Interferon-free antiviral combination therapies without nucleosidic polymerase inhibitors

J Hepatol. 2014 Nov;61(1 Suppl):S98-S107. doi: 10.1016/j.jhep.2014.08.014. Epub 2014 Nov 3.


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.

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).

Publication types

  • Review

MeSH terms

  • Antiviral Agents / therapeutic use*
  • Drug Therapy, Combination
  • Genotype
  • Hepacivirus / genetics
  • Hepatitis C / drug therapy*
  • Humans
  • Interferons / therapeutic use
  • Nucleic Acid Synthesis Inhibitors / therapeutic use
  • Oligopeptides / therapeutic use
  • Proline / analogs & derivatives
  • Proline / therapeutic use
  • Protease Inhibitors / therapeutic use*
  • Viral Nonstructural Proteins / antagonists & inhibitors*


  • Antiviral Agents
  • NS-5 protein, hepatitis C virus
  • NS3 protein, hepatitis C virus
  • Nucleic Acid Synthesis Inhibitors
  • Oligopeptides
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • telaprevir
  • 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
  • Interferons
  • Proline