Abstract
BACKGROUND: We hypothesised that initiating antiretroviral therapy (ART) soon after birth could limit HIV-1 reservoirs and promote ART-free remission. This study aims to assess remission in children with in-utero HIV-1 infection who received very early ART as neonates by performing analytical treatment interruption (ATI). METHODS: IMPAACT P1115 is an ongoing, open-label, proof-of-concept study at 30 research sites in 11 countries across Africa, Asia, and the Americas. Neonates (≥34 weeks gestational age) at high risk for in-utero HIV-1 were eligible. Neonates born to mothers with untreated HIV-1 (cohort 1) or mothers who might have been on ART (cohort 2) initiated three-drug oral nevirapine-based ART (6mg/kg per dose orally twice a day) within 48 h of birth (cohort 1), three-drug nevirapine-based prophylaxis (≥8 mg/kg per dose orally once a day), or nevirapine-based ART after HIV-1 diagnosis by age 10 days (cohort 2). Coformulated ritonavir 75 mg/m(2) and lopinavir 300 mg/m(2) orally twice a day was added when age appropriate for those with confirmed in-utero HIV-1. Nevirapine was discontinued 12 weeks after two consecutive plasma viral loads were below the assay limit. Children at least 2 years of age maintaining undetectable HIV-1 RNA since week 48 and who tested HIV-1 antibody negative, HIV-1 DNA not detected, and normal CD4 count and percentage qualified for ATI. The primary outcome was ART-free remission, defined as no HIV-1 RNA in plasma for 48 weeks or more off ART. A two-sided exact 95% CI was calculated to estimate the probability of remission. This study is registered with ClinicalTrials.gov (NCT02140255). FINDINGS: Among 54 children with in-utero HIV-1 enrolled between Jan 23, 2015, and Dec 14, 2017, six (11%) children (four girls, two boys; one in cohort 1, five in cohort 2) met criteria and underwent ATI at a median age of 5·5 years. Two children had early rebound at 3·4 weeks and 9·4 weeks. Four reached ART-free remission (67%; exact 95% CI 22-96), one of whom had late viral rebound at 79·3 weeks. All three children with viral rebound successfully resuppressed HIV-1 RNA below the assay limit on ART. Mild symptoms of acute retroviral syndrome occurred in two participants during rebound and resolved with ART resumption. INTERPRETATION: This study shows that ART-free remission for 48 weeks or longer is achievable with very early ART in children with in-utero HIV-1, but close monitoring for viral rebound and acute retroviral syndrome during ATI is needed. These findings, observed in resource-constrained countries, exhibit the feasibility of testing at birth and initiating very early ART, show the potential to limit HIV-1 reservoirs for ART-free remission, and inform future remission strategies. FUNDING: The US National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the US National Institute of Mental Health.