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Characterization of NS5A, NS3 and NS5B resistance- associated substitutions in patients with hepatitis C virus subtype 1a, 1b and 3a in Croatia

Antiviral therapy for hepatitis C virus has been considerably improved with the introduction of direct-acting antivirals (DAA), however naturally present resistance-associated substitutions (RAS) can significantly reduce sustained viral response in 5- 10% of patients. The aim of this study was to extensively characterize the presence of natural RAS in the NS3, NS5A and NS5B regions of HCV genome. The study included 306 consecutive patients with chronic hepatitis C subtype 1a, 1b or 3a infection receiving clinical care at the University Hospital for Infectious Diseases, Zagreb from 2016 to 2019. HCV RNA was extracted from serum while NS5A, NS3 and NS5B region were amplified in two step PCR. Subsequent sequencing analysis of nested PCR-products was performed on AB 3500 Genetic Analyzer, while resistance to direct acting antivirals was evaluated using the Geno2pheno [HCV] algorithm. RAS were observed with highly variable prevalence across different HCV subtypes. Subtype 1a patients had a very high prevalence of resistance conferring RAS in NS3 region (51.3%), low prevalence of resistance conferring RAS in NS5A region (4.4%) and no RAS in NS5B region. Subtype 1b patients however had high prevalence of NS5A resistance conferring RAS (19.5%) and low prevalence of NS3 resistance conferring RAS (4.9%) with high number of RAS causing reduced susceptibilty to NS3 inhibitors (22.0%). This was the only patient group with RAS causing reduced susceptibility to NS5B inhibitor sofosbuvir (30.5%). Subtype 3a patients were largely susceptible to DAAs with only 2.7% resistance conferring RAS in NS5A region and 0.9% resistance conferring RAS in NS3 region. Most commonly detected RAS were M28V, Y56F, Q80K, Y93H and N174S. Prevalence of RAS was much higher in patients infected with genotype 1 than subtype 3a of HCV. Tailored approach to DAA therapy could be beneficial for complex and difficult to treat patients.

Hepatitis C virus ; Resistance-associated substitutions ; Direct-acting antivirals ; Population-based sequencing

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