title: HCV genotype-1 subtypes and resistance-associated substitutions in drug-naive and in direct-acting antiviral treatment failure patients.
abstract: 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.
authors.affiliation: Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat-Gan, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Gozlan
authors.affiliation: Liver Disease Center, Sheba Medical Center, Ramat-Gan, Israel.|The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ziv
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authors.lastname: Ben-Ari
authors.affiliation: Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat-Gan, Israel.
authors.forename: Roy
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authors.lastname: Moscona
authors.affiliation: Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat-Gan, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Shirazi
authors.affiliation: Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat-Gan, Israel.
authors.forename: Aviya
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authors.lastname: Rakovsky
authors.affiliation: Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat-Gan, Israel.
authors.forename: Arij
authors.initials: A
authors.lastname: Kabat
authors.affiliation: Liver Disease Center, Sheba Medical Center, Ramat-Gan, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Veizman
authors.affiliation: Liver Disease Center, Sheba Medical Center, Ramat-Gan, Israel.
authors.forename: Tania
authors.initials: T
authors.lastname: Berdichevski
authors.affiliation: Liver Disease Center, Sheba Medical Center, Ramat-Gan, Israel.
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authors.affiliation: Liver Disease Center, Sheba Medical Center, Ramat-Gan, Israel.
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authors.affiliation: Liver Unit, Shaare Zedek Medical Center, Jerusalem, Israel.
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authors.affiliation: Liver Unit, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Inna
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authors.affiliation: The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Liver Institute, Rabin Medical Center, Petah-Tikva, Israel.
authors.forename: Marius
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authors.affiliation: The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Liver Institute, Rabin Medical Center, Petah-Tikva, Israel.
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authors.affiliation: The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Liver Institute, Rabin Medical Center, Petah-Tikva, Israel.
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authors.affiliation: The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Gastroenterology, Tel-Aviv Medical Center, Tel Aviv, Israel.
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authors.lastname: Shibolet
authors.affiliation: The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Gastroenterology, Tel-Aviv Medical Center, Tel Aviv, Israel.
authors.forename: Ehud
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authors.affiliation: Liver Unit, Carmel Medical Center, Haifa, Israel.
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authors.lastname: Zuckerman
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authors.forename: Michal
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authors.lastname: Carmiel-Haggai
authors.affiliation: Faculty of Medicine in the Galilee, Bar-Ilan University, Ramat-Gan, Israel.|Internal Medicine Department, Galilee Medical Center, Naharya, Israel.
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authors.affiliation: Liver Unit, Haemek Medical Center, Afula, Israel.
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authors.affiliation: Division of Gastroenterology, Kaplan Health Sciences Centre, Department of Medicine, Faculty of Medicine, Hebrew University, Rehovot, Israel.
authors.forename: Yaakov
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authors.lastname: Maor
authors.affiliation: Gastroenterology and Hepatology Institute, Meir Medical Center, Kfar Saba, Israel.
authors.forename: Yona
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authors.lastname: Kitay-Cohen
authors.affiliation: Virology Laboratory, Soroka Medical Center, Beer Sheva, Israel.
authors.forename: Yonat
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authors.lastname: Shemer-Avni
authors.affiliation: Virology Laboratory, Rambam Medical Center, Haifa, Israel.
authors.forename: Zipi
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authors.lastname: Kra-Oz
authors.affiliation: Maccabi Health Services, Mega Laboratory, Rehovot, Israel.
authors.forename: Licita
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authors.lastname: Schreiber
authors.affiliation: Genaphora Ltd, Rehovot, Israel.
authors.forename: Ofer
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authors.lastname: Peleg
authors.affiliation: Institute of Virology, University of Cologne, Cologne, Germany.
authors.forename: Saleta
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authors.affiliation: BC Centre for Excellence in HIV, Vancouver, BC, Canada.
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
authors.affiliation: Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat-Gan, Israel.|School of Public Health, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Mendelson
authors.affiliation: Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat-Gan, Israel.
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mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017211:Treatment Failure; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase