Table 2.

Summary of recent trials on in HIV-infected children

Study and setting	Population	Methods	Results	Summary and comment
CHER trial, South Africa (a) Interim analysis [26]	HIV-infected asymptomatic infants aged 6–12 weeks with CD4 >25%	377 children randomized to deferred ART based on CD4/clinical criteria (Def-ART, n = 125); immediate ART (early-ART, n = 252); primary outcome: death or treatment failure (immunological, virological or clinical)	At randomization, median age and CD4% was 7.4 weeks and 35%; at 40 weeks, 76% reduction in death and 75% reduction in disease progression to CDC severe stage B or stage C event in the early-ART arm (P < 0.001); enrolment in the Def-ART arm was stopped after the interim analysis	Results led to change in international guidelines to recommend immediate ART in infants
(b) Neurocognitive sub-study [27▪]	As above, with additional HEU and HU controls	Cross-sectional sub-study; examination using GMDS	90 HIV-infected children (63 early-ART and 26 Def-ART), 155 HEU and 164 HU controls were included; median age of 11 months; significantly lower general and locomotor scores in the Def-ART versus; early-ART arm; children in early-ART arm had similar scores to HIV-uninfected controls except for locomotor score	Early ART was associated with better neurological outcomes at 11 months; cross-sectional design, so unclear if the outcome changes over time on ART; children in the Def-ART arm had higher incidence of illness and hospitalization, which may have contributed to their poorer outcome
(c) Final analysis [25▪▪]	As in (a)	Children in the early-ART strategy were randomized to TI after 40 weeks (ART-40weeks, n = 126) or 96 weeks (ART-96 weeks, n = 126); ART was reinitiated if CD4 < 25% in infancy; otherwise, CD4 < 20% or CDC B/ C event; children in the Def-ART arm were on continuous therapy; primary outcome: composite endpoint of time failure to first-line ART (immunological, virological or clinical) or death	Median follow-up was 4.8 years, 9% lost to follow-up; overall mortality was 16.8% in the Def-ART arm and 9% in the early ART arms; 38% of children in the Def-ART arm, 25% in ART-40 weeks, and 21% in ART-96 weeks group reached the primary endpoint (P ≤ 0.02); time to reinitiation of ART was 33 weeks (IQR, 26–45) in the ART-40 weeks and 70 weeks (35–109) in ART-96 weeks arm; at end of the trial, 19 and 32% of patients remained off ART, respectively; very few children switched to second-line across all arms	Long-term survival benefit of early ART as compared to deferred ART, with good long-term outcomes despite TI; early time-limited ART appears to be a safe strategy but requires close clinical and CD4 monitoring; there was no early continuous ART arm with which to compare the outcomes of the two TI arms; insufficient power to detect difference in outcomes between the two TI arms
PREDICT study, Cambodia and Thailand (a) Final analysis [28▪▪]	HIV-infected children aged 1–12 years with CD4 of 15–24% and no history of AIDS illness	Children randomized to deferred ART based on CD4/clinical criteria (Def-ART, n = 150); immediate ART (early-ART, n = 150); primary outcome: AIDS-free survival	At randomization, median age and CD4% was 6.4 years and 20%; at 144 weeks, very low rate of events and no difference in AIDS-free survival across the two arms: 98.7% (95% CI, 94.7–99.7) in Def-ART and 98.9% (95% CI, 93.7–99.3) in early-ART, P = 0.6; also no difference in secondary outcomes of CDC B/C events, hospitalization or immune response	No difference in AIDS-free survival in children aged ≥1 year, but because of the low rate of event was underpowered to detect a difference; potential limitation of survival bias, as the study was mainly composed of older children, which may have contributed to the low rate of events; findings may not be generalizable to younger children <5 years
(b) Neurodevelopmental sub-study [29▪]	As above, plus HEU and HU controls.	Repeat examinations over follow-up time for HIV-infected children; cross-sectional design for HIV-uninfected controls; assessments include: Berry Visual Motor Integration, Purdue Pegboard, Colour Trials and Child Behavioural Checklist	284 HIV-infected children (139 early-ART and 145 Def-ART), 155 HEU and 164 HU controls were included; median age of 9 years at last examination; among HIV+ children, cognitive function and neurodevelopmental outcomes did not differ between the early versus deferred ART arms; HIV-infected children performed worse than uninfected controls	No difference in outcomes between early or deferred ART; HIV-infected children performed worse than uninfected controls; included few young children <3 years so may not be generalizable to all age groups

ART, antiretroviral therapy; CDC, Centres of Disease Control and Prevention; GMDS, Griffiths Mental Development Scales; HEV, HIV exposed uninfected; HU, HIV unexposed; TI, treatment interruption.