engleski

Resistance to direct antiviral therapy in treatment-naive patients infected with genotype 1 of hepatitis C virus in Croatia

Direct-acting antivirals (DAA) that selectively target nonstructural proteins of the hepatitis C virus (HCV) have been successful in obtaining high rates of sustained virologic response (SVR). Fast error-prone viral replication inevitably leads to emergence of quasispecies and possibly resistance- associated substitutions (RAS) which can be associated with inadequate treatment outcomes. The aim of this study was to assess the frequency of RAS to currently available DAA in patients infected with HCV genotype 1 prior to initiation of treatment with DAA. The study included 189 treatment-naive patients with chronic hepatitis C virus genotype 1 infection (109 subtype 1a, 80 subtype 1b) receiving care at the University Hospital for Infectious Diseases, Zagreb. Viral RNA was extracted from serum while NS5A, NS3 and NS5B region were amplified in two step PCR by using home-made protocols specific for each HCV subtype. The presence of resistance-associated mutations was evaluated by Sanger sequencing followed by mutational analysis according to geno2pheno [HCV] algorithm. The overall frequency of baseline resistance conferring RAS in genotype 1-infected patients was 11.1% (21/189) in NS5A region and 32.3% (61/189) in NS3 region with an observed difference across 1a and 1b subtypes. NS5A resistance conferring RAS were mainly present in subtype 1b infected patients (16/80, 20.0%) with similar prevalence of Y93H (9/80, 11.3%), L31M (4/80, 5.0%) and R30Q (5/80, 6.3%). NS3 resistance conferring RAS were mainly present in subtype 1a infected patients (57/109, 52.3%) with high prevalence of Q80K mutation (51/109, 46.8%) detected almost exclusively in clade I. Substitutions associated with reduced susceptibility to NS5B inhibitor Sofosbuvir (L159F) were present only in subtype 1b infected patients (25/80, 31.3%). In the recent years, HCV treatment policy in Croatia has shifted substantially with removal of treatment restrictions based on fibrosis stage and patient age. However, the choice of therapeutic regimen is still very much genotype based and therefore it is important to choose appropriate DAA combination in order to facilitate the achievement of SVR. We showed moderate to high prevalence of clinically relevant RAS, especially Y93H mutation in genotype 1b patients which causes resistance to all DAA except pibrentasvir. Tailored approach to DAA therapy could be highly beneficial for such patients.

Hepatitis C virus ; Genotype 1 ; Resistance-associated substitutions ; Direct-acting antivirals ; Population-based sequencing

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