title: Virology analyses of HCV genotype 4 isolates from patients treated with simeprevir and peginterferon/ribavirin in the Phase III RESTORE study.
abstract: Simeprevir is a hepatitis C virus NS3/4A protease inhibitor. Hepatitis C virus baseline NS3/4A polymorphisms and emerging mutations were characterized in treatment-naїve and treatment-experienced genotype 4-infected patients treated with simeprevir+peginterferon/ribavirin in the RESTORE study. Population sequencing of the NS3/4A region was performed and in vitro simeprevir activity against site-directed mutants or chimeric replicons with patient-derived NS3 protease sequences was assessed in a transient replicon assay. Simeprevir remained active against most (83/91 [91%]) baseline isolates tested in the chimeric replicon assay. Eight baseline isolates reduced simeprevir activity; these carried I132L or D168E substitutions reducing simeprevir median activity by 4.6- and 39-fold, respectively. Six of these eight isolates were from patients achieving sustained virologic response. Baseline NS3 Q80K polymorphism was not observed in the genotype 4-infected patients. Of the 107 simeprevir-treated patients, 37 did not achieve sustained virologic response for any reason. Of the 32 patients who failed treatment and had sequencing information, 28 (88%) had emerging mutations at NS3 positions 80, 122, 155, 156 and/or 168 at time of failure, similar to those in genotype 1. Emerging mutations were mainly D168V and D168E alone or combined with mutations at position 80. In general, isolates obtained at time of failure displayed high-level in vitro resistance to simeprevir (fold change ≥50) in a chimeric replicon assay with a median simeprevir fold change value of 440, consistent with observed mutations. In conclusion, emerging mutations in genotype 4 patients failing simeprevir+peginterferon/ribavirin treatment were similar to those in genotype 1 and conferred high-level resistance to simeprevir.
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Fevery
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Verbinnen
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Janssen
authors.affiliation: Janssen Research & Development LLC, Titusville, NJ, USA.
authors.forename: J
authors.initials: J
authors.lastname: Witek
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: W
authors.initials: W
authors.lastname: Jessner
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: De Meyer
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: O
authors.initials: O
authors.lastname: Lenz
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000235:genetics; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D024882:Drug Resistance, Viral; D005838:Genotype; D016174:Hepacivirus / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D012254:Ribavirin / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D000069616:Simeprevir / Q000494:pharmacology / Q000627:therapeutic use*; D000072230:Sustained Virologic Response; D017211:Treatment Failure; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D004279:DNA, Viral; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D012254:Ribavirin; D000069616:Simeprevir; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus
keywords: Hepatitis C virus; simeprevir; virology