We analysed data from the Khayelitsha and Gugulethu HAART programmes in the Republic of South Africa, which are part of the International Epidemiological Databases to Evaluate AIDS in Southern Africa (IeDEA-SA), and made comparisons with the Swiss HIV Cohort Study (SHCS).
Khayelitsha and Gugulethu Cohorts, Cape Town, South Africa
Khayelitsha and Gugulethu are townships located within the Cape Town metropolitan area with estimated populations of 400,000 and 300,000 people, respectively. Khayelitsha had, in 1999, the first routine government-run programme for the prevention of mother-to-child transmission of HIV in South Africa. Antiretroviral treatment has been available since 2001 at three government clinics providing HIV care, supported by Médecins Sans Frontières. In Gugulethu the Usaphu Luwethu (“Our Family Clinic”) antiretroviral treatment programme was initiated by the Desmond Tutu HIV Centre in September 2002. Ten primary-care HIV clinics form the patient referral base.
Enrolment into treatment programmes follows the South African government's Department of Health national guidelines, which are based on the 2002 WHO recommendations [6
]. Individuals are eligible for treatment if they are in WHO stage 4 (with the exception of extrapulmonary tuberculosis, which is a stage 4–defining illness but not a criterion for starting therapy in the Western Cape) or have a CD4 count below 200 cells/μl. Data are collected prospectively using structured records completed at each consultation, including information on WHO stage-defining illnesses [7
In Khayelitsha, viral load assessments are performed routinely before starting HAART, after 3 mo, and then every 6 mo. In Gugulethu viral load is assessed before starting HAART and every 4-mo thereafter. Plasma viral load was measured using a branch DNA hybridization technique (Bayer HIV-1 RNA 3.0 assay, Leverkusen, Germany) or nucleic acid sequence-based amplification (Nuclisens EasyQ assay, bioMérieux, Boxtel, The Netherlands). In South Africa, provincial and national guidelines recommend switching drug regimens after two consecutive viral loads above 5,000 copies/ml, but patients were not necessarily switched when they fulfilled these criteria.
All treatment, clinic consultations, and laboratory work are free of charge. In both sites patients receive counselling and adherence support. Patients on HAART who miss appointments are contacted where possible, and if required, traced through home visits. More details on the Khayelitsha and Gugulethu cohorts are given elsewhere [8
Swiss HIV Cohort Study
Set up in 1988, the Swiss HIV Cohort Study is a national prospective cohort study of HIV-infected patients followed up at outpatient departments of five University hospitals (Basel, Bern, Geneva, Lausanne, and Zurich) and two Cantonal hospitals (Lugano and St. Gallen) in Switzerland. A comparison with official AIDS notifications and deaths indicated that about 70% of all patients living with AIDS in Switzerland participate in the study [10
Data collection and study procedures are standardised. Detailed information on demographics, mode of HIV acquisition, risk behaviours, clinical events, laboratory results, and treatments is collected at registration and then at intervals of 6 mo. HIV-1 RNA (Roche Amplicor HIV-1 Monitor assay), CD4 counts, and other laboratory parameters are measured at least every 3 mo. Clinical AIDS diagnoses (Centers for Disease Control and Prevention [CDC] stage C) are recorded by the treating physicians on the basis of the 1993 CDC criteria [11
]. The decision to change therapy was informed by the International AIDS Society-USA guidelines. All services, including antiretroviral therapy and laboratory testing, are covered by compulsory health insurance. More details on the SHCS are given elsewhere [12
Eligibility Criteria and Definitions
The same eligibility criteria were applied to patients in Switzerland and South Africa. All treatment-naïve patients who started HAART at any point since 2001 (the year when HAART became available in the two South African sites), had at least one day of follow-up, and were aged 16 y or older were included. Patients from Switzerland who acquired HIV through intravenous drug use were excluded from the analysis because they are a group that is not represented in the South African cohorts. In the South African cohorts HIV transmission information is not routinely recorded, but most patients were infected through heterosexual contacts. HAART was defined as a combination of at least three antiretroviral drugs. The type of regimen was defined as PI-based (two NRTIs and one PI), NNRTI-based (two NRTIs and one NNRTI), and other. Boosted PIs are counted as one drug. The stage of disease was classified as less advanced (CDC stage A/B, WHO stage I/II) or advanced (CDC stage C, WHO stage III/IV).
Ethical Approval and Laboratory Quality Assurance
The local ethics committees of all seven study sites that participate in the SHCS approved the study, and written informed consent was obtained from all participants. Data collection in the townships Khayelitsha and Gugulethu, South Africa, as well as participation of these studies in the Antiretroviral Treatment in Lower Income Countries Collaboration (ART-LINC) collaboration of IeDEA, were approved by the ethics committee of the University of Cape Town, which did not require informed consent. All laboratories involved in South Africa and Switzerland participate in quality assurance programmes.
The following endpoints were considered: time to first treatment change (overall and by reason for change), virologic suppression (defined as HIV-1 RNA ≤500 copies/ml), viral rebound (defined as HIV-1 RNA above 500 copies/ml) after having achieved viral suppression, CD4 response, and death from all causes. Viral rebound is usually defined as two consecutive values above a given threshold. In our analysis we used a single value, as the measurement frequency differed between settings. In a sensitivity analysis we used two consecutive values above 500 copies/ml. The threshold of 500 copies/ml was chosen because assays of different sensitivities were used during the study period. Regimen change was defined as any change to the treatment regimen, including interruption and discontinuation, but excluding dosage adjustments. The treating physician indicated the reason for regimen changes, and these reasons were classified as failure (virologic, immunologic, or clinical), toxicity, and other. Specific definitions of reasons for regimen change, including, for example, lactic acidosis, were not standardised across sites. The severity of toxicities was not assessed.
Finally, we determined the proportion of initial regimens that complied with the national South African guidelines or, in the case of Switzerland, the International AIDS Society–USA guidelines current at the time of starting HAART.
We used an “intent-to-continue-treatment” approach and thus ignored changes to treatment, including treatment interruptions and terminations for virological endpoints and death. Time was measured from the start of HAART or from the first viral load measurement of 500 copies/ml or below to the time the outcome occurred, the time of the last follow-up visit, or 2 y after baseline, whichever came first. A patient was considered lost to follow-up if the time between the last visit of the patient and the closing date of the cohort was longer than 1 y. Only patients who potentially had 1 y of follow-up were included in the analysis of loss from follow-up.
We used Kaplan–Meier graphs and Cox proportional hazard models (for mortality and first treatment change) and logistic regression (for viral response and viral rebound) to estimate hazard ratios (HRs) and odds ratios (ORs) of endpoints occurring, in comparing the two South African cohorts with the Swiss cohort. For mortality, a separate model was fitted for the first 3 mo after starting HAART (the period with the highest mortality [14
]) and for months 4–24. Since background mortality differs between the two settings, we compared expected mortality rates in Switzerland and South Africa. We obtained estimates of non-HIV-related background mortality by sex and age group from the Global Burden of Disease project [15
], and used these rates to calculate expected numbers of deaths in the two South African cohorts. Similarly, we used rates available from the Swiss Federal Statistical Office to calculate expected deaths for the Swiss cohort.
For viral response the first viral load measurement within 6–12 mo after baseline was classified into ≤500 copies/ml (virologic suppression) or >500 copies/ml. We used logistic regression instead of a time-to-event approach, because the frequency and timing of viral load measurements differed between the two settings. Analyses were adjusted for baseline CD4 count, HIV-1 viral load, stage of disease, sex, and age.
We calculated the rate of changing the first treatment regimen by reason of change and time periods (1–3 mo, 4–6 mo, 7–12 mo, and 13–24 mo) by dividing the number of patients developing the event by the number of person-years at risk. We used Poisson regression to calculate confidence intervals (CIs) for rates. Cause-specific cumulative incidences were calculated applying a competing risk approach [17
]. We used competing risk Cox regression as described by Lunn and McNeil [19
] to jointly analyze treatment change due to failure, intolerance, and other reasons. This analysis was adjusted for the same variables as above.
All analyses were performed using Stata version 9.2. Results are presented as Kaplan–Meier probabilities, rates per 100 person-years, and HRs or ORs, with 95% CIs.