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. 2021 Sep 29;18(1):63.
doi: 10.1186/s12981-021-00389-1.

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

Helen Payne  1   2   3 , Man K Chan  4 , Sarah A Watters  5   6 , Kennedy Otwombe  7 , Nei-Yuan Hsiao  8 , Abdel Babiker  4 , Avy Violari  7 , Mark F Cotton  9 , Diana M Gibb  4 , Nigel J Klein  10
Affiliations

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

Helen Payne et al. AIDS Res Ther. .

Abstract

Background: Reduction 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.

Methods: Infants 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.

Findings: Longer 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).

Intepretation: Longer 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.

Funding: Wellcome Trust, National Institutes of Health, Medical Research Council.

Keywords: ART; CHER; Children; HIV-1 proviral DNA; Reservoir.

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Conflict of interest statement

There are no financial and non-financial competing interests to be declared.

Figures

Fig. 1
Fig. 1
Overview of the CHER trial treatment strategies and median duration on ART within arms from participants analysed for HIV proviral DNA. Median time to ART initiation in the deferred arm, ART-Def, was 26.1 weeks (IQR 20–42.9, n  =  79). Median duration of ART-interruption for ART-40 W was 31.3 (12.5–54.3, n  =  56) and 52.3 (11.4–152, n  =  94) weeks in ART-96 W
Fig. 2
Fig. 2
HIV-1 proviral DNA analysis from weeks 96 and 248 of the CHER trial. Y-axes represent HIV-1 proviral DNA (log10 copies per 106 PBMCs). Plot A: HIV-1 proviral DNA in ART-Def [n  =  44, median 2415 (IQR 499–7450)] and ART-96 W (n  =  73, median [325 (53–3670) copies of HIV-1 proviral DNA/106 PBMCs] at week 96 (p  =  0.0019). Plot B: HIV-1 proviral DNA at week 96 by age of starting ART (n  =  117). Plot C: HIV-1 proviral DNA in ART-Def (n  =  70, ART-40 W (n  =  56) and ART-96 W (n  =  43) at 248 weeks (Kruskal–Wallis test p  =  0.2553). Plot D: HIV-1 proviral DNA at week 248 by duration of ART received by 248 weeks. Plot E: HIV-1 proviral DNA at trial week 248 by weeks of continuous HIV-1 RNA suppression below 400 copies/ml
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