Prognostic Value of Blood Epigenetic Biomarkers of Aging in Persons With Well-Controlled HIV-1 Infection

BACKGROUND: Epigenetic age acceleration (EAA) predicts morbidity and mortality in the general population, but its prognostic utility in people with human immunodeficiency virus (HIV) (PWH) on suppressive antiretroviral therapy remains unclear. METHODS: Longitudinal observational cohort of 216 PWH with sustained virological suppression (median 6.5 years) recruited from the DUAL-GESIDA trial and La Paz Aging Cohort (Spain). Baseline blood DNA methylation was assessed to evaluate 8 epigenetic clocks, their principal-component (PC) derivatives, and the telomere length estimator. Over 10 years, we recorded AIDS, serious non-AIDS (SNAEs), and aging-related events. Associations between EAA and outcomes were evaluated by multivariate Cox models. RESULTS: One hundred five participants experienced ≥ 1 event, 162 events recorded in total (1 AIDS event, 65 SNAEs, and 96 aging-related events). A positive EAA by Horvath's clock was associated with a 50% higher risk of aging-related events. Participants with positive EAA according to PC-GrimAge, GrimAge V1-V2, as well as Hannum´s clock experienced more than 2-fold increased risk of SNAEs. Positive EAA by PC-GrimAge and PhenoAge was associated with an increased risk of non-AIDS cancer. Additionally, positive EAA according to GrimAge V1-V2 was linked to a 4-fold increase in all-cause mortality risk. All individuals who died (n = 17) had a baseline DunedinPACE value >1. No associations were found for the composite endpoint or cardiovascular events. CONCLUSIONS: In this preliminary study, GrimAge and PC-GrimAge were associated with increased risk of adverse outcomes in people with well-controlled HIV infection. These findings suggest their potential as long-term health-risk biomarkers, warranting validation in larger cohorts.