title: Simeprevir, daclatasvir and sofosbuvir for hepatitis C virus-infected patients with decompensated liver disease.
abstract: Approximately three million individuals in the United States are chronically infected with hepatitis C virus (HCV). Chronic HCV infection may lead to the development of compensated as well as decompensated liver cirrhosis. The Phase II IMPACT study was conducted in HCV genotype 1- or 4-infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed for the first time the combination of the three direct-acting antivirals simeprevir, daclatasvir and sofosbuvir. Treatment-naïve or treatment-experienced adults with Child-Pugh (CP) score <7 (CP A) and evidence of portal hypertension, or CP score 7-9 (CP B), received 12 weeks of simeprevir 150 mg, daclatasvir 60 mg and sofosbuvir 400 mg, once daily. The primary efficacy endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). Pharmacokinetics and safety were also assessed. Overall, 40 patients were enrolled (CP A: 19; CP B: 21). All 40 patients achieved SVR12. At week 8, the mean pharmacokinetic exposure to simeprevir, sofosbuvir, daclatasvir and GS-331007 (sofosbuvir metabolite) was 2.2-, 1.5-, 1.2- and 1.2-fold higher in patients with CP B than CP A, respectively. Grade 1/2 adverse events (AEs) occurred in 26 of 40 (65%) patients. One CP B patient had a Grade 3 AE (gastrointestinal haemorrhage), which was reported as a serious AE but not considered related to study drugs. Treatment for 12 weeks with simeprevir, daclatasvir and sofosbuvir was generally safe and well tolerated, and resulted in 100% of cirrhotic patients with portal hypertension or decompensated liver disease achieving SVR12.
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: F
authors.initials: F
authors.lastname: Poordad
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Gutierrez
authors.affiliation: Alios Biopharma, San Francisco, CA, USA.
authors.forename: T N
authors.initials: TN
authors.lastname: Kakuda
authors.affiliation: Janssen Research & Development LLC, Raritan, NJ, USA.
authors.forename: G
authors.initials: G
authors.lastname: Picchio
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Beets
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Vandevoorde
authors.affiliation: Janssen Research & Development LLC, Titusville, NJ, USA.
authors.forename: P
authors.initials: P
authors.lastname: Van Remoortere
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Jacquemyn
authors.affiliation: Janssen Research & Development LLC, Titusville, NJ, USA.
authors.forename: D
authors.initials: D
authors.lastname: Luo
authors.affiliation: Janssen Research & Development LLC, Beerse, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Ouwerkerk-Mahadevan
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Vijgen
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Van Eygen
authors.affiliation: Janssen Research & Development LLC, Beerse, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Beumont
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002219:Carbamates; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D048550:Hepatic Insufficiency / Q000209:etiology*; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D000069616:Simeprevir / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000069474:Sofosbuvir / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014481:United States; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D000069616:Simeprevir; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir
keywords: daclatasvir; hepatitis C; simeprevir; sofosbuvir