Early ART-initiation and longer ART duration reduces HIV-1 proviral DNA levels in children from the CHER trial

Helen Payne,Sarah A Watters,Nigel J Klein,Abdel Babiker,Nei-Yuan Hsiao,Man K Chan,Avy Violari,Diana M Gibb,Kennedy Otwombe,Mark F Cotton

doi:10.1186/s12981-021-00389-1

Abstract

BackgroundReduction of the reservoir of latent HIV-infected cells might increase the possibility of long-term remission in individuals living with HIV. We investigated factors associated with HIV-1 proviral DNA levels in children receiving different antiretroviral therapy (ART) strategies in the children with HIV early antiretroviral therapy (CHER) trial.MethodsInfants with HIV < 12 weeks old with CD4% ≥ 25% were randomized in the CHER trial to early limited ART for 40 or 96 weeks (ART-40 W, ART-96 W), or deferred ART (ART-Def). For ART-Def infants or following ART interruption in ART-40 W/ART-96 W, ART was started/re-started for clinical progression or CD4% < 25%. In 229 participants, HIV-1 proviral DNA was quantified by PCR from stored peripheral blood mononuclear cells from children who had received ≥ 24 weeks ART and two consecutive undetectable HIV-1 RNA 12–24 weeks apart. HIV-1 proviral DNA was compared between ART-Def and ART-96 W at week 96, and in all arms at week 248. Factors associated with HIV-1 proviral DNA levels were evaluated using linear regression.FindingsLonger duration of ART was significantly associated with lower HIV-1 proviral DNA at both 96 (p = 0.0003) and 248 weeks (p = 0.0011). Higher total CD8 count at ART initiation was associated with lower HIV-1 proviral DNA at both 96 (p = 0.0225) and 248 weeks (p = 0.0398). Week 248 HIV-1 proviral DNA was significantly higher in those with positive HIV-1 serology at week 84 than those with negative serology (p = 0.0042).IntepretationLonger ART duration is key to HIV-1 proviral DNA reduction. Further understanding is needed of the effects of “immune-attenuation” through early HIV-1 exposure.FundingWellcome Trust, National Institutes of Health, Medical Research Council.

Highlights

An estimated 3.3 million children under 15 years of age live with human immunodeficiency virus (HIV) worldwide, over 90% in sub-Saharan Africa [1, 2]
We explored the relationship between HIV-1 proviral DNA and clinical and immunological characteristics available from the children with HIV early antiretroviral therapy (CHER) trial, including baseline viral loads, CMV serostatus and quantification at randomisation, and HIV-1 serostatus and quantitative HIV-specific antibodies at trial week 84
In multivariable analysis (Table 4a), at 96 weeks, longer duration of antiretroviral therapy (ART) was significantly associated with lower levels of HIV-1 proviral DNA [ß = − 1.21, p = 0.0003]

Summary

Introduction

An estimated 3.3 million children under 15 years of age live with human immunodeficiency virus (HIV) worldwide, over 90% in sub-Saharan Africa [1, 2]. There is increasing interest in viral reservoirs following reports of HIV remission ( known as functional cure) in adults and children treated soon after infection [13]. One of 227 early-treated children from the children with HIV early antiretroviral therapy (CHER) trial stopped ART after 40 weeks, as per trial randomization, and remained negative for HIV diagnostic tests at the age of 9.5 years [16]. Virus persists at very low levels in plasma and is detectable as low levels of cell-associated DNA, but immunologically he is not unlike healthy children of similar age. We investigated factors associated with HIV-1 proviral DNA levels in children receiv‐ ing different antiretroviral therapy (ART) strategies in the children with HIV early antiretroviral therapy (CHER) trial

Methods

Results

Discussion

Conclusion