Epigenetic age acceleration changes 2 years after antiretroviral therapy initiation in adults with HIV: a substudy of the NEAT001/ANRS143 randomised trial.
Level 2 - randomized trial
Substudy of a randomized controlled trial analyzing longitudinal biomarker changes across randomized arms with an uninfected comparison group
PubMed 33794182 · doi:10.1016/S2352-3018(21)00006-0
What was done
Researchers assessed biological aging using DNA methylation in a substudy of the NEAT001/ANRS143 randomized trial. Frozen whole blood was analyzed from 168 antiretroviral therapy (ART)-naive adults with HIV at baseline and after 2 years of treatment, split evenly between two randomized regimens: ritonavir-boosted darunavir plus raltegravir (n=84) or ritonavir-boosted darunavir plus tenofovir disoproxil fumarate and emtricitabine (n=84). Measurements were compared against 44 age- and sex-matched HIV-negative controls. Epigenetic age acceleration (EAA) was calculated using Horvath, Hannum, GrimAge, and PhenoAge clocks, alongside DNA methylation-based leukocyte subset estimations.
What was found
Prior to ART, participants with HIV had significantly higher EAA than uninfected controls across most clocks: Horvath (mean difference 2.5 years, 95% CI 1.89–3.22, p=0.0008), GrimAge (2.8 years, 95% CI 1.97–3.68, p=0.0021), and PhenoAge (7.3 years, 95% CI 6.40–8.13, p<0.0001), while Hannum-EAA was not statistically significant (1.4 years, 95% CI 0.74–1.99, p=0.059). Baseline EAA was higher in individuals with CD4 counts <200 cells/μL (PhenoAge p=0.0015; Hannum p=0.034) and viral loads >100,000 copies/mL (PhenoAge p=0.017). After 2 years of ART, EAA decreased, but PhenoAge-EAA (mean difference 3.69 years, 95% CI 1.77–5.61, p=0.0002) and GrimAge-EAA (2.2 years, 95% CI 0.47–3.99, p=0.013) remained elevated compared to controls. No significant differences in EAA changes were observed between the two ART regimens. ART also partly normalized baseline leukocyte subset dysregulation.
Why it matters
The study demonstrates that initiating ART partially reverses biological aging acceleration driven by untreated HIV, but residual epigenetic aging persists at 2 years regardless of the specific antiretroviral drug combination used.
Limits
The control group was non-randomized and relatively small (n=44). Follow-up was restricted to 2 years, leaving long-term aging dynamics unmeasured. Epigenetic clock measurements are surrogate biomarkers, and their direct translation to clinical morbidity or mortality endpoints in this cohort was not evaluated.
Cited by
- supports HIV-positive individuals exhibit 5 to 7 years of epigenetic age acceleration in blood, which is reversed by 4 to 5 years following antiretroviral therapy.