title: Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice.
abstract: OBJECTIVE
  The current treatment regimen for chronic hepatitis C virus (HCV) infection is peg-interferon plus ribavirin combination therapy. The majority of developing therapeutic strategies also contain peg-interferon with or without ribavirin. However, interferon is expensive and sometimes intolerable for some patients because of severe side effects.
  
  
  METHODS
  Using human hepatocyte chimeric mice, we examined whether a short term combination therapy with the HCV NS3-4A protease inhibitor telaprevir and the RNA polymerase inhibitor MK-0608 with or without interferon eradicates the HCV from infected mice. The effect of telaprevir and MK-0608 combination therapy was examined using subgenomic HCV replicon cells.
  
  
  RESULTS
  Combination therapy with the two drugs enhanced inhibition of HCV replication compared with either drug alone. In in vivo experiments, early emergence of drug resistance was seen in mice treated with either telaprevir or MK-0608 alone. However, emergence was prevented by the combination of these drugs. Mice treated with a triple combination therapy of telaprevir, MK-0608, and interferon became negative for HCV RNA soon after commencement of the therapy, and HCV RNA was not detected in serum of these mice 12 weeks after cessation of the therapy. Furthermore, all mice treated with a high dose telaprevir and MK-0608 combination therapy for 4 weeks became negative for HCV RNA 1 week after the beginning of the therapy and remained negative after 18 weeks.
  
  
  CONCLUSIONS
  Eradication of HCV from mice with only 4 weeks of therapy without interferon points the way to future combination therapies for chronic hepatitis C patients.
authors.affiliation: Department of Medicine, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Ohara
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiraga
authors.forename: Michio
authors.initials: M
authors.lastname: Imamura
authors.forename: Eiji
authors.initials: E
authors.lastname: Iwao
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kamiya
authors.forename: Ichimaro
authors.initials: I
authors.lastname: Yamada
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kono
authors.forename: Mayu
authors.initials: M
authors.lastname: Onishi
authors.forename: Daizaburo
authors.initials: D
authors.lastname: Hirata
authors.forename: Fukiko
authors.initials: F
authors.lastname: Mitsui
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Kawaoka
authors.forename: Masataka
authors.initials: M
authors.lastname: Tsuge
authors.forename: Shoichi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Abe
authors.forename: C Nelson
authors.initials: CN
authors.lastname: Hayes
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ochi
authors.forename: Chise
authors.initials: C
authors.lastname: Tateno
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yoshizato
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D046528:Chimerism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D022781:Hepatocytes / Q000637:transplantation; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009842:Oligopeptides / Q000494:pharmacology*; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D014372:Tubercidin; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus; C486464:telaprevir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C518645:7-deaza-2'-C-methyladenosine