Virological Escape in HCV Genotype-1-Infected Patients Receiving Daclatasvir plus Ribavirin and Peginterferon Alfa-2A or Alfa-2B. Issue 5 (July 2014)

• Record Type: Journal Article
• Authors: McPhee, Fiona; Hernandez, Dennis; Zhou, Nannan; Yu, Fei; Ueland, Joseph; Monikowski, Aaron; Chayama, Kazuaki; Toyota, Joji; Izumi, Namiki; Yokosuka, Osamu; Kawada, Norifumi; Osaki, Yukio; Hughes, Eric A; Watanabe, Hideaki; Ishikawa, Hiroki; Kumada, Hiromitsu
• Is Part Of: Antiviral therapy. Volume 19:Issue 5(2014)
• Page Start: 479
• Page End: 490
• Publication Date: 2014-07
• Subjects: Antiviral agents -- Periodicals; Antiviral Agents -- therapeutic use; Virus Diseases -- therapy; Viruses -- drug effects; Antiviral agents; Periodical; Electronic journals; Periodicals; 616.9106
• DOI: 10.3851/IMP2729
• Languages: English
• ISSNs: 1359-6535

Abstract

Background: Daclatasvir (DCV; BMS-790052) is a picomolar inhibitor of HCV non-structural protein 5A (NS5A) and has demonstrated efficacy in patients chronically infected with HCV. Methods: In the double-blind, randomized studies AI444021 and AI444022, 71 Japanese patients chronically infected with HCV genotype 1 (predominantly genotype 1b) received DCV (10 mg or 60 mg) plus peginterferon alfa-2b or alfa-2a and ribavirin. Virological failure occurred in 14% (5/36) of treatment-naive patients and 54% (19/35) of prior alfa/ribavirin non-responders. Resistance testing was performed on baseline samples and samples with HCV RNA≥1, 000 IU/ml at week 1 through post-treatment week 24. Results: Baseline NS5A resistance-associated polymorphisms had less impact on virological response rates than IL28B genotype. All patients with virological failure had NS5A DCV-resistant variants at the time of failure. The predominant NS5A variants were L31V/M/I plus Y93H; this combination was detected in 100% (5/5) of treatment-naive patients and 74% (14/19) of non-responders with failure. Emergent resistance variants in prior non-responders (four viral breakthroughs, one relapse) were more varied with novel combinations such as L31F-DP32 and L28M-R30Q-A92K detected. Significant loss in DCV antiviral activity was generally only seen with ≥ two resistance-associated NS5A substitutions. All DCV-resistant variants were still detected at end of study. Conclusions: Virological failure in HCV genotype 1b treatment-naive Japanese patients receiving DCV plus alfa-2a/ribavirin or alfa-2b/ribavirin was associated with enrichment of NS5A resistance variants L31V/M-Y93H. In prior non-responders, emergent variants associated with failure also included NS5A-A92K or NS5A-DP32. As with L31-Y93 variants, these variants persisted.