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Original Article
Combination therapies with NS5A, NS3 and NS5B inhibitors on different genotypes of hepatitis C virus in human hepatocyte chimeric mice
  1. Niu Shi1,2,
  2. Nobuhiko Hiraga1,2,
  3. Michio Imamura1,2,
  4. C Nelson Hayes1,2,
  5. Yizhou Zhang1,2,
  6. Keiichi Kosaka1,2,
  7. Akihito Okazaki1,2,
  8. Eisuke Murakami1,2,
  9. Masataka Tsuge1,2,
  10. Hiromi Abe1,2,
  11. Hiroshi Aikata1,2,
  12. Shoichi Takahashi1,2,
  13. Hidenori Ochi2,3,
  14. Chise Tateno-Mukaidani2,4,
  15. Katsutoshi Yoshizato2,4,
  16. Hirotaka Matsui5,
  17. Akinori Kanai6,
  18. Toshiya Inaba5,
  19. Fiona McPhee7,
  20. Min Gao7,
  21. Kazuaki Chayama1,2,3
  1. 1Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
  2. 2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
  3. 3Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
  4. 4PhoenixBio Co., Ltd., Higashihiroshima, Japan
  5. 5Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
  6. 6Radiation Research Center for Frontier Science, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
  7. 7Bristol-Myers Squibb, Research and Development, Wallingford, Connecticut, USA
  1. Correspondence to Professor Kazuaki Chayama, Department of Gastroenterology and Metabolism, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; chayama{at}mba.ocn.ne.jp

Abstract

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.

  • HCV
  • Drug Development

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