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HCV Genotype-1 Subtypes and Resistance-Associated Substitutions in Drug-Naive and in Direct-Acting Antiviral Treatment Failure Patients

2016; SAGE Publishing; Volume: 22; Issue: 5 Linguagem: Inglês

10.3851/imp3123

2040-2058

Yael Gozlan, Ziv Ben‐Ari, Roy Moscona, Rachel Shirazi, Aviya Rakovsky, Arij Kabat, Ella Veizman, Tania Berdichevski, Peretz Weiss, Oranit Cohen‐Ezra, Yoav Lurie, Inna Gafanovich, Marius Braun, Michal Cohen‐Naftaly, Amir Shlomai, Oren Shibolet, Ehud Zigmond, Eli Zuckerman, Michal Carmiel-Haggai, Nimer Assy, Rawi Hazzan, ‪Yasmin Maor‬‏, Yona Kitay‐Cohen, Yonat Shemer‐Avni, Zipi Kra-Oz, Licita Schreiber, Ofer Peleg, Saleta Sierra, P. Richard Harrigan, Ella Mendelson, Orna Mor,

Biochemical and Molecular Research

Direct-acting antiviral (DAA) treatment regimens and response rates of patients with HCV genotype-1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions.In a multicentre cohort study (n=308), NS3 or NS5B sequencing (n=248) was used to discriminate between GT1 subtypes. The correlation between baseline NS3 and NS5A RASs on the 12-week sustained virological response (SVR12) rates of 160 of the patients treated with second-generation DAAs was also assessed. Post-treatment resistance analysis was performed on samples from 58 patients exhibiting DAA virological failure.GT1a, GT1b and GT1d subtypes were identified in 23.0%, 75.4% and 1.2% of tested samples. GT1b was most prevalent (97.7%, 128/131) among patients born in the former Soviet Union. The Q80K NS3 RAS was identified in 17.5% (10/57) of the GT1a carriers, most of whom were Israeli-born. NS3 and NS5A baseline RASs showed a negligible correlation with SVR12 rates. Treatment-emergent RASs were observed among 8.9% (4/45) and 76.9% (10/13) of first- and second-generation DAA failures, respectively, with D168V/E (NS3), Y93H and L31M (NS5A) being the most prevalent mutations.NS3 sequencing analysis can successfully discriminate between GT1 subtypes and identify NS3 amino acid substitutions. While pre-treatment NS3 and NS5A RASs marginally affect second-generation DAA SVR12 rates, post-treatment resistance analysis should be considered prior to re-therapy.