Rapid emergence of telaprevir resistant hepatitis C virus strain from wildtype clone in vivo

Authors

  • Nobuhiko Hiraga,

    1. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
    2. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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  • Michio Imamura,

    1. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
    2. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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  • Hiromi Abe,

    1. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
    2. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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  • C. Nelson Hayes,

    1. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
    2. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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  • Tomohiko Kono,

    1. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
    2. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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  • Mayu Onishi,

    1. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
    2. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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  • Masataka Tsuge,

    1. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
    2. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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  • Shoichi Takahashi,

    1. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
    2. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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  • Hidenori Ochi,

    1. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
    2. Laboratory for Digestive Diseases, RIKEN Center for Genomic Medicine, Hiroshima, Japan
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  • Eiji Iwao,

    1. Research and Development Unit, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan
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  • Naohiro Kamiya,

    1. Research and Development Unit, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan
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  • Ichimaro Yamada,

    1. Research and Development Unit, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan
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  • Chise Tateno,

    1. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
    2. PhoenixBio Co., Ltd., Higashihiroshima, Japan
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  • Katsutoshi Yoshizato,

    1. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
    2. PhoenixBio Co., Ltd., Higashihiroshima, Japan
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  • Hirotaka Matsui,

    1. Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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  • Akinori Kanai,

    1. Radiation Research Center for Frontier Science, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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  • Toshiya Inaba,

    1. Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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  • Shinji Tanaka,

    1. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
    2. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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  • Kazuaki Chayama

    Corresponding author
    1. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
    2. Liver Research Project Center, Hiroshima University, Hiroshima, Japan
    3. Laboratory for Digestive Diseases, RIKEN Center for Genomic Medicine, Hiroshima, Japan
    • Department of Medical and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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    • fax: +81-82-255-6220


  • Potential conflict of interest: E.I., N.K., I.Y. are employees of Mitsubishi Tanabe Pharma Corp. The other authors have nothing to declare.

  • Supported in part by a grant-in-aid for Scientific Research from the Japanese Ministry of Labor, Health and Welfare

Abstract

Telaprevir is a potent inhibitor of hepatitis C virus (HCV) NS3-4A protease. However, the emergence of drug-resistant strains during therapy is a serious problem, and the susceptibility of resistant strains to interferon (IFN), as well as the details of the emergence of mutant strains in vivo, is not known. We previously established an infectious model of HCV using human hepatocyte chimeric mice. Using this system we investigated the biological properties and mode of emergence of mutants by ultra-deep sequencing technology. Chimeric mice were injected with serum samples obtained from a patient who had developed viral breakthrough during telaprevir monotherapy with strong selection for resistance mutations (A156F [92.6%]). Mice infected with the resistant strain (A156F [99.9%]) developed only low-level viremia and the virus was successfully eliminated with interferon therapy. As observed in patients, telaprevir monotherapy in viremic mice resulted in breakthrough, with selection for mutations that confer resistance to telaprevir (e.g., a high frequency of V36A [52.2%]). Mice were injected intrahepatically with HCV genotype 1b clone KT-9 with or without an introduced resistance mutation, A156S, in the NS3 region, and treated with telaprevir. Mice infected with the A156S strain developed lower-level viremia compared to the wildtype strain but showed strong resistance to telaprevir treatment. Although mice injected with wildtype HCV showed a rapid decline in viremia at the beginning of therapy, a high frequency (11%) of telaprevir-resistant NS3 V36A variants emerged 2 weeks after the start of treatment. Conclusion: Using deep sequencing technology and a genetically engineered HCV infection system, we showed that the rapid emergence of telaprevir-resistant HCV was induced by mutation from the wildtype strain of HCV in vivo. (HEPATOLOGY 2011;).

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