title: The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to nonnucleoside polymerase or protease inhibitors.
abstract: Specific inhibitors of hepatitis C virus (HCV) replication that target the NS3/4A protease (e.g., VX-950) or the NS5B polymerase (e.g., R1479/R1626, PSI-6130/R7128, NM107/NM283, and HCV-796) have advanced into clinical development. Treatment of patients with VX-950 or HCV-796 rapidly selected for drug-resistant variants after a 14-day monotherapy treatment period. However, no viral resistance was identified after monotherapy with R1626 (prodrug of R1479) or NM283 (prodrug of NM107) after 14 days of monotherapy. Based upon the rapid selection of resistance to the protease and nonnucleoside inhibitors during clinical trials and the lack of selection of resistance to the nucleoside inhibitors, we used the replicon system to determine whether nucleoside inhibitors demonstrate a higher genetic barrier to resistance than protease and nonnucleoside inhibitors. Treatment of replicon cells with nucleoside inhibitors at 10 and 15 times the 50% effective concentration resulted in clearance of the replicon, while treatment with a nonnucleoside or protease inhibitor selected resistant colonies. In combination, the presence of a nucleoside inhibitor reduced the frequency of colonies resistant to the other classes of inhibitors. These results indicate that the HCV replicon presents a higher barrier to the selection of resistance to nucleoside inhibitors than to nonnucleoside or protease inhibitors. Furthermore, the combination of a nonnucleoside or protease inhibitor with a nucleoside polymerase inhibitor could have a clear clinical benefit through the delay of resistance emergence.
authors.affiliation: Department of HCV Biology, Virology Disease Biology Area, Roche Palo Alto LLC, 3431 Hillview Ave, Palo Alto, CA 94304, USA.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: McCown
authors.forename: Sonal
authors.initials: S
authors.lastname: Rajyaguru
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Pogam
authors.forename: Samir
authors.initials: S
authors.lastname: Ali
authors.forename: Wen-Rong
authors.initials: WR
authors.lastname: Jiang
authors.forename: Hyunsoon
authors.initials: H
authors.lastname: Kang
authors.forename: Julian
authors.initials: J
authors.lastname: Symons
authors.forename: Nick
authors.initials: N
authors.lastname: Cammack
authors.forename: Isabel
authors.initials: I
authors.lastname: Najera
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009705:Nucleosides / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D012093:Replicon / Q000235:genetics*; D012697:Serine Endopeptidases / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D003562:Cytidine; D003841:Deoxycytidine; D009705:Nucleosides; D009842:Oligopeptides; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C093542:NS4 protein, hepatitis C virus; C504520:2'-deoxy-2'-fluoro-2'-C-methylcytidine; C486464:telaprevir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases; C508950:4'-azidocytidine