Background We previously reported similar AIDS-free survival at 3 years in children who were >1 year old initiating antiretroviral therapy (ART) and randomized to early vs. deferred ART in the PREDICT Study. We now report neurodevelopmental outcomes. Methods 284 HIV-infected Thai and Cambodian children aged 1–12 years with CD4 counts between 15–24% and no AIDS-defining illness were randomized to initiate ART at enrollment (“early”, n=139) or when CD4 count became <15% or a CDC C event developed (“deferred”, n=145). All underwent age-appropriate neurodevelopment testing including Beery Visual Motor Integration (VMI), Purdue Pegboard, Color Trails and Child Behavioral Checklist (CBCL). Thai children (n=170) also completed Wechsler Intelligence Scale (IQ) and Stanford Binet Memory test. We compared week 144 measures by randomized group and to HIV-uninfected children (n=319). Results At week 144, the median age was 9 years and 69 (48%) of the deferred arm children had initiated ART. The early arm had a higher CD4 (33% vs. 24%, p<0.001) and a greater percentage of children with viral suppression (91% vs. 40%, p<0.001). Neurodevelopmental scores did not differ by arm and there were no differences in changes between arms across repeated assessments in time-varying multivariate models. HIV-infected children performed worse than uninfected children on IQ, Beery VMI, Binet memory and CBCL Conclusions In HIV-infected children surviving beyond one year of age without ART, neurodevelopmental outcomes were similar with ART initiation at CD4 15–24% vs. < 15%; but both groups performed worse than HIV-uninfected children. The window of opportunity for a positive effect of ART initiation on neurodevelopment may remain in infancy.

Summary Background The optimum time to start antiretroviral therapy for children diagnosed with HIV infection after 1 year of age is unknown. We assessed whether antiretroviral therapy could be deferred until CD4 percentages declined to less than 15% without affecting AIDS-free survival. Methods In our multicentre, randomised, open-label trial at nine research sites in Thailand and Cambodia, we enrolled children aged 1–12 years who were infected with HIV and had CD4 percentages of 15–24%. Participants were randomly assigned (1:1) by a minimisation scheme to start antiretroviral therapy at study entry (early treatment group) or antiretroviral therapy to start when CD4 percentages declined to less than 15% (deferred treatment group). The primary endpoint was AIDS-free survival (based on US Centers for Disease Control and Prevention category C events) at week 144, assessed with the Kaplan-Meier analysis and the log-rank approach. This study is registered with ClinicalTrials.gov, number NCT00234091. Findings Between March 28, 2006, and Sept 10, 2008, we enrolled 300 Thai and Cambodian children infected with HIV, with a median age of 6·4 years (IQR 3·9–8·4). 150 children were randomly allocated early antiretroviral therapy (one participant was excluded from analyses after withdrawing before week 0) and 150 children were randomly allocated deferred antiretroviral therapy. Median baseline CD4 percentage was 19% (16–22%). 69 children (46%) in the deferred treatment group started antiretroviral therapy during the study. AIDS-free survival at week 144 in the deferred treatment group was 98·7% (95% CI 94·7–99·7; 148 of 150 patients) compared with 97·9% (93·7–99·3; 146 of 149 patients) in the early treatment group (p=0·6). Interpretation AIDS-free survival in both treatment groups was high. This low event rate meant that our study was underpowered to detect differences between treatment start times and thus additional follow-up of study participants or future studies are needed to answer this clinical question. Funding US National Institutes of Health, Division of AIDS; National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; and National Institute of Mental Health.

Human immunodeficiency virus (HIV)-negative children born to HIV-infected mothers may exhibit differences in neurodevelopment (ND) compared to age- and gender-matched controls whose lives have not been affected by HIV. This could occur due to exposure to HIV and antiretroviral agents in utero and perinatally, or differences in the environment in which they grow up. This study assessed neurodevelopmental outcomes in HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children enrolled as controls in a multicenter ND study from Thailand and Cambodia. One hundred sixty HEU and 167 HUU children completed a neurodevelopmental assessment using the Beery Visual Motor Integration (VMI) test, Color Trails, Perdue Pegboard, and Child Behavior Checklist (CBCL). Thai children (n = 202) also completed the Wechsler Intelligence Scale (IQ) and Stanford-Binet II memory tests. In analyses adjusted for caregiver education, parent as caregiver, household income, age, and ethnicity, statistically significant lower scores were seen on verbal IQ (VIQ), full-scale IQ (FSIQ), and Binet Bead Memory among HEU compared to HUU. The mean (95% CI) differences were −6.13 (−10.3 to −1.96), p = 0.004; −4.57 (−8.80 to −0.35), p = 0.03; and −3.72 (−6.57 to −0.88), p = 0.01 for VIQ, FSIQ, and Binet Bead Memory, respectively. We observed no significant differences in performance IQ, other Binet memory domains, Color Trail, Perdue Pegboard, Beery VMI, or CBCL test scores. We conclude that HEU children evidence reductions in some neurodevelopmental outcomes compared to HUU; however, these differences are small and it remains unclear to what extent they have immediate and long-term clinical significance.

We evaluated the validity of CD4 count against CD4 percentage criteria of 2008 World Health Organization guideline for initiating antiretroviral therapy using the data of 446 Asian HIV - infected children aged 1 to 12 years who were screened to the PREDICT study. The overall sensitivity and specificity were 34% and 98%, respectively. Using the current CD4 count criteria would globally result in 66% missed opportunity to initiate treatment in a timely fashion. Raising CD4 count thresholds should be considered to increases its sensitivity and reduces missed opportunity.

Background Dyslipidemia is a common complication among HIV-infected children after antiretroviral therapy (ART). However, HIV itself can cause abnormal lipid metabolism. There is limited information of lipid profile among Asian HIV-infected children naïve to ART. Methods 274 HIV-infected ART-naïve Thai and Cambodian children 1–12 years of age with CD4 between 15–24% were included. Patients were fasted for ≥ 4 hours before blood was drawn. Abnormal lipid level was defined as triglyceride (TG) > 130 mg/dL, total cholesterol (TC) > 200 mg/dL, low density lipoprotein (LDL) > 130 mg/dL, and high density lipoprotein (HDL) ≤ 40 mg/dL. Result The mean (SD) was 76.6 (33.8) months for age and −1.3 (1.0) for weight Z-score. Mean (SD) CD4% was 19.9 (4.8) % and HIV RNA was 4.6 (0.6) log10 copies/ml. The median (SD) fasting time was 13.0 (2.7) hours. Mean (SD) for lipids were 116 mg/dl (62) for TG, 139 mg/dl (29) for TC, 73 mg/dl (29) for LDL and 45 mg/dl (19) for HDL. Overall 63.9% had dyslipidemia with hypertriglyceridemia and hypo HDL being the most common: 28% and 45% respectively, while 2% had hypercholesterolemia or hyper-LDL. After adjusting for age, having HIV RNA > 5 log10 copies/ml was associated with hypo-HDL with odds ratios of 8.1 (95% CI 2.7–24.3). Conclusions Up to two-third of ART-naïve, HIV-infected Asian children with mild to moderate immune suppression had dyslipidemia. Low HDL was the most common and was associated with high HIV viremia. The long term consequence of low HDL deserves further investigation in children.