title: Impact of resistance-associated variant dominancy on treatment in patients with HCV genotype 1b receiving daclatasvir/asunaprevir.
abstract: Sustained virological responses (SVR) by daclatasvir (DCV) and asunaprevir (ASV) therapy for genotype 1b hepatitis C virus (HCV) infected patients has been significantly affected by pre-existence of Y93 H resistance-associated variants (RAVs) in the non-structural protein 5A (NS5A) region. The aim of this study was to elucidate the dominancy of naturally occurring RAVs in viral quasispecies on treatment outcomes in patients with HCV. In total, 138 patients were prospectively selected from 152 patients treated with DCV and ASV, where evaluation of treatment outcomes at 12 weeks post-treatment was possible. Pre-treatment RAVs in the non-structural protein 3 and NS5A regions were detected by polymerase chain reaction (PCR)-Invader assays, and the ratio of Y93H RAVs in viral quasispecies was measured by quantitative PCR-Invader assay. Among 25 patients detected the Y93H RAV, the Y93H ratio was 1-25% in 5 patients, 26-75% in 7 patients, and ≥76% in 13 patients. Overall, SVR at 12 weeks after the completion of treatment (SVR12) was 91% (125/138), and those with Y93H ratios of <1%, 1-25%, 26-75%, and ≥76% were 99%, 100%, 71%, and 23%, respectively. Thus, the SVR12 decreased as the HCV Y93H ratio increased (P < 0.0001). The dominancy of pre-treatment RAVs of DCV and ASV affected its treatment outcomes, suggesting that evaluating the dominancy of HCV RAVs could be required for every other direct-acting antiviral agent treatments. J. Med. Virol. 89:99-105, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Tsunamasa
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.|Division of Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital, Kawasaki, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Okuse
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Division of Gastroenterology, Yokohama City Seibu Hospital, Yokohama, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Internal Medicine, Center for Liver Diseases, Kiyokawa Hospital, Suginami, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Shigefuku
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Matsunaga
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Nakano
authors.affiliation: Division of Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital, Kawasaki, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hiraishi
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.|Department of Internal Medicine, Center for Liver Diseases, Kiyokawa Hospital, Suginami, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Internal Medicine, Center for Liver Diseases, Kiyokawa Hospital, Suginami, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kurosaki
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
authors.forename: Namiki
authors.initials: N
authors.lastname: Izumi
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yotsuyanagi
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan. michstmu@marianna-u.ac.jp.|Division of Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital, Kawasaki, Japan. michstmu@marianna-u.ac.jp.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000627:therapeutic use*; D002219:Carbamates; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D016174:Hepacivirus / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007546:Isoquinolines / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D011759:Pyrrolidines; D013449:Sulfonamides / Q000627:therapeutic use*; D000072230:Sustained Virologic Response; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D007546:Isoquinolines; D011759:Pyrrolidines; D013449:Sulfonamides; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir; C571889:asunaprevir
keywords: HCV; asunaprevir; daclatasvir; resistance-associated variant; sustained virological response