title: Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial.
abstract: OBJECTIVE
  Simeprevir is an oral, once-daily inhibitor of hepatitis c virus (HCV) protease NS3/4A. We investigated the safety and efficacy of simeprevir with peg-interferon α-2a and ribavirin (PR) in a randomized, double-blind, placebo-controlled, phase 3 trial of patients with HCV genotype 1 infection who relapsed after previous interferon-based therapy.
  
  
  METHODS
  Patients were assigned randomly (2:1) to groups given simeprevir (150 mg, once daily) and PR (n = 260) or placebo and PR (n = 133) for 12 weeks. Patients then were given PR alone for 12 or 36 weeks (simeprevir group, based on response-guided therapy criteria) or 36 weeks (placebo group).
  
  
  RESULTS
  Simeprevir and PR was significantly superior to placebo and PR; rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were 79.2% vs 36.1%, respectively (43.8% difference; 95% confidence interval, 34.6-53.0; P < .001). Among patients given simeprevir, 92.7% met the response-guided therapy criteria and were eligible to complete PR at week 24; of these, 83.0% achieved SVR12. HCV RNA was undetectable at week 4 in 77.2% of patients given simeprevir and 3.1% given placebo. On-treatment failure and relapse rates were lower among patients given simeprevir and PR than those given placebo and PR (3.1% vs 27.1%, and 18.5% vs 48.4%, respectively). Patients given simeprevir did not have adverse events beyond those that occurred in patients given PR alone. Most adverse events were grades 1/2; the prevalence of anemia and rash was similar in both groups. Patients in both groups reported similar severity of fatigue and functional impairments during the study, but duration was reduced among patients given simeprevir.
  
  
  CONCLUSIONS
  In a phase 3 trial of patients who had relapsed after interferon-based therapy, the addition of simeprevir to PR was generally well tolerated, with an SVR12 rate of 79.2%. Most patients (92.7%) receiving simeprevir were able to shorten therapy to 24 weeks. ClinicalTrials.gov number: NCT01281839.
authors.affiliation: Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain. Electronic address: xforns@clinic.ub.es.
authors.forename: Xavier
authors.initials: X
authors.lastname: Forns
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: J.W. Goethe University Hospital, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: Auckland Hospital Clinical Studies Unit, Auckland, New Zealand.
authors.forename: Ed
authors.initials: E
authors.lastname: Gane
authors.affiliation: INSERM U954, Université de Lorraine, Centre Hospitalier Universitaire de Nancy, Vandoeuvre Les Nancy, France.
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Bronowicki
authors.affiliation: Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Andreone
authors.affiliation: Medical University of Warsaw, Wolska, Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Horban
authors.affiliation: Imperial College Healthcare National Health Service Trust, London, United Kingdom.
authors.forename: Ashley
authors.initials: A
authors.lastname: Brown
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Monika
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Oliver
authors.initials: O
authors.lastname: Lenz
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: Sivi
authors.initials: S
authors.lastname: Ouwerkerk-Mahadevan
authors.affiliation: Janssen Global Services, LLC, High Wycombe, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Scott
authors.affiliation: Janssen Global Services, LLC, Titusville, New Jersey.
authors.forename: Guy
authors.initials: G
authors.lastname: De La Rosa
authors.affiliation: Janssen Global Services, LLC, Titusville, New Jersey.
authors.forename: Ronald
authors.initials: R
authors.lastname: Kalmeijer
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: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D015415:Biomarkers / Q000097:blood; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005060:Europe; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D006526:Hepatitis C / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009656:North America; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012008:Recurrence; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D000069616:Simeprevir; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D006575:Heterocyclic Compounds, 3-Ring; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011480:Protease Inhibitors; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D000069616:Simeprevir; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C100416:peginterferon alfa-2a
keywords: Chronic Hepatitis C; DAA; Drug; PROMISE