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Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy.

ABSTRACT: Treatment interruption has been well tolerated and durable in some pediatric studies but none have compared treatment interruption with continued antiretroviral treatment (ART) following ART initiation in early HIV. The objective of this study was to compare outcomes in treatment interruption versus continued ART among early-treated infants.Randomized trial (OPH-03; NCT00428116).The trial included HIV-infected infants who initiated ART at less than 13 months of age, received ART for 24 months, and, if eligible (CD4% >25%, normal growth), were randomized to treatment interruption versus continued ART. Children in the treatment interruption group restarted ART if they met WHO ART-eligibility criteria. During 18-months postrandomization, primary outcomes were incidence of serious adverse events and growth. CD4%, viral load, morbidity, and growth were compared.Of 140 infants enrolled, 121 started ART, of whom 75 completed at least 24 months ART and 42 were randomized (21 per arm). ART was initiated at median age 5 months and randomization at 30 months. Among 21 treatment interruption children, 14 met ART restart criteria within 3 months. Randomization was discontinued by Data and Safety Monitoring Board due to low treatment interruption durability. At 18 months postrandomization, growth and serious adverse events were comparable between arms; hypercholesteremia incidence was higher in the continued arm (P?=?0.03). CD4% and viral load did not differ between arms [CD4% 35% and median viral load undetectable (<150 copies/ml) in both arms, P?=?0.9 for each comparison]. No infants had post-treatment viral control.Short treatment interruption did not compromise 18-month CD4%, viral control, growth, or morbidity compared with continued ART among infants who started ART in early HIV infection.

SUBMITTER: Wamalwa D

PROVIDER: S-EPMC5014697 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy.

Wamalwa Dalton D Benki-Nugent Sarah S Langat Agnes A Tapia Kenneth K Ngugi Evelyn E Moraa Helen H Maleche-Obimbo Elizabeth E Otieno Vincent V Inwani Irene I Richardson Barbra A BA Chohan Bhavna B Overbaugh Julie J John-Stewart Grace C GC

AIDS (London, England) 20160901 15

<h4>Objective</h4>Treatment interruption has been well tolerated and durable in some pediatric studies but none have compared treatment interruption with continued antiretroviral treatment (ART) following ART initiation in early HIV. The objective of this study was to compare outcomes in treatment interruption versus continued ART among early-treated infants.<h4>Design</h4>Randomized trial (OPH-03; NCT00428116).<h4>Methods</h4>The trial included HIV-infected infants who initiated ART at less tha ...[more]

PMID: 27177316

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Project description:BackgroundEarly antiretroviral therapy (ART) and virological suppression can affect evolving antibody responses to HIV infection. We aimed to assess frequency and predictors of seronegativity in infants starting early ART.MethodsWe compared HIV antibody results between two of three treatment groups of the Children with HIV Early Antiretroviral Therapy (CHER) trial, done from July, 2005, until July, 2011, in which infants with HIV infection aged 5·7-12·0 weeks with a percentage of CD4-positive T lymphocytes of at least 25% were randomly assigned to immediate ART for 96 weeks (ART-96W) or deferred ART until clinical or immunological progression (ART-Def). We measured antibody from all available stored samples for ART-96W and ART-Def at trial week 84 using three assays: fourth-generation enzyme immunoassay HIV antigen-antibody combination, HIV-1 and HIV-2 rapid antibody test, and quantitative anti-gp120 IgG ELISA. We also assessed odds of seropositivity with respect to age of ART initiation and cumulative viral load. The CHER trial was registered with ClinicalTrials.gov, number NCT00102960.FindingsThe median age of the infants from when samples were taken (184 samples from 268 infants) was 92 weeks (IQR 90·6-93·4). More specimens from the ART-96W group were seronegative than from the ART-Def group by enzyme immunoassay (ART-96W 49 [46%] of 107 vs ART-Def eight [11%] of 75; p<0·0001) and rapid antibody test (54 [53%] of 101 vs eight [11%] of 74; p<0·0001). Median anti-gp120 IgG concentration was lower in the ART-96W group (230 μg/μL [IQR 133-13 129]) than in the ART-Def group (6870 μg/μL [1706-53 645]; p<0·0001). If ART was started between 12 and 24 weeks of age, odds of seropositivity were increased 13·7 times (95% CI 3·1-60·2; p=0·001) compared with starting it between 0 and 12 weeks. All children starting ART aged older than 24 weeks were seropositive. Cumulative viral load to week 84 correlated with anti-gp120 IgG concentrations (coefficient 0·54; p<0·0001) and increased odds of seropositivity (odds ratio 1·59 [95% CI 1·1-2·3]) adjusted for ART initiation age.InterpretationAbout half of children starting ART before 12 weeks of age were HIV seronegative by almost 2 years of age. HIV antibody tests cannot be used to reconfirm HIV diagnosis in children starting early ART. Long-term effects of seronegativity need further study. Clear guidelines are needed for retesting alongside improved diagnostic tests.FundingWellcome Trust, Medical Research Council, and National Institutes of Health.

Project description:If strategies currently in development succeed in eradicating HIV reservoirs in peripheral blood and lymphoid tissues, residual sources of virus may remain in anatomic compartments. Paired blood and semen samples were collected from 12 individuals enrolled in a randomized, double-blind, placebo-controlled therapeutic vaccine clinical trial in people with HIV (PWH) who began antiretroviral therapy (ART) during acute or early infection (ClinicalTrials registration no. NCT01859325). After the week 56 visit (postintervention), all participants interrupted ART. At the first available time points after viral rebound, we sequenced HIV-1 env (C2-V3), gag (p24), and pol (reverse transcriptase) regions amplified from cell-free HIV RNA in blood and seminal plasma using the MiSeq Illumina platform. Comprehensive sequence and phylogenetic analyses were performed to evaluate viral population structure, compartmentalization, and viral diversity in blood and seminal plasma. Compared to that in blood, HIV RNA rebound in semen occurred significantly later (median of 66 versus 42 days post-ART interruption, P < 0.01) and reached lower levels (median 164 versus 16,090 copies/ml, P < 0.01). Three of five participants with available sequencing data presented compartmentalized viral rebound between blood and semen in one HIV coding region. Despite early ART initiation, HIV RNA molecular diversity was higher in semen than in blood in all three coding regions for most participants. Higher HIV RNA molecular diversity in the genital tract (compared to that in blood plasma) and evidence of compartmentalization illustrate the distinct evolutionary dynamics between these two compartments after ART interruption. Future research should evaluate whether the genital compartment might contribute to viral rebound in some PWH interrupting ART.IMPORTANCE To cure HIV, we likely need to target the reservoirs in all anatomic compartments. Here, we used sophisticated statistical and phylogenetic methods to analyze blood and semen samples collected from 12 persons with HIV who began antiretroviral therapy (ART) during very early HIV infection and who interrupted their ART as part of a clinical trial. First, we found that HIV RNA rebound in semen occurred significantly later and reached lower levels than in blood. Second, we found that the virus in semen was genetically different in some participants compared to that in blood. Finally, we found increased HIV RNA molecular diversity in semen compared to that in blood in almost all study participants. These data suggest that the HIV RNA populations emerging from the genital compartment after ART interruption might not be the same as those emerging from blood plasma. Future research should evaluate whether the genital compartment might contribute to viral rebound in some people with HIV (PWH) interrupting ART.

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Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy.

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Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy.

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