1. 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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Kai, Yugo, Hikita, Hayato, Tatsumi, Tomohide, Nakabori, Tasuku, Saito, Yoshinobu, Morishita, Naoki, Tanaka, Satoshi, Nawa, Takatoshi, Oze, Tsugiko, Sakamori, Ryotaro, Yakushijin, Takayuki, Hiramatsu, Naoki, Suemizu, Hiroshi, and Takehara, Tetsuo
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HEPATITIS C virus , *POLYMERASES , *LIVER cells , *ENZYME inhibitors , *DRUG resistance , *LABORATORY mice , *HYDROCARBONS , *ANTIVIRAL agents , *HETEROCYCLIC compounds , *IMIDAZOLES , *ISOQUINOLINE , *SULFONAMIDES , *ANIMAL experimentation , *COMBINATION drug therapy , *DRUG resistance in microorganisms , *EPITHELIAL cells , *HEPATITIS viruses , *TREATMENT effectiveness , *CHRONIC hepatitis C , *THERAPEUTICS - 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. [ABSTRACT FROM AUTHOR]- Published
- 2015
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