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Emergence of hepatitis C virus NS5A L31V plus Y93H variant upon treatment failure of daclatasvir and asunaprevir is relatively resistant to ledipasvir and NS5B polymerase nucleotide inhibitor GS-558093 in human hepatocyte chimeric mice

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Abstract

Background

Resistance-associated variants (RAVs) emerge at multiple positions spanning hepatitis C virus (HCV) NS3/4A and NS5A regions upon failure of asunaprevir/daclatasvir combination therapy. It has not been determined whether the emergence of such RAVs have an impact on re-treatment by a combination of ledipasvir and sofosbuvir, a potent regimen for HCV genotype 1 infection.

Methods

TK-NOG human hepatocyte chimeric mice were inoculated with sera from a patient with treatment failure of asunaprevir/daclatasvir therapy.

Results

They developed persistent HCV infection with triple variants of NS3/4A D168V, NS5A L31V plus Y93H. Administration of ledipasvir/GS-558093 (a NS5B nucleotide analog) in these mice failed to achieve end-of-treatment response or sustained virologic response, which was in sharp contrast to the results in mice with wild-type virus infection. The administration of telaprevir/GS-558093 successfully achieved it in those mice.

Conclusions

Treatment failure with asunaprevir/daclatasvir may limit further treatment options. This population may represent a growing unmet medical need.

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Fig. 1
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Abbreviations

HCV:

Hepatitis C virus

DAA:

Direct-acting antiviral

NS:

Non-structural protein

SVR:

Sustained virologic response

RAV:

Resistance-associated variant

TK:

Thymidine kinase

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Acknowledgments

We would like to thank M. Kuronuma from CIEA for outstanding technical assistance with the animal experiments. We sincerely thank Bristol-Myers Squibb (New York, NY) for providing asunaprevir and daclatasvir and Gilead Sciences Inc. (Foster City, CA) for providing ledipasvir and GS-558093.

Financial support

This work was partly supported by a Grant-in-Aid for Research on Hepatitis from Japan Agency for Medical Research and development.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Yugo Kai, Hayato Hikita, Tomohide Tatsumi, Tasuku Nakabori, Yoshinobu Saito, Naoki Morishita, Satoshi Tanaka, Takatoshi Nawa, Tsugiko Oze, Ryotaro Sakamori, Takayuki Yakushijin, Naoki Hiramatsu & Tetsuo Takehara

  2. Department of Laboratory Animal Research, Central Institute for Experimental Animals, Kawasaki, Japan

    Hiroshi Suemizu

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  1. Yugo Kai
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  2. Hayato Hikita
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Corresponding author

Correspondence to Tetsuo Takehara.

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Conflict of interest

Tetsuo Takehara received research grants from Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Corp., Chugai Pharmaceutical Co., Ltd., Toray Industries Inc. and MSD K.K., and lecturer fees from Bristol-Myers Squibb, MSD K.K. and Janssen Pharmaceutical K.K. Hayato Hikita received a research grant from Bristol-Myers Squibb and belonged to a course endowed by MSD K.K. Naoki Hamamatsu received a research grant from MSD K.K. The other authors declare that they have no conflict of interest.

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Kai, Y., Hikita, H., Tatsumi, T. et al. Emergence of hepatitis C virus NS5A L31V plus Y93H variant upon treatment failure of daclatasvir and asunaprevir is relatively resistant to ledipasvir and NS5B polymerase nucleotide inhibitor GS-558093 in human hepatocyte chimeric mice. J Gastroenterol 50, 1145–1151 (2015). https://doi.org/10.1007/s00535-015-1108-6

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