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.
- Author
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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
- Subjects
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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