Novel drug resistance-associated substitutions against pibrentasvir emerged in genotype 1b hepatitis C virus-infected human hepatocyte transplanted mice.

May 3, 2021

Contributor: Kazuki Ohya,Michio Imamura,Yuji Teraoka,Takuro Uchida,Hatsue Fujino,Takashi Nakahara,Atsushi Ono,Eisuke Murakami,Masami Yamauchi,Tomokazu Kawaoka,Daiki Miki,Masataka Tsuge,Hiromi Abe-Chayama,C Nelson Hayes,Hiroshi Aikata,Yuji Ishida,Chise Tateno,HoJoong Song,Yohei Miyayama,Makoto Hijikata,Kazuaki Chayama

Novel drug resistance-associated substitutions against pibrentasvir emerged in genotype 1b hepatitis C virus-infected human hepatocyte transplanted mice.

Combination therapy with glecaprevir and pibrentasvir (PIB) has high efficacy for patients with hepatitis C virus (HCV) infection except among those who experienced NS5A-P32 deletion (del) mutation during prior DAA treatment failure. However, some patients fail to achieve SVR through combination treatment even in the absence of NS5A-P32del. We analyzed emergence of NS5A resistance-associated substitutions (RASs) against PIB using HCV-infected mice. Male human hepatocyte transplanted mice were infected with genotype 1b wild-type HCV. Mice were treated with PIB, resulting in a transient decrease in serum HCV RNA levels but followed by relapse during the treatment. Direct sequence analysis showed emergences of various mutations in the NS5A region, including L31V/P32del, L31F/P32del/Y93H, NS5A-P29del/Y85C, and NS5A-F37Y. PIB was less effective in mice with NS5A-F37Y mutations compared to mice with wild-type HCV. NS5A-F37Y showed 5.4-fold resistance to PIB relative to wild-type based on analysis using HCV subgenomic replicon systems. The present in vivo and in vitro studies identified NS5A-F37Y as a novel RAS against PIB and showed the possibility of emergence of various NS5A RASs including P29del, P32del and F37Y following PIB treatment. These mutations might emerge and lead to failure to respond to DAA therapies including PIB-based regimens in chronic hepatitis C patients.
Copyright © 2021 Elsevier Inc. All rights reserved.

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About The Expert

Kazuki Ohya

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Michio Imamura

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Yuji Teraoka

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Takuro Uchida

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Hatsue Fujino

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Takashi Nakahara

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Atsushi Ono

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Eisuke Murakami

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Masami Yamauchi

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Tomokazu Kawaoka

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Daiki Miki

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Masataka Tsuge

Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.

Hiromi Abe-Chayama

Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

C Nelson Hayes

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Hiroshi Aikata

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

Yuji Ishida

Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; PhoenixBio Co., Ltd., Higashihiroshima, Japan.

Chise Tateno

Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; PhoenixBio Co., Ltd., Higashihiroshima, Japan.

HoJoong Song

Laboratory of Tumor Viruses, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

Yohei Miyayama

Laboratory of Tumor Viruses, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

Makoto Hijikata

Laboratory of Tumor Viruses, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

Kazuaki Chayama

Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Yokohama, Japan. Electronic address: chayama@hiroshima-u.ac.jp.

References

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