Direct-acting antiviral treatment outcomes in people infected with endemic compared to epidemic hepatitis C virus subtypes in England.

BACKGROUND: Current evidence suggests reduced efficacy of direct-acting antiviral (DAA) treatment among people with endemic Hepatitis C virus (HCV) subtypes rare to high-income countries. We aimed to determine real-world DAA treatment outcomes of people with endemic HCV subtypes in England. METHODS: Data were collected through a national treatment program. People who had their virus subtyped between 2019-2023, were resident in England and had an outcome recorded for their first DAA treatment episode, were included. Subtypes were divided into epidemic and endemic in England; endemic subtypes were confirmed with whole genome sequencing and resistance associated substitutions (RAS) were determined. Logistic regression was used to determine associations between treatment outcome and exposure variables. RESULTS: In people with an outcome recorded, 93 with an endemic and 8671 with an epidemic HCV subtype were identified, of whom 49.5% (46/93) and 91.8% (7953/8668) achieved a sustained virological response at 12 weeks post end of DAA treatment (SVR12), respectively. In the multivariable model, people with an endemic subtype had 93% (aOR 0.07 95%CI 0.04-0.12, P=<0.001) reduced odds of achieving SVR12. Treatment with sofosbuvir/velpatasvir or glecaprevir/pibrentasvir was successful for genotypes 1, 2, 4 and 5 (SVR12 100%, n=13) but not 3 (27.3%, n=22) endemic subtypes. Sofosbuvir/velpatasvir/voxilaprevir was successful for GT3 endemic subtypes at retreatment (SVR12 11/12, 91.7%). Treatment failures for genotypes 1, 3 and 4 were likely mediated by naturally occurring baseline NS5A RAS (median n=2). DISCUSSION: This study provides further evidence that endemic HCV subtypes lead to sub-optimal DAA efficacy, which may impact global HCV elimination.