Abstract
IMPORTANCE: Although hepatitis C virus (HCV) is an oncovirus, its association with the risk of pancreatic ductal adenocarcinoma (PDAC) is unclear. In addition, it is unknown whether there is differential risk for PDAC across HCV genotypes. OBJECTIVE: To assess the association between chronic HCV and PDAC. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, national, population-based cohort study was conducted across Veterans Health Administration (VA) sites. The study included veterans with HCV testing documented in the VA or VA-linked Medicare with at least 1 inpatient or outpatient visit between October 1, 2001, and September 30, 2020. Patients were followed-up for at least 18 months after this visit. Data were analyzed from October 2023 to September 2025. EXPOSURE: HCV status was categorized as chronic HCV, exposure to HCV, or no chronic HCV infection. MAIN OUTCOMES AND MEASURES: The association of HCV status with PDAC was evaluated using Cox proportional hazards regression, adjusting for demographic and clinical confounders. Analysis was substratified by HCV genotype. RESULTS: Of 6 330 856 people tested for HCV (5 841 571 men [92.3%]; median [IQR] age, 61.6 years [49.9-70.1]), 246 218 (3.9%) had chronic HCV and 209 492 (3.3%) were exposed. Of the 33 451 individuals (0.5%) who developed PDAC, age at diagnosis was younger among those with vs those without HCV (median [IQR] age, 65.0 [59.9-69.6] years vs 72.4 [66.7-79.0] years). Compared with no HCV infection, chronic HCV infection (adjusted hazard ratio [aHR], 1.76; 95% CI, 1.67-1.86) and HCV exposure (aHR, 1.18; 95% CI; 1.11-1.25) were associated with increased risk of incident PDAC. Hazards for PDAC were greater for HCV genotype 3 (aHR, 2.02; 95% CI, 1.67-2.45) and genotype 1 (aHR, 1.75; 95% CI, 1.64-1.87) than for genotype 2 (aHR, 1.35; 95% CI, 1.14-1.60) compared with no HCV infection. CONCLUSIONS AND RELEVANCE: In this cohort study of veterans, chronic HCV infection was associated with a 1.8-fold higher risk of PDAC diagnosis, and HCV genotypes 3 and 1 had greater PDAC risk than genotype 2. These findings prompt future research on the mechanisms underlying this association and the impact of HCV treatment on PDAC risk.