title: Mutational diversity of NS5A and NS3 during triple therapy (telaprevir, pegylated-interferon-α 2b and ribavirin) for genotype 1b chronic hepatitis C: The Kobe Hepatitis Therapeutic Group.
abstract: Telaprevir, a non-structural (NS)3/4A protease inhibitor, is a direct-acting antiviral drug that inhibits viral replication. Triple therapy with telaprevir, pegylated interferon, and ribavirin is a standard therapeutic regimen for patients with genotype 1b chronic hepatitis C virus (HCV) infection and a high viral load. Several factors, including mutations in the NS5A gene, are important predictors of the efficacy of interferon therapy. In this study, we examined the mutational diversity of NS5A and its impact on the efficacy of triple therapy. We enrolled patients with genotype 1b chronic HCV infection and a high viral load (31 males/17 females; mean age, 57.6 years), who were treated with triple therapy. This study was conducted at Kobe University Hospital and at three affiliated hospitals in Hyogo prefecture, Japan, between November 2011 and June 2013. A sustained viral response after 12 weeks (SVR12) was achieved in 37/48 patients (77%). Based on intent-to-treat analysis, SVR12 was significantly greater in patients with the major allele than in those with the minor allele for the IL28B single nucleotide polymorphism (SNP; 88 vs. 56%; P<0.05). The prevalence of the V2334I mutation in NS5A was significantly higher in patients who achieved SVR12, while that of G2356E was significantly higher in patients who did not achieve SVR12 (P<0.05). Mutations in the NS3 region that are thought to confer resistance to telaprevir were detected in 3/27 patients who achieved SVR12 (Val36, n=3) and in 5/10 patients who did not achieve SVR12 (Val36, n=4; Thr54, n=1). In conclusion, the IL28B SNP and mutations in the NS5A region were associated with the therapeutic response to triple therapy. Half of the patients who did not achieve SVR12 had mutations conferring resistance to telaprevir. However, pre-existing mutations in NS3 did not affect the efficacy of triple therapy.
authors.affiliation: Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Fugui
authors.initials: F
authors.lastname: Bai
authors.affiliation: Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yano
authors.affiliation: Department of Gastroenterology, Kobe Asahi Hospital, Kobe, Hyogo 653-0801, Japan.
authors.forename: Soo-Ryang
authors.initials: SR
authors.lastname: Kim
authors.affiliation: Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Seo
authors.affiliation: Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Miki
authors.affiliation: Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Saito
authors.affiliation: Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Hirano
authors.affiliation: Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Momose
authors.affiliation: Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Minami
authors.affiliation: Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Hatazawa
authors.affiliation: Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Hayakumo
authors.affiliation: Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Dewiyani Indah
authors.initials: DI
authors.lastname: Widasari
authors.affiliation: Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Hanggoro Tri
authors.initials: HT
authors.lastname: Rinonce
authors.affiliation: Sugano Clinic, Himeji, Hyogo 671-0223, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sugano
authors.affiliation: Division of Internal Medicine, Konan Hospital, Kobe, Hyogo 658-0064, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tani
authors.affiliation: Department of Gastroenterology, Hyogo Prefectural Kakogawa Medical Center, Kakogawa, Hyogo 675-8555, Japan.
authors.forename: Seitetsu
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Sugano Clinic, Himeji, Hyogo 671-0223, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Imoto
authors.affiliation: Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Azuma
authors.affiliation: Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Hak
authors.initials: H
authors.lastname: Hotta
authors.affiliation: Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009842:Oligopeptides / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009842:Oligopeptides; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; C417083:peginterferon alfa-2b