Journal of Gastroenterology

, Volume 50, Issue 11, pp 1145–1151 | Cite as

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

  • Yugo Kai
  • Hayato Hikita
  • Tomohide Tatsumi
  • Tasuku Nakabori
  • Yoshinobu Saito
  • Naoki Morishita
  • Satoshi Tanaka
  • Takatoshi Nawa
  • Tsugiko Oze
  • Ryotaro Sakamori
  • Takayuki Yakushijin
  • Naoki Hiramatsu
  • Hiroshi Suemizu
  • Tetsuo TakeharaEmail author
Rapid Communication



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.


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


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.


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


Resistance-associated variants (RAVs) Asunaprevir/daclatasvir Ledipasvir/sofosbuvir 



Hepatitis C virus


Direct-acting antiviral


Non-structural protein


Sustained virologic response


Resistance-associated variant


Thymidine kinase



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.

Compliance with ethical standards

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.

Supplementary material

535_2015_1108_MOESM1_ESM.docx (38 kb)
Supplementary material 1 (DOCX 37 kb)


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Copyright information

© Springer Japan 2015

Authors and Affiliations

  • Yugo Kai
    • 1
  • Hayato Hikita
    • 1
  • Tomohide Tatsumi
    • 1
  • Tasuku Nakabori
    • 1
  • Yoshinobu Saito
    • 1
  • Naoki Morishita
    • 1
  • Satoshi Tanaka
    • 1
  • Takatoshi Nawa
    • 1
  • Tsugiko Oze
    • 1
  • Ryotaro Sakamori
    • 1
  • Takayuki Yakushijin
    • 1
  • Naoki Hiramatsu
    • 1
  • Hiroshi Suemizu
    • 2
  • Tetsuo Takehara
    • 1
    Email author
  1. 1.Department of Gastroenterology and HepatologyOsaka University Graduate School of MedicineSuitaJapan
  2. 2.Department of Laboratory Animal ResearchCentral Institute for Experimental AnimalsKawasakiJapan

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