetes mellitus; COPD = chronic obstructive pulmonary disease.

controlled for gender, treatment was not significantly associated with outcome (p=0.191) while severity of disease was associated with outcome (p=0.05).

Discussion

Determinants and treatment outcomes

When comparing determinants and outcomes of CAP in the two antibiotic groups we found that gender played an important role in antibiotic choice, with >80% of males prescribed ceftriaxone. Additionally, more males in our study had a more severe form of pneumonia, as exemplified by a higher CURB-65 score. This is in line with previous studies; male gender is a risk factor for developing severe pneumonia with higher mortality.[3]

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and capacity challenges under which WH operates. HIV-positive status proved not to be a determinant of antibiotic choice. Notably, 41% of patients in our study were HIVpositive, but we found no link between their status and choice of antibiotic regimen. Prior antibiotic exposure is thought to be a major risk factor for antibiotic resistance. [16] However, in our study, it was not a determinant. This is not surprising because based on analysis of published literature on CAP resistance, Feldman[17] concluded that ‘little evidence suggests that infections with resistant pneumococci per se are more severe.’ In comparing treatment outcomes, we looked at death or cure and also compared different variables looking at the length of hospital stay. We found that more patients receiving ceftriaxone died compared with those receiving amoxicillin-clavulanate. This is because sicker patients (most of whom were male) were prescribed ceftriaxone. However, in the multivariate analysis used to predict mortality, gender and severity of disease were found to be associated independently with a higher mortality

Severity of disease also played an important role in the choice of antibiotic. Patients with higher CURB-65 scores were more likely to receive ceftriaxone than amoxicillinclavulanate. That ceftriaxone was prescribed for sicker patients may suggest that doctors believe that ceftriaxone is superior to amoxicillin-clavulanate. Studies have shown the cure rates of ceftriaxone to be 84% and that of amoxicillin-clavulanate to be 76%,[11,12] a fact that might have influenced antibiotic choice in CAP treatment by clinicians at WH. Severity of disease was also associated with a longer hospital stay, the link between severity of disease and hospital length of stay is well documented.[13] However, as Fine et al.[14] revealed, and as was subsequently confirmed by others,[15] the length of hospital stay for treatment of CAP is not solely determined by patient-dependent factors such as age, severity of disease and the presence of comorbid conditions, but is rather heterogeneous with great variation between hospitals reflecting physician- and hospital-specific behaviours. There is no reason to believe that this was the case in the current study, given the economic

Table 2. Determinants of antibiotic choice: Ceftriaxone % (n/N cases)

Crude OR

95% CI

p-value

Positive

52.4 (43/82)

1.21

0.688 - 2.125

0.510

Negative

48.3 (57/118)

1.00 3.947 - 16.679

0.001

Determinant HIV

Gender Female

16.9 (11/65)

1.00

Male

65.9 (89/135)

8.11

5.0 (1/20)

1.00

CURB-65 Score Mild (0 - 1) Moderate (2)

54.0 (60/112)

22.35

2.891 - 172.81

0.003

Severe (3 - 4)

57.4 (39/68)

25.55

3.232 - 201.98

0.002

0.596 - 1.959

0.799

Previous antibiotic exposure Yes

51.6 (33/64)

1.08

49.6 (67/135)

1.00

OR = odds ratio; CI = confidence interval.

and, after adjusting for their confounding effect, there were no statistically significant differences between the two antibiotic regimens. The ceftriaxone group had a longer duration of stay, averaging 6.22 days compared with 5.18 days in the amoxicillinclavulanate group. This was not statistically significant and the length of hospital stay may have been related to factors such a severity of disease and presence of comorbid conditions, rather than choice of antibiotic. In our study, HIV did not increase the risk of CAP-related death. The influence of HIV on CAP treatment outcomes has been the subject of several studies. In three of these studies, using univariate analyses of clinical outcomes of CAP, higher death rates were found among the HIV-infected patients.[18-20] However, not surprisingly, the higher death rates were among patients who were not receiving highly active antiretroviral therapy (HAART). Bordon et al.[21] conducted a study to evaluate the clinical outcomes of CAP among hospitalised HIV-infected patients and found that HIV did not significantly influence overall mortality rates or CAPrelated mortality rates. Even though a higher number of HIV-positive patients with pneumonia died in our study (20% HIVpositive v. 16% HIV-negative, irrespective of antibiotic choice), this was not statistically significant in line with Bordon et al.’s findings. With respect to length of hospital stay, the influence of HIV was also statistically insignificant. Johnson et al.[22] reported a longer hospital stay among HIV-infected patients. However, the patients studied were not receiving HAART. Studies have confirmed the link between introducing HAART and a reduction in the incidence of bacterial pneumonia cases.[23] Gender influence on death and length of stay as outcomes was statistically insignificant. Thus, while males are known to be more likely to suffer from a severe form of CAP, our results, based on a small sample size, suggest that they do not necessarily stay longer in hospital and that they are not more likely to die. This calls for a much larger sample size in future studies as these results are at odds with previous studies.[3,24]

Table 3. Summary of results Variables

Determinant of choice of antibiotic

Outcome

Length of hospital stay

Treatment cost

HIV

Nil association

Longer stay but not significant

Nil association

Gender

Significant difference

Males more affected

Nil association

CURB-65 score

Significant difference

Previous antibiotic exposure

Association but not significant

Nil association

Significant difference

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Severity of disease (higher CURB-65 score) had a statistically significant influence on death as a treatment outcome irrespective of antibiotic regimen. The CURB-65 score also had a statistically significant influence on the length of hospital stay. These results are in line with those from a recent study by Armiñanzas et al.[25] However, the mean age in Armiñanzas et al.’s study of 539 patients (51% male) was 78 years, which is much higher than in our study. The association between death as an outcome and previous antibiotic exposure, which could suggest potential resistance, was statistically insignificant. There was also no statistically significant relationship between the length of hospital stay and previous antibiotic exposure. Interestingly, from our results, the group that had been previously exposed to antibiotics had fewer deaths although a longer hospital stay, giving the impression that previous exposure to antibiotics (3 months prior to admission) in CAP is protective and reduces the risk of death. For amoxicillin-clavulanate at least, this is in agreement with the results from the case-control study by Einarsson et al.[26] Of interest, in our study, we observed that the mean age difference (Table 2) was statistically insignificant. Therefore, age as a factor did not independently contribute to the choice of antibiotic, or to any of the outcomes.

Complications and comorbid conditions

In addition to the comorbidities listed in Table 1, there was one case of prostate cancer, two of underlying fibrotic lung disease, three of epilepsy, seven of diabetes, three of stroke and four of chronic obstructive pulmonary disease. None of the seven diabetic patients in our study (two receiving amoxicillin-clavulanate and five receiving ceftriaxone) died and none stayed longer than the median 5 days. This is in contrast with a study by Moosa et al.[27] which showed an increased risk of mortality and morbidity. Although statistically insignificant, with respect to death as an outcome, the results in diabetes patients are in line with finding by Belk et al.[28] that, after controlling for other variables, patients with type 2 diabetes mellitus had a lower risk of in-hospital mortality (but longer length of stay) when hospitalised for pneumonia.

Costs implications

Pharmaco-economic analysis can be classified into three levels of costs:[29] (i) level 1 (pharmacy perspective) considers only the acquisition price of the study medication; (ii) level 2 adds to the level 1 costs all other costs directly related to antibiotic use and infection treatment – antibiotic-related items include medication preparation, dispensing and administration, therapeutic drug monitoring, treatment of adverse events and secondary treatment for failures; and (iii) level 3 costs include all level 2 items and other hospital costs incurred during treatment. The daily cost of occupying a hospital bed is highly variable and depends on the type of unit (intensive care or general), the levels of technology and services provided, and geographic location. Because the length of hospital stay in both groups showed no statistically significant differences, level 3 costs were similar for both treatment regimens. With level 2 costs, all other contributors were rendered irrelevant by similar treatment outcomes between the two antibiotics. In addition, there were no complications related to antibiotic use for both regimens. The only relevant aspect under level 2 costs was the frequency of administration of the antibiotic, with amoxicillin-clavulanate, because of its shorter half-life, requiring three injections in a 24-hour period while ceftriaxone requires oncea-day administration. This makes ceftriaxone more cost-effective.

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With respect to level 1 costs, ceftriaxone costs R3.40 per vial and requires 3.5 ml of sterile water to reconstitute and is given as a daily parenteral dose. On the other hand, amoxicillin-clavulanate costs R11.80 per vial, requires 20 ml of sterile water for reconstitution and is given three times a day. The oral formulations cost R11.88 for 875 +175 mg (10s) and R11.30 for 250 +125 mg (15s). Thus, ceftriaxone is >70% cheaper than amoxicillin-clavulanate over an average treatment period of 5 days. The above antibiotic prices are based on the latest tender prices at the time of this study.

Conclusion

Gender and severity of disease (CURB-65 score) were determinants of antibiotic choice in WH. Male gender predisposed patients to a ceftriaxone regimen as does a CURB-65 score of >2. There were no differences in the outcomes of CAP patients treated with ceftriaxone and those treated with amoxicillin-clavulanate. Irrespective of the antibiotic used, gender and severity of disease had an influence on treatment outcomes. Male gender was associated with a higher mortality and longer hospital stay; however, the average length of stay for both antibiotics was not significantly different. HIV status was neither a determinant of antibiotic choice nor had any influence on treatment outcomes. Our study demonstrated that there were no differences between the two groups of antibiotics and that severity of disease and gender have a large influence on the choice of antibiotic. When CAP patients were stratified by HIV status, no significant differences existed between the HIV-negative and HIV-positive groups. Since length of hospital stay was not different in either case, only level 1 and 2 costs needed to be considered when comparing the two regimens. On this basis, ceftriaxone is cheaper than amoxicillin-clavulanate. While previous exposure to antibiotics was noted, the specific antibiotic was not noted from each patient. Another limitation of the study is that even though the HIV status of the subjects was noted, whether these patients were receiving HAART or not, the severity of the immune-suppression (CD4+ count) and for those receiving HAART, the specific combination of drugs they were receiving, were not taken into consideration. For its random nature with respect to patient file selection, there were more males in this study than females. All patients in the study were recruited from the general medical wards. Cigarette smoking, a significant risk factor in the development of pneumonia was not studied. Nonetheless, this study provided data on which more research can be based to expand the economic impact of treatment choice in the management of CAP. Acknowledgements. The authors thank WH management and staff for their cooperation. Expert advice from Prof. Paul Rheeder is also acknowledged. References 1. Marrie TJ. Community-acquired pneumonia. Clin Infect Dis 1994;18(4):501-513. 2. File TM Jr. Community-acquired pneumonia. Lancet 2003;362(9400):1991-2001. [http://dx.doi. org/10.1016/S0140-6736(03)15021-0] 3. Falagas EM, Mourtzoukou EG, Vardakas KZ. Sex differences in the incidence and severity of respiratory tract infections. Respir Med 2007;101(9):1845-1863. [http://dx.doi.org/10.1016/j.rmed.2007.04.011] 4. Moosa PE, Phrabhakar K, Lakshmaiah V, Jayarama N. Study of bacterial pneumonia in type 2 diabetes clinical profile and outcome. Int J Infect Dis 2011;15(Suppl 1):S52. [http://dx.doi.org/10.1016/S12019712(11)60178-1] 5. Klein OL, Smith LJ, Tipping M, Peng J, Williams MV. Reduced diffusion lung capacity in patients with type 2 diabetes mellitus predicts hospitalization for pneumonia. Diabetes Res Clin Pract Suppl 2011;92(1): e12-e15. [http://dx.doi.org/10.1016/j.diabres.2010.12.012] 6. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community acquired pneumonia? JAMA 1997;278(17):1440-1445. [http://dx.doi.org/10.1001/jama.278.17.1440] 7. Niederman MS, Luna CM. Community-acquired pneumonia guidelines: A global perspective. Semin Respir Crit Care Med 2012;33(3):298-310. [http://dx.doi.org/10.1055/s-0032-1315642] 8. The British Thoracic Society; Community Acquired Pneumonia in Adults Guideline Group. Guidelines for the management of community acquired pneumonia in adults: Update 2009. Thorax 2009;64(Suppl III):iii1-iii55. [http://dx.doi.org/10.1136/thx.2009.121434]

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9. Feldman C, Brink A, Bateman GA, Maartens G, Bateman ED. Management of community-acquired pneumonia in adults. S Afr Med J 2007;97(12):1296-1306. 10. Lim WS, Van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: An international derivation and validation study. Thorax 2003;58(5):377-382. [http://dx.doi.org/10.1136/thorax.58.5.377] 11. De Klerk GJ, Van Steijn JHM, Lobatto S, et al. A randomised, multicentre study of ceftriaxone versus standard therapy in the treatment of lower respiratory tract infections. Int J Antimicrob Agents 1999;12(2):121-27. [http://dx.doi.org/10.1016/S0924-8579(99)00037-0] 12. Ball P. The clinical development and launch of amoxicillin/clavulanate for the treatment of a range of community-acquired infections. Int J Antimicrob Agents 2007;30(Suppl 2):113-117. [http://dx.doi. org/10.1016/j.ijantimicag.2007.07.037] 13. Capelastegui A, España PP, Quintana JM, et al. Management of community-acquired pneumonia and secular trends at different hospitals. Respir Med 2005;99(3):268-278. [http://dx.doi.org/10.1016/j. rmed.2004.08.010] 14. Fine MJ, Singer DE, Phelps AL, Hanusa BH, Kapoor WN. Differences in length of stay in patients with community-acquired pneumonia: A prospective four-hospital study. Med Care 1993;31(4):371-380. [http://dx.doi.org/10.1097/00005650-199304000-00008] 15. Feagan BG, Marrie TJ, Lau CY, et al. Treatment outcomes of community-acquired pneumonia at Canadian hospitals. Can Med Assoc J 2000;162(10):1415-1420. 16. Bauer T, Ewig S, Marcos MA, Schultze-Werninghaus G, Torres A. Streptococcus pneumoniae in community-acquired pneumonia. How important is drug resistance? Med Clin North Am 2001;85:1367-1379. 17. Feldman C. Clinical relevance of antimicrobial resistance in the management of pneumococcal community-acquired pneumonia. J Lab Clin Med 2004;143(5):269-283. [http://dx.doi.org/10.1016/j. lab.2004.02.002] 18. Feldman C, Klugman KP, Yu VL, et al. Bacteraemic pneumococcal pneumonia: Impact of HIV on clinical presentation and outcome. J Infect 2007;55(2):125-135. [http://dx.doi.org/10.1016/j. jinf.2007.04.001] 19. Park DR, Sherbin VL, Goodman MS, et al. Harborview CAP Study Group. The etiology of community acquired pneumonia at an urban public hospital: Influence of HIV infection and initial severity of illness. J Infect Dis 2001;184(3):268-277. [http://dx.doi.org/10.1086/322040]

20. Touchie C, Marrie TJ. Comparison of community-acquired pneumonia requiring admission to hospital in HIV- and non-HIV-infected patients. Can J Infect Dis 1996;7(4):253-258. + 21. Bordon J, Kapoor R, Martinez C, et al. CD4 cell counts HIV-RNA levels do not predict outcomes of community acquired pneumonia in hospitalized HIV infected patients. Int J Infect Dis 2011;15(12):e822-e827. [http://dx.doi.org/10.1016/j.ijid.2011.05.021] 22. Johnson DH, Carriere KC, Houston S. Hospitalization for community-acquired pneumonia in Alberta patients with human immunodeficiency virus infection: A case control study. Can Resp J 2003;10(5):265-270. 23. De Gaetano Donati K, Bertagnolio S, Tumbarelo M, et al. Effect of highly active antiretroviral therapy on the incidence of bacterial pneumonia in HIV infected subjects. Int J Antimicrob Agents 2000;16(3):357-360. 24. Gordon HS, Rosenthal GE. The relationship of gender and in-hospital death: Increased risk of death in men. Med Care 1999;37(3):318-324. [http://dx.doi.org/10.1097/00005650-199903000-00011] 25. Armiñanzas C, Velasco L, Calvo, N, et al. CURB-65 as an initial prognostic score in internal medicine patients. Eur J Intern Med 2013;24(5):416-419. [http://dx.doi.org/10.1016/j.ejim.2013.01.004] 26. Einarsson S, Kristjansson M, Kristinsson KG, Kjartansson G, Jonsson S. Pneumonia caused by penicillinnon-susceptible and penicillin-susceptible pneumococci in adults: A case-control study. Scand J Infect Dis 1998;30(3):253-256. 27. Moosa PE, Prabhakar K, Lakshmaiah V, Jayarama N. PP-025 Study of bacterial pneumonia in type 2 diabetes – clinical profile and outcome. Int J Infect Dis 2011;15(Suppl 1):S52. [http://dx.doi.org/10.1016/ S1201-9712(11)60178-1] 28. Belk KW, Craver CW, Blanchette CM. PDB25 Impact of diabetes in patients hospitalized for pneumonia. Value in Health 2012;15(4):A175. [http://dx.doi.org/10.1016/j.jval.2012.03.946] 29. Dresser LD, Niederman MS, Paladin JA. Cost-effectiveness of gatifloxacin vs ceftriaxone with a macrolide for the treatment of community-acquired pneumonia. Chest 2001;119(5):1439-1448. [http://dx.doi. org/10.1378/chest.119.5.1439]

Accepted 16 October 2013.

The impact of chronic pseudomonal infection on pulmonary function testing in individuals with cystic fibrosis in Pretoria, South Africa A Pentz, FC Paed (SA), Dip Allergol (SA); P Becker, PhD; R Masekela, PhD; O Coetzee, N Dip Clin Tech; R J Green, PhD, DSc Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Pretoria, South Africa Corresponding author: R J Green (robin.green@up.ac.za)

Background. Colonisation of the airway by Pseudomonas spp. in cystic fibrosis has been reported to be an important determinant of decline in pulmonary function. Objective. To assess pulmonary function decline and the presence of bacterial colonisation in patients with cystic fibrosis (CF) attending a CF clinic in a developing country. Methods. A retrospective audit of patients attending the CF clinic at Steve Biko Academic Hospital, Pretoria, South Africa, was performed. The data included spirometric indices and organisms routinely cultured from airway secretions (Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA)). Results. There were 29 study subjects. Analysis of variance for ranks (after determining that baseline pulmonary function, age, gender and period of follow-up were not contributing to pulmonary function decline) revealed a median decline in forced expiratory volume in 1 second, forced vital capacity and forced expiratory flow over 25 - 75% expiration of 12%, 6% and 3%, respectively, for individuals colonised by PA. There was no pulmonary function decline in individuals not colonised by PA, or in individuals colonised by SA. Conclusion. Pulmonary function decline in this South African centre is significantly influenced by chronic pseudomonal infection. Other influences on this phenomenon should be explored. S Afr Med J 2014;104(3):191-194. DOI:10.7196/SAMJ.7222

Cystic fibrosis (CF) is a genetic disease with an autosomal recessive inheritance pattern. The identified gene, the cystic fibrosis transmembrane conductance regulator (CFTR), is situated on the long arm of chromosome 7.[1] The pathological features in CF follow

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an abnormality or dysfunction in the CFTR gene leading to abnormal transport of chloride and sodium across epithelial membranes. This involves the pancreas, biliary tract, intestines, reproductive tract, airway and sweat glands, and in the airway leads to airway dehydration and disruption of mucociliary clearance. As a result of abnormal airway

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secretions, mucus becomes a nidus for regular infections by microorganisms.[2] The predominant organisms are Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA).[3] Colonisation by PA has major consequences for individuals with CF, including more frequent respiratory infectious exacerbations, impaired quality of life, growth retardation and decline in pulmonary function.[4] The concept of colonisation of the CF airway is the subject of significant debate. Some authors consider that recurrent culture of PA from airway secretions constitutes ‘chronic infection’ rather than colonisation, since the latter term implies benign presence of organisms.[5] In the current study, colonisation was considered to occur when the same bacterium was isolated in at least three sputum specimens on three different occasions but not during an acute exacerbation. Colonisation by PA has been reported to be the most important determinant of decline in lung function in subjects with CF.[6] Many CF centres around the world have employed measures to minimise the risk of, and from, PA. These measures include separation of chronically colonised patients from those without PA at clinics, aggressive eradication policies, and nebuliser and home hygiene. Spirometric measurements of pulmonary function (particularly forced expiratory volume in 1 second (FEV1)) are important measures of disease progression and survival in CF.[7] The rate of annual pulmonary function decline, as well as the associated or aetiological factors, have been explored in some population groups.[8,9] In South Africa, only two studies of pulmonary function decline in CF have been published.[10,11] The aim of the current study was to compare the association between pulmonary function measurements and the presence of bacterial colonisation by PA and SA in patients with CF attending the clinic at Steve Biko Academic Hospital (SBAH), Pretoria, South Africa.

Methods

A retrospective audit of the patient records of subjects followed up at the CF clinic at SBAH was performed. The data analysed included spirometry, organisms identified on regular sputum microbial culture, and other epidemiological variables (age at CF diagnosis, age at first recorded spirometry, first spirometric parameters, identification of PA or SA in sputum (if ever), last spirometry indices, and spirometry parameters performed in the middle of the period between the first and last spirometry). Subjects met the inclusion criteria if they had CF, had records of at least three pulmonary function tests, and were able to contribute sputa for determination of microbial colonisation, not associated with an acute exacerbation. CF had been diagnosed on the basis of two unequivocal sweat tests and confirmed by genetic testing in all subjects. Patients were enrolled if they were able to perform reliable spirometry. It was then determined whether or not each of these patients had current sputum growth of PA (December 2012). The individuals with PA in sputa were then enrolled as PA-positive if they had grown the organism on three or more occasions in the last year. At each of these time points the growth was associated with spirometry performed at that visit. All patients had sputum collected by expectoration or induced with hypertonic saline by nebulisation under supervision of a physiotherapist. Sputa were routinely collected from every patient at every clinic visit. Sputum quality was ensured as representative of lower airway secretions by means of a Bartlett score. The CF clinic at SBAH has 52 current patients, ranging in age from 8 months to 40 years. Most of the white patients are ΔF508 homozygous or heterozygous, but the clinic has four black African and mixed-race CF patients with other genetic aetiologies. Ninety per cent

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of the patients have pancreatic insufficiency. Clinic practice includes regular attempts to eradicate PA when it is identified for the first time, and patients with PA are treated in separate areas. The clinic manages all patients according to guidelines published by the Medical and Scientific Advisory Committee of the South African Cystic Fibrosis Association. Two clinic members are executive participants.[12] Spirometry was performed using a Koko legend spirometer (manufactured by nSpire Health, Inc. and supplied by SSEM Mthembu). Normal values were interpreted against the European Respiratory Society (ERS)/Polgar predicted values[13] and in accordance with the ERS criteria.[14] The best pulmonary function test value (based on FEV1) of three reproducible efforts (without bronchodilator administration) was recorded. FEV1, forced vital capacity (FVC), and forced expiratory flow over 25 - 75% expiration (FEF25-75) were recorded. A new decontaminated re-usable bacterial filter (Vibac Pulmonary Function filter) was used for each patient to prevent infectious cross-contamination. Spirometry was performed by a trained technician and equipment was calibrated daily. All values were expressed as percentages of expected, for age and height. The study was approved by the Human Ethics Committee of the University of Pretoria.

Statistical analysis

As the data were skewed, analysis of variance (ANOVA) for ranks was conducted. The important analysis in the study was PA and SA colonisation in relation to spirometric indices. Because baseline pulmonary function, age, gender and period of follow-up were not found to be significant co-variates, an ANOVA for ranks was employed to assess PA and SA respectively, not adjusting for the latter. For change in spirometry the median and interquartile range (IQR) were reported. Stata 12 was used for analyses and p≤0.05 was considered significant.

Results

There were 29 study subjects (median age 9.97 years, IQR 6.79 21.14) who met the criteria for inclusion in the study. CF genetic analysis revealed that 15 individuals were ΔF508 homozygous and eight were ΔF508 heterozygous. The remaining six individuals had other less common mutations. Spirometry indices at baseline revealed a median (IQR) FEV1, FVC and FEF25-75 of 78% (61 - 101), 87% (73 - 95) and 70% (38 - 106), respectively. At the end of the study, spirometry indices revealed a mean (IQR) FEV1, FVC and FEF25-75 of 61% (49 - 94), 77% (52 - 94) and 43% (22 - 107), respectively. These were not statistically different for the total group (p>0.05). The median (IQR) of the spirometric variables for the patients colonised by PA, and those not colonised, for the study entry time point and study end time point are reflected in Table 1. As baseline pulmonary function, age, gender and period of follow-up were not found to be significant covariates, an ANOVA for ranks was employed to assess the impact of PA and SA, respectively, on change in spirometric indices without adjusting for the latter (Table 2). With respect to colonisation of sputa by PA, 15 of the subjects attending the clinic (51.7%) were found to be colonised at study entry. The median age of the patients with PA colonisation was 19.9 years (IQR 15.8 - 26.9). The interaction of SA and PA in individuals colonised by both organisms revealed no statistical significance for any spirometric parameter. There were three patients colonised by both organisms. There was no difference in the rate of decline of pulmonary function between individuals with the common genetic mutation (ΔF508) homozygous status, those with heterozygous status, or when another mutation was present (p>0.05 for all indices).

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Table 1. Spirometric indices (%) at baseline and end of study for individuals with and without colonisation by P. aeruginosa Study start median (IQR)

Study end median (IQR)

FEV1 Total group

78 (61 - 101)

61 (49 - 94)

PA-negative

99.5 (78 - 105)

97 (60 - 107)

PA-colonised

71 (41 - 83)

50 (23 - 68)

87 (73 - 95)

77 (52 - 94)

FVC Total group PA-negative

93 (81 - 104)

97 (71 - 114)

PA-colonised

84 (56 - 87)

67 (41 - 80)

70 (38 - 106)

43 (22 - 107)

FEF25-75 Total group PA-negative

105 (55 - 118)

109 (69 - 138)

PA-colonised

38 (18 - 87)

22 (11 - 42)

PA = Pseudomonas aeruginosa; IQR = interquartile range; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; FEF25-75 = forced expiratory flow over 25 - 75% expiration.

Table 2. Change in pulmonary function variables over time in individuals with cystic fibrosis* Outcome (change from baseline)

Median (change from baseline) (IQR)

p-value

PA 0.028

FEV1 Negative

-2 (-10 - 10)

Positive

12 (2 - 22)

FVC

0.010

Negative

-7 (-12 - 4)

Positive

6 (4 - 18) 0.015

FEF25-75 Negative

-18.5 (-28 - 14)

Positive

3 (-1 - 22)

SA 0.393

FEV1 Negative

6 (1 - 19)

Positive

1 (-6 - 12)

FVC

0.730

Negative

4 (-6,5 - 17,5)

Positive

0 (-8 - 18) 0.679

FEF25-75 Negative

4 (-22 - 15)

Positive

-1 (-23 - 25)

ANOVA = analysis of variance; IQR = interquartile range; PA = Pseudomonas aeruginosa; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; FEF25-75 = forced expiratory flow over 25 - 75% expiration; SA = Streptococcus aureus. *ANOVA for ranks controlling for baseline spirometry.

Discussion

This study supports the hypothesis that that the pulmonary function of patients with positive Pseudomonas spp. cultures declines significantly over time, independent of starting pulmonary function,

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subject age or gender and period of follow-up. It is possible that the presence of PA is but a marker for another process that may or may not be related to the presence of PA. However, this seems unlikely in the light of what is known about PA. It is well known that CF leads to a decline in pulmonary function. However, this decline is different in different population groups.[10,15,16] The median age of the patients colonised by PA (19.9 years) in this study is significantly older than in many European centres, but this age is not the age of first colonisation.[17,18] The high rate of PA colonisation in the study subjects (51.7%) is greater than in some international studies,[9] but is comparable to local SA studies.[10,11] Even at study entry, patients who were colonised by PA had lower spirometric indices compared with patients who were not colonised at that stage (p=0.014, 0.0014 and 0.0061 for FEV1, FVC and FEF25-75, respectively). These findings mirror those of many, but not all, local and international studies and suggest that even in the developing world, where CF services may not be as robust as in the developed world, pulmonary function decline can be prevented if PA prevention and/or eradication is aggressively pursued. PA prevention and/or eradication may turn out to be the most costeffective intervention for CF individuals in developing countries. The current study revealed that a decline in pulmonary function was seen only in patients colonised with PA, and not in the group without colonisation, and that this was true for all spirometric indices (p<0.05 for all parameters). However, this has not been a consistent finding in all studies, Amin et al.[19] in Canada having found that PA was not responsible for a decline in lung function. In contrast, in a UK study by Taylor-Robinson et al.,[16] PA infection was associated with a more rapid rate of lung function decline. Similar results, with pulmonary decline, were reported in the USA and the UK.[4,20-22] In a study conducted among Swedish CF patients, overall lung function was well preserved with a low rate of annual decline. However, a more rapid lung function decline was evident in the group colonised by PA.[9] Similar results were obtained in the two studies performed in the Western Cape, South Africa,[10,11] in which the study populations with CF more closely resembled the current SBAH study. Pulmonary function decline may be expected to be more significant in CF subjects living in a developing country, where healthcare resources may not be as available as in the developed world. However, the current study reflects local and international data revealing that lung function decline is minimal in patients not colonised by PA. Certain strains of PA, not determined in the current study, have been found to be more significantly associated with pulmonary function decline, as revealed in a Canadian study conducted by Aaron et al.[8] and in contrast to studies in Australia and the UK. In a study by Davies et al.,[23] PA infection in patients with non-CF bronchiectasis was shown to be a marker of disease severity, but was not linked to an accelerated decline in pulmonary function. Other micro-organisms may be important in contributing to a decline in pulmonary function. The effect of multiple antibioticresistant PA infection on the decline of pulmonary function was found not to be significant in a study by Ren et al.[24] Furthermore, compared with SA alone, SA in combination with PA has been found to be more deleterious.[3] This was not found in the current study, but the number of individuals with both SA and PA was small. Aspergillus spp. sensitisation and persistent carriage lead to a more rapid decline in lung function.[25] Similarly, airway colonisation with Candida albicans predicts a greater rate of FEV1 decline and hospital-treated exacerbations in CF.[26] These are factors that could have contributed to the lung function decline in the current study, but analysis of these organisms was not included.

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Another finding in the SBAH study was that there was no significant difference in the spirometric indices for males and females. This may reflect the small sample size, but was interesting as two studies have documented a difference in lung function decline between males and females.[27,28] However, this finding is not consistent. In studies by Que et al.[29] in London and Arrington-Sanders et al.[30] in the USA, no significant differences in FEV1 between male and female patients was observed. Different populations behave differently, and there is therefore a real need to study this aspect in all regions of the world. Additionally, studies have found that female patients are at greater risk of being colonised by PA and have a poorer prognosis and decreased survival compared with male patients.[31,32] With regard to the spirometric index FEF25-75, this study revealed a marked difference between patients colonised by PA and those who were not colonised, with a significantly greater rate of change in the former group. Although this is debated, the obstruction to small airways is best described as FEF25-75 measurements, and these measurements are considered to be more sensitive than FEV1.[33] Numerous previous studies have revealed a decline in FEF25-75 over time in patients with CF.[34-36] It appears that PA has a very profound effect on this measure of airway function, and the current study reveals that it should be routinely performed in CF subjects, especially those colonised by PA.

Study limitations

This study was limited by the small sample size. Other limiting factors include lack of analyis of the multiple confounding factors that may be operational, including home environment, exposure to cigarette smoke, specific treatment modalities, differences between PA colonisation in males and females, and colonisation by different organisms. The fact that only three time points were analysed in the study may mask differences within these time points.

Conclusion

In this cohort of patients, carriage of PA was associated with worse pulmonary function measurements than in patients without PA when the first lung function tests were conducted, and with significant decline over time. Since this is not a universal finding, our study contributes meaningfully to the international database. Our findings also suggest that there are local variations in CF subjects and highlight the need to analyse data collected in every centre treating CF patients to uncover regional findings that may be important in guiding local health policy. Furthermore, the study highlights the discrepancies between spirometric indices in individuals with CF. More studies are required to investigate possible factors underlying these differences. Presented at the Combined Congress of the South African Thoracic Society and the Allergy Society of South Africa, Sun City, South Africa, 5 - 9 June 2013. Acknowledgement. The research was made possible by Department of Paediatrics research funds generated by publication outputs to the university by the Department of Higher Education, South Africa.

References

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3. Hubert D, Réglier-Poupet H, Sermet-Gaudelus I, et al. Association between Staphylococcus aureus alone or combined with Pseudomonas aeruginosa and the clinical condition of patients with cystic fibrosis. J Cyst Fibros 2013;12(5):S1569-S1993. [http://dx.doi.org/10.1016/j.jcf.2012.12.003] 4. Jarad NA, Higgs S. Factors associated with reduced FEV1 in adult patients with cystic fibrosis in a relatively affluent area. Chron Respir Dis 2005;2(3):133-137. 5. Granström M, Ericsson A, Strandvik B, et al. Relation between antibody response to Pseudomonas aeruginosa exoproteins and colonization/infection in patients with cystic fibrosis. Acta Paediatr Scand 1984;73(6):772-777. [http://dx.doi.org/10.1111/j.1651-2227.1984.tb17774.x] 6. Lillquist YP, Cho E, Davidson AG. Economic effects of an eradication protocol for first appearance of Pseudomonas aeruginosa in cystic fibrosis patients: 1995 vs. 2009. J Cyst Fibros 2011;10(3):175-180. [http://dx.doi.org/10.1016/j.jcf.2011.01.002] 7. Konstan MW, Wagener JS, van Devanter DR. Characterizing aggressiveness and predicting future progression of CF lung disease. J Cyst Fibros 2009;8(Suppl 1):S15-S19. [http://dx.doi.org/10.1016/ S1569-1993(09)60006-0] 8. Aaron SD, Vandemheen KL, Ramotar K, et al. Infection with transmissible strains of Pseudomonas aeruginosa and clinical outcomes in adults with cystic fibrosis. JAMA 2010;304(19):2145-2153. [http:// dx.doi.org/10.1001/jama.2010.1665] 9. Dennersten U, Lannefors L, Höglund P, et al. Lung function decline in the aging Swedish cystic fibrosis population. Respir Med 2009;103(7):1076-1082. [http://dx.doi.org/10.1016/j.rmed.2009.01.020] 10. Morrow BM, Argent AC, Distiller GB, Zar HJ, Westwood ATR. Rate of pulmonary function decline in South African children with cystic fibrosis. South African Journal of Child Health 2009;3(3):73-77. 11. Zar HJ, Moore B, Argent A, Ireland J, Westwood AT. Lung function in South African children with cystic fibrosis. S Afr Med J 1998;88(8):994-997. 12. Medical and Scientific Committee of the South African Cystic Fibrosis Association. The South African Cystic Fibrosis Consensus Document 2012. 4th ed. Johannesburg: South African Cystic Fibrosis Association, 2012. 13. Quanjer PH, Borsboom GJ, Brunekreef B, et al. Spirometric reference values for white European children and adolescents: Polgar revisited. Pediatr Pulmonol 1995;19(2):135-142. [http://dx.doi. org/10.1002/ppul.1950190209] 14. Standardized lung function testing. Official statement of the European Respiratory Society. Eur Respir J Suppl 1993;16(Mar):S1-S100. 15. Schluchter MD, Konstan MW, Davis PB. Jointly modeling the relationship between survival and pulmonary function in cystic fibrosis patients. Stat Med 2002;21(9):1271-1287. [http://dx.doi. org/10.1002/sim.1104] 16. Taylor-Robinson D, Whitehead M, Dederichsen F, et al. Understanding the natural progression in %FEV1 decline in patients with cystic fibrosis: A longitudinal study. Thorax 2012;67(10):860-866. [http://dx.doi.org/10.1136/thoraxjnl-2011-200953] 17. van Mansfeld R, Willems R, Brimicombe R, et al. Predictors of mucoid Pseudomonas colonization in cystic fibrosis patients. Pediatr Pulmonol 2008;43(5):463-471. [http://dx.doi.org/10.1002/ppul.20794] 18. Laurans M, Arion A, Fines-Guyon M, et al. Pseudomonas aeruginosa and cystic fibrosis: First colonization to chronic infection. Arch Pediatr 2006;13(Suppl 1):S22-S29. 19. Amin R, Lam M, Dupuis A, Ratjen F. The effect of early Pseudomonas aeruginosa treatment on lung function in pediatric cystic fibrosis. Pediatr Pulmonol 2011;46(6):554-558. [http://dx.doi.org/10.1002/ ppul.21417] 20. Hoffman LR, Kulasekara HD, Emerson J, Houston LS, Burns JL, Ramsey BVV. Pseudomonas aeruginosa lasR mutants are associated with cystic fibrosis lung disease progression. J Cyst Fibros 2009;8(1):66-70. [http://dx.doi.org/10.1016/j.jcf.2008.09.006] 21. Hunter RC, Klepac-Ceraj V, Lorenzi MM, Grotzinger H, Martin TR, Newman DK. Phenazine content in the cystic fibrosis respiratory tract negatively correlates with lung function and microbial complexity. Am J Respir Cell Mol Biol 2012;47(6):738-745. [http://dx.doi.org/10.1165/rcmb.20120088OC] 22. McPhail GL, Acton JD, Fenchel MC, Amin RS, Seid M. Improvements in lung function outcomes in children with cystic fibrosis are associated with better nutrition, fewer chronic Pseudomonas aeruginosa infections, and dornasealfa use. J Pediatr 2008;153(6):752-757. [http://dx.doi.org/10.1016/j. jpeds.2008.07.011] 23. Davies G, Wells AU, Doffman S, Watanabe S, Wilson R. The effect of Pseudomonas aeruginosa on pulmonary function in patients with bronchiectasis. Eur Respir J 2006;28(5):974-979. [http://dx.doi. org/10.1183/09031936.06.00074605] 24. Ren CL, Konstan MW, Yegin A, et al. Multiple antibiotic-resistant Pseudomonas aeruginosa and lung function decline in patients with cystic fibrosis. J Cyst Fibros 2012;11(4):293-299. [http://dx.doi. org/10.1016/j.jcf.2012.02.005] 25. Fillaux J, Brémont F, Murris M, et al. Assessment of Aspergillus sensitization or persistent carriage as a factor in lung function impairment in cystic fibrosis patients. Scand J Infect Dis 2012;44(11):842-847. [http://dx.doi.org/10.3109/00365548.2012.695454] 26. Chotirmall SH, O’Donoghue E, Bennett K, Gunaratnam C, O’Neil SJ, McElvaney NG. Sputum Candida albicans presages FEV1 decline and hospital-treated exacerbations in cystic fibrosis. Chest 2010;138(5):1186-1195. [http://dx.doi.org/10.1378/chest.09-2996] 27. Corey M, Edwards L, Levison H, Knowles M. Longitudinal analysis of pulmonary function decline in patients with cystic fibrosis. J Pediatr 1997;131(6):809-814. [http://dx.doi.org/10.1016/S00223476(97)70025-8] 28. Konstan MW, Morgan WJ, Butler SM, et al. Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis. J Pediatr 2007;151(2):134-139. [http:// dx.doi.org/10.1016/j.jpeds.2007.03.006] 29. Que C, Cullinan P, Geddes D. Improving rate of decline of FEV1 in young adults with cystic fibrosis. Thorax 2006;61(2):155-157. [http://dx.doi.org/10.1136/thx.2005.043372] 30. Arrington-Sanders R, Yi MS, Tsevat J, Wilmott RW, Mrus JM. Gender differences in health-related quality of life of adolescents with cystic fibrosis. Health Qual Life Outcomes 2006;Jan 24;4:5. 31. Demko CA, Byard PJ, Davis PB. Gender difference in cystic fibrosis: Pseudomonas aeruginosa. J Clin Epidemiol 1995;48(8):1041-1049. [http://dx.doi.org/10.1016/0895-4356(94)00230-N] 32. Chotirmall SH, Smith SG, Gunaratnam C, et al. Effect of estrogen on Pseudomonas mucoidy and exacerbations in cystic fibrosis. N Engl J Med 2012;366(21):1978-1986. [http://dx.doi.org/10.1056/ NEJMoa1106126] 33. Tiddens HAWM, Donaldson SHD, Rosenfeld M, Paré PD. Cystic fibrosis lung disease starts in the small airways: Can we treat it more effectively? Pediatr Pulmonol 2010;45(2):107-117. [http://dx.doi. org/10.1002/ppul.21154] 34. Cox DW, Kelly C, Rush R, O’Sullivan N, Canny G, Linnane B. The impact of MRSA infection in the airways of children with cystic fibrosis: A case-control study. Ir Med J 2011;104(10):305-308. 35. Lopes AJ, Mafort TT, de Sá Ferreira A, Santos de Castro MC, Cássia de Firmida M, de Andrade Marques E. Is the type of chronic pulmonary infection a determinant of lung function outcomes in adult patients with cystic fibrosis? Monaldi Arch Chest Dis 2012;77(3-4):122-128. 36. Vilozni D, Lavie M, Sarouk I, Efrati O. Progressive flow-to-volume dysanapsis in cystic fibrosis: A predictor for lung transplantation? Am J Respir Crit Care Med 2012;186(1):82-87. [http://dx.doi. org/10.1164/rccm.201202-0272OC]

Accepted 7 November 2013.

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Cardiometabolic markers to identify cardiovascular disease risk in HIV-infected black South Africans J M van Rooyen,1 DSc; C M T Fourie,1 RN, PhD; H S Steyn,2 DSc; G Koekemoer,2 PhD; H W Huisman,1 PhD; R Schutte,1 PhD; L Malan,1 RN, PhD; M Glyn,1 PhD; W Smith,1 PhD; C Mels,1 PhD; A E Schutte,1 PhD ypertension in Africa Research Team, School of Physiology, Nutrition and Consumer Sciences, Potchefstroom Campus, North-West University, H Potchefstroom, South Africa 2 Statistical Consultation Services, Potchefstroom Campus, North-West University, Potchefstroom, South Africa 1

Corresponding author: J M van Rooyen (johannes.vanrooyen@nwu.ac.za) Background. The prevalence of HIV is the highest in sub-Saharan Africa; South Africa (SA) is one of the most affected countries with the highest number of adults living with HIV infection in the world. Besides the traditional risk factors for cardiovascular disease (CVD) in the general population, in people living with HIV there are specific factors – chronic inflammation, metabolic changes associated with the infection, therapy, and lipodystrophy – that potentially increase the risk for developing CVD. Objective. This study proposes a screening discriminant model to identify the most important risk factors for the development of CVD in a cohort of 140 HIV-infected black Africans from the North West Province, SA. Methods. Anthropometric measures, systolic blood pressure, diastolic blood pressure and the carotid-dorsalis pedis pulse wave velocity were determined. Blood was analysed to determine the levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), lowdensity lipoprotein cholesterol, triglycerides (TGs) and glucose. Partial least squares discriminant analysis was performed as a supervised pattern recognition method. Independent Student’s t-tests were further employed to compare the means of risk factors on interval scales; for comparison of categorical risk factors between groups, χ2 tests were used. Results. A TG:HDL-C ratio ≥1.49, TC:HDL-C ratio ≥5.4 and an HDL-C level ≤0.76 mmol/l indicated CVD risk in this cohort of patients living with HIV. Conclusion. The results have important health implications for black Africans living with HIV as these lipid levels may be a useful indicator of the risk for CVD. S Afr Med J 2014;104(3):195-199. DOI:10.7196/SAMJ.7739

HIV prevalence is highest in sub-Saharan Africa, with South Africa (SA) being one of the most affected countries with the highest number of adults living with HIV in the world.[1] The use of antiretroviral therapy (ART) has improved the quality and life expectancy in the HIV-infected population worldwide.[2] The HIV-infected population in SA gained free access to ART through the antiretroviral (ARV) roll-out programme,[3] which has made HIV a manageable disease in SA. However, infection with HIV and the treatment thereof may affect the heart and vasculature, leading to the development of cardiovascular disease (CVD),[4] which currently, after cancer, is the most frequent cause of death among HIV-infected individuals.[2] In SA, CVDs such as hypertension, atherosclerotic disease and heart failure are increasing among the black African population,[5,6] which could be exacerbated by the high number of people living with HIV in SA. Furthermore, the HIV-infected population is ageing and, since age is a major non-modifiable risk factor for CVD, the risk for CVD may be expected to increase progressively in this population. [2] In relation to CVD, HIV infection is associated with an increase in insulin resistance, dyslipidaemia,[7] lipodystrophy,[8,9] endothelial dysfunction,[10] [12] accelerated atherosclerosis[11] and coagulation disorders. Lipid abnormalities, characterised by low high-density lipoprotein cholesterol (HDL-C) and high triglyceride (TG) levels form a large part of the risk for CVD in the HIV-infected population, and may be related to the viral infection, ART or both.[4] Even though black Africans normally exhibit lower fasting TG and higher HDL-C levels than whites,[13] the HDL-C levels of HIV-infected black South Africans were found to be

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lower than the levels normally associated with increased risk for the development of CVD.[14] Besides the risk factors for CVD seen in the general population, there are specific factors in people living with HIV that could increase risk, i.e. chronic inflammation, metabolic changes associated with the infection, its therapy and lipodystrophy. HIV-infected people are managed in clinics through the ARV roll-out programme in SA. Early identification and management of CVD complications is essential, but also difficult as resources are not always readily available. The development of a non-invasive tool to help identify individuals who are most likely to derive clinical benefit from CVD risk-reduction therapy is therefore of great importance. This study aimed to identify the most important risk factors for the development of CVD in a cohort of 140 HIV-infected black Africans from the North West Province, SA.

Methods

Study design and participants

This cross-sectional sub-study is embedded in the international Prospective Urban and Rural Epidemiology (PURE) study, which was designed to address questions regarding the cause and development of cardiovascular risk factors and disease.[15] In the present sub-study we included 154 HIV-uninfected and 140 HIV-infected persons known to be infected for at least three years. Data collection took place in 2008 and the 140 HIV-infected participants were used in a hierarchical cluster analysis[16] to separate participants with and without risk for the development of CVD. HIV-infected participants were stratified into risk and no risk groups and the following variables were assessed: age;

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body mass index (BMI); waist-to-hip ratio; systolic blood pressure (SBP); diastolic blood pressure (DBP); carotid-dorsalis pedis pulse wave velocity (cdPWV); total cholesterol (TC); HDL-C; low-density lipoprotein cholesterol (LDL-C); TG; TG:HDL-C ratio; TC:HDL-C ratio; and glucose. The group identified by the analysis as exhibiting CVD risk factors was cross validated for the cut-off values for CVD risk according to the SA guidelines.[17] All the participants in the CVD risk group exhibited one or more CVD risk factors. The cluster analysis was based on the cardiometabolic profile of the HIV-infected participants and was used to separate the HIV-infected participants into a group exhibiting risk factors for the development of CVD and a group without CVD risk factors. Of the participants, 63 received ART consisting of two nucleoside reverse transcriptase inhibitors (stavudine and lamivudine) plus one non-nucleoside reverse transcriptase inhibitor (efavirenz or nevirapine). Twenty of the 63 participants had received ART for >2 years. The mean CD4+ cell count for those receiving ART was 260 cells/μl and for those not receiving ART was 264 cells/μl. All participants provided signed informed consent after all procedures were explained in their home language. The study protocol complies with the Declaration of Helsinki as revised in 2008 and was approved by the Ethics Committee of the North-West University, Potchefstroom, SA (code 04M10).

Experimental protocol

During data collection, the participants arrived at the research locality of the rural or urban areas at 08h00 each morning after a 10 - 15-min drive (provided by the research team) from their communities. The participants were introduced to the planned research and, after the procedures were explained, they signed informed consent forms and received HIV pre-counselling from trained counsellors. In the course of the morning, demographic and lifestyle questionnaires were completed with the help of specially trained field workers in each subject’s home language. Lifestyle data included self-reported current tobacco and alcohol use as well as medical history. Referrals to the local clinic or hospital, if necessary, and feedback on HIV status and cardiovascular variables were provided to participants during individual post-counselling.

Anthropometric measurements

Height, weight, hip and waist circumference (WC) were measured (Precision Health Scale, A & D Company, Japan; Invicta Stadiometer, IP 1465, UK; Holtain unstretchable metal tape) using standardised procedures.[18]

Demographic questionnaire

Demographic and lifestyle information were obtained from the above-mentioned questionnaire.

Cardiovascular measurements

SBP and DBP were obtained with the validated OMRON HEM-757 apparatus (Omron Healthcare, Japan). After a 10-min rest period, blood pressure measurements were performed twice (5 min apart) on the right arm while the participant was seated upright and relaxed with his/her right arm supported at heart level. Appropriate sized cuffs were used for obese participants. Pulse wave velocity, a measure of arterial stiffness, was measured on the left side of each participant in the supine position. The measurement was determined using non-invasively accessible superficial pulses with the Complior SP device (Artech-Medical, France) in a segment over the carotid-dorsalis pedis vessels.

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Blood, serum and plasma samples

The subjects were required to fast overnight. Blood was drawn from the brachial vein using a sterile winged infusion set and syringes. Serum and plasma samples were prepared according to appropriate methods and stored at -80°C. In rural areas, samples were stored at -18°C (for no longer than five days) until transported to the laboratory facility and then stored at -80°C until analysis.

Biochemical analysis

Quantitative determinations of the TC, HDL-C, TG and glucose were performed with the Beckman Coulter DxC 800 Synchron Clinical System (Beckman Coulter Inc., USA). LDL-C was calculated by using the Friedewald formula.[19] HIV status was determined with the First Response rapid HIV card test (PMC Medical, India) using whole blood. If tested positive, the test was repeated with the Sensa card test (Seyama Solutions, SA).

Statistical analysis

Statistical analysis was performed using Statistica (version 10.0) and R (version 2.13). Independent Student’s t-tests were used to compare means of risk factors on interval scales; for comparison of categorical risk factors between groups, χ2 tests were used. Multivariate analysis was performed in the form of pattern recognition methods. Pattern recognition methods are commonly divided into supervised and unsupervised methods, where supervised methods make use of the grouping of information in the data. Prior to multivariate analysis, the input data were scaled using the transformation Y = log[X/X], where X is the arithmetic mean. This transformation was applied to make the scales of the CVD risk factors more comparable, so that the factors with larger scales would not dominate in the multivariate analysis. Hierarchical cluster analysis using the method of Ward[16] with an euclidean distance measure was then performed as an unsupervised pattern recognition method to create two clusters of cases with similar multivariate profiles concerning the CVD risk factors measured. These clusters contain cases with and without CVD risk within the 140 HIVinfected participants. Using these clusters as dependent variables and the risk factors as independent predictors, a partial least squares (PLS) discriminant analysis (DA) was performed as a supervised pattern recognition method. Although the PLS-DA model can be used to predict a person’s cluster membership given the CVD risk factors as input, our aim in fitting this model was to identify those risk factors that contribute most (in a multivariate sense) to the existence of the grouping (clusters) formed by the cluster analysis. The variable importance in the projection (VIP) from PLS-DA is a measure that is commonly used in this regard. Risk factors with a VIP value >1 were used as the criteria for variable selection.[20] To validate the interpretations made from the discriminant model, the following fit statistics are reported: percentage of variance explained for the risk factors (R2X), the percentage variance explained for the dependent variable (R2Y), the predictive R2Y values (Q2) and cross-validated estimates of sensitivity (percentage true positives) and specificity (percentage true negatives). The model dimension was selected using the Q2 statistics. The cross-validated estimates of sensitivity and specificity are calculated to confirm that the PLS-DA model did not overfit the data. Hence, whether the model could make accurate cluster predictions for cases unseen by the model was investigated. These estimates were calculated as follows: A PLS-DA model was constructed using all 140 cases. This model was used to determine a cut-off point for the model predicted value (used to make cluster predictions) by calculating the Youden index. [21] Then, 10 000 unique stratified samples of size 39 (24 from cluster 1 and 15 from

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cluster 2) were randomly selected and excluded from the data. This equated to an exclusion of ~30% of the data. For each of the 10 000 samples, a PLS-DA model was constructed using the remaining cases, after which the cluster membership of the withheld cases was predicted. For each of the 10 000 trials, the sensitivity and specificity were recorded and finally averaged to find the cross-validation estimates of sensitivity and specificity. Receiver-operating characteristic (ROC) analysis was used to determine the optimum cut-off values (based on the Youden index) for risk and no risk in HIV-infected participants to develop CVD for each of the selected variables.[21]

Results

In Table 1, the characteristics of HIV-infected participants are compared with the uninfected control participants. The HIV-infected participants had significantly lower SBP, TC and HDL-C levels. However, their TC:HDL-C and TG:HDL-C ratios were significantly higher compared with the uninfected control group. The dendrogram of the cluster analysis of the 140 infected participants is shown in Fig. 1, from which a clear separation of the cases is visible. To identify the risk factors that contribute most to the separation, a PLSDA model was constructed using the clusters formed (Fig. 1) as dependent variables and the risk factors as independent variables. One component was extracted for the PLS-DA model based on the Q2 value. The summary fit statistics of the PLS-DA model indicated that the model accounted for only 23.2% of the total variance observed in the scaled risk factors; however, the variance explained for the dependent variable is 61.5%. The Q2 value was 0.602, which indicated that the model did not overfit the data, and that good prediction performance could be expected if required. This was further confirmed by the cross-validation estimates of sensitivity and specificity, which were 94.4% and 93.3%, respectively. The respective standard errors of these estimates were 6% and 4.7%. From these statistics we concluded that the PLSDA model fits reasonably well and could be used to identify risk factors that separated the group into no- and high-CVD risk within the HIV-infected participants. There was no statistically significant difference between the risk and no-risk groups concerning age, gender, BMI, ART, alcohol or tobacco use. The CD4+ count (291 v. 225 cells/μl; p=0.08) also did not differ significantly when no-risk and risk groups were compared. VIP values are presented in Table 2, from which TG:HDL-C ratio, HDL-C and

Table 1. Characteristics of HIV-uninfected and -infected participants HIV-uninfected (N=154)

p-value

Demographic Age (years), mean (±SD)

48.3 (±8.25)

47.3 (±7.01)

0.28

Gender (male), n (%)

57 (37)

45 (32)

0.38

BMI (kg/m2)

23.7 (±5.91)

22.7 (±5.55)

0.15

WC (cm)

78.2 (±10.5)

76.1 (±11.7)

0.11

Waist:hip ratio

0.83 (±0.08)

0.82 (±0.09)

0.59

SBP (mmHg)

134 (±21.6)

129 (±18.9)

0.05

DBP (mmHg)

88.6 (±13.2)

86.8 (±11.6)

0.23

cdPWV (m/s)

8.81 (±1.70)

8.52 (±1.60)

0.15

TC (mmol/l)

4.25 (±1.18)

3.93 (±1.14)

0.02

HDL-C (mmol/l)

1.19 (±0.55)

0.92 (±0.45)

<0.01

LDL-C (mmol/l)

2.54 (±0.93)

2.49 (±0.91)

0.71

TG (mmol/l)

1.13 (±0.78)

1.19 (±0.26)

0.59

TC:HDL-C ratio

4.15 (±2.68)

4.91 (±1.94)

<0.01

TG:HDL-C ratio

1.17 (±1.51)

1.66 (±1.44)

<0.01

Glucose (mmol/l)

4.60 (±1.03)

4.57 (±0.77)

0.78

3.05 (0.5 - 34.4)

0.34

Anthropometric, mean (±SD)

Cardiovascular, mean (±SD)

Biochemical, mean (±SD)

hsCRP (mg/l), mean (95% CI) 2.62 (0.5 - 27.3) Lifestyle, n/N (%)† Tobacco use

68/142 (48)

37/118 (31)

<0.01

Alcohol use

72/142 (51)

46/118 (39)

0.06

SD = standard deviation; BMI = body mass index; WC = waist circumference; SBP = systolic blood pressure; DBP = diastolic blood pressure; cdPWV = carotid-dorsalis pedis pulse wave velocity; TC = total cholesterol; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TG = triglyceride; hsCRP = high-sensitivity C-reactive protein; CI = confidence interval. *p-values were obtained with independent Student’s t-tests or χ2 tests. † N = total participants who indicated their alcohol/tobacco use on the questionnaire.

Fig. 1. Dendrogram of the HIV-infected participants to show the clustering of variables.

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HIV-infected (N=140)

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TC:HDL-C ratio were identified as the risk factors that primarily cause group separation. Tobacco and alcohol use were not included Table 2. VIP values of different CVD risk markers Variable

VIP

TG:HDL-C ratio

2.66

HDL-C (mmol/l)

1.68

TC:HDL-C ratio

1.16

TG (mmol/l)

0.98

LDL-C (mmol/l)

0.65

TC (mmol/l)

0.52

Glucose (mmol/l)

0.22

Age (years)

0.07

BMI (kg/m2)

0.06

Waist:hip ratio

0.05

cdPWV (m/s)

0.04

SBP (mmHg)

0.03

DBP (mmHg)

0.01

The cut-off values between risk and no-risk for CVD in participants were: HDL-C 0.76 mmol/l; TC:HDL-C ratio 5.40; and TG:HDL-C ratio 1.49.

Discussion

By making use of the PLS-DA statistical analysis method, we identified those CVD risk variables that contributed most (in a multivariate sense) to the existence of the grouping (clusters) observed in the total HIVinfected group that consisted of ARV-treated and never-treated participants. The most important variables identified by the PLS-DA were TG:HDL-C, HDL-C and TC:HDL-C with values of VIP >1. ROC analysis indicated that a TG:HDL-C ratio ≥1.49, TC:HDL-C ratio ≥5.4 and an HDL-C level ≤0.76 mmol/l constituted risk values with the potential to contribute to the development of CVD in HIV-infected black Africans. The statistical PLS-DA method was employed to discriminate between HIVinfected participants with risk and no risk in the same group. Wold et al.[22] reported that PLS regression is useful for the analysis of noisy, incomplete data where multicollinearity is present. The PLS-DA method is also useful when a large number of variables are investigated simultaneously. In addition, the

4 TG:HDL ratio

TC:HDL ratio 2 4 6 8 10

HDL-cholesterol (mmol/l) 0.5 1.0 1.5 2.0 2.5

TC:HDL ratio 4 6 8 10

HDL-cholesterol (mmol/l) 0.5 1.0 1.5 2.0 2.5

TG:HDL ratio 2 4 6

VIP = variable importance in the projection; CVD = cardiovascular disease; TG = triglyceride; HDL-C = high-density lipoprotein cholesterol; TC = total cholesterol; LDL-C = low-density lipoprotein cholesterol; BMI = body mass index; cdPWV = carotiddorsalis pedis pulse wave velocity; SBP = systolic blood pressure; DBP = diastolic blood pressure.

in the PLS-DA as it was obtained from a self-reported questionnaire. High-sensitivity C-reactive protein (hsCRP) was included primarily in the PLS-DA but did not contribute to the cluster formation. To test the discriminatory ability of the three main risk factors identified, a PLS-DA model containing only HDL-C, TG:HDL-C and TC:HDL-C ratios (as independent variables) was fitted and cross-validated. The estimated sensitivity was 96.4% and the estimated specificity was 92.1%. The respective standard errors of these estimates were 4.9% and 4.8%. This confirms that the three risk factors identified contained almost all the discriminatory information, since similar results were obtained when using all 13 variables in the PLS-DA model. The distributional properties and the relationship among these three risk factors are illustrated as a matrix-plot (Fig. 2). Categorised boxplots of each risk factor are on the diagonal and scatterplots with appropriate labels are in the off-diagonal entries. Each box’s height indicates the variability (difference between third and first quartile), while the median is the central line. The whiskers give the range of values except for the extremes displayed as individual points. From ROC analysis, optimum cut-off values were determined for the participants.

0.5 1.0 1.5 2.0 2.5 HDL-cholesterol (mmol/l)

Fig. 2. Matrix plot of TG:HDL-C and TC:HDL-C ratios in no-risk (0 on boxplots;  on scatterplot) and risk (1 on boxplots; × on scatterplot) groups within the HIV-infected participants (HDL-C = high-density lipoprotein cholesterol; TG = triglyceride; TC = total cholesterol).

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PLS/VIP method is used to assist in the identification of relevant predictors (Table 2), while Chong and Jun[20] found that this outperforms other variable selection methods. HIV-related CVD is under-recognised and the clinical assessment thereof is a critical challenge for practitioners, especially in SA. Bearing in mind the enormous task facing the practitioners managing the ARV roll-out programme and the high number of people in SA living with HIV, the results of this study should simplify the identification of those individuals who exhibit a CVD risk. The discriminant model showed that the determination of HDL-C levels, and TG:HDL-C and TC:HDL-C ratios could be of clinical benefit for the identification of individuals at risk. It is well known that people living with HIV exhibit dyslipidaemia characterised by low HDL-C and high TG levels.[3] The latter was reported in newly identified HIVinfected South Africans,[14] although black Africans normally exhibit lower fasting TG and higher HDL-C levels than whites.[13] The HDL-C levels seen in the total HIV-infected group in this study (0.92 mmol/l) were below the level (1.28 mmol/l) generally regarded as an increased risk of developing CVD.[23] The cut-off values of TG:HDL-C (1.49) and HDL-C levels (0.76 mmol/l) seen in our study indicated that risk is lower than that described in the literature.[24,25] However, modified CVD risk equations and models such as the Framingham Risk Score have not been validated for use in black Africans living with HIV. Thus, in light of the ethnic differences in TG and HDL-C levels,[13,26] and the findings of this study, different cut-off values may be needed to define the dyslipidaemia in HIV-infected black Africans that indicates risk of developing CVD. However, to evaluate individual risk the composite risk factor profile of traditional risk factors such as gender, lifestyle (smoking and alcohol abuse) and family history of CVD must be considered. The strength of this study is that it contributes to CVD risk data in HIV-infected black South Africans, which are sparse. It would benefit practitioners, and be clinically advantageous to use metabolic variables such as TG:HDL-C and TC:HDL-C ratios as well as HDL-C levels, to discriminate between those individuals with risk, and those without risk, for the development of CVD.

Study limitations

Although there were no gender or treatment differences between the risk and no-risk groups, a limitation of the study is that this model did not discriminate between gender and those who were treated and those who did not receive treatment. It is difficult to differentiate between risk associated with HIV and that associated with ART.[4] As previously reported, not all HIV-infected individuals eligible for treatment have enrolled in the ART programme[27] and, in fact, in 2009, the treatment coverage in SA was <40%.[1] When the interaction between treatment and no treatment was determined statistically in the risk groups, interaction was seen only in the TC:HDL-C ratio. ART (including nevirapine and efavirenz) was associated with the normalisation of HDL-C levels and an increase in TC levels.[28]

Conclusion

Our study involved a cohort of people living with HIV in the North West Province, SA. Future research in larger prospective studies is warranted to assess the predictive power of lipid ratios and HDL-C levels for CVD development in people living with HIV in sub-Saharan Africa. Despite the limitations and the relatively small size of this study, we propose that by employing lipid ratios and HDL-C levels for screening, early identification of South Africans living with HIV and at risk for CVD may be achieved. A TG:HDL-C ratio ≥1.49, TC:HDL-C ratio ≥5.4 and an HDL-C level ≤0.76 mmol/l were indicative of CVD risk.

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These results have important health implications for black Africans living with HIV, as these lipid levels may be useful indicators of CVD risk in clinical settings. Acknowledgements. We thank Prof. A Kruger; the PURE-SA research team; the field workers and office staff at the Africa Unit for Transdisciplinary Health Research (AUTHeR), North-West University, SA; Dr S Yusuf (PURE-International) and the PURE project staff at the Population Health Research Institute (PHRI), Hamilton Health Sciences and McMaster University, Canada. This work was financially supported by the South Africa-Netherlands Research Programme on Alternatives in Development, South African National Research Foundation (NRF GUN no. 2069139 and FA2006040700010), North-West University, PHRI and the Medical Research Council of South Africa. References 1. United Nations Programme on HIV/AIDS. UNAIDS Report on the Global AIDS Epidemic 2010. Geneva: UNAIDS, 2010. http://www.unaids.org/documents/20101123_globalreport_em.pdf (accessed 12 March 2012). 2. Giannarelli C, Klein RS, Badimon JJ. Cardiovascular implications of HIV-induced dyslipidemia. Atherosclerosis 2011;219(2):384-389. [http://dx.doi.org/10.1016/j.atherosclerosis.2011.06.003] 3. Forsyth B, Vandormael A, Kershaw T, Grobbelaar J. The political context of AIDS-related stigma and knowledge in a South African township community. SAHARA J 2008;5(2):74-82. [http://dx.doi.org/ 10.1080/17290376.2008.9724904] 4. Dubé MP, Lipshultz E, Fichtenbaum CJ, Greenberg R, Schecter AD, Ficher SD. Effects of HIV infection and antiretroviral therapy on the heart and vasculature. Circulation 2008;118:e36-e40. [http://dx.doi. org/10.1161/CIRCULATIONAHA.107.189625] 5. van Rooyen JM, Kruger HS, Huisman HW, et al. An epidemiological study of hypertension and its determinants in a population in transition: The THUSA study. J Hum Hypertens 2000;14(12):779-787. [http://dx.doi.org/10.1038/sj.jhh.1001098] 6. Sliwa K, Wilkinson D, Hansen C, et al. Spectrum of heart disease and risk factors in a black urban population in South Africa (the Heart of Soweto Study): A cohort study. Lancet 2008;371(9616):915-922. [http://dx.doi. org/10.1016/S0140-6736(08)60417-1] 7. Riddler SA, Smit E, Cole SR, et al. Impact of HIV infection and HAART on serum lipids in men. JAMA 2003;289(22):2978-2982. [http://dx.doi.org/10.1001/jama.289.22.2978] 8. Carr A, Cooper DA. Lipodystrophy associated with an HIV-protease inhibitor. N Engl J Med 1998;339(18):1296. [http://dx.doi.org/10.1056/NEJM199810293391806] 9. Grinspoon SK. Metabolic syndrome and cardiovascular disease in patients with human immunodeficiency virus. Am J Med 2005;118(Suppl 2):23S-28S. [http://dx.doi.org/10.1016/j.amjmed.2005.01.047] 10. Constans J, Conri C. Circulating markers of endothelial function in cardiovascular disease. Clin Chim Acta 2006;368(1-2):33-47. [http://dx.doi.org/10.1016/j.cca.2005.12.030] 11. Hsue PY, Lo JC, Franklin A, et al. Progression of atherosclerosis as assessed by carotid intimamedia thickness in patients with HIV infection. Circulation 2004;109(13):1603-1608. [http://dx.doi. org/10.1161/01.CIR.0000124480.32233.8A] 12. Glazier JJ, Spears JR, Murphy MC. Interventional approach to recurrent myocardial infarction in HIV-1 infection. J Interv Cardiol 2006;19(1):93-98. [http://dx.doi.org/10.1111/j.1540-8183.2006.00111.x] 13. Seedat YK. Hypertension in black South Africans. J Hum Hypertens 1999;13:96-103. [http://dx.doi. org/10.1038/sj.jhh.1000773] 14. Fourie CMT, van Rooyen JM, Kruger A, Schutte AE. Lipid abnormalities in a never-treated HIV-1 subtype C-infected African population. Lipids 2010;45(1):73-80. [http://dx.doi.org/10.1007/s11745-009-3369-4] 15. Teo K, Chow CK, Vaz M, Rangarajan S, Yusuf S. The Prospective Urban Rural Epidemiology (PURE) study: Examining the impact of societal influences on chronic non-communicable diseases in low-, middle-, and high-income countries. Am Heart J 2009;158(1):1-7. [http://dx.doi.org/10.1016/j.ahj.2009.04.019] 16. Johnson RA, Wichern DW. Applied Multivariate Statistical Analysis. 4th ed. New Jersey: Prentice Hall, 1998. 17. Seedat YK, Rayner BL. South African Hypertension Guideline 2011. S Afr Med J 2012;102(1):57-88. 18. International Society for the Advancement of Kinanthropometry. International Standards for Anthropometric Assessment. Adelaide: ISAK, 2001:19-59. 19. Johnson R, McNutt P, MacMahon S, Robson R. Use of the Friedewald formula to estimate LDL-cholesterol in patients with chronic renal failure on dialysis. Clin Chem 1997;43(11):2183-2184. 20. Chong I-G, Jun C-H. Performance of some variable selection methods when multicollinearity is present. Chemometr Intell Lab Syst 2005;78(1-2):103-112. [http://dx.doi.org/10.1016/j.chemolab.2004.12.011] 21. Fluss R, Faraggu D, Reiser F. Estimation of the Youden index and its associated cutoff point. Biom J 2005;47(4):458-472. [http://dx.doi.org/10.1002/bimj.200410135] 22. Wold S, Sjöström M, Eriksson L. PLS-regression: A basic tool of chemometrics. Chemometr Intell Lab Syst 2001;58:109-130. [http://dx.doi.org/10.1016/S0169-7439(01)00155-1] 23. Miller NE, Thelle DS, Forde OH, Mjos OD. The Tromsø heart-study. High-density lipoprotein and coronary heart-disease: A prospective case-control study. Lancet 1977;309(8019):965-968. [http://dx.doi.org/10.1016/ S0140-6736(77)92274-7] 24. Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285(19):2486-2497. [http://dx.doi.org/10.1001/jama.285.19.2486] 25. International Diabetes Federation. The IDF Consensus Worldwide Definition of the Metabolic Syndrome. http://www.idf.org/webdata/docs/Metabolic_syndrome_definition.pdf (accessed 12 March 2012). 26. Zoratti R. A review on ethnic differences in plasma triglyceride and high-density-lipoprotein cholesterol: Is the lipid pattern the key factor for the low coronary heart disease rate in people of African origin? Eur J Epidemiol 1998;14(1):9-21. [http://dx.doi.org/10.1023/A:1007492202045] 27. Fourie CMT, van Rooyen JM, Kruger A, et al. Soluble urokinase plasminogen activator receptor (suPAR) is associated with metabolic changes in HIV-1-infected Africans: A prospective study. Inflammation 2012;35(1):221-229. [http://dx.doi.org/10.1007/s10753-011-9308-6] 28. van Leth F, Phanuphak P, Stroes E, et al. Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1. PLoS Med 2004;1(1):e19. [http://dx.doi. org/10.1371/journal.pmed.0010019]

Accepted 8 January 2014.

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High pleural fluid adenosine deaminase levels: A valuable tool for rapid diagnosis of pleural TB in a middle-income country with a high TB/HIV burden C P Onyenekwu, MB BS; A E Zemlin, MB ChB, MMed, FCPath (SA) (Chem); R T Erasmus, MB BS, FMCPath (Nig), FWACP (WA), DABCC, DHSM (SA), FCPath (SA) (Chem) Division of Chemical Pathology, Faculty of Health Sciences, National Health Laboratory Service and Stellenbosch University, Cape Town, South Africa Corresponding author: A E Zemlin (azemlin@sun.ac.za)

Background. South Africa has the highest burden of tuberculosis (TB) in the World Health Organization (WHO) African region. Using traditional TB diagnostic tools, the diagnosis of pleural TB (PTB) is highly unrewarding. Elevated levels of pleural fluid adenosine deaminase (FADA) have been shown to be useful in the diagnosis of PTB; however, similar levels may be found in some other medical conditions leading to misdiagnosis. Following queries from clinicians concerning the likely high false-positive (FP) rate of FADA from our laboratory, we performed a retrospective audit of all high FADA results generated over a 12-month period. Objectives. To determine the positive predictive value (PPV) of FADA, the frequent causes of FPs in our laboratory and the demographic characteristics of tuberculous pleural effusions (TPEs) and non-tuberculous pleural effusions (NTPEs). Methods. High FADA results generated in the past year were extracted with corresponding TB culture results, fluid cell count, cytology/ histology results, radiology reports and HIV results. Hospital records were reviewed for the final diagnosis in each case. Diagnosis of PTB was based on the WHO case definition of TB. Results. A total of 159 results were reviewed: 133 (83.6%) were TPE, hence FADA had a PPV of 83.6%. Neoplasm was the most common cause of an FP in 13/26 (50%) NTPEs. While TPE was more common than NTPE in younger people, both groups had an equal gender distribution. Conclusion. FADA had a high PPV for PTB in our laboratory. We recommend its continued use as a rapid and reliable diagnostic tool for PTB. S Afr Med J 2014;104(3):200-203. DOI:10.7196/SAMJ.7428

The burden of tuberculosis (TB) in South Africa (SA) is the third highest in the world after China and India and contributes one quarter of the burden of TB in the World Health Organization (WHO) African region.[1] The incidence of TB in the Western Cape is higher than the national incidence rate of 823/100 000 population, at 935/100 000 population.[2] Extrapulmonary TB constitutes 14.5% of TB cases in SA.[1] HIV/TB co-infection has been associated with pleural TB (PTB), a form of extrapulmonary TB.[3] Delays in the diagnosis of TB and the initiation of therapy, in addition to the high HIV/TB co-infection rates, are some of the obstacles to the achievement of the sixth millennium development goal in the WHO African region.[1] The diagnosis of PTB using traditional methods is challenging due to the low sensitivity of routine TB diagnostic tools,[4] viz. sputum smear microscopy (developed over 100 years ago and the most common method for TB diagnosis worldwide), culture for Mycobacterium tuberculosis (the current reference standard for TB diagnosis), and polymerase chain reaction-based techniques and rapid molecular tests (developed more recently for TB diagnosis and diagnosis of drug-resistant TB).[1] About 35 years ago, Piras et al.[5] first observed that adenosine deaminase (ADA), a zinc-containing metalloenzyme expressed in high levels by lymphocytes and monocytes, was elevated in PTB. Since then, several authors have confirmed this finding, supporting the use of high pleural fluid ADA (FADA) as a simple, rapid, sensitive, cost-effective and robust diagnostic tool for PTB.[6-10] This led to its widespread implementation and routine utilisation in countries such as SA with a

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high prevalence of TB. However, high FADA levels can also occur in other disease conditions and particularly in empyemas, lymphomas, carcinomas and parapneumonic effusions due to proliferation of large numbers of neutrophils and lymphocytes in these conditions, resulting in false-positive results and misdiagnosis.[11] The usefulness of FADA in the diagnosis of PTB depends on the prevalence of TB. In populations with a high prevalence, the sensitivity and specificity may be as high as 95% and 90%, respectively, but in low prevalence areas, the specificity can be considerably lower.[12] An essential component of clinical practice is the use of clinical laboratory test results in diagnostic decision-making; hence, there is a need for every diagnostic tool to be reliable, relevant and costeffective, particularly in a middle-income country where the disease burden is high. In response to queries from clinicians concerning the possible high false-positive (FP) rate of the FADA test in our laboratory, with many negative TB culture results, we performed a retrospective audit of all the high FADA results generated over a 1-year period.

Objectives

To determine (i) the positive predictive value (PPV) of high FADA test results for PTB; (ii) the most common causes of FPs and the demographic characteristics of tuberculous pleural effusions (TPEs) and non-tuberculous pleural effusions (NTPEs); (iii) the frequency of TPEs in HIV-positive and HIV-negative patients with pleural effusions; and (iv) the FADA levels in TPEs and NTPEs and in HIVpositive and -negative patients.

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Methods

Study setting and design

High FADA results generated at the Chemical Pathology Laboratory, Tygerberg Hospital (TH), over a 1-year period from 1 January to 31 December 2012 were reviewed. The hospital serves ~5.8 million people residing within the Western Cape, also serving as a referral centre for many hospitals and primary healthcare clinics in the region. The laboratory at TH is an accredited facility, which serves the hospital and satellite hospitals within the Western Cape; it receives up to 1 000 ADA requests annually, including non-pleural fluid specimens such as cerebrospinal, ascitic, pericardial and synovial fluids. Ethical approval for the audit was granted by the Health Research and Ethics Committee of Stellenbosch University, Tygerberg, SA. The audit was performed according to the Declaration of Helsinki. As this was a retrospective study and patient consent had been obtained prior to thoracocentesis, the need for individual patient consent for this study was waived by the ethics committee. Patient confidentiality was maintained throughout. Study criteria included all high (≥30 U/l) FADA results generated within the study period, from patients managed within TH, with corresponding TB culture requests. We excluded non-pleural fluid ADA results, empyemas, high FADA results without TB culture results, requests from satellite hospitals and requests with lost patient records. Specimens for ADA assays were collected in plain tubes and stored at 2 - 8oC before analysis. Laboratory analysis was performed on a weekly basis. Turbid or bloody specimens were centrifuged and haemolysed and grossly purulent samples were rejected. FADA activity was determined manually by spectrophotometry using the Giusti and Galanti method.[13] It is based on the enzymatic deamination of adenosine to inosine, with the release of ammonia which is determined by Berthelot’s reaction. One unit of ADA is defined as the amount of enzyme required to release 1 mmol/min of ammonia from adenosine at standard assay conditions. Each run was performed with a low- and a normallevel quality control material. FADA results meeting the study criteria were retrieved. Fluid cell count, HIV status, radiological, cytological and histological investigation reports were also extracted, where available. Patient hospital records were reviewed to obtain information on the final diagnosis. A diagnosis of TB was based on the WHO guidelines for case definitions of extrapulmonary TB.[14] The final diagnosis was classified into two broad groups of

TPEs and NTPEs, with sub-classifications as follows: • TPEs: • TPE-I: Identification of M. tuberculosis complex in fluid or biopsy specimen by culture; histological evidence of granulomas and positive stain for acidfast bacilli (AFB) in pleural biopsy; and/ or positive sputum or gastric wash-out culture with clinical and radiological evidence of TB without any other cause for pleural effusion. • TPE-II: The decision by a clinician to treat a patient with a full course of TB chemotherapy, based on strong clinical and radiological evidence, in the absence of other causes of pleural effusion. • NTPEs: • Neoplastic effusions: histological evi dence of a malignant effusion or a tumour, in the absence of other causes of pleural effusion. • Parapneumonic effusions: identification of an organism in the pleural fluid or clinical and radiological evidence of pneumonia, with response to antibiotic therapy. • Other: effusions due to conditions such as congestive cardiac failure, chronic liver disease, systemic lupus erythematosus and nephrotic syndrome.

Definition of true-positive (TP) and FP

• TP: FADA ≥30 U/l with the effusion fulfilling the criteria for TPE-I or TPE-II classification as defined above • FP: FADA ≥30 U/l with the effusion fulfilling the criteria for NTPE classification as defined above.

Calculation of PPV

The PPV of FADA was calculated as: PPV = TP/[TP + FP].

Statistical analysis

Data were analysed using Statistica (version 11.0). Continuous data are expressed as means (± standard deviations (SDs)). One-way

Results

A total of 614 FADA results were requested from within the hospital during the study period; 263 of these were high (≥30 U/l). After exclusion of 25 empyematous specimens, 61 requests without corresponding TB micros copy and culture results, 12 duplicate results and 6 lost hospital records, a total of 159 results were then analysed. There were 133 (83.6%) TPE and 26 (16.4%) NTPE, the latter giving FADA a PPV of 83.6% for PTB. Males and females were equally distributed in both groups. A significantly younger age distribution was observed in the TPE group (Fig. 1). Table 1 shows a summary of the mean age and frequency of the 159 results according to aetiological classification and gender. Employing the lymphocyte/neutrophil ratio, there was a slight but non-significant increase of the PPV of FADA to 89%. The mean (±SD) FADA level in the TPE group was 76.4 (±29.1) U/l and slightly higher than that of the NTPE group 74.1 (±54.9) U/l. This difference was, however, not significant (Fig. 2). TB culture was positive in 75 (56.4%) of the TPE group (TPE-I), in the remaining 58 (43.6%) TB culture-negative samples, classification as TPE was based on the fulfilment of criteria for TPE-II. Using microscopy techniques for AFB without culture, only 13 (9.8%) cases of TPE were positive. The HIV status was available for 118 (74.2%) patients, 56 (47.5%) of these were HIV-positive. Analysis of HIV/TB co-infection showed that a significantly higher number of 52 (93%) HIVpositive patients were TB-positive compared with 52 (84%) HIV-negative patients who were TB-positive (p<0.05). One-way ANOVA for FADA levels and HIV status showed a mean (±SD) FADA of 74.4 (±36.3) U/l in HIV-positive patients and this was lower than the mean (±SD) FADA of 78.7 (±32.7) U/l observed in the patients who were HIVnegative. This difference was, however, not statistically significant (Fig. 3).

Table 1. Demographic characteristics and aetiological classification of pleural effusion Age (years) mean (±SD)

Aetiology

Frequency, n

Sub-class (n)

TPE

133

TPE-I (75)* TPE-II (58)*

33.8 (±18.0)

M (67) F (66)

NTPE

Neoplastic (13) Parapneumonic (7) Others (6)

44.7 (±21.1)

M (13) F (13)

Gender (n)

TPE = tuberculous pleural effusion; NTPE = non-tuberculous pleural effusion; SD = standard deviation; M = male; F= female. *As defined in text.

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analysis of variance (ANOVA) was employed and p<0.05 was considered significant.

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FADA (U/I)

Age (years)

85 45 40

80 75 70

65 30

25 NTPE

TPE

NTPE

Diagnosis

Fig. 1. Age distribution of patients in tuberculous pleural effusion (TPE) and non-tuberculous pleural effusion (NTPE) groups. Current effect F(1, 157) = 7.5688; p≤0.010; Mann-Whitney U p<0.01. Vertical bars denote 95% confidence intervals.

90 85

FADA (U/I)

80 75 70 65 60 Negative

Positive HIV status

Fig. 3. Fluid adenosine deaminase (FADA) levels according to HIV status. Current effect F(1, 116) = 0.45747; p=0.50; Mann-Whitney U p=0.27. Vertical bars denote 95% confidence intervals.

Discussion

The diagnosis of PTB is challenging due to the poor performance of the current gold standard for TB diagnosis – TB culture. Elevated FADA levels have been used as a fast and convenient adjunct diagnostic tool for PTB, particularly in areas with high TB burden. However, other conditions may also cause an increase in FADA levels with a negative TB culture. An effusion may be reactive, in which case the TB culture would be negative due to the absence of bacilli. The effusion may be paucibacillary in nature and the decontamination step performed prior to culture may decrease the number of bacilli, further decreasing the sensitivity of TB culture, resulting in a false-negative. Quality control procedures are put in place for TB culture, using an M. tuberculosis H37RV strain as a positive control and phosphate buffer as a negative control with every batch of specimens at our laboratory. In response to queries from clinicians concerning many TB culture-negative results with

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TPE Diagnosis

Fig. 2. Fluid adenosine deaminase (FADA) levels in tuberculous pleural effusions (TPEs) and non-tuberculous pleural effusions (NTPEs). Current effect F(1, 157) = 0.09741; p=0.76; Mann-Whitney U p=0.03. Vertical bars denote 95% confidence intervals.

high FADA results, we reviewed all high FADA results generated over the study period. Our main objectives were to assess the PPV of FADA for PTB and to determine the conditions that cause FPs and the demographic characteristics of TPE and NTPE with high FADA levels. We observed a high PPV of 83.6%, which did not change significantly when the lymphocyte/neutrophil ratio was employed alongside, for the diagnosis of PTB. Of the NTPE, 13 (50%) were due to malignancies and nearly half of these were due to bronchial cancer, the other malignancies were single cases of ductal carcinoma of the breast, B cell lymphoma, parotid cancer, carcinoid tumour, basal cell carcinoma and infiltrating thymic tumour. A very poor sensitivity of 9.8% was observed for microscopy for AFB, while the reference standard for TB diagnosis, TB culture, had a sensitivity of 56.4%. TPEs occurred in a relatively younger age group than the NTPEs, but there was an equal gender distribution in the two groups. More HIVpositive patients had TPEs than HIV-negative patients, although their FADA levels were not significantly different. Our finding of a PPV of 83.6% at a cut-off of 30 U/l was in agreement with that of Burgess et al.,[8] who also reported a PPV of 84%, a negative predictive value (NPV) of 89%, sensitivity of 91% and specificity of 81%, though at a higher cut-off of 50 U/l. Zemlin et al.[10] observed similar diagnostic performance with FADA having a PPV of 85.5%, an NPV of 95.2%, sensitivity of 93.7% and specificity of 88.7% at an ADA cut-off of 52.4 U/l. A much higher PPV of 95% was reported by Riantawan et al. at a cut-off of 60U/l. [9] The nonsignificant increase in the PPV when a lymphocyte/neutrophil ratio of ≥0.75 was combined with ADA, differs from observations by Burgess et al.[8] who recommended the combined use of ADA with differential fluid cell count, after an observed increase in specificity and PPV, for a more efficient diagnosis of PTB. This differing result may be due to the exclusion of empyematous effusions from our study. Empyemas are a known cause of elevated ADA and usually have a predominance of neutrophils. Nearly 10% of the high ADA results generated in our laboratory during the study period were due to empyemas, which had missed being rejected. The poor sensitivity observed for the traditional diagnostic methods for PTB in the present study is a well-reported finding that makes diagnosis of PTB a challenge. The implication is that

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utilisation of either microscopy for AFB alone or TB culture of fluid would lead to many TB-positive patients being missed. Equal gender distribution seen in the TPE and NTPE groups differs from that of previous studies where there were generally slightly more males than females.[10,15] This may be due to changing patterns in access to healthcare, gender issues and changing epidemiological profiles, such as the rise of HIV infection particularly among women, which may contribute to the development of more TB cases in females.[16] We observed that more patients who were HIVpositive had TPEs than patients who were HIV-negative. This is in agreement with the current epidemiological profile for TB/HIV co-infection rates.[1] The older age distribution in the NTPE group might have been due to the aetiological conditions in this group, which are more common in older individuals. They consisted mainly of malignancies, parapneumonias and congestive cardiac failure. Most of the malignancies were due to bronchial cancer, which is in agreement with Zemlin et al.[10] Valdés et al.[17] found that parapneumonic effusions were the most frequent reason for a high FADA, followed by carcinomas (with pleural metastatic lesions) and lymphomas.

Study limitations

We reviewed only high FADA results and hence were not able to assess other measures of diagnostic accuracy apart from the PPV. However, previous studies have been carried out in our laboratory to assess the diagnostic accuracy of FADA for PTB,[8,10] which confirmed a high sensitivity and specificity. As the study was retrospective, high ADA results without corresponding microbiology results were excluded. In addition, the HIV status of the patients was not available in all cases. We excluded results of patients from satellite hospitals and clinics owing to difficulty in accessing the patient records from these facilities; however, this is unlikely to affect our findings as these hospitals, located within the Western Cape region, share a similar TB prevalence rate to that of TH. Despite the limitations, we feel that this study is robust in that it reviews results over 1 year. We utilised the WHO-recognised reference standard for TB diagnosis as the gold standard in assessing for diagnosis of TB throughout. There is room for a similar but more extensive audit in future, involving FADA results from our hospital, other regional referral hospitals in the country and the satellite healthcare facilities utilising our laboratory services.

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Conclusion

This audit has confirmed that high FADA results generated at our laboratory have a good precision rate for PTB. The few FPs that occurred are mostly due to malignancies, which occur in older people and can be diagnosed by cytology/histology and/or radiology, after confirming that the TB culture is negative. We reaffirm the fact that a high FADA is an indispensable TB diagnostic tool and recommend its continued use as a rapid means of diagnosing PTB in a middleincome country with a high TB/HIV burden. Acknowledgements. The authors are grateful to Mr W Kleinhans for his support with the retrieval of laboratory records and Prof. M Kidd for his assistance with the statistical analysis. References 1. World Health Organization. Global Tuberculosis Report 2013. Geneva: WHO, 2012. http://www.who. int/tb/publications/global_report/en/ (accessed 7 April 2013). 2. Western Cape Government. World TB Day, March 2012. 23 March 2012. http://www.westerncape. gov.2/news/world-tb-day-24-march-2012 (accessed 7 April 2013). 3. Frye MD, Pozsik CJ, Sahn SA. Tuberculous pleurisy is more common in AIDS than in non-AIDS patients with tuberculosis. Chest 1997;112(2):393-397. [http://dx.doi.org/10.1378/chest.112.2.393] 4. Kataria YP, Khurshid I. Adenosine deaminase in the diagnosis of tuberculous pleural effusion. Chest 2001;120(2):334-335. [http://dx.doi.org/10.1378/chest.120.2.334] 5. Piras MA, Gakis G, Budroni M, Andreoni G. Adenosine deaminase activity in pleural effusions: An aid to differential diagnosis. BMJ 1978;2(6154):1751-1752. [http://dx.doi.org/10.1136/bmj.2.6154.1751-a] 6. Martiz FJ, Malan C, Le Roux I. Adenosine deaminase estimation in the differentiation of pleural effusions. S Afr Med J 1982;62(16):556-558. 7. Blake J, Berman P. The use of adenosine deaminase assays in the diagnosis of tuberculosis. S Afr Med J 1982;62(1):556-558. 8. Burgess LJ, Martiz FJ, Le Roux I, Taljaard F. Combined use of pleural adenosine deaminase with lymphocyte neutrophil ratio. Increased specificity for the diagnosis of tuberculous pleuritis. Chest 1996;109(2):414-419. [http://dx.doi.org/10.1378/chest.109.2.414] 9. Riantawan P, Chaowalit P, Wongsangiem M, Rojanaraweewong P. Diagnostic value of pleural fluid adenosine deaminase in tuberculous pleuritis with reference to HIV coinfection and a Bayesian analysis. Chest 1999;116(1):97-103. [http://dx.doi.org/10.1378/chest.116.1.97] 10. Zemlin AE, Burgess LJ, Carstens ME. The diagnostic utility of adenosine deaminase isoenzymes in tuberculous pleural effusions. Int J Tuberc Lung Dis 2009;13(2):214-220. 11. Van Kiempema AR, Slaats EH, Wagenaar JP. Adenosine deaminase, not diagnostic for tuberculous pleurisy. Eur J Respir Dis 1987;71(1):15-18. 12. Khatami K. Pleural Tuberculosis. Shiraz E Medical Journal 2002;3(3):78-86. 13. Giusti G. Adenosine deaminase. In: Bergmayer H-U, ed. Methods of Enzymatic Analysis. 2nd ed. New York: Academic Press, 1974:1092-1099. 14. World Health Organization. Treatment of Tuberculosis: Guidelines. 4th ed. Geneva: WHO, 2010:2324. http://www.who.int/tb/publications/2010/9789241547833/en/ (accessed 11 April 2013). 15. Valdes L, Alvarez D, San José E, et al. Value of adenosine deaminase in the diagnosis of tuberculous pleural effusions in young patients in a region of high prevalence of tuberculosis. Thorax 1995;50:600603. [http://dx.doi.org/10.1136/thx.50.6.600] 16. Weyer K, R Matji. Epidemiology and Control of Tuberculosis. In: Weyer K, ed. Management of Tuberculosis. Pretoria: Foundation for Professional Development, South African Medical Association, 2004. 17. Valdés L, San José E, Alvarez D, Valle JM. Adenosine deaminase (ADA) isoenzyme analysis in pleural effusions: Diagnostic role, and relevance to the origin of increased ADA in tuberculous pleurisy. Eur Respir J 1996;9(4):747-751. [http://dx.doi.org/10.1183/09031936.96.09040747]

Accepted 16 January 2014.

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Integration of TB and ART services fails to improve TB treatment outcomes: Comparison of ART/TB primary healthcare services in Cape Town, South Africa R Kaplan,1 MD; J Caldwell,2 RN, RM, BCur; L-G Bekker,1 MB ChB, FCP (SA), PhD; K Jennings,2 MB ChB, DCH; C Lombard,3,4 MSc, PhD; D A Enarson,4,5 MD; R Wood,1 MB BCh, FCP (SA), DSc (Med); N Beyers,4 MB ChB, FCP (SA), MSc (Med), PhD esmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, D South Africa 2 City Health, City of Cape Town, South Africa 3 Biostatistics Unit, South African Medical Research Council, Cape Town, South Africa 4 Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa 5 International Union Against Tuberculosis and Lung Disease, Paris, France 1

Corresponding author: R Kaplan (richard.kaplan@hiv-research.org.za)

Background. The combined tuberculosis (TB) and HIV epidemics in South Africa (SA) have created enormous operational challenges for a health service that has traditionally run vertical programmes for TB treatment and antiretroviral therapy (ART) in separate facilities. This is particularly problematic for TB/HIV co-infected patients who need to access both services. Objective. To determine whether integrated TB facilities had better TB treatment outcomes than single-service facilities in Cape Town, SA. Methods. TB treatment outcomes were determined for newly registered, adult TB patients (aged ≥18 years) at 13 integrated ART/TB primary healthcare (PHC) facilities and four single-service PHC facilities from 1 January 2009 to 30 June 2010. A χ2 test adjusted for a cluster sample design was used to compare outcomes by type of facility. Results. Of 13 542 newly registered patients, 10 030 received TB treatment in integrated facilities and 3 512 in single-service facilities. There was no difference in baseline characteristics between the two groups with HIV status determined for 9 351 (93.2%) and 3 227 (91.9%) patients, of whom 6 649 (66.3%) and 2 213 (63%) were HIV-positive in integrated facilities and single-service facilities, respectively. The median CD4+ count of HIV-positive patients was 152 cells/µl (interquartile range (IQR) 71 - 277) for integrated facilities and 148 cells/µl (IQR 67 - 260) for single-service facilities. There was no statistical difference in the TB treatment outcome profile between integrated and single-service facilities for all TB patients (p=0. 56) or for the sub-set of HIV-positive TB patients (p=0.58) Conclusion. This study did not demonstrate improved TB treatment outcomes in integrated PHC facilities and showed that the provision of ART in the same facility as TB services was not associated with lower TB death and default rates. S Afr Med J 2014;104(3):204-209. DOI:10.7196/SAMJ.7696

The extent of the combined tuberculosis (TB) and HIV epidemics in South Africa (SA) has created enormous operational challenges for a health service that has traditionally run vertical programmes for TB and HIV, with treatment delivered by different healthcare staff, often in separate facilities. This is particularly problematic for TB/HIV co-infected patients who need to access both services. In Cape Town, SA, the TB prevalence in HIV-positive patients initiating antiretroviral therapy (ART) has been reported to be as high as 25%,[1] while 51% of TB patients enrolled in the primary healthcare (PHC) TB treatment programme were recorded as co-infected with HIV in 2009.[2] In the developing world, TB is known to be the leading cause of death in HIV-positive patients[3,4] and in 2008 - 2009, a TB-case fatality of 6% was reported in the Cape Town PHC TB programme for HIV-positive TB patients.[5] Despite the 2010 SA national ART guideline recommendations that ART should be initiated between 2 and 8 weeks after the initiation of TB treatment,[6] long referral delays have been reported between TB and ART facilities.[7,8] These delays could negatively influence TB treatment outcomes, particularly for co-infected patients with low

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CD4+ counts as the CAMELIA, STRIDE and SAPiT studies have documented. In these studies, death rates were significantly reduced for HIV/TB co-infected patients receiving TB treatment with CD4+ counts <50 cells/μl who initiated ART within 2 weeks after initiating TB treatment.[9-11] In recent years, the SA National Department of Health (NDoH) has promoted the integration of TB and HIV services to facilitate easy access to healthcare services for TB/HIV co-infected patients and to rationalise resources.[12] While the introduction of ART in facilities that provide TB treatment could be expected to decrease time from the initiation of TB treatment to the initiation of ART for co-infected patients and therefore impact favourably on TB death and default rates on an individual level, there are few reported data at healthcare facility level comparing TB treatment outcomes between integrated facilities that offer both TB treatment and ART and single-service facilities that only offer TB treatment. This study evaluated the association of the integration of TB treatment and ART with TB treatment outcomes to determine whether integrated TB facilities, providing both TB and ART, had lower death and default rates than single TB service facilities that

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referred patients off-site for ART. As the integration of facilities has been accompanied by the allocation of extra resources and staff, it was envisaged that integration could improve the general standard of care and, in turn, influence outcomes for both HIV-negative and -positive patients. We investigated the hypothesis that TB treatment outcomes would be better for all TB patients and for TB/HIV co-infected cases in facilities providing TB treatment and ART in one facility than in facilities that only provided TB treatment and required co-infected patients to access ART at a separate facility.

Methods

Population and sample

The target population for this study comprised adult TB patients, aged ≥18 years, who were registered in the national electronic TB register (ETR.net) in all PHC facilities that provided TB treatment in Cape Town over an 18-month period from 1 January 2009 to 30 June 2010.

Setting

During the study period, the Cape Town City Health Directorate and the Western Cape Department of Health provided TB treatment in 99 PHC facilities in eight sub-districts in Cape Town, SA. Of these, 68 provided TB treatment but not ART, while 31 provided integrated ART and TB treatment. All ART and TB services were provided free of charge. The TB treatment regimens during the study period were in accordance with the 2009 SA national TB management guideline.[13] New TB patients received fixed-dose combination tablets consisting of rifampicin, isoniazid, pyrazinamide and ethambutol for a 2-month intensive phase followed by rifampicin and isoniazid for a 4-month continuation phase. Treatment was received 7 days per week. Retreatment TB patients received 2 months of streptomycin 5 days a week plus fixed-dose combination tablets consisting of rifampicin, isoniazid, pyrazinamide and ethambutol 7 days a week for a 3-month intensive phase followed by rifampicin, isoniazid and ethambutol 7 days a week for a 5-month continuation phase. All TB patients were routinely offered HIV testing. Eligibility for ART was determined for HIV-positive patients through CD4+ count testing and World Health Organization (WHO) disease staging. Consistent with the SA national ART guideline at the time of our study, patients were eligible for ART if they had a CD4+ count <200 cells/μl or WHO stage 4 disease.[14] These patients were offered ART in the same facility, if available, and if not, were referred to another facility to access ART. The recommended ART first-line treatment regimen for co-infected patients during the initial period of the study was stavudine or zidovudine, lamivudine and efavirenz.[14] In March 2010, near the end of the study period, this was changed to tenofovir, lamivudine and efavirenz.[6] For the purpose of this study, integrated facilities were defined as facilities that provided both ART and TB treatment in the same building. Included in this definition were both partially integrated services that provided ART and TB treatment in different consulting rooms, and fully integrated services where both treatments were provided by the same clinician in the same consulting room. Single-service facilities only provided TB treatment with patients being referred off-site for ART. As this study aimed to examine the effect of integration of HIV and TB services, only high-burden TB facilities with a high HIV prevalence were included in the analysis. These were defined as facilities with a TB caseload >400 adult TB patients per year and a HIV prevalence >50% in all TB patients. Facilities were only included in the study if they had been either integrated or single service for the full study period. Patients who were initiated on treatment in

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hospital and were referred to a PHC clinic to continue their treatment were included in the analysis. However, to avoid possible duplication of cases, patients who were transferred between PHC clinics were excluded. Also excluded were patients with drug-resistant TB.

Study design

This was a retrospective cohort study using routine TB programme data. Facilities were considered as clusters with patients, linked to the facility over the period of sampling, as the individual-level data.

Data sources and management

Out of the 99 TB treatment facilities in Cape Town, 17 were either integrated or single service for the entire study period and met the inclusion criteria for high-burden facilities based on aggregated data for the 18-month period. Of these facilities, 13 were integrated and four were single-service facilities. Individual patient data from these 17 facilities were extracted for this analysis from the ETR.net for Cape Town. This is a customised computer software program developed for the NDoH National TB Control Programme for the collection of individual patient information for routine monitoring and evaluation of the performance of the programme. TB cases are routinely recorded in a paper-based TB treatment register at PHC-facility level. These data are then captured in the ETR.net. For this study, data were extracted from ETR.net and all unique patient identifiers removed prior to analysis; the facility code was retained to ensure that individuals could be linked to facilities for the cluster analysis. Data on ART uptake were recorded in ETR.net, but since we were comparing sites that provided ART with sites that did not, the potential for bias in how ART uptake was recorded was high and these data were not considered reliable for comparative purposes. This prohibited an analysis of the direct association of TB treatment outcomes with ART uptake.

Definitions

HIV status HIV-positive patients were defined as those with positive HIV tests recorded in ETR.net, or with unrecorded test results but were recorded to be receiving ART or co-trimoxazole or had CD4+ test results in ETR.net. HIV-negative patients were defined by recorded HIV-negative test results and no indication of ART or co-trimoxazole treatment in the ETR.net. All other patients were considered to be of unknown HIV status. TB treatment outcomes TB treatment outcomes used in this study were the outcomes recorded in ETR.net according to the internationally recommended WHO definitions of cure, completion, failure, death, default, transferred out and not evaluated.[15]

Statistical analysis

Descriptive features of the facilities by integration type were compared. The χ2 test, adjusted for a cluster sample design, was used to compare categorical variables such as the TB treatment outcome by type of facility. For continuous variables the median value was calculated for each facility and a two-sample Student’s t-test was used to compare these values between the two types of facilities (analysis at facility level).

Ethics approval

During collection of data for ETR.net, TB patients are not requested to provide informed consent for the collection of data. For this

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analysis, the Cape Town City Health TB programme approved the use of an anonymised database of routinely collected TB data for research purposes. Ethics approval for the use of these data was obtained from the Ethics Advisory Group of the International Union Against Tuberculosis and Lung Disease who were requested to waive the requirement for informed consent as the analysis was to be carried out on routinely collected programmatic data with all patient identifiers removed. This study was also approved by the University of Cape Town Research Ethics Committee.

HIV-positive patients The baseline demographics of the 8 862 HIV-positive patients were similar for patients in integrated facilities and single-service facilities (Table 2). Of all the HIV-positive patients, 4 855 (54.8%) were female and CD4+ counts were recorded for 8 411 (94.9%). The median CD4+ count was 151 cells/μl (IQR 70 - 273) and 5 291 (59.7%) had a CD4+ count <200 cells/μl. There was no difference in CD4+ count distribution between the two groups. Co-trimoxazole was provided to 8 466 (95.5%) of the HIV-positive patients.

Results

TB treatment outcomes

A total of 16 885 patients were registered at the 17 facilities during the study period. Of these, 3 343 patients were excluded from the analysis as they were either <18 years of age or had been transferred between PHC TB facilities. The remaining 13 542 TB patients were included in this analysis.

Baseline characteristics

All patients The baseline demographics for all 13 542 patients were similar for patients in integrated facilities and single-service facilities (Table 1). The median age was 34 years (interquartile range (IQR) 28 - 42) and 6 331 (46.7%) of the patients were female. HIV status was ascertained for 12 578 (92.9%) patients; 8 862 (65.4%) patients were HIV-positive, 3 716 (27.4%) were HIV-negative and the HIV status was unknown for 964 (7.1%) patients. Of the total, 4 059 (30%) patients were classified as retreatment cases after a previous TB episode. A total of 10 879 (80.3%) patients had pulmonary TB (PTB), 330 (2.4%) had both extrapulmonary (EPTB) and PTB, while 2 333 (17.2%) patients had EPTB. Of the 11 209 patients who had PTB or both PTB and EPTB, 5 557 (49.6%) were smear-positive, 5 019 (44.8%) were smearnegative and 633 (5.6%) had no smear result recorded.

All patients Fig. 1 compares the TB treatment outcome profile between integrated facilities and single-service facilities for all patients. The aggregated death and default rate for patients treated in all facilities was 16.4%. When compared across the two types of services, aggregated death and default rates were 17.2% (death 6.4%; default 10.8%) for integrated facilities and 14% (death 5.2%; default 8.8%) for singleservice facilities. The treatment success rate (aggregated cured and completion rates) was 74.1% for integrated facilities and 81.7% for single-service facilities. The treatment failure rate was similar for integrated facilities and single-service facilities (1.6% v. 1.7%, respectively). The transfer-out rate was 4.7% at integrated facilities and 1.9% at single-service facilities. There was no statistical difference in the treatment outcome profile between integrated and single-service facilities (p=0.56). HIV-positive patients Fig. 2 compares the treatment outcome profile between integrated facilities and single-service facilities for the sub-group of HIVpositive patients. Aggregated death and default rates were 17.2% (death 7.3%; default 9.9%) for integrated facilities and 14.1% (death

Table 1. Baseline characteristics of all TB patients aged ≥18 years registered at 13 integrated and four single-service facilities Patients in PHC facilities p-value

Characteristic

Total

Integrated

Single-service

Receiving TB treatment, n

13 542

10 030

3 512

Age (years), median (IQR)

34 (28 - 42)

33 (28 - 41)

34 (27 - 42)

0.45

Gender (female), n (%)

6 331 (46.7)

4 674 (46.6)

1 657 (47.2)

0.68

Positive

8 862 (65.4)

6 649 (66.3)

2 213 (63.0)

0.58

Negative

3 716 (27.4)

2 702 (26.9)

1 014 (28.9)

Unknown

964 (7.1)

679 (6.7)

285 (8.1)

PTB

10 879 (80.3)

8 030 (80.0)

2 849 (81.1)

EPTB

2 333 (17.2)

1 721 (17.2)

612 (17.4)

PTB/EPTB

330 (2.4)

279 (2.8)

51 (1.5)

New

9 483 (70.0)

7 059 (70.4)

2 424 (69.0)

Retreatment

4 059 (30.0)

2 971 (29.6)

1 088 (31)

0.58

Smear-positive

5 557 (49.6)

4 110 (49.5)

1 447 (49.9)

0.72

Smear-negative

5 019 (44.8)

3 706 (44.6)

1 313 (45.3)

No smear

633 (5.6)

493 (5.9)

140 (4.8)

HIV status, n (%)

Classification, n (%) 0.33

PTB and PTB/EPTB, n (%)

PHC = primary healthcare; TB = tuberculosis; IQR = interquartile range; PTB = pulmonary tuberculosis; EPTB = extrapulmonary tuberculosis.

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Table 2. Baseline characteristics of HIV-positive TB patients aged ≥18 years registered at 13 integrated and four single-service facilities Patients in PHC facilities Characteristic

Total

Integrated

Single-service

Receiving TB treatment, n (%)

8 862

6 649

2 213

Age (years), median (IQR)

34 (28 - 40)

33 (28 - 40)

34 (28 - 40)

0.32

Gender (female), n (%)

4 855 (54.8)

3 629 (54.6)

1 226 (55.4)

0.40

Median (IQR)

151 (70 - 273)

152 (71 - 277)

148 (67 - 260)

0.96

≤50

1 504 (17)

1 117 (16.8)

387 (17.5)

0.70

51 - 100

1 441 (16.3)

1 083 (16.3)

358 (16.1)

101 - 200

2 346 (26.5)

1 779 (26.8)

567 (25.6)

201 - 350

1 809 (20.4)

1 355 (20.4)

454 (20.5)

>350

1 311 (14.8)

1 025 (15.4)

286 (12.9)

Missing

451 (5.1)

290 (4.4)

161 (7.3)

PTB

6 725 (75.9)

5 017 (75.4)

1 708 (77.2)

EPTB

1 846 (20.8)

1 387 (20.9)

459 (20.7)

PTB/EPTB

291 (3.3)

245 (3.7)

46 (2.1)

New

6 138 (69.3)

4 639 (69.8)

1 499 (67.7)

Retreatment

2 724 (30.7)

2 010 (30.2)

714 (32.3)

Smear-positive

2 796 (39.9)

2 099 (39.7)

697 (39.7)

Smear-negative

3 747 (53.4)

2 790 (53)

957 (54.6)

No smear

473 (6.7)

373 (7.1)

100 (5.7)

Yes

8 446 (95.5)

6 349 (95.5)

2 117 (95.7)

396 (4.5)

300 (4.5)

96 (4.3)

p-value

CD4+ count (cells/μl), n (%)

Classification, n (%) 0.37

0.39

PTB and PTB/EPTB, n (%) 0.76

Receiving co-trimoxazole, n (%) 0.84

PHC = primary healthcare; TB = tuberculosis; IQR = interquartile range; PTB = pulmonary tuberculosis; EPTB = extrapulmonary tuberculosis.

5.8%; default 8.3%) for single-service facilities. The treatment success rate was 73.2% for integrated facilities and 81.2% for single-service facilities. Treatment failure rates were similar for integrated facilities and single-service facilities (1.8% v. 1.6%, respectively). The transferout rates was 5.1% at integrated facilities and 2.3% at single-service facilities. There was no statistical difference in the treatment outcome profile between integrated and single-service facilities (p=0.58).

Discussion

The results of this study, involving a large cohort of patients (N=13 542) who received TB treatment according to programmatic standards, reflect actual operational TB treatment outcomes in Cape Town. The study showed high unfavourable outcomes (aggregated death and a default rate of 16.4%) among all TB patients in highTB/HIV-burden PHC facilities. There was no significant difference in these outcomes between integrated facilities and single-service facilities. Overall single-service facilities had slightly better treatment outcomes with greater treatment success rates and lower death and default rates. However, there were more patients whose outcomes were not evaluated in the integrated facilities. Our results are similar to those of a much smaller study, which showed a decrease in time between the initiation of TB treatment and that of ART for TB/HIV co-infected patients when ART was introduced into routine TB services in Khayelitsha, Cape Town, but

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did not show an impact on TB treatment outcomes.[16] Other studies in Uganda and Kenya[17,18] have shown improvements in TB treatment success rates and a marked reduction in death and default rates after the integration of TB and ART services. However, both these studies reported higher death and default rates after integration of services than were observed in either the integrated or single-service facilities in our study. In Uganda, death and default rates were decreased from 33% to 25% after the integration of services and in Kenya, the lost to follow-up rate decreased from 36% to 12.5% and death rates were reduced from 20% to 5.4% over a 5-year period after integration of services. While this shows an impressive improvement in outcomes, aggregated death and default rates remain high, ranging from 17.2% to 25% in the Cape Town, Kenyan and Ugandan studies despite integration of services. In this study, the HIV prevalence in TB patients was very high (65.4%); almost 60% of patients had a CD4+ count <200 cells/μl and would have been eligible for ART under the 2004 SA national HIV treatment guideline.

Study limitations

A limitation of the study is that data on ART uptake and ART initiation dates were not uniformly collected in the TB services. We could, therefore, not perform a comparative study of ART uptake or determine whether the integration of services reduced the time

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100

100 80

74.1

17.2

40 20 1.6

Success

Failed

10.8

6.4 Died

17.2

40 20

4.7

1.8

2.4

Not Defaulted Transferred evaluated out

Success

Failed

9.9

7.3 Died

5.1

2.6

Not Defaulted Transferred evaluated out

100

81.2

81.7

20 1.7 0

Success

Failed

5.2 Died

14.1

14.0

73.2

8.8

1.9

1.6

0.7

Not Defaulted Transferred evaluated out

Success

Failed

5.8 Died

8.3

2.3

0.9

Not Defaulted Transferred evaluated out

Fig. 1. Comparison of the treatment outcome profiles of all TB patients aged ≥18 years registered at (A) 13 integrated and (B) four single-service facilities (p=0.56).

Fig. 2. Comparison of treatment outcome profiles of HIV-positive TB patients aged ≥18 years registered at (A) 13 integrated and (B) four single-service facilities (p=0.58).

between initiation of TB treatment and that of ART. Therefore this study could not determine the direct influence of ART on TB treatment outcomes. Other studies in Cape Town have shown poor uptake of ART and long delays in time from initiation of TB treatment to that of ART in both integrated and single-service facilities. Pepper et al.[19] noted that 34/100 TB patients who were eligible for ART did not initiate treatment in an integrated TB and ART facility in Cape Town and reported a median time of 58 days from initiation of TB treatment to initiation of ART for co-infected patients. Nglazi et al.[20] reported that 19.7% of ART-eligible TB patients did not initiate ART during their TB treatment in a large facility in Cape Town that had both ART and TB services on-site and recorded a median delay of 51 days between initiation of TB treatment and that of ART. A further limitation of our study was that many of the singleservice facilities were excluded from the analysis due to either a small annual TB caseload or low co-infection rate. The study therefore compared four single-service facilities with a combined caseload of 3 152 patients with 13 integrated facilities with a combined caseload of 10 030 patients. While this limited the power of the analysis to determine a statistically significant difference in outcomes, the trend of the analysis was for improved outcomes in the single-service facilities and not the integrated facilities. This study could also not determine the long-term influence of integrated services on mortality, as the analysis was restricted to the period of TB treatment. It is possible that integrated services would be better able to retain HIV-positive patients in care after TB treatment and therefore ensure better long-term outcomes for co-infected patients.

serious problems within the health services. This study has shown that in itself, the provision of ART in the same facility as TB services was not associated with improved TB treatment outcomes in the routine TB services. The exact reasons why the integration of services was not associated with better programmatic outcomes are not clear and warrant further operational research to inform services on how to improve integration. It is possible that an accurate recording of ART uptake and time taken to initiate ART, as part of routine indicators, would assist in assessing whether the provision of ART in TB facilities has actually improved access to ART.

Conclusion

While the scale-up of ART in Cape Town has improved access to HIV treatment for TB/HIV co-infected patients, the high HIV prevalence, low median CD4+ counts and high death and default rates remain

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Acknowledgements. This research was supported by a US Agency for International Development (USAID) Cooperative Agreement (TREAT TB Agreement No. GHN-A-00-08-00004-00). The contents are the responsibility of the authors and do not necessarily reflect the views of USAID. References

1. Lawn SD, Myer L, Bekker LG, Wood R. Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: Impact on treatment outcomes and implications for tuberculosis control. AIDS 2006;20(12):1605-1612. [http://dx.doi.org/10.1097/01.aids.0000238406.93249.cd] 2. Wood R, Lawn SD, Caldwell J, Kaplan R, Middelkoop K, Bekker LG. Burden of new and recurrent tuberculosis in a major South African city stratified by age and HIV-status. PLoS One 2011;6:e25098. [http:// dx.doi.org/10.1371/journal.pone.0025098] 3. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: Global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163(9):1009-1021. [http://dx.doi.org/10.1001/ archinte.163.9.1009] 4. Straetemans M, Bierrenbach AL, Nagelkerke N, Glaziou P, van der Werf MJ. The effect of tuberculosis on mortality in HIV positive people: A meta-analysis. PLoS One 2010;5:e15241. [http://dx.doi.org/10.1371/ journal.pone.0015241] 5. Kaplan R, Bekker LG, Caldwell J, et al. HIV Prevalence, CD4 Count Distribution and Case Fatality for TB Patients Treated in Primary Health Care Facilities in Cape Town. Abstract #306. 2nd South African TB Conference; 1 - 4 June 2010; Durban, SA. 6. National Department of Health. Clinical Guidelines for the Management of HIV & AIDS in Adults and Adolescents, 2010. Pretoria: NDoH, 2010. http://www.sahivsoc.org/upload/documents/Clinical_ Guidelines_for_the_Management_of_HIV_AIDS_in_Adults_Adolescents_2010.pdf (accessed 23 January 2014). 7. Lawn SD, Campbell L, Kaplan R, et al. Time to initiation of antiretroviral therapy among patients with HIVassociated tuberculosis in Cape Town, South Africa. J Acquir Immune Defic Syndr 2011;57(2):136-140. [http://dx.doi.org/10.1097/QAI.0b013e3182199ee9] 8. Lawn SD, Campbell L, Kaplan R, Little F, Morrow C, Wood R. Delays in starting antiretroviral therapy in patients with HIV-associated tuberculosis accessing non-integrated clinical services in a South African township. BMC Infect Dis 2011;11:258. [http://dx.doi.org/10.1186/1471-2334-11-258]

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9. Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011;365(16):1471-1481. [http://dx.doi.org/10.1056/NEJMoa1013911] 10. Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011;365(16):1482-1491. [http://dx.doi.org/10.1056/NEJMoa1013607] 11. Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011;365(16):1492-1501. [http://dx.doi.org/10.1056/NEJMoa1014181] 12. South African National AIDS Council, National Department of Health. National Strategic Plan on HIV, STIs and TB 2012 - 2016. Pretoria: NDoH, 2011. http://www.info.gov.za/view/DownloadFileAction?id=155622 (accessed 23 January 2014). 13. National Department of Health. National Tuberculosis Management Guidelines 2009. Pretoria: NDoH, 2009. http://familymedicine.ukzn.ac.za/Libraries/Guidelines_Protocols/TB_Guidelines_2009.sflb.ashx (accessed 23 January 2014). 14. National Department of Health. National Antiretroviral Treatment Guidelines. 1st ed. Pretoria: NDoH, 2004. http://southafrica.usembassy.gov/media/2004-doh-art-guidelines.pdf (accessed 23 January 2014). 15. World Health Organization. Treatment of Tuberculosis: Guidelines. 4th ed. Geneva: WHO, 2010. http:// www.who.int/tb/publications/2010/9789241547833/en/ (accessed 23 January 2014). 16. Brown C, Kerschberger B, Boulle A, et al. TB and HIV Service Integration within a South African Primary Health Care Setting Reduces the Time to ART Initiation without Negatively Impacting TB Outcomes.

Abstract #890.18th Conference on Retroviruses and Opportunistic Infections; 27 February - 2 March 2011; Boston, USA. 17. Hermans SM, Castelnuovo B, Katabira C, et al. Integration of HIV and TB services results in improved TB treatment outcomes and earlier prioritized ART initiation in a large urban HIV clinic in Uganda. J Acquir Immune Defic Syndr 2012;60(2):e29-e35. [http://dx.doi.org/10.1097/QAI.0b013e318251aeb4] 18. Shaffer DN, Obiero ET, Bett JB, et al. Successes and challenges in an integrated tuberculosis/HIV clinic in a rural, resource-limited setting: Experiences from Kericho, Kenya. AIDS Res Treat 2012;2012:238012. [http://dx.doi.org/10.1155/2012/238012] 19. Pepper DJ, Marais S, Wilkinson RJ, Bhaijee F, De Azevedo V, Meintjes G. Barriers to initiation of antiretrovirals during antituberculosis therapy in Africa. PLoS One 2011;6(5):e19484. [http://dx.doi. org/10.1371/journal.pone.0019484] 20. Nglazi MD, Kaplan R, Caldwell J, et al. Antiretroviral treatment uptake in patients with HIV-associated TB attending co-located TB and ART services. S Afr Med J 2012;102(12):936-939. [http://dx.doi.org/10.7196/ SAMJ.6024]

Accepted 22 January 2014.

Tuberculosis incidence in Cameroonian prisons: A 1-year prospective study J Noeske,1 MD, PhD; N Ndi,2 MD; G Amougou Elo,3 MD; S Mbondi Mfondih4 Independent Senior Consultant, National Tuberculosis Programme, Yaounde, Cameroon enitentiary Administration, Ministry of Justice, Yaounde, Cameroon P 3 Regional Delegation of Prison Administration, N’Gaoundere, Cameroon 4 Health/AIDS Programme, German International Cooperation, Yaounde, Cameroon 1 2

Corresponding author: J Noeske (juergennoeske@yahoo.fr) Background. Rates of tuberculosis (TB) transmission in prisons are reported to be high worldwide. However, a recent systematic review identified only 19 published studies reporting TB incidence in prisons, most of them from the last century and only one from subSaharan Africa. Objectives. To assess the persisting risk of smear-positive pulmonary tuberculosis (PTB) among prison populations benefiting from a comprehensive TB/HIV control programme in Cameroon, compared with that in the community. Methods. This descriptive and prospective study evaluated PTB incidence rates over a 1-year period. The study population was inmates of 10 major prisons, sampled by convenience, comprising about 45% of the country’s prison population. As PTB incident cases, all prisoners with incident PTB after a prison stay of ≥90 days were considered. The prison TB incidence rate was compared with that of the corresponding male population in the community. Results. The mean annual PTB incidence in Cameroonian prisons in this study was 1 700 cases in 100 000 person-years at risk, the incidence rate ratio being 9.4 (95% confidence interval 8.1 - 10.9). Conclusion. Findings suggest that internationally recommended prison TB control measures alone may not help protect prisoners from within-prison spread of TB. Imprisonment policies and conditions therefore require fundamental changes. S Afr Med J 2014;104(3):209-211. DOI:10.7196/SAMJ.7384

Rates of tuberculosis (TB) transmission in prisons are reported to be high worldwide.[1] Owing to the constant movement of prisoners to the community and vice versa, prisons are a recognised reservoir for TB transmission to the community. However, the magnitude of this public health problem remains largely unknown, particularly in sub-Saharan Africa (SSA).[2] While it is generally accepted that the most appropriate epidemiological measure for quantifying TB morbidity is incidence rates, a recent systematic review identified only 19 published studies reporting TB incidence in prisons, most of them from the last century and only one from SSA.[3,4] In Cameroon, TB and HIV control measures have been implemented as a pilot intervention over the past several years in 10 major urban, semi-urban and rural prisons by the Ministry of Justice

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(MoJ), with technical and financial assistance from a development agency. The 10 target prisons are situated in different regions of the country, and hold about 45% of the total prison population of 23 500. All 10 prisons were built in the 1960s and are therefore outdated. They are characterised by severe overcrowding, the overall mean overpopulation being 200% according to the MoJ, but reaching >1 000% in some cells and cell blocks. The official budget amounts to about US$0.45 per inmate per day. Medical services are substandard. The prison population consists of both pre-trial and sentenced detainees and is characterised by a large annual turnover (>70%), yet the average duration of stay exceeds 3 months for the majority of cases (>90%). About 85% of new prison entrants accept voluntary counselling and testing for HIV infection. The mean HIV infection rate among inmates dropped from 5.8% in 2011 to 5.0% in 2012,

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following a national trend, but is still almost double that of the comparable civilian population (2.9% in men in 2011, according to the third Demographic and Health Survey[5]). An average of three times more female inmates than males are infected (15.3% v. 5.5% in 2011, according to the unpublished annual activity report of the MoJ). TB control activities follow the guidelines and use the management tools of the National TB Control Programme (NTP). Case finding according to NTP guidelines is passive. In the 10 target prisons, however, three active case finding strategies have been added as routine procedure: medical screening at entry with identification of suspects based on a clinical score, contact tracing in the prison, and periodic (at least annual) mass screening in four larger and heavily overcrowded prisons where TB transmission has been shown to remain high in spite of the control measures implemented.[5] This study sought to assess the risk of smear-positive pulmonary tuberculosis (PTB) morbidity among prison populations in Cameroon compared with that in the corresponding community.

Methods

This was a descriptive and prospective study that collected PTB incidence data and calculated incidence rates over a 1-year period (October 2011 - September 2012). The study population comprised only inmates of the 10 prisons targeted by the HIV/TB Control Programme of the MoJ; prison healthcare and other staff were not considered. For each prison, data on prisoners diagnosed with PTB during the study period, as well as the date of their admission to prison, were extracted from the standardised TB patient registers (World Health Organization (WHO) format, adapted). Only microbiologically confirmed TB cases were taken into account. Information on the prison population was retrieved monthly (on the first day of each month) from the prison’s admission registers. As PTB disease incident cases, all prisoners with incident PTB after a length of stay of >90 days were considered; cases diagnosed with PTB during the first 3 months after entry were considered to have been prevalent cases at entry.[3] To determine the person-time of inmates at risk in any of the target prisons, the monthly count of inmates per prison was added up. The prison population in Cameroon is >96% male, aged between 15 and 54 years with a median age of about 30 years. To determine PTB incidence among the comparable general population, the NTP’s notification data for the male population aged between 15 and 54 years in the towns (for larger urban prisons) or administrative

districts (for semi-urban or rural prisons) where the prisons were situated were used. Population figures were calculated using the 2005 national census, estimating an annual population growth of 2.6%.[7] All data on PTB incidence in the prisons were captured in an EpiData entry database (version 3.1), mimicking an adapted version of the standard (WHO format) TB treatment register. Data on TB incidence in the communities were collected on an MS Excel sheet. Analyses were performed showing 95% confidence intervals (CIs) for proportions and p-values where appropriate. Written permission to conduct the study was obtained from the NTP. Ethical clearance was given by the Cameroon National Ethics Committee.

Results

Table 1 presents findings for each prison studied and for all 10 prisons together. Overall, for 10 468 person-years of risk, 178 TB cases were notified, or 1 700 cases per 100 000 person-years of follow-up. During the same period, the incidence (notification) of TB among the general population was 178 per 100 000 person-years of follow-up. The incidence rate ratio (IRR) was 9.4 (95% CI 8.1 - 10.9).

Discussion

TB prevalence studies in Cameroonian prisons during recent years have shown widely varying results.[6,8] This is the first systematic TB incidence study covering almost half of the country’s prison population in a variety of prisons. All 10 prisons included in the study were benefiting from a comprehensive TB and HIV control programme implemented several years previously and designed and executed according to international recommendations. Despite this, the mean PTB case notification rate among inmates remained almost 10 times higher (IRR 9.5) than the corresponding national average. The study findings showed that the burden of PTB varied from prison to prison. This may be due to various factors, including local differences in conditions of incarceration, in particular overcrowding and lack of ventilation; regional differences in TB and HIV incidence and prevalence; regional differences in rates of poverty; and local differences in access to quality prison health services. The results of this study are consistent with those of Baussano et al.,[4] who reported a median estimated annual incidence of TB of 1 943 per 100 000 persons for prisons in middle- and low-income countries. However, the reported median estimated IRR for TB

Table 1. Tuberculosis incidence in prisons and communities in Cameroon, 2011 - 2012 Incidence (/100 000) Prison

Cases (at risk), n

Prisons

General population

Incidence rate difference

IRR (95% CI)

CP Yaounde

63 (3 791)

1 662

138

1 524

11.9 (9.2 - 15.7)

CP Douala

42 (2 900)

1 448

200

1 248

7.2 (5.3 - 9.7)

CP Ebolowa

4 (380)

1 053

262

793

4.0 (1.5 - 10.9)

CP Maroua

30 (900)

3 333

297

3 036

10.9 (7.5 - 15.9)

CP Bafoussam

14 (999)

1 401

190

1 211

7.3 (4.2 - 12.5)

PP Foumban

7 (256)

2 734

212

2 522

12.6 (5.8 - 27.3)

PP Edea

7 (284)

2 465

219

2 246

11.0 (5.2 - 23.4)

PP Nkongsamba

3 (365)

822

239

583

3.4 (1.1 - 10.8)

PP Mbanga

7 (279)

2 509

481

2 028

5.1 (2.4 - 11.1)

PP Mora

1 (314)

318

270

6.6 (0.9 - 48.6)

Total, N

178 (10 468)

1 700

178

1 522

9.4 (8.1 - 10.9)

CP = Central Prison; PP = Principal Prison; IRR = incidence rate ratio; CI = confidence interval.

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of 32.8 (interquartile range (IQR) 15.4 - 36.1) was higher. This difference may be because the studies cited by Baussano et al. were done in the 1990s and/or in settings where TB outbreaks were not yet driven by the HIV epidemic. In SSA, figures for Ivory Coast alone reported a TB incidence rate in the penal camp of Bouake prison of 5 803/100 000 population and an IRR of 32.8 (IQR 27.1 - 39.6). This study also dates from the early 1990s (1990 - 1992), before the implementation of a national TB control programme aimed at collecting reliable case notification figures in the community and providing access to effective treatment. Our findings also illustrate what Basu et al.,[9] when modelling TB transmission in prisons, referred to as ‘institutional amplifiers’, demonstrating that even a substantial increase in case detection and treatment success rates alongside traditional control measures has little effect on the overall population incidence, as long as such hubs of transmission continue to exist. Likewise, Uys et al.,[10] when calculating TB transmission possibilities in low- and high-prevalence areas and settings, concluded that in high-prevalence settings transmission is relatively unresponsive to changes in the number of infectious people. Uys et al. coined the term ‘transmission elasticity’ to describe this phenomenon and warn against excessively optimistic projections regarding the effectiveness of ‘habitual’ control strategies. According to these authors, even if conventional control measures remain the priority, key interventions to reduce TB incidence, prevalence and mortality should include limiting the number of persons entering prisons, decreasing overcrowding, implementing environmental measures such as improved ventilation, and ensuring contact tracing. HIV/TB co-infection data are reported by the NTP without gender and age group breakdown. This study was therefore unable to compare HIV/TB co-infection rates among inmates with those in the comparable general population. However, according to our observations the role of HIV infection as a risk factor for PTB is significantly less important in prisons than among the general population: HIV/TB co-infection rates reported for 2011 were 11.2% among inmates with TB and 31.3% among the general population (NTP annual report 2011, unpublished). In the Cameroonian context, characterised by a generalised HIV epidemic and a considerable burden of TB due to HIV, this could be taken as an argument for the specific impact of confinement conditions on TB transmission.[6] Extrapolation of the results to the remaining prisons in Cameroon may underestimate TB incidence rates, considering that all 10 of the prisons studied have benefited from a comprehensive TB control programme. In terms of its strengths, this study gathered data prospectively and applied a recommended strategy for measuring morbidity in Cameroonian prisons. However, it was based on routinely collected data, which are only as accurate as the data collection system permits. The study had the following limitations: (i) the study population comprised only about 45% of Cameroon’s total

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prison population, which affected the representativeness of the results; (ii) person-time of observation was estimated by adding up the monthly count of inmates, which affected the accuracy of the incidence figures obtained; and (iii) the 15 - 20% of inmates undergoing their first 3 months of incarceration were not subtracted from the total person-time of observation, possibly contributing to an under-estimation of incidence rates.[3] The prison population targeted in this study remained relatively constant during the past 5 years with regard to monthly turnover rates and age and gender distribution. Adapting the denominator by excluding those 20% of inmates who could be assumed to be in the first 3 months of incarceration at any time would increase the incidence of PTB in prisons to 2 126 per 100 000 person-years, and the IRR would rise to 11.9 (IQR 10.3 - 13.8).

Conclusion

Our findings suggest that internationally recommended prison TB control measures alone may not adequately protect prisoners from within-prison spread of TB and thereby reduce the national TB burden. Rather, imprisonment policies and conditions require fundamental changes.[6,11] Author contributions. JN, NN, GAE and SMM planned the manuscript, GAE, NN and SMM collected the data, JN, NN, GAE and SMM analysed the data, JN drafted the first version of the manuscript, and all authors contributed towards critically revising the manuscript. All authors read and approved the final manuscript. References 1. World Health Organization. Literature review on TB control in prisons. http://who.int./tb/challenges/tp/ prisons/tb_in_prisons_lit_review_10Fev2008 (accessed 15 July 2013). 2. O’Grady J, Hoelscher M, Atun R, et al. Tuberculosis in prisons in sub-Saharan Africa – the need for improved health services, surveillance and control. Tuberculosis (Edinb) 2011;91(2):173-178. [http://dx.doi. org/10.1016/j.tube.2010.12.002] 3. Rieder HL, Anderson C, Dara M, et al. Methodological issues in quantifying the magnitude of the tuberculosis problem in a prison population. Int J Tuberc Lung Dis 2011;15(5):662-667. 4. Baussano I, Williams BG, Nunn P, Beggiato M, Fedeli U, Scano F. Tuberculosis incidence in prisons: A systematic review. PLoS Med 2010;7(12):e1000381. [http://dx.doi.org/10.1371/journal.pmed.1000381] 5. Institut National de la Statistique, Ministère de l’Économie de la Planification et de l’Aménagement du Territoire Ministère de la Santé Publique. 2011 Cameroon Demographic and Health Survey and Multiple Indicators Cluster Survey (DHS-MICS). Yaounde 2012. http://www.statistics-cameroon.org (accessed 14 September 2013). 6. Noeske J, Ndi N, Mbondi MS. Controlling TB against imprisonment conditions – a lost case: Experience from Cameroon. Int J Tuberc Lung Dis 2011;15(2):223-227. 7. Bureau Central des Recensements et des Etudes des Populations. Rapport de présentation des résultats définitifs. Yaounde 2010. http://www.statistics-cameroon.org/news.php?id=18 (accessed 15 July 2013). 8. Noeske J, Kuaban C, Amougou G, Piubello A, Pouillot R. Pulmonary tuberculosis in the central prison of Douala, Cameroon. East Afr Med J 2006;83(1):25-30. [http://dx.doi.org/10.4314/eamj.v83i1.9357] 9. Basu S, Stuckler D, McKee M. Addressing institutional amplifiers in the dynamics and control of tuberculosis epidemics. Am J Trop Med Hyg 2011;84(1):30-37. [http://dx.doi.org/10.4269/ajtmh.2011.0-0472] 10. Uys P, Marais BJ, Johnston-Robertson S, Hargrove J, Wood R. Transmission elasticity in communities hyperendemic for tuberculosis. Clin Infect Dis 2011;52(12):1399-1404. [http://dx.doi.org/10.1093/cid/ cir229] 11. Reid SE, Topp SM, Turnbull ER, et al. Tuberculosis and HIV control in sub-Saharan African prisons: ‘Thinking outside the prison cell’. J Infect Dis 2012;205(Suppl 2):S265-S273. [http://dx.doi.org/10.1093/ infdis/jis029]

Accepted 17 October 2013.

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GUEST EDITORIAL

Spina bifida: A few simple facts about a complex condition Open spina bifida (also known as myelomeningocele (SBM)) is the most complex birth defect involving the nervous system, and children born with this condition face a lifetime of medical care with numerous interventions. It is hard to think of another condition where initial management has such a profound effect on survival and ability. The March edition of CME is on SBM â&#x2C6;&#x2019; in fact, there are so many dimensions to this condition that the editor of CME has chosen to spread this topic over two editions of the journal. There are a few good reasons why SBM remains of relevance to health professionals in the 21st century, especially in South Africa. Firstly, SBM is often preventable. There is overwhelming evidence that women administered folic acid from before conception up to 12 weeks into pregnancy, either as a vitamin supplement or through food fortification, have a substantial reduction in their risk of having a baby with a neural tube defect, such as SBM. Although the risk is reduced by around two-thirds in most series, it is not abolished, pointing to a multifactorial aetiology, with other environmental and as yet unidentified genetic factors playing a role. A programme of folic acid fortification of staple foods was implemented in South Africa a decade ago. Although this has had an impact, the quantity may not be sufficient, and taking a supplement is advisable, especially in high-risk pregnancies. All healthcare workers in South Africa must be aware of these facts and never miss an opportunity to educate prospective parents. Simply stated, any woman at risk of pregnancy should take folic acid supplements. Secondly, SBM may be diagnosed early enough in pregnancy for prospective parents to be counselled about options such as continuation or termination of the pregnancy. As this is always a very difficult decision, counselling must be non-directive, ensuring that the parents are well informed and then fully supported in their decision, either way. Although screening should be considered in all pregnancies, this may not be possible throughout South Africa. However, women with high-risk pregnancies must be referred. With modern ultrasound technology and expertise, in most cases there is simply no excuse for missing the diagnosis. For babies born with SBM, the key to management is awareness and early diagnosis of the more common problems facing them.

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This includes immediate resuscitation and referral for closure of the open lesion within 24 hours (which must surely be achievable in South Africa), timely treatment of hydrocephalus, early urological management to prevent renal damage, and early developmental assessment to ensure appropriate educational support. While the majority of patients have normal intelligence, there is great variability in the needs and outcomes of this group. Long-term management includes the expertise of a wide range of other professionals, including orthopaedic surgeons (with the help of orthotists), stomatherapists, physiotherapists, occupational therapists, psychologists, and social workers. The role of the radiologist must not be overlooked, especially with regard to radiation exposure â&#x2C6;&#x2019; given the enormous number of investigations that may be required. Care is best offered in the context of a multidisciplinary clinic, but regrettably this is seldom the case and management is often fragmented, both in private practice and the state sector. A primary care doctor who ensures holistic care is of great value. With increasing long-term survival there has been greater appreciation of the challenges faced by adolescents with neurodisablity, and more attention is now paid to transition of care into adulthood. Given the complexity of this condition, it is hardly surprising that it has stimulated numerous ethical debates with implications that go beyond the spina bifida population, as exemplified by Lorberâ&#x20AC;&#x2122;s selection criteria in the UK, the Baby Jane Doe case in the USA, and the Groningen protocol for euthanasia of newborns in the Netherlands. These approaches may be contrasted to the recent enthusiasm for fetal surgery, which in turn has generated further dilemmas. When all is said and done, managing these patients well is very gratifying. Despite the many problems they face, hope and support enable a rewarding and meaningful life. Graham Fieggen Guest editor graham.fieggen@uct.ac.za S Afr Med J 2014;104(3):212. DOI:10.7196/SAMJ.8094

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CONTINUING MEDICAL EDUCATION

REVIEW

Spina bifida: A multidisciplinary perspective on a many-faceted condition G Fieggen,1 BSc (Med), MB ChB, MSc, MD, FCS (SA); K Fieggen,2 MB ChB, FCPaed (SA), Cert Med Genet (SA); C Stewart,3 MB ChB, MMed, MA, FCOG (SA); L Padayachy,1 MB ChB, MMed, FCNeurosurg (SA); J Lazarus,4 MB ChB, MMed Urology, MA, FCUrol (SA); K Donald,5 MB ChB, MPhil, FCPaed (SA), MRCPCH (UK), Cert Paed Neurology (SA); S Dix-Peek,6 MB ChB, MMed, FCOrth (SA); Z Toefy,7 RN; A Figaji,1 MB ChB, MMed, PhD, FCNeurosurg (SA) Division of Neurosurgery, University of Cape Town and Spina Bifida Clinic, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa Division of Medical Genetics, University of Cape Town and Spina Bifida Clinic, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa 3 Department of Obstetrics and Gynaecology, University of Cape Town and Fetal Medicine Unit, Groote Schuur Hospital, Cape Town, South Africa 4 Division of Urology, University of Cape Town and Spina Bifida Clinic, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa 5 Division of Developmental Paediatrics, University of Cape Town and Spina Bifida Clinic, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa 6 Division of Orthopaedic Surgery, University of Cape Town and Spina Bifida Clinic, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa 7 Spina Bifida Clinic, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa 1 2

Corresponding author: G Fieggen (graham.fieggen@uct.ac.za)

Open spina bifida or myelomeningocele (SBM) is the most common birth defect involving the central nervous system, second only in incidence to congenital cardiac disease. Outcomes in this disorder were poor until the mid-20th century, when modern neurosurgical techniques (closing the lesion and treating hydrocephalus) and treatment for the neuropathic bladder addressed the major causes of mortality, although SBM may still be poorly treated in the developing world. Initial management – or mismanagement – has a profound impact on survival and long-term quality of life. S Afr Med J 2014;104(3):213-217. DOI:10.7196/SAMJ.8079

Myelomeningocele is the most complex congenital abnormality compatible with long-term survival. − David McLone Open spina bifida or myelomeningocele (SBM) is the most common birth defect involving the central nervous system, second only in incidence to congenital cardiac disease. Although recognised since antiquity, with anthropological relics depicting affected individuals and suggestive descriptions in the writings of Hippocrates and Galen, the first definitive description was by the Dutch clinician Peter van Forest in 1610. His compatriot, Nicholas Tulp, famous for Rembrandt’s ‘The anatomy lesson of Dr Tulp’, introduced the term spina bifida 31 years later, along with the first clear illustration of the condition.[1] Despite various attempts at treatment, outcome remained very poor until the mid-20th century. The development of modern

neurosurgery (closure of the lesion and treatment of hydrocephalus) and the advent of treatment for the neuropathic bladder addressed the major causes of mortality. More recently, advances in antenatal diagnosis and perhaps, most important of all, successful prevention strategies through the use of preconception folic acid, led to a fall in the number of new cases. SBM is, however, still common throughout much of the developing world, and many patients remain poorly treated. There are few conditions where initial management (or mismanagement) has such a profound impact on survival and long-term quality of life. Appreciation of the value of various specialties working together led to the establishment of multidisciplinary spina bifida clinics. One such

Dyna Cefpodoxime Suspension 50 / 100 ml. Each 5 ml of suspension contians cefpodoxime proxetil equivalent to 40 mg cefpodoxime. (Preservative: Sodium benzoate 0,2 % m/v). Contains aspartame 20 mg/5 ml. Reg. No. / Nr.: RSA S4 43/20.1.1/1084 NAM NS3 12/20.1.1/0173. Dyna Cefpodoxime 100 mg tablets. Each film coated tablet contains cefpodoxime proxetil equivalent to cefpodoxime 100 mg. Reg.No. / Nr.: RSA S4 44/20.1.1/0012 NAM NS3 12/20.1.1/0058.For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority.

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clinic was established at Red Cross War Memorial Children’s Hospital in 1967 (J C de Villiers − personal communication). This review, and the accompanying articles written by members of this clinic, aims to highlight the key challenges in management, demonstrate the value of multidisciplinary care, and emphasise the need to offer better treatment in South Africa (SA) in order that these children and adults can achieve their true potential.

birth (Fig. 1). This is invariably accompanied by a range of other central nervous system abnormalities (Fig. 2). Spina bifida is part of a spectrum of conditions referred to by the term dysraphism, which encompasses a range of conditions (Table 1) that result from an embryological error, usually abnormal closure of the neural tube.

Terminology

Virtually the entire central nervous system develops from ectoderm, with the neuro-ectoderm thickening into a neural plate which then folds over to close in the midline through the process of primary neurulation.[2] This process occurs extremely early in embryonic life (completed by day 28) and errors lead to neural tube defects (NTDs). Presenting as either anencephaly at the rostral (brain) end or myelomeningocele at the caudal (spinal) end, the incidence of NTDs ranges from 0.77 to 6.1/1 000 live births in SA, with higher incidences reported in rural areas.[3] The lower sacral segments form through the more complex process of caudal regression or secondary neurulation and errors result in various forms of spina bifida occulta, such as caudal lipoma.

The term spina bifida is used to refer to a range of different conditions. The simplest form is incomplete closure of the posterior elements of one of the lower lumbar or sacral vertebrae. This is very common (around 10% of the population) and incidentally noted on X-ray, but seldom of any clinical relevance. Spina bifida occulta or closed spina bifida refers to a range of rare but characteristic congenital abnormalities involving the lower spinal cord, such as a lipoma, myelocystocele or split cord; usually there is an overlying cutaneous abnormality (such as a subcutaneous lipoma, naevus or hairy patch) and pathophysiologically the spinal cord is tethered and vulnerable. Spina bifida aperta or open spina bifida is almost always a myelomeningocele, where the spinal cord and meninges are exposed on the dorsal surface of the infant at

Embryology and prevention

Enlarged ventricles

Cerebellar vermis Syrinx

Myelomeningocele Open spinal cord Bone (vertebrae)

Fig. 1. Clinical photograph showing a typical myelomeningocele. The open spinal cord is readily appreciated, with the midline fold continuous rostrally with the central canal of the spinal cord. Leaking CSF can also be seen.

Fig. 2. Diagram showing sagittal impression of the myelomeningocele and Chiari II malformation.

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Table 1. Classification of dysraphism Cranial Open

Anencephaly (and occasional encephaloceles)

Closed

Encephalocele; cranial dermal sinus

Spinal Open

Spina bifida aperta: myelomeningocele/meningomyelocele

Closed

Spina bifida occulta

One of the most effective primary prevention strategies ever described is the prevention of NTDs by administration of folic acid prior to conception, a strategy that is supported by evidence from a number of prospective randomised trials in various countries. [4] One of the public health strategies this has led to is food fortification, which was successfully implemented in SA.[5] The mechanism by which folate supplementation reduces the incidence of NTDs is unknown − genetic factors clearly play an important role and the aetiology can truly be described as multifactorial.

Antenatal diagnosis

Although maternal serum alpha-fetoprotein remains a useful screening investigation, the focus has shifted to prenatal ultrasound screening, which should detect more than 90% of cases.[6] Performing an anatomical scan at 18 - 23 weeks requires appropriate training as a level 3 scanner, since the consequences of missing the diagnosis can be very costly, as evidenced by the magnitude of ‘wrongful birth’ medicolegal claims. An antenatal diagnosis of SBM should be followed by nondirective counselling, allowing the family to choose between terminating or continuing the pregnancy. Although a prospective trial showed some benefit following intrauterine closure of SBM,[7] there is still some scepticism about the true benefit of this intervention which is not yet available in SA. Anyone wishing to consider this option is encouraged to contact a paediatric neurosurgeon for advice at the earliest possible opportunity. At this stage, the greatest priority in our country is to

optimise primary prevention and ensure early prenatal diagnosis.

Perinatal management

For those parents who elect to continue with the pregnancy, decisions around mode of delivery should be based on obstetric criteria, although for most SBM babies born in SA the diagnosis is not made antenatally. Either way, it is obvious upon inspection of the newborn infant’s back. The key imperatives are: • initial resuscitation, taking particular care over the airway because of the potential for brainstem dysfunction • appreciation of the fact that the lesion on the back represents the open and exposed spinal cord, which must be kept clean and sterile, ideally protected by a salinesoaked gauze dressing • evaluation of the anatomical level of the lesion and correlating this with the neurological level (motor function in lower limbs). The definitive treatment is surgical closure before the lesion is colonised, ideally within 24 hours but definitely within 72 hours. The goal of surgery is to close the dura mater and skin over the spinal cord to prevent central nervous system infection, but this does not reverse the congenital neurological deficit. Although a neurosurgeon should be the practitioner best trained to perform this surgery, many of these children are still managed by other surgical specialists in SA and other developing countries. Some authors recommend administration of intravenous antibiotics if the lesion is

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leaking cerebrospinal fluid (CSF), as the latter may increase the risk of ventriculitis.[8] The use of antibiotics must not engender a false sense of security, and closure should still be performed as soon as possible as this is the most effective antimicrobial strategy. In developing countries, many of these children present too late for primary closure and if the back is kept clean, the lesion may epitheliase over a period of weeks. Surgery is usually still indicated in patients who present late, as the mass tends to enlarge with time. Postoperatively, the infant is nursed flat for 5 days to reduce pressure on the wound to avoid a CSF leak, oral feeds (ideally breastfeeding) are commenced, watching for evidence of bulbar dysfunction, and the head circumference is measured daily to monitor for hydrocephalus. The parents should be counselled by a social worker with regard to the imperative for folate prophylaxis and assisted in applying for a Care Dependency grant. A high incidence of latex allergy has been reported in SBM patients, but this was not borne out in a study in Cape Town, perhaps owing to a longstanding policy of avoiding the use of latex products in these patients from the outset.[9]

Other neurosurgical issues

Although only a minority of children born with SBM have hydrocephalus that is apparent at birth, most will go on to develop progressive hydrocephalus that requires treatment. This may entail insertion of a ventriculoperitoneal shunt, or in some centres, endoscopic surgery − third ventriculostomy,[10] possibly with choroid plexus coagulation to reduce CSF production.[11] With SBM, what one sees on the back is the tip of the iceberg as these patients invariably have a Chiari II malformation (often incorrectly referred to as the ArnoldChiari malformation), typical features of which are cerebellar herniation through the foramen magnum and brainstem distortion (Fig. 2). This is, however, a pancerebral malformation as the entire central nervous

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system is involved.[12] The onset of bulbar symptoms often led to posterior decompression surgery in times past, but recognition that early brainstem dysfunction is not due to cerebellar herniation alone has led to a substantial decrease in this procedure.[13] There are various possible causes for neurological deterioration in someone with a history of myelomeningocele, including shunt malfunction (first and foremost), Chiari II malformation, syringomyelia, progressive scoliosis and secondary tethering of the spinal cord. The last may present with neurological deterioration (such as new bladder symptoms or worsening gait) or back pain.

Urological

Bladder dysfunction is always present in SBM, resulting in a clinical picture referred to as the neurogenic or neuropathic bladder. This results in urinary incontinence as well as progressive renal damage due to recurrent urinary tract infections and dynamic factors such as high bladder storage pressures and secondary vesico-ureteric reflux. These complications can often be detected at primary care level by regular clinical assessment coupled with urinalysis and culture, serum chemistry and simple radiological studies where appropriate. More complex investigations such as invasive urodynamic studies are essential in evaluating function and planning management, but regrettably these are rarely available in SA. The primary goals of management are to normalise bladder pressure and achieve social continence. The cornerstone of management is clean intermittent catheterisation, which in our experience can be successfully used even under adverse socio-economic circumstances. This is often supplemented by anticholinergic drugs (either oral or intravesical) and surgery when conservative management fails.[14]

Developmental

Although the focus readily falls on the obvious spinal abnormality and its direct consequences, it is important to remember that SBM is invariably accompanied by the Chiari II malformation, a pancerebral malformation, as discussed above. To this may be added the effects of hydrocephalus and its management, epilepsy, endocrine dysfunction, repeated hospitalisations and other medical complications. Despite this, the majority of SBM patients have an intelligence quotient (IQ) in the average to low average range,[15] but in some IQ is in the high range. SBM is a complex neurodevelopmental disorder with a wellcharacterised cognitive pattern.[16] The value of early awareness of the strengths and weaknesses of the individual child is obvious. While an inclusive education policy is in place in SA, few mainstream schools in the public sector are able to fully meet the needs of these children, which include learning support, physical exercise such as sport, and accessible classrooms, toilets and other facilities.

Orthopaedic

Orthopaedic surgeons have much to offer these patients, either in correcting spinal deformity or optimising mobility. Spinal deformity tends to occur only in paraplegic patients and needs surgical correction if progressive. The neurological level, which is defined as the lowest motor segment with at least MRC grade 3/5 power, is the most important factor in determining walking potential and also determines the pattern of lower limb deformities.[17] Virtually all SBM patients require treatment of foot deformities with the goal of obtaining a plantigrade, mobile and braceable foot and avoiding trophic ulceration.[18] Deformities, including equinus, club foot, valgus and cavovarus, can be corrected by a range of operations. Trophic ulcers are due to a stiff plantigrade foot or a neglected injury in an insensate foot; treatment often requires rotating a flap to reconstitute normal skin and fat pad as well as removing the bony prominence under the ulcer. If inadequately treated, trophic ulcers lead to significant morbidity and can result in amputation. Other complications to look for include Charcot arthropathy and fractures that can present with swelling, warmth and oedema, mimicking cellulitis or septic arthritis.

Long-term quality of life

With early closure and effective treatment of common complications such as hydrocephalus and neuropathic bladder, the majority of these patients survive into adulthood â&#x2C6;&#x2019; a marked contrast to the situation 50 years ago when survival was around 10%. Most modern series report survival into adulthood of well over 50%,[19] although there remains a troubling risk of death in adults.[21] The focus now shifts to transition of care through adolescence and addressing the issues that impair quality of life, in addition to all the medical domains listed above. The neuropathic bladder is usually accompanied either by faecal incontinence or chronic constipation, which may necessitate daily bowel washouts. A relatively neglected area is that of sexuality and parenthood among adults with SBM.[21] Although IQ scores suggest a good prognosis, this tends to overestimate the capacity for social integration.[22] Various support groups and other organisations have evolved over the years, many of which work through the International Federation for Spina Bifida and Hydrocephalus (IFSBH).

Closed spinal dysraphism

Although folate prophylaxis and antenatal diagnosis have led to a fall in the number of children born with SBM, this has not affected the number of children born with closed dysraphism who have many of the same urological and orthopaedic challenges, but do not have hydrocephalus, Chiari II malformation or the cognitive issues typical of SBM. Although a magnetic resonance imaging (MRI) scan is usually required to make the diagnosis, it is usually apparent to the

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astute clinician given the almost invariable occurrence of an overlying cutaneous lesion. Missing the diagnosis may result in progressive neurological deterioration, which seldom improves following surgery.

Conclusion

SBM is a complex disorder that requires input from many different health professionals. The rewards for managing these children well are substantial as they can lead full and productive lives. Although there is no doubt about the value of a multidisciplinary clinic, the family practitioner, who co-ordinates care, is essential. With the resources available in SA, there is little doubt that these children deserve better care than they often receive. References 1. Goodrich J. A historical review of the surgical treatment of spin bifida. In: Özek M, Cinalli G, Maixner W, eds. Spina bifida: Management and Outcome. Milan: Springer, 2008;3-17. [http://dx.doi. org/10.1007/978-88-470-0651-5_1] 2. Wallingford J, Niswander L, Shaw G, Finnell R. The challenge of understanding and preventing neural tube defects. Science 2013;339:1222002. [http://dx.doi.org/10.1126/science.1222002] 3. Robertson H, Steyn N, Venter P, Christianson A. Neural tube defects and folic acid − a South African perspective. S Afr Med J 1997;87:928-931. 4. De-Regil LM, Fernández-Gaxiola AC, Dowswell T, Peña-Rosas JP. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database Syst Rev 2010;10:CD007950. [http://dx.doi.org/10.1002/14651858.CD007950.pub2.-A] 5. Sayed A, Bourne D, Pattison R, Nixon J, Henderson B. Decline in the prevalence of neural tube defects following folic acid fortification and its cost-benefit in South Africa. Birth Defects Research (Part A) 2008;82:211-216. [http://dx.doi.org/10.1002/bdra.20442] 6. Boyd P, Devigan C, Khoshnood B, et al. Screening policies in Europe for structural malformations and chromosome anomalies, and their impact on detection and termination rates for neural tube defects and Down’s syndrome. Br J Obstet Gynaecol 2008;115:689-696. [http://dx.doi.org/10.1111/j.14710528.2008.01700.x]

7. Adzick N, Thom E, Spong C, et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 2011;364:993-1004. [http://dx.doi.org/10.1056/NEJMoa1014379] 8. Boop F, Teo C. The perinatal management of the child born with a myelomeningocele. In: Loftus CE, ed. Neurosurgical Emergencies. Vol. II. Chicago: American Association of Neurological Surgeons, 1994:335-345. 9. Johar A, Lim D, Arif M, et al. Low prevalence of latex sensitivity in South African spina bifida children in Cape Town. Pediatr Allergy Immunol 2005;16:165-170. [http://dx.doi.org/10.1111/j.13993038.2005.00221.x] 10. Teo C, Jones R. Management of hydrocephalus by endoscopic third ventriculostomy in patients with myelomeningocele. Pediatr Neurosurg 1995;25:57-63. [http://dx.doi.org/10.1159/000121098] 11. Warf B, Campbell J. Combined endoscopic third ventriculostomy and choroid plexus cauterization as primary treatment of hydrocephalus for infants with myelomeningocele: Long-term results of a prospective intent-to-treat study in 115 East African children. J Neurosurg Pediatr 2008;2:310-316. [http://dx.doi.org/10.3171/PED.2008.2.11.310] 12. Miller E, Widjaja E, Blaser S, Dennis M, Raybaud C. The old and the new: Supratentorial MR findings in Chiari II malformation. Childs Nerv Syst 2008;24:563-575. [http://dx.doi.org/10.1007/s00381-0070528-x] 13. Gilbert J, Rorke L, James H, Jones K, Chernoff G. The pathological basis for the failure of surgery to relieve the symptomatic Arnold-Chiari malformation. Concepts Pediatr Neurosurg 1988;8:70-75. 14. Verpoorten C, Buyse G. The neurogenic bladder: Medical treatment. Pediatr Nephrol 2008;23:717-725. [http://dx.doi.org/10.1007/s00467-007-0691-z] 15. Barf H, Verhoef M, Jennekens-Schinkel A, Post M, Gooskens R, Prevo A. Cognitive status of young adults with spina bifida. Dev Med Child Neurol 2003;45:813-820. [http://dx.doi. org/10.1111/j.1469-8749.2003.tb00896.x] 16. Fletcher J, Ostermaier K, Cirino P, Dennis M. Neurobehavioral outcomes in spina bifida: Processes versus outcomes. J Pediatr Rehabil Med 2008;4:311-324. 17. Hoffer M, Feiwell E, Perry R, Perry J, Bonnett C. Functional level in patients with myelomeningocele. J Bone Joint Surg Am 1973;55:137-148. 18. Maynard M, Weiner L, Burke S. Neuropathic foot ulceration in patients with myelodysplasia. J Pediatr Orthop 1992;2:786-788. 19. Bowman R, McLone D, Grant D, Tomita T, Ito J. Spina bifida outcome: A 25-year prospective. Pediatr Neurosurg 2001;34:114-120. [http://dx.doi.org/10.1159/000056005] 20. Jernigan S, Berry J, Graham D, et al. Risk factors of sudden death in young adult patients with myelomeningocele. J Neurosurg Pediatr 2012;9:149-155. [http://dx.doi.org/10.3171/2011.11. PEDS11269] 21. de Vylder A. Sexuality, sex, pregnancy, and spina bifida. In: Özek M, Cinalli G, Maixner W, eds. Spina Bifida: Management and Outcome. Milan: Springer, 2008:397-404. [http://dx.doi.org/10.1007/978-88470-0651-5_31] 22. Vinchon M, Dhellemmes P. The transition from child to adult in neurosurgery. Adv Tech Stand Neurosurg 2007;32:3-24. [http://dx.doi.org/10.1007/978-3-211-47423-5_1]

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ARTICLE SUMMARY

Aetiology and antenatal diagnosis of spina bifida K Fieggen,1 MB ChB, FCPaed (SA), Cert Med Genet (SA); C Stewart,2 MB ChB, MMed, MA, FCOG (SA) 1 2

Division of Medical Genetics, University of Cape Town, South Africa Department of Obstetrics and Gynaecology, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa

Corresponding author: K Fieggen (karen.fieggen@uct.ac.za)

Terminology and definitions

Spinal neural tube defects (NTDs) (spina bifida) result from failure of neural tube closure, which normally occurs at 15 - 28 days after conception. The commonest type is a meningomyelocele that contains meninges, cerebrospinal fluid (CSF), spinal cord and/or nerve roots.

Epidemiology and aetiology

Birth prevalence figures for spina bifida vary, but are around 0.1%. In South Africa, the reported incidence ranges from 0.77 to 6.1/1 000 live births, with higher incidences in rural areas. Isolated NTDs are typically true multifactorial disorders reflecting a combination of genetic and environmental influences. The recurrence risk for a woman who has had a single child with an NTD is 2 - 5% and increases if more than one child is affected.

Genetic factors

NTDs can be associated with chromosomal abnormalities and Mendelian single-gene disorders. These ‘syndromic’ cases must be recognised for accurate prognosis and counselling. Many genetic factors contribute to the development of NTDs, but their precise role remains poorly elucidated.

Environmental factors Folic acid

Periconceptional supplementation with folic acid reduces the birth incidence of NTDs by as much as 70%. Food is fortified with folate in South Africa, but this should be complemented with folate-rich foods and/or additional supplementation.

Teratogens and risk factors

Anti-epileptic drugs (AEDs) are the most important class of drugs associated with NTDs. Valproic acid confers the highest risk. Change of therapy during established pregnancy is not recommended, but prepregnancy planning and counselling are invaluable. Epilepsy should be controlled with the lowest dose of the fewest drugs in young women, and folic acid supplementation is recommended.

Other important risk factors include poor nutrition, maternal diabetes, obesity and pyrexia. Epidemiological associations include geographical regions, seasonal changes, ethnicity, socio-economic status and parity.

Antenatal diagnosis

Antenatal diagnosis of NTDs is possible in >90% of cases screened, using a detailed anatomy scan at 18 - 23 weeks. The spine is examined systematically in the sagittal, coronal and transverse planes. Adequate visualisation is dependent on the machine, the patient, the position of the fetus and the experience of the operator. Direct diagnosis of a spinal NTD is often difficult and more commonly it is suspected when intracranial features co-exist. Prognostic factors include the level of the lesion and its size, with the former being the most important prognosticator of motor function. Severity of ventriculomegaly has prognostic value for intellectual outcome. Neither the absence of talipes, nor the presence of fetal leg movement, predicts normal motor function. If the lesion is associated with other abnormalities, chromosomal analysis should be considered. Maternal serum alpha-fetoprotein is raised in open spina bifida. Alpha-fetoprotein has an important role in screening.

Counselling and further management

After an antenatal diagnosis of NTD, parents need to have accurate, nondirective counselling about the diagnosis, prognosis and implications for the future, as well as options for further management, including termination of pregnancy.

Prevention

Pre-pregnancy advice to all women should include nutritional information, family planning, teratogen avoidance, optimal control of risk factors and information on periconceptional folic acid supplementation.

Conclusion

Spina bifida remains a common multifactorial birth defect in South Africa, with the potential for prevention and antenatal diagnosis. S Afr Med J 2014;104(3):218. DOI:10.7196/SAMJ.8039

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ARTICLE SUMMARY

Perinatal management of spina bifida L Padayachy,1 MB ChB, MMed, FCNeurosurg (SA); D Ochieng’,2 MB ChB Division of Neurosurgery, University of Cape Town and Spina Bifida Clinic, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa 2 Division of Neurosurgery, University of Cape Town, South Africa 1

Corresponding author: L Padayachy (l.padayachy@uct.ac.za)

The timing of diagnosis is the main determinant of the management of patients with myelomeningocele (MMC) – whether ante- or postnatally. Antenatal diagnosis is made using a combination of maternal serum alpha-fetoprotein (MSAFP) measurement, fetal ultrasonography and, where necessary, amniocentesis. Routine antenatal screening should, in 2014, detect most cases of MMC before delivery. MMC is a complex diagnosis, which will probably overwhelm the family – therefore good counselling is essential. Some parents may decide to terminate the pregnancy; be aware that this decision may be strongly influenced by the advice of the treating doctor. With appropriate medical care, most patients with this condition can enjoy a good quality of life. The current accepted mortality in patients with MMC is about 25%, with 15% dying in the first 5 years. Once the parents choose to continue with the pregnancy, a decision has to be made on appropriate obstetric management and mode of delivery. The evidence suggests that there is no difference in the long-term ambulation status of infants with MMC who went through labour than those delivered by elective caesarean section. The major priorities immediately after birth are protecting the open lesion to prevent infection and detecting brainstem dysfunction related to the Chiari II malformation. Immediate assessment and management should include ABCs, APGAR score, and adequate resuscitation – looking especially for signs of brainstem involvement. The lesion is evaluated for size, level and content and assessed for any associated congenital abnormalities (vertebral defects, anal atresia, cardiac defects, tracheo-oesophageal fistula, renal anomalies, and limb abnormalities (VACTERL syndrome)). The lesion is then covered with a warm saline-soaked dressing. All MMCs are open lesions. The most effective antimicrobial treatment is early surgical closure. However, some authorities believe that if there is leakage of cerebrospinal fluid (CSF) the lesion should be considered ‘ruptured’ and recommend antibiotic cover because of the potential for infection, covering Gram negatives and anaerobes. Thermoregulation is a major issue in the immediate postnatal period and the infant should be nursed prone in an incubator.

Most infants will breastfeed, but if there are signs of swallowing dysfunction or aspiration, a nasogastric tube is passed. Once stable, further neurological evaluation includes measuring the head circumference, assessing the anterior fontanelle to check for hydrocephalus, ascertaining the highest level of motor function by checking for spontaneous movement of the lower limbs, assessing anal tone by looking at buttock muscle bulk and whether or not the anus is patulous, and examining for signs of Chiari II malformation. Refer for neurosurgical closure within 24 hours – at most 48 hours because of the risk of infection if closure is delayed. Surgical management is divided into three phases: closing the MMC; treating the associated hydrocephalus; and long-term surgical management. At the last stage, further family counselling should take place to evaluate the social and financial implications. Bladder function should be evaluated by a urologist at an early stage. The infants are usually incontinent, but acute urinary retention has been seen, particularly after insertion of a ventriculoperitoneal shunt (VPS). Intrauterine fetal surgery has shown some benefit by decreasing the rate of shunt dependence at 1 year of age, by reducing fetal or neonatal death, and by improving motor outcomes. However, there are substantial risks to mother and fetus and appropriate selection criteria and timing remain contentious. Hydrocephalus may be apparent early, or may present later after closure of the MMC. If obvious at birth, an external ventricular drain can be inserted at the same time as closure of the MMC. Hydrocephalus can be monitored during this period with daily head circumference measurement and ultrasound assessment of ventricular size. Most MMC patients need a VPS. Long-term surgical management is a multidisciplinary task. Follow-up occurs through childhood and often into adulthood. The perinatal management of children born with MMC remains a challenging task, with early identification and timeous referral to specialist centres having a significant impact on survival.

S Afr Med J 2014;104(3):219. DOI:10.7196/SAMJ.8038

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ARTICLE SUMMARY

The paediatric neuropathic bladder J Lazarus, MB ChB, MMed Urology, MA, FCUrol (SA) Division of Urology, Red Cross War Memorial Children’s Hospital, University of Cape Town, South Africa Corresponding author: J Lazarus (j.lazarus@uct.ac.za) Paediatric neuropathic bladder dysfunction can cause irreversible renal damage and urinary incontinence. This condition is usually caused by a congenital neural tube defect. The majority of affected children can be successfully managed with the standard medical treatment of clean intermittent catheterisation and anticholinergic medication (typically oxybutynin). A small subset of patients experience severe side-effects or insufficient suppression of detrusor overactivity on oral oxybutynin and require alternative medical or surgical management.

Introduction

The pathophysiology of the neurogenic bladder can be generalised as being due to a spinal reflex arc that occurs when the bladder becomes autonomous from higher centres. Paediatric neurogenic bladder dysfunction is most commonly caused by a congenital neural tube defect, such as myelomeningocele (MMC) or tethered spinal cord syndrome. Alternatively, it may be caused by traumatic spinal cord injury, transverse myelitis or anorectal malformation. The standard conservative management of paediatric neurogenic bladder comprises oral anticholinergics and clean intermittent catheterisation.

Assessment

Many children with neurogenic bladder have urinary incontinence and the potential for progressive renal damage because of high bladder storage pressures, secondary vesico-ureteric reflux and recurrent urinary tract infections (UTIs). Assessment is aimed at identifying children who are at risk of renal damage, and should include a thorough medical history, bladder diary, neurological examination, and urinalysis and culture to identify infection. Serial renal ultrasonography allows monitoring of the renal tract, and cystography can be used to reveal the configuration of the bladder and detect vesico-ureteric reflux that occurs as a secondary phenomenon. Nuclear imaging, glomerular filtration rate estimation and, at a later stage, a serum creatinine level can be used to assess kidney function. Urodynamic assessment is essential for the diagnosis and prognosis of paediatric neurogenic bladder. Urodynamic studies (UDSs) – functional

studies of the lower urinary tract – evaluate the storage and emptying functions of the bladder. UDSs can be simple and non-invasive (bladder diary and flow rate) or invasive (cystometrogram and video-urodynamics).

Management

The primary goals of paediatric neurogenic bladder management are to normalise vesical pressure and achieve social continence. In addition, 58% of children with untreated MMC exhibit progressive renal deterioration by 3 years of age; therefore the early treatment of these children can also improve renal function. Oral anticholinergics, such as oxybutynin, block cholinergic receptors, causing relaxation of the bladder’s smooth muscle, and are well established as first-line pharmacotherapeutic agents in adults and children. The majority of children with neurogenic bladder (70 - 90%) are effectively managed with oral anticholinergics and clean intermittent catheterisation, avoiding the need for surgical intervention, such as augmentation cystoplasty or bladder outlet surgery. The limitations of oral anticholinergic use are the associated side-effects and a subset of children failing to adequately respond to this therapy. Inadequate responses are characterised by ongoing urinary incontinence, which can reduce quality of life and cause progressive upper-tract dilatation and loss of renal cortical mass. Side-effects of anticholinergic agents include dry mouth, blurred vision, constipation, facial flushing and dizziness. For children who are not controlled on anticholinergics and clean intermittent catheterisation, other options need to be explored. They may have persistent hydronephrosis, new renal scarring, vesico-ureteric reflux, persistent incontinence or recurrent UTIs. Salvage options include intravesical oxybutynin, botulinum toxin (Botox) injection into the bladder or surgical alternatives including augmentation cystoplasty.

Conclusion

Children with neuropathic bladders that result from MMC require lifelong monitoring and treatment, ideally in a multidisciplinary environment. South African medical services need to render appropriate care to this vulnerable group of patients. S Afr Med J 2014;104(3):220. DOI:10.7196/SAMJ.8046

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FOR FURTHER PRODUCT INFORMATION CONTACT PHARMA DYNAMICS AT P O BOX 30958, TOKAI, 7966 TEL: 021 707 7000 • FAX: 021 7015898 www.pharmadynamics.co.za CUSTOMER CARE LINE: 0860-PHARMA (742 762)

March 2014, Vol. 104, No. 3

2014/02/25 1:32 PM

CONTINUING MEDICAL EDUCATION

ARTICLE SUMMARY

An approach to the developmental and cognitive profile of the child with spina bifida N Ramsundhar, MB ChB, FCPaed (SA); K Donald, MB ChB, MPhil, FCPaed (SA), MRCPCH (UK), Cert Paed Neurology (SA) Division of Developmental Paediatrics, University of Cape Town and Spina Bifida Clinic, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa Corresponding author: K Donald (kirsty.donald@uct.ac.za) Open spina bifida or myelomeningocele (MMC) is the most common congenital central nervous system defect, resulting from primary neurulation failure. The spinal abnormalities and their consequences are well known. It is associated with a wide range of developmental abnormalities of the brain, resulting in a complex neurodevelopmental disorder with great phenotypic heterogeneity. The cognitive deficits are less well characterised and tend to be under-recognised, especially in resource-limited environments, and may have a significant impact on the lives of children with this disorder.

Brain findings

The brain anomalies described in open spina bifida are varied and contribute to the complex phenotypic outcomes in neurocognition and behaviour. Closed forms of spina bifida seldom have brain anomalies; therefore the term spina bifida refers to patients with MMC. Several factors have an impact on the severity and type of cognitive outcome. The strongest association with cognitive dysfunction is the presence of hydrocephalus and its complications, found in 80 - 90% of cases. This typically results in attenuation of cerebral white matter, particularly in the posterior aspects of the brain, which is important in the development of spatial skills. Complications of treatment, such as shunt obstruction or shunt infection with ventriculitis, may have a dramatic impact on neurocognitive outcome. The Chiari II malformation is invariably present in patients with a MMC. Although the main focus is on malformation of the hindbrain and the cerebellum, it is a pancerebral malformation affecting the entire central nervous system. Partial dysgenesis of the corpus callosum is another commonly associated abnormality in spina bifida MMC. The long-term neurocognitive outcome may also be complicated by epilepsy (and its treatment), endocrine problems and the impact of other medical problems that may result in repeated hospitalisations. Spina bifida patients from resource-poor environments are at higher risk of poor cognitive outcomes, and spinal cord lesions above the level of T12 correlate inversely with cognitive ability.

Cognitive profile

Children with spina bifida usually have higher verbal than performance intelligence quotient (IQ) scores. Specific performance IQ deficits include weaknesses in motor, visual-spatial and mathematical tasks. Total scores tend to be less useful than more specific subscales as there are frequently significant discrepancies, even within domains. The early identification of children with spina bifida who have developmental problems is important for appropriate intervention and support. Optimal care involves a multidisciplinary team approach. Standardised developmental screening and more formal assessments should ideally be performed without delay to determine the child’s level of functioning and his/her weaknesses and strengths. Although many therapeutic interventions are available, there is currently no evidence-based approved therapy for children with learning disabilities in the performance domain. Ideally, development should be regularly reviewed for monitoring the response to therapies, and to ensure optimal health. The prevention of complications will reduce hospitalisations, which are associated with a negative impact on development. Even in the absence of hydrocephalus, children with spina bifida should undergo at least one formal neuro-imaging study to rule out other associated brain abnormalities. Ideally, a developmental paediatrician should monitor the child’s neurobehavioural and developmental progress and assist in determining their suitability for mainstream or special education. In South Africa, the decision regarding the best placement of the child generally requires early liaison with the regional educational psychologist serving the local department of education. Although an inclusive education policy is in place in South Africa, there are few public sector mainstream schools that can accommodate children who require any significant degree of medical or physical support. The role of the developmental and rehabilitation team, as well as active planning and advocacy for schooling options, are critical elements in facilitating their optimal outcome. S Afr Med J 2014;104(3):221. DOI:10.7196/SAMJ.8048

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FOR FURTHER PRODUCT INFORMATION CONTACT PHARMA DYNAMICS AT P O BOX 30958, TOKAI, 7966 TEL: 021 707 7000 • FAX: 021 7015898 www.pharmadynamics.co.za CUSTOMER CARE LINE: 0860-PHARMA (742 762)

March 2014, Vol. 104, No. 3

2014/02/25 1:32 PM

PULSE

Launch of Diaphage

Cipla announces the launch of Diaphage (metformin), a new addition to its diabetic portfolio. Metformin is now well established as the primary ‘anchor’ oral agent for the management of diabetes. Diaphage is indicated for type 2 diabetes mellitus when diet has failed, and especially if the patient is overweight. Diaphage can be given alone as initial therapy or in combination with other oral antidiabetic medicines or injectable insulin. Diaphage is available in all three strengths (500, 850 and 1 000 mg) and affords patients a saving of up to 39% v. the originator product. Initially one 500 mg tablet is taken 2 - 3 times a day with/or after food. After 10 - 15 days, the dose should be adjusted or increased to 850 mg/1 000 mg twice daily. Increasing the dose gradually can help to improve gastrointestinal tolerability. For full prescribing information, refer to the package insert.

WDGMC celebrates 10 years of medical care and training

Wits Donald Gordon Medical Centre (WDGMC), South Africa (SA)’s only private academic teaching hospital, celebrated 10 years of medical training and care and unveiled the latest refurbishments to the hospital at an event held on 27 November 2013. ‘WDGMC has come a long way since its inauguration in the early 2000s. We have successfully trained over 30 specialists, the majority of whom are now utilising their skills in the public sector,’ said Dr Sue Tager, CEO of WDGMC. ‘We also launched the first living-donor liver transplant programme in SA earlier this year, with several successful procedures. As we continue to train medical professionals in this ground-breaking procedure, we expect it to have a significant impact on the number of people on the waiting lists for liver transplants in the years ahead.’ WDGMC began when Dr Max Price, former Dean of the Faculty of Health Sciences at the University of the Witwatersrand, and a group of concerned doctors in private practice perceived that specialist and sub-specialist medicine was under threat as a result of the shift from specialised medicine to primary medicine in the health sector. ‘Price and his colleagues realised that this shift was coming at the cost of adequate training at a specialised level, which would in turn impact negatively on any form of lower-level medicine,’ said Dr Tager. ‘The initial idea was to try to harness resources from the private sector to ensure the availability of equipment to train doctors in

the public sector in the various areas of specialist and sub-specialist medicine. In order to improve the South African healthcare space in the long term, Price and his colleagues felt it was best to formalise an offering, while also providing a teaching platform. The need to develop an institution offering both medical care and medical academic training was thus identified – resulting in the formation of WDGMC.’ Training of specialist practitioners started in 2007. Since then numbers have increased from three registrars and one fellow to 17 fellows and six registrars. The hospital is also doing well in terms of attracting patients. ‘WDGMC is different to other private healthcare facilities because it is an academic facility that has a completely different relationship with its doctors. The people who work here have built the place. It’s not a tenant-landlord relationship; it’s an investment in the future: a commitment, with goals that are different – our goals here are not just to make money, but to ensure the future of healthcare and training in SA. At WDGMC, the patient is always at the centre of everything we do, and this is what the doctors here live by. As we continue to move forward, I believe that anything is possible. ‘I still hope to achieve a national impact in medicine in SA, whether it is one unified ‘mega institute’ that trains specialist and sub-specialist doctors for the country, or in a franchised kind of environment, where we replicate what we have done at other universities. ‘I would like to see WDGMC become a leader in the training of specialists and sub-specialists in South Africa, for South Africa, and know that we can build models of care here in terms of multidisciplinary medicine and healthcare delivery which can be replicated elsewhere at a service and training level,’ concluded Dr Tager. For further information, visit the WDGMC website at http://www.dgmc.co.za

Prof. Adam Habib, Vice-Chancellor of the University of the Witwatersrand, Dr Sue Tager, CEO of WDGMC, and Dr Max Price, Vice-Chancellor of the University of Cape Town.

FOR FURTHER PRODUCT INFORMATION CONTACT PHARMA DYNAMICS AT P O BOX 30958, TOKAI, 7966 TEL: 021 707 7000 • FAX: 021 7015898 www.pharmadynamics.co.za CUSTOMER CARE LINE: 0860-PHARMA (742 762)

March 2014, Vol. 104, No. 3

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2014/02/25 2:00 PM

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Located in diplomatic enclave. Offers family medicine, physical therapy and specialist clinics. Also provides diagnostic ultrasound, echocardiography, and venous doppler studies with a state-ofthe-art GE machine. Serves the South African High Commission and a large expatriate South African clientele. Also contracted to corporates and international insurance companies such as Allianz, CIGNA, Van Breda, AXA PPP, etc. Point of care pathology tests from an attached primary care laboratory offering hematology, chemistry, coagulation & RDT microbiology. In-house pharmacy offering wide range of primary care therapeutics. Competitive remuneration offered: salary, fee sharing, or combination.

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MEDICAL PRACTITIONER (full-time in clinical research) Requirements • MB ChB • Ability to follow clinical • Community service completed protocols with accurate, legible • Current HPCSA registration documentation (independent general practice) • MPS malpractice insurance (or • Knowledge on current national equivalent) guidelines (EDL) Salary: Market-related Application: Application forms avwailable from MCR, 40 Pienaar St, Brits. Contact person: Dr CE Louw, Tel: 012 252 1140, 082 414 9433 email: celouw.mcr@lantic.net Fax: 012 252 1139

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PROFESSIONAL ADVERTISING

PRACTICE for sale Busy GP practice for sale in central Hillcrest, KZN. Fully equipped modern rooms within a multidisciplinary medical centre. Hours: 08h00 - 17h00, Mon-Fri. No after-hour work. Practice turnover R280K. Owner selling due to health reasons. Asking for R750 000.

Contact : andre@hillcare.co.za

PRAKTYK vir oorname Solo dispenserende praktyk te sentraal Vrystraat. Eienaar tree af. Provinsiale hospitaal in dorp. Billike voorwaardes vir oorname.

Kontak : 082 371 9257

PHYSICIAN wanted Specialist physician or pulmonologist: 5 physician practice in Pretoria looking for new associate. Associate pulmonologist retiring from hospital practice to home practice. Great opportunity to join well-established hospital physician group.

For enquiries contact: richard.s@internists.co.za

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PROFESSIONAL ADVERTISING

OPPORTUNITIES FOR CHIEF MEDICAL OFFICER based in Baku, Azerbaijan The International SOS clinic in Baku offers international standards of medical care and a wide range of medical services in a safe, professional and friendly environment. Our clinic is staffed by internationallytrained and highly skilled medical professionals and provides general and family practice services and 24/7 emergency medical services. As a Chief Medical Officer, you will be responsible for the supervision and the medical management of the International SOS clinic and the development of a quality focused general practice environment. In addition to the clinical focus the role is responsible to position International SOS as the principal health care provider in the local international community This is a permanent rotational position working 6 weeks on duty followed by 6 weeks off duty. International SOS will provide you with an expatriate package including Accommodation, Continuing Medical Education and return flights for each off-duty period. This location is not suitable for a family. Multicultural teams are waiting for you to join and take care of expatriates and national workers! DESIRED SKILLS & EXPERIENCE We are seeking an experienced and qualified Doctor who will have: • A minimum of 7 years’ post graduation experience gained within general practice and/or emergency medicine • Experience in leading a small team and administration • Experience in pediatrics • Experience in women’s health • Fluent English • Current ACLS, ATLS, PALS certifications COMPANY DESCRIPTION International SOS (http://www.internationalsos.com) is the world’s leading international healthcare, medical and security assistance, and concierge Services Company. Operating in over 70 countries, International SOS provides integrated medical, clinical, security, and customer care solutions to organizations with international operations. A global team of over 10,000 employees led by 1000 full-time physicians and 200 security specialists provides services including planning, preventative programs, in-country expertise and emergency response to 66 percent of the Fortune Global 500 companies.

Please also visit our careers webpage at: http://www.internationalsos.com/en/careers.htm

Working for PathCare always produces excellent results!!

Pathologists PathCare Laboratories have a position available for a Microbiology Pathologist in Cape Town, a Clinpath Pathologist in Welkom and a Clinpath or Haematology Pathologist in Port Elizabeth. If you believe you would thrive in a multidisciplinary private laboratory, and have similar goals and values to our own, we encourage you to contact us for this position. Requirements: ▪ M.Med or FC Pathology (SA) ▪ Current registration with the HPCSA as a Pathologist ▪ Relevant working experience ▪ Excellent communication and interpersonal skills ▪ Ability to maintain confidentiality and impartiality.

To apply, please email lindyb@pathcare.co.za Closing date: 14 March 2014 www.pathcare.co.za

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PROFESSIONAL ADVERTISING

DEPARTMENT OF SOCIAL DEVELOPMENT It is our intention to promote representivity (race, gender and disability) in the Public Service through the filling of this posts and candidates whose transfer / promotion/ appointment will promote representivity will receive preference. APPLICATIONS: The Director General, Department of Social Development, Private Bag X901, Pretoria, 0001. Physical Address: HSRC Building, 134 Pretorius Street. FOR ATTENTION: Ms E de Waal CLOSING DATE: 24 March 2014 POST: Deputy Director, Medical Case Assessment and Adjudication Directorate: Case Assessment TOTAL PACKAGE: R587 358 p.a. This inclusive remuneration package consists of a basic salary, the states’ contribution to the Government Employees Pension Fund and a flexible portion that may be structured i.t.o. the applicable rules. CENTRE: Harlequins Office Park, Pretoria REQUIREMENTS: An MBChB Degree PLUS five years professional experience in the medical field. Registration as medical practitioner with the HPCSA. Knowledge of the Public Service Legislation. Knowledge of Social Security Legislation. Knowledge of Medical Practices and Guidelines.

Competencies needed: Communication (written and verbal) skills. Planning and organising skills. Problem solving skills. Diagnostic and analytical skills. Project management skills. Computer literacy. Facilitation and presentation skills. Client orientation skills. People management skills. Policy development and analysis skills. Monitoring skills. Report writing skills. Interpersonal and liaison skills.

Attributes: Ability to work under pressure. Ability to work in a team and independently. Innovative and creative. Assertiveness. Achievement orientated. Cost consciousness. Business ethics. Confidentiality.

KEY RESPONSIBILITIES: Prepare files for medical assessment with recommendation to the Medical Tribunal Members. Develop, implement and review guidelines, norms and standards, forms and procedural documentation for adjudication in line with the Social Assistance Act. Conduct quality assurance and prepare feedback reports regarding social appeals. Prepare periodic reports regarding Social Assistance appeals and analyse medical trends of appeals adjudicated and SASSA rejections/reconsiderations. Coordinate, monitor and oversee referral process for second medical opinions. Assist with development, implementation, monitoring and evaluation of the compliance system (to legislation, medical guidelines and policies). Monitor the effective functioning of the medical adjudication processes in provinces as applicable. Conduct quality assurance and prepare feedback reports. NOTE: A curriculum vitae with a detailed description of duties, the names of two referees, certified copies of qualifications and identity document must accompany your signed application for employment (Z83). Shortlisted candidates for SMS posts will be required to undergo competence assessment. The successful candidate will sign an annual performance agreement, complete a financial disclosure form and also be required to undergo a security clearance. If the candidate is applying for an OSD post, certificates of service must be attached to the CV. No faxed or e-mailed applications will be considered. It is the applicant’s responsibility to have foreign qualifications evaluated by the South African Qualification Authority (SAQA). Failure to submit the requested documents will result in your application not being considered. Personnel suitability checks will be conducted on short listed candidates and the appointment is subject to positive outcomes of the checks. Correspondence will be limited to shortlisted candidates only. If you have not been contacted within three months after the closing date of this advertisement, please accept that your application was unsuccessful. “The Department of Social Development supports persons with disabilities”

ENQUIRIES: Dr J Olivier (012) 741 6877

SAMJ PROFS MARCH 2014.indd 5

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VACANCY BULLETIN EXCITING OPPORTUNITIES FOR PERSONS WHO WANT TO MAKE A DIFFERENCE

DEpArtMEnt oF HEAltH DIrEctorAtE: HEAltH IMpAct AssEssMEnt (norton rosE HousE, 8 rIEbEEk strEEt, cApE town) Medical Specialist Grade 1 to 3 (Quality Assurance) rEMunErAtIon pAckAGE: GrADE 1: r 747 564 pEr AnnuM • GrADE 2: r 854 751 pEr AnnuM • GrADE 3: r 991 974 pEr AnnuM (A portion of the pAckAge cAn be structured According to the individuAl’s personAl needs.) rEquIrEMEnts: MInIMuM EDucAtIonAl quAlIFIcAtIon: Appropriate qualification that allows registration with the Health Professions Council of South Africa (HPCSA) as Medical Specialist in Public Health. rEGIstrAtIon wItH A proFEssIonAl councIl: Registration with the HPCSA as a Public Health Specialist. ExpErIEncE: GrADE 1: None after registration with the HPCSA as Medical Specialist in Public Health. GrADE 2: A minimum of 5 years appropriate experience as Medical Specialist after registration with the HPCSA (or recognised foreign Health Professional Council in respect of a foreign qualified employee) as Medical Specialist in Public Health. GrADE 3: A minimum of 10 years appropriate experience as Medical Specialist after registration with the HPCSA (or recognised foreign Health Professional Council in respect of a foreign qualified employee) as Medical Specialist in Public Health. InHErEnt rEquIrEMEnt oF tHE job: Availability to travel within the province to visit health services on a regular basis. coMpEtEncIEs (knowlEDGE/skIlls): Appropriate experience in public health management/health programmes development. • Insight into public health policies and programmes. • Adequate managerial skills. • Good communication as well as analytical and problem-solving skills. • Computer literacy. • Ability to conduct independent research and report research findings to a professional and non-professional audience. DutIEs (kEy rEsult ArEAs/outputs): Develop and oversee the implementation of a quality improvement policy and framework that focuses on improved patient experience for all services in the department. • Develop implementation tools for the quality improvement framework (including Occupational health and IPC) in line with the National and Provincial APP and other relevant requirements. • Analyse and report on the impact of quality improvement initiatives (including Occupational health and IPC) in the department. • Capacity development in quality improvement. • Provide formal supervision to one or more Public Health registrars within the programme and informal support for registrar teaching within the programme. • Plan, conduct and apply health systems and services research relevant to the improvement of quality of care as outlined in Healthcare 2030 and other national and provincial quality improvement initiatives. • Academic activities consistent with the mandate of the University for research, teaching and social responsiveness. notE: This is a post on the joint establishment of the University of Stellenbosch and the Western Cape Department of Health. Candidates who are deemed as “registrable” may also apply. The appointment of successful applicants will only be effected once proof of application for registration or the proof of registration is provided. EnquIrIEs: Dr T Naledi, tel. no. (021) 483-5085 plEAsE subMIt your ApplIcAtIon For tHE AttEntIon oF Ms c VErsFElD to tHE DIrEctor: HuMAn rEsourcE MAnAgeMent, depArtMent of heAlth, po box 2060, cApe town, 8000.

InstructIons to ApplIcAnts: Z83 forms (obtainable from any Government department or www.westerncape.gov.za) must: Be completed in full, clearly reflect the name of the position, name and date of the publication (candidates may use this as reference), be signed, accompanied by a comprehensive CV, the names of 3 referees and certified copies of ID, driver’s licence and qualification/s. A separate application form must be completed for each post. Applications without the aforementioned will not be considered. Applications must be forwarded to the address as indicated on the advertisement. No late, faxed or e-mailed applications will be accepted. CV’s will not be returned. Excess personnel will receive preference. Applications, which are received after the closing date, will not be considered. Further communication will be limited to short-listed candidates. If you have not received a response from the Department within 3 months of the closing date, please consider your application as unsuccessful. It will be expected of candidates to be available for selection interviews on a date, time and place as determined by the Department.

The Department of Health is guided by the principles of Employment Equity. Disabled candidates are encouraged to apply and an indication in this regard will be appreciated.

H401016E med Journal.indd 1 SAMJ PROFS MARCH 2014.indd 6

closing date: 7 March 2014

TBWA\H401016\E

As directed by the Department of public service & Administration, applicants must note that further checks will be conducted once they are short-listed and that their appointment is subject to positive outcomes on these checks, which include security clearance, qualification verification, criminal records, credit records and previous employment.

2014/02/14 11:02 AM 2014/02/25 2:00 PM

CPD

NOTIFICATION

Dear CPD client, We wish to take this opportunity to thank you for your continued support through the completion of our online CPD questionnaires as well as to share some exciting news with you. HMPG’s journal CPD questionnaires will be moving to the Medical Practice Consulting (MPC) CPD platform (www.mpconsulting.co.za) as part of a strategy to consolidate all South African Medical Association (SAMA) members’ CPD certificates and history. All SAMA CPD certificates (whether for annual conferences, branch meetings or workshops) are already available online on the MPC CPD platform and moving all active HMPG online CPD questionnaires to the same platform will mean that all SAMA member CPD certificates will be issued in one central, convenient location – resulting in less admin for our CPD clients. An additional benefit is that the MPC CPD manager can complete your IAR form on your behalf (no more countless hours of reconciling CPD records before a compliance audit) and submit your CPD history to the HPCSA once you have approved it and are happy with the results. All that is required of you, when you are ready, is to click a single button to submit your CPD Activity Record to the HPCSA. Nothing will, of course, ever be submitted without your prior approval and consent. The MPC system also adds additional functionality to the CPD questionnaires and the system has been set up to make the process as easy to follow as possible. The South African Medical Association (SAMA) board has concluded that the CPD services associated with the South African Medical Journal (incorporating Continuing Medical Education) and the South African Journal of Bioethics and Law will only be offered to registered and fully paid-up SAMA members, as per the SAMA member benefit schedule; therefore, you will be required to register a profile on the MPC CPD system (if you do not already have one – if you already have one, login as usual) and to supply your SAMA membership number. You will be required to do this only once. Your membership will be validated in real-time and you will be able to access the journal CPD questionnaires. This once-off registration should not take more than 2 minutes and you will be on your way to completing the CPD questionnaires. Below are some questions and answers that will assist you in getting started.

When will the CPD questionnaires move to MPC? All HMPG-issued journal CPD questionnaires will move to the MPC CPD platform from February 2014 onwards. This will include all prior CPD questionnaires that are still active.

What website do I access to complete the HMPG questionnaires? www.mpconsulting.co.za

Who is MPC? Medical Practice Consulting (MPC) is a group company of SAMA. MPC has historically hosted CPD at SAMA’s annual conferences, issued all SAMA member CPD certificates and has hosted SAMA’s online branch elections. By moving active HMPG journal CPD questionnaires to the MPC system, SAMA members will have all their CPD certificates in one central, convenient location. MPC has also been supplying the Foundation for Professional Development distance learning courses online for the last 2 years and has hosted some of the largest online training initiatives in the South African healthcare industry.

What do I need to register a profile on the MPC CPD system? MPC does not retain any confidential information on their database, so you will not be requested to share your telephone number, practice or home address. All that is required for registration is your name, surname, specialty, SAMA membership number and HPCSA number (which is included on your CPD certificate to comply with HPCSA CPD requirements).

How long will registration take? Completing registration should take no longer than 2 minutes – please remember to have your HPCSA (MP Number) and SAMA membership number at hand.

What about my historic CPD certificates on the www.cpdjournals.co.za website? If you register on the MPC CPD platform with the same email address as you were using on the www.cpdjournals.co.za website, MPC will import all your CPD certificates for the last 36 months into your MPC CPD manager for you. Alternatively you can still login to www.cpdjournals.co.za and save any CPD certificates that are still valid (remember that CEUs have a 24-month shelf life and expire after 24 months).

What happens if I run into technical difficulties? Simply complete an online contact form and MPC will assist you with your technical problem. If your SAMA number for some reason does not match that in the SAMA membership database, MPC will assist with rectifying the problem. MPC’s contact details are available online: www.mpconsulting.co.za/contact-us Sincerely, Gert Steyn CEO, Health and Medical Publishing Group (HMPG)

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CPD

MARCH 2014

Effective in 2014, the CPD programme for the SAMJ will be administered by Medical Practice Consulting: CPD questionnaires must be completed online at www.mpconsulting.co.za

True (A) or false (B): Annually, 1% of gold miners die – 4% sent home sick 1. Underground gold miners are highly prone to developing silicosis, with attendant TB (latent or active), because of their long-term exposure to silica dust. Cardiovascular prevention: Lifestyle and statins – competitors or companions? 2. Beneficial lifestyle factors are non-smoking, exercise for ≥30 min daily, and maintaining an ideal body weight, an ideal diet and a modest alcohol intake. 3. The Mediterranean diet – high intake of vegetables, legumes, fruits and nuts, cereal, fish, and monounsaturated fats, with small amounts of meat, poultry, and high-fat dairy products – reduces coronary heart disease (CHD) deaths by 33%. 4. Statins have been proven to be effective in primary prevention of CHD. Cardiometabolic markers to identify cardiovascular disease (CVD) risk in HIV-infected black South Africans 5. Besides the traditional risk factors for CVD, in people living with HIV there are specific factors (chronic inflammation, metabolic changes associated with HIV infection, therapy and lipodystrophy) that potentially increase their risk.

The impact of chronic pseudomonal infection on pulmonary function testing in individuals with cystic fibrosis in Pretoria, South Africa 9. Cystic fibrosis is an X-linked dominant inherited genetic disease. 10. As a result of abnormal airway secretions, mucus becomes a nidus for regular infections by micro-organisms, predominantly Staphylococcus aureus and Streptococcus pneumoniae. Spina bifida (SB): A multidisciplinary perspective on a manyfaceted condition 11. The goal of early surgery in SB is to close the dura mater and skin over the spinal cord to prevent infection and to reverse the congenital neurological defect. 12. Most infants with open SB have a Chiari II malformation. 13. Bladder dysfunction is always present in open SB. Perinatal management of SB 14. Referral for surgical closure of myelomeningocele (MMC) should take place no later than 48 hours after birth. 15. The most effective antimicrobial treatment of MMC is early surgical closure.

Systematic review of the evidence for rational dosing of colistin 6. Carbapenem resistance is emerging in Klebsiella pneumoniae and Enterobacter spp.

The paediatric neuropathic bladder 16. Urodynamic assessment is essential for the diagnosis and prognosis of paediatric neurogenic bladder. 17. The standard conservative management of paediatric neurogenic bladder consists of oral anticholinergics and clean intermittent catheterisation.

New imaging approaches for improving diagnosis of childhood tuberculosis (TB) 7. Mediastinal and hilar lymphadenopathy are the hallmarks of primary pulmonary TB in children. 8. Because of the insignificant radiation burden, computed tomography is becoming a standard imaging option for diagnosis of TB in children.

An approach to the developmental and cognitive profile of the child with SB 18. Closed forms of SB are seldom associated with brain anomalies. 19. The strongest association with cognitive dysfunction is the presence of hydrocephalus and its complications. 20. Children with SB generally display better scores in verbal intelligence quotient (IQ) than performance IQ.

CPD questions include articles from CME. The full versions of each article can be found on the SAMJ website (http://www.samj.org.za)

A maximum of 3 CEUs will be awarded per correctly completed test.

INSTRUCTIONS 1. Read the journal. All the answers will be found there. 2. Go to www.mpconsulting.co.za to answer the questions. Accreditation number: MDB001/007/01/2014 (Clinical)

March 2014, Vol. 104, No. 3

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4014 i-sens_297x210_MJSA_HR.pdf

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VOL. 104 NO. 3

168

The cons of INH TB prophylaxis – pros to follow

174

Research ethics evolution: Nuremberg to Helsinki

178

New imaging for the diagnosis of childhood TB Markers to identify cardiovascular disease risk in HIV CME: Spina bifida Progress towards the Millennium Development Goals

SAMF

MARCH 2014 VOL. 104 NO. 3 150-221

Cardiovascular prevention: Lifestyle and statins

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

Please direct all order queries to: Edward – Fax: 086 600 6218 email: edwardm@hmpg.co.za Tax invoice to be posted on dispatch of order.

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