title: Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1.
abstract: BACKGROUND
  The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region.
  
  
  METHODS
  Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing.
  
  
  RESULTS
  Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently.
  
  
  CONCLUSIONS
  History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.
authors.affiliation: Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Iio
authors.affiliation: Ootakanomori Hospital, Kashiwa, Japan.
authors.forename: Noritomo
authors.initials: N
authors.lastname: Shimada
authors.affiliation: Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Abe
authors.affiliation: Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Atsukawa
authors.affiliation: Machida Municipal Hospital, Tokyo, Japan.
authors.forename: Kai
authors.initials: K
authors.lastname: Yoshizawa
authors.affiliation: Kagawa Prefectural Central Hospital, Takamatsu, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Takaguchi
authors.affiliation: Saga University Hospital, Saga, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Eguchi
authors.affiliation: Shin-Kokura Hospital, Kitakyushu, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Nomura
authors.affiliation: Kuramitsu Clinic, Akita, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kuramitsu
authors.affiliation: Teine Keijinkai Hospital, Sapporo, Japan.
authors.forename: Jong-Hon
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Teine Keijinkai Hospital, Sapporo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsui
authors.affiliation: National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Hirashima
authors.affiliation: Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Tsubota
authors.affiliation: Nagoya Red Cross Hospital, Nagoya, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kusakabe
authors.affiliation: Japan Community Health Care Organization, Chukyo Hospital, Nagoya, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Hasegawa
authors.affiliation: Toyokawa City Hospital, Toyokawa, Japan.
authors.forename: Tomokatsu
authors.initials: T
authors.lastname: Miyaki
authors.affiliation: Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Shinkai
authors.affiliation: Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nojiri
authors.affiliation: Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan. ytanaka@med.nagoya-cu.ac.jp.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000008:administration & dosage*; D002219:Carbamates; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D007546:Isoquinolines / Q000008:administration & dosage*; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011759:Pyrrolidines; D000069616:Simeprevir / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage*; D017211:Treatment Failure; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D007546:Isoquinolines; D011759:Pyrrolidines; D013449:Sulfonamides; D000069616:Simeprevir; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir
keywords: DCV/ASV; Direct acting antivirals; HCV; Resistance-associated variants; Simeprevir failure