Background Interim results from the CHER trial showed that early antiretroviral therapy (ART) was life-saving for HIV-infected infants. Given limited options and potential for toxicity with life-long ART, CHER compared early limited ART with deferred ART. Methods CHER was an open 3-arm trial in HIV-infected asymptomatic infants aged <12 weeks with CD4% ≥25%. Infants were randomized to deferred (ART-Def) or immediate ART for 40weeks (ART-40W) or 96weeks (ART-96W), followed by interruption. Criteria for ART initiation in ART-Def and re-initiation after interruption were CD4% <25% in infancy; otherwise <20% or CDC severe stage B or stage C disease. Lopinavir-ritonavir, zidovudine, lamivudine was the first-line regimen at ART initiation and re-initiation. The primary endpoint was time-to-failure of first-line ART (immunological/clinical/virological) or death. Comparisons were by intent-to-treat, using time-to-event methods. Findings 377 infants were enrolled: median age 7.4weeks; CD4% 35% and HIV RNA log 5.7copies/ml. Median follow-up was 4.8 years; 34 (9%) were lost-to-follow-up. Median time to ART initiation in ART-Def was 20 (IQR 16–25) weeks. Time to restarting ART after interruption was 33 (26–45) weeks in ART-40W and 70 (35–109) weeks in ART-96W; at trial end 19% and 32% respectively, remained off ART. Proportions of follow-up time spent on ART were 81%, 70% and 69% in ART-Def, ART-40W and ART-96W arms. 48/125(38%), 32/126(25%) and 26/126(21%) children reached the primary endpoint; hazard ratio (95%CI), relative to ART-Def, was 0.59(0.38-0.93, p=0.02) for ART-40W and 0.47(0.27-0.76, p=0.002) for ART-96W. Seven children (3 ART-Def, 3 ART-40W, 1 ART-96W) switched to second-line ART. Interpretation Early limited ART had superior clinical/immunological outcome with no evidence of excess disease progression during subsequent interruption and less overall ART exposure than deferred ART. Longer time on primary ART permits longer subsequent interruption with marginally better outcomes.

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ObjectiveTo describe the degree of HIV disease progression in infants initiating antiretroviral therapy (ART) by three months of age in a programmatic setting in South Africa.DesignThis was a programmatic cohort study.MethodsElectronic and manual data extraction from databases and antiretroviral registers in 20 public clinics in Cape Town and electronic data extraction from a large ART service at Chris Hani Baragwanath Hospital in Soweto were performed. Records of all infants initiated on ART by three months of age between June 2007 and September 2010 were extracted. Demographics, immunological and clinical stage at ART initiation were analyzed descriptively by chi-square, two-sample t-test and Kaplan–Meier methods.ResultsA total of 403 records were identified: 88 in Cape Town and 315 in Soweto. Median age at ART initiation was 8.4 [interquartile range (IQR): 7.2–9.7] weeks. At ART initiation, 250 infants (62%) had advanced HIV disease (CD4% <25% or absolute CD4<1500 cells/mm3 or WHO clinical Stage 3 or 4). Median age at ART initiation by site was 10.3 (IQR: 8.2–11.9) weeks in Cape Town and 8.6 (IQR: 7.7–10.0) weeks in Soweto infants (p<0.0001). In Cape Town, 73 infants (83%) had advanced HIV disease at ART initiation, compared to 177 infants (56%) in Soweto (p<0.0001). On logistic regression, each month increase in age at ART initiation lowered the odds of initiating ART in an optimal state (OR: 0.56, CI: 0.36–0.94) and increased the odds of advanced HIV disease at ART initiation (OR: 1.69, CI: 1.05–2.71).ConclusionsART initiation by three months of age may not adequately prevent disease progression. New emphasis on early diagnosis and rapid initiation of ART in the first weeks of life are essential to further reduce infant mortality.

BACKGROUND Data describing the true extent of antiretroviral therapy (ART)-induced dyslipidemia and insulin resistance in perinatally-infected children on ART in Africa is sparse. METHODS Fasting total cholesterol, LDL, HDL, triglycerides, insulin and glucose were performed on the first 100, of 190 pediatric ART clinic attendees. Diet assessment was performed by a trained dietician. Lipoatrophy was formally graded by consensus between two expert HIV pediatricians. Durations of previous ART exposures, clinical stage, pre-ART viral load, nadir and current CD4 were recorded. Dual energy X-ray Absorptiometry (DEXA) was performed on a subset of 42 patients selected semi-randomly. RESULTS Prevalences of insulin resistance, abnormal total cholesterol, LDL, HDL and triglyceride were 10%, 13%, 12%, 13 % and 9% respectively. Overall, 40% had at least one lipid abnormality or insulin resistance. Adjusted mean LDL cholesterol increased by 0.24mmol/L for each additional year of cumulative lopinavir/r exposure (p=0.03) after correcting for age, gender, body mass index, previous stavudine exposure, age at ART initiation, dietary fat and refined carbohydrate, while adjusted mean LDL cholesterol was 0.9mmol/L higher in children exposed to efavirenz within the previous six months (p=0.02). Adjusting for age, gender and ethnicity, DEXA revealed that greater trunk fat and lower peripheral subcutaneous fat were associated with elevated triglycerides but not with total cholesterol, LDL, HDL or HOMA. Similarly, the presence of visually obvious lipoatrophy was associated with elevated triglycerides but not with total cholesterol, LDL, HDL, HOMA or lactate. CONCLUSIONS Prevalences of insulin resistance and dyslipidemia were high. Cumulative lopinovir is an independent risk factor for dyslipidemia, with efavirenz exposure having only transitory effect.