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. 2015 Nov;50(11):1145-51. doi: 10.1007/s00535-015-1108-6. Epub 2015 Jul 25.


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.

Keywords: Asunaprevir/daclatasvir; Ledipasvir/sofosbuvir; Resistance-associated variants (RAVs).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / therapeutic use
  • Benzimidazoles / therapeutic use
  • Drug Combinations
  • Drug Resistance, Multiple, Viral / genetics*
  • Female
  • Fluorenes / therapeutic use
  • Hepacivirus / drug effects
  • Hepacivirus / genetics*
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / virology
  • Hepatitis, Viral, Animal / drug therapy*
  • Hepatitis, Viral, Animal / virology
  • Hepatocytes / virology
  • Humans
  • Imidazoles / therapeutic use
  • Isoquinolines / therapeutic use
  • Male
  • Middle Aged
  • Sofosbuvir / therapeutic use
  • Sulfonamides / therapeutic use
  • Transplantation Chimera
  • Treatment Failure


  • Antiviral Agents
  • Benzimidazoles
  • Drug Combinations
  • Fluorenes
  • Imidazoles
  • Isoquinolines
  • Sulfonamides
  • ledipasvir
  • daclatasvir
  • asunaprevir
  • Sofosbuvir