title: Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial.
abstract: OBJECTIVE
  Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in phase III trials for chronic hepatitis C virus (HCV) infection. We performed a phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of simeprevir, peginterferon-α2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV.
  
  
  METHODS
  We analyzed data from patients who did not respond (null response), had a partial response, or relapsed after treatment with PegIFN and RBV, randomly assigned to receive simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n = 396), or placebo plus PegIFN and RBV for 48 weeks (n = 66). All patients were followed for 24 weeks after planned end of treatment; the primary end point was the proportion of patients with sustained virologic response (SVR; undetectable HCV RNA) at that time point.
  
  
  RESULTS
  Overall, rates of SVR at 24 weeks were significantly higher in the groups given simeprevir than those given placebo (61%-80% vs 23%; P < .001), regardless of prior response to PegIFN and RBV (simeprevir vs placebo: prior null response, 38%-59% vs 19%; prior partial response, 48%-86% vs 9%; prior relapse, 77%-89% vs 37%). All groups had comparable numbers of adverse events; these led to discontinuation of simeprevir or placebo and/or PegIFN and RBV in 8.8% of patients given simeprevir and 4.5% of those given placebo.
  
  
  CONCLUSIONS
  In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR at 24 weeks compared with patients given placebo, PegIFN, and RBV and was generally well tolerated. ClinicalTrials.gov number: NCT00980330.
authors.affiliation: JW Goethe University Hospital, Frankfurt, Germany. Electronic address: Zeuzem@em.uni-frankfurt.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: University Clinic Leipzig, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: Auckland Clinical Studies, Auckland, New Zealand.
authors.forename: Edward
authors.initials: E
authors.lastname: Gane
authors.affiliation: Universitätsklinik für Innere Medizin III, Wien, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.affiliation: Queen Mary's University of London, London, United Kingdom.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Foster
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Fried
authors.affiliation: Hôpital Henri-Mondor, Université Paris-Est, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hezode
authors.affiliation: NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, United Kingdom.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: Weill Cornell Medical College, New York, New York.
authors.forename: Ira
authors.initials: I
authors.lastname: Jacobson
authors.affiliation: Russian State Medical University, Moscow, Russia.
authors.forename: Igor
authors.initials: I
authors.lastname: Nikitin
authors.affiliation: Scripps Clinic, La Jolla, California.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Pockros
authors.affiliation: The Texas Liver Institute/University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Fred
authors.initials: F
authors.lastname: Poordad
authors.affiliation: Janssen Global Services LLC, High Wycombe, Buckinghamshire, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Scott
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Oliver
authors.initials: O
authors.lastname: Lenz
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Monika
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Janssen Research & Development, Titusville, New Jersey.
authors.forename: Vanitha
authors.initials: V
authors.lastname: Sekar
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Goedele
authors.initials: G
authors.lastname: De Smedt
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Rekha
authors.initials: R
authors.lastname: Sinha
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Beumont-Mauviel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006575:Heterocyclic Compounds, 3-Ring / Q000627:therapeutic use*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D000069616:Simeprevir; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D006575:Heterocyclic Compounds, 3-Ring; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013449:Sulfonamides; D011092:Polyethylene Glycols; D012254:Ribavirin; D000069616:Simeprevir; C100416:peginterferon alfa-2a
keywords: AE; Clinical Trial; DAA; Direct-Acting Antivirals; EOT; FSS; Fatigue Severity Scale; HCV; PegIFN; PegIFN-α; RBV; RVR; SVR; SVR24; adverse event; end of treatment; hepatitis C virus; peginterferon-α; peginterferon-α2a; rapid virologic response; ribavirin; sustained virologic response; sustained virologic response at 24 weeks after the planned end of treatment