Direct-acting antiviral therapy is associated with a reduced risk of selected immune-mediated inflammatory diseases in chronic hepatitis C infection: A real-world cohort study

BACKGROUND: Chronic hepatitis C virus (HCV) infection is associated with immune dysregulation and an increased risk of immune-mediated inflammatory diseases (IMIDs). While direct-acting antiviral (DAA) therapy achieves high rates of sustained virologic response, its long-term effects on the risk of IMIDs remain incompletely understood. METHODS: We conducted a retrospective cohort study using data from the TriNetX global research network (2015-2024) to evaluate the association between DAA therapy and the risk of IMIDs among adults with chronic HCV infection. Patients were categorized into DAA-treated and untreated cohorts. Propensity score matching (1:1) was applied to balance baseline characteristics between groups. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Sensitivity analyses, along with predefined positive and negative control outcomes, were performed to assess robustness. Subgroup analyses were conducted to assess potential effect modifiers. RESULTS: After matching, 35,266 patients were included in each cohort. DAA therapy was associated with a significantly reduced risk of several IMIDs, including rheumatoid arthritis (HR 0.83, 95% CI 0.71-0.97), autoimmune hepatitis (HR 0.55, 95% CI 0.31-0.96), and immune thrombocytopenic purpura (HR 0.64, 95% CI 0.44-0.93). These associations were consistent across multiple predefined time-at-risk windows. Subgroup analyses revealed that the protective associations were more pronounced among females and middle-aged individuals (41-64 years). CONCLUSIONS: DAA therapy in patients with chronic HCV infection is associated with a reduced risk of specific IMIDs, suggesting potential systemic immunologic benefits beyond hepatic outcomes.