Abstract
Co-occurrence of injection drug use (IDU) and hepatitis C virus infection (HCV) is common in people living with HIV (PLWH) and leads to significantly increased mortality. Epigenetic clocks derived from DNA methylation (DNAm) are associated with disease progression and all-cause mortality. In this study, we hypothesized that epigenetic age mediates the relationships between the co-occurrence of IDU and HCV with mortality risk among PLWH. We tested this hypothesis in the Veterans Aging Cohort Study (n = 927) by using four established epigenetic clocks of DNAm age (i.e., Horvath, Hannum, Pheno, Grim). Compared to individuals without IDU and HCV (IDU-HCV-), participants with IDU and HCV (IDU+HCV+) showed a 2.23-fold greater risk of mortality estimated using a Cox proportional hazards model (hazard ratio: 2.23; 95% confidence interval: 1.62-3.09; p = 1.09E-06). IDU+HCV+ was associated with a significantly increased epigenetic age acceleration (EAA) measured by 3 out of 4 epigenetic clocks, adjusting for demographic and clinical variables (Hannum: p = 8.90E-04, Pheno: p = 2.34E-03, Grim: p = 3.33E-11). Furthermore, we found that epigenetic age partially mediated the relationship between IDU+HCV+ and all-cause mortality, up to a 13.67% mediation proportion. Our results suggest that comorbid IDU with HCV increases EAA in PLWH that partially mediates the increased mortality risk.