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.

BackgroundImmune restoration is often incomplete after ART in HIV patients, both quantitatively and qualitatively. We studied the incidence and probability of CD4/CD8 normalization in an adult Thai HIV cohort and explored the predictive value of the ratio for developing of non-AIDS defining events (NAEs).MethodsWe analyzed data from HIV-infected Thai adults between 1996 and 2017 in the HIV-NAT 006 prospective long-term cohort in Bangkok, Thailand. Normalization was defined as CD4/CD8 ratio ≥ 1 on two consecutive visits, and normalization probability was calculated using the Kaplan–Meier method. NAEs were a composite endpoint including cardiovascular or cerebrovascular diseases, chronic kidney diseases, non-AIDS defining malignancies and death. Multivariate Cox regression was used to evaluate demographic, disease and treatment characteristics associated with CD4/CD8 ratio normalization and NAEs.ResultsA total of 800 ART-naïve patients with baseline CD4/CD8 ratio of < 0.8 who started combination ART, and had sustained virological suppression were enrolled. Participants were on ART for a median of 8.9 years and virologically suppressed for 6.1 years. The probabilities of CD4/CD8 normalization at 2, 5 and 10 years after virological suppression were 5.1%, 18.6% and 39.1%, respectively. Factors associated with normalization in multivariate analysis were female sex (hazard ratio [HR]: 2.47, 95% CI 1.71–3.56, p < 0.001) and baseline CD4 counts ≥ 350 cells/mm3 (HR: 3.62, 95% CI 2.36–5.55), p < 0.001) vs. < 200 cells/mm3 as reference. The second analysis explored the predictive value of CD4/CD8 ratio for NAEs. Older age (HR: 1.09, 95% CI 1.05–1.13, p < 0.01) and current CD4/CD8 ratio < 0.3 (HR: 3.02, 95% CI 1.27–7.21, p = 0.01) or between 0.3 and 0.45 (HR: 2.03, 95% CI 1.03–3.98, p = 0.04) vs. > 0.45 were independently associated with higher risk of progression to NAEs in the multivariate analysis.ConclusionsOur findings showed that complete immune recovery is uncommon in an Asian setting and earlier ART initiation at higher CD4 counts may have increased the ratio sooner. The findings demonstrate the use of CD4/CD8 ratio as a prognostic marker for clinical progression of NAEs.Trial registration HIV-NAT 006 cohort, clinical trial number: NCT00411983

In these Thai patients with advanced HIV disease, CMV viremia was frequent, and CMV DNA >500 copies/mL predicted increased mortality despite ART initiation. This calls for increased attention to screening of active CMV infection in advanced HIV patients in developing countries. Trials assessing preemptive anti-CMV therapy may be warranted.

ObjectivesThe aim of the study was to determine the incidence of, and risk factors for, nevirapine (NVP)-associated hepatotoxicity and rash in HIV-infected Thai men and women, including pregnant women, receiving NVP-containing highly active antiretroviral therapy (HAART). MethodsNVP-containing HAART was prescribed to eligible men and women enrolled in the Prevention of Mother-To-Child Transmission of HIV (PMTCT) and MTCT-Plus programmes. All pregnant women received zidovudine (ZDV)/lamivudine (3TC)/NVP from 414 weeks of gestational age if their CD4 cell count was 200 cells/mL or from 428 weeks if their CD4 cell count was 4200 cells/mL. Patients followed for at least 8 weeks after starting HAART or until delivery were included in the analyses. ResultsOf 409 patients, 244 were pregnant women, 87 were nonpregnant women and 78 were men. Hepatotoxicity occurred in 15.6% of all patients. Men had a significantly higher rate of asymptomatic hepatotoxicity (P 5 0.021). Pregnant women receiving HAART for PMTCT (92% had CD4 cell counts 4250 cells/mL) had a significantly higher rate of symptomatic hepatotoxicity (P 5 0.0003) than pregnant women receiving HAART for therapy. Rash occurred in 16.1% of all patients. The patients' sex and baseline CD4 cell count were not associated with the risk of hepatotoxicity or rash. NVP was discontinued in 4.2% and 6.8% of patients because of hepatotoxicity and rash, respectively. ConclusionsThe incidence of NVP-related hepatotoxicity and rash in Thai adults is similar to incidences reported for other populations. While larger studies are needed, our data support continued use of NVP-containing regimens as first-line treatment in developing countries for HIV-infected patients, including pregnant women. Pregnant women with high CD4 cell counts may experience higher rates of symptomatic hepatotoxicity and thus require careful clinical and laboratory monitoring.

Background There are limited data on the immune profiles of HIV-positive children, compared with healthy controls, and no such data for Asian children. Objectives To immunophenotype HIV-positive Asian children, including long-term non-progressors (LTNPs), compared with age-matched healthy controls. Methods We used flow cytometry to analyze 13 lymphocyte and monocyte subsets from 222 untreated, HIV-positive children with 15%–24% CD4+ T cells and no AIDS-related illnesses and 142 healthy children (controls). Data were compared among age categories. Profiles from LTNPs (n=50), defined as children≥ 8 years old with CD4+ T-cell counts ≥ 350 cells/mm3, were compared with data from age-matched non-LTNPs (n=17) and controls (n=53). Results Compared with controls, HIV-positive children had lower values (cell count per mm3 and percent distribution) for helper T cells and higher values for cytotoxic T cells, with reductions in populations of naïve helper and cytotoxic T cells, B cells, and natural killer (NK) cells. HIV-positive children had high values for activated helper and cytotoxic T cells. Compared with non-LTNPs, LTNPs had higher values of helper and cytotoxic T cells, naïve and memory T-cell subsets, and B and NK cells. Surprisingly, counts of activated helper and cytotoxic T cells were also higher among LTNPs. LNTPs were more frequently male. Conclusions Untreated, HIV-infected Asian children have immune profiles that differ from those of controls, characterized by low values for helper T cells, naive T cells, B cells, and NK cells but high values for cytotoxic, activated helper, and cytotoxic T cells. The higher values for activated T cells observed in LTNPs require confirmation in longitudinal studies. Clinical Implications The distinct immunologic profile of LTNPs might identify lymphocyte subsets associated with HIV disease progression.