title: Resistance to mericitabine, a nucleoside analogue inhibitor of HCV RNA-dependent RNA polymerase.
abstract: Mericitabine (RG7128), an orally administered prodrug of PSI-6130, is the most clinically advanced nucleoside analogue inhibitor of the RNA-dependent RNA polymerase (RdRp) of HCV. This review describes what has been learnt so far about the resistance profile of mericitabine. A serine to threonine substitution at position 282 (S282T) of the RdRp that reduces its replication capacity to approximately 15% of wild-type is the only variant that has been consistently generated in serial in vitro passage experiments. To date, no evidence of genotypic resistance to mericitabine has been detected by population or clonal sequence analysis in any baseline or on-treatment samples collected from >600 patients enrolled in Phase I/II trials of mericitabine administered as monotherapy, in combination with pegylated interferon/ribavirin, or in combination with the protease inhibitor, danoprevir, for 14 days in the proof-of-concept study of interferon-free therapy.
authors.affiliation: National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France. jean-michel.pawlotsky@hmn.aphp.fr
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pawlotsky
authors.forename: Isabel
authors.initials: I
authors.lastname: Najera
authors.forename: Ira
authors.initials: I
authors.lastname: Jacobson
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D016896:Treatment Outcome
chemical_list: C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; D000998:Antiviral Agents; D003841:Deoxycytidine; D012324:RNA-Dependent RNA Polymerase