title: Elimination of HCV via a non-ISG-mediated mechanism by vaniprevir and BMS-788329 combination therapy in human hepatocyte chimeric mice.
abstract: We previously reported that interferon (IFN)-free direct-acting antiviral combination treatment succeeded in eradicating genotype 1b hepatitis C virus (HCV) in human hepatocyte chimeric mice. In this study, we examined the effect of vaniprevir (MK7009, NS3/4A protease inhibitor) and BMS-788329 (NS5A inhibitor) combination treatment on HCV genotype 1b and the expression of IFN-stimulated genes (ISGs) using a subgenomic replicon system and the same animal model. Combination treatment with vaniprevir and BMS-788329 significantly reduced HCV replication compared to vaniprevir monotherapy in HCV replicon cells (Huh7/Rep-Feo cells). HCV genotype 1b-infected human hepatocyte chimeric mice were treated with vaniprevir alone or in combination with BMS-788329 for four weeks. Vaniprevir monotherapy reduced serum HCV RNA titers in mice, but viral breakthrough was observed in mice with high HCV titers. Ultra-deep sequence analysis revealed a predominant replacement by drug-resistant substitutions at 168 in HCV NS3 region in these mice. Conversely, in mice with low HCV titers, HCV was eradicated by vaniprevir monotherapy without viral breakthrough. In contrast to monotherapy, combination treatment with vaniprevir and BMS-788329 succeeded in completely eradicating HCV regardless of serum viral titer. IFN-alpha treatment significantly increased ISG expression; however, vaniprevir and BMS-788329 combination treatment caused no increase in ISG expression both in cultured cells and in mouse livers. Therefore, combination treatment with vaniprevir and BMS-788329 eliminated HCV via a non-ISG-mediated mechanism. This oral treatment might offer an alternative DAA combination therapy for patients with chronic hepatitis C.
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiraga
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yoshimi
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kan
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Miyaki
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Tsuge
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Abe
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors.forename: C Nelson
authors.initials: CN
authors.lastname: Hayes
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aikata
authors.affiliation: Liver Research Project Center, Hiroshima University, Hiroshima, Japan; PhoenixBio Co., Ltd., Higashihiroshima, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: Liver Research Project Center, Hiroshima University, Hiroshima, Japan; PhoenixBio Co., Ltd., Higashihiroshima, Japan.
authors.forename: Chise
authors.initials: C
authors.lastname: Tateno
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Merck & Co., Inc., USA.
authors.forename: Joan D
authors.initials: JD
authors.lastname: Ellis
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan. Electronic address: chayama@hiroshima-u.ac.jp.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D002460:Cell Line; D003521:Cyclopropanes; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination / Q000379:methods; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy*; D022781:Hepatocytes / Q000821:virology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D011392:Proline / Q000031:analogs & derivatives; D012367:RNA, Viral / Q000235:genetics; D013449:Sulfonamides; D016896:Treatment Outcome; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D007211:Indoles; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D012367:RNA, Viral; D013449:Sulfonamides; D011392:Proline; C540393:vaniprevir; D007930:Leucine
keywords: BMS-788329; DAA; HCV; Human hepatocyte chimeric mouse; Interferon-stimulated gene; Vaniprevir