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Article Reference Adherence to antiretroviral therapy in young children in Cape Town, South Africa, measured by medication return and caregiver self-report: a prospective cohort study
BACKGROUND Antiretroviral therapy (ART) dramatically improves outcomes for children in Africa; however excellent adherence is required for treatment success. This study describes the utility of different measures of adherence in detecting lapses in infants and young children in Cape Town, South Africa. METHODS In a prospective cohort of 122 HIV-infected children commenced on ART, adherence was measured monthly during the first year of treatment by medication return (MR) for both syrups and tablets/capsules. A questionnaire was administered to caregivers after 3 months of treatment to assess experience with giving medication and self-reported adherence. Viral and immune response to treatment were assessed at the end of one year and associations with measured adherence determined. RESULTS Medication was returned for 115/122 (94\%) children with median age (IQR) of 37 (16-61) months. Ninety-one (79\%) children achieved annual average MR adherence or = 90\%. This was an important covariate associated with viral suppression after adjustment for disease severity (OR = 5.5 [95\%CI: 0.8-35.6], p = 0.075), however was not associated with immunological response to ART. By 3 months on ART, 13 (10\%) children had deceased and 11 (10\%) were lost to follow-up. Questionnaires were completed by 87/98 (90\%) of caregivers of those who remained in care. Sensitivity of poor reported adherence (missing or = 1 dose in the previous 3 days) for MR adherence 90\% was only 31.8\% (95\% CI: 10.7\%-53.0\%). Caregivers of 33/87 (38.4\%) children reported difficulties with giving medication, most commonly poor palatability (21.8\%). Independent socio-demographic predictors of MR adherence or = 90\% were secondary education of caregivers (OR = 4.49; 95\%CI: 1.10-18.24) and access to water and electricity (OR = 2.65; 95\%CI: 0.93-7.55). Taking ritonavir was negatively associated with MR adherence or = 90\% (OR = 0.37; 95\%CI: 0.13-1.02). CONCLUSION Excellent adherence to ART is possible in African infants and young children and the relatively simple low technology measure of adherence by MR strongly predicts viral response. Better socio-economic status and more palatable regimens are associated with better adherence.
Article Reference Assessing the contribution of the immune reconstitution inflammatory syndrome to mortality in developing country antiretroviral therapy programs
Article Reference Authors' response: the importance of asking the right question
Article Reference Defaulting from antiretroviral treatment programmes in sub-Saharan Africa: a problem of definition
Article Reference Early mortality and loss to follow-up in HIV-infected children starting antiretroviral therapy in Southern Africa
BACKGROUND Many HIV-infected children in Southern Africa have been started on antiretroviral therapy (ART), but loss to follow up (LTFU) can be substantial. We analyzed mortality in children retained in care and in all children starting ART, taking LTFU into account. PATIENTS AND METHODS Children who started ART before the age of 16 years in 10 ART programs in South Africa, Malawi, Mozambique, and Zimbabwe were included. Risk factors for death in the first year of ART were identified in Weibull models. A meta-analytic approach was used to estimate cumulative mortality at 1 year. RESULTS Eight thousand two hundred twenty-five children (median age 49 months, median CD4 cell percent 11.6\%) were included; 391 (4.8\%) died and 523 (7.0\%) were LTFU in the first year. Mortality at 1 year was 4.5\% [95\% confidence interval (CI): 2.8\% to 7.4\%] in children remaining in care, but 8.7\% (5.4\% to 12.1\%) at the program level, after taking mortality in children and LTFU into account. Factors associated with mortality in children remaining in care included age [adjusted hazard ratio (HR) 0.37; 95\% CI: 0.25 to 0.54 comparing or =120 months with 18 months], CD4 cell percent (HR: 0.56; 95\% CI: 0.39 to 0.78 comparing or =20\% with 10\%), and clinical stage (HR: 0.12; 95\% CI: 0.03 to 0.45 comparing World Health Organization stage I with III/IV). CONCLUSIONS In children starting ART and remaining in care in Southern Africa mortality at 1 year is 5\% but almost twice as high at the program level, when taking LTFU into account. Age, CD4 percentage, and clinical stage are important predictors of mortality at the individual level.
Article Reference Electronic medical record systems, data quality and loss to follow-up: survey of antiretroviral therapy programmes in resource-limited settings
OBJECTIVE To describe the electronic medical databases used in antiretroviral therapy (ART) programmes in lower-income countries and assess the measures such programmes employ to maintain and improve data quality and reduce the loss of patients to follow-up. METHODS In 15 countries of Africa, South America and Asia, a survey was conducted from December 2006 to February 2007 on the use of electronic medical record systems in ART programmes. Patients enrolled in the sites at the time of the survey but not seen during the previous 12 months were considered lost to follow-up. The quality of the data was assessed by computing the percentage of missing key variables (age, sex, clinical stage of HIV infection, CD4+ lymphocyte count and year of ART initiation). Associations between site characteristics (such as number of staff members dedicated to data management), measures to reduce loss to follow-up (such as the presence of staff dedicated to tracing patients) and data quality and loss to follow-up were analysed using multivariate logit models. FINDINGS Twenty-one sites that together provided ART to 50 060 patients were included (median number of patients per site: 1000; interquartile range, IQR: 72-19 320). Eighteen sites (86\%) used an electronic database for medical record-keeping; 15 (83\%) such sites relied on software intended for personal or small business use. The median percentage of missing data for key variables per site was 10.9\% (IQR: 2.0-18.9\%) and declined with training in data management (odds ratio, OR: 0.58; 95\% confidence interval, CI: 0.37-0.90) and weekly hours spent by a clerk on the database per 100 patients on ART (OR: 0.95; 95\% CI: 0.90-0.99). About 10 weekly hours per 100 patients on ART were required to reduce missing data for key variables to below 10\%. The median percentage of patients lost to follow-up 1 year after starting ART was 8.5\% (IQR: 4.2-19.7\%). Strategies to reduce loss to follow-up included outreach teams, community-based organizations and checking death registry data. Implementation of all three strategies substantially reduced losses to follow-up (OR: 0.17; 95\% CI: 0.15-0.20). CONCLUSION The quality of the data collected and the retention of patients in ART treatment programmes are unsatisfactory for many sites involved in the scale-up of ART in resource-limited settings, mainly because of insufficient staff trained to manage data and trace patients lost to follow-up.
Article Reference Paediatric antiretroviral treatment programmes in sub-Saharan Africa: a review of published clinical studies
Knowledge of the experience and outcomes of current paediatric antiretroviral treatment (ART) programmes in sub-Saharan Africa can inform new programmes in the region as well as enhance existing ones. This is urgently needed to facilitate the scale-up of treatment, which is needed to address the burden of paediatric HIV cases on the continent. We reviewed the characteristics and outcomes of programmes with clinical paediatric ART studies published prior to 1 January 2008. The outcomes of the studies were comparable to similar ones from developed countries; however, the duration of follow-up was relatively limited in almost all the studies reviewed. One-year survival probability was between 84\% and 91\%, and considerable improvement in the clinical, immunologic and viral status of the paediatric patients was generally recorded. Loss to follow-up was less than 10\% in all but two studies. Adherence to treatment was good and few adverse events were reported. This is despite the fact that many programmes were subject to enormous constraints in terms of health services, and despite widespread use of adult fixed-dose combinations for paediatric patients, including young infants. While the majority of children commencing ART were severely ill, most children were old (median age 5 years for almost all studies) with relatively few infants and young children (age
Article Reference Public-health and individual approaches to antiretroviral therapy: township South Africa and Switzerland compared
BACKGROUND The provision of highly active antiretroviral therapy (HAART) in resource-limited settings follows a public health approach, which is characterised by a limited number of regimens and the standardisation of clinical and laboratory monitoring. In industrialized countries doctors prescribe from the full range of available antiretroviral drugs, supported by resistance testing and frequent laboratory monitoring. We compared virologic response, changes to first-line regimens, and mortality in HIV-infected patients starting HAART in South Africa and Switzerland. METHODS AND FINDINGS We analysed data from the Swiss HIV Cohort Study and two HAART programmes in townships of Cape Town, South Africa. We included treatment-naïve patients aged 16 y or older who had started treatment with at least three drugs since 2001, and excluded intravenous drug users. Data from a total of 2,348 patients from South Africa and 1,016 patients from the Swiss HIV Cohort Study were analysed. Median baseline CD4+ T cell counts were 80 cells/mul in South Africa and 204 cells/mul in Switzerland. In South Africa, patients started with one of four first-line regimens, which was subsequently changed in 514 patients (22\%). In Switzerland, 36 first-line regimens were used initially, and these were changed in 539 patients (53\%). In most patients HIV-1 RNA was suppressed to 500 copies/ml or less within one year: 96\% (95\% confidence interval [CI] 95\%-97\%) in South Africa and 96\% (94\%-97\%) in Switzerland, and 26\% (22\%-29\%) and 27\% (24\%-31\%), respectively, developed viral rebound within two years. Mortality was higher in South Africa than in Switzerland during the first months of HAART: adjusted hazard ratios were 5.90 (95\% CI 1.81-19.2) during months 1-3 and 1.77 (0.90-3.50) during months 4-24. CONCLUSIONS Compared to the highly individualised approach in Switzerland, programmatic HAART in South Africa resulted in similar virologic outcomes, with relatively few changes to initial regimens. Further innovation and resources are required in South Africa to both achieve more timely access to HAART and improve the prognosis of patients who start HAART with advanced disease.
Article Reference Retention among adults initiating antiretroviral therapy in South Africa: 2002-2007
Article Reference Substitutions due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large South African cohort
INTRODUCTION The patterns and reasons for antiretroviral therapy (ART) drug substitutions are poorly described in resource-limited settings. METHODS Time to and reason for drug substitution were recorded in treatment-naive adults receiving ART in two primary care treatment programmes in Cape Town. The cumulative proportion of patients having therapy changed because of toxicity was described for each drug, and associations with these changes were explored in multivariate models. RESULTS Analysis included 2,679 individuals followed for a median of 11 months. Median CD4+ T-cell count at baseline was 85 cells/microl. Mean weight was 59 kg, mean age was 32 years and 71\% were women. All started non-nucleoside reverse transcriptase inhibitor-based ART (60\% on efavrienz) and 75\% started on stavudine (d4T). After 3 years, 75\% remained in care on-site, of whom 72\% remained on their initial regimen. Substitutions due to toxicity of nevirapine (8\% by 3 years), efavirenz (2\%) and zidovudine (8\%) occurred early. Substitutions on d4T occurred in 21\% of patients by 3 years, due to symptomatic hyperlactataemia (5\%), lipodystrophy (9\%) or peripheral neuropathy (6\%), and continued to accumulate over time. Those at greatest risk of hyperlactataemia or lipodystrophy were women on ART or =6 months, weighing or =75 kg at baseline. DISCUSSION A high proportion of adult patients are able to tolerate their initial ART regimen for up to 3 years. In most instances treatment-limiting toxicities occur early, but continue to accumulate over time in patients on d4T. Whilst awaiting other treatment options, the risks of known toxicities could be minimized through early identification of patients at the highest risk.
Article Reference Temporal changes in programme outcomes among adult patients initiating antiretroviral therapy across South Africa, 2002-2007
OBJECTIVE Little is known about the temporal impact of the rapid scale-up of large antiretroviral therapy (ART) services on programme outcomes. We describe patient outcomes [mortality, loss-to-follow-up (LTFU) and retention] over time in a network of South African ART cohorts. DESIGN Cohort analysis utilizing routinely collected patient data. METHODS Analysis included adults initiating ART in eight public sector programmes across South Africa, 2002-2007. Follow-up was censored at the end of 2008. Kaplan-Meier methods were used to estimate time to outcomes, and proportional hazards models to examine independent predictors of outcomes. RESULTS Enrolment (n = 44 177, mean age 35 years; 68\% women) increased 12-fold over 5 years, with 63\% of patients enrolled in the past 2 years. Twelve-month mortality decreased from 9\% to 6\% over 5 years. Twelve-month LTFU increased annually from 1\% (2002/2003) to 13\% (2006). Cumulative LTFU increased with follow-up from 14\% at 12 months to 29\% at 36 months. With each additional year on ART, failure to retain participants was increasingly attributable to LTFU compared with recorded mortality. At 12 and 36 months, respectively, 80 and 64\% of patients were retained. CONCLUSION Numbers on ART have increased rapidly in South Africa, but the programme has experienced deteriorating patient retention over time, particularly due to apparent LTFU. This may represent true loss to care, but may also reflect administrative error and lack of capacity to monitor movements in and out of care. New strategies are needed for South Africa and other low-income and middle-income countries to improve monitoring of outcomes and maximize retention in care with increasing programme size.
Article Reference The impact of gender and income on survival and retention in a South African antiretroviral therapy programme
OBJECTIVES Despite the rapid expansion of antiretroviral therapy (ART) services in Africa, there are few data on whether outcomes differ for women and men and what factors may drive such variation. We investigated the association of gender and income with survival and retention in a South African ART programme. METHODS A total of 2196 treatment-naïve adults were followed for 1 year on ART. Proportional hazards regression was used to explore associations between baseline characteristics and survival and loss-to-follow-up (LTFU). RESULTS Patients were predominantly female (67\%). Men presented at an older age and with more advanced HIV disease, and during early ART the crude death rate was higher among men than women (22.8 vs 12.5/100 person-years; P = 0.002). However in multivariate analysis, gender was not significantly associated with survival after adjusting for baseline clinical and immunovirological status (HR = 1.46, 95\% CI = 0.96-2.22; P = 0.076). In late ART (4-12 months), there was no gender difference in mortality rates (3.5 vs 3.8/100 person-years; P = 0.817). In multivariate analysis, survival was strongly associated with age (HR = 1.05, 95\% CI = 1.02-1.09; P 0.001), CD4 count 150 vs 50 cells/microl (HR = 0.35, 95\% CI = 0.14-0.87; P = 0.023) and any monthly income vs none (HR = 0.47, 95\% CI = 0.25-0.88; P = 0.018). Having some monthly income was protective against LTFU at 1 year on ART (adjusted HR = 0.56, 95\% CI = 0.39-0.82; P = 0.002). CONCLUSION Men's high early mortality on ART appears due largely to their presentation with more advanced HIV disease. Efforts are needed to enroll men into care earlier in HIV disease and to reduce socio-economic inequalities in ART programme outcomes.
Article Reference Time to Initiation of Antiretroviral Therapy Among Patients With HIV-Associated Tuberculosis in Cape Town, South Africa
We studied the time interval between starting tuberculosis treatment and commencing antiretroviral treatment (ART) in HIV-infected patients (n=1433; median CD4 count 71 cells/μL, IQR,32-132) attending three South African township ART services between 2002-2008. The overall median delay was 2.66 months (IQR,1.58-4.17). In adjusted analyses, delays varied between treatment sites but were shorter for patients with lower CD4 counts and those treated in more recent calendar years. During the most recent period (2007-2008), 4.7\%, 19.7\% and 51.1\% of patients started ART within 2, 4 and 8 weeks of TB treatment, respectively. Operational barriers must be tackled to permit further acceleration of ART initiation as recommended by 2010 WHO ART guidelines.
Article Reference Men and antiretroviral therapy in Africa: our blind spot
Most antiretroviral therapy (ART)-related policies remain blind to men's treatment needs. Global and national programmes need to address this blindness urgently, to ensure equitable access to ART in Africa.
Article Reference Monitoring the South African National Antiretroviral Treatment Programme, 2003-2007: the IeDEA Southern Africa collaboration
OBJECTIVES To introduce the combined South African cohorts of the International epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration as reflecting the South African national antiretroviral treatment (ART) programme; to characterise patients accessing these services; and to describe changes in services and patients from 2003 to 2007. DESIGN AND SETTING Multi-cohort study of 11 ART programmes in Gauteng, Western Cape, Free State and KwaZulu-Natal. SUBJECTS Adults and children (16 years old) who initiated ART with or =3 antiretroviral drugs before 2008. RESULTS Most sites were offering free treatment to adults and children in the public sector, ranging from 264 to 17,835 patients per site. Among 45,383 adults and 6,198 children combined, median age (interquartile range) was 35.0 years (29.8-41.4) and 42.5 months (14.7-82.5), respectively. Of adults, 68\% were female. The median CD4 cell count was 102 cells/microl (44-164) and was lower among males than females (86, 34-150 v. 110, 50-169, p0.001). Median CD4\% among children was 12\% (7-17.7). Between 2003 and 2007, enrolment increased 11-fold in adults and 3-fold in children. Median CD4 count at enrolment increased for all adults (67-111 cells/microl, p0.001) and for those in stage IV (39-89 cells/microl, p0.001). Among children 5 years, baseline CD4\% increased over time (11.5-16.0\%, p0.001). CONCLUSIONS IeDEA-SA provides a unique opportunity to report on the national ART programme. The study describes dramatically increased enrolment over time. Late diagnosis and ART initiation, especially of men and children, need attention. Investment in sentinel sites will ensure good individual-level data while freeing most sites to continue with simplified reporting.
Inproceedings Reference Mortality, loss to follow-up and transfer-out in paediatric ART programmes in Southern Africa
Background: Paediatric HIV infections in sub-Saharan Africa considerably increase mortality in African children. The aim of the present study was to describe the patient characteristics and to analyze mortality, loss to follow-up (LTFUP) and transfer-out (TO) among HIV-infected children on antiretroviral therapy (ART) in the IeDEA-Southern Africa collaboration, and to evaluate the effect on mortality assuming different mortality rates among LTFUP. Methods: Treatment-naïve children who started ART before the age of 16 years were included. A child was judged to be LTFUP if the last visit was more than 6 months before the closing date of the database. Weibull models were used to calculate crude mortality rates at one year after start of ART and assuming a mortality rate of 45\% among LTFUP. Results: A total of 9,460 HIV-infected children from 11 different cohorts in South Africa (77.2\%), Malawi, Mozambique and Zimbabwe were included. Overall, 5,228 (55.3\%) were younger than five years (range among cohorts 18.9\% to 78.7\%). Crude mortality at one year after start of ART ranged from 0.7\% to 17.7\% in children aged 5 years and from 0\% to 8.9\% in children ≥5 years. Corresponding figures for LTFUP were 1.9\% to 33.7\% (overall 13.3\%), and 0\% to 45.5\% for TO (overall 12.5\%). Assuming 45\% mortality among children LTFUP, mortality estimates at one year ranged from 1.5\% to 19.8\% in children aged 5 years and 0\% to 9.8\% in children ≥5 years. Conclusion: In children in Southern Africa, mortality at 1 year after starting ART varies widely and LTFUP may lead to underestimation of true mortality. The observed variation does not appear to be related to different rates of LTFUP suggesting the importance of programme- and individual-level factors. Therefore, dedicated sampling- or linkage-based field studies among children LTFUP or TO are needed.
Article Reference Outcomes of the South African National Antiretroviral Treatment Programme for children: the IeDEA Southern Africa collaboration
OBJECTIVES To assess paediatric antiretroviral treatment (ART) outcomes and their associations from a collaborative cohort representing 20\% of the South African national treatment programme. DESIGN AND SETTING Multi-cohort study of 7 public sector paediatric ART programmes in Gauteng, Western Cape and KwaZulu-Natal provinces. SUBJECTS ART-naive children ( or = 16 years) who commenced treatment with or = 3 antiretroviral drugs before March 2008. OUTCOME MEASURES Time to death or loss to follow-up were assessed using the Kaplan-Meier method. Associations between baseline characteristics and mortality were assessed with Cox proportional hazards models stratified by site. Immune status, virological suppression and growth were described in relation to duration of ART. RESULTS The median (interquartile range) age of 6 078 children with 9 368 child-years of follow-up was 43 (15 - 83) months, with 29\% being 18 months. Most were severely ill at ART initiation. More than 75\% of children were appropriately monitored at 6-monthly intervals with viral load suppression ( 400 copies/ml) being 80\% or above throughout 36 months of treatment. Mortality and retention in care at 3 years were 7.7\% (95\% confidence interval 7.0 - 8.6\%) and 81.4\% (80.1 - 82.6\%), respectively. Together with young age, all markers of disease severity (low weight-for-age z-score, high viral load, severe immune suppression, stage 3/4 disease and anaemia) were independently associated with mortality. CONCLUSIONS Dramatic clinical benefit for children accessing the national ART programme is demonstrated. Higher mortality in infants and those with advanced disease highlights the need for early diagnosis of HIV infection and commencement of ART.
Article Reference Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring
BACKGROUND In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia. DESIGN AND METHODS Multicohort study of 17 ART programmes. All sites monitored CD4 cell count and had access to second-line ART and 10 sites monitored viral load. We compared times to switching, CD4 cell counts at switching and obtained adjusted hazard ratios for switching (aHRs) with 95\% confidence intervals (CIs) from random-effects Weibull models. RESULTS A total of 20 113 patients, including 6369 (31.7\%) patients from 10 programmes with access to viral load monitoring, were analysed; 576 patients (2.9\%) switched. Low CD4 cell counts at ART initiation were associated with switching in all programmes. Median time to switching was 16.3 months [interquartile range (IQR) 10.1-26.6] in programmes with viral load monitoring and 21.8 months (IQR 14.0-21.8) in programmes without viral load monitoring (P 0.001). Median CD4 cell counts at switching were 161 cells/microl (IQR 77-265) in programmes with viral load monitoring and 102 cells/microl (44-181) in programmes without viral load monitoring (P 0.001). Switching was more common in programmes with viral load monitoring during months 7-18 after starting ART (aHR 1.38; 95\% CI 0.97-1.98), similar during months 19-30 (aHR 0.97; 95\% CI 0.58-1.60) and less common during months 31-42 (aHR 0.29; 95\% CI 0.11-0.79). CONCLUSION In resource-limited settings, switching to second-line regimens tends to occur earlier and at higher CD4 cell counts in ART programmes with viral load monitoring compared with programmes without viral load monitoring.