Multisite NS5A Resistance Mutations Leading to Virological Breakthrough in Hepatitis C Virus Genotype 1b: A Case Report

Background The clinical application of direct-acting antiviral agents has substantially enhanced the sustained virological response (SVR) rates in chronic hepatitis C virus (HCV) infection. Nevertheless, treatment failure continues to occur, primarily due to resistance-associated substitutions arising from HCV's high genetic variability, while real-world data on multigenic resistance in HCV genotype 1b remain limited. Herein, we describe a patient with HCV genotype 1b infection (baseline HCV RNA level of \(\:6.1\times\:{10}^{5}\)IU/mL) who experienced virological breakthrough, with viral rebound to 4.92 × 10⁵ IU/mL, after 12 weeks of elbasvir/grazoprevir (Zepatier) therapy. Case presentation: A 60-year-old man presenting with dry mouth and bitter taste was confirmed to have HCV genotype 1b infection. Resistance testing revealed co-occurring mutations at four sites within the HCV NS5A region: R30Q, L31M, Q54H, and Y93H. The patient received a 12-week course of salvage therapy with sofosbuvir/velpatasvir/voxilaprevir, achieving and maintaining SVR, with HCV RNA levels remaining < 15 IU/mL through 154 weeks of follow-up. Conclusions This case highlights treatment failure associated with four-site NS5A resistance mutations in HCV genotype 1b. It also reminds clinicians of the potential risk of multi-locus drug-resistant mutations even in the so-called "easy-to-treat" HCV genotype 1b, highlighting the importance of strengthened virological monitoring throughout therapy and prompt resistance testing following treatment failure.