title: Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study.
abstract: BACKGROUND
  Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir.
  
  
  METHODS
  We enrolled patients with chronic HCV genotype 1 infections who had previously not responded to pegylated interferon (peginterferon) and ribavirin or were treatment naive. Patients were randomly assigned in a 2:1:2:1 ratio to receive 150 mg simeprevir and 400 mg sofosbuvir daily for 24 weeks with (group 1) or without (group 2) ribavirin or for 12 weeks with (group 3) or without (group 4) ribavirin, in two cohorts: previous non-responders with METAVIR scores F0-F2 (cohort 1) and previous non-responders and treatment-naive patients with METAVIR scores F3-F4 (cohort 2). The primary endpoint was sustained virological response 12 weeks after stopping treatment (SVR12). Analysis was done by intention to treat. Safety data from cohorts 1 and 2 were pooled for analysis. This study is registered with ClinicalTrials.gov, number NCT01466790.
  
  
  RESULTS
  168 patients were enrolled and randomised, and 167 started treatment (n=80 in cohort 1 and n=87 in cohort 2). SVR12 was achieved in 154 (92%) patients (n=72 [90%, 95% CI 81-96] in cohort 1 and n=82 [94%, 87-98] in cohort 2). The most common adverse events in the pooled groups were fatigue (n=52 [31%]), headache (n=33 [20%]), and nausea (n=26 [16%]). Grade 4 adverse events were seen in one (2%) of 54 patients in each of groups 1 and 3 and in three (10%) of 31 patients in group 2, whereas grade 3-4 events were reported in less than 5% of all patients, except increased blood amylase concentration. Serious adverse events were seen in four (2%) patients, all in groups 1 and 2. Four (2%) patients discontinued all study treatment because of adverse events, three before week 12.
  
  
  CONCLUSIONS
  Combined simeprevir and sofosbuvir was efficacious and well tolerated.
  
  
  BACKGROUND
  Janssen.
authors: Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. Electronic address: lawitz@txliver.com.
authors: Eric
authors: E
authors: Lawitz
authors: Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Mark S
authors: MS
authors: Sulkowski
authors: Texas Clinical Research Institute, Arlington, TX, USA.
authors: Reem
authors: R
authors: Ghalib
authors: Fundación de Investigación, San Juan, PR, USA.
authors: Maribel
authors: M
authors: Rodriguez-Torres
authors: Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA.
authors: Zobair M
authors: ZM
authors: Younossi
authors: Borland-Groover Clinic, Jacksonville, FL, USA.
authors: Ana
authors: A
authors: Corregidor
authors: Orlando Immunology Center, Orlando, FL, USA.
authors: Edwin
authors: E
authors: DeJesus
authors: Atlanta Medical Center, Atlanta, GA, USA.
authors: Brian
authors: B
authors: Pearlman
authors: University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors: Mordechai
authors: M
authors: Rabinovitz
authors: Atlanta Gastroenterology Association, Atlanta, GA, USA.
authors: Norman
authors: N
authors: Gitlin
authors: Yale Liver Center and Yale University School of Medicine, New Haven, CT, USA.
authors: Joseph K
authors: JK
authors: Lim
authors: Scripps Clinic, La Jolla, CA, USA.
authors: Paul J
authors: PJ
authors: Pockros
authors: Harborview Medical Center, Seattle, WA, USA.
authors: John D
authors: JD
authors: Scott
authors: Janssen Research & Development, Beerse, Belgium.
authors: Bart
authors: B
authors: Fevery
authors: Novellas Healthcare, Zellik, Belgium.
authors: Tom
authors: T
authors: Lambrecht
authors: Janssen Research & Development, Beerse, Belgium.
authors: Sivi
authors: S
authors: Ouwerkerk-Mahadevan
authors: Janssen Research & Development, Beerse, Belgium.
authors: Katleen
authors: K
authors: Callewaert
authors: Gilead Sciences Inc, Foster City, CA, USA.
authors: William T
authors: WT
authors: Symonds
authors: Janssen Research & Development, Titusville, NJ, USA.
authors: Gaston
authors: G
authors: Picchio
authors: Janssen Research & Development, Titusville, NJ, USA.
authors: Karen L
authors: KL
authors: Lindsay
authors: Janssen Research & Development, Beerse, Belgium.
authors: Maria
authors: M
authors: Beumont
authors: Weill Cornell Medical College, New York, NY, USA.
authors: Ira M
authors: IM
authors: Jacobson
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D006575:Heterocyclic Compounds, 3-Ring / Q000627:therapeutic use*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D012016:Reference Values; D012254:Ribavirin / Q000627:therapeutic use; D018570:Risk Assessment; D012720:Severity of Illness Index; D000069616:Simeprevir; D000069474:Sofosbuvir; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives*
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; D014542:Uridine Monophosphate; C100416:peginterferon alfa-2a; D000069474:Sofosbuvir