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

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

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 als...

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Bibliographic Details
Published in:Antiviral therapy Vol. 22; no. 5; p. 431
Main Authors: Gozlan, Yael, Ben-Ari, Ziv, Moscona, Roy, Shirazi, Rachel, Rakovsky, Aviya, Kabat, Arij, Veizman, Ella, Berdichevski, Tania, Weiss, Peretz, Cohen-Ezra, Oranit, Lurie, Yoav, Gafanovich, Inna, Braun, Marius, Cohen-Naftaly, Michal, Shlomai, Amir, Shibolet, Oren, Zigmond, Ehud, Zuckerman, Eli, Carmiel-Haggai, Michal, Nimer, Assy, Hazzan, Rawi, Maor, Yaakov, Kitay-Cohen, Yona, Shemer-Avni, Yonat, Kra-Oz, Zipi, Schreiber, Licita, Peleg, Ofer, Sierra, Saleta, Harrigan, P Richard, Mendelson, Ella, Mor, Orna
Format: Journal Article
Language:English
Published: England 01-01-2017
Subjects:
Adult
Aged
Amino Acid Substitution
Antiviral Agents - therapeutic use
Drug Therapy, Combination
Female
Genotype
Hepacivirus - classification
Hepacivirus - genetics
Hepatitis C - drug therapy
Hepatitis C - virology
Humans
Male
Middle Aged
Mutation
Treatment Failure
Treatment Outcome
Viral Nonstructural Proteins - genetics
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Description
Summary: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.
ISSN:2040-2058
DOI:10.3851/imp3123