Successful treatment of an entecavir-resistant hepatitis B virus variant

Authors

  • Hiromi Yatsuji,

    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. Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
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  • 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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  • Nami Mori,

    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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  • Tsuyoshi Hatakeyama,

    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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  • 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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  • 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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  • Yoshifumi Fujimoto,

    1. 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 Liver Disease, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Yokohama, 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. Laboratory for Liver Disease, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan
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  • Toshiro Maekawa,

    1. Laboratory for Liver Disease, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan
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  • Fumitaka Suzuki,

    1. Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
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  • Hiromitsu Kumada,

    1. Department of Gastroenterology, Toranomon Hospital, Tokyo, 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 Liver Disease, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan
    • Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate school of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi 734-8551, Japan.
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Abstract

Emergence of a lamivudine (LAM)-resistant hepatitis B virus (HBV) with amino acid substitutions in the YMDD motif is a well-documented problem during long-term LAM therapy. Entecavir (ETV) is a new drug approved for treatment of HBV infection with or without LAM-resistant mutants. This report describes an ETV-resistant strain of HBV, which emerged after prolonged ETV therapy in a patient who did not respond to LAM therapy. Direct sequence analysis of the ETV-resistant strain showed appearance of amino acid substitution rtS202G in the reverse transcriptase (RT) domain, together with rtL180M + M204V substitution that had developed at the emergence of LAM-resistant mutant. In vitro analysis demonstrated that the rtL180M + M204V + S202G mutant strain displayed a 200-fold and a 5-fold reduction in susceptibility to ETV compared with the wild- type and the rtL180M + M204V mutant strain, respectively. Adefovir was effective against the ETV-resistant strain both in vitro and during the clinical course. In conclusion, this study showed that virological and biochemical breakthrough due to ETV could occur in patients infected with LAM-resistant HBV and confirmed that the addition of rtS202G substitution to the rtL180M + M204V mutant strain is responsible for ETV resistance and we could treat the resistant mutant successfully. J. Med. Virol. 79:1811–1817, 2007. © 2007 Wiley-Liss, Inc.

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