Background
HIV infection and substance use have been associated with accelerated epigenetic aging. However, limited data exist on the long-term implications associated with age acceleration and HIV among persons who inject drugs (PWID).
Methods
We included participants from the AIDS Linked to the Intravenous Experience (ALIVE) study, a community-based cohort of PWID. DNA was isolated from buffy coat samples and treated with bisulfite before being analyzed using the Illumina MethylationEPIC BeadChip. Four measures of epigenetic age were generated: PhenoAge, Horvath age, Hannum age, and GrimAge. All participants were linked annually to the National Death Index-Plus to determine time and vital status since 1988. We used linear mixed effect regressions to compare the trajectories of epigenetic age acceleration and Cox regression to determine the hazard of all-cause mortality by epigenetic age and HIV status. All models controlled for demographics, current injection drug use, and current smoking.
Results
Of 396 participants (127 people with HIV [PWH]) with 792 person-years of follow-up, the median age at baseline was 48.5 years. Of these, the majority were Black (89%) and male (69%). Compared to people without HIV (PWoH), PWH exhibited age acceleration based on multiple epigenetic clocks. This acceleration was further exacerbated by poorly controlled HIV viral load. People with HIV had 2 years (b = 1.79, 95% CI = 0.74, 2.84) and 4 years (b = 4.00, 95% CI = 2.30, 5.69) of age acceleration in GrimAge and PhenoAge, respectively, compared to PWoH. Those with a detectable viral load had faster age acceleration, with 3 years (b = 3.14, 95% CI = 2.13, 4.15) and ~7 years (b = 6.65, 95% CI = 5.01, 8.28) of GrimAge and PhenoAge acceleration, respectively. No differences were observed using Horvath’s clock. Both HIV and epigenetic age acceleration were independently associated with all-cause mortality. Compared to PWoH demonstrating PhenoAge deceleration, PhenoAge acceleration with or without HIV was associated with a 3.28 (95% CI: 2.06, 5.02) and 2.12 (95% CI: 1.32, 3.41) times higher hazard of all-cause mortality, respectively.
Conclusions
HIV infection and detectable viral load are associated with epigenetic age acceleration. Age acceleration and HIV infection independently and jointly increase mortality risk among persons who inject drugs. These findings highlight the importance of addressing molecular aging to reduce mortality burden among PWID.
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