title: Resistance-Associated NS5A Variants of Hepatitis C Virus Are Susceptible to Interferon-Based Therapy.
abstract: OBJECTIVE
  The presence of resistance-associated variants (RAVs) of hepatitis C virus (HCV) attenuates the efficacy of direct acting antivirals (DAAs). The objective of this study was to characterize the susceptibility of RAVs to interferon-based therapy.
  
  
  METHODS
  Direct and deep sequencing were performed to detect Y93H RAV in the NS5A region. Twenty nine genotype 1b patients with detectable RAV at baseline were treated by a combination of simeprevir, pegylated interferon and ribavirin. The longitudinal changes in the proportion of Y93H RAV during therapy and at breakthrough or relapse were determined.
  
  
  RESULTS
  By direct sequencing, Y93H RAV became undetectable or decreased in proportion at an early time point during therapy (within 7 days) in 57% of patients with both the Y93H variant and wild type virus at baseline when HCV RNA was still detectable. By deep sequencing, the proportion of Y93H RAV against Y93 wild type was 52.7% (5.8%- 97.4%) at baseline which significantly decreased to 29.7% (0.16%- 98.3%) within 7 days of initiation of treatment (p = 0.023). The proportion of Y93H RAV was reduced in 21 of 29 cases (72.4%) and a marked reduction of more than 10% was observed in 14 cases (48.7%). HCV RNA reduction was significantly greater for Y93H RAV (-3.65±1.3 logIU/mL/day) than the Y93 wild type (-3.35±1.0 logIU/mL/day) (p<0.001).
  
  
  CONCLUSIONS
  Y93H RAV is more susceptible to interferon-based therapy than the Y93 wild type.
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Itakura
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kurosaki
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Takada
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Nakakuki
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Itakura
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Tamaki
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yasui
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakanishi
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: First Department of Internal Medicine, University of Yamanashi, Chuou Yamanashi, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Maekawa
authors.affiliation: First Department of Internal Medicine, University of Yamanashi, Chuou Yamanashi, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors.forename: Namiki
authors.initials: N
authors.lastname: Izumi
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000008:administration & dosage*; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D016174:Hepacivirus / Q000201:enzymology / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007372:Interferons / Q000008:administration & dosage*; D008297:Male; D020125:Mutation, Missense; D012254:Ribavirin / Q000008:administration & dosage; D000069616:Simeprevir / Q000008:administration & dosage; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D012254:Ribavirin; D000069616:Simeprevir; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase