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.

Objectives To evaluate the effect of early versus deferred antiretroviral therapy (ART) on neurodevelopment of infants from Cape Town participating in the CHER (Children with HIV Early Antiretroviral Therapy) trial. Design HIV-infected infants were randomised to early (<3 months) or deferred ART. HIV-uninfected infants (HIV-exposed and HIV-unexposed) provide background data. Methods Neurological examination and Griffiths Mental Development Scales (GMDS) were administered between 10–16 months of age, by testers blind to HIV status and randomised allocation. Mean quotients were compared using paired t-tests. Results 64 infants on early ART and 26 on deferred ART (of potential 77 and 38 respectively on CHER trial) were assessed at median age 11 months (range 10-16). On the GMDS, all scores were lower in the deferred arm and the General Griffiths and Locomotor Scores were significantly lower: mean (standard deviation): 100.1 (13.8) vs 106.3 (10.6) p=0.02; and 88.9 (16.3) vs 97.7 (12.5), p<0.01, respectively. Children with HIV who received early ART performed as well as children without HIV except on the locomotor subscale. Both infected and uninfected mean GMDS scores were within the average range. Conclusions Infants initiated on early ART have significantly better Locomotor and General Scores on the GMDS at median age 11 months compared to infants on deferred ART, despite careful monitoring and ready access to ART in the latter.

BACKGROUND The natural history and manifestation of HIV-related neurological disease have been ameliorated by combination antiretroviral therapy (ART). We describe the characteristics of white matter signal abnormalities (WMSA) on magnetic resonance imaging (MRI) in children with HIV-related neurological disease. METHODS We reviewed MRI scans of children with suspected HIV-related neurological disease despite early ART, and correlated with clinical, neurodevelopmental data, virological markers and time on ART. These children were also on the Children with HIV Early Antiretroviral (CHER) trial. RESULTS MRI scans were performed at a mean age 31.9 months (range 8-54) on 44 children: 10 on deferred and 34 on early treatment arms, commencing ART at mean age of 18.5 and 8 weeks respectively. Multiple high signal intensity lesions on T2 /FLAIR were documented in 22 patients (50%), predominantly in frontal (91%) and parietal (82%) white matter. No differences in neurodevelopmental scores comparing children with and without WMSA were found. Neither lesion load nor distribution showed significant correlation with neurodevelopmental scores or neurological examination. Normal head growth was more common in the WMSA group (p=0.01). There was a trend for association of WMSA and longer time on ART (p=0.13) and nadir CD4% (p=0.08). CONCLUSION Half of children referred with HIV-related brain disease had WMSA on T2/FLAIR. Our findings of the association with normal head growth and duration of ART require further study. We suspect that WMSA can occur early and that initiating ART by 8 weeks of life may be too late to prevent HIV from entering the CNS.

Objective Investigating consequences of early or late antiretroviral therapy (ART) initiation in infancy on young brain development using magnetic resonance spectroscopy (MRS). Design Most pediatric HIV/ART-related neurological studies are from neuropsychological/clinical perspectives. MRS can elucidate the mechanisms underpinning neurocognitive outcomes by quantifying the brain’s chemical condition through localized metabolism to provide insights into health and development. Methods Basal ganglia metabolite concentrations were assessed in thirty-eight 5-year-old HIV-infected children previously participating in a randomized trial comparing early limited ART to deferred continuous ART, as well as 15 uninfected controls (12 HIV exposed). Metabolite levels were compared between 26 infected children who initiated ART at/before 12 weeks and 12 who initiated afterwards, and were correlated with clinical HIV and treatment-related measures. Results HIV-infected children initiating ART after 12 weeks had lower creatine, choline and glutamate (p’s<0.05) than those initiating ART at/before 12 weeks. The CD4/CD8 ratio at baseline correlated with N-acetyl-aspartate (r=0.56, p=0.003) and choline (r=0.36, p=0.03) at 5 years, irrespective of treatment regimen and ART interruption. In comparison with uninfected controls, 80% of whom were HIV exposed in utero, children on early treatment had higher N-acetyl-aspartate (p=0.006) and choline (p=0.03). Conclusions Despite early ART (<12 weeks), low baseline CD4/CD8 predicts brain metabolite levels in later childhood. Also, HIV-exposure and antiretroviral exposure for preventing vertical HIV transmission may hinder metabolite health, but needs further investigation.