Safety and Drug–Drug Interaction Burden of Direct‐Acting Antiviral Therapy for Hepatitis C: A Single‐Center Community Hospital Analysis

Background Polypharmacy leads to drug–drug interactions (DDIs) with direct‐acting antivirals (DAAs). We quantified the DDI burden (Liverpool categories) and evaluated its association with effectiveness and safety. We assessed renal function as a predictor of adverse events (AEs) and reported loss to follow‐up (LTFU). Methods We retrospectively analyzed 145 adults with chronic hepatitis C treated with glecaprevir/pibrentasvir (GLE/PIB) or sofosbuvir/velpatasvir (SOF/VEL) between February 2018 and October 2024. The primary endpoint was sustained virological response 12 weeks after the end of treatment (SVR12); when SVR12 was missing, SVR24 was substituted (hierarchical SVR). Concomitant drugs were screened using the Liverpool HEP Drug Interaction Checker. The predictors of AEs were assessed using multivariable logistic regression and receiver operating characteristic analysis. A conservative intention‐to‐treat analysis included missing SVR data as a failure. Results The median patient age was 67 years, and 23.4% of patients had cirrhosis. Polypharmacy (≥ 5 drugs) occurred in 26.9% of patients, DDIs in 50.3%, multiple DDIs in 14.5%, and contraindicated pairs in 1.4% (all GLE/PIB). AEs occurred in 16.6% of patients, were largely Grades 1–2, and began around Week 2. LTFU was 11.0%. The hierarchical SVR was 99.2%, whereas the conservative analysis was 88.3%. A Cr concentration ≥ 0.86 mg/dL independently predicted AEs (adjusted OR 3.4; 95% CI 1.24–9.2), whereas DDI burden and polypharmacy did not. Conclusions Despite frequent DDIs, DDI burden was not independently associated with SVR or AEs. DAA therapy was highly effective and well tolerated. Renal function showed a modest association with AEs.