Direct-Acting Antivirals and Risk of Hepatitis C Extrahepatic Manifestations.

Importance: Hepatitis C virus (HCV) infection is associated with various extrahepatic manifestations (EHMs) that can significantly impact patients' quality of life and overall health outcomes. Objective: To assess the association between successful direct-acting antiviral (DAA) treatment and the risk of EHMs in individuals with chronic HCV infection. Design, Setting, and Participants: This population-based retrospective cohort study used data from 1990 to 2021, with a median follow-up of 2.5 years for outcome assessment. People treated with DAAs were matched to those who were never treated by year of HCV diagnosis and inverse probability of treatment weights (IPTW) were estimated to adjust for differences in baseline characteristics between treated and untreated people. The study took place in British Columbia, Canada, using the BC Hepatitis Testers Cohort, which includes more than 1 300 000 people tested for HCV between 1990 to 2015. Data were analyzed from February 2024 to March 2025. Exposure: Successful HCV treatment with DAAs, defined as achieving sustained virologic response (SVR). Main Outcomes and Measures: Incidence of 5 groups of EHMs: chronic kidney disease and end-stage kidney disease (CKD and ESKD), type 2 diabetes (T2D), stroke, major adverse cardiac events (MACE), and neurocognitive disorders (NCD). Results: Of 22 576 individuals included in this study (mean [SD] age at HCV diagnosis, 42.0 [12.0] years; 14 950 male [66.2%]), 11 953 received DAA treatment and achieved SVR, 386 received treatment but did not achieve SVR, and 10 237 never received treatment. The incidence rates (per 1000 person-years) in untreated vs treated with SVR groups were: 21.0 (95% CI, 19.0-23.1) vs 14.7 (95% CI, 13.4-16.1) for CKD and ESKD, 8.9 (95% CI, 7.7-10.2) vs 6.3 (95% CI, 5.5-7.2) for stroke, 26.7 (95% CI, 24.5- 29.1) vs 19.3 (95% CI, 17.8-20.9) for MACE, 19.2 (95% CI, 17.3-21.2) vs 10.3 (95% CI, 9.2-11.5) for NCD, and 6.4 (95% CI, 5.4-7.7) vs 9.2 (95% CI, 8.1-10.4) for T2D. In multivariable IPTW-weighted regression models, successful DAA treatment was associated with lower risk of CKD and ESKD (adjusted cause-specific hazard ratio [acsHR], 0.54; 95% CI, 0.47-0.63), stroke (acsHR, 0.66; 95% CI, 0.54-0.81), MACE (acsHR, 0.58; 95% CI, 0.52-0.66), and NCD (acsHR, 0.52; 95% CI, 0.45-0.61) compared with no treatment. However, no significant association was found for T2D (acsHR, 1.04; 95% CI, 0.84-1.29). Conclusions and Relevance: In this cohort study of 22 576 individuals with chronic HCV infection, successful HCV treatment with DAAs was associated with lower risk of several EHMs. These findings highlight the importance of early HCV screening and treatment to prevent EHMs and improve overall health outcomes.