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Four of 6 Early-Treated Infants Attain Sustained ART-Free Remission
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CROI 2024 (Conference on Retroviruses and Opportunistic Infections), March 3-6, 2024, Denver
Mark Mascolini
Four of 6 infants infected with HIV in utero and treated with antiretroviral therapy (ART) within 2 days of birth suspended treatment without viral rebound for more than 48 weeks in the international IMPAACT P1115 trial [1]. But proposed eligibility criteria and biomarker parameters-including plasma viral load below 200 copies by treatment week 24 and sustained undetectable viral load from 48 weeks on-did not predict ART-free remission since 2 of 6 children had viral rebounds within 8 weeks of treatment suspension.
The so-called Mississippi baby began ART within the first 30 hours of life, inadvertently stopped therapy, and coasted through 27 months with no antiretrovirals and no viral rebound [2]. This startling result reported by Deborah Persaud (Johns Hopkins University, Baltimore) and others led these researchers to propose that very early ART in newborns limits HIV reservoirs enough to enable eventual ART-free remission.
IMPAACT P1115 started with 54 neonates enrolled in 2015-2017 with confirmed in utero HIV infection and ART within the first 48 hours of life. Six children (11%) met eligibility criteria to suspend ART: plasma viral load below 200 copies by study week 24, sustained undetectable plasma viral load from week 48 on, and stopping breastfeeding at least 6 weeks before treatment interruption evaluation.
Before the planned treatment suspension, children needed a normal CD4 count for their age and CD4 percent at or above 25%. They had to be negative for HIV antibody by fourth-generation ELISA in two consecutive samples collected at least 8 weeks apart. They could have no HIV DNA detected in 850,000 or more peripheral blood mononuclear cells (PBMCs) in two consecutive samples collected at least 8 weeks apart and determined by a CLIA-certified pansubtype droplet digital PCR HIV DNA assay.
Four children who met these criteria lived in Uganda and 1 each in Tanzania and Zimbabwe. Triple ART began with nevirapine plus 2 nucleos(t)ides in day 1 of life in 4 newborns and on day 2 in 2. They later added lopinavir/ritonavir. The earliest age at which viral target could not be detected by an HIV RNA assay ranged 3.3 to 17.1 days (9.0 and 17.1 days in the 2 children who did not attain sustained remission). The earliest age at which HIV DNA could not be detected in PBMCs ranged from 0.3 to 49.0 weeks (25.1 and 49.0 weeks in the 2 children who did not attain sustained remission).
ART stopped at a median age of 5.5 years. Detection of lopinavir in samples from all participants before treatment interruption and in no samples after ART stopped confirmed ART-free remission in the 4 children who reached that goal.
Viral load rebounded after 3 and 8 weeks in the 2 children who did not achieve ART-free remission. The 4 children who did achieve remission stopped ART for 48, 52, 64, and 80 weeks. The last child had a viral rebound at 80 weeks, while the other 3 continue to remain off ART without a rebound (exact 95% confidence interval 22% to 96%).
Two of 3 children with rebounds had the acute retroviral syndrome when rebounding. All 3 rebounders resuppressed their HIV between 6.7 and 20 weeks after the rebound.
Persaud and colleagues noted that lack of safety and pharmacokinetic data on newer antiretroviral combinations when they were planning the trial precluded use of contemporary regimens in these children. The COVID pandemic prevented treatment suspension at ages as young as 2 years, as planned, so the trial could not assess ART-free remission in children younger than 5 years. The researchers believe the data collected so far provide "proof-of-concept that very early ART in neonates with in utero HIV-1 significantly curtailed viral reservoirs and enabled ART-free remission."
References
1. Persaud D, Coletti A, Nelson BS, et al. ART-free HIV-1 remission in very early treated children: results from IMPAACT P1115. CROI 2024 (Conference on Retroviruses and Opportunistic Infections), March 3-6, 2024, Denver. Abstract 184.
2. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med. 2013;369:1828-35. doi: 10.1056/NEJMoa1302976. https://www.nejm.org/doi/10.1056/NEJMoa1302976
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