Risk of Intrahepatic and Extrahepatic Cancers in Hepatitis C Virus Infection: A Nationwide Cohort Study in Korea,...

We evaluated the association between hepatitis C virus (HCV) infection and the risk of intrahepatic and extrahepatic cancers. Specifically, we compared "1st" versus "1st or 2nd" primary cancers to capture the true disease burden, which is often underestimated in conventional analyses. Additionally, we evaluated the chemopreventive effect of direct-acting antiviral (DAA) therapy on these risks.

Using the Korean National Health Insurance database (2005-2023), we compared 119 565 HCV-infected individuals with 2 267 700 controls. Adjusted subdistribution hazard ratios (aHRs) were calculated using competing risk models. Direct-acting antivirals (DAA) effectiveness was evaluated in a sub-cohort of 23 147 patients (2016-2020) using time-dependent Cox models to account for immortal time bias.

In the analysis of 1st or 2nd cancers, HCV infection significantly increased the risk of intrahepatic (aHR 16.35; 95% CI, 15.81-16.90) and extrahepatic cancers (aHR 1.14; 95% CI, 1.12-1.16). Notably, expanding the endpoint to include 2nd cancers increased the aHR for extrahepatic cancer from 1.09 to 1.14, indicating that traditional analyses underestimate the true burden. Significant risk elevations were observed for haematological, biliary, pancreatic, and renal cancers. In the DAA sub-cohort analysis using the time-dependent model, DAA treatment significantly reduced the risk of intrahepatic cancer (aHR 0.54-0.61) and extrahepatic cancers (aHR 0.77) after adjusting for competing risks.

HCV infection significantly increases both intrahepatic and extrahepatic cancer risks. Excluding 2nd cancer underestimates this burden. Given that DAA therapy significantly reduces the risk of both intrahepatic and extrahepatic cancers, accelerating HCV elimination policies is imperative.