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ART-free HIV-1 remission in children with in-utero HIV-1 after very early ART (IMPAACT P1115): a multicentre,
Deborah Persaud1, Anne Coletti2, Bryan S Nelson3
1The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Insights
Early antiretroviral therapy (ART) in neonates with in-utero HIV-1 infection can lead to ART-free remission. Close monitoring is crucial during analytical treatment interruption (ATI) due to potential viral rebound.
Area of Science:
- Pediatric Infectious Diseases
- Virology
- Immunology
Background:
- Infants born with in-utero Human Immunodeficiency Virus type 1 (HIV-1) infection are at risk of persistent viral reservoirs.
- Early initiation of antiretroviral therapy (ART) is hypothesized to limit viral reservoirs and promote remission.
Purpose of the Study:
- To assess the feasibility of achieving sustained, ART-free remission in children with in-utero HIV-1 infection who received very early ART.
- To evaluate the safety and efficacy of analytical treatment interruption (ATI) in this cohort.
Main Methods:
- An open-label, proof-of-concept study (IMPAACT P1115) enrolled high-risk neonates.
- Eligible neonates initiated nevirapine-based ART within 48 hours of birth, with ritonavir/lopinavir added as appropriate.
- Children meeting specific criteria (age ≥2 years, undetectable viral load, negative HIV-1 DNA, normal CD4 count) underwent ATI.
Main Results:
- Six of 54 enrolled children proceeded to ATI at a median age of 5.5 years.
- Four children (67%) achieved ART-free remission for 48 weeks or longer.
- Two children experienced early viral rebound, and one had late rebound; all successfully resuppressed HIV-1 RNA on ART.
Conclusions:
- Very early ART initiation in neonates with in-utero HIV-1 infection can lead to ART-free remission.
- Analytical treatment interruption (ATI) is a viable strategy to assess remission but requires close monitoring for viral rebound and acute retroviral syndrome.
- Findings support the feasibility of early testing and treatment at birth to limit HIV-1 reservoirs and inform future remission strategies, even in resource-constrained settings.
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/m2 and lopinavir 300 mg/m2 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.
