Combination therapy with NS5A, NS3 and NS5B inhibitors on different genotype of hepatitis C virus in human hepatocyte chimeric mice.
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Objective: We recently demonstrated that combination treatment with NS3 protease and NS5B polymerase inhibitors succeeded in eradicating the virus in genotype 1b hepatitis C virus (HCV)-infected mice. In this study, we investigated the effect of combining an NS5A replication complex inhibitor (RCI) with either NS3 protease or NS5B inhibitors on elimination of HCV genotypes 1b, 2a and 2b. Design: The effects of Bristol-Myers Squibb (BMS)-605339 (NS3 protease inhibitor; PI), BMS-788329 (NS5ARCI) and BMS-821095 (NS5B non-nucleoside analogue inhibitor) on HCV genotypes 1b and 2a were examined using subgenomic HCV replicon cells. HCV genotype 1b, 2a or 2b-infected human hepatocyte chimeric mice were also treated with BMS-605339, BMS-788329 or BMS-821095 alone or in combination with two of the drugs for 4 weeks. Genotypic analysis of viral sequences was achieved by direct and ultra-deep sequencing. Results: Anti-HCV effects of BMS-605339 and BMS-821095 were more potent against genotype 1b than against genotype 2a. In in-vivo experiments, viral breakthrough due to the development of a high prevalence of drug-resistant variants was observed in mice treated with BMS-605339, BMS-788329 and BMS-821095 in monotherapy. In contrast to monotherapy, 4 weeks of combination therapy with the NS5A RCI and either NS3 PI or NS5B inhibitor succeeded in completely eradicating the virus in genotype 1b HCV-infected mice. Conversely, these combination therapies failed to eradicate the virus in mice infected with HCV genotypes 2a or 2b. Conclusions: These oral combination therapies may serve as a Peg-alfa-free treatment for patients chronically infected with HCV genotype 1b.
Thesis or Dissertation
Niu Shi, Nobuhiko Hiraga, Michio Imamura, C Nelson Hayes, Yizhou Zhang, Keiichi Kosaka, Akihito Okazaki, Eisuke Murakami, Masataka Tsuge, Hiromi Abe, Hiroshi Aikata, Shoichi Takahashi, Hidenori Ochi, Chise Tateno-Mukaidani, Katsutoshi Yoshizato, Hirotaka Matsui, Akinori Kanai, Toshiya Inaba, Fiona McPhee, Min Gao, Kazuaki Chayama; Combination therapies with NS5A, NS3 and NS5B inhibitors on different genotypes of hepatitis C virus in human hepatocyte chimeric mice; Gut 2013;62:1055-1061. (doi: 10.1136/gutjnl-2012-302600)
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Philosophy in Medical Science
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Graduate School of Biomedical Science
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