Background: Chronic hepatitis C virus (HCV) infection affects >1% of the U.S. population, higher among U.S. Veterans. Direct-acting antiviral (DAA) medications are effective for viral cure, termed sustained virologic response (SVR), but repeat viremia after SVR is recognized. Prior work has been limited by use of electronic medical record data. We aim to better understand repeat viremia in the DAA era through detailed chart review.
Methods: We identified 1,129 individuals from Veteran's Health Administration (VHA) who achieved SVR using DAA therapy but subsequently had detectable serum HCV nucleic acid. A random subset of 110 were chart reviewed and assigned one of four categories using laboratory, diagnosis, and chart review data: definite reinfection (25.5%), probable reinfection (25.5%), false positive (11.8%), and presumed late relapse (37.3%). We conducted between-group analysis of variance to identify demographic, behavioral, and laboratory features specific to each.
Results: In our medical record cohort (n=1,129), substance use and unstable housing were common and median time to repeat viremia was 1.9 years. In our chart review cohort (n=110), younger age (18-34) and substance use were more frequent in definite or probable reinfection. Presumed relapse had comparatively more comorbid hepatocellular carcinoma (HCC) (20%, p<0.05) and more than half occurred prior to 1 year. The unique category of false positive has not previously been reported.
Conclusions: This study deepens understanding of HCV reinfection and relapse and highlights important features including the HCV and opioid syndemic, contribution of laboratory error, possibility of a viral reservoir in HCC, and clinical engagement implications for those with ongoing risk.
Keywords: Hepatitis C; direct acting antivirals; hepatitis C reinfection; hepatitis C relapse; sustained virologic response.
Published by Oxford University Press on behalf of Infectious Diseases Society of America 2025.