title: Complex Pattern of Resistance-Associated Substitutions of Hepatitis C Virus after Daclatasvir/Asunaprevir Treatment Failure.
abstract: OBJECTIVE
  We aimed to clarify the characteristics of resistance-associated substitutions (RASs) after treatment failure with NS5A inhibitor, daclatasvir (DCV) in combination with NS3/4A inhibitor, asunaprevir (ASV), in patients with chronic hepatitis C virus genotype 1b infection.
  
  
  METHODS
  This is a nationwide multicenter study conducted by the Japanese Red Cross Liver Study Group. The sera were obtained from 68 patients with virological failure after 24 weeks of DCV/ASV treatment. RASs in NS5A and NS3 were determined by population sequencing.
  
  
  RESULTS
  The frequency of signature RASs at position D168 of NS3 was 68%, and at positions L31 and Y93 of NS5A was 79 and 76%, respectively. The frequency of dual signature RASs in NS5A (L31-RAS and Y93-RAS) was 63%. RASs at L28, R30, P32, Q54, P58, and A92 in addition to dual signature RAS were detected in 5, 5, 1, 22, 2, and 0 patients, respectively. In total, triple, quadruple, and quintuple RASs in combination with dual signature RAS were detected in 35, 10, and 1.5% patients, respectively. These RASs were detected in patients without baseline RASs or who prematurely discontinued therapy. Co-existence of D168 RAS in NS3 and L31 and/or Y93 RAS in NS5A was observed in 62% of patients.
  
  
  CONCLUSIONS
  Treatment-emergent RASs after failure with DCV/ASV combination therapy are highly complex in more than 50% of the patients. The identification of complex RAS patterns, which may indicate high levels of resistance to NS5A inhibitors, highlights the need for RAS sequencing when considering re-treatment with regimens including NS5A inhibitors.
authors: Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors: Jun
authors: J
authors: Itakura
authors: Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors: Masayuki
authors: M
authors: Kurosaki
authors: Department of Gastroenterology, Japanese Red Cross Asahikawa Hospital, Asahikawa, Hokkaido, Japan.
authors: Chitomi
authors: C
authors: Hasebe
authors: Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Osaka, Japan.
authors: Yukio
authors: Y
authors: Osaki
authors: Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan.
authors: Kouji
authors: K
authors: Joko
authors: Department of Gastroenterology, Japanese Red Cross Akita Hospital, Akita, Akita, Japan.
authors: Hitoshi
authors: H
authors: Yagisawa
authors: Department of Gastroenterology, Yokohama City Minato Red Cross Hospital, Yokohama, Kanagawa, Japan.
authors: Shinya
authors: S
authors: Sakita
authors: Department of Gastroenterology, Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan.
authors: Hiroaki
authors: H
authors: Okushin
authors: Department of Gastroenterology, Nasu Red Cross Hospital, Otawara, Tochigi, Japan.
authors: Takashi
authors: T
authors: Satou
authors: Department of Gastroenterology, Date Red Cross Hospital, Date, Hokkaido, Japan.
authors: Hiroyuki
authors: H
authors: Hisai
authors: Department of Gastroenterology, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan.
authors: Takehiko
authors: T
authors: Abe
authors: Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Hiroshima, Japan.
authors: Keiji
authors: K
authors: Tsuji
authors: Department of Gastroenterology, Takatsuki Red Cross Hospital, Takatsuki, Osaka, Japan.
authors: Takashi
authors: T
authors: Tamada
authors: Department of Gastroenterology, Japanese Red Cross Okayama Hospital, Okayama, Okayama, Japan.
authors: Haruhiko
authors: H
authors: Kobashi
authors: Department of Gastroenterology, Japanese Red Cross Tottori Hospital, Tottori, Tottori, Japan.
authors: Akeri
authors: A
authors: Mitsuda
authors: Department of Gastroenterology, Japanese Red Cross Karatsu Hospital, Karatsu, Saga, Japan.
authors: Yasushi
authors: Y
authors: Ide
authors: Department of Gastroenterology, Takamatsu Red Cross Hospital, Takamatsu, Kagawa, Japan.
authors: Chikara
authors: C
authors: Ogawa
authors: Department of Gastroenterology, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Nagasaki, Japan.
authors: Syotaro
authors: S
authors: Tsuruta
authors: Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa, Japan.
authors: Kouichi
authors: K
authors: Takaguchi
authors: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
authors: Miyako
authors: M
authors: Murakawa
authors: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
authors: Yasuhiro
authors: Y
authors: Asahina
authors: First Department of Internal Medicine, University of Yamanashi, Chuou, Yamanashi, Japan.
authors: Nobuyuki
authors: N
authors: Enomoto
authors: Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
authors: Namiki
authors: N
authors: Izumi
mesh_terms: D000368:Aged; D002219:Carbamates; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D002219:Carbamates; D007093:Imidazoles; D007546:Isoquinolines; D011759:Pyrrolidines; D013449:Sulfonamides; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir