Rapid emergence of telaprevir resistant hepatitis C virus strain from wild type clone in vivo.

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Hepatology. 2011 May 29. doi: 10.1002/hep.24460. [Epub ahead of print]

Rapid emergence of telaprevir resistant hepatitis C virus strain from wild type

clone in vivo.

Hiraga N, Imamura M, Abe H, C, Kono T, Onishi M, Tsuge M, Takahashi

S, Ochi H, Iwao E, Kamiya N, Yamada I, Tateno C, Yoshizato K, Matsui H, Kanai A,

Inaba T, Tanaka S, ma K.

Source

Department of Medicine and Molecular Science, Division of Frontier Medical

Science, Programs for Biomedical Research, Graduate School of Biomedical

Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center,

Hiroshima University, Hiroshima, Japan.

Abstract

Telaprevir is a potent inhibitor of hepatitis C virus (HCV) NS3-4A protease.

However, 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 wild type strain but showed strong resistance to

telaprevir treatment. Although mice injected with wild type HCV showed a rapid

decline in viremia at the beginning of therapy, a high frequency (11%) of

telaprevir-resistant NS3 V36A variants emerged two 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 wild type strain of

HCV in vivo. (HEPATOLOGY 2011.).

Copyright © 2011 American Association for the Study of Liver Diseases.

PMID: 21626527 [PubMed - as supplied by publisher]

[Guest guest]

Hepatology. 2011 May 29. doi: 10.1002/hep.24460. [Epub ahead of print]

Rapid emergence of telaprevir resistant hepatitis C virus strain from wild type

clone in vivo.

Hiraga N, Imamura M, Abe H, C, Kono T, Onishi M, Tsuge M, Takahashi

S, Ochi H, Iwao E, Kamiya N, Yamada I, Tateno C, Yoshizato K, Matsui H, Kanai A,

Inaba T, Tanaka S, ma K.

Source

Department of Medicine and Molecular Science, Division of Frontier Medical

Science, Programs for Biomedical Research, Graduate School of Biomedical

Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center,

Hiroshima University, Hiroshima, Japan.

Abstract

Telaprevir is a potent inhibitor of hepatitis C virus (HCV) NS3-4A protease.

However, 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 wild type strain but showed strong resistance to

telaprevir treatment. Although mice injected with wild type HCV showed a rapid

decline in viremia at the beginning of therapy, a high frequency (11%) of

telaprevir-resistant NS3 V36A variants emerged two 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 wild type strain of

HCV in vivo. (HEPATOLOGY 2011.).

Copyright © 2011 American Association for the Study of Liver Diseases.

PMID: 21626527 [PubMed - as supplied by publisher]