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  Conference on Retroviruses
and Opportunistic Infections
February 12-16, 2022
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One Third on ART 48 Hours From Birth Eligible for ART Interruption
  2022 CROI, February 12-16 and 22-24, 2022
Mark Mascolini
Two years after starting antiretroviral therapy (ART) within 48 hours of birth, 30% of IMPAACT P1115 study participants were potentially eligible for ART suspension to assess HIV remission [1]. At study week 108, two thirds of infants had nondetectable cell-associated HIV DNA and almost 90% tested negative for HIV antibody.
The much-plumbed reservoir of HIV in resting memory CD4 cells poses a deep challenge to remission and possible cure of HIV infection. Case studies already link shallower reservoirs to lengthy remissions with delayed viral rebounds after ART stops. One attempt to identify candidates for ART interruption that aims at treatment-free remission, IMPAACT P1115, follows infants who begin ART within the first 48 hours of life [2]. The hope is that shutting down HIV replication with ART in the first days of life will greatly limit reservoir size and make it possible for some people exposed to HIV in utero to dispense with ART for life.
From January 2015 through December 2017, researchers at Johns Hopkins University and across the US and Africa enrolled 460 infants at 30 sites in 11 countries. Cohort 1 consisted of 440 high-risk infants who started pre-emptive nevirapine-based ART within 48 hours of birth. Thirty-four of 36 neonates diagnosed with in utero HIV infection continued ART and remained in the study. Cohort 2 included 20 infants diagnosed with in utero HIV who started nevirapine-based ART within 48 hours of birth, enrolled in the study in the first 10 days of life, and stayed in the study on ART. All infants took two nucleoside reverse transcriptase inhibitors with nevirapine. Lopinavir/ritonavir was added later.
To stay in the study, infants had to meet certain virologic suppression criteria: (1) viral below 200 copies at week 24, (2) remaining below 200 copies during weeks 24 to 48, and (3) getting below 20 or 40 copies, depending on the assay used, after week 48. After 2 years of age, children could be assessed for ART interruption if they maintained a viral load below the limit of detection, tested negative for HIV-1 antibody, and had no detectable cell-associated HIV DNA. The researchers measured cell-associated DNA with a CLIA-certified droplet digital (ddPCR) assay that had a lower quantitation limit below 4.09 copies per million peripheral blood mononuclear cells (PBMCs).
Thirty-three of 34 infants in cohort 1 lived in Africa and 1 in Asia. Cohort 2 had 14 infants in Africa, 2 in North America, and 4 in South America. Median age at study entry stood at 22.2 hours in cohort 1 and 8 days in cohort 2. Median age at first ART was 7.3 hours in cohort 1 and 32.8 hours in cohort 2. Thirty-three infants in cohort 1 (97%) and 13 in cohort 2 (65%) were breastfed. No mothers of cohort 1 infants took antiretrovirals during pregnancy or delivery, compared with 7 mothers (37%) in cohort 2.
Estimated Kaplan-Meier probability of confirmed viral suppression with undetectable HIV RNA at 26 weeks was 48% in cohort 1 (95% confidence interval [CI] 30% to 64%) and 40% in cohort 2 (95% CI 17% to 62%). At week 24 cell-associated DNA fell by a median 1.0 log10 copies per million PBMCs in each cohort. Six of 31 infants (19%) in cohort 1 and 4 of 18 (22%) in cohort 2 had no detectable cell-associated DNA at study week 24.
Kaplan-Meier estimated probability of avoiding virologic failure (a viral load above 200 copies at week 24 or confirmed detectable viremia thereafter) at 2 years of age stood at 33% in cohort 1 (95% CI 17% to 49%) and at 57% in cohort 2 (95% CI 28% to 78%). Through 2 years of age, univariable Cox proportional hazards regression identified three baseline factors associated with delayed time to virologic failure through 2 years of age in cohort 1: male sex (hazard ratio [HR] 0.3, 95% CI 0.1 to 0.9), starting ART 24 to 48 hours after birth versus 0 to 24 hours (HR 0.1, 95% CI 0.02 to 0.9), and every 1-log (10-fold) lower earliest HIV RNA (HR 0.6, 95% CI 0.4 to 0.9). In cohort 2 univariate analysis linked one factor to delayed time to virologic failure: every 1-log per million PBMCs lower earliest cell-associated HIV DNA (HR 0.1, 95% CI 0.03 to 0.8).
At age 2 years (study week 108), 10 of 12 infants (83%) in cohort 1 tested negative for HIV antibody, as did 7 of 7 in cohort 2. At the same point 7 of 11 infants in cohort 1 (64%) and 5 of 7 (71%) in cohort 2 had nondetectable cell-associated HIV DNA. In a combined analysis of cohorts 1 and 2, Kaplan-Meier-estimated eligibility for ART interruption through 2 years of age stood at 30% (95% CI 18% to 42%).
IMPAACT P1115 researchers concluded that “a substantial proportion” of infants in this ongoing study who maintained an undetectable viral load through 2 years of age had HIV reservoir sizes low enough to make them candidates for ART interruption.
1. Persaud D, Chadwick EG, Nelson BS, et al. Two-year virologic outcomes of very early art for infants in the IMPAACT P1115 study. 2022 CROI, February 12-16 and 22-24, 2022. Abstract 31.
2. ClinicalTrials.gov. Very early intensive treatment of HIV-infected infants to achieve HIV remission. ClinicalTrials.gov Identifier NCT02140255. https://clinicaltrials.gov/ct2/show/NCT02140255