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Original article

HCV genotype-1 subtypes and resistance-associated substitutions in drug-naive and in direct-acting antiviral treatment failure patients

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, Assy Nimer, Rawi Hazzan, Yaakov Maor, Yona Kitay-Cohen, Yonat Shemer-Avni, Zipi Kra-Oz, Licita Schreiber, Ofer Peleg, Saleta Sierra, P Richard Harrigan, Ella Mendelson, Orna Mor

Corresponding author name: Orna Mor
Corresponding author e-mail: orna.mor@sheba.health.gov.il

Citation: Antiviral Therapy 2017; 22:431-441
doi: 10.3851/IMP3123

Date accepted: 18 December 2016
Date published online: 09 January 2017

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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