Cohort Profile: The Khayelitsha antiretroviral programme, Cape Town, South Africa

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1 International Journal of Epidemiology, 2017, e21(1 9) doi: /ije/dyw057 Advance Access Publication Date: 20 May 2016 Cohort Profile Cohort Profile Cohort Profile: The Khayelitsha antiretroviral programme, Cape Town, South Africa Kathryn Stinson, 1,2 Eric Goemaere, 1,2 David Coetzee, 2,3 Gilles van Cutsem, 1,2 Katherine Hilderbrand, 1,2 Meg Osler, 2 Claudine Hennessey, 2 Lynne Wilkinson, 1 Gabriela Patten, 1 Carol Cragg, 3 Shaheed Mathee, 3 Vivian Cox 1 and Andrew Boulle 2,3, * 1 Médecins Sans Frontières, Khayelitsha, Cape Town, South Africa, 2 Centre for Infectious Disease Epidemiology & Research, School of Public Health & Family Medicine, University of Cape Town, South Africa and 3 Department of Health, Provincial Government of the Western Cape, Cape Town, South Africa *Corresponding author. School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. andrew.boulle@uct.ac.za Accepted 15 January 2016 Background and why the cohort was set up Khayelitsha is Cape Town s largest township, approximately 35 km from the city centre. It was originally developed as a dormitory town to house the increasing influx of African migrant workers in the 1980 s during the apartheid period. It has an estimated population of , and 38% unemployment. Of the total population, 45% live in formal low-cost housing, 72% have access to a flush toilet and 81% use electricity for lighting their dwelling. In many areas, population density is high due to continued migration from the Eastern Cape Province and South Africa s bordering states. 1 Khayelitsha has the highest HIV prevalence in the Western Cape Province, with 34.3% of pregnant women being HIV-positive in 2012 (increasing from 19.3% in 2000) compared with 29.5% nationally. 2 The first government services in South Africa to routinely provide antiretrovirals were the maternity services in Khayelitsha, which started providing zidovudine (ZDV) for the prevention of mother-to-child transmission (PMTCT) of HIV in Médecins Sans Frontières (MSF) began to support the government to run HIV services in Khayelitsha in 1999, with a view to developing a pilot programme for the provision of antiretroviral treatment (ART), partnering to establish HIV care services in 2000 and ART in May The initial cohort study was set up with support from the University of Cape Town to demonstrate the feasibility of ART in a high HIV-burden African setting, using a public health approach to ART provision, generic antiretrovirals and an adherence model predicated on patient education and empowerment. 4 The early programme was implemented amid global and national scepticism as to the effectiveness and safety of ART in African settings. 5 7 This resulted in an early programme focus on survival, patient retention, virological suppression and tolerability. 8 By 2004, ART became the standard of care in South Africa for patients who were clinically eligible. The Khayelitsha programme has since expanded rapidly, having started more than patients on ART by the end of In that it is one of the longest-standing and largest treatment programmes in South Africa, and one in which there continues to be extensive innovation around models of service delivery, there is a great deal of interest in the continued tracking of clinical outcomes and the effectiveness of health service interventions. Current research objectives pertain to: the clinical, epidemiological and operational aspects of expanded service delivery, including paediatric, adolescent and adult patient outcomes; longterm temporal trends in treatment durability; describing VC The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association 1

2 2 International Journal of Epidemiology, 2017, Vol. 46, No. 2 virological and immunological monitoring and resistance; and the incidence of HIV-associated conditions, including TB co-infection. Who is in the cohort and what protocols have been followed? Khayelitsha is an open cohort with continuous recruitment. Initially ( ) three large, provincially-run ART sites operated, each with a team of nurses and counsellors supported by one or two doctors. Services expanded to eight additional sites from , administered by the metropolitan health authority. Until 2012, the research cohort was restricted to patients in care at the three original and largest clinics, constituting 75% of the cohort. Data are collected prospectively, beginning with each patient s first visit to the ART service. HIV testing and counselling have increased dramatically, from in 2003 to > patients in Patients are commonly referred for treatment to ART services through acute care, maternity and TB services from within Khayelitsha. Treatment eligibility The clinical and patient preparation protocols in use are the South African national guidelines as adopted by the Provincial Department of Health, with minor modifications (Table 1). Before 2010, ART eligibility criteria for adults included a CD4 cell count 200 cells/ml orwho stage IV illness irrespective of CD4 count, excluding extrapulmonary TB. From April 2010, national guidelines changed the CD4 threshold to < 350 cells/ml for pregnant women and those with TB. In April 2013, further guideline changes allowed for initiation of patients with a CD4 cell count < 350 cells/ml or WHO Stage III or IV illness, and of all patients with TB and pregnant women irrespective of CD4 count. From 2015, national guidelines have recommend the provision of ART for all HIV-infected adults with a CD4 cell count 500 cells/ml. 10 Between 2002 and 2006, 11 eligibility criteria for paediatric ART included WHO stage II/III (2004) and III/IV disease (2006), 12 with CD4 percentages of total lymphocytes < 20% (children < 18 months) and < 15% ( 18 months). From April 2010, all HIV-positive infants under 12 months were eligible for ART, and this was expandedin2012toinclude all children aged months 13 in addition to immunological criteria for ART initiation in older children (Table 1). ART regimens From 2001, the first-line regimen comprised zidovudine(azt), lamivudine (3TC) and either nevirapine (NVP) or efavirenz (EFV), and the second-line regimen stavudine (d4t), didanosine (ddi) and indinavir. 14,15 In late 2003, d4t replaced AZT, aligning with the pending South African national guidelines. At this time, virological failure was ascertained through two consecutive viral loads > 5000 copies/ml, and the standard second-line treatment offered comprised ddi/azt/lopinavir/ritonavir (LPV/r), 15 3TC replacing ddi in TDF replaced d4t in the first-line regimen in 2010, and FTC replaced 3TC between 2012 and 2013 with the phased introduction of a fixed-dose combination (Figure 1). 16 Among all adult patients alive and in care in mid 2012, 1579 (8%) were documented to be on one of the standard second-line regimens. From 2002, donor-provided paediatric ART regimens comprised AZT, 3TC and NVP, with ritonovir as an alternative for PMTCT-exposed children or those on concurrent TB treatment. 17 From the end of 2003, LPV/r became available, and the government started to provide paediatric ART in 2004, these guidelines stipulating ART containing d4t, 3TC and LPV/r for children < 3 years or d4t, 3TC and EFV in children >3 years old. 18 In 2010, national guidelines recommended abacavir (ABC), 3TC and LPV/r in children aged < 3 years or weighing 10 kg, and ABC, 3TC and EFV in older children. Those on d4twith no side effects were to continue, with ABC substituted for indications of lipodystrophy. The evolution of regimen guidelines and the uptake of these are reflected in Table 1 and Figure 1, respectively. Laboratory monitoring The initial protocol for monitoring CD4 count and viral load provided for baseline and 6-monthly measurements, with an additional viral load measurement after 3 months on ART. The baseline viral load was dropped in 2006 in treatmentnaïve adults, together with the 3-month viral load measurement in all patients. From 2010 onwards, the 6-month viral loadmonitoringwasshiftedto4monthsonart,toprovide earlier identification of poorly adherent patients. From 2013, the 6-month CD4 count was dropped together with CD4 counts beyond the first year on ART, and viral load monitoring beyond 1 year on ART was reduced to annual measurements. Safety monitoring has been aligned with regimens and has included alanine-transferase (NVP), creatinine (TDF) and haemoglobin monitoring (AZT). Adherence support Khayelitsha is frequently cited for the adherence support package for patients, which has evolved over time. Initial models of adherence support were patient-centred, including the recommendation of a treatment supporter (friend

3 Table 1. Eligibility and management over time Guideline version May 2001 Apr 2004 Apr 2010 Apr 2013 Adults Eligibility Stage WHO IV (excluding EPTB) WHO IV (excluding EPTB) WHO IV WHO III or IV CD4 count 200 cells/ml 200 cells/ul 350/ml for TB/pregnancy 350/ml in other adults 200/ml in other adults Other MDR/XDR TB Sero-discordant couples All with TB/pregnancy or breastfeeding Regimen First-line AZT,3TC,NVPjEFV a d4t,3tc,nvpjefv b TDF,FTCj3TC,EFVjNVP FDC (TDF,FTC,EFV) preferred Second-line d4t,ddi,nfvjidvjsqv a AZT,ddI,LPV/r TDFjAZT,3TCjFTC,LPV/r f Unchanged Third-line RAL,DVR/r,ETR g Children Eligibility Stage Modified WHO II/III Stage III or IV Stage III or IV CD4 count < 20% (< 18 m) or < 25% or < 750/ml (1 5 yo) < 15% (> ¼ 18 m) < 350/ml (> ¼ 5 yo) < 350/ml (> ¼ 5 yo) Other Prolonged or recurrent All children < 1 year old h All children <5 years old hospitalization Regimen First-line AZTjd4T,3TC,NVPjEFV a d4tjazt,3tc,rtvjlpv/r c ABC,3TC,LPV/rjEFV (>36 m) ABC,3TC,LPV/rjEFV (> 36 m) Second-line AZTjABC,ddI,NVPjEFV c AZT,3TCjddI,LPV/r AZT,3TCjABC,LPV/r Third-line Specialist referral Monitoring Viral load Baseline, 3, 6, 12 m and annual Baseline, 6, 12 m and annual d 6 m, 12 m and annual 4 m, 12 m, and annual CD4 count Baseline, 6, 12 m and annual Baseline, 6, 12 m and annual Unchanged Baseline, 6 m, 12 m i Failure definition 2 x VL > ¼ 5000/ml 2 x VL > ¼ 400/ml, 2nd > ¼ 5000/ml e 2xVL> ¼ 1000 VL, viral load; m, months; yo, years old; EPTB, extrapulmonary tuberculosis. a Regimens were changed in Khayelitsha to the pending national guidelines in September Weight-based dosing used in children from 2003 onwards wherever possible. b Tenofovir available from mid 2008 for patients with lactic acidosis (lactate > ¼ 5 mmol/l) or toxicity to both AZT and d4t. c d4t & AZT for those with fridges and LPV/r where children were > ¼ 6 months old. Many Khayelitsha children continued to receive NVP instead of a protease inhibitor unless there was known PMTCT exposure. d Baseline viral load was dropped for treatment-naïve adults in e Clinical, immunological and virological criteria were all considered appropriate failure definitions for children in this guideline, which was tolerant to ongoing viraemia if immunological and clinical responses were good. Atazanavir introduced in 2011 for patients who could not tolerate LPV/r or where it was contra-indicated. g Available only on approval of a national committee, tailored based on resistance testing. h Changed to all children < 2 years old in CD4 counts not routinely measured beyond a year on ART if > ¼.200 cells/ml at 1 year. TB, tuberculosis; EPTB, extrapulmonary tuberculosis; MDR, multi drug-resistant; XDR, extensively drug-resistant; AZT, zidovudine; 3TC, lamivudine; NVP, nevirapine; IDV, indinavir; NFV, nelfinavir; SQV, saquinavir; d4t, stavudine; ddi, didanosine; LPV/r, ritonavir-boosted lopinavir; TDF, tenofovir; FTC, emtricitabine; RAL, raltegravir; DVR/r, rintovir-boosted duranavir; ETR, etravirine; ABC, abacavir. f i International Journal of Epidemiology, 2017, Vol. 46, No. 2 3

4 4 International Journal of Epidemiology, 2017, Vol. 46, No. 2 Propor on of pa ent s on different component drugs of the regimen First NRTI Second NRTI NNRTI or family member with knowledge of the person s HIV status), a home visit before ART initiation, and participation in peer support groups held twice-monthly. 19,20 These were relaxed with treatment scale-up, which necessitated a less intensive adherence support model. Since 2011, a group-based adherence support model adherence clubs has been implemented for chronic stable patients to make it easier to access ongoing ART care and treatment and relieve service burden. These clubs meet on average five times a year (every 2 months, except over year-end), and are managed by lay health workers, with annual laboratory monitoring tests and clinician review. 14,21 How often are patients followed up? The cohort study records all routine health service visits. The frequency of patient visits has declined over time. Initially patients were seen weekly for the first 2 weeks, then fortnightly until 8 weeks and then monthly. Currently patients are seen monthly until stable, then every 2 3 months. Club patients constitute an ever-growing proportion of the cohort, amounting to 18% of patients in care at 162 clubs associated with Khayelitsha services at the end of June 2012, with 26% of patients in clubs in June The systems in use are able to identify patients who have missed appointments by more than 14 days (in order to retain them in care) or have been lost to follow-up, operationally defined as no visit being recorded for 90 days or more. Analytically, a wider window of 180 days without a visit is often used for defining loss to follow-up. Formal analyses are typically closed before database closure in order to enable each patient to have the opportunity to meet the loss to follow-up definition Patients are NRTI Nucleoside/ de reverse-transcriptase inhibitor NNRI Non-nucleoside reverse-transcriptase inhibitor Figure 1. Uptake of first line ART regimens over time in adults, recorded as lost to follow-up for a variety of reasons, including unascertained mortality or transfer, failure of clerical systems to record patients who are in care, or true loss to follow-up. 26,27 Patients who are lost to follow-up are much more likely to have died, have lower CD4 counts or be viraemic at the time of loss. 28 The operational capacity to recall patients to care has declined over time, from having dedicated resources to trace patients in the community, to only limited facility-level resources to phone patients and try to re-engage them in care. Whereas, in the early years of the cohort, missing data were verified to be missing through re-review of source patient records, data completeness is currently maximized where possible through linkage to other electronic data sources as described below. What has been measured? Data systems Nevirapine Efavirenz Lamivudine Zidovudine Stavudine Tenofovir This Figure demonstrates the evolution in the prescribing of regimens in response to changing guidelines as reflected in Table 1, restricted to adult patients for illustrative purposes. From the cohort s inception, patient demographics and clinical status at ART initiation and subsequent clinical and laboratory data have been routinely collected by service staff based on standardized clinical records which are captured into an online electronic patient information system after each consultation. Data are validated for coherency, and where potential errors are identified, are checked against source records. Clinical follow-up data comprise weight, WHO stage, HIV-associated and stage-defining comorbidities, ART regimens and prophylactic drugs. Initially all drug-related adverse events were collected, but currently only treatment-limiting toxicities are reflected through the reasons for regimen substitution (Table 2). The electronic patient information system has been in place since inception at the three original clinics. These

5 International Journal of Epidemiology, 2017, Vol. 46, No. 2 5 Table 2. Routinely collected data for patients initiated on ART Patient-level data Administrative and demographic data o Gender and date of birth o Identifiers including names, addresses, contact details and the South African civil identification number are available in the patient information system for use by service staff, but are not included in cohort datasets which are anonymized Clinical data o Provision is made for recording stage-defining illnesses prior to registration a Visit-level data Visit date and next appointment date Clinical observations and findings o TB screening; b height and weight; a WHO clinical stage o Stage-defining comorbidities a o Pregnancy o Treatment-limiting toxicities and adverse events a Laboratory tests c o CD4 count and viral load o Full blood count; liver and renal function tests o Microbiological tests including for TB Medication o Antiretrovirals prescribed recorded by individual drug o Duration of antiretroviral prescription o Antiretroviral dosage a o Prophylactic drugs such as co-trimoxazole, isoniazid and fluconazole a o Reasons for regimen substitution a o Drug-related adverse events a,d a Only in the original three sites. b Only in the largest single site. c Available electronically since d Only reliably recorded in first 5 years. data have been the source of historical cohort publications and contributions to collaborative datasets. Since 2006, eight additional sites have started offering ART and have provided patient-level data from a separate information system via quarterly dispatches, which are merged with the online data to create a sub-district-level cohort dataset. Patient movements between facilities can be identified before anonymization through the availability of a shared unique patient identifier in use by the patient registration systems in each facility, linked to the provincial hospital information system master patient index. More recently, electronic linkage to the South African vital registration system and results from laboratory services have enhanced outcome ascertainment and strengthened data completeness. 29,30 Major findings to date Patient characteristics over time From January 2001 until end-december 2012, treatment-naïve patients enrolled for ART. Half of the patients had enrolled in the first 9 years of the programme ( by the end of 2009). Mothers constituted a large proportion of the first patients referred to ART services before national ART scale up in 2004, due to the earlier introduction of PMTCT. Women have continued to constitute two-thirds of the cohort over time, being younger at enrolment than men (median age 31 vs 36 years, P < 0.001). Children under 16 years of age comprise 4% of the cohort enrolments (n ¼ 1 327), with the median age at enrolment being 3 years [interquartile range (IQR): 1 7 years]. Wheras there has been a proportional decrease over time in paediatric ART enrolment as a result of effective PMTCT and greater adult enrolment (Table 3), there has been an absolute increase in paediatric ART enrolments due to increasing coverage and a shift from hospital to primary-care paediatric ART initiation. Median baseline CD4 cell count in adults during this period (present for 84% of the cohort), rose from 57 cells/ ll (IQR: cells/ll) between 2001 and 2003 to 136 cells/ll (IQR: cells/ll) between 2007 and 2009 and to 221 cells/ll (IQR: cells/ll) in 2012, reflecting both increasing enrolment and South African national

6 6 International Journal of Epidemiology, 2017, Vol. 46, No. 2 Table 3. Characteristics of patients initiating ART, Calendar period of starting ART Total N (%) % % % % Adult ( 16 years) n (%) % % % % % Median age (years, IQR) 33 (28 39) 31 (28 37) 33 (28 39) 33 (28 39) 33 (27 39) Male (%) % % % % % Median baseline CD4 count 146 (72 214) 57 ( ) 98 (44 159) 136 (67 191) 182 (99 256) Paediatric (< 16 years) n (%) % 76 10% 311 6% 427 4% 513 3% Age (n, %) (0 4 years) % 36 47% % % % (5 9 years) % 28 37% 93 30% % % (10 15 years) % 12 16% 22 7% 65 15% % Median age (years, IQR) 3 (1 7) 5 (3 7) 3 (1 6) 3 (1 7) 4 (0 9) Male (n, %) % 43 57% % % % Baseline immune suppression (n, %) % 50 66% % % % Median CD4, cells/μl Year of ART ini a on 124 National ART program launch Initiation threshold at CD4 of 350 for all and all TB co-infected irrespective of CD Initiation threshold at CD4 of 350 for pregnant and TB co-infected patients First public sector programs, CD4 initiation threshold of 200 cells/µl or WHO stage IV Adults ini a ng ART Figure 2. Median CD4 cell count at ART initiation, Khayelitsha, ART-naïve adults. 221 guideline changes in CD4 threshold over time (Figure 2). Baseline CD4 trends in children show a significant decrease in the proportion of children with severe immune suppression between 2001 and 2007 (66% to 39%, measured using age-specific thresholds and applying WHO guidelines), 31 this decreasing to 31% between 2010 and 2012 (v 2 P < 0.001). The proportion of patients with TB at enrolment peaked in 2009 at 42%, declining thereafter to 27% in 2012, reflecting shifting dynamics in portals of entry to ART care and the level of immunosuppression at ART initiation. Percentage of co-infection reflects three of the 11 sites. The remaining eight sites collected reliable TB co-infection data prospectively from Virological status measured at mid 2012 shows that 53% of patients were confirmed to be suppressed in the previous 12 months, and that a further 27% were suppressed with their last measurement more than 12 months previously; 6% were viraemic or failing treatment within

7 International Journal of Epidemiology, 2017, Vol. 46, No. 2 7 the previous year, 2% had previously been viraemic or failing without subsequent testing and 12% had not yet had a viral load test. Of patients on first-line and second-line regimens. 55% and 47%, respectively, had documented virological suppression within the past year. The cumulative proportion of patients retained across all years was 65% at 5 years and 53% at 10 years. In line with the initial intention of the cohort, to help demonstrate the feasibility and effectiveness of ART in high-burden African settings, the cohort has published on survival, virological and immunological successes, and associations with these, in highly cited papers in 2004 and 2010 which followed patients to 2 years and 5 years, respectively. 14,32 The cohort has also played an important part in describing comparative outcomes between settings, as part of collaborative analyses, followed to 1, 2 and 4 years respectively, helping characterize the high early mortality on ART in the setting, but also the subsequent attenuation or reversal of this differential at longer durations on ART. 35 Further collaborative analyses have helped develop prognostic models for the setting, 36 estimate life expectancy 37 and describe gender differentials in outcomes, 38 among many others as part of the ART-LINC and IeDEA collaborations. 39,40 The cohort has also helped: inform programme clinical design through analyses which demonstrated the toxicity of d4t when used in the early years of the programme 41 and inferior virological outcomes when rifampicin and NVP were co-administered in patients co-infected with tuberculosis; 42 explore the need for safety monitoring of NVP; 43 validate an approach to empirical tuberculosis treatment; 44 describe the relative contribution of ART and other interventions to the treatment response of Kaposi s sarcoma; 45 and demonstrate the adherence value of early viral load measurement. 46 The cohort also formed the backbone of a nested clinical trial demonstrating the added value of isoniazid preventive therapy in addition to ART. 47 The cohort has pioneered service delivery approaches, the early publications validating the patient-centred public health approach, and subsequent analyses demonstrating the safety and effectiveness of non-clinical adherence clubs. 48 The ability to differentiate true losses to care from unascertained mortality helped identify categories of patients at high risk of true loss, such as those initiating ART at higher CD4 counts and pregnant women. 49 What are the main strengths and weaknesses? As one of the longstanding and largest treatment cohorts in Southern Africa, Khayelitsha continues to be at the forefront of clinical and service innovation. It remains well placed to answer epidemiological, clinical and health service research questions related to mature ART programmes in the region, and the emergent challenges related to the ever-increasing service burden. The inclusion more recently of newer treatment facilities creates the opportunity to reflect on treatment throughout the Khayelitsha sub-district, overcoming some of the limitations of cohorts restricted to individual facilities. A limitation of the cohort is that, in many instances, pre-art data are limited to laboratory-ascertained CD4 counts before enrolment at an ART clinic. Although the abilitytolinktomortality,laboratory and hospital databases provides important opportunities for current and future work, the quality of ascertainment of comorbidities has declined with increasing programme size. The services comprising the cohort are now fully governmentrun, which also creates some vulnerability to staff, management and infrastructure challenges to the routine monitoring. Can I get hold of the data? Where can I find out more? The cohort dataset is curated by the University of Cape Town, and analyses are produced in collaboration with stakeholders from MSF, and with the health services of the Provincial Government of the Western Cape (PGWC) and the City of Cape Town metropolitan government, who fully fund all aspects of treatment provision. The cohort is also a key contributor to collaborative analyses, including the International Epidemiological Databases to Evaluate AIDS (IeDEA) Southern Africa collaboration. 39 For analysis, data are stripped of identifiers and patient consent is not requested as the data are all considered routinely collected data as part of standard-of-care service provision. Approval to perform routine data analysis has been granted by the Human Research Ethics Committee, University of Cape Town. Requests for external collaboration are welcomed, and decisions about participation in analyses and sharing of data are taken jointly by government, UCT and MSF collaborators on the cohort study. Enquiries related to data access or collaborative studies should be directed to the principal investigator [andrew.boulle@uct.ac.za]. Profile in a Nutshell One of the oldest and largest antiretroviral treatment (ART) programmes in South Africa, the Khayelitsha cohort was set up to demonstrate the feasibility of scale-up of primary-level ART services in a high-burden HIV setting.

8 8 International Journal of Epidemiology, 2017, Vol. 46, No. 2 Started in 2001, the cohort enrolled more than children and adults on ART by the end of 2014, in 11 facilities. Follow-up is routinely monitored through an electronic platform. Patients are defined as lost to follow-up for a variety of reasons, including unascertained mortality or transfer, failure of clerical systems to record patients who are in care, or true loss to follow-up. The cumulative proportion of patients retained to end-2012 is 65% at 5 years and 53% at 10 years. The data set comprises socio-demographic variables, visits and drug dispensing, and clinical outcomes with additional linkage to centralized laboratory results and the death registry. Funding Whereas initially MSF funded antiretrovirals, laboratory monitoring and key clinical and clerical staff, now the services are entirely funded by government, with limited support from MSF for service innovations. Research support to the cohort is currently funded by IeDEA and MSF, and the University of Cape Town also receives funding through the Global Fund for AIDS, Tuberculosis and Malaria in support of routine functioning of HIV and tuberculosis information systems. Conflict of interest: No conflicts of interest were reported by any of the authors. References 1. City of Cape Town Strategic Development Information and GIS Department Census Suburb Description: Khayelitsha. Cape Town: Strategic Development Information and GIS Department, National Department of Health. The 2012 National Antenatal Sentinel HIV & Herpes Simplex Type-2 Prevalence Survey in South Africa Pretoria. Pretoria, South Africa: National Department of Health, Coetzee D, Hilderbrand K, Boulle A, Draper B, Abdullah F, Goemaere E. Effectiveness of the first district-wide programme for the prevention of mother-to-child transmission of HIV in South Africa. Bull World Health Organ 2005;83: World Health Organization. Antiretroviral Therapy in Primary Health Care: Experience of the Khayelitsha Programme in South Africa. Geneva: World Health Organization, Gilks C, AbouZhar C, Türmen T. HAART in Haiti - evidence needed. Bull World Health Organ 2001;79: Harries A, Nyangulu D, Hargreaves N, Kaluwa O, Salaniponi F. Preventing antiretroviral anarchy in sub-saharan Africa. Lancet 2001;358: Horton R. African AIDS beyond Mbeki: tripping into anarchy. Lancet 2000;356: Coetzee D, Hildebrand K, Boulle A et al. Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa. AIDS 2004;18: Médecins Sans Frontières, Western Cape Province Department of Health, City of Cape Town Department of Health, Centre for Infectious Disease Epidemiology and Research UoCT. Khayelitsha : 10 Years Of HIV/TB Care at Primary Health Care Level. Khayelitsha, South Africa: Médecins Sans Frontières, National Department of Health. National Consolidated Guidelines for the Prevention of Mother-to-child Transmission of HIV (PMTCT) and the Management of HIV in Children, Adolescents and Adults. Pretoria, South Africa: National Department of Health, Meyers T, Moultrie H, Naidoo K, Cotton M, Eley B, Sherman G. Challenges to pediatric HIV care and treatment in South Africa. J Infect Dis 2007;196(Suppl 3):S World Health Organization. Antiretroviral Therapy of HIV Infection in Infants and Children: Towards Universal Access. Recommendations for a Public Health Approach. Geneva: World Health Organization, National Department of Health. Initiation of Antiretroviral Treatment to All HIV-Positive Children Aged 5 Years and Under Regardless of CD4 Count and/or WHO Clinical Staging. Pretoria, South Africa: National Department of Health, Boulle A, Van Cutsem G, Hilderbrand K et al. Seven-year experience of a primary care antiretroviral treatment programme in Khayelitsha, South Africa. AIDS 2010;24: Van Cutsem G, Hilderbrand K, Coetzee D et al., s(eds). Outcomes and emerging challenges after 5 years of ART in Khayelitsha, South Africa. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, February Center for HIV Information, University of California, San Francisco, CA, National Department of Health. Clinical Guidelines for the Management of HIV & AIDS in Adults and Adolescents. Pretoria, South Africa: South African NAtional AIDS Council, Jaspan HB, Berrisford AE, Boulle AM. Two-year outcomes of children on non-nucleoside reverse transcriptase inhibitor and protease inhibitor regimens in a South African pediatric antiretroviral program. Pediatr Infect Dis J 2008;27: National Department of Health. National Antiretroviral Treatment Guidelines. 1st edn. Pretoria, South Africa: National Department of Health, Médecins Sans Frontières, University of CapeTown Department of Public Health, Provincial Administration of the Western Cape SA. Antiretroviral Therapy in Primary Health Care: The experience of the Khayelitsha Programme in South Africa. Case Study. Geneva: World Health Organization, Coetzee D, Boulle A, Hildebrand K, Asselman V, Van Cutsem G, Goemaere E. Promoting adherence to antiretroviral therapy: the experience from a primary care setting in Khayelitsha, South Africa. AIDS 2004;18:S Luque-Fernandez MA, Van Cutsem G, Goemaere E et al. Effectiveness of patient adherence groups as a model of care for stable patients on antiretroviral therapy in Khayelitsha, Cape Town, South Africa. PLoS One 2013;8:e Wilkinson LS. ART adherence clubs: A long-term retention strategy for clinically stable patients receiving antiretroviral therapy. S Afr J HIV Med 2013;14: Grimsrud AT, Cornell M, Egger M, Boulle A, Myer L. Impact of definitions of loss to follow-up (LTFU) in antiretroviral therapy

9 International Journal of Epidemiology, 2017, Vol. 46, No. 2 9 program evaluation: variation in the definition can have an appreciable impact on estimated proportions of LTFU. J Clin Epidemiol 2013;66: Shepherd BE, Blevins M, Vaz LM et al. Impact of definitions of loss to follow-up on estimates of retention, disease progression, and mortality: Application to an HIV program in Mozambique. Am J Epidemiol 2013;178: Chi BH, Yiannoutsos CT, Westfall AO et al. Universal definition of loss to follow-up in HIV treatment programs: a statistical analysis of 111 facilities in Africa, Asia, and Latin America. PLoS Med 2011;8:e Egger M, Spycher BD, Sidle J et al. Correcting mortality for loss to follow-up: a nomogram applied to antiretroviral treatment programmes in Sub-Saharan Africa. PLoS Med 2011;8:e Cornell M, Lessells R, Fox MP et al. Mortality among adults transferred and lost to follow-up from antiretroviral therapy programmes in South Africa: a multicentre cohort study. 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