title: Combination of a hepatitis C virus NS3-NS4A protease inhibitor and alpha interferon synergistically inhibits viral RNA replication and facilitates viral RNA clearance in replicon cells.
abstract: The present standard of care for hepatitis C virus (HCV) infection is pegylated alpha interferon (IFN-alpha) in combination with ribavirin. However, specific antivirals such as HCV NS3-NS4A protease inhibitors are now in clinical development, and these agents can potentially be used in combination with the present treatments. Therefore, it is important to investigate the potential benefits or adverse effects of these new combinations by using available in vitro HCV culture systems first. In the present study we demonstrate that the combination of a specific HCV NS3-NS4A protease inhibitor and IFN-alpha synergistically inhibits HCV RNA replication in replicon cells, with little or no increase in cytotoxicity. Furthermore, the benefit of the combination was sustained over time, such that a greater than 3-log reduction in HCV RNA levels was achieved following 9 days of treatment. The viral RNA appeared to be cleared from the replicon cells after 14 days of treatment, and no viral RNA rebound was observed upon withdrawal of the inhibitors. In each case, the antiviral effects obtained with higher concentrations of either the protease inhibitor alone or IFN-alpha alone can be achieved by a combination of both agents at lower concentrations, which may potentially reduce the risk of possible adverse effects associated with high doses of either agent.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Lin
authors.forename: Ann D
authors.initials: AD
authors.lastname: Kwong
authors.forename: Chao
authors.initials: C
authors.lastname: Lin
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012367:RNA, Viral / Q000096:biosynthesis* / Q000378:metabolism; D011994:Recombinant Proteins; D012093:Replicon / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D007370:Interferon Type I; D011480:Protease Inhibitors; D012367:RNA, Viral; D011994:Recombinant Proteins; 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