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…

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 Takehara

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.