title: Interferon-free antiviral combination therapies without nucleosidic polymerase inhibitors.
abstract: The establishment of robust HCV cell culture systems and characterization of the viral life cycle provided the molecular basis for highly innovative, successful years in HCV drug development. With the identification of direct-acting antiviral agents (DAAs), such as NS3/4A protease inhibitors, NS5A replication complex inhibitors, nucleotide and non-nucleoside polymerase inhibitors, as well as host cell targeting agents, novel therapeutic strategies were established and competitively entered clinical testing. The first-in-class NS3/4A protease inhibitors telaprevir and boceprevir, approved in 2011, were recently outpaced by the pan-genotypic nucleotide polymerase inhibitor sofosbuvir that in combination with pegylated interferon and ribavirin, further shortens therapy durations and also offers the first interferon-free HCV treatment option. In the challenging race towards the goal of interferon-free HCV therapies, however, several oral DAA regimens without nucleotide polymerase inhibitors that combine a NS3/4A protease inhibitor, a NS5A inhibitor and/or a non-nucleoside polymerase inhibitor yielded competitive results. Second generation NS3/4A protease and NS5A inhibitors promise an improved genotypic coverage and a high resistance barrier. Results of novel DAA combination therapies without the backbone of a nucleotide polymerase inhibitor, as well as treatment strategies involving host targeting agents are reviewed herein.
authors.affiliation: Department of Medicine 1, Johann Wolfgang Goethe-University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Tania Mara
authors.initials: TM
authors.lastname: Welzel
authors.affiliation: Department of Medicine 1, Johann Wolfgang Goethe-University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Dultz
authors.affiliation: Department of Medicine 1, Johann Wolfgang Goethe-University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Electronic address: zeuzem@em.uni-frankfurt.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D019384:Nucleic Acid Synthesis Inhibitors / Q000627:therapeutic use; D009842:Oligopeptides / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use*; 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; D007372:Interferons; D019384:Nucleic Acid Synthesis Inhibitors; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; 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; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: All oral; Direct-acting antiviral agents (DAAs); Host-targeting agents (HTAs); Interferon-free HCV treatment; NS3/4A protease inhibitors (PI); NS5A inhibitors; Non-nucleoside polymerase inhibitors (NNI)