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, 50 (11), 1145-51

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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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 et al. J Gastroenterol.

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.

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

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