TY - JOUR T1 - Combination therapies with NS5A, NS3 and NS5B inhibitors on different genotypes of hepatitis C virus in human hepatocyte chimeric mice JF - Gut JO - Gut SP - 1055 LP - 1061 DO - 10.1136/gutjnl-2012-302600 VL - 62 IS - 7 AU - Niu Shi AU - Nobuhiko Hiraga AU - Michio Imamura AU - C Nelson Hayes AU - Yizhou Zhang AU - Keiichi Kosaka AU - Akihito Okazaki AU - Eisuke Murakami AU - Masataka Tsuge AU - Hiromi Abe AU - Hiroshi Aikata AU - Shoichi Takahashi AU - Hidenori Ochi AU - Chise Tateno-Mukaidani AU - Katsutoshi Yoshizato AU - Hirotaka Matsui AU - Akinori Kanai AU - Toshiya Inaba AU - Fiona McPhee AU - Min Gao AU - Kazuaki Chayama Y1 - 2013/07/01 UR - http://gut.bmj.com/content/62/7/1055.abstract N2 - 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 (NS5A RCI) 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. ER -