title: Daclatasvir plus simeprevir with or without ribavirin for the treatment of chronic hepatitis C virus genotype 1 infection.
abstract: OBJECTIVE
  We evaluated the combination of daclatasvir (pan-genotypic NS5A inhibitor) and simeprevir (NS3/4A protease inhibitor), with or without ribavirin, in hepatitis C virus genotype 1-infected patients.
  
  
  METHODS
  This phase II, open-label study enrolled treatment-naive patients or prior null responders with genotype 1b (n=147) or 1a (n=21) infection. Genotype 1b-infected patients were randomized 1:1 to receive daclatasvir 30mg plus simeprevir 150mg once daily with or without ribavirin; those who completed the initial 12-week treatment were re-randomized 1:1 to stop treatment or continue treatment through to week 24. Genotype 1a-infected patients received daclatasvir plus simeprevir with ribavirin for 24weeks. The primary endpoint was the proportion of patients with sustained virologic response at posttreatment week 12 (SVR12).
  
  
  RESULTS
  For genotype 1b, 84.9% (45/53) and 74.5% (38/51) of treatment-naive patients and 69.6% (16/23) and 95.0% (19/20) of prior null responders to peginterferon and ribavirin achieved SVR12 with daclatasvir plus simeprevir alone and with ribavirin, respectively. Treatment duration did not have a well-defined impact on response. For genotype 1a, daclatasvir plus simeprevir with ribavirin provided a 66.7% (8/12) response rate in treatment-naive patients and was not effective in prior null responders. Data suggest that baseline resistance polymorphisms influenced SVR12 rates. Daclatasvir plus simeprevir was well tolerated with or without ribavirin with low incidences of serious adverse events and adverse events leading to discontinuation.
  
  
  CONCLUSIONS
  Daclatasvir plus simeprevir, with or without ribavirin, was effective with a 12- or 24-week duration in genotype 1b-infected patients and was well tolerated. ClinicalTrials.gov identifier: NCT01628692.
authors.affiliation: Klinikum der Goethe Universität, Frankfurt, Germany. Electronic address: zeuzem@em.uni-frankfurt.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hézode
authors.affiliation: INSERM U954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre les Nancy, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bronowicki
authors.affiliation: U850 INSERM, Univ. Limoges, CHU Limoges, F-87000 Limoges, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Loustaud-Ratti
authors.affiliation: Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gea
authors.affiliation: Hospital Vall Hebron, Barcelona and CIBEREHD del Instituto Carlos III, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Buti
authors.affiliation: Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Olveira
authors.affiliation: Pándy Kálmán Hospital, Gyula, Hungary.
authors.forename: Tivadar
authors.initials: T
authors.lastname: Banyai
authors.affiliation: Texas Digestive Disease Consultants, Arlington, TX, USA.
authors.forename: M Tarek
authors.initials: MT
authors.lastname: Al-Assi
authors.affiliation: IFI Institut für Interdisziplinäre Medizin, Hamburg, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Petersen
authors.affiliation: Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Thabut
authors.affiliation: Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Adrian
authors.initials: A
authors.lastname: Gadano
authors.affiliation: Nashville Medical Research Institute, Nashville, TN, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Pruitt
authors.affiliation: Saint Laszlo Hospital, Budapest, Hungary.
authors.forename: Mihály
authors.initials: M
authors.lastname: Makara
authors.affiliation: Hôpital Saint Joseph, Marseilles, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Bourlière
authors.affiliation: Université Paris Descartes, AP-HP, Unité d'Hépatologie, Hôpital Cochin, INSERM UMS-20, Institut Pasteur, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: Janssen Infectious Disease BVBA, Beerse, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Beumont-Mauviel
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: Gaston
authors.initials: G
authors.lastname: Picchio
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Bifano
authors.affiliation: Bristol-Myers Squibb Research and Development, Wallingford, CT, USA.
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors.forename: Navdeep
authors.initials: N
authors.lastname: Boparai
authors.affiliation: Bristol-Myers Squibb Research and Development, Wallingford, CT, USA.
authors.forename: Kin
authors.initials: K
authors.lastname: Cheung
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hughes
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Noviello
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects; D002219:Carbamates; D004279:DNA, Viral / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects; D000069616:Simeprevir / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D004279:DNA, Viral; D007093:Imidazoles; D011759:Pyrrolidines; D012254:Ribavirin; D000069616:Simeprevir; D014633:Valine; C549273:daclatasvir
keywords: All-oral therapy; Daclatasvir; Direct-acting antiviral; Genotype 1; Hepatitis C virus; NS3 protease inhibitor; NS5A inhibitor; Simeprevir