Epigenetic age acceleration and mortality among persons with poorly controlled HIV.

We sought to assess the relationship between HIV infection and disease severity with epigenetic age and to examine the combined association of epigenetic age acceleration and HIV infection with mortality. Participants were drawn from the ALIVE study, a community-based cohort of persons who inject drugs (PWID) in Baltimore, MD, USA. DNA from buffy coat samples was bisulfite-treated and assayed using the Illumina MethylationEPIC BeadChip. Repeated assessment of epigenetic age was indexed using PhenoAge, Horvath age, Hannum age, GrimAge, and DunedinPACE. Annual linkage to the National Death Index-Plus provided mortality data. Linear mixed-effects regressions compared epigenetic age acceleration trajectories. Cox models estimated hazard ratios for all-cause mortality by epigenetic age and HIV status, adjusting for demographics, risk behaviors, estimated cell composition, and ancestry principal components. Among 396 participants (127 with HIV [PWH]) and 3862 person-years of follow-up, the median baseline age was 48.5 years; 89% were Black and 69% male. PWH showed greater epigenetic age acceleration than people without HIV (PWoH), especially those with detectable viremia, low CD4 counts, and low CD4:CD8 ratios. Both HIV and epigenetic age acceleration were independently associated with all-cause mortality. Compared to PWoH without PhenoAge acceleration, PhenoAge acceleration with or without HIV was associated with 3.28 (95% CI: 2.06, 5.02) and 2.12 (95% CI: 1.32, 3.41) times higher mortality hazard, respectively. HIV infection, uncontrolled viremia, and poor immune recovery are linked to epigenetic age acceleration, contributing to mortality risk among PWID, underscoring the need to address molecular aging to mitigate mortality in this population.