SAMJ Vol 108, No 2 (2018) by HMPG

FEBRUARY 2018

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GUEST EDITORIAL Early exposure to tobacco smoke and environmental pollution IN PRACTICE Lack of assisted deliveries impacting neonatal and maternal health Pre-exposure prophylaxis: Roll-out among South African university students REVIEW Hospital-based palliative care services in the Western Cape RESEARCH Neonatal and paediatric bloodstream infections: Pathogens, antimicrobial resistance and prescribing practice Heroin detoxification during pregnancy Colorectal cancer in South Africa: Presentation, treatment and 5-year survival

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FEBRUARY 2018 PRINT EDITION

GUEST EDITORIAL

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

Early-life exposures to environmental tobacco smoke and indoor air pollution in the Drakenstein Child Health Study: Impact on child health A Vanker, R P Gie, H J Zar

EDITOR’S CHOICE

CORRESPONDENCE

The African Hospitalist Fellowship A Westwood

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

ERRATUM

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30 days in medicine B Farham

MANAGING EDITORS Claudia Naidu Naadia van der Bergh

IN PRACTICE 11

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

CLINICAL UPDATE Failure to perform assisted deliveries is resulting in an increased neonatal and maternal morbidity and mortality: An expert opinion R C Pattinson, V Vannevel, D Barnard, S Baloyi, G S Gebhardt, K le Roux, N Moran, J Moodley

ISSUES IN MEDICINE 14 Truvada (emtricitabine/tenofovir) pre-exposure prophylaxis roll-out among South African university students: Lots of positives, but let us keep an eye on possible surprises K Montjane, S Dlamini, C Dandara 17

MEDICINE AND THE LAW Is there transparency in the pricing of medicines in the South African private sector? V Bangalee, F Suleman

HEALTHCARE DELIVERY Burkitt’s lymphoma: The prevalence of HIV/AIDS and the outcome of treatment P B Hesseling, F Kouya, E Katayi, G Mbah, P Wharin

REVIEW 21 The development of hospital-based palliative care services in public hospitals in the Western Cape, South Africa L Gwyther, R Krause, C Cupido, J Stanford, H Grey, T Credé, A de Vos, J Arendse, P Raubenheimer 25 Validation of the Simplified Motor Score in patients with traumatic brain injury at a major trauma centre in South Africa J J P Buitendag, A Ras, V Y Kong, J L Bruce, G L Laing, D L Clarke, P Brysiewicz

RESEARCH 30 Clinical characteristics and causes of heart failure, adherence to treatment guidelines and mortality of patients with acute heart failure: Experience at Groote Schuur Hospital, Cape Town, South Africa P Z Szymanski, M Badri, B M Mayosi 35 Neonatal and paediatric bloodstream infections: Pathogens, antimicrobial resistance patterns and prescribing practice at Khayelitsha District Hospital, Cape Town, South Africa H Crichton, N O’Connell, H Rabie, A C Whitelaw, A Dramowski 41 Characteristics and early outcomes of children and adolescents treated with darunavir/ritonavir-, raltegravir- or etravirine-containing antiretroviral therapy in the Western Cape Province of South Africa J Nuttall, V Pillay 47 Heroin detoxification during pregnancy: A systematic review and retrospective study of the management of heroin addiction in pregnancy K V Gilfillan, L Dannatt, D J Stein, B Vythilingum 54 Colorectal cancer in South Africa: An assessment of disease presentation, treatment pathways and 5-year survival M Brand, P Gaylard, J Ramos

February 2018, Print edition

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Safety and aﬀordability of an elective Saturday list at Pietersburg Hospital, Limpopo, South Africa* M M Z U Bhuiyan, R Mavhungu

Physical activity levels in urban-based South African learners: A cross-sectional study of 7 348 participants* A van Biljon, A J McKune, K D DuBose, U Kolanisi, S J Semple

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency in South Africa* Y Ganie, C Aldous, Y Balakrishna, R Wiersma

Five-year follow-up of participants diagnosed with chronic airflow obstruction in a South African Burden of Obstructive Lung Disease (BOLD) survey* B W Allwood, R Gillespie, M Bateman, H Olckers, L Taborda-Barata, G L Calligaro, R van Zyl-Smit, C B Cooper, N Beyers, E D Bateman

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FEBRUARY 2018

Background photo: The South African Red Cross shows a Siyayinqoba Educational video on TB and HIV to a family in Khatlehong, near Johannesburg | Damien Schumann

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Box photos: Early-life exposure to indoor air pollution impacts on child health | Tracey Derrick, on behalf of the Drakenstein Child Health Study; Roll-out of Truvada aims to offer protection to South African university and college students at risk of HIV | Shutterstock; Heroin addiction | Shutterstock

February 2018, Print edition

REVIEW Hospital-based palliative care services in the Western Cape RESEARCH Neonatal and paediatric bloodstream infections: Pathogens, antimicrobial resistance and prescribing practice Heroin detoxification during pregnancy Colorectal cancer in South Africa: Presentation, treatment and 5-year survival

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

GUEST EDITORIAL

Early-life exposures to environmental tobacco smoke and indoor air pollution in the Drakenstein Child Health Study: Impact on child health Lower respiratory tract infections (LRTIs) are the leading cause of childhood morbidity and mortality in South Africa (SA). Despite sustained efforts to decrease this, including better access to vaccination and strengthening of primary healthcare services, childhood LRTIs continue to impact significantly on child health.[1,2] SA, a middle-income country, has undergone much social and political change in the past two decades, resulting in urban migration and the mushrooming of peri-urban communities with subsequent health, education and environmental challenges.[3] Despite an increase in electrification, many households continue to rely on alternative fuel sources for cooking and heating.[4] Burning of alternative fuels (such as paraffin, wood, coal and other biomass substances), often in inadequately ventilated homes, contributes to indoor air pollution, a recognised risk factor for respiratory disease.[5] Further, environmental tobacco smoke exposure continues to be problematic despite anti-smoking legislation.[6] The Drakenstein Child Health Study (DCHS), an SA birth cohort study of 1 000 mother-child pairs, longitudinally investigates the epidemiology, risk factors, aetiology and long-term outcome of childhood diseases, including respiratory illnesses.[7] The study site is in a peri-urban, poor socioeconomic community in the Drakenstein subdistrict, 50 km from Cape Town. Pregnant women were enrolled from two public primary healthcare clinics, Mbekweni (serving a predominantly black African population) and Newman (predominantly mixed-ancestry population), and all deliveries occurred at Paarl Hospital. Children are followed up until at least 5 years of age. The impact of indoor air pollution (IAP) and environmental tobacco smoke (ETS) exposure on child health was investigated in the DCHS. To measure exposures comprehensively, two home visits, one in the antenatal period (third trimester) and the second postnatally (between 4 and 6 months of the infant’s life), were conducted to assess the home environment and to measure the most common indoor air pollutants and byproducts of combustion. Devices placed in participants’ homes measured exposure to particulate matter (PM10), carbon monoxide (CO), nitrogen dioxide (NO2), sulphur dioxide (SO2) and volatile organic compounds (VOCs).[8] Measurements of IAP were obtained from 863 antenatal and 723 postnatal home visits, providing important SA data on IAP and potential sources of pollution. Measured benzene (VOC) levels were significantly above acceptable SA ambient standards,[9] and together with CO and NO2, increased levels were associated with fossil fuel use.[8] Tobacco smoking by pregnant women is often under-reported globally, although household ETS exposure may be high.[10,11] In the DCHS, urine cotinine measures were used to validate maternal selfreported smoking and exposure.[12] Tobacco smoking and exposure was found to be highly prevalent, with a smoking prevalence of >50% in mixed-ancestry mothers. Alarmingly, 18% of infants were born with urine cotinine levels in keeping with active smoking, while a further 30% had levels indicating passive smoke expo sure. [12] The impact of the exposures on birth outcomes was significant, with antenatal maternal smoking associated with lower birth weight.[12]

The timing of environmental exposures on the subsequent development of LRTI in infancy has not been well described. Most interestingly, we found that antenatal exposures were the main risk factors associated with LRTI, with maternal smoking in pregnancy or PM10 exposure most strongly associated with LRTI. Further, maternal smoking in pregnancy or antenatal passive smoke or PM10 exposure was associated with wheezing in infants.[13] Interestingly, toluene, a volatile organic compound, was a novel exposure associated with severe LRTI requiring hospitalisation.[13] Environmental exposures therefore had a substantial impact on child health and on LRTI. The effect on LRTI of antenatal compared with postnatal exposure suggests an in utero developmental lung effect. This study highlights antenatal and early life as a critical period for lung development. Urgent and effective smoking cessation programmes as well as public health interventions focusing on IAP are required. Woman of childbearing age, pregnant women and children in poor communities represent vulnerable populations at risk for long-term health effects of these exposures. Early-life LRTI and environmental exposures have increasingly been associated with the development of chronic obstructive pulmonary disease in adulthood. Further longitudinal study of this cohort will provide important information on the long-term respiratory outcomes. Acknowledgements. We thank the study and clinical staff at Paarl Hospital and Mbekweni and Newman clinics, in particular the fieldworker teams, SGS Environmental Services for supporting this project, and the participants and their families. Funding. This study was funded by the Bill & Melinda Gates Foundation (OPP1017641), Discovery Foundation, a South African Thoracic Society AstraZeneca Respiratory Fellowship, the National Research Foundation, SA, CIDRI Clinical Fellowship and the South African Medical Research Council.

A Vanker Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa; and South African Medical Research Council Unit on Child and Adolescent Health, University of Cape Town, South Africa aneesa.vanker@uct.ac.za

R P Gie Department of Paediatrics and Child Health, Tygerberg Children’s Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

February 2018, Print edition

*P 1 c C e a P

GUEST EDITORIAL

H J Zar Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa; and South African Medical Research Council Unit on Child and Adolescent Health, University of Cape Town, South Africa 1. Rudan I, O’Brien KL, Nair H, et al. Epidemiology and etiology of childhood pneumonia in 2010: Estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for 192 countries. J Global Health 2013;3(1):10401. https://doi.org/10.7189/jogh.03.010401 2. Zar HJ, Barnett W, Myer L, Nicol MP. Childhood pneumonia – the Drakenstein Child Health Study. S Afr Med J 2016;106(7):642-643. https://doi.org/10.7196/SAMJ.2016.v106i7.11108. 3. Statistics South Africa. The South African MPI: Creating a Multidimensional Poverty Index Using Census Data. Pretoria: Stats SA, 2014. http://www.statssa.gov.za/?page_id=1854&PPN=Report-03-10-08 (accessed 6 December 2017). 4. Statistics South Africa. General Household Survey 2013. Pretoria: Stats SA, 2014. http://www.statssa. gov.za/publications/P0318/P03182013.pdf (accessed 6 December 2017). 5. Gordon SB, Bruce NG, Grigg J, et al. Respiratory risks from household air pollution in low and middle income countries. Lancet Respir Med 2014;2(10):823-860. https://doi.org/10.1016/S22132600(14)70168-7

6. Reddy P, Zuma K, Shisana O, Kim J, Sewpaul R. Prevalence of tobacco use among adults in South Africa: Results from the first South African National Health and Nutrition Examination Survey. S Afr Med J 2015;105(8):648-655. https://doi.org/10.7196/SAMJnew.7932 7. Zar HJ, Barnett W, Myer L, Stein DJ, Nicol MP. Investigating the early-life determinants of illness in Africa: The Drakenstein Child Health Study. Thorax 2015;70(6):592-594. https://doi.org/10.1136/ thoraxjnl-2014-206242. 8. Vanker A, Barnett W, Nduru PM, Gie RP, Sly PD, Zar HJ. Home environment and indoor air pollution exposure in an African birth cohort study. Sci Total Environ 2015;536(1 Dec):362-367. https://doi. org/10.1016/j.scitotenv.2015.06.136 9. Government Gazette, Republic of South Africa. National Ambient Air Quality Standards. Pretoria, 2009. https://www.gov.za/documents/national-environmental-management-air-quality-act-nationalambient-air-quality-standards (accessed 6 December 2017). 10. Caleyachetty R, Tait CA, Kengne AP, Corvalan C, Uauy R, Echouffo-Tcheugui JB. Tobacco use in pregnant women: analysis of data from Demographic and Health Surveys from 54 low-income and middle-income countries. Lancet Global Health 2014;2(9):e513-e520. https://doi.org/10.1016/S2214109X(14)70283-9. 11. Öberg M, Jaakkola MS, Woodward A, Peruga A, Prüss-Ustün A. Worldwide burden of disease from exposure to second-hand smoke: A retrospective analysis of data from 192 countries. Lancet 2011;377(9760):139-146. https://doi.org/10.1016/S0140-6736(10)61388-8. 12. Vanker A, Barnett W, Brittain K, et al. Antenatal and early life tobacco smoke exposure in an African birth cohort study. Int J Tuberc Lung Dis 2016;20(6):729-737. https://doi.org/10.5588/ijtld.15.0697 13. Vanker A, Barnett W, Workman L, et al. Early-life exposure to indoor air pollution or tobacco smoke and lower respiratory tract illness and wheezing in African infants: A longitudinal birth cohort study. Lancet Planet Health 2017;1(8):e328-e336. https://doi.org/10.1016/S2542-5196(17)30134-1

S Afr Med J 2018;108(2):71-72. DOI:10.7196/SAMJ.2018.v108i2.13088

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February 2018, Print edition

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

EDITOR’S CHOICE

The development of hospital-based palliative care services in public hospitals in the Western Cape, South Africa

Colorectal cancer in SA: Presentation, treatment pathways and 5-year survival

Colorectal cancer (CRC) is the fourth most common cancer in SA, and the sixth most lethal. Approximately 25% of patients will have synchronous metastatic disease at the time of their primary CRC diagnosis. Although chemotherapy is used in most stages of the disease, surgical resection of the primary tumour and metastases remains the most successful treatment modality to achieve cure or prolong survival. To date, no data on CRC presentation and management have been published in SA. Brand et al.[2] look at CRC presentation, general management patterns and overall survival in the SA private healthcare sector, using a retrospective review of a private healthcare funder’s database from 1 January 2008 to 31 December 2015. A total of 3 412 patients were included in the study, 2 267 with CRC only and 1 145 with liver (LM) or pulmonary metastases (PM). The mean age was 64.1 years (range 21 - 97), and 54.6% were male; these did not differ statistically between the study groups. Twenty percent of patients with LM or PM underwent surgical resection of their metastases. Five-year survival rates following surgical resection of all disease for CRC only, CRCLM, CRCPM and CRCLMPM were 71.7%, 57.3%, 31.5% and 26.0%, respectively. SA CRC patients treated in the private healthcare sector have similar disease presentation to that in published international series, with similar outcomes following various treatment pathways; however, it seems that fewer resections of metastases are undertaken compared with international trends.

Characteristics and early outcomes of children and adolescents treated with darunavir/ritonavir-, raltegravir- or etravirine-containing antiretroviral therapy in the Western Cape

There is an increasing need for third-line treatment regimens in HIV-infected children with antiretroviral treatment (ART) failure. Data are limited on darunavir/ritonavir (DRV/r)-, raltegravir (RAL)and etravirine (ETR)-containing regimens in treatment-experienced children from resource-constrained settings receiving these drugs as part of routine care. Nuttall and Pillay[3] describe the characteristics and early outcomes of treatment-experienced children (<20 years of age) in the Western Cape Province of SA treated with DRV/r-, RAL- or ETR-containing regimens. Thirty-five children of median age 8.8 years (interquartile

range (IQR) 5.5 - 11) who had received ART for a median of 6.9 years (IQR 5 - 9.9) and started a DRV/r-, RAL- or ETR-containing regimen were included. Before starting such a regimen, the median CD4+ lymphocyte count and HIV-1 RNA level were 405.5 cells/µL (IQR 251.5 - 541) and 28 314 copies/mL (IQR 5 595.5 – 120 186.5) (log 4.5 (IQR 3.7 - 5)), respectively, in 24 subjects with available results. After a median of 2 years (IQR 1.3 - 4) on treatment, 29/30 (96.7%) and 23/30 (76.7%) subjects with available results had HIV-1 RNA levels of <400 and <50 copies/mL, respectively. The study found DRV/r-, RAL- and ETR-containing regimens to be effective in a group of treatment-experienced children and adolescents with multidrug-resistant HIV. Although the treatment regimens in this study were individualised based on HIV genotyping results, further research evaluating the safety and efficacy of standardised third-line treatment regimens in children of all ages is needed.

Neonatal and paediatric bloodstream infections at Khayelitsha District Hospital, Cape Town

The epidemiology of neonatal and paediatric community-acquired and healthcare-associated bloodstream infections (BSI) at SA district hospitals is under-researched. In this retrospective review of neonatal and paediatric BSI (0 - 13 years) at Khayelitsha District Hospital, Cape Town, SA, over 3 years (1 March 2012 - 28 February 2015), the authors used laboratory, hospital, patient and prescription data to determine BSI rates, blood culture yield and contamination rates, pathogen profile, antimicrobial resistance, patient demographics, BSI outcome and antibiotic prescribing practice.[4] From 7 427 blood cultures submitted, the pathogen yield was low (2.1%, 156/7 427) while blood culture contamination rates were high (10.5%, 782/7 427). Paediatric and neonatal BSI rates were 4.5 and 1.4/1 000 patient days, respectively. Gram-positive BSI predominated (59.3%); Staphylococcus aureus (26.8%) and Escherichia coli (21.6%) were common pathogens. The median patient age was 3 months, with a predominance of males (57.7%) and a 12.8% prevalence of HIV infection. Crude BSI-associated mortality was 7.1% (11/156), the death rate being higher in neonates than in infants and children (6/40 (15.0%) v. 5/116 (4.3%), respectively; p=0.03) and in patients with Gram-negative compared with Gram-positive bacteraemia (6/66 (9.1%) v. 5/89 (5.6%), respectively; p=0.5). Most BSI episodes were community-acquired (138/156; 88.5%), with high levels of extendedspectrum β-lactamase (ESBL) carriage among Klebsiella pneumoniae and E. coli isolates (5/5 (100%) and 8/33 (24.2%), respectively). Antimicrobial management of BSI was inappropriate in 30.6% of cases (45/147), including incorrect empirical antibiotic (46.7%), dual antibiotic cover (33.3%) and inappropriately broad-spectrum antibiotic use (17.8%). Antimicrobial-resistant pathogens (notably ESBL-producing Enterobacteriaceae) were common in community-acquired BSI. Paediatric clinicians at district hospitals require ongoing training in antibiotic stewardship and blood culture sampling. BF 1. Gwyther L, Krause R, Cupido C. The development of hospital-based palliative care services in public hospitals in the Western Cape, South Africa. S Afr Med J 2018;108(2):86-89. https://doi.org/10.7196/ SAMJ.2018.v108i2.12524 2. Brand M, Gaylard P, Ramos J. Colorectal cancer in South Africa: An assessment of disease presentation, treatment pathways and 5-year survival. S Afr Med J 2018;108(2):118-122. https://doi.org/10.7196/ SAMJ.2018.v108i2.12338 3. Nuttall J, Pillay V. Characteristics and early outcomes of children and adolescents treated with darunavir/ ritonavir-, raltegravir- or etravirine-containing antiretroviral therapy in the Western Cape Province of South Africa. S Afr Med J 2018;108(2):105-110. https://doi.org/10.7196/SAMJ.2018.v108i2.12573 4. Crichton H, O’Connell N, Rabie H, Whitelaw AC, Dramowski A. Neonatal and paediatric bloodstream infections: Pathogens, antimicrobial resistance patterns and prescribing practice at Khayelitsha District Hospital, Cape Town, South Africa. S Afr Med J 2018;108(2):99-104. https://doi.org/10.7196/SAMJ.2018. v108i2.12601

February 2018, Print edition

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

CORRESPONDENCE

The African Hospitalist Fellowship

To the Editor: As someone who was consulted in the evolution of the Hospitalist Fellowship programme described by Daniels et al.,[1] I read their article with considerable interest. The programme recognises that paediatric specialists coming out of a largely clinical training require a kind of finishing school to equip them for the real world of hospital paediatrics in the public sector in South Africa (SA) and on the African continent. The authors note that the programme deliberately gives limited exposure to outpatient and district-related activities, concentrating rather on the hospital side of consultant paediatric work. I would contend that in SA there are very few hospitals in which such an ‘isolationist’ perspective for a specialist paediatrician would be appropriate to the context of the hospital. In the rest of Africa, this is likely to be even less the case. The primary healthcare approach reminds us that health services and facilities should be linked both to the community and to each other. Any clinician lead in general paediatrics in a hospital must therefore have a good sense of the referral systems and pathways within the local health system, and the context from which children with acute or long-term problems come to that hospital. Similarly, care provided by inpatient and outpatient services within the hospital need to be strongly linked to each other, especially for children with long-term conditions. As the authors indicate, theirs is a programme in evolution. I would urge that adjustments should include greater exposure to

the regional health system of the hospital (including regular outreach experiences), and experience in outpatient services. Theore tical input regarding health systems and the care for children with long-term conditions might usefully be added to the leadership and management course that is already included in the training of the paediatric hospitalists. It should also be noted that the sub-specialty referred to[2] is designed for paediatricians working in regional hospitals as well as those working in a community paediatrics stream. I wish the authors well with this initiative as it develops and finds its place in the spectrum of paediatric generalist training opportunities in Africa, including SA. Anthony Westwood Associate Professor, Department of Paediatrics, Faculty of Health Sciences, University of Cape Town, South Africa anthony.westwood@uct.ac.za

1. Daniels AD, Buys H, Dunkley R, Wilmshurst JM. The African Hospitalist Fellowship. S Afr Med J 2017;107(11):945-947. https://doi.org/10.7196/SAMJ.2017.v107i11.12718 2. Swingler G, Hendricks M, Hall D, et al. Can a new paediatric sub-speciality improve child health in South Africa? S Afr Med J 2012;102(9):738-739. https://doi.org/10.7196/SAMJ.5714

S Afr Med J 2018;108(2):73. DOI:10.7196/SAMJ.2018.v108i2.13058

Erratum In the article ‘Acne in South African black adults: A retrospective study in the private sector’ by Zulu et al., which appeared on pp. 1106 - 1109 of the December 2017 SAMJ, the affiliation for author Y Balakrishna should have been listed as ‘Biostatistics Unit, South African Medical Research Council, Durban, South Africa’. The online version of the article (https://doi.org/10.7196/SAMJ.2017.v107i12.12419) was corrected on 15 January 2018. S Afr Med J 2018;108(2):144. DOI:10.7196/SAMJ.2018.v108i2.13110

February 2018, Print edition

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The convenient pocket-sized design enables you to fit it comfortably into your hospital bag or coat pocket, so it 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), a joint initiative of the can always be at hand for ready reference. South African Medicines Formulary (SAMF), a joint initiative of the University of Cape Town’s Division of Clinical Pharmacologyyand the Health and Medical Publishing Group, University of Cape Town’s Division of Clinical Pharmacolog and the Health and Medical Publishing Group, publishers for the South African Medical Association, provides easy access to the latest, scientifically accurate publishers for the South African Medical Association, provides easy access to the latest, scientifically accurate information, including full drug profiles, clinical notes and special prescriber’s points. The thoroughly updated information, including full drug profiles, clinical notes and special prescriber’s points. The thoroughly updated 12th edition of SAMF is your essential reference to the rational, cost-effective and safe use of medicines. 12th edition of SAMF is your essential reference to the rational, cost-effective and safe use of medicines.

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

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30 days in medicine Arthroscopy offers no benefit in subacromial shoulder pain

Shoulder arthroscopy is widely used, although its benefits are far from clear. Impingement of the rotator cuff tendons occurs frequently in patients aged >40 years and usually presents as a painful arc. As long ago as 1972, open decompression of the area was proposed, removing osseous spurs, often combined with tendon release and a bursectomy. This is generally now an arthroscopic procedure, frequently undertaken. A recent multicentre trial that covered 32 hospitals and 51 surgeons in the UK was reported in The Lancet. Eligible patients had subacromial pain for at least 3 months, with intact rotator cuff tendons, and had completed conservative management including exercise therapy and at least one steroid injection. Participants were randomly assigned to arthroscopic subacromial decompression, investigational arthroscopy only (which was a placebo), or no intervention. Surgical groups had better outcomes from shoulder pain and function compared with no treatment, but this difference was not clinically important. In addition, surgical decompression appeared to offer no benefit over arthroscopy only. These findings bring into question the value of this operation for these indications, of which patients should be aware when offered surgery. Beard DJ, Rees JL, Cook JA, et al. Arthroscopic subacromial decompression for subacromial shoulder pain (CSAW): A multicentre, pragmatic, parallel group, placebo-controlled, three-group, randomised surgical trial. Lancet 2017 (epub 20 November 2017). https://doi.org/10.1016/S0140-6736(17)32457-1

Decreasing incidence of dementia found in birth cohort study

With an ageing population, the incidence of dementia appears to be increasing as we live longer. However, a recent analysis of the Einstein Aging Study, published in JAMA Neurology, shows that there is a declining incidence of dementia in those born after 1929. Individuals aged â&#x2030;Ľ70 years were enrolled in the Einstein Aging Study between 1993 and 2015 to examine trends in dementia incidence and concomitant trends in cardiovascular comorbidities. In this study, 1 348 people from Bronx County, New York, USA, were analysed for all-cause dementia incidence. Participants did not have dementia at enrolment. The analysis showed that the incidence of dementia decreased in successive birth cohorts. The incidence per 100 person years was 5.09 in birth cohorts before 1920, 3.11 between 1920 and 1924, 1.73 between 1925 and 1929 and 0.23 in cohorts born after 1929, with the change point among those born after July of that year. At the same time, the prevalence of stroke and mycardial infarct also decreased, but the incidence of diabetes increased. Whether this decreasing incidence will contribute to a reduced burden of dementia given the ageing population remains to be seen. Derby CA, Katz MJ, Lipton RB, et al. Trends in dementia incidence in a birth cohort analysis of the Einstein Aging Study. JAMA Neurol 2017;74(11):1345-1351. https://doi.org/10.1001/jamaneurol.2017.1964

Stenting does not improve exercise time in patients with medically treated angina

The main aim of percutaneous coronary intervention (PCI), colloquially called stenting, is symptom relief, generally improved exercise tolerance and time. However, a recent study in The Lancet suggests that this invasive procedure is no better than a placebo intervention. ORBITA is a blinded, multicentre randomised trial of PCI v. a placebo procedure for angina relief, carried out at five sites in the UK. Participants had severe (>70%) single-vessel stenosis, and received 6 weeks of medication optimisation after enrolment. Pre-randomisation assessments of cardiopulmonary exercise testing, symptom questionnaires and stress echocardiography were carried out before they were randomised 1:1 to undergo PCI or a placebo procedure. Follow-up was at 6 weeks, with the same assessments, measuring a difference in exercise time between the two groups. Among the 230 patients randomised (105 assigned to PCI and 95 to the placebo procedure), there was no significant difference in the exercise time increment between the two groups. There were, however, serious adverse events, including pressure wire-related problems and five major bleeding events, in both groups. Al-Lamee R, Thompson D, Dehbi H-M, et al. Percutaneous coronary intervention in stable angina (ORBITA): A double-blind, randomised controlled trial. Lancet 2018;391(10115):31-40. https://doi. org/10.1016/S0140-6736(17)32714-9

Patients in Africa are twice as likely to die after surgery as their global counterparts

Results from the African Surgical Outcomes Study show that patients in Africa are twice as likely to die after surgery compared with the global average for postoperative deaths. Prof. Bruce Biccard and colleagues carried out a 7-day international prospective observational cohort study of patients aged â&#x2030;Ľ18 years undergoing any inpatient surgery in 25 countries in Africa. A total of 11 422 patients were recruited from 247 hospitals, serving 810Â 000 people, served by 0.7 specialist surgeons, obstetricians and anaesthetists per 100 000 population, carrying out 212 surgical procedures per 100 000 patients a year. Patients were younger, and with a lower risk profile, than reported in high-income countries. In spite of this, postoperative complications occurred in 1 977 out of 10 885 patients, and 239 out of 11 193 patients died. Infection was the most common complication. Biccard BM, Madiba TE, Kluyts H-L, et al. Perioperative patient outcomes in the African Surgical Outcomes Study: A 7-day prospective observational cohort study. Lancet 2018 (epub 3 January 2018). https://doi. org/10.1016/S0140-6736(18)30001-1

B Farham Editor ugqirha@iafrica.com

February 2018, Print edition

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

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CLINICAL UPDATE

Failure to perform assisted deliveries is resulting in an increased neonatal and maternal morbidity and mortality: An expert opinion R C Pattinson,1 MD, FRCOG, FCOG (SA); V Vannevel,1 MD, MMed (O&G) (KU Leuven, Belgium); D Barnard,1 MB ChB, FCOG (SA), MMed (O&G); S Baloyi,2 MB ChB, CML, CRIA, Dip Obst (SA), FMAS, Dip MAS, FCOG (SA), MMed (O&G), PGDip Fam Med, MSc, PGDPH; G S Gebhardt,3 MB ChB, Dip Obst (SA), MMed (O&G), FCOG (SA), MSc (Med Sci), PhD; K le Roux,4 MB ChB, MMedSci (Uppsala), DA (SA), Dip Obst (SA); N Moran,5 BM BCh, MA, FCOG (SA); J Moodley,6 MB ChB, FRCOG, FCOG, MD S outh African Medical Research Council/University of Pretoria Maternal and Infant Health Strategies Unit, Department of Obstetrics and Gynaecology, School of Medicine, Faculty of Health Sciences, University of Pretoria, South Africa 2 Academic Head, Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 3 Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa 4 Honorary Lecturer, Department of Family Medicine, Faculty of Health Sciences, Walter Sisulu University, Mthatha, Eastern Cape, South Africa; Honorary Lecturer, Primary Health Care Directorate, University of Cape Town, South Africa; Zithulele Hospital, Eastern Cape, South Africa 5 Head of Clinical Department: Obstetrics and Gynaecology, KwaZulu-Natal Department of Health, South Africa; Honorary Lecturer, Department of Obstetrics and Gynaecology, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, South Africa 6 Chair: National Committee for Confidential Enquiries into Maternal Deaths, South Africa 1

Corresponding author: V Vannevel (valerie.vannevel@up.ac.za, valerie.vannevel@gmail.com)

The need to perform assisted vaginal delivery (AVD) has been regarded as self-evident. In high-income countries, rates of AVD range between 5% and 20% of all births. In South Africa, the rate of AVD is only 1%. This has resulted in increased neonatal morbidity and mortality due to intrapartum asphyxia, and increased maternal morbidity and mortality due to a rise in second-stage caesarean deliveries. In this article, we address the possible causes leading to a decrease in AVD and propose measures to be taken to increase the rates of AVD and subsequently reduce morbidity and mortality. S Afr Med J 2018;108(2):75-78. DOI:10.7196/SAMJ.2018.v108i2.12786

The need to perform assisted vaginal delivery has been regarded as self-evident. Textbooks state: ‘Assisted vaginal delivery (AVD) offers the option of an operative procedure to safely and quickly remove the infant, mother and obstetrician from a difficult or even hazardous situation. When spontaneous vaginal delivery does not occur within a reasonable time, a successful AVD or operative vaginal delivery trial avoids caesarean delivery with its attendant uterine scar and implications for future pregnancy and avoids potential birth asphyxia from prolonged fetal and cord compression.’[1] ‘Forceps and ventouse deliveries are among the most common obstetric interventions. Sober judgement and a thorough understanding of the normal mechanism of labour and the instruments to be used are the keys to success.’[2] There have been no randomised trials comparing caesarean delivery (CD) with AVD. The only review remotely applicable is one by Majoko and Gardener[3] on the trial of instrumental delivery in theatre v. immediate CD for anticipated difficult assisted births. In this review they could find no studies. The Cochrane Library has a review on the choice of instruments for AVD by O’Mahony et al.[4] Majoko and Gardener[3] state: ‘The majority of women have spontaneous vaginal births, but some women need assistance in the second stage with delivery of the baby, using either the obstetric forceps or ventouse extraction. Rates of instrumental vaginal delivery

range from 5% to 20% of all births in high income countries. The majority of instrumental vaginal deliveries are conducted in the delivery room, but in a small proportion (2% to 5%), a trial of instrumental vaginal delivery is conducted in theatre with preparations made for proceeding to CD.’ A recent cross-sectional study on the use of assisted deliveries in 40 low- and middle-income countries in Latin America, sub-Saharan Africa and Asia[5] showed that only 1% of patients were delivered using AVD (either vacuum or forceps). The primary obstacle to performing an AVD was lack of healthcare workers trained in the procedure. The high incidence of AVD in high-income countries could be attributed to the presence of better-skilled healthcare workers and available equipment. However, a proportion of AVDs are likely to be due to the wide use of epidural analgesia in labour, which has been shown to increase the risk for AVD.[6]

The current situation in South Africa

AVD is performed during the second stage of labour, and the clinical indications are related to maternal and fetal wellbeing. Maternal indications • Failure to progress in the second stage of labour, for example owing to maternal exhaustion or occipitoposterior presentation. Signs of cephalopelvic disproportion (CPD) leading to obstructed labour must, however, be excluded.

February 2018, Print edition

IN PRACTICE

• Medical conditions where maternal pushing is contraindicated or should be minimised, such as severe hypertension, or cardiac or respiratory disease. Fetal indications • Fetal distress in the second stage of labour (without signs of CPD). Data from the Birthplace in England Collaborative Groups study on perinatal outcomes of low-risk pregnancies[7] show a perinatal mortality rate (PNMR) of <1/1 000 births in this population. The assisted delivery rate was 13.5% (7.3% ventouse and 6.2% forceps deliveries). In South Africa (SA), data from the Perinatal Problem Identifi cation Programme (PPIP) are analysed and reported in a Saving Babies report. The eighth report,[8] which analysed data from 2010 and 2011, shows a PNMR for babies weighing ≥1 000 g of 25.6/1 000. Intrapartum asphyxia and birth trauma was the major underlying cause of perinatal death, with a rate of 4.87/1 000 (when macerated stillbirths were excluded and fresh stillbirths and early neonatal deaths included). Data from 2012 and 2013[9] show a PNMR of 24.8/1 000 for babies weighing ≥1 000 g, with intrapartum asphyxia and birth trauma still comprising one of the major causes of perinatal mortality with a rate of 4.26/1 000 births. These data show that 15 20% of all perinatal deaths are due to intrapartum asphyxia and birth trauma (19.0% in 2010 - 2011, 17.1% in 2012 - 2013). The assisted delivery rate in SA (reported in 2010 - 2011) was 0.52% for ventouse and 0.15% for forceps. The CD rate was 21%. When the intrapartum asphyxia and birth trauma death rate was correlated with the ventouse delivery rate, there was a significant negative correlation of r=–0.307, p=0.036 (Fig. 1). A negative correlation means that the fewer assisted deliveries by ventouse were performed, the more intrapartum asphyxia and birth trauma deaths were observed in that district. This could be explained by good obstetric care leading to an increased use of AVD and a subsequently lower rate of perinatal deaths due to intrapartum asphyxia and birth trauma. An overall assisted delivery rate of <1% is too low and is probably due to loss of skill in performing AVD and/or lack of willingness to perform it, as well as lack of the necessary equipment. Even at the tertiary level there is lack of ability to perform AVD, as shown in Table 1: only three out of four doctors and midwives at a provincial

Ventouse deliveries, %

4 3 2 1 0

IPA+T rate, /1 000 Fig. 1. Correlation between IPA+T rate and ventouse delivery rate, 2010 2011.[8] (IPA+T = intrapartum asphyxia and birth trauma rate. Each dot represents a district.)

tertiary hospital could perform a ventouse delivery, whereas for forceps the figure is only two out of four. AVD is a key activity to reduce perinatal deaths by reducing delay and is therefore an important function for community health centres (CHCs) in the correct circumstances. We have to distinguish between a clinic/midwifery obstetric unit and a district hospital with CD facilities. A midwife at a remote clinic should have only one indication for AVD: failure to progress during the second stage of labour with the fetal head on the perineum. This includes cases where there is maternal exhaustion or fetal distress. All advanced midwives should be able to perform at least a ventouse delivery. The fact that these skills are almost totally absent in the CHCs (Table 1) speaks for itself and must contribute to the high mortality rate due to intrapartum asphyxia and birth trauma. Patients with persistent occipitoposterior or other malpresentations where the head is not yet fully descended will be better off with a trial of AVD in a hospital where CD can be performed, rather than a failed rotational ventouse at the clinic and then transport to a hospital. The problem of attaining and maintaining the right level of skill could explain the very low rates of AVDs. In a survey of clinicians involved in obstetrics in KwaZulu-Natal Province, SA, the vast majority indicated that they were more comfortable doing a CD than an AVD, and only 9% used AVD after training (through the Essential Steps in Managing Obstetric Emergencies programme).[11] The main reasons for this were lack of confidence, experience and supervision and fear of litigation. Lennox[12] added words of warning: ‘The decision to perform and successfully carry out an operative vaginal delivery may require a much higher level of judgement and skill than that involved in CD.’ The reasons why AVD has fallen out of favour in SA may include: • Prevention of mother-to-child transmission of HIV (PMTCT) guidelines advising against the use of instrumental delivery, particularly ventouse delivery • A misconception that instrumental delivery increases the likelihood of brain injury for the baby • A concern that conducting instrumental delivery may be a risk for subsequent litigation. The subsequent rise in CDs has resulted in an increase in maternal deaths due to haemorrhage during or after CD, which account for a third of all deaths due to obstetric haemorrhage in SA.[13] A second-stage CD is more difficult to perform and associated with higher morbidity than CD in the first stage of labour due to haemorrhage, extended hospital stay, a greater risk of bladder trauma and unintended extensions of the uterine incision.[14] In a prospective cohort study in Bristol, UK, the outcomes of mothers and neonates after delivery by second-stage CD were compared with the outcomes after AVD in theatre (anticipated difficult AVD).[15] The patients delivered by CD had significantly more haemorrhage (>1 000 mL), a higher rate of prolonged hospital stay (>6 days) and more neonatal intensive care unit admissions due to low Apgar scores and low umbilical artery pH. The haemorrhage was also more severe if the CD was performed by a less skilled surgeon. Expediting delivery by either CD or AVD is often done to avoid long-term neurological complications such as cerebral palsy. Several retrospective studies comparing neonatal morbidity after CD v. AVD have been published. Werner et al.[16] found that forceps deliveries were associated with a significantly reduced risk of adverse neonatal neurological outcome (when regarding seizures and intraventricular and subdural haemorrhage as the morbidities most predictive of future neurodevelopmental deficits). Forceps delivery was also

February 2018, Print edition

IN PRACTICE

Table 1. Ability to perform assisted vaginal delivery in healthcare facilities in 12 districts in South Africa[10] Procedure Ventouse (by doctor or midwife) Forceps (by doctor or midwife) Ventouse by midwife Forceps by midwife

CHC (N=54), n (%)* 3 (5.6) 3 (5.6) 2 (3.7) 1 (1.9)

DH (N=63), n (%) 36 (57.1) 38 (60.3) 12 (19.0) 9 (14.3)

RH (N=13), n (%) 10 (76.9) 9 (69.2) 3 (23.1) 2 (15.4)

PT (N=4), n (%) 3 (75.0) 2 (50.0) 1 (25.0) 1 (25.0)

CHC = community health centre; DH = district hospital; RH = regional hospital; PT = provincial tertiary hospital. *N = number of healthcare workers; n (%) = number (%) able to perform procedure.

associated with significantly fewer 5-minute Apgar scores <7. A study by Towner et al.[17] suggests abnormal labour to be a common risk factor for intracranial haemorrhage, as the rates did not differ between AVD and CD. An additional benefit of AVD over CD is the cost benefit.[18] There are very few data available on mother-to-child transmission (MTCT) of HIV with AVD. A large population-based surveillance study in the UK and Ireland (National Study of HIV in Pregnancy and Childhood)[19] has collected data on deliveries since 2008. Of the 9 072 live births reported, 251 were assisted vaginal deliveries. One infant was reported to have acquired HIV. However, there were other significant risk factors that could have contributed to this transmission, such as poor maternal adherence to antiretroviral (ARV) therapy and possible breastfeeding. The Royal College of Obstetricians and Gynaecologists guideline on operative vaginal delivery[20] states that blood-borne viral infections of the mother are no contraindication to operative vaginal delivery. One should, however, avoid difficult deliveries with an increased risk of fetal abrasion or scalp trauma, as this could increase vertical MTCT. The Cochrane review on choice of instruments for AVD[4] states that theoretically any scalp injury could increase the risk of MTCT. Soft vacuum cups are associated with a lower risk of scalp injury, but have a higher failure rate than other types of vacuum. Metal vacuum cups seem to have a higher success rate than hand-held vacuums, but there were only three trials available for this comparison. Newer randomised trials have found no difference in success rates.[21,22] Hand-held vacuums may be more easily available and require no other equipment. A reduction in deaths of pregnant women and their infants is possible if skills in AVD and the culture of performing AVD are established. It is a misconception that AVD leads to birth asphyxia and maternal morbidity. In fact, it is the other way round: failure to do an assisted delivery is a major cause of birth asphyxia and CD-related maternal morbidity. To improve our quality of care for women in labour and their infants, we must improve the skills of performing assisted deliveries and increase the number of people able, willing and confident to do so.

Requirements to increase appropriate use of AVD

1. Standardised equipment • Disposable ventouse at every delivery site. This should be in addition to an electrically operated vacuum machine, with re-usable cups. • Wrigley’s forceps at every hospital conducting deliveries. 2. Training • A dedicated training course on managing the second stage of labour, including assisted deliveries, using good-quality mannequins and one-on-one tuition. This training must also include training on diagnosing the correct position of the fetal head. Such a course

can be incorporated into the Essential Steps in the Management of Obstetric Emergencies (ESMOE) programme and should be part of all registrars’ training in obstetrics and gynaecology. • ‘Current educational methodology promotes the use of skills and drills scenarios employing mannequins and models to teach clinical skills. For example, most postgraduate deaneries in the UK require evidence of such training as this forms part of the trainees’ core logbook of clinical skills. Thus, methods to achieve, evaluate and maintain competence in AVD vaginal delivery need to be established.’[4] 3. Supportive environment for converting training into actual performance of instrumental delivery in the workplace • Change in the PMTCT guideline: removing the guideline that instrumental deliveries should be avoided in HIV-infected women and stating that AVD can be performed in women who are HIV-positive, as long as there is a clear indication for instrumental delivery. In the absence of supporting scientific data, the benefit of AVD for both mother and neonate often outweighs the theoretical risk of vertical transmission after scalp injury. The indications for instrumental delivery should not differ according to HIV status. All HIV-positive women should be on ARVs during labour, which will minimise the risk of vertical transmission. Further care should be taken to avoid scalp injury during the procedure: the vacuum should be released prior to removal of the cup, and the site on the scalp where the cup was attached can be cleansed after removal of the cup and kept away from maternal secretions thereafter. • A clear guideline from the South African Nursing Council stating that advanced midwives are expected to perform ventouse deliveries when indicated as part of their scope of practice, and must have performed this skill a minimum number of times (e.g. 5 times) as part of their logbook requirements. • Emphasis on the need for all medical interns to have performed at least three ventouse deliveries as part of their logbook requirements. • Emphasis on the need for registrars in family medicine to have performed at least three ventouse deliveries as part of their logbook requirements. • Emphasis on the need for registrars in obstetrics and gynaecology to have performed at least 10 ventouse deliveries as part of their logbook requirements, including at least one directly observed and signed for by a supervising specialist. • Circular to be sent to all maternity delivery facility chief executive officers, medical and nursing managers, and heads of obstetrics and gynaecology and paediatric departments explaining the essential need for women delivering at that facility to have access to instrumental delivery when indicated clinically, and explaining the likely benefits in terms of reduced morbidity and litigation. The circular should specify the categories of staff that are expected to have skills in conducting the procedure.

February 2018, Print edition

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Conclusion

Reviving the culture of performing AVD in SA is likely to reduce the current high rates of perinatal morbidity and mortality due to birth asphyxia. Furthermore, it will reduce maternal morbidity and mortality arising from second-stage CD. This change in culture can only be achieved through a concerted effort by healthcare managers, maternity care educators and trainers, and by the clinical supervisors working in the labour ward. Acknowledgements. We thank the National Department of Health for assistance in making this report possible. The report was submitted to and approved by the National Committee for Confidential Enquiries into Maternal Deaths and the National Perinatal Morbidity and Mortality Committee. Author contributions. All authors contributed to this article. Funding. None. Conflicts of interest. None. 1. Lindow SW, Hayashi R. Assisted vaginal delivery. In: James D, Steer PJ, Weiner CP, Gonik B, Crowther CA, Robson SC. High Risk Pregnancy: Management Options. 4th ed. St Louis, Mo.: Elsevier Saunders, 2011:1245-1259. 2. Brand SSF. Forceps and ventouse delivery. In: Cronjé HS, Cilliers BF, Pretorius MS. Clinical Obstetrics: A South African Perspective. 3rd ed. Pretoria: Van Schaik, 2010:328-344. 3. Majoko F, Gardener G. Trial of instrumental delivery in theatre versus immediate caesarean section for anticipated difficult assisted births. Cochrane Database Syst Rev 2012, Issue 10. Art. No.: CD005545. http://dx.doi.org/10.1002/14651858.cd005545.pub3 4. O’Mahony F, Hofmeyr GJ, Menon V. Choice of instruments for assisted vaginal delivery. Cochrane Database Syst Rev 2010, Issue 11. Art. No.: CD005455. https://doi.org/10.1002/14651858.cd005455.pub2 5. Bailey PE, van Roosmalen J, Mola G, Evans C, de Bernis L, Dao B. Assisted vaginal delivery in low and middle income countries: An overview. BJOG 2017;124(9):1335-1344. https://doi.org/10.1111/14710528.14477 6. Anim-Somuah M, Smyth RMD, Jones L. Epidural versus non-epidural or no analgesia in labour. Cochrane Database Syst Rev 2011, Issue 12. Art. No.: CD000331. https://doi.org/10.1002/14651858. cd000331.pub3

7. Birthplace in England Collaborative Group. Perinatal and maternal outcomes by planned place of birth for healthy women with low risk pregnancies: The Birthplace in England national prospective cohort study. BMJ 2011;343:d7400. https://doi.org/10.1097/01.aoa.0000426077.71832.25 8. Pattinson RC. Saving Babies 2010 - 2011: Eighth Report on Perinatal Care in South Africa. Pretoria: Tshepesa Press, 2013. 9. Pattinson RC, Rhoda N. Saving Babies 2012 - 2013: Ninth Report on Perinatal Care in South Africa. Pretoria: Tshepesa Press, 2014. 10. Pattinson RC, Makin JD, Pillay Y, van den Broek N, Moodley J. Basic and comprehensive emergency obstetric and neonatal care in 12 South African health districts. S Afr Med J 2015;105(4):256-260. https://doi.org/10.7196/SAMJ.9181 11. Devjee A. A survey of health professionals on the current use of forceps/ventouse and skills for operative vaginal delivery. Obstet Gynaecol Forum 2015;25(3):37-39. 12. Lennox C. Difficult labour. In: Lawson JB, Harrison KA, Bergstrom S. Maternity Care in Developing Countries. London: RCOG Press, 2001:179-200. 13. Pattinson RC, ed. Saving Mothers 2011 - 2013: The Sixth Report of the National Committee for Confidential Enquiry into Maternal Deaths in South Africa. Pretoria: Government Printer, 2014. 14. Allen VM, O’Connell CM, Baskett TF. Maternal and perinatal morbidity of caesarean delivery at full cervical dilatation compared with caesarean delivery in the first stage of labour. BJOG 2005;112(7):986990. https://doi.org/10.1111/j.1471-0528.2005.00615.x 15. Murphy DJ, Liebling RE, Verity L, Swingler R, Patel R. Early maternal and neonatal morbidity associated with operative delivery in second stage of labour: A cohort study. Lancet 2001;358(9289):1203-1207. https://doi.org/10.1016/s0140-6736(01)06341-3 16. Werner EF, Janevic TM, Illuzzi J, Funai EF, Savitz DA, Lipkind HS. Mode of delivery in nulliparous women and neonatal intracranial injury. Obstet Gynecol 2011;118(6):1239-1246. https://doi. org/10.1097/aog.0b013e31823835d3 17. Towner D, Castro MA, Eby-Wilkens E, Gilbert WM. Effect of mode of delivery in nulliparous women on neonatal intracranial injury. N Engl J Med 1999;341(23):1709-1714. https://doi.org/10.1056/ nejm199912023412301 18. Allen VM, O’Connell CM, Farrell SA, Baskett TF. Economic implications of method of delivery. Am J Obstet Gynecol 2005;193(1):192-197. https://doi.org/10.1016/j.ajog.2004.10.635 19. Peters H, Francis K, Harding K, Tookey PA, Thorne C. Operative vaginal delivery and invasive procedures in pregnancy among women living with HIV. Eur J Obstet Gynecol Reprod Biol 2017;210:295-299. https://doi.org/10.1016/j.ejogrb.2016.12.016 20. Royal College of Obstetricians and Gynaecologists. Operative Vaginal Delivery. London: RCOG, 2011. https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg26/ (accessed 9 June 2017). 21. Ismail NAM, Saharan WSL, Zaleha MA, Jaafar R, Muhammad JA, Razi ZRM. Kiwi Omnicup versus Malmstrom metal cup in vacuum assisted delivery: A randomized comparative trial. J Obstet Gynaecol Res 2008;34(3):350-353. https://doi.org/10.1111/j.1447-0756.2007.00701.x 22. Mola GDL, Kuk JM. A randomised controlled trial of two instruments for vacuum-assisted delivery (Vacca Re-Usable Omnicup and the Bird anterior and posterior cups) to compare failure rates, safety and use effectiveness. Aust N Z J Obstet Gynaecol 2010;50(3):246-252. https://doi.org/10.1111/j.1479828x.2010.01166.x

Accepted 26 September 2017.

ISSUES IN MEDICINE

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Truvada (emtricitabine/tenofovir) preexposure prophylaxis roll-out among South African university students: Lots of positives, but let us keep an eye on possible surprises K Montjane,1 BSc, BHSc; S Dlamini,2 MB ChB, FCP (SA), Cert ID (SA); C Dandara,1 BSc Hons, PhD

harmacogenetics Research Group, Division of Human Genetics, Department of Pathology and Institute of Infectious Disease and Molecular P Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 2 Division of Infectious Disease and HIV Medicine, Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 1

Corresponding author: C Dandara (collet.dandara@uct.ac.za)

Antiretroviral therapy (ART) has fundamentally altered the natural history of HIV/AIDS, sharply reducing HIV-related morbidity and prolonging longevity. However, there seems to be a resurgence in HIV infection rates in some parts of the world that has prompted consideration of pre-exposure prophylaxis (pre-EP) and vaccination. Despite their good viral suppression profiles, most drugs used as part of ART also have unwanted adverse drug reactions/effects (ADRs). In this article we acknowledge the utility of pre-EP in combating HIV transmission, but we also highlight the need to prepare for management of other unexpected outcomes such as ADRs and viral resistance, to ensure the success of the programme. S Afr Med J 2018;108(2):79-81. DOI:10.7196/SAMJ.2018.v108i2.13035

February 2018, Print edition

IN PRACTICE

Truvada is an antiretroviral (ARV) pill that combines two ARV drugs, tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), and has well-established efficacy in reducing the risk of contracting HIV if taken daily. Data from the South African (SA) Human Sciences Research Council show that women aged 15 - 25 years are most at risk of contracting HIV.[1] This report appears to have been one of the catalysts in prompting the Higher Education and Training HIV/ AIDS Programme (HEAIDS) and the National Department of Health to roll out Truvada to university and college students, because of the overlap with this high-risk age group. It is important to note that many studies with Truvada and preventive vaginal gels, involving thousands of women, have failed in SA and other Southern African Development Community countries.[2,3] These studies include trials such as FACTS and VOICE,[4-6] and it is thought that failure was due to lack of adherence and not ineffectiveness. The roll-out of Truvada therefore aims to offer protection to students at risk of HIV infection, in the hope that they will have better adherence, and has been extended to HIV-negative students across nine institutions of higher learning across SA. According to the director of HEAIDS, university students represent a group in which high rates of transactional sex occur, coupled with a low uptake of condoms (HEAIDS press release, 27 September 2017). It has been noted that transactional sex with so-called ‘sugar daddies’/‘blessers’ is a significant risk factor and social driver in the context of HIV infection among young people.[7] Relationships marked by age and material differences are increasingly common among university students and may involve exposure to unsafe sexual practices, among other things.[8] Truvada intervention will empower mostly young women to be in control of their infection status, as HIV prevalence and incidence rates remain disproportionately higher in females than in males.[9] However, as much as Truvuda is a potentially useful intervention, little is known about the drivers of product acceptability to end-users of such methods for HIV prevention. In a study that explored the end-user’s product preference for multipurpose prevention technology delivery forms in SA and Kenya, it was found that only 27% of women aged 18 - 30 years preferred the Truvada.[10] This is the age group into which most of the college and university students who are the target for Truvada roll-out fall. It is evident that we need to ask some questions: (i) is there sufficient evidence that college and university students will have better adherence than participants enrolled in previous studies in this country? (ii) since one of the drivers of uptake and adherence is perception of HIV risk, how certain are we that the college and university students perceive their risk as high? and (iii) lastly, as evidence shows that pre-exposure prophylaxis (pre-EP) is more likely to succeed if its roll-out is combined with interventions that target social drivers of HIV vulnerability specific to college and university students, will such interventions also be rolled out? There has been particular interest in Truvada since announcement of the roll-out, owing to its effectiveness profile. There is no doubt that if it is taken correctly, with optimal adherence, there is a huge potential to reduce numbers of new infections, estimated as more than 250 000 in the year 2016.[11] What this article seeks to highlight is that, despite the many positives, we should also be aware of possible surprises consequent to Truvada roll-out in healthy, HIVnegative young people. These are some of the questions we need to ask: (i) what are the possible effects of non-compliance with Truvada? (ii) what would be the consequences to participants who start off negative and are then infected, but continue to take Truvada intermittently? (iii) what are the possibilities of inducing resistance to Truvada in this young sexually active population?; and (iv) what effect is Truvada pre-EP likely to have on attitudes of sexually

active people to other sexually transmitted diseases or infections? Furthermore, how prepared is our healthcare system to handle and manage the multifaceted challenges that will potentially arise from the roll-out in the nine institutions? Massive simultaneous roll-out of awareness programmes to educate on possible consequences of nonadherence, and training of healthcare practitioners to handle this new phenomenon of Truvada preEP, are necessary.

Possible long-term effects

It is important to note that both TDF and FTC have documented adverse effects (adverse drug reactions, or ADRs). A meta-analysis by Siemieniuk et al.[12] showed that TDF/FTC was associated with stillbirth/early neonatal death and early premature delivery in HIVpositive participants, although there were no data on HIV-negative participants. Several studies have reported that another effect of the two drugs is lowering bone mineral density,[13,14] so an additional concern is the possible long-term effects of Truvada pre-EP on the general health of the population. Surveillance of ADRs and related toxicities remains a challenge in the public health sectors of developing countries,[15] mainly owing to lack of coherent structures or systems for pharmacovigilance and drug surveillance that track, assess and monitor safety profiles of ARVs. Patients on ARV therapy (ART) are usually monitored through a spontaneous surveillance method that is currently inefficient in detecting ADRs.[15] In resourcelimited health sectors like that of SA, pre-EP for healthy individuals will compete for scarce resources that are failing to contain a growing disease burden.

What about the cost?

In September 2016, SA started to implement the World Health Organization (WHO) evidence-based guidelines for universal test and treat (UTT). This strategy aims to test 90% of infected people, treat 90% of those tested, and have viral loads suppressed in 90% of individuals treated. SA already has one of the biggest ART programmes in the world, mostly funded by the fiscus, and implementation of UTT will significantly increase the number of people on ART. An increase in the budget will therefore be required in an already unfavourable economic climate. UTT will undoubtedly push demand for healthcare services in a context of a double burden of disease, high demand for medical personnel, and inadequate infrastructure. Public hospitals are already barely coping with the influx of patients, with complaints including medication stock-outs and sluggish financial support from donors, whose contribution has flatlined for the past 6 years.[16] To add a huge number of sexually active but healthy people to this overburdened healthcare platform would hasten its further deterioration. TDF has been associated with severe nephrotoxicity, changes in markers of renal function, serious renal adverse events, and decreases in bone mineral density.[17] It should also be taken into consideration that most data on TDF ADRs are from controlled trials in populations that are genetically different from much of SA’s student population. Furthermore, many individuals in resource-limited settings use a dual system of healthcare, traditional and conventional. With an estimated 26.6 million users of traditional medicine in SA,[18] new drug-herb interactions are likely to emerge. The challenges that policies such as UTT pose for developing countries have been well outlined, and have been predicted for sub-Saharan Africa (SSA).[19,20] The same challenges outlined by Bigna et al.[19,20] are applicable in the roll-out of Truvada to healthy individuals in SA. It was concluded that SSA cannot afford UTT, and in this case it is our submission that SA cannot afford the cost and implications of Truvada roll-out. SSA should always

February 2018, Print edition

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strategise in implementing WHO policies, factoring in local resource constraints. [19] We do not want to believe that Truvada roll-out is influenced by pharmaceutical companies that stand to gain regardless of the consequences to the country. There is no doubt that Truvada roll-out will require additional resources, so for a successful outcome, funds need to be made available in a sustainable manner. Total health expenditure is predicted to reach almost 10% of the gross domestic product in SA by 2017/18, amounting to a staggering USD12 billion (ZAR178 billion).[21] In the 2017 budget, the SA National Treasury allocated an additional USD63 million (ZAR885 million) to the response to HIV, in particular the implementation of UTT.[22] However, SA still faces a flood of new HIV infections, with an estimated 266 618 in 2016.[11]

Conclusion

Generally, ART has been associated with ADRs, and exposing healthy individuals to Truvada could put them at risk of renal failure and other complications.[20] It is our opinion that, as we look at the positive side of Truvada roll-out, due care should be taken in its implementation, as there are environmental and genomic factors specific to SA populations. We write this letter in the hope that as the Truvada pre-EP programme is rolled out, appropriate preparations are made to ensure its success and possible mitigation measures put in place to ameliorate the negatives. Acknowledgements. None. Author contributions. KM: co-conceptualised the idea, wrote the first draft, corrected, commented on all subsequent drafts and approved the final draft. SD: commented on all drafts, especially clinical aspects, and approved the final version of the manuscript. CD: conceptualised the idea, supervised KS in writing the first and subsequent drafts, commented on all drafts, approved the final version and submitted to the journal on behalf of co-authors. Funding. CD’s research group is funded by the South African Medical Research Council (SAMRC) and the National Research Foundation. KS has a bursary with the SAMRC. Conflicts of interest. None. 1. Zuma K, Shisana O, Rehle TM, et al. New insights into HIV epidemic in South Africa: Key findings from the National HIV Prevalence, Incidence and Behaviour Survey, 2012. Afr J AIDS Res 2016;15(1):67-75. https://doi.org/10.2989/16085906.2016.1153491

2. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med 2012;367(5):411-422. https://doi.org/10.1056/NEJMoa1202614 3. Van der Straten A, van Damme L, Haberer JE, Bangsberg DR. Unraveling the divergent results of preexposure prophylaxis trials for HIV prevention. AIDS 2012;26(7):F13-F19. https://doi.org/10.1097/ QAD.0b013e3283522272 4. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010;329(5996):11681174. https://doi.org/10.1126/science.1193748 5. Anderson PL, Glidden DV, Liu A, et al. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Science Transl Med 2012;4(151):151ra25. https:// doi.org/10.1126/scitranslmed.3004006 6. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med 2015;372(6):509-518. https://doi.org/10.1056/ NEJMoa1402269 7. Shisana O, Rehle T, Simbayi LC, et al. and the SABSSM III Implementation Team. South African National HIV Prevalence, Incidence, Behaviour and Communication Survey 2008: A Turning Tide among Teenagers? Cape Town: HSRC Press, 2009. http://hdl.handle.net/20.500.11910/4803 (accessed 1 January 2017). 8. Shefer T, Clowes L, Vergnani T. Narratives of transactional sex on a university campus. Cult Health Sex 2012;14(4):435-447. https://doi.org/10.1080/13691058.2012.664660 9. Gomez-Olive FX, Angotti N, Houle B, et al. Prevalence of HIV among those 15 and older in rural South Africa. AIDS Care 2013;25(9):1122-1128. https://doi.org/10.1080/09540121.2012.750710 10. Weinrib R, Minnis A, Agot K, et al. End-users’ product preference across three multipurpose prevention technology delivery forms: Baseline results from young women in Kenya and South Africa. AIDS Behav 2017;21:1-13. https://doi.org/10.1007/s10461-017-1911-6 11. Johnson LF, Chiu C, Myer L, et al. Prospects for HIV control in South Africa: A model-based analysis. Glob Health Action 2016;9:30314. https://doi.org/10.3402/gha.v9.30314 12. Siemieniuk RA, Foroutan F, Mirza R, et al. Antiretroviral therapy for pregnant women living with HIV or hepatitis B: A systematic review and meta-analysis. BMJ Open 2017;7(9):e019022. https://doi. org/10.1136/bmjopen-2017-019022 13. Purdy JB, Gafni RI, Reynolds JC, Zeichner S, Hazra R. Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J Pediatr 2008;152(4):582-584. https://doi.org/10.1016/j.jpeds.2007.12.020 14. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011;203(12):1791-1801. https://doi.org/10.1093/infdis/jir188 15. Masenyetse LJ, Manda SO, Mwambi HG. An assessment of adverse drug reactions among HIV positive patients receiving antiretroviral treatment in South Africa. AIDS Res Ther 2015;12:6. https://doi. org/10.1186/s12981-015-0044-0 16. Kates J, Wexler A, Lief E. Financing the Response to HIV in Low and Middle-income Countries. Menlo Park, Calif.: Kaiser Family Foundation, 2014. http://www.hst.org.za/publications/NonHST%20 Publications/20130923_KFF_UNAIDS_Financing.pdf (accessed 1 January 2018). 17. Ustianowski A, Arends JE. Tenofovir: What we have learnt after 7.5 million person-years of use. Infect Dis Ther 2015;4(2):145-157. https://doi.org/10.1007%2Fs40121-015-0070-1 18. Mander M, Ntuli L, Diederichs N, Mavundla K. Economics of the traditional medicine trade in South Africa: Health care delivery. S Afr Health Rev 2007;2007(1):189-196. http://hdl.handle.net/10520/ EJC35482 (accessed 2 January 2018). 19. Bigna JJR, Plottel CS, Koulla-Shiro S. Challenges in initiating antiretroviral therapy for all HIVinfected people regardless of CD4 cell count. Infect Dis Poverty 2016;5(1):85. https://doi.org/10.1186/ s40249-016-0179-9 20. Nansseu JR, Bigna JJ. Antiretroviral therapy related adverse effects: Can sub-Saharan Africa cope with the new ‘test and treat’ policy of the World Health Organization? Infect Dis Poverty 2017;6(1):24. https://doi.org/10.1186/s40249-017-0240-3 21. World Bank. World development indicators. https://data.worldbank.org/data-catalog/worlddevelopment-indicators (accessed 1 January 2018). 22. National Treasury, South Africa. 2017 budget speech. http://www.treasury.gov.za/documents/ national%20budget/2017/speech/speech.pdf (accessed 1 January 2018).

Accepted 12 December 2017.

February 2018, Print edition

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

IN PRACTICE

MEDICINE AND THE LAW

Is there transparency in the pricing of medicines in the South African private sector? V Bangalee,1 BPharm, MPharm, PhD; F Suleman,1,2 BPharm, MPharm, PhD Discipline of Pharmaceutical Sciences, School of Health Sciences, Westville Campus, University of KwaZulu-Natal, Durban, South Africa Prince Claus Chair of Development and Equity for the theme Affordable (Bio)Therapeutics for Public Health (September 2016 - September 2018), Faculty of Sciences, Utrecht University, Utrecht, The Netherlands 1 2

Corresponding author: V Bangalee (bangalee@ukzn.ac.za)

Recent investigations by the Competition Commission of South Africa (SA) of suspected excessive pricing of cancer medicines in SA by three global pharmaceutical companies have once again drawn attention to increasing medicine pricing transparency and warrant further public debate. S Afr Med J 2018;108(2):82-83. DOI:10.7196/SAMJ.2018.v108i2.12815

Recent investigations by the Competition Commission of South Africa (SA) of suspected excessive pricing of cancer medicines in South Africa (SA) by three global pharmaceutical companies, i.e. Roche Holding AG (Roche), Pfizer Inc. (Pfizer) and Aspen Pharmacare Holdings Ltd (Aspen), have once again drawn attention to the need for medicine pricing transparency. These companies have been accused of engaging in excessive pricing, price discrimination and/or exclusionary conduct in the provision of breast cancer medicine in SA.[1] Previously, in the SA private sector, medicine price inflation, medicine price transparency and medicine price uniformity represented significant problems in an unregulated medicines market.[2] The loss of benefits to consumers resulting from the high levels of discounting and payment of incentives within the pharmaceuticals supply chain had raised serious concerns in the National Department of Health and made it difficult to determine the true price of a medicine.[3] The single exit price (SEP) regulation, first introduced in 2004 for all medicines in the private sector, is an example of SA’s attempt to control prices and improve pricing transparency in the supply chain. The SEP, which is a composite of the ex-manufacturer’s price, logistics fee and value added tax (VAT), standardised in SA at 14%, mandated that manufacturers sell their products at one price to all their customers (other than the State), regardless of the nature of the customer’s order size and consumption levels.[4,5] Under this regulation, manufacturers were allowed to set their SEP at the time of introduction of the product, which may be raised once on an annual basis. They may, however, make several temporary price reductions during the year for competitive reasons.[6] However, over a decade since its introduction as a price-control measure for medicines, complaints about access to affordable medi cines in SA still persist. After the initial cost reduction brought about by the SEP, there has not been any formal adjudication of prices against comparable products in SA. Prices remain artificially inflated compared with the same products available internationally,[7] as is the premise for the case against Pfizer, which is being investigated for excessive pricing of the lung cancer medication Xalkori (crizotinib) in SA.[1] Similarly, Aspen, which is the dominant firm in the provision of Leukeran (chlorambucil), Alkeran (melphalan) and Myleran (busulfan) in SA, has seemingly taken advantage of their monopoly in

the market and are under investigation for excessive pricing of these medicines.[1] After observing that medicine prices and out-of-pocket spending on medicines were increasing, consumer advocates and policy makers have called for greater price transparency.[8] Several factors have been recognised that constitute reduced transparency in the supply chain. Among these is a lack of transparency in determining the logistics fee segment of the SEP. The logistics fee is determined through negotiations between the manufacturer or importer and the logistics service provider; however, the process and contracts are not made public. Manufacturers pay wholesalers and distributors a logistics fee from the SEP, but it is not evident if all logistics service providers are able to negotiate the same fee or if the fee is as reflected in the medicines database (South African Medicine Price Registry).[9] The nature of these negotiations, which include concealment by manufacturers of prices or a price-setting approach, represents a barrier to price transparency in the SEP.[10] The allegation by stakeholders, such as Transpharm, that the logistics fee is being exploited by pharmaceutical companies, led to the following proposals.[11] Firstly, transparency in the logistics fee is required by Regulation 21(2)(d) of the Medicines and Related Substances Act, 1965 (Act No. 101 of 1965), as amended. Secondly, Regulation 5(2)(f) states that the manufacturer and logistics provider must agree on a fee; and, thirdly, that under Regulation 5(2)(g) there be a cap on the logistics fee (as opposed to a fixed fee).[11] In addition to the logistics fee, SA’s current patent laws further contribute to artificially inflated prices. As argued by some parties, pharmaceutical manufacturers have a broad discretion in deter mining the prices they charge, and patent protection provides a source of monopoly that allows manufacturers a higher profit than the marginal cost of production.[7] ‘Ever-greening’ of products also remains a significant issue, as manufacturers prolong their patents through marginal adaptations to product formulations. In most instances, these adaptations do not offer any clinically significant advantages to patients – the more pertinent consequence being the barrier to generic medicine entry for many years beyond the original patent. This limits medicine accessibility and artificially sustains the inflated cost of a medicine.[7] Roche has been suspected of using the ever-greening strategy for its breast cancer medicines (Herceptin

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(trastuzumab) and Herclon (trastuzumab)) to the detriment of patients and in contravention of the Competition Act.[1] Under the current SEP regulation, companies of originator medi cines still have the freedom to set launch prices. However, the Pricing Committee is responsible for determining annual price increases in accordance with the SEP regulation methodology. Consequently, pricing of these medicines remains largely at the discretion of the manufacturer. In this regard, government has proposed the introduction of an international benchmarking system, in which the prices of originator medicines will be compared with those in a basket of countries (Australia, Canada, New Zealand and Spain, together with SA). For generic medicines, the ex-manufacturer price is to be set at least 40% lower than the existing price of the originator medicine.[12] The process is likely to reduce the SEP of medicines in SA and create some transparency of pricing at the ex-manufacturer level. This legislative framework has been in the pipeline since 2006, but has faced stiff lobbies in terms of implementation. If implemented, it would reduce originator medicine costs by ~25%.[13] In addition to international benchmarking, the application of pharmacoeconomics analyses on a voluntary basis has also been proposed to determine medicine prices. This provision, however, requires considerable resources and capacity on the part of the manufacturers to prepare submissions, as well as by the Pricing Committee to critically assess the submissions and make defensible determinations on that basis.[9] Arguments against increased transparency of negotiations and publication of detailed individualised pricing data derive mainly from manufacturers, as it carries the risk of allowing competitors to be aware of other manufacturers’ pricing strategies and therefore exposes companies to antitrust liability. Antitrust laws prohibit activities that restrict competition. This exchange of commercially sensitive information between competitors may facilitate price co-ordination and result in standardisation of prices. Thus, any system aimed at increasing price transparency should always be cautionary of antitrust rules and try to simultaneously establish a fair price for medicines.[14] It is also vital that there is greater transparency and consistency in the pricing of medicines across the SA public and private healthcare sectors. The economic objectives of the National Drug Policy have been to attain affordable prices for all SA citizens, but there are irregularities and discrepancies in medicine pricing across the two sectors. Price variations exist because public, private and nongovernmental sectors procure medicines separately. Comparative state tender prices have revealed that some medicines are available to the state at approximately one-tenth of the cost of the same medicine in the private sector.[7] Roche has been implicated in price discrimination by charging differential prices for breast cancer medicines in the private and public healthcare sectors by restricting the sale of Herceptin and Herclon to a particular sector.[1] It has been estimated that a 12-month course of Herceptin costs ≥R500 000 in the private sector, whereas Roche offers substantially lower prices for Herclon in the public sector.[1] The need for more consistent prices becomes imperative in lieu of the move to introduce universal health coverage in SA. Finally, it has been suggested that transparency in the pricing of medicines would empower patients to make more informed choices, understand how prices are set and become aware of price discrimination.[10] According to standard economic theory, in most markets, price transparency leads to lower and more uniform prices. Unfortunately, there has been little research conducted to determine if this premise also holds true for the pharmaceutical market.

Conclusion

SA’s medicine pricing interventions are synonymous with an acrimonious history of implementation. Despite government’s success in implementing several key polices to reduce medicine prices, considerable more research is required to ascertain if implemented policies have produced the appropriate positive outcomes. Much of the published literature on SA’s policy development has covered aspects of the history and a general overview; however, there is a dearth of studies that have looked at policy impact and implication. These studies have become more important as SA moves towards universal healthcare coverage, as this transformation requires inte grating the strongest facets of all policies to ensure sustainable access to quality, affordable essential medicines. Transparency in pricing needs to be achieved as well, but to policy makers alone or also to the general public? Does the business model need to be changed for pharmaceuticals? These are questions that the European Union, the USA and even the World Health Organization are currently grapp ling with. Acknowledgements. None. Author contributions. VB and FS both contributed to the article. Funding. Research reported in this publication was supported by the Fogarty International Center (FIC), National Institutes of Health (NIH) Common Fund, Office of Strategic Coordination, Office of the Director (CF/OSC/OD/NIH), Office of AIDS Research, Office of the Director (OAR/OD/NIH), National Institute of Mental Health (NIMH/NIH), award number D43TW010131. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Conflicts of interest. None.

1. Business Report. #BadPharma: Pharmaceutical companies behind high cost for cancer medication. 2017. https://www.iol.co.za/business-report/badpharma-pharmaceutical-companies-behind-highcost-for-cancer-medication-9770177 (accessed 11 December 2017). 2. Carapinha and Company. Single exit price legislation: A source of harm to competition. 2016. http://www.carapinha.com/single-exit-price-legislation-a-source-of-harm-to-competition/#sthash. nXKTewtG.dpuf (accessed 11 December 2017). 3. Bangalee V, Suleman F. Has the increase in the availability of generic drugs lowered the price of cardiovascular drugs in South Africa? Health SA 2016;21:60-66. https://doi.org/10.1016/j. hsag.2015.10.004 4. Bodhania M. Pharmaceutical sector presentation for private health sector Indaba. 2007. http:// www.slideserve.com/moeshe/pharmaceutical-sector-presentation-for-private-health-sector-indaba (accessed 11 December 2017). 5. Nicolosi E, Gray A. Potential cost savings from generic medicines – protecting the prescribed minimum benefits. S Afr Fam Pract 2009;51(1):59-63. 6. Ngozwana S. Policies to control prices of medicines: Does the South African experience have lessons for other African countries? In: Banda G, Tibandebage P, Wamae W, eds. Making Medicines in Africa. Hampshire, UK: Palgrave Macmillan, 2016:203-223. 7. Makholwa A. Medicine pricing: New prescriptions needed. 2014. http://ftp.bhfglobal.com/newprescriptions-needed (accessed 14 December 2017). 8. Hawkins L. Review Series on Pharmaceutical Pricing Policies and Interventions: Working Paper 4: Competition Policy. World Health Organization/Health Action International Project on Medicine Prices and Availability. Geneva: WHO/HAI, 2011. 9. Gray A, Suleman F. Pharmaceutical pricing in South Africa. In: Babar Z, ed. Pharmaceutical Prices in the 21st Century. Switzerland: Springer, 2015:251-265. 10. Austin DA, Gravelle JG. Does price transparency improve market efficiency? Implications of empirical evidence in other markets for the health sector. 2007. https://www.fas.org/sgp/crs/misc/RL34101.pdf (accessed 11 December 2017). 11. Board of Healthcare Funders of Southern Africa. Health sector inquiry: Pharmaceutical task group’s response to third party submissions concerning the pharmaceutical sector. http://www.compcom. co.za/wp-content/uploads/2015/05/PTG-Submission-Response-to-Stakeholders1.pdf (accessed 11 December 2017). 12. Taylor B. Rationing of medicines and health care technology: Pooling of resources and purchasing of health care. S Afr Health Rev 2007;1:123-137. 13. Van den Heever A. Review of competition in the South African health system. 2012. http://www. compcom.co.za/wp-content/uploads/2014/09/Review-of-Competition-in-the-South-African-HealthSystem.pdf (accessed 11 December 2017). 14. Daems R, Maes E. Global pharmaceutical management: Building a fair pricing policy (No. 2014/05). 2014. http://web2.msm.nl/RePEc/msm/wpaper/MSM-WP2014-05.pdf (accessed 3 January 2018).

Accepted 18 September 2017.

February 2018, Print edition

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

IN PRACTICE

HEALTHCARE DELIVERY

Burkitt’s lymphoma: The prevalence of HIV/AIDS and the outcome of treatment P B Hesseling,1 MD; F Kouya,2 MD; E Katayi,2 MD; G Mbah,2 RN; P Wharin,3 MD epartment of Paediatrics and Child Health, Tygerberg Children’s Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University, D South Africa 2 Cameroon Baptist Convention Health Board, Bamenda, Cameroon 3 Beryl Thyer Memorial Africa Trust, Warkton, UK 1

Corresponding author: P B Hesseling (pbh@sun.ac.za)

The prevalence of HIV in Burkitt’s lymphoma (BL) patients and the outcome of treatment in Cameroon were unknown. Records of all patients diagnosed with BL at three Cameroon Baptist Convention hospitals were reviewed to ascertain the recorded HIV status and outcome of treatment. Of 979 patients diagnosed with BL, 717 were tested for HIV and 11 (1.5%) were HIV-positive. Three of eight patients treated with both cyclophosphamide (CPM)-based chemotherapy and antiretrovirals were alive at 62, 96 and 111 months, respectively. The HIV rate was comparable to that of 1% for the general population of children aged <15 years. Low-cost high-frequency CPM was the only available treatment option for BL and was associated with 37.5% long-term survival in a resource-limited setting. S Afr Med J 2018;108(2):84-85. DOI:10.7196/SAMJ.2018.v108i2.12441

The population of Cameroon in 2014 was 22 773 014, of whom ~40% (9 109 205) were aged <15 years. It was estimated that 94 000 of these children (1%) were infected with HIV, and only 11% of these received antiretroviral (ARV) therapy.[1] In 2013, the prevalence of HIV infection in pregnant women in the north-west and south-west regions was 4.6% and 6.8%, respectively, and the mother-to-child transmission rate in 18-month-old breastfed infants was 25%.[1] Children diagnosed with Burkitt’s lymphoma (BL) between 2003 and 2015 at Banso and Mbingo Baptist hospitals in the north-west and Mutengene Baptist Hospital in the south-west were all treated with cyclophosphamide-based chemotherapy regimens, with an overall long-term survival rate of 55%.[2]

Objective

To record the prevalence of HIV and the outcome of treatment in a large cohort of patients with BL.

Methods

Our database is a Pediatric Oncology Network Database (POND) cancer registry for the period 2003 - 2013. The number of patients in whom enzyme-linked immunosorbent assay was positive for HIV, the CD4+ count when available, and whether ARV treatment was given or not were extracted from the database. The diagnosis of BL was based on a fine-needle tumour aspirate, a bone marrow aspirate, a cytological cerebrospinal fluid examination and an abdominal ultrasound scan. The long-term outcome was established by personal follow-up of every HIV-positive patient or their families. Chemotherapy induction treatment consisted of cyclophos phamide (CPM) 40 mg/kg on days 1, 8 and 15, followed by consolidation chemotherapy with 1 - 3 more doses of CPM with or without intravenous (IV) vincristine 1.5 mg/m2 and IV methotrex ate 1.0 g/m2 for advanced or non-responsive disease. The duration of chemotherapy was 2 months. Rescue treatment of early relapses consisted of 3 weekly pulses of CPM and vincristine, and relapses

beyond 1 year were treated in full again. [3] ARV treatment was not freely available in the early years of the study. More recent treatment always consisted of three drugs, based on World Health Organization guidelines and the national protocol. Examples of first-line treatment are as follows: age <3 years – abacavir + lamivudine + lopinavir/ ritonavir; age 3 - 10 years and adolescents weighing <35 kg – abacavir + lamivudine + efavirenz; and age 11 - 19 years or weight >35 kg – tenofovir + lamivudine (or emtricitabine) + efavirenz. Ethical approval for the BL treatment protocols was obtained from the Institutional Review Board of the Cameroon Baptist Convention Health Board.

Results

Of 979 patients diagnosed with BL, 717 (73.2%) were tested for HIV and 11 (1.5%) tested positive. Their ages ranged from 2 to 13 years (median 7 years). The age at diagnosis of BL, St Jude stage of the BL, CD4+ count if done, ARV treatment given, current status and duration of long-term survival are listed in Table 1. On 30 Octo ber 2016, three of eight patients (37.5%) who had received the recommended ARV treatment and were still on ARV maintenance treatment were long-term survivors at 111, 96 and 62 months, respectively. Three patients who were not treated with ARVs died within 3 - 15 months, and five patients treated with ARVs died within 3 - 39 months after the onset of treatment from progressive disease. There was no chemotherapy-related death. The CD4+ count at diagnosis was recorded in only four patients.

Discussion

Children with HIV have an increased risk of developing malignancies, and BL accounted for 21% of malignancies in HIV-positive children in South Africa, with a projected cure rate of 54.6% at 60 months using modern chemotherapy.[4] Modern chemotherapy for BL has a potential cure rate of >90% in HIV-negative patients,[5] but at considerable cost and the risk of significant morbidity. Our BL

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Table 1. Patient details and outcome

Patient no. 1 2 3 4 5 6 7 8 9 10 11

Age (years) 5 12 7 3 9 2 4 3 8 12 13

St Jude stage III III III III III III II III III IV III

CD4+ count (cells/µL) No record 145 No record 559 No record No record No record No record No record 80 30

ARV treatment No Yes Yes Yes No Yes Yes No Yes Yes Yes

Current status Dead Dead Alive Alive Dead Alive Dead Dead Dead Dead Dead

Length of survival (months) 15 6 96 111 3 62 4 3 39 39 3

ARV = antiretroviral.

patients were treated with chemotherapy of much lower intensity because of limited access to drugs and supportive care.[6] Long-term survival of 5 - 9 years in three of eight patients (37.5%) who received both chemotherapy and ARVs is encouraging. The documented HIV prevalence rate of 1.5% in this large cohort of BL patients is comparable to the 1% HIV prevalence rate for the general population of children in Cameroon.

Conclusion

HIV-positive children with BL are best treated with a contextappropriate chemotherapy regimen. Acknowledgements. Poster presentation at the 48th congress of the International Society of Paediatric Oncology (SIOP), Dublin, October 2016. Author contributions. PBH: Principal investigator, FK: physician in charge of the children’s cancer service, EK: physician in charge of the HIV service of the Cameroon Baptist Convention Health Board, GM: research

Funding. Funding was received from the Beryl Thyer Memorial Africa Trust (UK), World Child Cancer (UK) and the Swiss Cancer League. Conflicts of interest. None.

1. Joint United Nations Programme on HIV/AIDS (UNAIDS). 2015 progress report on the Global Plan towards the elimination of new HIV infections among children and keeping their mothers alive. http:// www.unaids.org/sites/default/files/media_asset/JC2774_2015ProgressReport_GlobalPlan_en.pdf (accessed 30 December 2017). 2. Hesseling P, Kouya F, Mbah G, et al. Burkitt lymphoma: Long term outcome in 738 children treated with cyclophosphamide-based protocols in rural Cameroon from 2003 to 2013 (abstract O-043). Pediatr Blood Cancer 2015;62(S4):S156. https://doi.org/10.1002/pbc.25715 3. Hesseling PB, Njume E, Kouya F, et al. The Cameroon 2008 Burkitt lymphoma protocol: Improved survival with treatment adapted to disease stage and response to treatment. Pediatr Hematol Oncol 2012;29(2):119-129. https://doi.org/10.3109/08880018.2011.644881 4. Davidson A, Wainwright RD, Stones DK, et al. Malignancies in South African children with HIV. J Pediatr Hematol Oncol 2014;36(2):111-117. https://doi.org/10.1097/MPH.0b013e31829cdd49 5. Patte C, Auperin A, Michon I, et al. The Societe Francaise d’Oncologie Pediatrique LMB 89 Protocol: Highly effective multi-agent chemotherapy tailored to the tumour burden and initial response in 561 unselected children with B-cell lymphoma and L3 leukaemia. Blood 2001;97(11):3370-3379. https:// doi.org/10.1182/blood.V97.11.3370 6. Hesseling P, Israels T, Harif M, Chantada G, Molyneux E. Practical recommendations for the management of children with endemic Burkitt lymphoma in a resource limited setting. Pediatr Blood Cancer 2013;60(3):357-362. https://doi.org/10.1002/pbc.24407

assistant responsible for the cancer registry and data co-ordination, PW: involved in planning and follow-up.

Accepted 5 September 2017.

February 2018, Print edition

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The development of hospital-based palliative care services in public hospitals in the Western Cape, South Africa L Gwyther,1 MB ChB, FCFP, MSc Pall Med; R Krause,2 MB ChB, MFamMed, MPhil Pall Med; C Cupido,3 MB ChB, FCP (SA); J Stanford,4 MB ChB, MPhil Pall Med; H Grey,4 BSc Nursing, Dipl Oncol Nursing, MBA, PGD Pall Med; T Credé,5 MB ChB, FCP (SA); A de Vos,6 MSocSci Clinical Social Work; J Arendse,7 BTech Oncology, Dipl Midwifery, Palliative Care Cert; P Raubenheimer,8 MB BCh, FCP (SA) alliative Medicine, Division of Family Medicine, Faculty of Health Sciences, University of Cape Town, and Hospice Palliative Care Association of P South Africa, Cape Town, South Africa 2 Palliative Medicine, Division of Family Medicine, Faculty of Health Sciences, University of Cape Town, and Groote Schuur Hospital, Cape Town, South Africa 3 Division of General Medicine, Faculty of Health Sciences, University of Cape Town, and Victoria Hospital, Cape Town, South Africa 4 Knysna-Sedgefield Hospice, Knysna, South Africa 5 Division of General Medicine, Faculty of Health Sciences, University of Cape Town, and Mitchell’s Plain Hospital, Cape Town, South Africa 6 Social Work Services, Groote Schuur Hospital, Cape Town, South Africa 7 Groote Schuur Hospital, Cape Town, South Africa 8 Division of General Medicine, Department of Medicine, Faculty of Health Sciences, University of Cape Town, and Groote Schuur Hospital, Cape Town, South Africa 1

Corresponding author: L Gwyther (liz.gwyther@uct.ac.za)

With the recent approval of a South African (SA) National Policy Framework and Strategy for Palliative Care by the National Health Council, it is pertinent to reflect on initiatives to develop palliative care services in public hospitals. This article reviews the development of hospital-based palliative care services in the Western Cape, SA. Internationally, palliative care has been integrated into hospital services, with Higginson[1] describing hospital palliative care teams in the UK palliative care needs assessment report in 1997. Weissman and Meier[2] describe the importance of an indicator guide to identify patients in need of palliative care in the hospital setting in the USA. They also stress the need to improve palliative care skills in clinicians caring for patients with serious illnesses and indicate specific criteria for referral to a hospital palliative care service. The importance of integration of palliative care into health services was highlighted with the adoption of the 2014 World Health Assembly (WHA) resolution,[3] ‘Strengthening of palliative care as a component of comprehensive care throughout the life course’. The WHA resolution draws on the World Health Organization’s definition of palliative care[4] as ‘an approach that improves the quality of life of patients and their families facing problems associated with lifethreatening illness, through the prevention and relief of suffering, the early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual’. The resolution states that palliative care is an ‘ethical responsibility of health systems, and that it is the ethical duty of health care

professionals’ to relieve suffering. Palliative care is applicable to any diagnosis that may result in a person’s death. It is applicable early in the diagnosis of a life-threatening illness, in conjunction with treatment that is aimed at containing the illness. Therefore, all healthcare professionals should be competent to provide palliative care alongside disease-specific treatment. Referral for specialist palliative care, such as may be provided by a hospice, would then only be for patients with challenging symptoms and/or psychosocial issues.

Development of palliative care in South Africa

Palliative care services in SA started in the non-governmental sector in the 1980s. Hospices were established in communities that could afford to support them and initially provided end-of-life care, mainly to cancer and HIV patients – from the mid-1990s onwards. Depending on admission criteria to a hospice service, patients with cancer, HIV, end-stage organ failure, progressive neurological disorders and tuberculosis (TB), particularly drug-resistant TB, receive palliative care – usually in the patient’s home. Hospice services in SA are nurse led with support from an interdisciplinary team, including social workers, spiritual counsellors and doctors. South Coast Hospice in Port Shepstone, KwaZulu-Natal initiated an integrated community-based home care service in response to the increasing number of HIV patients requiring palliative care.[5] This integrated approach developed partnerships with the government

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sector, leading to a greater awareness of the benefits of palliative care by the state sector. The first hospital-based palliative care team in SA was established in Charlotte Maxeke Johannesburg Academic Hospital in 2001.[6] The awareness of the benefits of palliative care in the hospital setting led to the development of isolated pockets of excellence providing palliative care in the public health sector in SA. Chief of these services is Wits Palliative Care, Gauteng Centre of Excellence for Palliative Care, Chris Hani Baragwanath Hospital in Soweto. The programme developed from a hospital-based palliative care team established in 1999, which ran the N’Doro project funded by Irish Aid for 3 years (2003 - 2006), providing specialist palliative care services, outreach visits to the Soweto community, consultations for patients in Chris Hani Baragwanath Hospital, as well as training of healthcare professionals, conducting research and undertaking advocacy activities for palliative care.[2] A research study undertaken by the Health Systems Research Unit at the South African Medical Research Council, evaluating the N’Doro project, demonstrated a reduction in hospital costs and additional benefits to the hospital care system by reducing congestion and ensuring that hospital beds are freed for acute care.[7]

Palliative care in Western Cape hospitals

In the Western Cape, palliative care services extended into public service hospitals, with various models being introduced and developed based on local needs. The development of these hospital services has been underpinned by research that demonstrated the benefits of palliative care in hospitals. Drawing on the UK Gold Standards Framework (GSF), Drs L van Niekerk and C Cupido established a palliative care service – the Abundant Life programme – at Victoria Hospital, a large district hospital (with specialist services) in Cape Town. Seed funding for nursing and administrative support was provided by donors, especially Rotary.[8] Patients, initially mainly those with advanced organ failure, and family members attend an outpatient group clinic held fortnightly. A multidisciplinary approach assists in educating the patient and family about their illness and prognosis, providing practical advice on coping with the illness, as well as emotional support. The Abundant Life patients were shown to have fewer admissions, fewer days in hospital, higher rates of supported home deaths and lower hospital costs than the control group.[9] The referrals have grown from 200 patients in the first 2 years and 70 active patients at the end of 2011, to >600 referrals for 2016 and 250 active patients. The service has extended from the medical wards into the surgical wards, referral criteria have been broadened and a part-time palliative care nurse has been appointed to a provincial position at Victoria Hospital. Donor funding continues to support a large part of this programme. Groote Schuur Hospital (GSH), a large tertiary teaching hospital in Cape Town, introduced palliative care in 2011, when Dr T Credé, head of the medical Emergency Unit at the hospital, identified the need to improve end-of-life care for patients presenting with acute or chronic conditions, who were not expected to survive beyond 24 hours and were often not prioritised for admission, given the pressure with regard to acute and elective beds. Four unfunded palliative care beds were opened in a ward with bed space to ensure patients admitted from the Emergency Unit and their families received the appropriate care. The ward staff, St Luke’s hospice and the Hospice Palliative Care Association of SA provided training and mentorship to GSH staff, creating a space for dignified endof-life care in the hospital. Having dedicated beds where patients are cared for in the last 24 hours of their life, has not only led to a

new expertise in the treatment of such patients, but has also enabled new nurse-led expertise in the hospital. Nurses have generally been very positive about the experience of re-focusing comprehensive care with regard to this cohort of challenging patients. The main cohort of patients seen in the Emergency Unit are those with major strokes, and the median length of stay is 25 hours. The success of this project, together with the research findings from StuartClark et al.,[9] which demonstrated a 42% 12-month mortality rate among medical patients at GSH, and research of Van Niekerk and Raubenheimer,[10] who identified a high proportion of patients expected to benefit from end-of-life and palliative care, were used to motivate for a permanent hospital palliative care team for medical patients with acute conditions admitted to GSH. Van Niekerk and Raubenheimer[10] reported that 20.3% of patients in general medical wards had life-limiting illnesses, potentially requiring palliative care. They also commented on the young age of patients, the high prevalence of end-stage renal failure and HIV/TB among those assessed as needing palliative care. The GSH palliative care service is run by a nurse-led, doctor-supported team introduced initially into the acute medical wards, but subsequently expanded to the Emergency Unit, the Renal Unit (particularly for patients with end-stage renal disease not accepted into the provincial renal replacement programme) and more recently in 2017 to the surgery and gynaecology wards. The hospital palliative care team consists of 2 palliative care professional nurses, 2 auxiliary social workers, spiritual care volunteers and medical support from the University of Cape Town palliative care team in the Division of Family Medicine. There is a very close working relationship with the departments of Social Work, Allied Health and Nursing in the hospital. The main objectives of the team are to provide a comprehensive palliative care assessment, assist with discharge planning using the multidisciplinary team, optimise pain and symptom control, provide psychosocial and spiritual support to the patient and their families, liaise with and refer to community-based services and follow up telephonically, including bereavement calls. The team develops an individual care plan for each patient, which guides care once the patient is discharged home. The discharge plan includes referral to a community-based service, often the hospice, which enables the patient to live as actively as possible with their illness and supports their family in providing care at home. From January to December 2016 (in the medical pavilion only), the GSH palliative care team received 79 referrals per month, provided care to 852 unique patients and gave 861 telephonic consultations to discharged patients. The most common conditions for which referrals are received are end-stage cardiac failure (44%), metastatic cancer (40%), end-stage renal failure – not for the renal replacement programme (19%), progressive neurological conditions and endstage chronic obstructive pulmonary disease (COPD) (8% each).

Hospital/hospice partnerships

District hospitals have also introduced palliative care services, mainly in conjunction with local hospice support. Stellenbosch Hospital has provided a ward to Stellenbosch Hospice and provides medicines and support services to the 10-bed hospice. Knysna Provincial Hospital staff meet fortnightly with the staff from the Knysna-Sedgefield and Plettenberg Bay hospices to discuss challenging problems. Patients are admitted to the palliative care programme if they have been admitted to the hospital at least twice in 4 weeks or have been assessed as terminally ill and are currently in hospital. Patients are seen by the palliative care team in the medical wards at the hospital and a palliative care plan is developed for each patient referred. In addition, Knysna-Sedgefield Hospice staffs the 6-bed intermediate care facility

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Table 1. Identifying patients who require palliative care: Summary of the Supportive and Palliative Care Indicators Tool[13] General indicators for palliative care referral Performance status is poor or deteriorating (the person is in bed or a chair for ≥50% of the day); reversibility is limited Dependent on others for most care needs owing to physical and/or mental health problems ≥2 unplanned hospital admissions in the past 6 months Significant weight loss (5 - 10%) over the past 3 - 6 months, and/or a low body mass index Persistent troublesome symptoms, despite optimal treatment of underlying condition(s) Patient asks for supportive and palliative care, or treatment withdrawal Clinical indicators for ≥1 advanced conditions E.g. cancer, heart/vascular disease, kidney disease, respiratory disease, liver disease, dementia/frailty, neurological disease Indicators for infectious diseases are still to be agreed with regard to the South African setting

on the hospital grounds and occasionally patients requiring palliative care are referred to this facility. Patients are discussed by the team and a palliative care plan is developed for each patient to ensure a holistic approach to symptom management. This comprehensive integrated approach is feasible in small communities, but has the same barriers to access to palliative care as larger centres.

Identifying patients who require palliative care

The main barrier to palliative care access is the identification of palliative care patients. The GSF Prognostic Indicator Guidance (PIG)[11,12] and the Supportive and Palliative Care Indicators Tool (SPICT)[13,14] are documents that are used internationally to assist the clinician to implement palliative care principles of pain and symptom management with psychosocial and spiritual support. At GSH and Victoria Hospital a simplified and modified 1-page tick-sheet based on the GSF-PIG is used to assist with the identification of palliative care patients (including HIV patients). There is a need to develop and validate a SA-specific referral tool for palliative care in hospital and community settings. Referrals are ‘open’ to all health professionals, and can be from doctors, nurses, allied health professionals and social workers involved in the care of ward patients (Table 1). Hand-in-hand with a simplified referral form, basic education and awareness regarding palliative care among all healthcare professionals contribute to a steady referral pattern. Seventy-two nurses and social workers from GSH underwent the 40-hour training programme in palliative care presented by the Hospice Palliative Care Association of SA to ensure that they are able to assist the hospital palliative care team and identify patients who would benefit from such care. Therefore, with the minimal resources allocated and low levels of funding, the GSH palliative care team have been able to prioritise a generalist and inclusive approach to palliative care, with the specialist sister acting not only as an expert clinician, but also as a mentor and trainer of ward staff and the allied health support team. The ward staff and associated allied health teams have been given the training and support they need to provide palliative care.

Linking with community resources

To ensure comprehensive continued care of patients, hospital-based palliative care services have understood the fundamental need to develop strong ties with community resources. The palliative care team approach has been instrumental in establishing a strong referral process with post-discharge primary home-based care, either to hospices or provincial non-governmental organisation (NGO)-contracted homebased carers. A combined care approach ensures easy referral, care plans that are patient centred and better team support. Palliative care as a hospital-based specialty is still in its infancy in SA and there is enormous opportunity for growth in a traditional

specialty-based setting, such as a hospital. The number of hospitalised patients who are in their last year of life, presents a unique opportunity for identifying patients and instituting care plans that are patient centred and can also be followed up in the community setting. Capturing data on hospital palliative care is essential and provides important opportunities for research and advocacy around palliative care and for updating African palliative care guidelines for life-threatening illnesses. A recent needs assessment of palliative care in SA indicated that only 17.8% of patients who could benefit from palliative care at the end of their lives receive such care.[13] The NGO sector, traditional provider of palliative care, cannot meet the total need for palliative care in SA; the government should also not expect NGOs to substitute for governmental obligations.[14] It is therefore essential that all healthcare professionals in SA are able to identify people needing palliative care, initiate basic palliative care to ensure better care in the last year of a patient’s life and link such patients with community services to continue provision of palliative care in the patient’s home. This article describes models for palliative care at tertiary, provincial and district hospital level, which could inform the development of hospital-based palliative care as the national policy for palliative care is implemented in SA. Palliative care is an essential component of universal health coverage. It ‘is recognised as fundamental to improving quality of life, well-being, comfort and human dignity for individuals’. The integration of palliative care into hospitals recognises these imperatives and contributes to better quality of care with a strong, patient-centred approach for people with lifethreatening illnesses and their families. Acknowledgements. We acknowledge the staff of palliative care hospital teams, as well as the patients and their families. Author contributions. RK, LG and PR conceived the article. LG wrote the introduction and development sections. RK, PR and TC composed the section on GSH. LG, HG and JS were responsible for the partnership section. RK, LG, PR and CC wrote on identifying patients. LG and RK compiled the community resources section. All co-authors reviewed the article, added comments and made editorial changes, which were included by LG. Funding. None. Conflicts of interest. None. 1. Higginson IJ. Health care needs assessment: Palliative and terminal care. In: Stevens A, Raftery J, eds. Health Care Needs Assessment. Oxford: Wessex Institute of Public Health Medicine, 1997:183-260. 2. Weissman DE, Meier DE. Identifying patients in need of a palliative care assessment in the hospital setting: A consensus report from the center to advance palliative care. J Palliat Med 2011;14(1):17-23. https://doi.org/10.1089/jpm.2010.0347 3. World Health Assembly. Strengthening of palliative care as a component of comprehensive care throughout the life course. http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_R19-en.pdf (accessed 8 December 2017). 4. World Health Organization. Definition of palliative care. http://www.who.int/cancer/palliative/ definition/en/ (accessed 8 December 2017).

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5. Defilippi K. Integrated community-based home care: Striving towards balancing quality with coverage in South Africa. Ind J Palliat Care 2005;11(1):34. https://doi.org/10.4103/0973-1075.16643 6. Kirk J, Collins K. Difference in quality of life of referred hospital patients after hospital palliative care team intervention: Clinical practice. S Afr Med J 2006;96(2):101-102. 7. Hongoro C, Dinat N. A cost analysis of a hospital-based palliative care outreach program: Implications for expanding public sector palliative care in South Africa. J Pain Symptom Manage 2011;41(6):10151024. https://doi.org/10.1016/j.jpainsymman.2010.08.014 8. DesRosiers T, Cupido C, Pitout E, et al. A hospital-based palliative care service for patients with advanced organ failure in sub-Saharan Africa reduces admissions and increases home death rates. J Pain Symptom Manage 2014;47(4):786-792. https://doi.org/10.1016/j.jpainsymman.2013.05.021 9. Stuart-Clark H, Vorajee N, Zuma S, et al. Twelve-month outcomes of patients admitted to the acute general medical service at Groote Schuur Hospital. S Afr Med J 2012;102(6):549-553. https://doi. org/10.7196/samj.5615 10. Van Niekerk L, Raubenheimer PJ. A point-prevalence survey of public hospital inpatients with palliative care needs in Cape Town, South Africa. S Afr Med J 2013;104(2):138-141. https://doi. org/10.7196/samj.7262 11. Gold Standards Framework. GSF prognostic indicator guidance. http://www.goldstandardsframework. org.uk/cd-content/uploads/files/General%20Files/Prognostic%20Indicator%20Guidance%20 October%202011.pdf (accessed 29 March 2017).

12. O’Callaghan A, Laking G, Frey R, Robinson J, Gott M. Can we predict which hospitalised patients are in their last year of life? A prospective cross-sectional study of the Gold Standards Framework Prognostic Indicator Guidance as a screening tool in the acute hospital setting. Palliat Med 2014;28(8):1046-1052. https://doi.org/10.1177/0269216314536089 13. Supportive and Palliative Care Indicators Tool. http://www.spict.org.uk/the-spict/ (accessed 29 March 2017). 14. Highet G, Crawford D, Murray SA, Boyd K. Development and evaluation of the Supportive and Palliative Care Indicators Tool (SPICT): A mixed-methods study. BMJ Support Palliat Care 2014;4(3):285-290. https://doi.org/10.1136/bmjspcare-2013-000488 15. Gwyther L. How is palliative care part of the right to health? The South African evidence. PhD thesis, University of Cape Town (in progress). 16. London L. What is a human rights-based approach to health and does it matter? Health Human Rights 2008;10(1):65-80. https://doi.org/10.2307/20460088

Accepted 29 August 2017.

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Validation of the Simplified Motor Score in patients with traumatic brain injury at a major trauma centre in South Africa J J P Buitendag,1 MB ChB; A Ras,1 MB ChB; V Y Kong,1 MB ChB, MSc, PhD, MRCS; J L Bruce,1 MB ChB, FCS (SA); G L Laing,1 MB ChB, MSc, PhD, FCS (SA); D L Clarke,1,2 MB ChB, MPhil, MBA, MSc, PhD; P Brysiewicz,3 BSocSc, BA, MCur, PhD ietermaritzburg Metropolitan Trauma Service, Department of Surgery, Nelson R Mandela School of Medicine, College of Health Sciences, P University of KwaZulu-Natal, Durban, South Africa 2 Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 School of Nursing and Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa 1

Corresponding author: J J P Buitendag (johan_buitendag@yahoo.com) Background. This study used data from a large prospectively entered database to assess the efficacy of the motor score (M score) component of the Glasgow Coma Scale (GCS) and the Simplified Motor Score (SMS) in predicting overall outcome in patients with traumatic brain injury (TBI). Objective. To safely and reliably simplify the scoring system used to assess level of consciousness of trauma patients in the acute setting. Methods. A retrospective observational review of the Pietermaritzburg Metropolitan Trauma Service hybrid electronic medical registry database was performed during the period January 2013 - December 2015. Patients were classified into three groups using their GCS as an injury severity score. These were mild TBI (GCS 13 - 15), moderate TBI (GCS 9 - 12) and severe TBI (GCS <9). The Glasgow M score was specifically evaluated to determine the relationship between the individual motor component and patient outcome. Results. GCS scores and M scores were analysed in a total of 830 patients. There was a decline in survival rate when the M score on admission was ≤4. The decline was more significant when the M score was ≤3. Survival rates were 26.8% (11/41) for patients with an M score of 1, 63.6% (14/22) for those with a score of 2, 56.5% (13/23) for those with a score of 3, 80.0% (20/25) for those with a score of 4, and 95.5% (121/128) for those with a score of 5. Of 591 patients with an M score of 6, 580 (98.1%) survived. Mortality rose dramatically with declining SMS. This was highly significant. When the M score was plotted against mortality in 830 patients, there was a correct prediction in 769 cases (accuracy 92.7%, sensitivity 67.6%, specificity 95%). The area under the receiver operating characteristic (ROC) curve was 0.9037, with a standard deviation (area) of 0.0227. When comparing the SMS against mortality, the accuracy was 77.1%, the sensitivity 84.5% and the specificity 76.4%. The fitted ROC area was 0.891 and the empirical ROC area 0.86. Conclusion. The M score component of the GCS and the SMS accurately predict outcome in patients with TBI. In cases where the full GCS is difficult to assess, the M score and SMS can be used safely as a triage tool. S Afr Med J 2018;108(2):90-93. DOI:10.7196/SAMJ.2018.v108i2.12757

The Lancet Commission on Global Surgery has shown that there is a huge unmet need for surgical and trauma care globally.[1] According to the Commission, surgical conditions account for ~30% of the global burden of disease, yet it is estimated that two-thirds of the world’s population cannot access safe surgery and anaesthesia. This problem is especially acute in low- and middle-income countries. One of the major traumatic conditions on which such discrepancies impact is traumatic brain injury (TBI).[2-5] The incidence of TBI in sub-Saharan Africa is 150 - 170 per 100 000 compared with a global average of 106 per 100 000, yet the literature on the topic is relatively sparse, especially in comparison with that on other diseases with a high burden such as HIV and tuberculosis.[2-5] It is not unreasonable to describe TBI as a forgotten and neglected epidemic, and trauma care in South Africa (SA) is perennially under-resourced for the burden of disease it is expected to manage. In addition, rural trauma care has major limitations in terms of human resources, infrastructure and equipment.[2-5] Any system that increases complexity in such a setting is counterproductive, and any system that can reliably and safely simplify management must be supported. The Glasgow Coma Scale (GCS) is a clinical scoring system that after 40 years remains

the cornerstone of the acute management and triage of patients with TBI.[6-8] However, there is a growing concern that the traditional GCS suffers from needless complexity, which makes it less than ideal for managing large volumes of patients in resource-constrained settings. [9-12] A number of authors have proposed the use of an abbreviated score known as the Simplified Motor Score (SMS). [13,14] Numerous studies have shown that the SMS reliably predicts the presence of TBI, the need for neurosurgical intervention and the need for intubation. Any system that reduces complexity in a strained environment without compromising quality of care deserves to be welcomed and encouraged.

Objective

In the light of the debate around the role and complexity and reliability of the GCS, we set out to review our experience with TBI and to compare the ability of the SMS, the individual motor score (M score) component of the GCS and the total GCS to predict the severity of TBI and the need for neurosurgery. We hoped to show that the SMS was as reliable and accurate as the GCS in predicting outcome in TBI.

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This was a retrospective review of a prospectively entered database undertaken at the Pietermaritzburg Metropolitan Trauma Service (PMTS), Pietermaritzburg, South Africa. The PMTS provides definitive trauma care to the city of Pietermaritzburg, the capital of KwaZulu-Natal (KZN) Province. It is one of the largest academic trauma centres in KZN and also serves as the referral centre for 19 other rural hospitals in the province, with a total catchment population of over three million. The hybrid electronic medical registry (HEMR) combines an electronic and paper-based patient record system with the facility of an electronic registry. All trauma patients in Pietermaritzburg are captured on this system. The review was performed for the period January 2013 - December 2015. The GCS M score was specifically evaluated to determine the relationship between the individual motor component and patient outcome. The M score was compared with risk of death and need for surgery. We also determined the sensitivity and specificity of the total GCS in predicting the following outcomes: need for intubation, presence of a significant finding on computed tomography (CT), need for surgery, and mortality. We went on to derive the SMS for each patient based on the recorded motor component of the GCS. An SMS of 0 was considered to be equivalent to a GCS M score of 1 - 4, an SMS of 1 to an M score of 5, and an SMS of 2 to an M score of 6. We compared the SMS with the overall GCS score and with the GCS M score for the same outcomes as listed above.

Statistical analysis

We constructed receiver operating characteristic (ROC) curves and measured the areas under these curves to compare the predictive value of the GCS, M score and SMS against need for intubation, presence of a significant finding on CT, need for surgery, and mortality. We also calculated the 95% confidence intervals (CIs) of the areas under the curves for each outcome.

Ethics approval

Ethics approval for the study and for maintenance of the registry was obtained from the Biomedical Research Ethics Committee of the University of KwaZulu-Natal (ref. no. BE 207/09).

100 68.8%

75 50

94.5%

98.1%

80.2% 54.4%

29.9%

25 0 1

4 M score

A total of 830 patients were studied. Fig. 1 shows that there was a decline in survival rate when the M score on admission was ≤4. The decline was more significant when the M score was ≤3. Of a total of Table 1. M score v. survival Count, N 41 22 23 25 128 591

Survival, n 11 14 13 20 121 580

Died, n 30 8 10 5 7 11

Survival, % 26.8 63.6 56.5 80.0 94.5 98.1

M score = motor score.

Fig. 1. M score v. survival. (M score = motor score.) 100

Survival, %

Results

M score 1 2 3 4 5 6

41 patients with an M score of 1, only 11 (26.8%) survived. Survival rates were 63.6% (14/22) for those with a score of 2, 56.5% (13/23) for those with a score of 3, 80.0% (20/25) for those with a score of 4, and 95.5% (121/128) for those with a score of 5. Of 591 patients with a M score of 6, 580 (98.1%) survived. Table 1 summarises these data, and Table 2 the data when the M score was converted to the SMS. Mortality rose dramatically with declining SMS, as shown in Fig. 2. When plotting the M score against mortality, the prediction was correct in 769/830 patients (accuracy 92.7%, sensitivity 67.6%, specificity 95%). The area under the ROC was 0.9037 with a standard deviation (SD) (area) of 0.0227. The ROC for M score and mortality was assessed. When comparing SMS score against mortality, the accuracy was 77.1%, the sensitivity 84.5% and the specificity 76.4%. The fitted ROC area was 0.891 and the empirical ROC area 0.86. Table 3 breaks down the SMS and M score into their respective components and compares them with each outcome. Table 4 compares the M score and the SMS with all four outcomes (mortality, need for intubation, need for neurosurgery, and positive CT findings). The ROC curve for M score v. intubation was assessed. The accuracy was 92.9%, the sensitivity 61.3% and the specificity 98.2%. The fitted ROC area was 0.973, the empirical ROC area 0.957 and the standard deviation (area) 0.0058. When we compared SMS v. intubation, the accuracy was 84.8%, the sensitivity 97.5% and the specificity 82.7%. The fitted ROC area was 0.974 and the empirical ROC area 0.953. The SD (area) was 0.0061. Comparing M score v. neurosurgery, the accuracy was 71.2%, the sensitivity 5.8% and the specificity 88.4%. The fitted ROC area was 0.626 and the empirical ROC area 0.514. The SD (area) was 0.0320. The ROC curve for SMS

Survival, %

Methods

94.5%

98.1%

75 52.3% 50 25 0 0

SMS

Fig. 2. SMS v. survival. (SMS = Simplified Motor Score.)

Table 2. SMS v. survival Obeys commands Localises pain Withdrawal to pain or less response

SMS score 2 1 0

M score 6 5 4

Count, N 591 128 111

SMS = Simplified Motor Score; M score = motor score.

February 2018, Print edition

Survival, n 580 121 58

Died, n 11 7 53

Survival, % 98.1 94.5 52.3

REVIEW

Table 3. SMS v. variables M score 1 2 3 4 5 6

Count, N 41 22 23 25 128 591

Intubation, n 37 20 16 18 25 3

Neuro. transfer, n 1 5 4 8 39 116

CT findings, n 41 22 21 21 108 469

SMS Withdrawal to pain or less response (SMS 0/GCS M ≤4)

Localises pain (SMS 1/GCS M 5) Obeys commands (SMS 2/GCS M 6)

SMS = Simplified Motor Score; M score = motor score; Neuro. = neurosurgical; CT = computed tomography; GCS = Glasgow Coma Scale.

Table 4. Comparison of ROC curve findings with M score v. SMS

Cases, N Correct, n Accuracy, % Sensitivity, % Specificity, % Positive cases missed, n Negative cases missed, n Area under ROC curve SD (area) Fitted ROC area Empirical ROC area

M score v. mortality 830 769 92.7 67.6 95 23

SMS v. mortality 830 640 77.1 84.5 76.4 11

M score v. intubation 830 771 92.9 61.3 98.2 46

SMS v. intubation 830 704 84.8 97.5 82.7 3

M score v. neurosurgery 830 591 71.2 5.8 88.4 163

SMS v. neurosurgery 830 532 64.1 32.9 72.3 116

M score v. CT findings 830 230 27.7 12.3 98.6 598

SMS v. CT findings 830 335 40.4 31.2 82.4 469

179

123

182

0.9037

0.8905

0.9734

0.9743

0.6258

0.6124

0.5043

0.5398

0.0227 0.904 0.873

0.0334 0.891 0.86

0.0058 0.973 0.957

0.0061 0.974 0.953

0.0320 0.626 0.514

0.0368 0.612 0.517

0.0494 0.504 0.578

0.0590 0.54 0.576

ROC = receiver operating characteristic; M score = motor score; SMS = Simplified Motor Score; CT = computed tomography; SD = standard deviation.

v. neurosurgery showed accuracy of 64.1%, sensitivity of 32.9% and specificity of 72.3%. The fitted ROC area was 0.612 and the empirical ROC area 0.517. The SD (area) was 0.0368. We contend that this indicates that in a setting where resources are limited, most patients who are accepted by neurosurgery on the basis of the SMS will do well and have a good prognosis. The ROC curve of M score v. positive CT findings showed accuracy of 27.7%, sensitivity of 12.3% and specificity of 98.6%. The fitted ROC area was 0.504 and the empirical ROC area 0.578. The SD (area) was 0.0494. The ROC curves for SMS v. positive CT findings showed accuracy of 40.4%, sensitivity of 31.2% and specificity of 82.4%. The fitted ROC area was 0.54 and the empirical ROC area 0.576, with an SD (area) of 0.0590.

Discussion

Teasdale and Jennett[6-8] first proposed the GCS in 1974 and modified it in subsequent publications. Since then the GCS has become ubiquitous, and it remains a clinical scoring system in an era when advanced imaging is increasingly used to assess patients and to predict outcome. However, more recently the GCS has been criticised for being confusing, unreliable and excessively complex. [9-11] It has become apparent that the total score does not always accurately reflect a patient’s condition. This is especially the case in trauma, where it may be difficult to assess verbal or eye response in a patient who is intubated or has suffered maxillofacial trauma. In the light of this, a number of authors have investigated whether individual components of the GCS are able to predict the outcome of TBI.[11-14] The component most commonly studied has

been the M score. The SMS has been proposed as a system that provides a meaningful, objective prognostic assessment of a patient’s level of consciousness and is capable of predicting outcome.[11-14] The SMS ignores the eye and verbal response and focuses exclusively on the M score, and is defined as follows: obeys commands = 2; localises to pain = 1; and withdraws to pain or less response = 0. A patient with an SMS of <2 is at significantly increased risk of having a TBI that will require neurosurgical intervention or intubation, or that will cause death. As long ago as 1988, Choi et al.[9] reported that using the patient’s M score and age was as accurate and reliable as using the GCS in predicting outcome in these patients.[9] Since then, several authors have reported that the M score is both sensitive and specific in predicting mortality from TBI.[11-14] Our current data are very much in keeping with these findings, and this has major clinical implications. The development of the SMS provides a simplified but reliable tool to assess level of consciousness in trauma patients. Our current data and data from the international literature confirm that the SMS can predict key outcomes accurately. It is therefore a highly suitable and appropriate tool for use in our environment. The resources available to manage the burden of trauma in SA are perennially insufficient. Triage is therefore a reality in our environment, and accurate prioritisation of trauma patients is essential. A triage tool that is accurate and easy to use is especially important in managing TBI, as patients often need to be transported over long distances for imaging and for management. [1,15,16] The complexity of the traditional GCS and its variability make it particularly unsuited for use in a country like SA, where there is a significant degree of

February 2018, Print edition

REVIEW

heterogeneity of experience and competence among staff in the field and in rural district hospitals. In addition, communication between staff at the receiving and referral institutions is often less than ideal, making a simplified score very desirable. The score that can be assessed in almost all patients, even those in the intensive care unit, is the M score. Our findings and those of authors in other countries confirm that the M score by itself and the SMS accurately predict mortality and outcome in patients with a TBI. Their use in trauma care in SA should be supported and encouraged. Although on the basis of the ROCs both the M score and the SMS are poor predictors of CT findings and the need for neurosurgical intervention, it is unrealistic to expect the SMS to predict these clinical endpoints. The SMS is a triage tool for use in the field and in rural institutions to identify patients who need urgent resuscitation and referral to more appropriate levels of care. For this purpose, the SMS appears to be as accurate as the GCS.

Study limitations

This study, like most, has limitations. The data were only collected from a single centre. Some entries into the electronic database had missing data, and these patients could not be included. Misclassification bias should also be kept in mind and must be considered in all information that was entered by staff members.

Conclusion

This study confirms reports from international authors that the M score and the SMS can reliably predict a significant TBI as well as mortality. The simplicity of the scores and the ease with which they can be determined make them particularly suitable for use in our relatively austere prehospital and rural environments. Use of these scores in trauma care in SA should be supported and encouraged. Acknowledgements. None. Author contributions. JJPB, DLC and AR analysed the data and wrote the manuscript. VYK, JLB, GLL and PB reviewed the manuscript.

Funding.Â None. Conflicts of interest.Â None. 1. Meara J, Greenberg S. The Lancet Commission on Global Surgery Global surgery 2030: Evidence and solutions for achieving health, welfare and economic development. Surgery 2015;157(5):834-835. https://doi.org/10.1016/j.surg.2015.02.009 2. Jerome E, Laing G, Bruce J, Sartorius B, Brysiewicz P, Clarke D. An audit of traumatic brain injury (TBI) in a busy developing-world trauma service exposes a significant deficit in resources available to manage severe TBI. S Afr Med J 2017;107(7):621-625. https://doi.org/10.7196/SAMJ.2017. v107i7.10562 3. Kong V, Bruce J, Sartorius B, et al. Civilian cerebral gunshot wounds in rural South African patients are associated with significantly higher mortality rates than in urban patients. Eur J Trauma Emerg Surg 2017. https://doi.org/10.1007/s00068-017-0800-z 4. Wong J, Linn K, Shinohara R, Mateen F. Traumatic brain injury in Africa in 2050: A modeling study. Eur J Neurol 2015;23(2):382-386. https://doi.org/10.1111/ene.12877 5. Hyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC. The impact of traumatic brain injuries: A global perspective. NeuroRehabilitation 2007;22(5):341-353. 6. Jennett B, Teasdale G. Aspects of coma after severe head injury. Lancet 1977;309(8017):878-881. https://doi.org/10.1016/S0140-6736(77)91201-6 7. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. Lancet 1974;304(7872):81-84. https://doi.org/10.1016/S0140-6736(74)91639-0 8. Teasdale G, Jennett B. Assessment and prognosis of coma after head injury. Acta Neurochir 1976;34(14):45-55. https://doi.org/10.1007/BF01405862 9. Choi S, Narayan R, Anderson R, Ward J. Enhanced specificity of prognosis in severe head injury. J Neurosurg 1988;69(3):381-385. https://doi.org/10.3171/jns.1988.69.3.0381 10. Green S. Cheerio, laddie! Bidding farewell to the Glasgow Coma Scale. Ann Emerg Med 2011;58(5):427430. https://doi.org/10.1016/j.annemergmed.2011.06.009 11. Gill M, Windemuth R, Steele R, Green S. A comparison of the Glasgow Coma Scale score to simplified alternative scores for the prediction of traumatic brain injury outcomes. Ann Emerg Med 2005;45(1):37-42. https://doi.org/10.1016/j.annemergmed.2004.07.429 12. Haukoos J, Gill M, Rabon R, Gravitz C, Green S. Validation of the Simplified Motor Score for the prediction of brain injury outcomes after trauma. Ann Emerg Med 2007;50(1):18-24. https://doi. org/10.1016/j.annemergmed.2006.10.004 13. Gill M, Steele R, Windemuth R, Green S. A comparison of five simplified scales to the out-of-hospital Glasgow Coma Scale for the prediction of traumatic brain injury outcomes. Acad Emerg Med 2006;13(9):968-973. https://doi.org/10.1111/j.1553-2712.2006.tb00344.x 14. Thompson D, Hurtado T, Liao M, Byyny R, Gravitz C, Haukoos J. Validation of the Simplified Motor Score in the out-of-hospital setting for the prediction of outcomes after traumatic brain injury. Ann Emerg Med 2011;58(5):417-425. https://doi.org/10.1016/j.annemergmed.2011.05.033 15. Laing G, Bruce J, Skinner D, Allorto N, Clarke D, Aldous C. Development, implementation, and evaluation of a hybrid electronic medical record system specifically designed for a developing world surgical service. World J Surg 2013;38(6):1388-1397. https://doi.org/10.1007/s00268-013-2438-2 16. Laing G, Skinner D, Bruce J, Aldous C, Oosthuizen G, Clarke D. Understanding the burden and outcome of trauma care drives a new trauma systems model. World J Surg 2014;38(7):1699-1706. https://doi.org/10.1007/s00268-014-2448-8

Accepted 12 September 2017.

February 2018, Print edition

HOSPITALISATION PRESENTS AN IDEAL OPPORTUNITY TO REASSESS CHRONIC HF THERAPY1

NE W

RESET CHRONIC HF THERAPY IN THE HOSPITAL WITH ENTRESTO®1,2 In the largest trial ever conducted in Heart Failure, where ~ 60% of patients had a previous hospitalisation,3,4 ENTRESTO® demonstrated...

20%

reduced risk of CV death or HF hospitalisation vs enalapril (p<0.001), with comparable safety and tolerability4

38%

lower rate of 30-day readmission for HF vs enalapril (p=0.006)5

Results were consistent across patients with or without previous hospitalisations4 For any Entresto® product related enquiries, please contact the Novartis Customer Contact Centre on 0861 929 929 CV=cardiovascular; HF=heart failure References: 1. Krim SR, Campbell PT, Desai S, et al. Management of patients admitted with acute decompensated heart failure. Oschner J. 2015;15:284-289. 2. Entresto® package insert. Novartis, South Africa; September 2017. 3. McMurray JJV, Packer M, Desai AS, et al; for PARADIGM-HF Committees Investigators. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail. 2014;16(7):817-825. 4. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 5. Desai AS, Claggett BL, Packer M, et al. Influence of sacubitril/valsartan (LCZ696) on 30-day readmission after heart failure hospitalization. J Am Coll Cardiol. 2016;68(3):241-248. SCHEDULING STATUS: S3 ENTRESTO® 50 mg film-coated tablets Reg. No. 50/7.6/1016; ENTRESTO® 100 mg film-coated tablets Reg. No. 50/7.6/1017; ENTRESTO® 200 mg film-coated tablets Reg. No. 50/7.6/1018 COMPOSITION: ENTRESTO® 50 mg filmcoated tablets contain 24 mg sacubitril and 26 mg valsartan. ENTRESTO® 100 mg film-coated tablets contain 49 mg sacubitril and 51 mg valsartan. ENTRESTO® 200 mg film-coated tablets contain 97 mg sacubitril and 103 mg valsartan. PHARMACOLOGICAL CLASSIFICATION: A7.6 Vascular medicines Others INDICATIONS: ENTRESTO® is indicated as a second-line therapy, replacing ACE inhibitors or ARB for treatment of symptomatic heart failure (NYHA class II-IV) in patients with systolic dysfunction. ENTRESTO® is administered in combination with other heart failure therapies as appropriate. DOSAGE AND DIRECTIONS FOR USE: Adults: • The target dose of Entresto® is 200 mg twice daily. • The recommended starting dose of Entresto® is 100 mg twice daily. • A starting dose of 50 mg twice daily is recommended for patients taking low doses of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB). • Dose up titration by resembling the dose every 3 – 4 weeks is recommended until a dose of 200 mg twice daily is achieved of tolerance. Geriatric patients: Patients over the age of 65 years may have impaired renal function, therefore a lower starting dose is recommended. Pediatric patients: The safety and efficacy in paediatric patients aged below 18 years has not been established. Renal impairment: contraindicated in patients with severe impaired renal function. Hepatic impairment: No dose adjustment is required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment use of Entresto® is not recommended. METHOD OF ADMINISTRATION: for oral use. May be administered with or without food. CONTRAINDICATIONS: • Hypersensitivity to the active substance, sacubitril, valsartan, or to any of the excipients. • Concomitant use with ACE inhibitors. Entresto® must not be administered until 36 hours after discontinuing ACE inhibitor therapy. • Known history of angioedema related to previous ACE inhibitor or ARB therapy. • Hereditary or idiopathic angioedema. • Hypertrophic obstructive cardiomyopathy. • Bilateral renal artery stenosis. • Renal artery stenosis in patients with a single kidney. • Aortic valve stenosis. • Concomitant therapy with potassium sparing diuretics such as spironolactone, triamerene, amiloride • Porphyria • Lithium therapy • Concomitant use with renin antagonists • Pregnancy and lactation • Severe renal impairment • Concomitant use with aliskiren-containing products WARNINGS AND SPECIAL PRECAUTIONS: Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS): Entresto® must not be administered with an ACE inhibitor or another ARB due to the risk of angioedema. Entresto® must not be initiated until 36 hours after taking the last dose of ACE inhibitor or ARB therapy. If treatment with Entresto® is stopped, ACE inhibitor or ARB therapy must not be initiated until 36 hours after the last dose of Entresto®. • Entresto® must not be used concomitantly with aliskiren. Hypotension: If hypotension occurs, dose adjustment of diuretics, concomitant antihypertensive medicines, and treatment of other causes of hypotension (e.g. hypovolemia) should be considered. If hypotension persists despite such measures, the dosage of Entresto® should be reduced or the product should be temporarily discontinued. Sodium and/or volume depletion should be corrected before starting treatment with Entresto®. Impaired renal function: Down titration of Entresto should be considered in patients who develop a clinically significant decrease in renal function. Hyperkalemia: Medications known to raise potassium levels (e.g. potassium-sparing diuretics, potassium supplements) should not be used with ENTRESTO®. If clinically significant hyperkalemia occurs, measures such as reducing dietary potassium, or adjusting the dose of concomitant medications should be considered. Monitoring of serum potassium is recommended especially in patients with risk factors such as diabetes mellitus, hypoaldosteronism or receiving a high potassium diet. Angioedema: If angioedema occurs, Entresto® should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. Entresto® must not be re-administered. Patients with a prior history of angioedema were not studied. Black patients may have increased susceptibility to develop angioedema. Patients with renal artery stenosis: is contraindicated. Interactions with statins: Caution should be exercised upon co-administration with statins Pregnancy and lactation: Entresto should not be used during pregnancy or lactation. INTERACTIONS: ◊ Concomitant use contraindicated: Aliskiren, Use with ACE inhibitors. Entresto® must not be started until 36 hours after taking the last dose of ACE inhibitor or ARB therapy. ACE inhibitor therapy must not be started until 36 hours after the last dose of Entresto®. ◊ Caution when used concomitantly with statins, sildenafil, lithium, potassium-sparing diuretics including mineral corticoid antagonists (e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium, non-steroidal anti-inflammatory agents (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 Inhibitors), inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampin, cyclosporin) or MPR2 (e.g. ritonavir). Side effects: Very common (≥10%): Hyperkalaemia, hypotension, renal impairment. Common (1 to 10%): Anaemia, Cough, dizziness, renal failure, diarrhoea, hypokalaemia, fatigue, headache, syncope, nausea, asthenia, orthostatic hypotension, vertigo, hypoglycaemia, gastritis Uncommon (0.1 to 1%): Angioedema, postural dizziness, pruritis, rash Packs: 14, 28 or 56 tablets packed in PVC/PVDC blister packs. Note: Before prescribing consult full prescribing information

Novartis South Africa (Pty) Ltd. Magwa Crescent West, Waterfall City, Jukskei View, 2090. Tel +27 11 3476000. Company Reg No: 1946/020671/07 For any product related enquiries, please contact the Novartis Customer Contact Centre on 0861 929 929 ZA1801763992 Exp 20/01/2019

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2018/01/22 2:21 PM

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

RESEARCH

Clinical characteristics and causes of heart failure, adherence to treatment guidelines, and mortality of patients with acute heart failure: Experience at Groote Schuur Hospital, Cape Town, South Africa P Z Szymanski,1 MB ChB; M Badri,2 PhD; B M Mayosi,1 MB ChB, DPhil 1 2

Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa Department of Medicine, Cardiac Clinic, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa

Corresponding author: P Z Szymanski (dr.patryk@gmail.com) Background. There is limited information on acute heart failure (AHF) and its treatment in sub-Saharan Africa. Objective. To describe the clinical characteristics and causes of heart failure (HF), adherence to HF treatment guidelines, and mortality of patients with AHF presenting to Groote Schuur Hospital (GSH), Cape Town, South Africa. Methods. This sub-study of The Sub-Saharan Africa Survey of Heart Failure (THESUS-HF) was a prospective and observational survey that focused on the enrolment and follow-up of additional patients with AHF presenting to GSH and entered into the existing registry after publication of the primary THESUS-HF article in 2012. The patients were classified into prevalent (existing) or incident (new) cases of HF. Results. Of the 119 patients included, 69 (58.0%) were female and the mean (standard deviation) age was 49.9 (16.3) years. The majority of prevalent cases were patients of mixed ancestry (63.3%), and prevalent cases had more hypertension (70.0%), diabetes mellitus (36.7%), hyperlipidaemia (33.3%) and ischaemic heart disease (IHD) (36.7%) than incident cases. The top five causes of HF were cardiomyopathy (20.2%), IHD (19.3%), rheumatic valvular heart disease (RHD) (18.5%), cor pulmonale (11.8%) and hypertension (10.1%), with the remaining 20.1% consisting of miscellaneous causes including pericarditis, toxins and congenital heart disease. Most patients received renin-angiotensin system blockers and loop diuretics on discharge. There was a low rate of beta-blocker, aldosterone antagonist and digoxin use. Rehospitalisation within 180 days occurred in 25.2% of cases. In-hospital mortality was 8.4% and the case fatality rate at 6 months was 26.1%. Conclusion. In Cape Town, the main causes of AHF are cardiomyopathy, IHD and RHD. AHF affects a young population and is associated with a high rate of rehospitalisation and mortality. There is serious under-use of beta-blockers, aldosterone antagonists and digoxin. Emphasis on the rigorous application of treatment guidelines is needed to reduce readmission and mortality. S Afr Med J 2018;108(2):94-98. DOI:10.7196/SAMJ.2018.v108i2.12519

Heart failure (HF) is a worldwide phenomenon that affects millions of people yearly and carries a high mortality. It is estimated that 37.7 million people worldwide are affected by HF.[1] The past three decades have seen a rise in research on HF. Large multicentre studies from the USA (e.g. ADHERE) and Europe (e.g. EHFS II) have provided greater insight into the aetiology, treatment and outcomes of patients with HF in the developed world.[2,3] Observational studies from sub-Saharan Africa (SSA) show that hypertension, rheumatic valvular heart disease (RHD) and idiopathic cardiomyopathies are the main causes of HF affecting a young population.[4-6] This epidemiological pattern is strikingly different from that in the developed world, where a much older population suffers from HF, with ischaemic heart disease (IHD) the primary cause.[2,3] Despite these differences, the epidemiological transition is resulting in the rise of diabetes mellitus (DM), hypertension and IHD in SSA.[7,8] In 2008, communicable, maternal, perinatal and nutritional conditions accounted for the majority of deaths in South Africa (SA). However, of the non-communicable diseases, cardiovascular disease was the main cause of death.[9] There is limited information on the use of evidence-based interventions and outcomes of HF in Africa. Contemporary epidemiological, aetiological and treatment information is needed in order to develop appropriate health policies for its diagnosis, management, prevention and control.[10,11]

Objective

To explore the treatment practices of doctors and outcomes of patients with congestive or acute heart failure (AHF) at Groote Schuur Hospital (GSH), a tertiary-level academic institution in Cape Town, SA, that serves as a referral hospital for 5 million people. The clinical features and causes of HF were also explored.

Methods

Study design and clinical setting

This was a sub-study of The Sub-Saharan Africa Survey of Heart Failure (THESUS-HF), a prospective, multicentre, observational survey of patients with AHF admitted to 12 university hospitals in nine countries.[5] The sub-study reported here is based on the enrolment of additional patients with AHF presenting to GSH and followed up in the existing THESUS-HF registry. Patients with AHF (incident (i.e. de novo) or prevalent (i.e. decompensation of previously diagnosed HF)) were added to the registry after the publication of the primary THESUS-HF article in 2012.[5]

Inclusion and exclusion criteria

The inclusion and exclusion criteria were the same as the criteria in the THESUS-HF study.[5] Briefly, patients aged >12 years with a diagnosis of AHF based on clinical evaluation and confirmed by echocardiography were enrolled. The exclusion criteria were

February 2018, Print edition

RESEARCH

acute ST-elevation myocardial infarction, known severe renal failure (patients undergoing dialysis or with a creatinine level >350 μmol/L), nephrotic syndrome, hepatic failure or other causes of hypo albuminaemia.

The prevalent cases were more likely to be people of mixed ancestry, and this group had more hypertension, DM, hyperlipidaemia, IHD, pericardial disease and cardiomyopathy and higher New York Heart Association (NYHA) functional class than incident cases.

Case definition and data collection

Causes of HF

The diagnosis of HF was based on the standard case definition as described in THESUS-HF.[5] The diagnosis of HF was made on finding the clinical syndrome of effort intolerance (i.e. shortness of breath, dyspnoea and/or fatigue) associated with features of fluid retention (i.e. peripheral oedema, orthopnoea, paroxysmal nocturnal dyspnoea, raised jugular venous pressure, pulmonary oedema and/ or tender hepatomegaly) in the presence of clinical signs of cardiac dysfunction (i.e. low blood pressure, displaced apex, presence of third heart sound). The presence of cardiac dysfunction was confirmed by echocardiography performed by a trained echocardiographer. The cause of HF was based on information obtained from the history, physical examination, echocardiography, and special aetiological investigations interpreted by the admitting team on the index admission. Where no cause for HF was stated, the research team determined the aetiology from the given data. For this study, consecutive patients enrolled into the GSH THESUS-HF registry from 1 June 2012 to 31 May 2014 (24 months) with >90% completed data were selected. The THESUS-HF registry holds the basic clinical information as determined by the clinical history and previous medical records, along with an echocardiogram report confirming the diagnosis of HF. Furthermore, patients were followed up for 180 days to document their clinical outcomes of rehospitalisation and death. Their baseline demographic and clinical information, echocardiographic findings, treatment and clinical outcomes were entered onto a data capture sheet by the research nurse and echocardiographer. Outstanding demographic, clinical, treatment and outcomes data were collected through folder review, pharmacy records and telephonic consultations with the study participants. All completed data capture sheets were entered into the THESUS-HF database.

Statistical analysis

Data were analysed using the Statistical Package for the Social Sciences (SPSS) version 23 (IBM Corp., USA) and ROOT.[12] Normally distributed continuous data are presented as means with standard deviations (SDs), and non-Gaussian distributed variables as medians plus ranges. Categorical data are presented as percentages. The case fatality rate was calculated at discharge and at 6 months of follow-up.

Ethical considerations

The University of Cape Town Human Research Ethics Committee granted ethics approval for this study (ref. no. 579/2014). All patients entered into the THESUS-HF registry gave written informed consent.

Results

Baseline patient characteristics on admission

One hundred and twenty patients were enrolled in the THESUS-HF registry at GSH between 1 June 2012 and 31 May 2014. One patient was excluded owing to missing clinical details. Table 1 shows the baseline clinical characteristics for the total cohort (N=119) and compares the incident cases (first presentations) with the prevalent cases (recurrent presentations). The mean (SD) age of the cohort was 49.9 (16.3) years. Sixty-nine patients (57.5%) were female, and the main population groups were black African (n=59, 49.6%) and mixed ancestry (n=54, 45.4%).

The main causes of HF were cardiomyopathy (n=24, 20.2%), IHD (n=23, 19.3%) and valvular heart disease (n=22, 18.5%). Hyper tension accounted for 10.1% (n=12) of the cohort. Owing to the small sample size, cardiomyopathy represents the cumulative causes of cardiomyopathy, and includes peripartum cardiomyopathy, idiopathic dilated cardiomyopathy and HIV cardiomyopathy. Fig. 1 shows the causes of HF.

Therapies for HF: Admission and discharge/day 7 admission

Intravenous (IV) loop diuretics were the most commonly used IV therapy on admission (n=94, 79.0%), while renin-angiotensin system blockers were the most commonly used oral treatment (n=70, 59.3%). Mechanical ventilation and dobutamine were used in only 0.9% (n=1) and 1.7% (n=2) of cases, respectively. Reninangiotensin system blockers (73.0%, n=81), loop diuretics (74.6%, n=82) and beta-blockers (42.7%, n=47) were most commonly issued on discharge. On discharge only 26.1% of patients (n=15) received aldosterone antagonists and 15.5% (n=17) digoxin. IV dopamine, IV digoxin and oral hydralazine were never prescribed. Table 2 shows the IV and oral therapies used in incident and prevalent cases.

Length of stay, rehospitalisation and case fatality rate

The mean (SD) length of stay in hospital for all cases was 9.2 (12.2) days, with a median of 6 days (range 1 - 109). Rehospitalisation within 180 days occurred in 25.2% (n=30) of the total cohort. Twelve patients (10.1%) were lost to follow-up. The main reason for this was no reply to telephonic calls (n=11), and one patient moved to another province. The rate of death during hospital admission was 8.4% (10/119 patients), and the case fatality rate at 6 months was 26.1% (31/119 patients).

Discussion

The main findings of this study include a relatively young population suffering from HF, with prevalent cases more likely to have DM, hypertension, IHD and more advanced disease. Furthermore, cardiomyopathy, IHD and RHD account for the majority of causes of HF. There was under-use of beta-blockers, aldosterone antagonists and digoxin. Finally, rehospitalisation and case fatality rates were high. The mean age of patients with AHF was 49.9 years, and 58.0% were female. These findings are similar to what has been observed in other registries from SSA.[4,5,13,14] This is significant, as it demonstrates that HF in Cape Town affects the breadwinner generation, rather than the elderly as has been noted in the developed world. In contrast, the average age of patients with AHF in Europe and North America is 70 years.[2,3] There was also a difference in clinical characteristics between patients with new-onset disease and those with a previous diagnosis of HF. The patients with prevalent disease were mostly from the mixed-ancestry community. This may be representative of Cape Town’s population demographics, the mixed-ancestry community constituting the largest group in the Western Cape.[15] Furthermore, patients with prevalent disease had more hypertension, DM, hyperlipidaemia and IHD. Comparison of coronary artery disease

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Table 1. Baseline clinical characteristics of 119 patients with AHF at GSH, Cape Town, SA Characteristics Age (yr), mean (SD) Sex, n (%) Female Male Race, n (%) Black White Mixed ancestry Asian AHF admissions in past 12 months, n (%) 0 1 2 3 Hypertension, n (%) DM, n (%) Smoking, n (%) Hyperlipidaemia, n (%) IHD, n (%) Atrial fibrillation, n (%) Stroke, n (%) Pericardial disease, n (%) RHD, n (%) Cardiomyopathy, n (%) Cor pulmonale, n (%) HIV, n (%) PVD, n (%) NYHA, n (%) I II III IV BMI (kg/m2), mean (SD) Systolic BP (mmHg), mean (SD) Diastolic BP (mmHg), mean (SD) Heart rate (bpm), mean (SD) Respiratory rate (/min), mean (SD) Oedema, n (%) 0 1+ 2+ 3+ Pulmonary oedema, n (%) 0 1 2 3 LVEF (%), mean (SD) Creatinine (μmol/dL), mean (SD) Urea (mmol/L), mean (SD) Sodium (mmol/L), mean (SD) Haemoglobin (g/dL), mean (SD) White cell count (× 109/L), mean (SD)

All cases (N=119) 49.9 (16.3)

Incident cases (N=89) 48.6 (16.2)

Prevalent cases (N=30) 53.7 (16.4)

69 (58.0) 50 (42.0)

53 (59.6) 36 (40.4)

16 (53.3) 14 (46.7)

59 (49.6) 4 (3.4) 54 (45.4) 2 (1.7)

51 (57.3) 3 (3.4) 35 (39.3) 0

8 (26.7) 1 (3.3) 19 (63.3) 2 (6.7)

89 (74.8) 22 (18.5) 4 (3.4) 4 (3.4) 58 (48.7) 26 (21.8) 46 (38.7) 13 (10.9) 17 (14.3) 6 (5.0) 5 (4.2) 3 (2.5) 12 (10.1) 11 (9.2) 7 (5.9) 14 (11.8) 2 (1.7)

89 (100)

37 (41.6) 15 (16.9) 31 (34.8) 3 (3.4) 6 (6.7) 5 (5.6) 3 (3.4) 0 10 (11.2) 4 (4.5) 3 (3.4) 10 (11.2) 2 (2.2)

22 (73.3) 4 (13.3) 4 (13.3) 21 (70.0) 11 (36.7) 15 (50) 10 (33.3) 11 (36.7) 1 (3.3) 2 (6.7) 3 (10.0) 2 (6.7) 7 (23.3) 4 (13.3) 4 (13.3) 0

23 (23.7) 20 (20.6) 44 (45.4) 10 (10.3) 27.4 (9.8) 134.6 (33.2) 81.9 (22.5) 102.5 (22.7) 22.8 (5.3)

23 (34.3) 17 (25.4) 24 (35.8) 3 (4.5) 27.6 (10.5) 137.4 (32.9) 82.4 (23.3) 102.7 (24.3) 23.0 (5.7)

0 3 (10.0) 20 (66.7) 7 (23.3) 26.7 (7.6) 126.3 (33.3) 80.5 (20.1) 101.9 (17.3) 22.0 (3.5)

37 (31.1) 1 (0.8) 21 (17.6) 60 (50.4)

27 (30.3) 1 (1.1) 17 (19.1) 44 (49.4)

10 (33.3) 0 4 (13.3) 16 (53.3)

46 (38.7) 4 (3.4) 28 (23.5) 41 (34.5) 34.1 (16.9) 109.7 (75.4) 10.2 (7.5) 136.9 (6.3) 12.3 (2.6) 9.7 (4.5)

33 (37.1) 2 (2.2) 26 (29.2) 28 (31.5) 35.9 (17.4) 110.2 (83.9) 9.7 (7.2) 137.0 (6.6) 12.1 (2.7) 9.8 (4.5)

13 (43.3) 2 (6.7) 2 (6.7) 13 (43.3) 28.2 (14.0) 108.4 (43.5) 11.6 (8.3) 136.9 (5.7) 12.7 (2.4) 9.2 (4.5)

p-value 0.143 0.349

0.005

n/a

0.006 0.025 0.105 <0.001 <0.001 0.526 0.372 0.015 0.374 0.005 0.066 0.490 0.558 <0.001

0.680 0.115 0.688 0.865 0.370 0.762

0.038

0.085 0.912 0.250 0.943 0.329 0.482

AHF = acute heart failure; GSH = Groote Schuur Hospital; SA = South Africa; SD = standard deviation; DM = diabetes mellitus; IHD = ischaemic heart disease; RHD = rheumatic valvular heart disease; PVD = peripheral vascular disease; NYHA = New York Heart Association class; BMI = body mass index; BP = blood pressure; bpm = beats per minute; LVEF = left ventricular ejection fraction; n/a = not applicable. Oedema: 0 = complete absence of skin indentation with mild digital pressure in all dependent areas, 1+ = indentation of skin that resolves over 10 - 15 s, 2+ = indentation of skin easily created with limited pressure and disappears slowly (≥15 - 30 s), 3+ = large areas of indentation easily produced and slow to resolve (>30 s). Pulmonary oedema: 0 = no rales heard after clearing cough, 1 = moist or dry rales heard in lower third of one or both lung fields that persist after cough, 2 = moist or dry rales heard throughout the lower half to two-thirds of one or both lungs, 3 = moist or dry rales heard throughout both lung fields.

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risk factors in the present study with those of other HF studies in SSA shows a greater burden of DM and smoking (Table 3). Finally, their baseline NYHA functional class was higher, possibly indicating a group of patients with more advanced HF, which may reflect suboptimal treatment of HF along with poor follow-up and education regarding HF. 25

Patients, %

20 15 10 5

Co ng en ita l

ase ise

n ns io Pe ri

car dia ld

rte

he r Ot

Hy pe

on ale

ase

pu lm

ise

Co r

ase ise

he art d

Va lvu lar

ic h ea rt d

Isc ha em

Ca rdi o

my op

ath y

Fig. 1. Causes of heart failure. (‘Other’ includes toxins, arrhythmias and Graves’ disease.)

In SSA, hypertension, RHD and the endemic cardiomyopathies account for the majority of HF cases.[5] In this study, cardiomyopathy, IHD and RHD were the leading causes of AHF in Cape Town, accounting for 60% of cases referred to tertiary care. Of interest is the high prevalence of IHD. Observational studies from SSA report the incidence of IHD as a cause of HF to be 0.4 - 9%.[4,5,13,14] In this study, 19.3% of patients were diagnosed with an ischaemic cause of HF. One of the possible reasons for the disparity in observations may be the effects of urbanisation. It has been shown that movement of people from rural areas to urban centres results in a change in diet and lifestyle, predisposing to the development of IHD.[7,8] Another reason may be that a specialist cardiology service was available to this study cohort, which may have allowed for better diagnostic tests (angiography and echocardiography), resulting in increased diagnosis of IHD. Hypertensive HF was less prevalent in this study than in other series from SSA. The reason for this is not clear, and requires further investigation. The rate of beta-blocker use was low at discharge in this study (42.7%) compared with EHFS II (61%), but was similar to rates of use observed in the Tanzania Heart Failure (TaHeF) study (42%) and THESUS-HF (50%).[3,5,14] The low rate of beta-blocker use may be due to the severity of HF treated. In this cohort, over half of the patients presented with NYHA functional classes III and IV combined. On discharge, 26.1% of patients received aldosterone antagonists and 15.5% received digoxin. This is considerably lower than has been

Table 2. Prescribed medication on admission and discharge or day 7 admission All cases Discharge/d 7, Treatment Admission, n (%) n (%) Nitrates (IV) 4 (3.5) 0 Furosemide (IV) 94 (79.0) 20 (18.0) Dobutamine 2 (1.7) 0 Mechanical ventilation 1 (0.9) 0 ACE inhibitor/ARB 70 (59.3) 81 (73.0) Loop diuretics 24 (20.7) 82 (74.6) Beta-blockers 21 (18.3) 47 (42.7) Digoxin 15 (13.2) 17 (15.5) Nitrates 4 (3.5) 9 (8.2) Aldosterone 15 (12.9) 29 (26.1) antagonists Simvastatin 36 (30.8) 36 (32.4) Aspirin 30 (25.6) 32 (28.8) All anticoagulation* 45 (38.5) 32 (28.8)

Incident cases Discharge/d 7, Admission, n (%) n (%) 3 (3.5) 0 71 (79.8) 13 (15.9) 2 (2.4) 0 0 0 48 (54.5) 57 (69.5) 17 (19.8) 60 (74.1) 13 (15.3) 32 (39.5) 9 (10.6) 12 (14.8) 3 (3.5) 4 (4.9) 9 (10.5) 19 (23.2)

Prevalent cases Discharge/d 7, Admission, n (%) n (%) 1 (3.3) 0 23 (76.7) 7 (24.1) 0 0 1 (3.3) 0 22 (73.3) 24 (82.8) 7 (23.3) 22 (75.9) 8 (26.7) 15 (51.7) 6 (20.7) 5 (17.2) 1 (3.3) 5 (17.2) 6 (20.0) 10 (34.5)

21 (24.1) 19 (21.8) 32 (36.8)

15 (50.0) 11 (36.7) 13 (43.3)

21 (25.6) 19 (23.2) 26 (31.7)

15 (51.7) 13 (44.8) 6 (20.7)

IV = intravenous; ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker. *Warfarin, heparin, enoxaparin.

Table 3. Comparison of CAD risk factors in the present study with HF studies from SSA and other parts of the world Study, country Current study Stewart et al.,[4] SA Lokker et al.,[18] SA Mwita et al.,[19] Botswana Ogah et al.,[13] Nigeria Makubi et al.,[14] Tanzania THESUS-HF[5] EHFS II,[3] Europe ADHERE,[2] USA

Diabetes (%) 21.8 10 24 15.5 10 12 11.1 62.5 44

Hypertension (%) 48.7 55 70 54.9 64.3 45 55 32.8 73

Smoking (%) 38.7 48 NR NR 3.3 NR 9.8 NR NR

CAD = coronary artery disease; HF = heart failure; SSA = sub-Saharan Africa; SA = South Africa; THESUS-HF = The Sub-Saharan Africa Survey of Heart Failure; EFHS II = EuroHeart Failure Survey II; ADHERE = Acute Decompensated Heart Failure National Registry; CAD = Coronary Artery Disease; NR = not reported.

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described in the rest of SSA, where aldosterone and digoxin are prescribed in 60 - 75% and 31 - 72% of cases, respectively.[4,5,13,14] The side-effect profiles, potential drug interactions and close monitoring of these therapies in a population group where compliance to follow-up and access to specialist care is suboptimal may explain their limited use. Hydralazine use was low, possibly because of its limited availability at GSH and also its known low use by physicians in SSA. [5] In this study, 28.8% of patients were discharged on aspirin. This is a far lower figure than is described in THESUS-HF, where >50% of patients were discharged on aspirin despite the low prevalence of ischaemic HF.[5] This study shows a population with a high prevalence of IHD. Whether the use of aspirin in this study is in keeping with the prevalence of IHD as identified in this cohort needs to be evaluated further. The mean length of stay of 9.2 days is similar to the number of admission days described in studies from developed nations and SSA.[3-5,13] The 6-month readmission rate was 25.2%. The reasons for this high readmission rate may be three-fold. First, suboptimal adherence to evidence-based treatments may be resulting in high readmission rates. Second, gaps in patients’ understanding of HF and the importance of treatment follow-up and lifestyle adherence may be a further contributory factor.[16] Finally, hospital bed pressure may lead to premature discharge of HF patients. The in-hospital and 6-month mortality rates were 8.4% and 26.1%, respectively. This is higher than is described in the rest of SSA. THESUS-HF, the largest multicentre study on HF to date, reported an in-hospital mortality rate of 4.2% and a 6-month mortality rate of 17.8%.[5] These high mortality rates may be due to the different aetiological pattern in Cape Town, with a significant contribution of IHD and a lower prevalence of hypertension as the primary cause of AHF. There was also low use of life-saving medications such as beta-blockers and aldosterone inhibitors. These observations stress the importance of adhering to evidence-based treatment guidelines. Furthermore, the management of HF is complex and requires a multidisciplinary approach encompassing routine follow-up with patient education, optimisation of treatment and social support.[17]

Study limitations

This study has a number of limitations. The sample size was small and may under-represent the causes of HF. A second limitation was that rehospitalisation to other institutions may not have been documented in all cases. Furthermore, only admission and discharge treatment practices are described. It may be that the use of aldosterone and beta-blockers as well as other HF treatment increased during ambulatory care in the community. There is also lack of data on dosages of drugs that confer survival benefit in HF. Finally, 10.1% of the patient cohort was lost to follow-up, which may have contributed to under-estimation of the case fatality rate.

Conclusion

This study provides important insights into the demographics, causes, treatment and outcomes of AHF in Cape Town. It confirms observations in earlier SSA HF studies that a young adult population is affected by HF. Cardiomyopathy, IHD and RHD account for 60% of cases of AHF. However, of concern is the high prevalence of IHD in this cohort, the highest reported so far in SSA. Furthermore, there was serious under-use of beta-blockers, aldosterone antagonists and digoxin. The high readmission rate and 6-month mortality rate may

reflect suboptimal adherence to evidence-based treatment guidelines. There needs to be emphasis on the rigorous application of treatment guidelines to reduce readmission and mortality associated with AHF in Cape Town. Acknowledgements. We thank Sisters Dee Isaacs and Veronica Francis for help with the recruitment of patients and collection of data for this study, and Mr Lwazi Mhlanti for the development of the database and data capturing. We also acknowledge the THESUS-HF Consortium (Drs G Cotter, A Damasceno and K Sliwa) for permission to conduct the substudy in Cape Town. Author contributions. PZS drafted the manuscript and managed the data collection. MB performed the data analysis and assisted with data preparation for statistical analysis. BMM supervised the study and was a major contributor to the study design and final manuscript. Funding. The study was funded by the Discovery Foundation (through an MMed Fellowship to PZS), the Lily and Ernst Hausmann Research Trust, the South African Medical Research Council and AstraZeneca. Conflicts of interest. None. 1. Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol 2016;13(6):368378. https://doi.org/10.1038/nrcardio.2016.25 2. Adams KF, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: Rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149(2):209-216. https://doi.org/10.1016/j.ahj.2004.08.005 3. Nieminen MS, Brutsaert D, Dickstein K, et al. EuroHeart Failure Survey II (EHFS II): A survey on hospitalized acute heart failure patients: Description of population. Eur Heart J 2006;27(22):2725-2736. https://doi.org/10.1093/eurheartj/ehl193 4. Stewart S, Wilkinson D, Hansen C, et al. Predominance of heart failure in the Heart of Soweto Study cohort: Emerging challenges for urban African communities. Circulation 2008;118(23):2360-2367. https://doi.org/10.1161/CIRCULATIONAHA.108.786244 5. Damasceno A, Mayosi BM, Sani M, et al. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries. Arch Intern Med 2012;172(18):1386-1394. https://doi.org/10.1001/ archinternmed.2012.3310 6. Ntusi NBA, Mayosi BM. Epidemiology of heart failure in sub-Saharan Africa. Expert Rev Cardiovasc Ther 2009;7(2):169-180. https://doi.org/10.1586/14779072.7.2.169 7. Mendez GF, Cowie MR. The epidemiological features of heart failure in developing countries: A review of the literature. Int J Cardiol 2001;80(2-3):213-219. https://doi.org/10.1016/s0167-5273(01)00497-1 8. Stewart S, Carrington M, Pretorius S, Methusi P, Sliwa K. Standing at the crossroads between new and historically prevalent heart disease: Effects of migration and socio-economic factors in the Heart of Soweto cohort study. Eur Heart J 2011;32(4):492-499. https://doi.org/10.1093/eurheartj/ehq439 9. Alwan A, Armstrong T, Cowan M, Riley L. Noncommunicable Diseases Country Profiles 2011. World Health Organization, 2011:1-207. http://www.who.int/nmh/publications/ncd_profiles2011/en/ (accessed 2 January 2018). 10. Commerford P, Mayosi B. An appropriate research agenda for heart disease in Africa. Lancet 2006;367(9526):1884-1886. https://doi.org/10.1016/S0140-6736(06)68822-3 11. Sliwa K, Mayosi BM. Recent advances in the epidemiology, pathogenesis and prognosis of acute heart failure and cardiomyopathy in Africa. Heart 2013;99(18):1317-1322. https://doi.org/10.1136/ heartjnl-2013-303592 12. Brun R. ROOT – an object oriented data analysis framework. Nucl Instrum Methods Phys Res A 1997;389(1-2):81-86. https://doi.org/10.1016/S0168-9002(97)00048-X 13. Ogah OS, Stewart S, Falase AO, et al. Contemporary profile of acute heart failure in Southern Nigeria: Data from the Abeokuta Heart Failure Clinical Registry. JACC Heart Fail 2014;2(3):250-259. https://doi. org/10.1016/j.jchf.2013.12.005 14. Makubi A, Hage C, Lwakatare J, et al. Contemporary aetiology, clinical characteristics and prognosis of adults with heart failure observed in a tertiary hospital in Tanzania: The prospective Tanzania Heart Failure (TaHeF) study. Heart 2014;100(16):1235-1241. https://doi.org/10.1136/heartjnl-2014-305599 15. Statistics South Africa. Census 2011: Census in Brief. Pretoria: Stats SA, 2012. http://www.statssa.gov. za/census/census_2011/census_products/Census_2011_Census_in_brief.pdf (accessed 2 January 2018). 16. Van der Wal MHL, Jaarsma T, van Veldhuisen DJ. Non-compliance in patients with heart failure: How can we manage it? Eur J Heart Fail 2005;7(1):5-17. https://doi.org/10.1016/j.ejheart.2004.04.007 17. Mpe MT, Klug EQ, Sliwa KS, Hitzeroth J, Smith DA. Heart Failure Society of South Africa (HeFSSA) perspective on the European Society of Cardiology (ESC) 2012 chronic heart failure guideline. S Afr Med J 2013;103(9):661-667. https://doi.org/10.7196/SAMJ.7319 18. Lokker ME, Gwyther L, Riley JP, van Zuylen L, van der Heide A, Harding R. The prevalence and associated distress of physical and psychological symptoms in patients with advanced heart failure attending a South African medical center. J Cardiovasc Nurs 2016;31(4):313-322. https://doi.org/10.1097/ JCN.0000000000000256 19. Mwita JC, Dewhurst MJ, Magafu MG, et al. Presentation and mortality of patients hospitalised with acute heart failure in Botswana. Cardiovasc J Afr 2016;28(2):112-117. https://doi.org/10.5830/CVJA-2016-067

Accepted 15 August 2017.

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RESEARCH

Neonatal and paediatric bloodstream infections: Pathogens, antimicrobial resistance patterns and prescribing practice at Khayelitsha District Hospital, Cape Town, South Africa H Crichton,1 MB ChB, DCH; N O’Connell,1 MB ChB, FCPaed (SA), MMed (Paed); H Rabie,2 MB ChB, FCPaed (SA), MMed, MSc (ID); A C Whitelaw,3 MB ChB, MSc, FCPath (SA) (Micro); A Dramowski,2 MB ChB, PhD, FCPaed (SA), MMed (Paed), Cert ID (SA) Paed, DCH Department of Paediatrics, Khayelitsha District Hospital, Cape Town, South Africa Department of Paediatrics and Child Health, Division of Paediatric Infectious Diseases, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 3 Division of Medical Microbiology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University; and National Health Laboratory Service, Tygerberg Hospital, Cape Town, South Africa 1 2

Corresponding author: H Crichton (crchel002@gmail.com) Background. The epidemiology of neonatal and paediatric community-acquired and healthcare-associated bloodstream infections (BSI) at South African (SA) district hospitals is under-researched. Objective. Retrospective review of neonatal and paediatric BSI (0 - 13 years) at Khayelitsha District Hospital, Cape Town, SA, over 3 years (1 March 2012 - 28 February 2015). Methods. We used laboratory, hospital, patient and prescription data to determine BSI rates, blood culture yield and contamination rates, pathogen profile, antimicrobial resistance, patient demographics, BSI outcome and antibiotic prescribing practice. Results. From 7 427 blood cultures submitted, the pathogen yield was low (2.1%, 156/7 427) while blood culture contamination rates were high (10.5%, 782/7 427). Paediatric and neonatal BSI rates were 4.5 and 1.4/1 000 patient days, respectively. Gram-positive BSI predominated (59.3%); Staphylococcus aureus (26.8%) and Escherichia coli (21.6%) were common pathogens. The median patient age was 3 months, with a predominance of males (57.7%) and a 12.8% prevalence of HIV infection. Crude BSI-associated mortality was 7.1% (11/156), the death rate being higher in neonates than in infants and children (6/40 (15.0%) v. 5/116 (4.3%), respectively; p=0.03) and in patients with Gramnegative compared with Gram-positive bacteraemia (6/66 (9.1%) v. 5/89 (5.6%), respectively; p=0.5). Most BSI episodes were communityacquired (138/156; 88.5%), with high levels of extended-spectrum β-lactamase (ESBL) carriage among Klebsiella pneumoniae and E. coli isolates (5/5 (100%) and 8/33 (24.2%), respectively). Antimicrobial management of BSI was inappropriate in 30.6% of cases (45/147), including incorrect empirical antibiotic (46.7%), dual antibiotic cover (33.3%) and inappropriately broad-spectrum antibiotic use (17.8%). Conclusions. Antimicrobial-resistant pathogens (notably ESBL-producing Enterobacteriaceae) were common in community-acquired BSI. Paediatric clinicians at district hospitals require ongoing training in antibiotic stewardship and blood culture sampling. S Afr Med J 2018;108(2):99-104. DOI:10.7196/SAMJ.2018.v108i2.12601

Bacterial bloodstream infections (BSI), both community acquired (CA) and healthcare associated (HA), are an important cause of neonatal and paediatric morbidity and mortality worldwide.[1] A meta-analysis of CA-BSI data from Africa in paediatric and adult patients established that non-typhoidal Salmonella, Escherichia coli, Staphylococcus aureus and Streptococcus pneumoniae are major pathogens, with CA-BSI associated mortality of 18% and a blood culture pathogen yield of 8.2%.[2] Data on HA neonatal and paediatric BSI (HA-BSI) in Africa are scant, but confirm high case fatality, a predominance of Klebsiella pneumoniae, E. coli and S. aureus, and high levels of antimicrobial resistance (AMR) among nosocomial pathogens.[3,4] The increasing frequency of AMR among BSI pathogens is of great concern for African countries, where access to care and broadspectrum antimicrobials is often limited.[5-8] Important resistance phenotypes in BSI isolates include extended-spectrum β-lactamases (ESBL) and carbapenemase-producing Enterobacteriaceae. Data from a cross-sectional study at a South African (SA) children’s hospital showed the presence of ESBL in 83% of K. pneumoniae isolates,[9] along with the more recent emergence of carbapenem resistance due

to carbapenemases.[10] Common carbapenemases include New Delhi metallo-β-lactamase-1 (NDM-1) and OXA-48-like enzymes.[11] The widespread and uncontrolled use of cephalosporins has contributed to the increased prevalence of ESBL-producing organisms, which may lead to increased BSI mortality, longer hospital stays and increased healthcare costs.[12-14] The changing spectrum of pathogens, AMR patterns and clinical impact necessitates ongoing auditing, monitoring and publication of data on local pathogen profiles and antibiotic sensitivity patterns to inform clinical management and infection prevention efforts. [6,13,14] For neonates and children admitted to SA district hospitals, research on the epidemiology and AMR patterns of CA- and HA-BSI will inform development of appropriate empirical antibiotic recommendations. Furthermore, there are very limited data on paediatric clinicians’ prescribing practices to inform antimicrobial stewardship programmes at district hospitals.

Objective

To investigate the epidemiology of neonatal and paediatric BSI at Khayelitsha District Hospital (KDH) in Cape Town, SA, reporting

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BSI rates, pathogen profile, AMR patterns, risk factors for BSIassociated mortality and antibiotic prescribing practice.

Methods Setting

KDH serves an urban community of ~500 000 people. The popula tion is young (one-third <15 years of age) and mainly black African (99%), and most live in poor socioeconomic circumstances.[15] The hospital’s paediatric service comprises a 32-bed paediatric ward, a 6-bed paediatric short-stay ward in the emergency centre, a 12-bed neonatal unit and a 10-bed kangaroo mother care (KMC) unit. Patients are admitted from the community via the emergency centre or by referral through a network of primary care providers known as community health clinics. Moderately and critically ill children are referred to tertiary-level hospitals in the Cape metropolitan region.

Investigation and management of BSI

Blood cultures are obtained from neonates and children presenting with clinical signs and/or risk factors for severe bacterial infection (including fever, lethargy, shock, meningism, pneumonia, HIV infec tion and severe acute malnutrition) or following clinical deterioration during hospitalisation with suspected healthcare-associated infection (HAI). Blood cultures performed at KDH are processed at the National Health Laboratory Service (NHLS) microbiology laboratory at Tygerberg Hospital, using the automated BacT/Alert system (BioMerieux, France). Positive cultures were identified using standard microbiological methods, and susceptibility testing was performed using either the standard Kirby-Bauer disc diffusion method or the automated Vitek 2 AES (BioMerieux, France). Susceptibility results were interpreted using Clinical and Laboratory Standards Institute criteria. Empirical antibiotic recommendations for CA severe bacterial infections include a third-generation cephalosporin (cefotaxime or ceftriaxone) for suspected meningitis and ampicillin for lower respiratory tract infections; gentamicin is added to ampicillin for infants and immunocompromised patients. Neonates receive penicillin G and gentamicin as first-line therapy or cefotaxime and ampicillin if meningitis is suspected. Empirical treatment for HA-BSI is piperacillin-tazobactam and amikacin, with escalation to meropenem in cases of suspected meningitis and in neonates and paediatric patients requiring transfer to tertiary care/an intensive care unit (ICU).

Data extraction and analysis

We retrospectively reviewed paediatric and neonatal BSI episodes at KDH between 1 March 2012 (when the hospital first opened) and 28 February 2015 using laboratory records, hospital data, patient folders and antimicrobial prescription charts to determine BSI rates, blood culture yield and contamination rates, pathogen profile, AMR rates, patient demographics, BSI outcome and antibiotic prescribing practice. The total number of blood cultures submitted during the study period was determined, with extraction of all positive blood cultures from children (0 - 13 years) from the NHLS electronic database. Inpatient days for the paediatric, neonatal, KMC and shortstay wards were obtained from the hospital data manager. All positive blood culture isolates were classified as either pathogens or contaminants using the Centers for Disease Control and Prevention criteria.[16] Positive blood cultures isolating the same pathogen within 14 days were considered a single episode of BSI. Similarly, positive blood cultures with a pathogen and a contaminant were considered a single episode of BSI. In vitro susceptibility of pathogens was determined from the NHLS records, and AMR phenotypes were described using proposed criteria.[17]

Isolates of E. coli and K. pneumoniae with reduced susceptibility to cefotaxime and/or ceftazidime were regarded as ESBL-producing organisms. No molecular tests were performed to confirm this, since these were retrospective data; however, plasmid-mediated ampC-like β-lactamases are very unusual in these organisms. Positive blood cultures sampled <48 hours after hospital admission were considered to represent CA-BSI, whereas those obtained >48 hours after admission were classified as HA-BSI. Patients referred from a long-term healthcare institution or readmissions within 30 days of discharge were classified as HA-BSI. BSI and blood culture contamination rates were determined, with 95% confidence intervals (CIs). Demographic data were obtained from the laboratory records and hospital folder review, including age, weight, HIV status, antibiotic prescription record and outcome of hospitalisation. We calculated weight-for-age z-scores (WAZ) using World Health Organization anthropometric data and defined normal weight for age as WAZ ≥0, underweight for age as –2 - 0, moderately underweight as –2 - –3 and severely underweight as <–3. Where patient folders could be located, antibiotic prescriptions for the BSI episode were systematically reviewed by the authors (who include paediatricians, paediatric infectious diseases specialists and a microbiologist). Appropriateness of the empirical and targeted antibiotic prescriptions and compliance with local antibiotic recommendations were evaluated by the authors to achieve consensus regarding the appropriateness of each patient’s empirical and targeted antibiotic prescription/s. Prescriptions were deemed appropriate if they were adequate to treat the patient’s clinical diagnosis and in compliance with local treatment guidelines. Prescriptions were considered inappropriate if they were unsuitable to treat the patient’s clinical diagnosis or in contravention of local treatment guidelines. Inappropriate prescriptions were subcategorised as follows: incorrect empirical antibiotic choice, dual antibiotic cover, and failure to use the most narrow-spectrum antibiotic available.

Statistical analysis

The BSI rate was calculated by dividing the total number of BSI episodes by the total inpatient days over the 3-year period. The pathogen rate and contamination rate were calculated by dividing the total number of pathogens and contaminants, respectively, by the total number of blood cultures submitted. Standard practice is for only a single blood culture bottle to be taken at each blood culture collection episode, and the total number of bottles therefore represented the total number of blood culture collection episodes. A χ2 test for linear trend was used to assess changes in neonatal and paediatric BSI rates over time. Continuous and categorical data were analysed using Student’s t-tests and Fisher’s exact tests/χ2 tests, as appropriate. Stata statistical software version 13.1 (StataCorp, USA) was used. To determine factors associated with mortality from BSI, binary logistic regression analysis was performed. Factors with a univariate p-value of <0.1 were entered into the model. A p-value of <0.05 was considered statistically significant.

Ethical approval

Ethical approval and waiver of individual informed consent was obtained from the Human Health Research Ethics Committee of Stellenbosch University (ref. no. S13/09/171) and the KDH ethics committee (ref. no. WC_2015RP15_794).

Results

Over the 3-year study period, the culture positivity rate was 12.6% (938/7 427 blood cultures), including 156 BSI episodes (2.1% pathogen yield) and 782 contaminated blood cultures (10.5%); contaminants

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Most blood culture samples from the patients with the 156 BSI episodes were submitted from the emergency centre (122/156, 78.2%), followed by the neonatal nursery (27/156, 17.3%) and the paediatric ward (7/156, 4.5%). The majority of episodes were CA-BSI (138/156, 88.5%), with 18 episodes (11.5%) of HA-BSI. Most BSI episodes were monomicrobial (145/156, 92.9%), but 11 episodes (7.1%) were poly microbial, with two pathogens each (i.e. total pathogen yield of 167 BSI pathogens)

included coagulase-negative staphylococci (n=561, 71.7%), Micrococcus spp. (n=70, 9.0%), non-pathogenic streptococci (n=38, 4.9%), Corynebacterium spp. (n=32, 4.1%) and Bacillus spp. (n=31, 4.0%). Most contaminated blood cultures were submitted from the emergency centre (488/782, 62.4%). The neonatal and paediatric BSI rates were 1.4/1 000 patient days (95% CI 0.9 - 1.9) and 4.5/1 000 patient days (95% CI 3.7 - 5.3), respectively, with no significant change over the study period (Fig. 1).

BSI rate/1 000 inpatient days

6 5.6

5 4

χ2 for trend unchanged; p=0.64.*

4.2

3.9

3 2

1.6

χ2 for trend unchanged; p=0.23.†

1.8 1

1 0 1

Year BSI rate (paediatrics)

BSI rate (neonates)

Linear BSI rate (paediatrics)

Linear BSI rate (neonates)

Fig. 1. Trends in paediatric and neonatal BSI rates. (BSI = bloodstream infection; *Paediatrics BSI rate year 1 (BSI/inpatient days × 1 000): 39/9 234 × 1 000; year 2: 50/3 930 × 1 000; year 340/10 297 × 1 000; †Neonatal BSI rate year 1: 8/5 046 × 1 000; year 2: 12/6 705 × 1 000; year 3: 7/7 504 × 1 000.)

(Table 1). Of the 11 polymicrobial BSI episodes, two were in neonates and nine in children. Gram-positive bacteria were the predominant pathogen type isolated (99/167, 59.3%), followed by Gramnegative pathogens (67/167, 40.1%), with only one fungal BSI pathogen. The most frequent pathogens in neonates <28 days of age (n=40) were group B streptococci (20/40, 50.0%), S. aureus (7/40, 17.5%) and E. coli (6/40, 15.0%). Among infants aged >28 days and children (n=116), the most prevalent BSI pathogens were S. aureus (38/116, 32.8%), E. coli (30/116, 25.9%) and S. pneumoniae (11/116, 9.5%). Patients with BSI had a median age of 3 months (interquartile range (IQR) 0.6 - 11 months) and a male predominance (57.7%) (Table 2). HIV status was unknown in only 9.6% (15/156); among the 141 patients with confirmed HIV status, the prevalence of HIV infection was 12.8% (18/141). Of the children 57.4% were HIV-exposed but uninfected (81/141). The most common BSI pathogens among HIV-infected children were S. pneumoniae (n=5), followed by E. coli and S. aureus. The most prevalent comorbid conditions included prematurity (19.2%), malnutrition (severely underweight) (10.3%), tuberculosis (5.6%) and cerebral palsy (3.0%).

Table 1. Microbiological profile of paediatric BSI episodes* Pathogens isolated from 156 BSI episodes % of total BSI % of % >28 organisms* neonates days of age (N=167) % of group† (N=40) (N=116)

% of deaths (N=11)

36 9 4 5 5

21.6 5.4 2.4 3.0 3.0

53.6 13.4 6.0 7.5 7.5

15.0 7.5 0 5.0 0

25.9 5.2 3.4 2.6 4.3

27.3 18.1 0 0 0

6 2 99 45 12 26 10 2 4 1 1

3.6 1.2

9.0 3.0

0 0

5.2 1.7

9.1 0

26.8 7.2 15.6 6.0 1.2 2.4

45.5 12.1 26.3 10.1 2.0 4.0

17.5 0 50.0 5.0 5.0 0

32.8 10.3 5.2 6.9 0 3.4

9.1 0 27.3 9.1 0 0

0.6

100

Isolates, n (N=167) 67

BSI episodes Gram-negative organisms Enterobacteriaceae Escherichia coli Klebsiella pneumoniae Salmonella non-typhi Other‡ Non-fermenting Gram-negative bacilli§ Other Neisseria meningitidis Haemophilus influenzae Gram-positive organisms Staphylococcus aureus Streptococcus pneumoniae Group B streptococcus Enterococcus spp. Listeria monocytogenes Other¶ Fungi Candida parapsilosis

BSI = bloodstream infection. *145/156 (92.9%) BSI episodes monomicrobial, 11 (7.1%) polymicrobial with two pathogens each (total yield 167 BSI pathogens). † Groups: Gram-negative organisms, Gram-positive organisms, fungi. ‡ Other Enterobacteriaceae: Salmonella typhi, Shigella flexneri, Serratia marcescens, Citrobacter freundii. § Non-fermenting Gram-negative bacilli: Acinetobacter baumannii, Pseudomonas aeruginosa, Chryseobacterium indologenes. ¶ Other Gram-positives: viridans group streptococcus, group A streptococcus.

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Table 2. Demographics of patients with BSI (N=156) Variable Gender (male), n (%) Age (days), median (IQR) Age category, n (%) <28 days 28 - 364 days 1 - 5 years >5 - 13 years HIV status, n (%) Infected Negative, unexposed Exposed, uninfected Unknown Ward at diagnosis, n (%) Emergency unit Paediatric ward Neonatal nursery/KMC Outcome, n (%) Died Survived Impact, n (%) District hospital Tertiary ward Transferred to ICU Duration of hospitalisation (days), median (IQR) Time to HA-BSI onset (days), median (IQR)

LC-BSI (N=156) 90 (57.7) 94 (18 - 343)

CA-BSI (N=138) 78 (56.5) 113 (30 - 358)

HA-BSI (N=18) 12 (66.7) 15 (1 - 49)

40 (25.6) 77 (49.4) 26 (16.7) 13 (8.3)

31 (22.5) 71 (51.4) 23 (16.7) 13 (9.4)

9 (50.0) 6 (33.3) 3 (16.7) 0

18 (11.5) 73 (46.8) 50 (32.1) 15 (9.6)

16 (11.6) 57 (41.3) 50 (36.2) 15 (10.9)

2 (11.1) 16 (88.9) 0 0

122 (78.2) 7 (4.5) 27 (17.3)

117 (84.8) 6 (4.3) 15 (10.9)

5 (27.8) 1 (5.6) 12 (66.6)

11 (7.0) 145 (93.0)

9 (6.5) 129 (93.5)

2 (11.1) 16 (88.9)

70 (44.9) 59 (37.8) 27 (17.3) 10 (5 - 17) n/a

63 (45.7) 51 (37.0) 24 (17.3) 9 (4 - 14 n/a

7 (38.9) 8 (44.4) 3 (16.7) 21.5 (17 - 26) 5 (2 - 9)

p-value 0.41 0.006 0.05

0.001

0.47

BSI = bloodstream infection; LC = laboratory confirmed; CA = community acquired; HA = hospital acquired; IQR = interquartile range; KMC = kangaroo mother care; ICU = intensive care unit; n/a = not applicable.

Eighteen episodes (11.5%) of HA-BSI were documented, with a median hospital stay of 5 days (IQR 2 - 8) preceding HA-BSI onset. Ten HA-BSI episodes (55.6%) occurred in the neonatal nursery among premature babies. HA-BSI pathogens were K. pneumon iae (n=4), E. coli (n=3), group B streptococci (n=3), S. aureus (n=2), Enterococcus spp. (n=2), Pseudomonas aeruginosa (n=1), S. pneumoniae (n=1), Serratia marcescens (n=1) and non-typhoidal Salmonella (n=1). Two patients died following episodes of E. coli and E. faecalis HA-BSI, at a median of 34 days from BSI onset. The clinical impact of the 156 BSI episodes was severe: 86 patients (55.1%) required transfer to tertiary care, including 27 (17.3%) who required ICU admission for ventilation and/or inotropic support. The overall crude in-hospital BSI-associated mortality rate was 7.1% (11/156), the case fatality rate being higher among neonates (0 - 28 days) compared with infants/older children (6/40 (15.0%) v. 5/116 (4.3%), respectively; p=0.03). The median hospital stay from admission to death for patients with CA-BSI was 9 days (IQR 4 - 15). The BSI-associated crude mortality rate in HIV-infected children was higher than that in HIV-uninfected/HIV-unknown children (3/18 (16.6%) v. 8/138 (5.8%), respectively; p=0.05). Mortality was higher among patients with Gram-negative BSI than among those with Gram-positive and fungal infections, but not significantly so (6/66 (9.1%) v. 5/90 (5.6%), respectively; p=0.5). There was no difference in crude mortality rates between neonates/children with HA-BSI compared with CA-BSI (2/18 (11.1%) v. 9/138 (6.5%), respectively; p=0.62). On multivariate analysis, age <28 days and malnutrition (WAZ <–3) were significantly associated with mortality (odds ratio 8.6 (95% CI 1.7 - 45.0) and 11.3 (95% CI 1.7 - 74.0), respectively; p=0.01). Among the children who died, most deaths occurred after transfer to the ICU (5/11, 45.5%), followed by deaths in the

emergency centre (4/11, 36.4%) and the neonatal nursery (2/11, 18.2%). AMR rates were high for both CA-BSI and HA-BSI pathogens; among the CA-BSI pathogens, 8/33 (24.2%) E. coli and 5/5 (100%) K. pneumoniae were ESBL producers. Folder review of the 13 CA- ESBL BSI episodes found that only one of the 13 children had been admitted to hospital in the preceding 30 days, suggesting community acquisition of the ESBL-producing pathogens. Of the HA-BSI pathogens, all the K. pneumoniae (n=4) but none of the E. coli were ESBL producers. BSI-associated crude mortality was significantly higher among children with CA-BSI pathogens that produced ESBLs v. all other CA-BSI pathogens (3/13 (23.1%) v. 6/125 (4.8%), respectively; p=0.04). Of the 42 S. aureus isolates, 4 (9.5%) were methicillin-resistant CA-BSI. Meropenem provided greatest in vitro coverage for HA-BSI pathogens, with susceptibility in 16/18 (88.9%), followed by piperacillin-tazobactam (14/18, 77.8%) and amikacin (7/18, 38.9%). The institution’s recommended regimen for HAI (piperacillintazobactam plus amikacin) provided good empirical coverage (16/18, 88.9%). Of CA-BSI pathogens, 68.1% were susceptible (in vitro) to first-line antibiotics (ampicillin and/or gentamicin) and 69.6% were susceptible to ceftriaxone. No carbapenem-resistant Enterobacteriaceae, vancomycin-resistant enterococci or fluconazoleresistant Candida species were isolated. For the 156 BSI episodes, 147 complete patient folders and prescription charts (94.2%) were located for review. Nearly one-third of patients (45/147, 30.6%) were assessed through expert review as having received inappropriate antimicrobial therapy (empirical, targeted or both) (Table 3). The leading causes of inappropriate antibiotic use were incorrect empirical antibiotic choice (21/45,

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Table 3. Antimicrobial management of BSI (N=147)* Appropriate Inappropriate† Incorrect empirical antibiotic prescribed Dual antibiotic cover Narrowest-spectrum agent not used Inadequate documentation Incorrect antibiotic switch Blood culture result not followed up Second-line protocol not followed Earlier oral switch indicated but not made Stock shortages Initial escalation of antibiotic therapy required

n (%) 102 (69.4) 45 (30.6) 21/45 (46.7) 15/45 (33.3) 8/45 (17.8) 7/45 (15.6) 5/45 (11.1) 4/45 (8.9) 4/45 (8.9) 2/45 (4.4) 2/45 (4.4) 1/45 (2.2)

BSI = bloodstream infection. *9 folders could not be retrieved or had incomplete antimicrobial prescription records. † In some cases there was more than one reason for assessing antimicrobial management of the BSI episode as inappropriate.

46.7%), dual antibiotic cover (15/45, 33.3%) and failure to use the most narrow-spectrum antibiotic available (8/45, 17.8%).

Discussion

Our study documented pathogen yields markedly lower than reported from other African settings (8.2%).[2] Several factors, including district hospital level of care, antibiotics administered prior to admission and inadequate volumes of blood, may have contributed to the lower yield. According to the Integrated Management of Childhood Illness guidelines,[18] any child who fulfils the criteria for serious illness should receive intramuscular ceftriaxone prior to transfer, which may contribute to the lower pathogen yield observed and may also contribute to the proportionately higher prevalence of ESBLs in CA Enterobacteriaceae. Of great concern is the high rate of blood culture contamination identified, which in addition to creating clinical uncertainty has a financial impact on the hospital owing to the costs of further testing and management, as well as implications for the patient, who has to undergo further investigations and a prolonged hospital stay. The contamination rate was more than three times higher than the internationally accepted rate of 3%.[19] This could be attributed to the difficulty in obtaining blood cultures from severely ill children, the busy emergency centre setting, staff and stock shortages, inadequate or irregular training of staff, high staff turnover, limited resources, and unfamiliarity with the blood culturing protocol. Factors known to contribute to increased blood culture contamination rates include young patient age (<36 months) and inexperienced physicians (trainees v. specialists).[19,20] Given the high contamination rates, urgent interventions such as regular training workshops on the correct sampling technique, feedback of monthly contamination rates to clinical staff, and intermittent checks of blood volume inoculum (by weighing culture bottles) should be implemented. In addition, all wards and the emergency centre should ensure that there is sufficient stock of sterile blood culture packs and consumables. At our institution, Gram-positive BSI pathogens (59.3%) predominated, particularly among CA-BSI, and in contrast to many African BSI studies reporting Gram-negative predominance.[2,21] Gram-negative pathogens predominated in HA-BSI episodes, in keeping with findings of neonatal and paediatric BSI studies at two tertiary hospitals in Cape Town.[5,21,22] A large proportion of BSI patients (55.1%) required transfer to tertiary-level hospitals, which highlights the impact of BSI on children as well as the healthcare costs involved. Of note is the high number of CA ESBL organisms in

our study, with a mortality rate three times higher than the overall crude mortality rate. Further scrutiny of CA ESBL BSI would have been beneficial in terms of determining the number of clinic visits with antibiotic administration prior to admission, and possible contributing factors leading to the emergence of resistance at a community level. Knowledge of local organisms and their sensitivity profiles in a peripheral hospital is invaluable for development and revision of institutional antimicrobial guidelines. Regular review of AMR rates in neonatal and paediatric CA-BSI isolates will be required in view of the 68 - 70% current coverage of CA-BSI pathogens with empirical therapy (ampicillin/gentamicin or ceftriaxone). The institution’s empirical recommendations for HA-BSI provided high in vitro coverage, although the number of BSI in this category was very low. Inappropriate empirical antibiotic choice accounted for almost half (46.7%) of the prescriptions that were evaluated as inappropriate. Incorrect initial antimicrobial choice has been associated with increased mortality in a study in SA ICUs (27% v. 11% when antibiotic choice was apppropriate).[23] In addition, 33.3% of prescriptions had dual antibiotic cover, where antibiotics were added to treatment plans and prescription charts were not amended. Based on the many inappropriate prescribing practices identified in this study, we recommend ongoing antibiotic stewardship audits, pharmacy audits and regular antibiotic stewardship clinical ward rounds to improve prescriber awareness and patient outcomes at district hospitals. Assessment of clinicians’ reasons for instituting, changing or deviating from recommended prescribing practice was problematic, owing to very poor documentation in the hospital records. Correct prescribing procedures need to be adhered to and documentation in clinical notes needs to be improved. At present, few structured antibiotic stewardship rounds are conducted in district-level hospitals owing to limited resources and expertise (i.e. lack of on-site microbiology, infectious diseases and/or clinical pharmacology personnel). Similarly, improvements to documentation in clinical patient case notes should be highlighted to ensure continuity of care and assist in future audits. Healthcare professionals should take care to document the time of positive blood culture and the corresponding antibiotic choice. In the case of upscaling to second-line antibiotics, the clinical reason should be carefully documented. Prescription charts should be reviewed daily to ensure that all medications are correct and stopped timeously. The South African Antibiotic Stewardship programme prescription chart[24] should be used at district-level hospitals to improve prescribing practices. This will aid judicious prescribing practices and improve antibiotic stewardship rounds and audits at a district level.

Study limitations

Our study has several limitations: a relatively small number of BSI episodes and short study duration, which limit the ability to draw conclusions regarding antimicrobial susceptibility and prescribing trends; inability to observe blood culture inoculum volume and sampling technique (which influence blood culture yield and contamination rates); and inability to document recent hospitalisation and previous antibiotic exposures as variables affecting classification of CA- v. HA-BSI and blood culture yield, respectively. We reported a crude BSI-associated in-hospital mortality rate, and owing to the retrospective nature of the study it was not possible to determine whether deaths were due to the BSI alone or attributable to another event. The median number of days from blood culture specimen collection to death in the CA-BSI (9 days) and HA-BSI cohorts (34 days) suggests that additional factors may have contributed to our patients’ deaths. A further limitation was reliance

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on electronic records to evaluate antimicrobial prescription practices, with exclusion of nine records (5.8%) that were incomplete. Frequent antibiotic stock shortages influenced prescribing practice and may have resulted in delayed institution of targeted antibiotic therapy or de-escalation to narrow-spectrum agents. Despite these limitations, we believe that this first description of the epidemiology, outcome and therapy of neonatal and paediatric BSI at a large urban SA district hospital has provided valuable data to inform quality improvement in blood culture sampling and antibiotic stewardship.

Conclusions

Neonatal and paediatric BSI patterns at this SA district hospital show a predominance of Gram-positive, community-acquired pathogens and concerning levels of ESBL carriage among CA Enterobacteriaceae. Ongoing training of paediatric clinicians is needed to address high rates of blood culture contamination and inappropriate antibiotic prescribing practices. Acknowledgements. None. Author contributions. All authors (HC, AD, ACW, NO’C, HR) contributed to the study design and critical review of the manuscript. All authors read and approved the final manuscript. Funding. None. Conflicts of interest. None. 1. Liu L, Johnson HL, Cousens S, et al. Global, regional and national causes of child mortality: An updated systemic analysis for 2010 with time trends since 2000. Lancet 2012;379(9832):2151-2161. https://doi.org/10.1016/S0140-6736(12)60560-1 2. Reddy EA, Shaw AV, Crump J. Community-acquired bloodstream infections in Africa: A systematic review and meta-analysis. Lancet 2010;10(6):417-432. https://doi.org/10.1016/S1473-3099(10)70072-4 3. Aiken AM, Mturi N, Njuguna P, et al.; Kilifi Bacteraemia Surveillance Group. Risk and causes of paediatric hospital-acquired bacteraemia in Kilifi District Hospital, Kenya: A prospective cohort study. Lancet 2011;378(9808):2021-2027. https://doi.org/10.1016/S0140-6736(11)61622-X 4. Dramowski A, Madide A, Bekker A. Neonatal nosocomial bloodstream infections at a referral hospital in a middle-income country: Burden, pathogens, antimicrobial resistance and mortality. Paediatr Int Child Health 2015;35(3):265-272. https://doi.org/10.1179/2046905515Y.0000000029 5. Morkel G, Bekker A, Marais BJ, Kirsten G, van Wyk J, Dramowski A. Bloodstream infections and antimicrobial resistance patterns in a South African neonatal intensive care unit. Paediatr Int Child Health 2014;34(2):108-114. https://doi.org/10.1179/2046905513Y.0000000082 6. Kenyon CR, Fatti G, Schreuder N, Bonorchis K, Meintjies G. The value of blood culture audits at peripheral hospitals. S Afr Med J 2012;102(4):224-225.

7. Mendelson M, Whitelaw A, Nicol M, Brink A. Wake up, South Africa! The antibiotic ‘horse’ has bolted. S Afr Med J 2012;102(7):607-608. https://doi.org/10.7196/SAMJ.5759 8. Hwang A, Gums J. The emergence and evolution of antimicrobial resistance: Impact on a global scale. Bioorg Med Chem 2016;24(24):6440-6445. https://doi.org/10.1016/j.bmc.2016.04.027 9. Buys H, Muloiwa R, Bamford C, Ely B. Klebsiella pneumoniae bloodstream infections at a South African children’s hospital 2006 - 2011, a cross-sectional study. BMC Infect Dis 2016;16:570. https:// doi.org/10.1186/s12879-016-1919-y 10. Perovic O, Singh-Moodley A, Dusé A, et al. National sentinel site surveillance for antimicrobial resistance in Klebsiella pneumoniae isolates in South Africa, 2010 - 2012. S Afr Med J 2014;104(8):563568. https://doi.org/10.7196/SAMJ.7617 11. National Institute for Communicable Disease. Surveillance of antimicrobial resistance. Commun Dis Comm 2017;16(5a):7-10. http://www.nicd.ac.za/wp-content/uploads/2017/03/NICD-CommunicableDiseases-Communique_May2017_final2.pdf (accessed 4 December 2018). 12. Benner K, Prabhakaran P, Lowros AS. Epidemiology of infections due to extended-spectrum beta-lactamase-producing bacteria in a paediatric intensive care unit. J Pediatr Pharmacol Ther 2014;19(2):83-90. https://doi.org/10.5863/1551-6776-19.2.83 13. Ndir A, Diop A, Faye P, Cisse M, Ndoye B, Astagneau P. Epidemiology and burden of bloodstream infections caused by extended-spectrum beta-lactamase producing Enterobacteriaceae in a paediatric hospital in Senegal. PLoS One 2016;11(2):1-13. https://doi.org/10.1371/journal.pone.0.143729 14. Blomberg B, Manji KP, Urassa W, et al. Antimicrobial resistance predicts death in Tanzanian children with blood stream infection: A prospective cohort study. BMC Infect Dis 2007;43(7):1-14. https://doi. org/10.1186/1471-2334-7-43 15. City of Cape Town. 2011 Census Suburb Khayelitsha. 2013. http://resource.capetown.gov.za/ documentcentre/Documents/Mapsandstatistics/2011_Census_CT_Suburb_Khayelitsha_Profile.pdf (accessed 2 November 2016). 16. Centers for Disease Control and Prevention and National Healthcare Safety Network. Bloodstream infection event (central line-associated bloodstream infection and non-central line-associated bloodstream infection). www.cdc.gov/nhsn/pdfs/pscmanual/4psc_clabscurrent.pdf (accessed 2 Nov ember 2016). 17. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012;18(3):268-281. https://doi.org/10.1111/j.14690691.2011.03570.x 18. National Department of Health, South Africa. Integrated Management of Childhood Illness Guidelines. 2014. paediatrics.ukzn.ac.za/Files/2014%20IMCI%20CHART%20BOOKLET%20Final. pdf (accessed 26 April 2017). 19. Hall K, Lyman J. Updated review of blood culture contamination. Clin Microbiol Rev 2006;19(4):788802. https://doi.org/10.1128/CMR.00062-05 20. Pavlovsky M, Press J, Peled N, Yagupsky P. Blood culture contamination in paediatric patients: Young children and young doctors. Pediatr Infect Dis J 2006;25(7):611-614. https://doi.org/10.1097/01. inf.0000220228.01382.88 21. Lochan H, Bamford C, Eley B. Blood cultures in sick children. S Afr Med J 2013;103(12):918-920. https://doi.org/10.7196/SAMJ.6979 22. Dramowski A, Cotton M, Rabie H, Whitelaw A. Trends in paediatric bloodstream infections at a South African referral hospital. BMC Pediatr 2015;15(33):1-11. https://doi.org/10.1186/s12887-015-0354-3. 23. Paruk F, Richards G, Scribante J, Bhagwanjee S, Mer M, Perrie H. Antibiotic prescription practices and their relationship to outcome in South African intensive care units: Findings of the prevalence of infection in South African Intensive Care Units (PISA) Study. S Afr Med J 2012;102(7):613-616. https://doi.org/10.7196/SAMJ.5833 24. Federation of Infectious Diseases Society of Southern Africa (FIDSSA), South African Antibiotic Stewardship Programme prescription chart. http://www.fidssa.co.za/SAASP/Prescription_Chart (accessed 2 November 2016).

Accepted 7 August 2017.

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Characteristics and early outcomes of children and adolescents treated with darunavir/ritonavir-, raltegravir- or etravirine-containing antiretroviral therapy in the Western Cape Province of South Africa J Nuttall, MB ChB, MSc; V Pillay, MB ChB, MPH Paediatric Infectious Diseases Unit, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town and Red Cross War Memorial Children’s Hospital, Cape Town, South Africa Corresponding author: J Nuttall (james.nuttall@uct.ac.za) Background. There is an increasing need for third-line treatment regimens in HIV-infected children with antiretroviral treatment (ART) failure. Data are limited on darunavir/ritonavir (DRV/r)-, raltegravir (RAL)- and etravirine (ETR)-containing regimens in treatmentexperienced children from resource-constrained settings receiving these drugs as part of routine care. Objective. To describe the characteristics and early outcomes of treatment-experienced children (<20 years of age) in the Western Cape Province of South Africa treated with DRV/r-, RAL- or ETR-containing regimens. Methods. This was a retrospective review of treatment-experienced children receiving a DRV/r-, RAL- or ETR-containing regimen as recommended by a paediatric expert review committee, based on HIV drug resistance testing. Results. Thirty-five children of median age 8.8 years (interquartile range (IQR) 5.5 - 11) who had received ART for a median of 6.9 years (IQR 5 - 9.9) and started a DRV/r-, RAL- or ETR-containing regimen were included. Before starting such a regimen, the median CD4+ lymphocyte count and HIV-1 RNA level were 405.5 cells/µL (IQR 251.5 - 541) and 28 314 copies/mL (IQR 5 595.5 – 120 186.5) (log 4.5 (IQR 3.7 - 5)), respectively, in 24 subjects with available results. After a median of 2 years (IQR 1.3 - 4) on treatment, 29/30 (96.7%) and 23/30 (76.7%) subjects with available results had HIV-1 RNA levels of <400 and <50 copies/mL, respectively. Conclusions. This study found DRV/r-, RAL- and ETR-containing regimens to be effective in a group of treatment-experienced children and adolescents with multidrug-resistant HIV. Although the treatment regimens in this study were individualised based on HIV genotyping results, further research evaluating the safety and efficacy of standardised third-line treatment regimens in children of all ages is needed. S Afr Med J 2018;108(2):105-110. DOI:10.7196/SAMJ.2018.v108i2.12573

By 2012, the estimated number of children (0 - 14 years of age) receiving antiretroviral therapy (ART) in South Africa (SA) was 140 541, representing an estimated 63% of those requiring treat ment. [1,2] As increasing numbers of children are started on first- and second-line ART, the demand for third-line regimens in children and adolescents with treatment failure is likely to increase. It is estimated that currently <1% of people on ART globally are receiving third-line regimens, and it is unknown what proportion of these are children.[3] An unpublished systematic review presented in 2015 assessing second- and third-line ART options for children and adolescents concluded that there is insufficient evidence to directly evaluate alternative second- and third-line ART options for children, and that current recommendations are still based on inference from adult trials.[4] The World Health Organization (WHO) recommends that national programmes should develop policies for third-line ART that should incorporate integrase strand transfer inhibitors (INSTIs), second-generation protease inhibitors (PIs) and secondgeneration non-nucleoside reverse transcriptase inhibitors (NNRTIs) with minimal risk of cross-resistance to previously used regimens. Recommended third-line ART regimens in the WHO 2016 guidelines[5] are: (i) darunavir/ritonavir (DRV/r) plus dolutegravir (DTG) (or raltegravir (RAL)) with or without one to two nucleoside reverse transcriptase inhibitors (NRTIs); (ii) DRV/r plus two NRTIs

with or without one NNRTI; or (iii) RAL (or DTG) plus two NRTIs, depending on the preceding first- and second-line ART regimens. Although safety and efficacy of DRV/r, etravirine (ETR) and RAL have been reported in specific age groups of ART-naive and ARTexperienced children and adolescents, there is a paucity of data on treatment-experienced children from resource-constrained settings receiving these drugs as part of routine care.[6-14] In addition, DRV/r is not recommended in children <3 years of age owing to toxicity concerns in animal studies, and ETR, a second-generation NNRTI, is not recommended in children <6 years of age owing to lack of safety and efficacy data. Until very recently, DTG was only recommended by the US Food and Drug Administration (FDA) for adolescents >12 years of age and >40 kg body weight.[15] The FDA has recently approved DTG from 6 to <12 years and ≥30 kg in a dose of 35 mg once daily, but suitable formulations that allow for administration of this dose are not yet registered in SA.[16] In SA, DTG has only been approved from 18 years of age.

Objective

To describe the characteristics and early outcomes of treatmentexperienced children and adolescents (<20 years of age) in the Western Cape Province of SA who initiated an ART regimen that included one or more of DRV/r, RAL and ETR.

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Methods

The Western Cape paediatric ART expert review committee (ERC) was constituted in October 2013. Clinicians managing children and adolescents with antiretroviral (ARV) drug resistance on genotype resistance testing (GRT) submitted a standardised application form requesting guidance on further treatment to the ERC. The main eligibility criterion for treatment with DRV/r, RAL or ETR was the presence of PI resistance on GRT, defined as a lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r) mutation score (MS) of ≥15 using the Stanford University HIV genotypic resistance interpretation algorithm.[17] Individualised treatment recommendations for patients were made on a consensus basis by the ERC taking into account age, weight, previous ARV exposure, concomitant medication, availability of paediatric formulations of newer-generation ARV drugs, and an assessment of adherence to medication provided by the applicant. In April 2015, a consensus treatment algorithm based on local and international expert opinion, available data and international guidelines was adopted by the ERC in an attempt to standardise recommendations based on patterns of ARV drug resistance and MSs. According to this algorithm, all patients with an LPV/r or ATV/r MS of ≥15 would receive DRV/r plus either lamivudine (3TC) or emtricitabine (FTC), and either zidovudine (AZT) or abacavir (ABC) depending on which had the lowest MS. Tenofovir (TDF) was considered in patients aged >12 years and weighing >40 kg with normal renal function. Indications for the inclusion of RAL included low-level or higher resistance to DRV/r (MS ≥15) or no active NRTIs being available (ABC, AZT and TDF MS ≥30). ETR was considered for inclusion in the regimen in addition to RAL if the genotype indicated low-level or higher resistance to DRV/r, no active NRTIs were available and the ETR MS was <30, particularly if there was no known previous exposure to NNRTIs. Children and adolescents who were already receiving ARV regimens containing DRV/r, RAL or ETR prior to the establishment of the provincial ERC were also reviewed by the ERC and included in the study database. These patients were identified by the Western Cape HIV/AIDS, sexually transmitted infections and tuberculosis (HAST) pharmaceutical policy specialist because they were receiving drugs that were not included on the provincial pharmaceutical code list at the time. The clinicians managing these patients were requested by the HAST pharmaceutical policy specialist to submit application forms and HIV resistance tests to the Western Cape ERC motivating for the continued use of these ARV regimens. Children and adolescents were managed at a wide spectrum of healthcare facilities ranging from primary care clinics to district, regional and tertiary hospitals by the attending clinician who submitted the application to the ERC. There was no standardised adherence support or follow-up by specialists other than what was routinely provided at the healthcare facility where the patient was managed. Recommended monitoring was according to provincial guidelines: HIV-1 RNA after 6 and 12 months on treatment and then annually if suppressed or 3 - 6-monthly if not suppressed, CD4+ lymphocyte count annually until >200 cells/µL, and monitoring of serum creatinine and full blood count recommended in patients on TDF and AZT, respectively.[18] The data sources for this study comprised the following: application forms and HIV resistance test results, including Stanford University HIV genotypic resistance interpretation results performed at the time of the application, submitted by referring clinicians to the Western Cape ERC; ARV treatment recommendations by the ERC; and available laboratory test results following initiation of the

recommended ARV regimens. The lead author (JN) is a member of the ERC and accessed the data from the electronic submissions to the ERC that are emailed to the ERC members by the Western Cape HAST pharmaceutical policy specialist. The following data on treatment-experienced children and adolescents (<20 years of age at the time of application) who initiated a DRV/r-, RAL- or ETR-containing ART regimen prior to October 2016 were entered by one of the authors (VP) into a study database: demographic and HIV disease characteristics, previous ARV exposure, spectrum of HIV drug resistance mutations, ARV treatment regimens approved by the ERC, and early treatment outcomes. For the purposes of this study, the following definitions were used: a first-line treatment regimen refers to the first ART regimen (comprising three or more ARV drugs) that a child or adolescent was initiated on; a second-line treatment regimen refers to a single-class switch from NNRTI to PI or vice versa, regardless of NRTI changes; and a third-line treatment regimen refers to an ART regimen that includes one or more of the ARVs DRV/r, RAL and ETR, even though the child or adolescent may have received less than two, or three or more, previous ART regimens. Data were coded using unique study number identifiers and stored in a secure password-protected study database accessible only to the study investigators. Data quality was ensured by the lead author (JN) manually checking data entry accuracy by comparing application forms and HIV resistance test results with the database. A descriptive analysis was performed of the following patient characteristics at the time of application to the ERC: age, gender, level of healthcare facility at which the patient was being managed, CD4+ lymphocyte counts and/or percentages, HIV-1 RNA levels, and current and previous ARV regimens. In addition, ARV drug resistance mutations and MS (according to the Stanford University HIV genotypic resistance interpretation algorithm performed at the time that the genotypic resistance test/s were done or, if not done then, at the time of application to the ERC[17]) were analysed along with the ARV treatment recommendations made by the ERC. Mutations were not re-entered into a current version of the Stanford algorithm, and cumulative or composite genotypes were not performed. Treatment outcome measures analysed were HIV-1 RNA levels and CD4+ lymphocyte counts/percentages measured within 12 months of commencing a third-line ART regimen and at the time of analysis. CD4+ lymphocyte counts and percentages as well as HIV-1 RNA levels were measured by the National Health Laboratory Service. Standard measures of frequency were used to express data. Median and interquartile range (IQR) values were used to describe numerical variables, while frequencies and percentages were used to describe categorical variables. Data were analysed using the Stata release 12.0 statistical software package (StataCorp, USA). The study was approved by the Departmental Research Committee, Department of Paediatrics and Child Health, University of Cape Town, and the Human Research Ethics Committee, Faculty of Health Sciences, University of Cape Town (ref. no. 259/2015).

Results

Between October 2013 and October 2016, 45 applications were reviewed. At the time of application, 13 children (28.9%) were already receiving a DRV/r-containing ART regimen; 11 of them were also receiving RAL. No child was receiving ETR. Fourteen children (31.1%) were receiving holding regimens (nine were on 3TC monotherapy and five on triple-NRTI regimens). A further 22 children started a DRV/r-, RAL- or ETR-containing ART regimen between October 2013 and October 2016. The total

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study population comprised 35 children. The number of children starting a DRV/r-, RAL- or ETR-containing ART regimen each year from 2010 to 2016 was 1, 4, 3, 2, 4, 13 and 8. A temporary holding regimen consisting of 3TC monotherapy or a triple-NRTI regimen was recommended by the ERC for the 10 children excluded from this analysis. The characteristics of the 35 study participants receiving a DRV/r-, RAL- or ETR-containing ART regimen are shown in Table 1. Twelve of the 35 participants (34.3%) had received only one previous ART regimen before starting on the DRV/r-, RAL- or ETR-containing regimen (all RTV- or LPV/r-based first-line ART, including singledrug substitutions from RTV to LPV/r, a single NRTI switch, or temporary 3TC monotherapy). The proportion of participants with resistance to selected ARV drugs prior to starting treatment on a DRV/r-, RAL- or ETR-containing ART regimen is summarised in Fig. 1. Thirtytwo (91.4%) and 31 (88.6%) participants had an MS of ≥15 to LPV/r and ATV/r, respectively, using the Stanford University HIV genotypic interpretation algorithm. Eighteen participants (51.4%) had mutations conferring low- (n=17, 48.6%) or intermediate-level (n=1, 2.9%) resistance to DRV/r. None had high-level resistance. The proportion of study subjects with each PI mutation, including DRV resistance-associated mutations, detected prior to starting treatment on a DRV/r-, RAL- or ETR-containing ART regimen is shown in Fig. 2. Sixteen participants (45.7%) had mutations conferring low- (n=6, 17.1%), intermediate- (n=8, 22.9%) or high-level (n=2, 5.7%) resistance to ETR. Resistance testing did not include INSTI

mutations, as none of the participants had been exposed to this class of drugs at the time of genotyping. The DRV/r-, RAL- or ETR-containing ART regimens, median duration on treatment at the time of analysis and CD4+ and HIV-1 RNA outcomes are summarised in Table 2. Since not all participants had blood tests performed at 6 and/or 12 months on treatment, the outcomes are expressed as median (IQR) values within 12 months of starting treatment and at the time of the analysis. We were able to access significantly fewer CD4+ lymphocyte count results than HIV-1 RNA results, both within 12 months of starting treatment (n=23) and at the time of analysis (n=21). Among 32 (91.4%) and 30 (85.7%) participants with HIV-1 RNA results available within 12 months of starting treatment and at a median of 2 years (IQR 1.3 4), respectively, 96.9% had HIV-1 RNA levels <400 copies/mL at both time points. Of participants with available results, 75.0% and 76.7% had HIV-1 RNA levels <50 copies/mL within 12 months of treatment and at a median of 2 years (IQR 1.3 - 4), respectively, while only one had HIV-1 RNA levels of ≥400 copies/mL at the two time points. The ERC received no reports of drug-related adverse events or deaths.

Discussion

This is the largest description of children and young adolescents treated with third-line ARVs in a public sector programme in SA. Based on the recommendations of the ERC, 34/35 children (97.1%) received DRV/r, 25/34 (73.5%) received RAL in addition to DRV/r, and only 3/34 (8.8%) receiving DRV/r received both RAL and ETR in addition (Table 2). Despite the study subjects having

Table 1. Characteristics of study participants (N=35) receiving a DRV/r-, RAL- or ETR-containing ART regimen in the Western Cape Province, SA Characteristic Age (yr), median (IQR) Female, n (%) Year of 1st-line ART initiation, n (%) Before 2004 2004 - 2007 2008 - 2011 2012 - 2014 Years on ARVs prior to starting a DRV/r-, RAL- or ETR-containing ART regimen, median (IQR) Number of ARVs exposed to prior to starting a DRV/r-, RAL- or ETR-containing ART regimen, median (IQR) NRTIs NNRTIs PIs Previous exposure to unboosted PI (full-dose ritonavir)-containing 1st-line ART, n (%) ART treatment site at time of referral to ERC, n (%) Primary care clinic District hospital Regional hospital/tertiary referral hospital Provincial distribution at time of referral to ERC, n (%) Within Cape Town metropolitan area Outside Cape Town metropolitan area Prior to starting a DRV/r-, RAL- or ETR-containing ART regimen, median (IQR) CD4+ lymphocyte count (cells/μL) CD4+ lymphocyte percentage HIV-1 RNA, copies/mL HIV-1 RNA, log

8.8 (5.5 - 11) 15 (42.9) 2 (5.7) 23 (65.7) 7 (20.0) 3 (8.6) 6.9 (5 - 9.9)

4 (2 - 4) 1 (0 - 1) 1 (1 - 2) 13 (37.1) 13 (37.1) 3 (8.6) 19 (54.3) 28 (80.0) 7 (20.0) 405.5 (251.5 - 541) (n=24) 14.9 (8.3 - 20.3) (n=13) 28 314 (5 595.5 - 120 186.5) (n=24) 4.5 (3.7 - 5.0) (n=24)

DRV/r = darunavir/ritonavir; RAL = raltegravir; ETR = etravirine; ART = antiretroviral therapy; SA = South Africa; IQR = interquartile range; ARVs = antiretrovirals; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; ERC = expert review committee.

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51.4%

68.6% 45.7%

68.6%

EFV

60.0%

51.4%

60.0%

NVP

91.4%

94.3%

91.4%

88.6%

15 10 5 R PV

E TR

TDF

/FTC

3TC

AZT

ABC

/r LPV

r AT V /

0 DRV

Participants with ARV resistance, n and %

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PIs

NRTIs

NNRTIs

Low-level resistance (MS 15 - <30) Intermediate-level resistance (MS 30 - <60) High-level resistance (MS ≥60)

2.9% 11.4%

5.7%

14.3%

5.7%

2.9%

L24I

D30N L33F* K43T M46I I50L I50V* I54V O58E T74P* T74S L76V* V82A V82C V82L V82M V82S I84V* L90M

2.9%

8.6% 8.6%

2.9%

14.3%

25.7%

34.3%

45.7%

57.1%

62.9%

68.6%

L10F L10I L10V V11I* K20T

Participants with each PI mutation detected, n and %

Fig. 1. Proportion of study subjects with resistance to selected ARV drugs prior to starting treatment on a DRV/r -, RAL- or ETR-containing antiretro viral therapy regimen. Drug resistance interpretation by mutation score category is according to the Stanford University HIV genotypic resistance interpretation algorithm performed at the time that the genotypic resistance test/s were done or, if not done then, at the time of application to the Expert Review Committee. (ARV = antiretroviral; DRV/r = darunavir/ritonavir; RAL = raltegravir; ETR = etravirine; ATV/r = atazanavir/ritonavir; DRV/r = darunavir/ritonavir; LPV/r = lopinavir/ritonavir; ABC = abacavir; AZT = zidovudine; 3TC/FTC = lamivudine/emtricitabine; TDF = tenofovir; NVP = nevirapine; EFV = efavirenz; RPV = rilpivirine; PIs = protease inhibitors; NRTIs = nucleoside reverse transcriptase inhibitors; NNRTIs = non-nucleoside reverse transcriptase inhibitors; MS = mutation score according to the Stanford University HIV genotypic resistance interpretation algorithm.[17])

PI mutations

Fig. 2. Proportion of study subjects with each PI mutation detected prior to starting treatment on a DRV/r-, RAL- or ETR-containing ARV therapy regimen. (PI = protease inhibitor; DRV/r = darunavir/ ritonavir; RAL = raltegravir; ETR = etravirine; ARV = antiretroviral; *DRV resistance-associated mutations.)

multidrug-resistant HIV prior to starting treatment with these regimens, including low-level DRV/r resistance in almost 50%, we found impressive early treatment outcomes. Both within 12 months of treatment and after a median period of 2 years (IQR 1.3 - 4) on treatment, >96.5% of the participants with available results (86 - 91%

at the two time points, respectively) had achieved HIV-1 RNA levels <400 copies/mL. Although significantly fewer CD4+ lymphocyte counts and percentage results were available both before and after starting a third-line regimen, the median CD4+ lymphocyte count of 717 cells/µL (IQR 513 - 980) after a median of 2 years on treatment indicates good immunological reconstitution in participants with available results. Just over half of the children received treatment with third-line ARV regimens at regional or tertiary hospitals, the remainder attending district-level hospitals or primary care clinics (Table 1). Decentralisation of care from large urban hospital settings to smaller rural hospitals and clinics is critically important in improving access to treatment for patients who may not be able to reach centralised healthcare facilities owing to financial and transport constraints. This is an important strength of this study. It is significant that approximately a third of the participants (34.3%) had received only one previous ART regimen (RTV- or LPV/r-based first-line ART, including single-drug substitutions from RTV to LPV/r, a single NRTI switch, or temporary 3TC monotherapy) before starting on the DRV/r-, RAL- or ETR-containing regimen, which was effectively a second-line ART regimen for these participants. In SA guidelines prior to 2010, the recommended second-line ART regimen for children or adolescents failing PI-based first-line ART was an NNRTI plus two NRTIs.[19] In the current SA guidelines (2014),[20] there is no standardised second-line treatment regimen for children failing first-line PI-based ART and no standardised third-line ART regimens. It is recommended that these children should be referred to an ERC so that treatment with third-line agents (including DRV/r, RAL and ETR) can be considered following interpretation of the GRT and taking into account prior ARV exposure.[20] Although current WHO guidelines recommend a second-line regimen comprising two NRTIs plus either EFV or RAL for children failing first-line LPV/r-based ART, there is a lack of data to support these recommendations.[5] The WHO guidelines do not define specific criteria for the inclusion of INSTIs, NNRTIs or NRTIs into third-line ART regimens. [5] In a French cohort of 12 highly ARV-experienced adolescents all treated with a combination of DRV/r, RAL and ETR with additional ARVs in some patients, 11/12 (91.7%) achieved HIV-1 RNA levels of <400 copies/mL after a median of 12 months, with 6 (50.0%) achieving <50 copies/mL. In addition, medication was generally well tolerated with no grade 3 or 4 adverse events reported and no treatment discontinuations.[6] Other than phase 2 trials under controlled conditions, two other retrospective studies involving treatment-experienced adolescents in Spain receiving RALor ETR-based regimens in combination with other ARVs have found comparable safety and efficacy outcomes.[7,8,10-12] Although GRT is a prerequisite for accessing these medications in the SA public sector, specific indications for resistance testing are not included in the 2014 national guidelines, and access to GRT has not been uniform in the SA public sector. Before 2015, GRT was generally only available to patients with private medical insurance or through research studies or donor-funded access programmes in the public sector. Since April 2015, access to GRT in the Western Cape public health sector has required written motivation by the clinician manging the patient and approval by the provincial Department of Health. Patients on a PI-based ART regimen with HIV-1 RNA non-suppression (defined as at least three HIV-1 RNA measurements of ≥1 000 copies/mL (≥ log 4.5) at least 8 - 12 weeks apart), with the most recent HIV-1 RNA level result within 3 - 6 months of the application, are eligible for GRT. In addition, children and early adolescents (<15 years of age) must have been receiving a PI-based

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Table 2. DRV/r-, RAL- or ETR-containing ART regimens started in study participants (N=35), with overall immunological and virological outcomes on treatment ART regimen DRV/r + 2 NRTIs DRV/r + RAL + 1 NRTI DRV/r + RAL + 2 NRTIs DRV/r + RAL + ETR + 1 NRTI ETR + LPV/r + 1 NRTI

Children, n (%) 9 (25.7) 8 (22.8) 14 (40.0) 3 (8.6) 1 (2.9)

Treatment duration Years, median (IQR) Duration of DRV/r-, RAL- or ETR-containing ART at time of analysis 2 (1.3 - 4) Outcomes CD4+ count (cells/μL), median (IQR)

Within 12 months 649 (506 - 900) (n=23) 27.1 (20.8 - 36.4) (n=23) (n=32) 24 (75.0) 31 (96.9) 1 (3.1)

CD4+ lymphocyte percentage, median (IQR) HIV-1 RNA (copies/mL), n (%) <50 <400 ≥400

At time of analysis 717 (513 - 980) (n=21) 27.2 (20.8 - 35.6) (n=21) (n=30) 23 (76.7) 29 (96.7) 1 (3.3)

DRV/r = darunavir/ritonavir; RAL = raltegravir; ETR = etravirine; ART = antiretroviral therapy; NRTI = nucleoside reverse transcriptase inhibitor; IQR = interquartile range.

ART regimen for at least 1 year, and adults and late adolescents (≥15 years of age) must have been receiving a PI-based ART regimen for at least 2 years.[18] An important factor that may have contributed to the development of significant PI resistance in the study subjects is failure to have achieved viral suppression while on treatment with an unboosted PI-based ART regimen. Such regimens were previously used to treat children <6 months of age and children requiring concomitant rifampicin (RIF)-based antituberculosis treatment. Unboosted PIs are known to be associated with the development of major PI resistance mutations in children with virological failure.[21-23] In our study, 13/35 subjects (37.1%) had received previous treatment with a RTV-based regimen. Pharmacokinetic interactions between RIF and LPV/r resulting in subtherapeutic plasma LPV levels may also predispose to the development of PI resistance.[24-26] Adjustment of first- or second-line ART regimens to avoid this problem may not have been done in all cases. However, detailed information on TB co-infection and treatment was not included in this study. The presence of high rates of NNRTI resistance mutations conferring resistance to ETR in nearly 50% of subjects is likely to reflect virological failure on first- or second-line NNRTI-based ART regimens. However, genotyping is not routinely performed at the time of first-line ART failure, and this may be an underestimation of the true prevalence of NNRTI mutations conferring resistance to ETR. Once the patient is no longer receiving NNRTI-based ART, some mutations may remain present at low levels not detected by routine genotyping done at the time of second-line ART failure. Previous studies have described high-level ETR resistance in almost 50% of children failing first-line NNRTI-based ART.[27,28] These findings call into question the role of ETR in second- and third-line ART regimens in NNRTI-exposed individuals. Although adult and some paediatric formulations of DRV, RAL and ETR are registered in SA, these are often inappropriate for young children, in whom doses must be adjusted for age and weight changes. Young children who are unable to swallow tablets require dispersible or chewable tablets or oral suspensions. Although RAL chewable tablets are now available in SA, oral suspensions of DRV, RAL and ETR are not registered here and are only available on

compassionate access programmes from manufacturers and with approval from the Medicines Control Council of SA. In addition, DRV/r is not currently available as a co-formulated medication, so RTV needs to be provided separately, adding to the pill burden of third-line regimens. Access to and palatability of RTV oral suspension remains a significant barrier to third-line ART for younger children.

Study limitations

This study has a number of limitations related to its retrospective nature and the fact that participants were managed at multiple healthcare facilities across the province without direct oversight by members of the ERC. We were unable to obtain complete data on HIV-1 RNA levels and CD4+ lymphocyte counts on all study participants both before and after they started their DRV/r-, RAL- or ETR-containing ART regimens. Some participants had started these regimens months or years prior to being reviewed by the ERC, and the data were not always supplied by the referring clinicians or could not be traced from an earlier electronic laboratory reporting system. Since this was not a prospective study, monitoring of HIV-1 RNA levels, CD4+ lymphocyte counts and adverse events may not always have been performed according to standard provincial monitoring guidelines. Information regarding maternal ART and exposure of participants to prevention of mother-to-child transmission of HIV would have contributed to an understanding of participants with NNRTI mutations in whom there was no history of previous NNRTI-based ART regimens. The children and adolescents reviewed by the ERC and started on third-line ART regimens may not be representative of other children who are failing first- or secondline ART in other regions and who may not have undergone genotyping. Documentation of prior treatment with unboosted PI-based ART and prior concomitant PI-based ART treatment and antituberculosis treatment was common, but data were not available for all participants. This study involved a small number of participants receiving individualised ARV combinations based on current and historical genotype results and prior ARV history interpreted by an ERC and is not able to compare the relative effectiveness of the different treatment regimens used.

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Conclusions

This study found DRV/r-, RAL- or ETR- containing ART regimens to be effective in a group of ART-experienced children and adolescents with multidrug-resistant HIV. Although the ART regimens in this study were individualised based on genotyping results, further research evaluating the safety and efficacy of standardised thirdline treatment regimens in children of all ages and adolescents is needed in order to improve access in settings where genotyping is not routinely available. Acknowledgements. Members of the paediatric ERCs: National: L Levin, M Archary, P Jeena, A Coovadia, J Nuttall, K Jamaloodien, N Jagaroo; provincial: M Cotton, H Rabie, B Eley, M Hsiao, J Nuttall, J Voget. Author contributions. JN and VP conceived, designed and obtained ethical approval for the study, developed the study database, analysed the data, and prepared and approved the manuscript for submission. Funding. None. Conflicts of interest. None. 1. United Nations Children’s Fund. Towards an AIDS-Free Generation – Children and AIDS: Sixth Stocktaking Report, 2013. New York: UNICEF, 2013. https://www.unicef.org/publications/files/ Children_and_AIDS_Sixth_Stocktaking_Report_EN.pdf (accessed 30 April 2017). 2. Joint United Nations Programme on HIV/AIDS. 2013 Progress Report on the Global Plan Towards the Elimination of New HIV Infections among Children by 2015 and Keeping Their Mothers Alive. Geneva: UNAIDS, June 2013. http://www.unaids.org/sites/default/files/media_asset/20130625_progress_global_ plan_en_0.pdf (accessed 30 April 2017). 3. World Health Organization. Antiretroviral Medicines in Low- and Middle-income Countries: Forecasts of Global and Regional Demand for 2014 - 2018 (technical report). Geneva: WHO, July 2015. http:// www.who.int/hiv/pub/amds/arv-forecast2014-2018/en/ (accessed 30 April 2017). 4. Lazarus E, Nicol S, Penazzato M, Cotton M, Tablante E, Violari A. Second and third line antiretroviral therapy options for children and adolescents: A systematic review. Presented at the 7th International Workshop on HIV Pediatrics, Vancouver, Canada, 17 - 18 July 2015. Abstract 23. http://regist2.virologyeducation.com/abstractbook/2015_8.pdf (accessed 30 April 2017). 5. World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. 2nd ed. WHO, 2016. http:// www.who.int/hiv/pub/arv/arv-2016/en/ (accessed 30 April 2017). 6. Thuret I, Chaix M-L, Tamalet C, et al. Raltegravir, etravirine and r-darunavir combination in adolescents with multidrug-resistant virus. AIDS 2009;23(17):2364-2366. https://doi.org/10.1097/ qad.0b013e328331a456 7. Blanche S, Bologna R, Cahn P, et al. Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents. AIDS 2009;23(15):2005-2013. https://doi.org/10.1097/ qad.0b013e328330abaa 8. Violari A, Bologna R, Kumarasamy N, et al. Safety and efficacy of darunavir/ritonavir in treatment-experienced pediatric patients: Week 48 results of the ARIEL trial. Pediatr Infect Dis J 2015;34(5):e132-e137. https://doi.org/10.1097%2Finf.0000000000000644 9. Flynn P, Komar S, Blanche S, et al. Efficacy and safety of darunavir/ritonavir at 48 weeks in treatmentnaive, HIV-1-infected adolescents: Results from a phase 2 open-label trial (DIONE). Pediatr Infect Dis J 2014;33(9):940-945. https://doi.org/10.1097/inf.0000000000000308

10. Briz V, Palladino C, Navarro M, et al. Etravirine-based highly active antiretroviral therapy in HIV1-infected paediatric patients. HIV Med 2011;12(7):442-446. https://doi.org/10.1111%2Fj.14681293.2010.00907.x 11. Tudor-Williams G, Cahn P, Chokephaibulkit K, et al. Etravirine in treatment-experienced, HIV-1infected children and adolescents: 48-week safety, efficacy and resistance analysis of the phase II PIANO study. HIV Med 2014;15(9):513-524. https://doi.org/10.1111%2Fhiv.12141 12. Briz V, Leon-Leal JA, Palladino C, et al. Potent and sustained antiviral response of raltegravir-based highly active antiretroviral therapy in HIV type 1-infected children and adolescents. Pediatr Infect Dis J 2012;31(3):273-277. https://doi.org/10.1097/INF.0b013e31824580e8 13. Nachman S, Zheng N, Acosta EP, et al. Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years. Clin Infect Dis 2014;58(3):413-422. https://doi. org/10.1093%2Fjpids%2Fpiu146 14. Kindra G, Sipambo N, Moultrie H, Fairlie L. Outcomes in treatment with darunavir/ritonavir in ARTexperienced paediatric patients. S Afr Med J 2015;105(5):330-331. https://doi.org/10.7196%2FSAMJ.9211 15. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. http://aidsinfo.nih.gov/contentfiles/lvguidelines/ pediatricguidelines.pdf (accessed 23 March 2017). 16. Full US Prescribing Information for Tivicay. https://www.gsksource.com/pharma/content/dam/ GlaxoSmithKline/US/en/Prescribing_Information/Tivicay/pdf/TIVICAY-PI-PIL.PDF (accessed 30 April 2017). 17. Stanford University HIV drug resistance database. https://hivdb.stanford.edu/ (accessed 30 April 2017). 18. Provincial Government of the Western Cape, South Africa. The Western Cape Consolidated Guidelines for HIV Treatment: Prevention of Mother-to-Child Transmission of HIV (PMTCT), Children, Adolescents and Adults. HIV/AIDS/STI/TB (HAST) Directorate, Department of Health, Provincial Government of the Western Cape, April 2015. http://www.paediatrics.uct.ac.za/sites/default/files/image_ tool/images/38/Western%20Cape%20Consolidated%20HIV%20guidelines%20November%202015.pdf (accessed 30 April 2017). 19. Meyers T, Eley B. Guidelines for the management of HIV-infected children (National Department of Health, South Africa 2005). South Afr J HIV Med 2005;6(4):33. https://doi.org/10.4102%2Fsajhivmed. v6i4.580 20. National Department of Health, South Africa. National Consolidated Guidelines for the Prevention of Mother-to-child Transmission of HIV (PMTCT) and the Management of HIV in Children, Adolescents and Adults. Pretoria: NDoH, December 2014. http://www.health.gov.za/index.php/2014-03-17-09-0938/policies-and-guidelines/category/230-2015p# (accessed 30 April 2017). 21. Van Zyl G, van der Merwe L, Claassen M, et al. Protease inhibitor resistance in South African children with virologic failure. Pediatr Infect Dis J 2009;28(12):1125-1127. https://doi.org/10.1097%2Finf.0b013 e3181af829d 22. Taylor BS, Hunt G, Abrams EJ, et al. Rapid development of antiretroviral drug resistance mutations in HIV-infected children less than two years of age initiating protease inhibitor-based therapy in South Africa. AIDS Res Hum Retroviruses 2011;27(9):945-956. https://doi.org/10.1089%2Faid.2010.0205 23. Van Zyl G, Rabie H, Nuttall J, Cotton M. It is time to consider third-line options in antiretroviral-expe rienced paediatric patients? J Int AIDS Soc 2011;14(1):55. https://doi.org/10.1186%2F1758-2652-14-55 24. Ren Y, Nuttall J, Egbers C, et al. Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis. J Acquir Immune Defic Syndr 2008;47(5):566-569. https://doi.org/10.1097 %2Fqai.0b013e3181642257 25. La Porte C, Colbers E, Bertz R, et al. Pharmacokinetics of adjusted dose lopinavir-ritonavir combined with rifampicin in healthy volunteers. Antimicrob Agents Chemother 2004;48(5):1553-1560. https://doi. org/10.1128%2Faac.48.5.1553-1560.2004 26. Mcilleron H, Ren Y, Nuttall J, et al. Lopinavir exposure is insufficient in children given double doses of lopinavir/ritonavir during rifampicin-based treatment for tuberculosis. Antivir Ther 2011;16(3):417-421. https://doi.org/10.3851%2Fimp1757 27. Puthanakit T, Jourdain G, Hongsiriwon S, et al. HIV-1 drug resistance mutations in children after failure of first-line nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy. HIV Med 2010;11(9):565-572. https://doi.org/10.1111%2Fj.1468-1293.2010.00828.x 28. Steegen K, Bronze M, Papathanasopoulos MA, et al. HIV-1 antiretroviral drug resistance patterns in patients failing NNRTI-based treatment: Results from a national survey in South Africa. J Antimicrob Chemother 2017;72(1):210-219. https://doi.org/10.1093%2Fjac%2Fdkw358

Accepted 14 August 2017.

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Heroin detoxification during pregnancy: A systematic review and retrospective study of the management of heroin addiction in pregnancy K V Gilfillan,1 FCPsych, MMed (Psych); L Dannatt,2 FCPsych, MMed (Psych); D J Stein,2,3 FRCPC, PhD; B Vythilingum,1,2 FCPsych, MMed (Psych) Kenilworth Clinic, Cape Town, South Africa Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa 3 Medical Research Council Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: L Dannatt (lisa.dannatt@uct.ac.za)

Background. There is general consensus that methadone maintenance is the gold standard in the management of pregnant heroin users. However, in South African state hospitals, methadone withdrawal is the routine procedure offered to these patients, as methadone maintenance programmes are unavailable in the public sector. Objectives. To conduct a systematic review of the literature on heroin detoxification in pregnancy, and to document pregnancy outcomes in heroin users detoxified with methadone at Groote Schuur Hospital (GSH), Cape Town, from 2006 to 2010. Methods. A literature search was undertaken to identify key publications on the management of heroin addiction in pregnancy. Patients for the study were identified from the GSH methadone registry, and data were collected from the clinical files. Results. A total of 20 relevant publications were identified and reviewed. Early case reports described an increased risk of stillbirths and fetal distress after methadone detoxification, but more recent case series involving larger numbers of patients showed positive outcomes. In our study, six pregnant patients received methadone withdrawal over a 5-year period at GSH, and all the neonates had good Apgar scores and were discharged home within 3 days of delivery. Conclusions. There is limited evidence on the management of heroin addiction during pregnancy, and the only two guidelines identified suggest that methadone maintenance is preferable to methadone withdrawal. The favourable pregnancy outcomes in this small sample of patients managed with methadone withdrawal suggest that it may be safe and deserves further study. S Afr Med J 2018;108(2):111-117. DOI:10.7196/SAMJ.2018.v108i2.7801

Diacetylmorphine was first synthesised by C R Alder Wright in 1874 as a highly potent, acetylated form of morphine. By 1898, Bayer pharmaceutical company marketed this drug under the trademark name of heroin. It was initially sold as a non-addictive morphine substitute and cough suppressant. However, heroin was soon found to be twice as powerful as morphine because it is highly fat soluble and rapidly crosses the blood-brain barrier. Despite subsequent strict controls imposed on the use of heroin, it remains the most widely used opiate.[1] In 2009, there were an estimated 12 - 14 million heroin users worldwide.[1] Europe and Asia remain the key opiate consumption markets, but reports indicate that opiate use in Africa is increasing.[1] The 2010 South African Community Epidemiology Network on Drug Use (SACENDU) statistics reveal that 5 - 20% of patients in specialist treatment centres in South Africa (SA) use heroin as their primary illicit drug of choice. In SA, heroin is primarily used by individuals aged 22 - 30 years,[2] and 20 - 40% of those treated for heroin abuse are female, which is a higher percentage than for most other illicit substances. Opiate use is associated with menstrual irregularities, which combined with the often erratic lifestyles of drug-abusing women leads to a high rate of unplanned pregnancies. Heroin-dependent pregnant women represent an extremely vulnerable group of patients, who present with various medical, obstetric and psychiatric problems. There has been considerable debate about how best to manage these

patients, as the needs of both fetus and mother require careful attention. The ideal goal during pregnancy is for the mother to abstain from any drug use. When faced with a pregnant patient who is actively abusing heroin, one needs to offer treatment that will best minimise any further fetal and maternal harm. Given the highly addictive nature of opiates, it is difficult for many of these individuals to remain drug free, and some form of maintenance treatment is therefore usually offered. An alternative to maintenance treatment is opioid withdrawal using methadone. Methadone detoxification involves using tapering doses of methadone to create a smooth transition from heroin use to a drug-free state. Withdrawal from methadone during pregnancy is not generally recommended in the literature,[3-5] except in specific situations such as when a motivated patient expresses a wish to withdraw from all opiates, or when methadone maintenance is unavailable â&#x20AC;&#x201C; a state of affairs that is prevalent across all SA public treatment facilities. Because pregnant women are rarely included in psychotropic clinical trials, relatively little information is available about the use of medication during pregnancy. The evidence-based management of pregnant patients who are dependent on opioids is therefore particularly challenging. While guidance is scarce, the prevailing opinion is that methadone maintenance is the gold standard of treatment in pregnancy.[3-5] This option is not available in SA state

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facilities, where only methadone withdrawal is offered. It is therefore useful to review the data in the literature on the efficacy of methadone withdrawal in pregnancy.

Objectives

To conduct a systematic review of the literature on heroin detoxification in pregnancy, and to report on pregnancy outcomes of heroin users who were detoxified with methadone at Groote Schuur Hospital (GSH), a teaching hospital in Cape Town, SA, during the 5-year period 2006 - 2010. No cases were noted in the records between 2006 and 2007.

Methods

Systematic review

The electronic databases PubMed, PsychINFO and the Cochrane Library were searched using a combination of the following search terms: pregnancy, heroin, opiate, methadone, buprenorphine, and treatment. Using the above terms, 14 English articles were located. Of these articles, 5 were relevant to the study. However, by using the article references, a total of 18 relevant articles were found and reviewed. All relevant articles in English, reporting original data related to the treatment of heroin addiction in pregnancy, were included. Using the above terms, 12 English articles were located on a PubMed search. Of these articles, 3 were relevant to the study. How ever, by using the article references, a total of 18 relevant articles were found and reviewed.

Clinical study

Location GSH is a tertiary state hospital in Cape Town. The patients were managed in the labour ward or in C23, the emergency psychiatric ward. Subjects The study population included all pregnant heroin-addicted patients who underwent methadone detoxification at GSH between 2006 and 2010, although the first recorded case was in 2008. The labour ward and C23 keep a register of all patients who have received methadone. Methadone detoxification at GSH A history of substance use is obtained from all patients admitted to maternity, bearing in mind that signs of heroin withdrawal appear within 8 hours after last dose and peak at 36 - 72 hours. GSH stocks equity methadone, which contains two milligrams of methadone per millilitre. Following a positive history for heroin use, symptoms of heroin withdrawal are assessed. These symptoms are assessed using the Objective Opiate Withdrawal Scale (OOWS). This is a 13-item interview and observation tool that assesses for signs of heroin withdrawal. In pregnant women, 5 mg/2.5 mL of oral methadone is admin istered if the OOWS score is 3 - 4. In women with an OOWS score of >4, 10 mg/5 mL methadone is given. The OOWS is repeated 2 hours later and further methadone administered as per the above scores. A maximum of 30 mg is administered; however, a doctor may give permission to give top-up doses in severe cases. Once the baseline dose has been established, a total dose of methadone can be given 12-hourly. This is withdrawn slowly. Further care depends on patient motivation and financial support. Patients who are not motivated to stop using heroin continue methadone during their hospital stay and are referred to

a rehabilitation centre to continue motivational interviewing and psychosocial support. Patients who are motivated to stop using heroin can continue detoxification with support and follow-up. For patients who are financially able and willing, maintenance methadone is continued for the duration of the pregnancy. Data collection Pregnant patients treated during the study period were identified by means of information obtained from the methadone register. Both methadone registers were scrutinised carefully to ensure that all pregnant patients treated at GSH were identified. The outcomes of these pregnancies were then determined by looking at specific maternal and fetal parameters as listed in the ‘Prospective case series’, ‘Literature reviews’ and ‘Case studies’ sections of Table 1. Ethical considerations The study was approved by the University of Cape Town Human Research Ethics Committee (ref. no. 072/2010), and permission was granted to access information from the clinical files. Only information relevant to the study was extracted from the patient files, and all the identifying data were kept confidential.

Results

Systematic review

A total of 20 relevant articles were found, which were reported in 15 publications. The majority were prospective case series, but others included retrospective case series, case reports, literature reviews and descriptive studies (Table 1). Heroin is not considered to be grossly teratogenic, but it is highly lipophilic and readily crosses the placenta. Untreated heroin use is associated with intrauterine growth restriction, premature delivery, increased neonatal mortality and neonatal abstinence syndrome (NAS), which is characterised by a variety of signs and symptoms in the neonate that indicate dysfunction of the autonomic nervous system, gastrointestinal tract and respiratory system. There is therefore a need for any kind of intervention that will reduce or eliminate maternal heroin use in order to improve pregnancy outcomes. Maas et al.[8] published an intervention study in 1990 that compared the pregnancy outcomes of mothers joining a methadone detoxification programme with those of mothers who continued uncontrolled street-drug use. They found that 17 out of 58 women successfully completed heroin detoxification during the antenatal period. The incidence of neonatal abstinence syndrome was reduced after maternal participation in the detoxification programme – 55% v. 88%. Newborns of mothers who had successfully detoxified experienced fewer withdrawal symptoms, and no adverse obstetric complications were reported in this group. According to most widely accepted recommendations, withdrawal of methadone is not advised before 14 weeks’ gestation because of the potential risk of inducing abortion, and should not be performed after the 32nd week of pregnancy because of possible withdrawalinduced stress.[4,5] This view is largely the result of two influential case reports published in the 1970s. Rementeria and Nunag[5] described a stillbirth at term following acute methadone withdrawal, and Zuspan et al.[18] described a case of increased amniotic fluid epinephrine levels during methadone withdrawal, which resolved once the methadone dose was increased. These initial concerns have since been challenged. In a retrospective study in 2003, Luty et al.[20] reviewed 101 case reports of methadone withdrawal conducted at various stages of pregnancy. They concluded that detoxification treatment was not associated with

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Table 1. Summary of systematic review Title Authors Literature review and prospective case series Adverse neurodevelopmental Hunt et al.[6] outcome of infants exposed to opiate in utero

Prospective case series Maternal narcotic abuse and the newborn Infrequent neonatal opiate withdrawal following maternal methadone detoxification during pregnancy Opioid detoxification in pregnancy

Alroomi et al.[7] Maas et al.[8]

Dashe et al.[9]

Journal and year

Summary

Early Human Development, 2008

Review of the literature examining neurodevelopmental outcome in infants with NAS. 33 opiate-exposed infants who were identified after development of NAS compared with controls. Opiate-exposed infants showed neurodevelopmental impairment and reduced growth.

Archives of Disease in Childhood, 1988 Journal of Perinatal Medicine, 1990

Opiate-exposed infants have higher rates of NAS, preterm delivery, IUGR and neonatal mortality. Influence of maternal participation in a methadone detox programme was compared with street drug use on neonatal morbidity in 75 neonates. NAS occurred in 63% of neonates, and was less frequent after methadone detox. 34 pregnant opiate-dependent women offered methadone detoxification. 59% were successfully detoxified with no adverse pregnancy outcomes, or relapse to illicit substances. 84 pregnant opiate-dependent women offered methadone maintenance. 11 attempted detoxification, but ~50% returned to maintenance therapy. 64% continued to use illicit substances while in programme. 175 opioid-dependent pregnant women given methadone maintenance, methadone withdrawal alone, or withdrawal followed by maintenance. Given the poor maternal outcomes with withdrawal alone, maintenance should be considered as the primary treatment approach. Differences in criminal activity were measured in 439 pregnant women entering five different treatment programmes. The reduction in crime-related costs was greatest in residential substance abuse facilities. The cost of the treatment facility was more than covered by the cost-saving in crime reduction. Outcomes of 6 pregnant methadone-maintained opiatedependent women in an enhanced programme were compared with those of 6 women receiving conventional methadone maintenance. The enhanced-programme participants had better pregnancy outcomes than the controls. The pregnancy outcomes of 367 opiate-dependent women were compared with 215 non-drug-dependent women. The groups were further divided into those receiving an enhanced prenatal programme v. standard care. Infant mortality was reduced in the opiatedependent group in the enhanced programme. Substitution with methadone or buprenorphine improves pregnancy outcomes.

Obstetrics and Gynaecology, 1998

Methadone maintenance Kashiwagi et al.[10] programme in a Swiss perinatal centre: Management and outcome of 89 pregnancies Methadone maintenance Jones et al.[11] v. methadone taper during pregnancy: Maternal and neonatal outcomes

Acta Obstetricia et Gynecologica Scandinavica, 2005

he cost of crime and the benefits Daley et al.[12] T of substance abuse treatment for pregnant women

Journal of Substance Abuse Treatment, 2000

American Journal on Addictions, 2008

Improving treatment outcome in pregnant opiate-dependent women.

Chang et al.[13]

Journal of Substance Abuse Treatment, 1992

Management of pregnant drugdependent women

Finnegan[14]

Annals of the New York Academy of Sciences, 1978

Lejeune et al.[15]

Drug and Alcohol Dependence, 2006

Wang[16]

Journal of Obstetric, Gynecologic, and Neonatal Nursing, 1999 Addiction, 2008

rospective multicentre P observational study of 260 infants born to 259 opiate-dependent mothers on methadone or highdose buprenophine substitution Literature reviews Methadone treatment during pregnancy

Treating pregnant women dependent on opioids is not the same as treating pregnancy and opioid dependence

Winklbaur et al.[17]

Methadone treatment is only beneficial if administered as part of a comprehensive care package.

Use of opioid medication for detox or maintenance should follow established national guidelines, but should be done in a co-ordinated and supportive environment. continued...

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Table 1. (continued) Summary of systematic review Title Case studies Narcotic withdrawal in pregnancy: Stillbirth incidence with a case report

Authors

Journal and year

Summary

Rementeria and Nunag[5]

American Journal of Obstetrics and Gynecology, 1973

Fetal stress from methadone withdrawal

Zuspan et al.[18]

American Journal of Obstetrics and Gynecology, 1975

Detoxification with buprenorphine of a pregnant heroin addict

Annitto[19]

American Journal on Addictions, 2000

Luty et al.[20]

Journal of Substance Abuse Treatment, 2003

Edelin et al.[21]

Obstetrics and Gynaecology, 1989

Allen[22]

Bulletin of the New York Academy of Medicine, 1991 Archives of Disease in Childhood, Fetal and Neonatal Edition, 2011

Methadone maintenance has become the mode of therapy for most patients based on early case reports.

Journal of Obstetrics and Gynaecology Canada, 2011

Review of the literature of substance abuse in pregnancy. Methadone maintenance recommended owing to reduced relapse to illicit substances.

Retrospective case series Is opiate detoxification unsafe in pregnancy?

Methadone maintenance in pregnancy: Consequences to care and outcomes

Descriptive studies Detoxification considerations in the medical management of substance abuse in pregnancy The management of heroin misuse in pregnancy: Time for a rethink? Systematic review Substance use in pregnancy

Mactier[23]

Wong et al.[3]

Description of one patient who had a stillbirth following third-trimester methadone withdrawal. The authors therefore caution against methadone withdrawal in the third trimester. Description of one patient who developed increased amniotic fluid epinephrine levels while undergoing methadone withdrawal. The authors recommend avoiding detoxification. Description of a patient withdrawn successfully using buprenorphine. The author cautions that more information is needed regarding buprenorphine withdrawal. 101 pregnant opiate-dependent women underwent detoxification at various pregnancy stages. Methadone detox was not associated with adverse effects in the second or third trimester. Pregnancy outcomes of 26 narcotic-addicted women enrolled in a methadone maintenance programme compared with 37 polydrug users not in the programme. No major difference in outcomes found between the two groups.

There is increasing evidence of adverse effects upon developing cortical and visual function in children of treated heroin-addicted mothers. Studies are needed that take into account longer-term outcomes for the child.

NAS = neonatal abstinence syndrome; IUGR = intrauterine growth retardation.

any risk of miscarriage in the second trimester or with premature delivery in the third trimester. Similarly, Dashe et al.[9] conducted a prospective study in which 35 opioid-addicted pregnant patients were offered inpatient opiate detoxification with methadone; 59% of them successfully completed heroin detoxification, did not relapse, and had no adverse pregnancy outcomes. Apart from the risk of fetal harm during methadone detoxification, the major concern with not providing long-term methadone treatment is an increased risk of relapse to illicit drug use. There is a perception that mothers engaged in maintenance programmes are less likely than those who are not to use illicit drugs, or to engage in other drug-seeking behaviours such as prostitution. Wong et al.[3] conducted a literature review of substance abuse in pregnancy in order to provide recommendations on management. They concluded that methadone maintenance treatment is associated with longer adherence to treatment and a decreased risk of relapse to opioid use, and therefore proposed that the preferred standard of care for pregnant opioid-dependent women is substitution therapy. However, some studies have shown that methadone maintenance treatment does not guarantee abstinence. Kashiwagi et al.[10] explored pregnancy outcomes among women in a major Swiss methadone

maintenance programme, and 64% of the women were found to be co-users of cocaine and/or heroin. Apart from not always curtailing illicit drug use, management with methadone poses its own risks. Fetal methadone dependence has been associated with fetal death, growth restriction, preterm birth, meconium aspiration and NAS.[7] It has been estimated that 60 - 87% of neonates born to methadone-maintained mothers require treatment for NAS. Neonates suffering from NAS grow poorly in the neonatal period, and have reduced height compared with controls at 3 years of age.[12] The longer-term implications of methadone maintenance treatment are also not clear. Hunt et al.[6] conducted a study on infants who had developed NAS, and found that they had evidence of both cognitive and psychomotor deficit on psychometric testing compared with non-opiate-exposed controls. Recent literature has also reported an increased incidence of ocular abnormalities in infants of methadonemaintained mothers. The possibility of long-term visual and cortical defects is alarming, and requires further research. Methadone withdrawal is the standard management of pregnant heroin addicts in state hospitals in SA. This is largely due to financial constraints, as methadone maintenance management is more costly

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than withdrawal. This concept has, however, been challenged by Daley et al.,[12] who suggest that the healthcare costs should not be viewed in isolation. They argue that maintenance treatment reduces maternal criminal behaviour by reducing illicit drug use, which has secondary cost implications for society. The authors conducted a study in Massachusetts, USA, which indicated that the cost of crime far outweighed that of substance abuse treatment. It seems that medical professionals need to shift the focus of attention from the medical management of cravings and fluctuating maternal opiate levels to providing a more comprehensive care package. Studies conducted by Chang et al.[13] and Finnegan[14] found that methadone maintenance, in addition to intensive antenatal care, is compatible with an uneventful pregnancy and birth of a healthy infant.

The GSH study

Because methadone is a highly addictive schedule 6 drug, its administration is recorded in a methadone register. This register shows that only six pregnant heroin-addicted patients received methadone detoxification at GSH between 2006 and 2010, although the first case recorded was in 2008. The clinical details of these patients are shown in Tables 2 - 4. A total of six pregnant patients received methadone withdrawal at GSH between 2008 and 2010. Their ages ranged from 17 to 37 years. Four of the six patients were single and one was divorced, and half of them were of high parity. Apart from patient D, all the patients booked late (defined as booking after 20 weeks’ gestation). All the patients were HIV-negative, and none had current syphilis infection. Surprisingly, none of the patients abused alcohol, and patients B and F were the only two patients who used other substances – benzodiazepines and methamphetamine, respectively. All six patients underwent detoxification at some point during their pregnancies, with patients A and B requiring detoxification prior to delivery. There was no record of any psychiatric follow-up for any of the patients after detoxification, apart from patient D, who could afford a private rehabilitation facility. Four of the patients delivered at term, patient B delivered at 33 weeks’ gestation following heroin detoxification with methadone, and patient F delivered spontaneously 1 week short of term. Half of the patients required caesarean section. Patient A required an emergency caesarean section for fetal distress due to placental abruption;

however, it was not clear from the records if this was due to her ongoing heroin use or another obstetric cause. Interestingly, all the neonates had Apgar scores ranging from 7 to 10, and none of them required resuscitation. None of the neonates showed signs of NAS. All the patients were discharged from the maternity ward within 3 days after delivery.

Discussion

After review of the various studies found in the literature, it is apparent that data on the safety and efficacy of methadone detoxification are limited. There are, however, good data on the need to develop comprehensive treatment programmes that go beyond the dispensing of methadone and/or other medication. Pregnancy is often described as a useful period for encouraging behavioural changes. However, methadone alone, whether given as detoxification or maintenance, does not correct underlying psychosocial problems or address behaviour changes. The best outcomes are most likely to be reached by using an integrated care plan incorporating pharmacological, psychotherapeutic and social interventions. The most striking feature of our case series is the relatively low number of patients who received methadone detoxification, despite the rising rates of heroin use and the burden of disease encountered in Cape Town. Given that the 2010 SACENDU statistics reveal that heroin is the primary substance of abuse among 13% of substance abusers in the Western Cape Province,[2] it may be speculated that heroin-addicted pregnant patients are inadequately screened for, or are offered detoxification with only benzodiazepines and analgesics. There are two possible explanations for this. Firstly, these patients may face tremendous stigma, not only from their families and society but also from healthcare providers, and they may therefore be treated with little sympathy, being perceived as attempting to manipulate the system by requesting methadone treatment. Secondly, healthcare workers may be concerned about the risk of exposing the fetus to another potentially harmful substance. Five of the six patients had received methadone detoxification prior to delivery, while patient B went into labour during her withdrawal. Of the five patients who completed their detoxification, three resumed using heroin prior to their delivery, with patient A requiring a second detoxification at the time of delivery. In this small sample, the relapse rate is low given the fact that only one patient received continued psychosocial support after discharge. This low

Table 2. Maternal demographic data

Age, years Marital status Gestation, weeks Obstetric history Blood results Booking, weeks Antenatal Visits, n Complications Nicotine use Alcohol use Other substance use

A 24 Divorced 37+ G5P2M1SB1 Rh+ HIV– VDRL– 29

B 37 Single 33 G1P0 Rh+ HIV– VDRL– 32

8 No Yes No Heroin

2 Admitted Yes No Heroin Benzodiazepines

Patient C 21 Single 42+ G1P0 Rh+ HIV– VDRL– 31

D 34 Single 39 G5P1M2T1 Rh+ HIV– VDRL– 11

E 17 Single 38+ G1P0 Rh+ HIV– VDRL– 24

F 28 Married 36 G4P3 Rh+ HIV– VDRL– 33

4 No No No Heroin

5 No No No Heroin

4 No Yes No Heroin

1 No Yes No Heroin Meth

G = gravida; P = para; M = miscarriage; SB = stillbirth; T = termination; Meth = methamphetamine.

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Table 3. Heroin use and methadone withdrawal

Antenatal management of heroin use Admission (for detox) Place Duration After detox

Patient C

Yes STH 30 Jun - 7 Sep 2009

Yes GSH 5 Jun 2008

No known follow-up

Ongoing use of heroin post detox Admission date to maternity wards and reason

Yes

Labour and delivery No

27 Oct for detox

Date of last heroin use Methadone use during admission to maternity

27 Oct 28 - 30 Oct: 10 mL/20 mg 31 Oct - 1 Nov: 8 mL/16 mg 2 - 3 Nov: 6 mL/12 mg

Yes Yes GSH GSH 9 - 11 Mar 2010 21 - 23 Apr 2010 CTDC referral Private rehab Yes

5 Jun for detox

24 May in labour

4 Jun 9 - 11 Jun: 8 mL/16 mg

22 May None

16 Jun for elective caesarean section 21 Apr None

Yes Yes GSH GSH 15 - 21 Jul 2010 9 - 11 Mar 2010 STH detox STH detox ward ward Yes No 11 Aug with pre-labour ROM

23 Mar in labour

28 Jul None

9 Mar None

STH = Stikland Hospital; GSH = Groote Schuur Hospital; CTDC = Cape Town Drug Counselling Centre; ROM = rupture of membranes.

Table 4. Neonatal data

Delivery Mode Indication Date

Apgar score 1 min 5 min Sex of neonate Measurements Birth weight, g Head circumference, cm Resuscitation NAS Discharge Date Treatment

Patient D

CS AP, FDS

CS FDS

CS Previous CS

4 Nov 2009

Vacuum Spontaneous labour 10 Jun 2008

25 May 2010

16 Jun 2010

NVD Spontaneous labour Pre-labour ROM on 23 Mar 2010 11 Aug 2010, given oxytocin NVD 13 Aug 2010

8/10 10/10 F

7/10 9/10 M

9/10 10/10 M

9/10 10/10 F

8/10 10/10 M

9/10 9/10 F

2 200 33

2 110 34

3 960 36

2 600 31

3 540 33

3 240 34

No No

7 Nov Referred to C23, self-discharge against advice

13 Jun Diazepam

28 May No meds

19 Jun No meds

14 Aug No meds

24 Mar No meds

NVD Pre-labour ROM

CS = caesarean section; NVD = normal vertex delivery; AP = abruptio placentae; FDS = fetal distress syndrome; ROM = rupture of membranes; F = female; M = male; NAS = neonatal abstinence syndrome; C23 = emergency psychiatric ward.

rate of relapse indicates that methadone detoxification may be a successful way of managing these patients. One of the main criticisms of withdrawal treatment is the high rate of relapse to heroin use, which was shown not to be the case in this small population. This having been said, a relapse rate of 60% is not negligible, and ideally, further psychosocial measures should be implemented to assist in maintaining abstinence.

A major concern with methadone maintenance treatment is the high risk of NAS. This syndrome is characterised by central nervous system excitability in newborn infants, and in many cases requires pharmacological withdrawal treatment. All the infants of the six patients described were born without showing any sign of opioid withdrawal, had good Apgar scores and required no resuscitation. As mentioned earlier, the literature suggests that NAS requiring

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treatment occurs in at least two-thirds of infants born to mothers on methadone maintenance. The positive neonatal outcome in this group is therefore significant, as it highlights a major advantage of methadone detoxification over maintenance. Rementeria and Nunag[5] cautioned against detoxification after 32 weeks’ gestation owing to concerns about precipitating early delivery. Four of the six patients (A, B, E and F) were detoxified after 32 weeks, with patient A requiring a second detoxification at term, and two of the four (A and B) went into labour during the detoxification process, patient B having premature delivery at 33 weeks. These findings support the view that detoxification is safest during the second trimester. An interesting finding in these six patients was the low rate of comorbid substance abuse, and the fact that none of them were infected with HIV or with syphilis. This group of patients is usually at high risk for polysubstance abuse and sexually transmitted infections. The absence of these common additional problems may also partly explain the relatively good neonatal outcomes in the group. The apparent discrepancy in the resources available to heroinaddicted pregnant women in developed countries compared with SA is disheartening. The focus of most research has shifted from determining the merits of maintenance v. withdrawal to determining which medication is superior in maintenance management. SA state facilities continue to offer only methadone as substitution medication, and only for a limited period while undergoing withdrawal. This management of heroin withdrawal by detoxification and lack of opiate substitution treatment in government facilities in SA highlights the need for a greater focus on pharmacological harm reduction strategies in low- and middleincome countries.

Study limitations

The limitations of the current data set include the small sample size, the retrospective ratings, and the lack of any follow-up information. Despite this, however, these data suggest that favourable outcomes of pregnancies managed with methadone withdrawal are possible. Additional research is nevertheless required to confirm these preliminary findings.

Conclusions

There is limited evidence on the management of heroin addiction during pregnancy, and the only two guidelines identified suggest that methadone maintenance is preferable to methadone withdrawal. The favourable pregnancy outcomes in this small sample of patients managed with methadone withdrawal suggest that it may be safe and deserves further study.

Acknowledgements. DJS is supported by the South African Medical Research Council. Author contributions. KVG: first author; LD: second author; DJS: second supervisor; BV: primary supervisor. Funding. None. Conflicts of interest. None.

1. United Nations Office on Drugs and Crime. World Drug Report 2011, pp. 45-55. https://www.unodc.org/ unodc/en/data-and-analysis/WDR-2011.html (accessed 13 December 2017). 2. Pluddemann A, Dada S, Parry C, et al. Monitoring alcohol & drug abuse trends in South Africa (July 1996 - December 2009): Phase 27. SACENDU Research Brief 2010;13(1):1-11. http://hdl.handle. net/20.500.11910/3905 (accessed 5 January 2018). 3. Wong S, Ordean A, Kahan M, et al. Substance use in pregnancy. J Obstet Gynaecol Can 2011;33(4):367384. https://doi.org/10.1016%2Fs1701-2163%2816%2934855-1 4. Fischer G, Bitschau M, Peternell A, et al. Pregnancy and substance abuse. Arch Womens Ment Health 1999;2(2):57-65. https://doi.org/10.1007%2Fs007370050037 5. Rementeria JL, Nunag NN. Narcotic withdrawal in pregnancy: Stillbirth incidence with a case report. Am J Obstet Gynecol 1973;116(8):1152-1156. https://doi.org/10.1016%2F0002-9378%2873%2990953-8 6. Hunt RW, Tzioumi D, Collins E, Jeffery HE. Adverse neurodevelopmental outcome of infants exposed to opiate in-utero. Early Hum Dev 2008;84(1):29-35. https://doi.org/10.1016%2Fj.earlhumdev.2007.01.013 7. Alroomi LG, Davidson J, Evans TJ, Galea P, Howat R. Maternal narcotic abuse and the newborn. Arch Dis Child 1988;63(1):81-83. https://doi.org/10.1136/adc.63.1.81 8. Maas U, Kattner E, Weingart-Jesse B, et al. Infrequent neonatal opiate withdrawal following maternal methadone detoxification during pregnancy. J Perinat Med 1990;18(2):111-118. https://doi.org/10.151 5%2Fjpme.1990.18.2.111 9. Dashe JS, Jackson GL, Olscher DA, et al. Opioid detoxification in pregnancy. Obstet Gynaecol 1998;92(5):854-858. https://doi.org/10.1097%2F00006250-199811000-00022 10. Kashiwagi M, Arlettaz R, Lauper U, et al. Methadone maintenance program in a Swiss perinatal centre (I): Management and outcome of 89 pregnancies. Acta Obstet Gynecol Scand 2005;84(2):140-144. https:// doi.org/10.1080%2Fj.0001-6349.2005.00497.x 11. Jones HE, O Grady KE, Malfi D, Tuten M. Methadone maintenance vs methadone taper during pregnancy: Maternal and neonatal outcomes. Am J Addict 2008;17(5):372-386. https://doi. org/10.1080/10550490802266276 12. Daley M, Argerio M, McCarty D, et al. The cost of crime and the benefits of substance treatment for pregnant women. J Subst Abuse Treat 2000;19(4):445-458. https://doi.org/10.1016/s0740-5472(00)00138-0 13. Chang G, Carroll KM, Behr HM, Kosten TR. Improving treatment outcome in pregnant opiate-dependent women. J Subst Abuse Treat 1992;9(4):327-330. https://doi.org/10.1016/0740-5472(92)90026-k 14. Finnegan LP. Management of pregnant drug-dependent women. Ann N Y Acad Sci 1978;311(1):135-146. https://doi.org/10.1111%2Fj.1749-6632.1978.tb16770.x 15. Lejeune C, Simmat-Durand L, Gourarier L, Aubisson S. Prospective multicenter observational study of 260 infants born to 259 opiate-dependent mothers on methadone or high-dose buprenophine substitution. Drug Alcohol Depend 2006;82(3):250-252. https://doi.org/10.1016/j.drugalcdep.2005.10.001 16. Wang EC. Methadone treatment during pregnancy. J Obstet Gynecol Neonatal Nurs 1999;28(6):615-622. https://doi.org/10.1111/j.1552-6909.1999.tb02170.x 17. Winklbaur B, Kopf N, Ebner N, Jung E, Thau K, Fischer G. Treating pregnant women dependent on opioids is not the same as treating pregnancy and opioid dependence: A knowledge synthesis for better treatment for women and neonates. Addiction 2008;103(9):1429-1440. https://doi.org/10.1111/j.13600443.2008.02283.x 18. Zuspan FP, Gumpel JA, Mejia-Zelaya A, et al. Fetal stress from methadone withdrawal. Am J Obstet Gynecol 1975;122(1):43-46. https://doi.org/10.1016%2F0002-9378%2875%2990613-4 19. Annitto WJ. Detoxification with buprenorphine of a pregnant heroin addict. Am J Addict 2000;9(1):9297. https://doi.org/10.1080/10550490050172272 20. Luty J, Nikolaou V, Bearn J. Is opiate detoxification unsafe in pregnancy? J Subst Abuse Treat 2003;24(4):363-367. https://doi.org/10.1016/S0740-5472(03)00035-7 21. Edelin KC, Gurganious L, Golar K, Oellerich D, Kyei-Aboagye K, Hamid MA. Methadone maintenance in pregnancy: Consequences to care and outcome. Int J Gynecol Obstet 1989;28(3):311-312. https://doi. org/10.1016/0020-7292(89)90748-0 22. Allen MH. Detoxification considerations in the medical management of substance abuse in pregnancy. Bull N Y Acad Med 1991;67(3):270-276. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1807924/?page=1 (accessed 15 January 2018). 23. Mactier H. The management of heroin misuse in pregnancy: Time for a rethink? Arch Dis Child Fetal Neonatal Ed 2011;96(6):F457-F460. https://doi.org/10.1136/adc.2009.181057

Accepted 31 August 2017.

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

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Colorectal cancer in South Africa: An assessment of disease presentation, treatment pathways and 5-year survival M Brand,1 FCS (SA), PhD, Cert Surgical Gastroenterology (SA); P Gaylard,2 PhD; J Ramos,3 MB BCh, FCS (SA) Department of Surgery, Faculty of Health Sciences, University of Pretoria, South Africa; School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 2 Data Management and Statistical Analysis, Johannesburg, South Africa 3 Wits Donald Gordon Medical Centre, Johannesburg, South Africa; Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1

Corresponding author: M Brand (martinbrand78@gmail.com) Background. Colorectal cancer (CRC) is the fourth most common cancer in South Africa (SA), and the sixth most lethal. Approximately 25% of patients will have synchronous metastatic disease at the time of their primary CRC diagnosis. Although chemotherapy is used in most stages of the disease, surgical resection of the primary tumour and metastases remains the most successful treatment modality to achieve cure or prolong survival. To date, no data on CRC presentation and management have been published in SA. Objectives. To determine CRC presentation, general management patterns and overall survival in the SA private healthcare sector. Methods. A retrospective review of a private healthcare funder’s database from 1 January 2008 to 31 December 2015. International Statistical Classification of Diseases and Related Health Problems (10th revision) (ICD-10) diagnosis codes were used to identify colorectal cancer and liver and/or pulmonary metastatic disease. Procedure codes assigned to hospital admissions were used to identify type of surgical treatment. Chemotherapy was identified by the World Health Organization Anatomical Therapeutic Chemical Classification System of medicines. Treatment patterns were determined and 5-year survival rates for these were calculated. Survival was estimated using the Kaplan-Meier method, and Cox proportional hazards regression was used for between-group comparisons of survival. Data analysis was carried out using SAS version 9.4 for Windows. Results. A total of 3 412 patients were included in the study, 2 267 with CRC only and 1 145 with liver (LM) or pulmonary metastases (PM). The mean age was 64.1 years (range 21 - 97), and 54.6% were male; these did not differ statistically between the study groups. Twenty percent of patients with LM or PM underwent surgical resection of their metastases. Five-year survival rates following surgical resection of all disease for CRC only, CRCLM, CRCPM and CRCLMPM were 71.7%, 57.3%, 31.5% and 26.0%, respectively. Conclusions. SA CRC patients treated in the private healthcare sector have similar disease presentation to that in published international series, with similar outcomes following various treatment pathways; however, it seems that fewer resections of metastases are undertaken compared with international trends. S Afr Med J 2018;108(2):118-122. DOI:10.7196/SAMJ.2018.v108i2.12338

In South Africa (SA), colorectal cancer (CRC) is the fourth most common cancer among both men and women. The crude incidence is 7.17/100 000/year for men and 5.80/100 000/year for women,[1] and CRC ranks sixth in cancer-related mortality.[2] The cumulative lifetime risk of developing CRC in SA is 1.24 for males and 0.74 for females.[1] At the time of CRC diagnosis, 20 - 25% of patients will have metastatic disease,[3] the liver being the most common site.[4] More than half of the patients who undergo curative resection may expect to have tumour recurrence, either locally or as metastatic disease.[5] CRC therefore represents a significant healthcare burden. Five-year overall survival rates for CRC are 93.2% for stage I, 72.2 84.7% for stage II, 52.3 - 83.4% for stage III and 8.1% for stage IV. [6] Stage IV disease treated with chemotherapy alone has a median overall survival of 12 months.[7] Various treatment algorithms have been incorporated into international guidelines, but common to most is that, when possible, surgical resection of the primary lesion and its metastases offers the best survival benefit for patients.[8] So far, a specific treatment algorithm tailored to SA patients has not been published.

Objectives

To describe the presentation of CRC patients in a privately insured population in SA, general clinical management trends, and 5-year overall survival for various disease stages.

Methods

Study design and data collection

A retrospective review of a private healthcare funder’s database from 1 January 2008 to 31 December 2015 was undertaken. Ethics approval was granted by the University of the Witwatersrand Human Research Ethics Committee (ref. no. M141027), and consent to obtain deidentified data was given by the principal officer of the private healthcare funder. The initial dataset was based on claims by and clinical information on active members of the medical scheme. Data were extracted from tables developed by the medical scheme for analysis where the table development included data validation. Unique entities were identified from these data tables of members with a validated CRC diagnosis. Patients included in this study were enrolled on the scheme’s oncology benefit for the treatment of CRC. International Statistical

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Classification of Diseases and Related Health Problems (10th revision) (ICD-10) diagnosis codes were used to identify CRC only, with or without liver and/or pulmonary metastatic disease. Once identified, secondary or unspecified malignant neoplasms of the digestive organs or respiratory tract were sought for in this patient population. The authors examined each identified record to determine whether or not the additional diagnosis was relevant to the initial CRC diagnosis. Sites of metastases other than the liver and lungs were excluded. All procedure codes assigned to hospital admissions were captured, and each code was examined by the authors to identify surgical treatments relevant to resections of CRC and CRC metastases. All other procedures were excluded. Chemotherapy was identified by the World Health Organization Anatomical Therapeutic Chemical Classification System of medicines. The number of days from diagnosis of CRC and/or CRC metastases and from surgical resection were collected. Death was based on date of withdrawal from the medical scheme, and survival on ongoing contribution to the scheme. Patients were excluded if they were aged <18 years or were diagnosed before 1 January 2008, and if they were diagnosed on or after 1 January 2014 to ensure that we did not miss any treatment modalities and that patients had at least 1 year of follow-up. Each patient’s treatment was assessed as surgical resection of the cancer with or without chemotherapy, chemotherapy without surgical resection, or no treatment (no surgical resection or chemotherapy). Four patient groups were used for analysis: (i) CRC only; (ii) CRC and liver metastases (CRCLM); (iii) CRC and pulmonary metastases (CRCPM); and (iv) CRC, liver and pulmonary metastases (CRCLMPM).

Disease presentation, proportions of cancer with or without meta stases, and management pathways of the study group are presented in Fig. 2. One-third of patients either presented with or developed LM and/or PM, the most common being LM. Two-thirds of these patients underwent surgical resection, but only 7.2% (83/1 145) of patients with metastatic disease underwent meta statectomy. The most common was resection of LM, but only 10.0% (60/601) of patients with LM underwent liver resection; of these, 6.7% (4/60) underwent more than one liver resection. Of patients with CRC only, the majority underwent resection of their primary lesion. No treatment was recorded by the medical aid scheme for 16.5% of patients. Fig. 3 depicts overall survival regardless of therapy. Using the CRConly group as reference, the risk of death was higher for all the other three cancer groups, and highest for CRCLMPM. Five-year overall survival (5YOS) for CRCPM was better than for CRCLM. Table 2 describes treatment-related 5-year survival. The best 5YOS was for CRC without metastatic disease treated by surgical resection and chemotherapy. For patients with metastatic disease, CRCLM resection preceded by chemotherapy provided the best 5YOS of 40.7%. CRCPM resection with chemotherapy had 5YOS of 31.7%. There were 5-year overall survivors who did not have surgical

Whole data set, N=5 093

CRC diagnosis before 1 Jan 2008 excluded

Statistical analysis

Crude incidence was calculated and represented as 100 000/ year. Categorical variables were summarised as percentages, and continuous variables were summarised as means, standard deviations (SDs), medians and interquartile ranges. Survival was estimated using the Kaplan-Meier method and Cox proportional hazards regression was used for between-group comparisons of survival. The 5% significance level was used. Data analysis was carried out using SAS version 9.4 for Windows (SAS Institute, USA).

n=3 913

CRC diagnosis after 31 Dec 2014 excluded

Results

A total of 3 412 patients were included in the study (Fig. 1). Their demographic features are set out in Table 1. The total number of members on 1 January 2015 was 2 658 100, with 5 093 diagnosed with CRC. The crude incidence of CRC in this insured population increased from 18.9/100 000 in 2008 to 21.3/100 000 in 2015. The gender composition for each patient group was similar, apart from the proportion of males being significantly higher in the CRCLM group compared with the CRC-only group (p=0.037) (Table 1). The mean (SD) age of the CRC-only group (64.1 (12.8) years) was significantly higher than that of the CRCLMPM group (61.5 (11.7) years) (p<0.0001). There was no statistically significant difference between the CRCLM, CRCPM and CRCLMPM groups (Table 1).

n=3 414

Patients aged <18 years excluded

n=3 412

Fig. 1. Data selection, 1 January 2008 - 31 December 2015. (CRC = colo rectal cancer.)

Table 1. Overview of CRC patients Survival, n (%) Age (yr), mean (range) Gender, n (%) Males Females

All cases 3 412 64.1 (21 - 97)

CRC only 2 267 (66.4) 64.7 (21 - 97)

CRCLM 601 (17.6) 63.6 (25 - 93)

CRCPM 182 (5.3) 62.6 (23 - 85)

CRCLMPM 362 (10.6) 61.5 (23 - 87)

1 862 (54.6) 1 550 (45.4)

1 203 (53.1) 1 064 (46.9)

357 (59.4) 244 (40.6)

97 (53.3) 85 (46.7)

205 (56.6) 157 (43.4)

CRC = colorectal cancer; LM = liver metastases; PM = pulmonary metastases.

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incidence rates of CRC in Europe, overall and in males and females, are 29.5/100 000, 37.3/100 000 and 23.6/100 000, respectively.[1] The corresponding figures for sub-Saharan Africa are 5.8/100 000, 6.4/100 000 and 5.4/100 000, respectively.[1] The incidence in this study falls in between that for developed countries and African statistics, possibly indicating that screening and surveillance of CRC are better than in developing countries but may not be as stringent as in developed countries.

N=3 412

CRC only, n=2 267 (66.4%)

CRC + LM/PM. n=1 145 (33.6%) LM only, n=601 (52.5%) PM only, n=182 (15.9%) LM + PM, n=362 (31.6%)

Surgical treatment, n=1 460 (64.4%)

Management and overall survival of CRC groups

CRC only In our study, patients who received chemotherapy either before or after resection of the primary CRC appeared to have improved survival compared with those who underwent surgical resection only (Table 2). CRC treatment has been shown to be more effective when surgery is combined with chemotherapy.[9] The long survival of the chemotherapy-only group in this study is not in keeping with international series, and cannot be explained owing to the limited available clinical information such as accurate tumour staging.

Surgical treatment*, n=687 (60.0%)

Chemotherapy only, n=432 (19.1%)

CRC only, n=509 (44.4%) LM, n=60 (10.0%) PM, n=13 (7.1%) LM + PM, n=10 (2.8%)

No treatment, n=375 (16.5%)

Chemotherapy only, n=378 (33.0%)

No treatment, n=80 (7.0%)

Fig. 2. Disease presentation and management. (CRC = colorectal cancer; LM = liver metastases; PM = pulmonary metastases. *Patients may or may not have received chemotherapy.) CRC only CRCPM CRCLMPM CRCLM

1.0

Estimated survival probability

0.8

0.6

0.4

0.2

0.0 0

Survival time (yr)

Fig. 3. Overall survival of disease groups, regardless of treatment. (CRC = colorectal cancer; LM = liver metastases; PM = pulmonary metastases.)

resection of metastases, but the figure was significantly lower than if they had had all their disease resected.

CRCLM Complete resection of CRCLM is the only treatment associated with long-term survival, with 37 - 54% 5YOS following surgical resection as opposed to 4 - 9% without surgical resection,[10] and potential cure in up to 16% of patients.[11] In this series, 5YOS following resection of all disease was 57.3% if chemotherapy was administered before tumour resection, and 40.7% if surgery preceded chemotherapy (Table 2). Synchronous resection of the primary lesion as well as the liver metastases has been reported to have 40 - 47% 5YOS.[12] We were not able to determine 5YOS for synchronous resection in this study. CRCLM resection is safe, with a mortality rate of <2% and a major morbidity rate of ~12.5%,[13,14] including patients aged >75 years, who can achieve 5YOS of 58%.[15] Patients may undergo repeated liver resections for recurrent CRCLM with similar survival figures to patients who only have one liver resection and no recurrence. One case series reported 47% 5YOS for repeat liver resection.[10] We were not able to perform survival analyses for repeated resections owing to the low numbers of these procedures. CRCPM Since the more widespread use of chemotherapy for pulmonary CRC metastases, overall survival has improved.[16] PM are typically single or multiple nodules, as opposed to a miliary type of spread or lymphangitis carcinomatosa, and hence more amenable to surgical resection.[17] 5YOS following pulmonary metastectomy has been reported as 24 61.4%,[18] and in this study was 31.5% (Table 2). The CRCPM resection mortality rate is <1% and the morbidity rate is ~14%.[19]

Discussion

This is the first study to determine survival outcomes of CRC with or without LM and/or PM in a selected, privately insured SA population. We have demonstrated that one-third of patients with CRC present with or develop LM and/or PM, of whom 7% undergo surgical metastatectomy. 5YOS is best for patients with disease isolated to the colon or rectum that is resected and treated with chemotherapy. Furthermore, there is improved survival with surgical resection in combination with chemotherapy of LM and/or PM.

CRCLMPM 5YOS for patients with pulmonary metastectomy following hepatic metastectomy is 31.6%.[17] In this study, 5YOS was 26.0% (Table 2). Our figures also highlight the fact that relatively few patients undergo surgical resection of their metastatic disease. Median overall survival has been shown to be significantly improved with complete or macroscopically clear resection margins of CRCLMPM compared with palliative chemotherapy,[20] as well as resection of the primary CRC only in stage IV disease.[21]

Incidence and presentation of CRC

Study limitations

The global incidence rates of CRC, overall and in males and females, are 17.2/100 000, 20.6/100 000 and 14.3/100 000, respectively. The

There are limitations to this study. Data were retrieved from a single private healthcare funder’s database which represents 53% of the

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Table 2. Five-year overall survival according to treatment pattern Group CRC only Surgery only Surgery and chemotherapy Chemotherapy upfront followed by surgery Chemotherapy only, no surgical resection CRCLM Chemotherapy upfront followed by surgical resection of all cancer CRC surgery followed by chemotherapy and further resections CRC surgery only and chemotherapy, no metastases resected Chemotherapy only, no surgical resection CRCPM Chemotherapy and resection of all cancer CRC surgery only and chemotherapy, no metastases resected Chemotherapy only, no surgical resection CRCLMPM Chemotherapy and resection of all cancer CRC surgery only and chemotherapy, no metastases resected Chemotherapy only, no surgical resection

Survival, n (%)

95% CI

489 (60.1) 886 (71.7) 85 (69.9) 432 (56.3)

54.2 - 66.5 67.6 - 75.3 56.1 - 80.1 50.5 - 61.6

19 (57.3) 41 (40.7) 23 (15.6) 180 (9.8)

30.5 - 77.0 20.0 - 60.5 9.9 - 22.4 5.6 - 15.5

13 (31.5) 62 (25.4) 65 (22.4)

23.4 - 40.0 12.2 - 40.9 11.8 - 35.2

10 (26.0) 101 (13.1) 133 (5.3)

8.5 - 47.9 6.8 - 21.6 1.6 - 12.4

CI = confidence interval; CRC = colorectal cancer; LM = liver metastases; PM = pulmonary metastases.

open market. This database is primarily designed for health economic data capture with limited clinical information. These results are based on treatments claimed from the medical scheme. Members may not necessarily submit all treatment claims to the scheme; for example, they may receive treatment as part of a clinical trial, use self-funded medication, or receive treatment from state facilities. Because of the paucity of clinical information, only general treatment patterns are reported. The survival estimates and Kaplan-Meier plot are limited by the fact that the analysed data do not originate from primary clinical data, but from secondary medical aid administrative and claims data. There may therefore be loss of accuracy and missing information. Furthermore, we could not adjust for covariates. However, we believe that the Kaplan-Meier plot remains the best way to display survival data, and we capped the estimates to 5 years, beyond which there are too few patients at risk for reliable estimates. We have provided 95% confidence intervals for these estimates. Whether CRC in SA differs from internationally published series or whether patients are being managed appropriately cannot be determined from this study. Furthermore, our results cannot be extrapolated to the public healthcare sector, as the treatment of this disease appears to differ significantly with regard to disease presentation as well as access to chemotherapy and biological agents.

Future research

Appropriate clinical information should be collected by private healthcare funders to facilitate audit as well as to understand clinical decision-making and outcomes. The importance of multidisciplinary teams (MDTs) cannot be over-emphasised in the assessment of CRC with metastases to determine optimal patient management. A prospective study of an MDT showed that despite 84% of clinicians being certain of their management plan, following the MDT discussion 36% changed their management plan; 72% of these changes were major ones.[22] Furthermore, studies have shown lower survival rates following non-adherence to MDT decisions.[23] Finally, a national CRC registry should be established so that understanding of disease epidemiology, presentation, outcomes and therapeutic resources can be improved.

Conclusions

CRC patients treated in the SA private healthcare sector have improved survival following resection of the primary tumour and metastatic disease, which is further enhanced by the use of chemotherapy as opposed to chemotherapy alone or no treatment. Acknowledgements. The authors thank Discovery Health, specifically the Clinical Policy Unit, for their immense assistance with data extraction and management. Author contributions. MB: conceived the study idea, accessed the data, cowrote the manuscript; PG: performed the statistical analysis, co-wrote the manuscript; JR: contributed to the study idea, co-wrote the manuscript. Funding. Wits Donald Gordon Medical Centre Research Grant. The statistical analysis of the data was also funded by the Wits Donald Gordon Medical Centre. Conflicts of interest. None.

1. Cancer Association of South Africa. 2012 National Cancer Registry. http://www.cansa.org.za/ files/2017/03/SA-National-Cancer-Registry-2012-web-Feb-2017.pdf (accessed 8 April 2017). 2. International Agency for Research on Cancer. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/Default.aspx (accessed 16 December 2016). 3. Dervenis C, Xynos E, Sotiropoulos G, et al. Clinical practice guidelines for the management of metastatic colorectal cancer: A consensus statement of the Hellenic Society of Medical Oncologists (HeSMO). Ann Gastroenterol 2016;29(4):390-416. https://doi.org/10.20524/aog.2016.0050 4. Nordlinger B, van Cutsem E, Rougier P, et al. Does chemotherapy prior to liver resection increase the potential for cure in patients with metastatic colorectal cancer? A report from the European Colorectal Metastases Treatment Group. Eur J Cancer 2007;43(14):2037-2045. https://doi.org/10.1016/j. ejca.2007.07.017 5. August DA, Ottow RT, Sugarbaker PH. Clinical perspective of human colorectal cancer metastasis. Cancer Metastasis Rev 1984;3(4):303-324. https://doi.org/10.1007/BF00051457 6. O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004;96(19):1420-1425. https://doi. org/10.1093/jnci/djh275 7. Stintzing S. Management of colorectal cancer. F1000Prime Rep 2014;6:108. https://doi.org/10.12703/ P6-108 8. Van Cutsem E, Cervantes A, Nordlinger B, Arnold D; ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25(Suppl 3):iii1-iii9. https://doi.org/10.1093/annonc/mdu260 9. Nishioka Y, Moriyama J, Matoba S, et al. Prognostic impact of adjuvant chemotherapy after hepatic resection for synchronous and early metachronous colorectal liver metastases. Dig Surg 2017 (epub 19 August 2017). https://doi.org/10.1159/000478791 10. Lemke J, Cammerer G, Ganser J, et al. Survival and prognostic factors of colorectal liver metastases after surgical and nonsurgical treatment. Clin Colorectal Cancer 2016;15(4):e183-e192. https://doi. org/10.1016/j.clcc.2016.04.007

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RESEARCH

11. Tomlinson J, Jarnagin W, DeMatteo R, et al. Actual 10-year survival after resection of colorectal liver metastases. J Clin Oncol 2007;25(29):4575-4582. https://doi.org/10.1200/JCO.2007.11.0833 12. Adam R, de Gramont A, Figueras J, et al. of the EGOSLIM (Expert Group on OncoSurgery management of LIver Metastases) group. Managing synchronous liver metastases from colorectal cancer: A multidisciplinary international consensus. Cancer Treat Rev 2015;41(9):729-741. https://doi. org/10.1016/j.ctrv.2015.06.006 13. Schiffman SC, Kim KH, Tsung A, Marsh JW, Geller DA. Laparoscopic versus open liver resection for metastatic colorectal cancer: A meta-analysis of 610 patients. Surgery 2015;157(2):211-222. https://doi. org/10.1016/j.surg.2014.08.036 14. Kokudo N, Tada K, Seki M, et al. Anatomical major resection versus non-anatomical limited resection for liver metastases from colorectal carcinoma. Am J Surg 2001;181(2):153-159. https://doi. org/10.1016/S0002-9610(00)00560-2 15. Gandy RC, Stavrakis T, Haghighi KS. Short- and long-term outcomes of elderly patients undergoing liver resection for colorectal liver metastasis. Aust N Z J Surg 2016 (epub 30 Oct 2016). https://doi. org/10.1111/ans.13690 16. Riquet M, Foucault C, Cazes A, et al. Pulmonary resection for metastases of colorectal adenocarcinoma. Ann Thorac Surg 2010;89(2):375-380. https://doi.org/10.1016/j.athoracsur.2009.10.005 17. Iizasa T, Suzuki M, Yoshida S, et al. Prediction of prognosis and surgical indications for pulmonary metastasectomy from colorectal cancer. Ann Thorac Surg 2006;82(1):254-260. https://doi. org/10.1016/j.athoracsur.2006.02.027

18. Pfannschmidt J, Dienemann H, Hoffmann H. Surgical resection of pulmonary metastases from colorectal cancer: A systematic review of published series. Ann Thorac Surg 2007;84(1):324-338. https://doi.org/10.1016/j.athoracsur.2007.02.093 19. Goonerante D, Gray C, Lim M et al.; Colorectal Lung Metastases Research Group (CRLMRG). Survival outcome in New Zealand after resection of colorectal cancer lung metastases. Aust N Z J Surg 2013;83(12):959-962. https://doi.org/10.1111/ans.12012 20. Park JH, Lee KH, Han SW et al. The beneficial effect of palliative resection in metastatic colorectal cancer: 10 years of experiences from a single institute. J Clin Oncol 2012;30(Suppl. 4):626. https://doi. org/10.1038/bjc.2013.94 21. Lee KC, Ou YC, Hu WH, Liu CC, Chen HH. Meta-analysis of outcomes of patients with stage IV colorectal cancer managed with chemotherapy/radiochemotherapy with and without primary tumor resection. Onco Targets Ther 2016;9:7059-7069. https://doi.org/10.2147/OTT.S112965 22. Oxenberg J, Papenfuss W, Esemuede I, et al. Multidisciplinary cancer conferences for gastrointestinal malignancies result in measureable treatment changes: A prospective study of 149 consecutive patients. Ann Surg Oncol 2015;22(5):1533-1539. https://doi.org/10.1245/s10434-014-4163-y 23. Leo F, Venissac N, Poudenx M, Otto J, Mouroux J. Multidisciplinary management of lung cancer: how to test its efficacy? J Thorac Oncol 2007;2(1):69-72. https://doi.org/10.1097/JTO.0b013e31802bff56

Accepted 19 September 2017.

February 2018, Print edition

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

RESEARCH

Safety and affordability of an elective Saturday list at Pietersburg Hospital, Limpopo, South Africa M M Z U Bhuiyan, MBBS, DTH, FRCSG, MMed; R Mavhungu, BSc (Med Sci) Department of General Surgery, Pietersburg Hospital and Faculty of Health Sciences, University of Limpopo, Turfloop, South Africa Corresponding author: M M Z U Bhuiyan (bhuiyanmirza@gmail.com)

Background. The backlog of patients waiting for operations continues to be a problem in many public hospitals in South Africa (SA), with elective surgery procedures being postponed for up to 2 years. Objective. To determine the rate of death in hospital or out of hospital within 30 days of an elective procedure performed on a Saturday, and to determine the cost incurred by paying staff members who perform these operations. Method. A prospective, observational descriptive cohort study of all patients undergoing inpatient general surgery operations during weekdays and weekends between 1 September 2015 and 31 August 2016 (1 year) at Pietersburg Hospital (PBH), Limpopo, SA. Microsoft Excel 2010 (Microsoft, USA) was used to analyse and derive descriptive statistics. The finance department at the hospital calculated the overtime pay for theatre staff who operated on Saturdays. Results. The study included 1 352 operations (607 elective and 745 emergency procedures). Saturday elective operations contributed 133/607 (22%), and the rate of death for these operations was 1.5%. The most common procedures performed on a Saturday were hernia repair and amputation. The cost for 8 hours of work on a Saturday was ZAR13 900, amounting to a total of ZAR333 600 for 24 Saturdays. Conclusion. Performing minor surgery on a Saturday had a mortality rate of 1.5%, and a theatre staff cost of ~ZAR2 317 per patient, excluding surgeons’ fees. If surgeons were to be paid the costs would be ZAR3 450 per patient. S Afr Med J 2018;108(2):123-125. DOI:10.7196/SAMJ.2018.v108i2.12426

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i2.12426

Physical activity levels in urban-based South African learners: A cross-sectional study of 7 348 participants A van Biljon,1 MSc (Kinderkinetics); A J McKune,2,3 PhD (Sport and Exercise Science); K D DuBose,4,5 PhD (Exercise Physiology); U Kolanisi,6 PhD (Consumer Science); S J Semple,3 PhD (Sport and Exercise Science) Department of Human Movement Science, Faculty of Science and Agriculture, University of Zululand, KwaDlangezwa, South Africa Discipline of Biokinetics, Exercise and Leisure Sciences, School of Health Sciences, University of KwaZulu-Natal, South Africa 3 Discipline of Sport and Exercise Science, Research Institute for Sport and Exercise, Faculty of Health, University of Canberra, Australia 4 Department of Kinesiology, East Carolina University, Greenville, NC, USA 5 East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA 6 Department of Consumer Science, Faculty of Science and Agriculture, University of Zululand, KwaDlangezwa, South Africa 1 2

Corresponding author: A van Biljon (vanbiljona@unizulu.ac.za) Background. Establishing profiles of physical activity (PA) is critical in tackling the chronic diseases associated with lack of PA and avoiding healthcare costs. Objective. To investigate PA levels in urban-based South African (SA) primary school learners. Methods. The Physical Activity Questionnaire for Older Children was completed by 7 348 learners (3 867 males and 3 481 females) aged 8 14 years, of whom 49% were white, 39% black and 12% from other ethnic groups. Differences in PA levels by ethnic origin and province were determined using an analysis of covariance after adjusting for gender (p<0.05). Bonferroni corrections controlled for multiple comparisons. A fitted regression model examined age-related differences in PA adjusting for province.

February 2018, Print edition

RESEARCH

Results. Of SA learners aged 8 - 14 years, 57% (n=4 224) engaged in moderate levels of PA. Thirty-one percent (n=2 247) did not meet internationally recommended amounts of moderate to vigorous physical activity. Overall, males reported higher PA levels than females (p<0.0001). PA levels declined with age from 11 to 14 years by 14% and 20% in males and females, respectively. Black learners had higher PA levels than white learners (p=0.0039). There were also significant differences in PA levels between the provinces (p<0.0001). Conclusion. This study provides evidence of differences in PA levels between gender, age and ethnic groups, and between provinces. A targeted approach to increase PA in high-risk populations in SA is warranted. Increased PA will help reduce the risk of chronic diseases and will contribute to the health of SA’s population and the growth of the country’s economy. S Afr Med J 2018;108(2):126-131. DOI:10.7196/SAMJ.2018.v108i2.12766

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i2.12766

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency in South Africa Y Ganie,1,2 FCP (Paed), Cert Endocrinology and Metabolism (SA) Paed; C Aldous,3 PhD; Y Balakrishna,4 MSc; R Wiersma,5 PhD epartment of Paediatrics and Child Health, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, D Durban, South Africa 2 Division of Paediatric Endocrinology, Inkosi Albert Luthuli Central Hospital, KwaZulu-Natal, Durban, South Africa 3 Department of Internal Medicine, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa 4 Biostatistics Unit, South African Medical Research Council, Durban, South Africa 5 Department of Paediatric Surgery, Inkosi Albert Luthuli Central Hospital and Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa 1

Corresponding author: Y Ganie (yasmeen.ganie@novavitagroup.com) Background. Congenital adrenal hyperplasia (CAH) caused by deficiency of the 21-hydoxylase (21-OH) enzyme is the most common form of CAH worldwide. Objective. To evaluate the prevalence of CAH due to 21-OH deficiency, and its clinical presentation and biochemical profiles in affected children. Methods. We performed a retrospective subset analysis of 44 children with confirmed CAH. Results. All the children had classic CAH. The majority (59.8%) had classic salt-wasting (CSW) CAH and 40.1% had simple virilising (SV) CAH. The median age of presentation was 8.1 years (interquartile range (IQR) 4.5 - 11) in the SV group and 2 months (IQR 2 weeks - 5 months) in the CSW group (p=0.0001). No difference in age of presentation was noted between males and females (p=0.541). The clinical presentation was significantly different between the CSW and SV groups, and between males and females in the CSW group (p<0.0001). Most of the females with 46,XX CSW CAH (66.7%) presented with disorders of sex development (DSD), while the remaining 33.3% presented with DSD and dehydration and shock. All the males with 46,XY CSW CAH presented with dehydration and shock. Overall, 37.9% (11/29) of the children were obese or overweight at presentation. Gonadotrophin-releasing hormone-dependent central precocious puberty was observed on follow-up in 29.4% (10/34) of the children at a median of 6.7 years (IQR 5 - 7.7). Conclusion. The diagnosis of CAH is delayed in males and females in both SV and CSW forms of the disorder, which probably contributes to under-reporting of cases and a high mortality rate. S Afr Med J 2018;108(2):132-137. DOI:10.7196/SAMJ.2018.v108i2.12579

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i2.12579

February 2018, Print edition

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

RESEARCH

Five-year follow-up of participants diagnosed with chronic airflow obstruction in a South African Burden of Obstructive Lung Disease (BOLD) survey B W Allwood,1,2 PhD; R Gillespie,1 MSc (Nursing); M Bateman,1 MD; H Olckers,1 BTech Hons; L Taborda-Barata,3 PhD; G L Calligaro,1 MD; R van Zyl-Smit,1 PhD; C B Cooper,4 PhD; N Beyers,4 PhD; E D Bateman,1 PhD ivision of Pulmonology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa; and University of D Cape Town Lung Institute, South Africa 2 Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 3 CICS – Health Sciences Research Centre, University of Beira Interior, Portugal 4 David Geffen School of Medicine, University of California, Los Angeles, USA; and Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 1

Corresponding author: B W Allwood (brianallwood@gmail.com) Background. A community-based prevalence survey performed in two suburbs in Cape Town, South Africa (SA), in 2005, using the international Burden of Obstructive Lung Disease (BOLD) method, confirmed a prevalence of chronic airflow obstruction (CAO) in 23.1% of adults aged >40 years. Objectives. To study the clinical course and prognosis over 5 years of patients with CAO identified in the 2005 survey. Methods. Patients with CAO in 2005 were invited to participate. Standard BOLD and modified questionnaires were completed. Spirometry was performed using spirometers of the same make as in 2005. Results. Of 196 eligible participants from BOLD 2005, 45 (23.0%) had died, 8 from respiratory causes, 10 from cardiovascular causes and 6 from other known causes, while in 21 cases the cause of death was not known. On multivariate analysis, only age and Global initiative for Obstructive Lung Disease (GOLD) stage 4 disease at baseline were significantly associated with death. Of the 151 survivors, 11 (5.6% of the original cohort) were unavailable and 33 (16.8%) declined or had medical exclusions. One hundred and seven survivors were enrolled in the follow-up study (54.6%, median age 63.1 years, 45.8% males). Post-bronchodilator spirometry performed in 106 participants failed to confirm CAO, defined as a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio of <0.7, in 16 participants (15.1%), but CAO was present in 90. The median decline in FEV1 was 28.9 mL/year (interquartile range –54.8 - 0.0) and was similar between GOLD stages. The median total decline in FVC was 75 mL, and was significantly greater in GOLD stage 1 (–350 mL) than in stages 2 or 3 (–80 mL and +140 mL, respectively; p<0.01). Fifty-eight participants with CAO in 2005 (64.4%) remained in the same GOLD stage, while 21 (23.3%) deteriorated and 11 (12.2%) improved by ≥1 stage. Only one-third were receiving any treatment for chronic obstructive pulmonary disease (COPD). Conclusions. The prevalence, morbidity and mortality of CAO and COPD in SA are high and the level of appropriate treatment is very low, pointing to underdiagnosis and inadequate provision of and access to effective treatments and preventive strategies for this priority chronic non-communicable disease. S Afr Med J 2018;108(2):138-143. DOI:10.7196/SAMJ.2018.v108i2.12688

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i2.12688

February 2018, Print edition

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True (A) or false (B): Burkitt’s lymphoma: The prevalence of HIV/AIDS and the outcome of treatment 1. Modern chemotherapy for Burkitt’s lymphoma has a potential cure rate of >90% in HIV-negative patients, but at considerable cost and the risk of significant morbidity.

Characteristics and early outcomes of children and adolescents treated with darunavir/ritonavir-, raltegravir- or etravirinecontaining antiretroviral therapy in the Western Cape 11. Currently fewer than 1% of people on antiretroviral therapy globally are receiving third-line regimens.

The development of hospital-based palliative care services in public hospitals in the Western Cape 2. Palliative care is applicable to any diagnosis that may result in a person’s death. 3. Palliative care is applicable early in the diagnosis of a lifethreatening illness, in conjunction with treatment that is aimed at containing the illness, and so any healthcare professional should be able to provide this care, along with disease-specific treatment. 4. Hospice services in South Africa (SA) are nurse led with support from an interdisciplinary team, including social workers, spiritual counsellors and doctors.

Colorectal cancer (CRC) in SA: An assessment of disease presentation, treatment pathways and 5-year survival 12. CRC is the fourth most common cancer in SA, and the sixth most lethal. 13. Approximately 45% of patients will have synchronous metastatic disease at the time of their primary CRC diagnosis. 14. The cumulative lifetime risk of developing CRC in SA is 1.24 for males and 0.74 for females.

Clinical characteristics and causes of heart failure, adherence to treatment guidelines, and mortality of patients with acute heart failure (HF): Experience at Groote Schuur Hospital, Cape Town 5. It is estimated that 37.7 million people worldwide are affected by HF. 6. Observational studies from sub-Saharan Africa show that hypertension, rheumatic valvular heart disease and idiopathic cardiomyopathies are the main causes of HF affecting a young population. 7. This epidemiological pattern is strikingly different from that in the developed world, where a much older population suffers from HF, with ischaemic heart disease the primary cause. Neonatal and paediatric bloodstream infections: Pathogens, antimicrobial resistance patterns and prescribing practice at Khayelitsha District Hospital, Cape Town, SA 8. Bacterial bloodstream infections, both community acquired and healthcare associated, are not an important cause of neonatal and paediatric morbidity and mortality worldwide. 9. Non-typhoidal Salmonella, Escherichia coli, Staphylococcus aureus and Streptococcus pneumoniae are major pathogens among paediatric and adult patients across Africa. 10. Antimicrobial-resistant pathogens (notably ESBL-producing Enterobacteriaceae) were common in community-acquired bloodstream infections in this particular hospital.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency in SA 15. Congenital adrenal hyperplasia (CAH) caused by deficiency of the 21-hydroxylase enzyme is the most common form of CAH worldwide. 16. The most common type of congenital adrenal hyperplasia is the classic salt-wasting form. 17. The simple virilising type of CAH is characterised by cortisol deficiency and androgen excess, but adequate amounts of aldosterone. Five-year follow-up of participants diagnosed with chronic airflow obstruction in a SA Burden of Obstructive Lung Disease (BOLD) survey 18. Chronic obstructive pulmonary disease (COPD) is recognised as among the top five causes of death globally, and rates are declining more slowly than for other chronic non-communicable diseases. 19. More than 90% of COPD deaths occur in low- and middleincome countries. 20. Longitudinal surveys of COPD progression suggest that the rate of lung function loss is greater in individuals with lesser degrees of airflow obstruction.

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