Highlight
Four principal takeaways from IMPAACT P1115:
– Initiating three‑drug ART within 48 hours of birth in infants with in‑utero HIV‑1 can lead to ART‑free remission of at least 48 weeks in a subset of carefully selected children.
– Of 54 neonates with in‑utero infection enrolled, 6 met stringent criteria and underwent analytical treatment interruption (ATI); 4 of these maintained HIV‑1 RNA undetectable off ART for ≥48 weeks (67% of the ATI group; exact 95% CI 22–96).
– Stringent entry criteria led to a small ATI cohort (11% of enrolled infants); when denominated across all enrolled children, sustained remission was rare (4/54 ≈ 7.4%), underscoring selection effects.
– ATI carried manageable risks: viral rebound occurred in three children (two early, one late), all re‑suppressed on ART, and acute retroviral symptoms were mild and reversible with ART resumption.
Background: clinical context and unmet need
Perinatal transmission of HIV‑1 remains a major global pediatric health problem despite progress in prevention of mother‑to‑child transmission (PMTCT). Infants infected in utero are seeded with viral reservoirs very early, which typically requires lifelong antiretroviral therapy (ART) to prevent disease progression and limit transmission. Lifelong ART imposes adherence burdens, potential toxicities, and health systems challenges—especially in low‑ and middle‑income settings. A long‑standing hypothesis is that initiating potent combination ART as close to the time of exposure as possible could markedly limit initial reservoir seeding, preserve HIV‑specific immune function, and in some cases permit sustained ART‑free remission (functional cure). Observational adult cohorts of post‑treatment controllers and prior pediatric case reports (notably early treated infants with transient remission) have suggested this is possible but rare. IMPAACT P1115 was designed as a proof‑of‑concept, multicenter study to test whether very early neonatal ART could enable durable ART‑free remission in children infected in utero.
Study design and methods
IMPAACT P1115 is an open‑label, multicenter, phase 1/2 proof‑of‑concept study conducted at 30 sites across 11 countries in Africa, Asia, and the Americas. Key design features:
Population and enrollment
– Neonates ≥34 weeks gestational age born to mothers at high risk for in‑utero HIV‑1 infection were eligible.
– Cohort definitions reflected maternal ART status: cohort 1 (mothers with untreated HIV‑1) and cohort 2 (mothers who may have been on ART).
– Enrollment occurred between Jan 23, 2015, and Dec 14, 2017; 54 infants with confirmed in‑utero HIV‑1 infection were enrolled.
Intervention and early management
– Infants began a three‑drug, nevirapine‑based ART regimen within 48 hours of birth (dosing and regimen details per protocol) or nevirapine‑based prophylaxis pending diagnostic confirmation.
– When age‑appropriate and confirmed HIV‑1 infection was established, coformulated lopinavir/ritonavir was added.
– Nevirapine was discontinued 12 weeks after two consecutive plasma viral loads were below the assay limit.
Eligibility for ATI and primary endpoint
– Children at least 2 years old who had maintained undetectable plasma HIV‑1 RNA since week 48, tested HIV‑1 antibody negative, had undetectable HIV‑1 DNA, and normal CD4 counts/percentages were eligible to undergo supervised analytical treatment interruption (ATI).
– The primary outcome was ART‑free remission, defined as absence of detectable plasma HIV‑1 RNA for ≥48 weeks off ART. A two‑sided exact 95% confidence interval was used for the remission probability estimate.
Key findings and results
Cohort progression and ATI eligibility
– Of 54 infants with confirmed in‑utero HIV‑1 infection, 6 (11%) met the prespecified, stringent criteria for ATI and underwent treatment interruption at a median age of 5.5 years (range implied by age criteria and follow‑up data).
– The ATI group included four girls and two boys; one participant came from cohort 1 (maternal untreated HIV‑1), five from cohort 2.
Primary outcome: ART‑free remission
– Four of the six children undergoing ATI achieved the primary endpoint: ART‑free remission for ≥48 weeks (67%; exact 95% CI 22–96).
– One of these four subsequently experienced late viral rebound at 79.3 weeks off ART, illustrating that remission durable to 48 weeks does not guarantee life‑long control.
Viral rebound, clinical course, and re‑suppression
– Two children experienced early viral rebound at 3.4 weeks and 9.4 weeks off ART.
– In total, three participants had viral rebound during follow‑up; all three resumed ART and successfully re‑suppressed plasma HIV‑1 RNA below the assay limit.
– Mild acute retroviral syndrome symptoms occurred in two participants during rebound and resolved after ART resumption. No life‑threatening events related to ATI were reported in the published summary.
Interpretation of effect sizes and denominators
– The 67% remission proportion applies to the highly selected ATI subgroup (6 children). The exact 95% CI (22–96) reflects small numbers and wide uncertainty.
– When considered across all enrolled children (intent‑to‑enroll denominator), sustained ART‑free remission was observed in 4/54 infants (~7.4%), highlighting that stringent biomarker‑based selection narrowed the ATI candidate pool.
Safety and programmatic feasibility
– The study demonstrates operational feasibility of birth testing and immediate ART initiation across resource‑constrained settings represented in the trial network.
– Close virological monitoring during ATI permitted rapid ART reinitiation and clinical resolution of symptomatic rebound.
Expert commentary: implications, mechanisms, and limitations
Biological plausibility and mechanistic considerations
– Very early ART likely limits the magnitude and diversity of the initial reservoir by interrupting viral amplification and infection of long‑lived cellular compartments in the first hours to days of life.
– Early ART may better preserve HIV‑specific adaptive immune responses and reduce immune activation that fuels reservoir formation.
– Heterogeneity in outcomes likely reflects a combination of factors: timing of in‑utero infection (earlier fetal infection vs late third‑trimester), the size and distribution of residual reservoirs (measured imperfectly by HIV‑1 DNA assays), host genetic and immune factors, and potentially maternal viral dynamics and ART exposure.
Clinical and ethical considerations around ATI
– Analytical treatment interruption remains the only direct way to assess functional remission, but it carries risks of viral rebound, acute illness, and potential transmission. In children, parental consent, close follow‑up, and clear re‑start criteria are essential.
– The low absolute number of children qualifying for ATI underscores both the stringency required to minimize risk and the caution regulators and ethics boards rightly demand.
Limitations and generalizability
– Small numbers undergoing ATI produce imprecise estimates and wide confidence intervals; findings should be considered proof‑of‑concept rather than definitive.
– Selection bias: children who were antibody negative, had undetectable DNA and sustained aviremia likely represent a subset with the smallest reservoirs and most favorable biology. Results cannot be extrapolated to all infants with in‑utero infection.
– The open‑label design and lack of randomized comparator limits causal inferences about timing versus other factors driving remission.
– Laboratory assays for reservoir size and immune correlates remain imperfect; better predictive biomarkers are needed to avoid unnecessary ATI exposure.
Translational and policy implications
– The study supports policies to expand point‑of‑care birth testing and immediate ART initiation in high‑risk neonates, both to prevent morbidity and to create opportunities for remission‑focused research.
– Implementing birth testing and neonatal ART requires investments in newborn diagnostic capacity, supply chains, and follow‑up systems—especially in low‑resource settings where most perinatal infections occur.
Future directions and research priorities
Key next steps to build on IMPAACT P1115 include:
– Larger, prospective cohorts and randomized designs (where ethical and feasible) to better estimate remission probabilities and identify predictive markers.
– Standardized, sensitive reservoir assays and immune phenotyping to stratify ATI candidates and study mechanisms of control versus rebound.
– Investigations of adjunctive strategies (therapeutic vaccines, broadly neutralizing antibodies, immune modulators) combined with very early ART to increase remission likelihood and durability.
– Longitudinal safety datasets to assess neurodevelopmental and immunologic impacts of prolonged very early ART and subsequent ATI in children.
Conclusion
IMPAACT P1115 provides important proof‑of‑concept evidence that initiating combination ART within the first 48 hours of life can, in selected children with in‑utero infection, permit ART‑free HIV‑1 remission for 48 weeks or longer. The findings demonstrate feasibility of birth diagnosis and neonatal treatment in diverse global settings and illuminate a potential path toward functional cure strategies in pediatric HIV. However, the small number of ATI candidates and the occurrence of late rebound in at least one child highlight the need for cautious interpretation, rigorous monitoring during ATI, and further research to expand remission opportunities safely and predictably.
Funding and trial registration
The study was funded by 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. The trial is registered at ClinicalTrials.gov (NCT02140255).
Reference
Persaud D, Coletti A, Nelson BS, Jao J, Capparelli EV, Costello D, Tierney C, Kekitiinwa AR, Nematadzira T, Njau BN, Moye J, Jean‑Philippe P, Korutaro V, Nalugo A, Mbengeranwa T, Chidemo T, Mmbaga BT, Sakasaka PA, Cotton M, Jennings C, Hoffmann C, Hovind L, Bryson Y, Chadwick EG; IMPAACT P1115 Study Team. ART‑free HIV‑1 remission in children with in‑utero HIV‑1 after very early ART (IMPAACT P1115): a multicentre, open‑label, phase 1/2 proof‑of‑concept study. Lancet HIV. 2025 Nov;12(11):e743‑e752. doi: 10.1016/S2352‑3018(25)00189‑4. Epub 2025 Sep 25. PMID: 41015049.