title: Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial.
abstract: BACKGROUND
  Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1-3 HCV infection.
  
  
  METHODS
  In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1-3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18-70 years, had an HCV RNA concentration of 50,000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 μg per week) and ribavirin (1000-1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov, number NCT01188772.
  
  
  RESULTS
  In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events--fatigue, headache, nausea, and chills--were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77-97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80-98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37-77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12.
  
  
  CONCLUSIONS
  Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1.
  
  
  BACKGROUND
  Gilead Sciences.
authors.affiliation: The Texas Liver Institute, San Antonio, TX, USA. lawitz@txliver.com
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.forename: Jay P
authors.initials: JP
authors.lastname: Lalezari
authors.forename: Tarek
authors.initials: T
authors.lastname: Hassanein
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.forename: Fred F
authors.initials: FF
authors.lastname: Poordad
authors.forename: Aasim M
authors.initials: AM
authors.lastname: Sheikh
authors.forename: Nezam H
authors.initials: NH
authors.lastname: Afdhal
authors.forename: David E
authors.initials: DE
authors.lastname: Bernstein
authors.forename: Edwin
authors.initials: E
authors.lastname: Dejesus
authors.forename: Bradley
authors.initials: B
authors.lastname: Freilich
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Dieterich
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.forename: Donald
authors.initials: D
authors.lastname: Jensen
authors.forename: Gary A
authors.initials: GA
authors.lastname: Abrams
authors.forename: Jama M
authors.initials: JM
authors.lastname: Darling
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.forename: K Rajender
authors.initials: KR
authors.lastname: Reddy
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sulkowski
authors.forename: Natalie H
authors.initials: NH
authors.lastname: Bzowej
authors.forename: Robert H
authors.initials: RH
authors.lastname: Hyland
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.forename: Ming
authors.initials: M
authors.lastname: Lin
authors.forename: Michael
authors.initials: M
authors.lastname: Mader
authors.forename: Robert
authors.initials: R
authors.lastname: Hindes
authors.forename: Efsevia
authors.initials: E
authors.lastname: Albanis
authors.forename: William T
authors.initials: WT
authors.lastname: Symonds
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Berrey
authors.forename: Andrew
authors.initials: A
authors.lastname: Muir
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005838:Genotype; D006261:Headache / Q000139:chemically induced; D016174:Hepacivirus / Q000145:classification / Q000472:pathogenicity; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D012367:RNA, Viral / Q000032:analysis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use*; D055502:Secondary Prevention; D000069474:Sofosbuvir; D013997:Time Factors; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D014542:Uridine Monophosphate; C100416:peginterferon alfa-2a; D000069474:Sofosbuvir