title: Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance.
abstract: The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development, and direct-acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.
authors.affiliation: Systems Medicine, Inflammation and Infection Research Centre, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney 2052, Australia. a.eltahla@unsw.edu.au.
authors.forename: Auda A
authors.initials: AA
authors.lastname: Eltahla
authors.affiliation: Systems Medicine, Inflammation and Infection Research Centre, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney 2052, Australia. luciani@unsw.edu.au.
authors.forename: Fabio
authors.initials: F
authors.lastname: Luciani
authors.affiliation: School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney 2052, Australia. p.white@unsw.edu.au.
authors.forename: Peter A
authors.initials: PA
authors.lastname: White
authors.affiliation: Systems Medicine, Inflammation and Infection Research Centre, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney 2052, Australia. a.lloyd@unsw.edu.au.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Lloyd
authors.affiliation: Systems Medicine, Inflammation and Infection Research Centre, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney 2052, Australia. r.bull@unsw.edu.au.
authors.forename: Rowena A
authors.initials: RA
authors.lastname: Bull
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D009154:Mutation; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: NS5B; RNA dependent RNA polymerase; antiviral resistance; direct-acting antiviral; hepatitis C virus; polymerase inhibitor