Novel drug resistance-associated substitutions against pibrentasvir emerged in genotype 1b hepatitis C virus-infected human hepatocyte transplanted mice
| Autor: | Takashi Nakahara, Masataka Tsuge, C. Nelson Hayes, Hiroshi Aikata, Kazuaki Chayama, Eisuke Murakami, Kazuki Ohya, Hiromi Abe-Chayama, Tomokazu Kawaoka, Takuro Uchida, Atsushi Ono, Yuji Ishida, Masami Yamauchi, HoJoong Song, Chise Tateno, Hatsue Fujino, Makoto Hijikata, Michio Imamura, Yuji Teraoka, Yohei Miyayama, Daiki Miki |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Pyrrolidines Combination therapy Sequence analysis viruses Hepatitis C virus Biophysics Hepacivirus Mice SCID Drug resistance medicine.disease_cause Antiviral Agents Biochemistry Mice 03 medical and health sciences 0302 clinical medicine Drug Resistance Viral medicine Animals Humans NS5A Molecular Biology Mutation business.industry virus diseases Cell Biology Glecaprevir biochemical phenomena metabolism and nutrition Hepatitis C Virology digestive system diseases Pibrentasvir 030104 developmental biology 030220 oncology & carcinogenesis Hepatocytes Benzimidazoles business |
| Zdroj: | Biochemical and Biophysical Research Communications. 559:78-83 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2021.04.062 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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