title: Combination therapies with NS5A, NS3 and NS5B inhibitors on different genotypes of hepatitis C virus in human hepatocyte chimeric mice.
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.
  
  
  METHODS
  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.
authors: 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.
authors: Niu
authors: N
authors: Shi
authors: Nobuhiko
authors: N
authors: Hiraga
authors: Michio
authors: M
authors: Imamura
authors: C Nelson
authors: CN
authors: Hayes
authors: Yizhou
authors: Y
authors: Zhang
authors: Keiichi
authors: K
authors: Kosaka
authors: Akihito
authors: A
authors: Okazaki
authors: Eisuke
authors: E
authors: Murakami
authors: Masataka
authors: M
authors: Tsuge
authors: Hiromi
authors: H
authors: Abe
authors: Hiroshi
authors: H
authors: Aikata
authors: Shoichi
authors: S
authors: Takahashi
authors: Hidenori
authors: H
authors: Ochi
authors: Chise
authors: C
authors: Tateno-Mukaidani
authors: Katsutoshi
authors: K
authors: Yoshizato
authors: Hirotaka
authors: H
authors: Matsui
authors: Akinori
authors: A
authors: Kanai
authors: Toshiya
authors: T
authors: Inaba
authors: Fiona
authors: F
authors: McPhee
authors: Min
authors: M
authors: Gao
authors: Kazuaki
authors: K
authors: Chayama
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D022781:Hepatocytes / Q000637:transplantation; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007546:Isoquinolines; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C583042:BMS-605339; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Drug Development; HCV