title: Efficacy, safety and pharmacokinetics of simeprevir and TMC647055/ritonavir with or without ribavirin and JNJ-56914845 in HCV genotype 1 infection.
abstract: BACKGROUND
  A Phase 2a, open-label study (NCT01724086) was conducted to assess the efficacy and safety of a once-daily, 2-direct-acting-antiviral-agent (2-DAA) combination of simeprevir + TMC647055/ritonavir ± ribavirin and of the 3-DAA combination of simeprevir + TMC647055/ritonavir + JNJ-56914845 in chronic hepatitis C virus genotype (GT)1-infected treatment-naïve and prior-relapse patients.
  
  
  METHODS
  The study comprised four 12-week treatment panels: Panel 1 (n = 10; GT1a) and Panel 2-Arm 1 (n = 12; GT1b): simeprevir 75 mg once daily + TMC647055 450 mg once daily/ritonavir 30 mg once daily + ribavirin 1000-1200 mg/day; Panel 2-Arm 2 (n = 9; GT1b): simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg without ribavirin; Panel 3: simeprevir 75 mg + TMC647055 600 mg/ritonavir 50 mg with (Arm 1: GT1a; n = 7) or without (Arm 2: GT1b; n = 8) ribavirin; Panel 4: simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg + JNJ-56914845 30 mg once daily (Arm 1: n = 22; GT1a/GT1b) or 60 mg once daily (Arm 2: n = 22; GT1a/GT1b). Primary endpoint was sustained virologic response 12 weeks after end of treatment (12 weeks of combination treatment; SVR12).
  
  
  RESULTS
  In Panel 1 and Panel 2-Arm 1, 5/10 and 6/12 (50%) GT1a/GT1b + ribavirin patients achieved SVR12, versus 3/9 (33%) GT1b without ribavirin patients in Panel 2-Arm 2. In Panel 3-Arm 1 and Panel 3-Arm 2, 6/7 (86%) GT1a + ribavirin and 4/8 (50%) GT1b without ribavirin patients, respectively, achieved SVR12. In Panel 4, 10/14 (71%) and 14/15 (93%) GT1a patients in Arms 1 and 2 achieved SVR12 compared with 8/8 and 7/7 (100%) GT1b patients in each arm, respectively. No deaths, serious adverse events (AEs), Grade 4 AEs or AEs leading to treatment discontinuation occurred.
  
  
  CONCLUSIONS
  The 2- and 3-DAA combinations were well tolerated. High SVR rates of 93% and 100% in GT1a- and GT1b-infected patients, respectively, were achieved in this study by combining simeprevir with JNJ-56914845 60 mg and TMC647055/ritonavir.
  
  
  BACKGROUND
  NCT01724086 (date of registration: September 26, 2012).
authors.affiliation: Department of Gastroenterology & Hepatology, ZNA Antwerp, Antwerpen, Belgium. stefan.bourgeois@zna.be.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bourgeois
authors.affiliation: Department of Hepatology and Gastroenterology, Universitair Ziekenhuis Gent, Ghent, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Van Vlierberghe
authors.affiliation: Liver Unit, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Moreno
authors.affiliation: Department of Gastroenterology and Hepatology, AZ Sint-Jan AV Hospital, Bruges, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Orlent
authors.affiliation: Department of Liver and Biliopancreatic Disorders, University Hospitals KU Leuven, Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.affiliation: EPIMED/Vivantes-Auguste-Viktoria-Klinikum, Berlin, Germany.
authors.forename: Keikawus
authors.initials: K
authors.lastname: Arastéh
authors.affiliation: Hepato-gastroenterology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Horsmans
authors.affiliation: Department of Medicine, University Medical Center Mainz, Mainz, Germany.
authors.forename: Jörn M
authors.initials: JM
authors.lastname: Schattenberg
authors.affiliation: IFI, Liver Center Hamburg, Asklepiosklinik St. Georg, Hamburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Buggisch
authors.affiliation: Department of Gastroenterology and Hepatology, Universitair Ziekenhuis Antwerpen, Antwerp, Belgium.
authors.forename: Sven
authors.initials: S
authors.lastname: Francque
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Vijgen
authors.affiliation: Alios BioPharma Inc, South San Francisco, CA, USA.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Kakuda
authors.affiliation: Janssen Research & Development BVBA, Beerse, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Hoeben
authors.affiliation: Janssen Pharmaceuticals LLC, Titusville, NJ, USA.
authors.forename: Donghan
authors.initials: D
authors.lastname: Luo
authors.affiliation: Janssen Research & Development BVBA, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Vandebosch
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Jacquemyn
authors.affiliation: Janssen Pharmaceuticals LLC, Titusville, NJ, USA.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Remoortere
authors.affiliation: Janssen Research & Development BVBA, Beerse, Belgium.
authors.forename: René
authors.initials: R
authors.lastname: Verloes
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002219:Carbamates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics; D006576:Heterocyclic Compounds, 4 or More Rings / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012254:Ribavirin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069616:Simeprevir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014633:Valine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: C575713:27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione; D000998:Antiviral Agents; D002219:Carbamates; C000595241:GSK2336805; D006576:Heterocyclic Compounds, 4 or More Rings; D013449:Sulfonamides; D012254:Ribavirin; D000069616:Simeprevir; D014633:Valine; D019438:Ritonavir
keywords: Direct-acting antiviral agents; Efficacy; Hepatitis C virus; JNJ-56914845; Ribavirin; Safety; Simeprevir; TMC647055/ritonavir; genotype 1