title: Significance of variants associated with resistance to NS5A inhibitors in Japanese patients with genotype 1b hepatitis C virus infection as evaluated using cycling-probe real-time PCR combined with direct sequencing.
abstract: BACKGROUND
  Dual oral therapy with daclatasvir plus asunaprevir yielded an SVR rate of 85% among patients with genotype 1b HCV. Treatment failure mainly occurred in patients with pre-existing HCV with NS5A-Y93H mutation. The significance of the mutation was evaluated.
  
  
  METHODS
  The percent of serum NS5A-Y93H strains relative to the total strains was quantified using cycling-probe real-time PCR combined with direct sequencing in 444 patients with genotype 1b HCV, and the factors associated with mutation were analyzed. The mutation rates during interferon therapy were measured sequentially.
  
  
  RESULTS
  NS5A-Y93H strains (1-100% of the total strains) were detected in 87 patients (19.6%). Mutant strains were detected more frequently among women than among men, in patients with a favorable allele in the IL28B-related gene SNP than among those with unfavorable alleles, and among patients without HCC and/or with serum AFP levels less than 6.0 ng/ml than among those with HCC and/or levels of 6.0 ng/ml or more. A multivariate analysis revealed that IL28B-related gene polymorphisms were significant factors associated with mutant strains. Although the frequency of patients with mutant strains was equivalent among patients depending on their previous interferon therapies, a sequential analysis during the interferon administrations revealed that the mutant strains disappeared earlier than the wild-type strains.
  
  
  CONCLUSIONS
  NS5A-Y93H mutation was associated with sex, serum AFP levels, and IL28B-related gene polymorphisms in patients infected with genotype 1b HCV. The indications for NS5A inhibitor use should be determined based on these factors, since mutant strains seem to be sensitive to interferon.
authors.affiliation: Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Kouyama
authors.affiliation: Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Naiki
authors.affiliation: Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Sugawara
authors.affiliation: Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Ando
authors.affiliation: Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Nakao
authors.affiliation: Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Motoya
authors.affiliation: Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
authors.forename: Mie
authors.initials: M
authors.lastname: Inao
authors.affiliation: Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Nakayama
authors.affiliation: Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan. smochida@saitama-med.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Mochida
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000097:blood; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D000069616:Simeprevir / Q000627:therapeutic use; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D055815:Young Adult; D000095022:Interferon Lambda; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D000069616:Simeprevir; D017361:Viral Nonstructural Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a
keywords: HCV; Interferon; NS5A inhibitor; Y93H mutation