title: Anti-interferon-α neutralizing antibody induced telaprevir resistance under the interferon-α plus telaprevir treatment in vitro.
abstract: Although the development of anti-interferon (IFN)-α neutralizing antibodies (NAbs) is likely to be a common clinical problem for patients with various diseases treated with IFN, anti-IFN-α NAb has been exceptionally considered to have no clinical significance in the treatment of chronic hepatitis C with pegylated IFN-α (Peg-IFN-α). However, we recently clarified that the presence of NAb was associated with a non-response to the Peg-IFN plus ribavirin (RBV) therapy. In this study, we used the HCV-replicon system with genotype 1b, and investigated the role of anti-IFN-α NAb in the response to telaprevir (TVR)-containing new antiviral therapy for hepatitis C virus (HCV). Anti-IFN-α NAb-positive sera specifically inhibited the anti-HCV effects of IFN-α, without any effect on the activity of IFN-β in vitro. The NAb-positive sera also inhibited the IFN-α-dependent induction of interferon-stimulated genes, MxA and OAS-1, in a dose-dependent manner. Although TVR monotherapy decreased the HCV-RNA in vitro, the HCV-RNA was increased again with the development of TVR-resistant mutations. When IFN-α was administrated with TVR, the replication of HCV was continuously suppressed for more than a month. However, in the presence of anti-IFN-α NAb-positive sera, even when IFN-α was combined with TVR, the levels of HCV-RNA exhibited a time-course similar to that with TVR monotherapy, and HCV with TVR-resistant mutations emerged. In conclusion, our findings suggest that the presence of IFN-α NAb decreases the antiviral effects of IFN-α and may be related to the development of TVR-resistant mutated viruses.
authors.affiliation: Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan.
authors.forename: Chisa
authors.initials: C
authors.lastname: Kuga
authors.affiliation: Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan. Electronic address: enomoto@hyo-med.ac.jp.
authors.forename: Hirayuki
authors.initials: H
authors.lastname: Enomoto
authors.affiliation: Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Aizawa
authors.affiliation: Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Takashima
authors.affiliation: Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ikeda
authors.affiliation: Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Ishii
authors.affiliation: Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Iwata
authors.affiliation: Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Saito
authors.affiliation: Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Iijma
authors.affiliation: Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Nishiguchi
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D000998:Antiviral Agents / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000276:immunology / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D009154:Mutation / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D057134:Antibodies, Neutralizing; D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C486464:telaprevir
keywords: Anti-interferon-α neutralizing antibody; Chronic hepatitis C; Telaprevir