title: Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection.
  
  
  METHODS
  In QUEST-1, a phase 3, randomised, double-blind multicentre trial undertaken in 13 countries (Australia, Europe, North America, Puerto Rico, and New Zealand), 394 patients (aged ≥18 years) with chronic HCV genotype 1 infection and no history of HCV treatment, stratified by HCV subtype and host IL28B genotype, were randomly assigned in a 2:1 ratio with a computer-generated allocation sequence to receive simeprevir (150 mg once daily, orally) plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (simeprevir group), or placebo orally plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (placebo group). Treatment duration was 24 weeks or 48 weeks in the simeprevir group according to criteria for response-guided therapy (ie, HCV RNA <25 IU/mL [undetectable or detectable] at week 4 and <25 IU/mL undetectable at week 12) and 48 weeks in the placebo group. Patients, study personnel, and the sponsor were masked to the treatment group assignment. The primary efficacy endpoint was sustained virological response 12 weeks after the planned end of treatment (SVR12) and was assessed with an intention-to-treat analysis. The results of the primary analysis (week 60) are presented for safety and SVR12. This trial is registered with ClinicalTrials.gov, number NCT01289782.
  
  
  RESULTS
  Treatment with simeprevir, peginterferon alfa 2a, and ribavirin was superior to placebo, peginterferon alfa 2a, and ribavirin (SVR12 in 210 [80%] patients of 264 vs 65 [50%] of 130, respectively, adjusted difference 29·3% [95% CI 20·1-38·6; p<0·0001). Adverse events in the first 12 weeks of treatment led to discontinuation of simeprevir in two (<1%) patients and discontinuation of placebo in one patient (<1%); fatigue (106 [40%] vs 49 [38%] patients, respectively) and headache (81 [31%] vs 48 [37%], respectively) were the most common adverse events. The prevalences of anaemia (42 [16%] vs 14 [11%], respectively) and rash (72 [27%] vs 33 [25%]) were similar in the simeprevir and placebo groups. Addition of simeprevir did not increase severity of patient-reported fatigue and functioning limitations, but shortened their duration.
  
  
  CONCLUSIONS
  Simeprevir once daily with peginterferon alfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin.
  
  
  BACKGROUND
  Janssen Infectious Diseases-Diagnostics.
authors.affiliation: Weill Cornell Medical College, New York, NY, USA. Electronic address: imj2001@med.cornell.edu.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.affiliation: Kirby Institute, University of New South Wales, Darlinghurst, NSW, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Dore
authors.affiliation: Queen Mary, University of London, London, UK.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Foster
authors.affiliation: University of North Carolina at Chapel Hill, NC, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Fried
authors.affiliation: Institutul de Boli Infectioase, Bucharest, Romania.
authors.forename: Monica
authors.initials: M
authors.lastname: Radu
authors.affiliation: Smolensk Regional Clinical Hospital, Smolensk State Medical Academy, Smolensk Oblast, Russia.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Rafalsky
authors.affiliation: Vinnytsia National Medical University, Vinnytsia, Ukraine.
authors.forename: Larysa
authors.initials: L
authors.lastname: Moroz
authors.affiliation: Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, Palermo, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Craxi
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Monika
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Janssen Infectious Diseases, 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 Research and Development, Titusville, NJ, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: De La Rosa
authors.affiliation: Janssen Research and Development, Titusville, NJ, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Kalmeijer
authors.affiliation: Janssen Global Services, High Wycombe, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Scott
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Rekha
authors.initials: R
authors.lastname: Sinha
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Beumont-Mauviel
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage; D012254:Ribavirin / Q000008:administration & dosage*; D000069616:Simeprevir; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
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