title: Impact of ribavirin on HCV replicon RNA decline during treatment with interferon-α and the protease inhibitors boceprevir or telaprevir.
abstract: BACKGROUND
  Ribavirin increases early and sustained virological response rates in patients chronically infected with HCV who receive pegylated interferon-α and novel HCV protease inhibitors.
  
  
  METHODS
  To better characterize antiviral efficacies of these upcoming therapies, Huh7 cells harbouring a subgenomic HCV replicon system were cultivated with various doses and combinations of ribavirin, interferon-α, and the protease inhibitors boceprevir and telaprevir. Antiviral efficacy parameters were estimated from HCV RNA decay, and synergistic effects of combination therapies were analysed with the Bliss independency model.
  
  
  RESULTS
  Single-drug antiviral activities showed dose-dependent HCV RNA reductions in replicon cells (50% inhibitory concentration of 386.16 μM, 81.67 IU, 0.44 μM and 0.81 μM after 48 h for ribavirin, interferon-α, boceprevir and telaprevir, respectively). For the dual combination of ribavirin with either boceprevir or telaprevir, no deviation from additivity was observed whereas the reduction of HCV RNA was synergistic for ribavirin with interferon-α (P<0.001). Triple combinations with ribavirin, interferon-α and protease inhibitors showed the most profound HCV RNA decay.
  
  
  CONCLUSIONS
  The beneficial in vitro antiviral effect of ribavirin with interferon-α and novel HCV protease inhibitors demonstrates that ribavirin may be required as an antiviral backbone in the near future.
authors.affiliation: Department of Internal Medicine I, Goethe-University Hospital, Frankfurt, Germany. hofmann@med.uni-frankfurt.de
authors.forename: Wolf Peter
authors.initials: WP
authors.lastname: Hofmann
authors.forename: Tje Lin
authors.initials: TL
authors.lastname: Chung
authors.forename: Carola
authors.initials: C
authors.lastname: Osbahr
authors.forename: Simone
authors.initials: S
authors.lastname: Susser
authors.forename: Ursel
authors.initials: U
authors.lastname: Karey
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mihm
authors.forename: Christoph
authors.initials: C
authors.lastname: Welsch
authors.forename: Jörn
authors.initials: J
authors.lastname: Lötsch
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008962:Models, Theoretical; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012367:RNA, Viral / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012093:Replicon / Q000187:drug effects* / Q000235:genetics; D012254:Ribavirin / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011480:Protease Inhibitors; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; C100416:peginterferon alfa-2a