title: Characterization of hepatitis C virus (HCV) quasispecies dynamics upon short-term dual therapy with the HCV NS5B nucleoside polymerase inhibitor mericitabine and the NS3/4 protease inhibitor danoprevir.
abstract: In the INFORM-1 study, 73 patients with chronic hepatitis C virus infection received mericitabine plus danoprevir for up to 13 days. Seventy-two patients experienced a continuous decline in HCV RNA levels during treatment, and of these patients, 14 had viral loads that remained >1,000 IU/ml by day 13 and 1 met the definition for viral breakthrough. In-depth NS5B and NS3/4A population and clonal sequencing studies and mericitabine and danoprevir drug susceptibility testing were performed to assess the variability and quasispecies dynamics before and upon monotherapy or dual therapy. Sequence analysis of the viral quasispecies indicated that the mericitabine resistance mutation S282T was not present at baseline, nor was it selected (even at a low level) during treatment. Protease inhibitor resistance mutations, either as predominant or as minority species, were detected in 18 patients at baseline. No enrichment of minority protease inhibitor-resistant variants present at baseline was observed during treatment; viral population samples were fully susceptible to mericitabine and/or danoprevir, despite the presence within their quasispecies of minority variants confirmed to have reduced susceptibility to danoprevir or other protease inhibitors. It was also observed that certain NS3 amino acid substitutions affected protease inhibitor drug susceptibility in a compound-specific manner and varied with the genetic context. In summary, the slower kinetics of viral load decline observed in some patients was not due to the selection of danoprevir or mericitabine resistance during treatment. Over 2 weeks' therapy, mericitabine suppressed the selection of danoprevir resistance, results that could differ upon longer treatment periods.
authors.affiliation: Roche, Nutley, New Jersey, USA.
authors.forename: S
authors.initials: S
authors.lastname: Le Pogam
authors.forename: J M
authors.initials: JM
authors.lastname: Yan
authors.forename: M
authors.initials: M
authors.lastname: Chhabra
authors.forename: M
authors.initials: M
authors.lastname: Ilnicka
authors.forename: H
authors.initials: H
authors.lastname: Kang
authors.forename: A
authors.initials: A
authors.lastname: Kosaka
authors.forename: S
authors.initials: S
authors.lastname: Ali
authors.forename: D J
authors.initials: DJ
authors.lastname: Chin
authors.forename: N S
authors.initials: NS
authors.lastname: Shulman
authors.forename: P
authors.initials: P
authors.lastname: Smith
authors.forename: K
authors.initials: K
authors.lastname: Klumpp
authors.forename: I
authors.initials: I
authors.lastname: Nájera
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003521:Cyclopropanes; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D054833:Isoindoles; D007769:Lactams / Q000494:pharmacology / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic; D009154:Mutation; D010919:Placebos; D011392:Proline / Q000031:analogs & derivatives; D012367:RNA, Viral / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D019562:Viral Load / Q000187:drug effects; 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; D003521:Cyclopropanes; D003841:Deoxycytidine; D004791:Enzyme Inhibitors; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D010919:Placebos; D011392:Proline; D012367:RNA, Viral; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus; C553752:danoprevir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase