title: Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial.
abstract: BACKGROUND
  The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV.
  
  
  METHODS
  For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978.
  
  
  RESULTS
  We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event.
  
  
  CONCLUSIONS
  Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis.
  
  
  BACKGROUND
  Gilead Sciences.
authors.affiliation: Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA 98101, USA. kris.kowdley@vmmc.org
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.forename: Israel
authors.initials: I
authors.lastname: Crespo
authors.forename: Tarek
authors.initials: T
authors.lastname: Hassanein
authors.forename: Mitchell N
authors.initials: MN
authors.lastname: Davis
authors.forename: Michael
authors.initials: M
authors.lastname: DeMicco
authors.forename: David E
authors.initials: DE
authors.lastname: Bernstein
authors.forename: Nezam
authors.initials: N
authors.lastname: Afdhal
authors.forename: John M
authors.initials: JM
authors.lastname: Vierling
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Gordon
authors.forename: Jane K
authors.initials: JK
authors.lastname: Anderson
authors.forename: Robert H
authors.initials: RH
authors.lastname: Hyland
authors.forename: Hadas
authors.initials: H
authors.lastname: Dvory-Sobol
authors.forename: Di
authors.initials: D
authors.lastname: An
authors.forename: Robert G
authors.initials: RG
authors.lastname: Hindes
authors.forename: Efsevia
authors.initials: E
authors.lastname: Albanis
authors.forename: William T
authors.initials: WT
authors.lastname: Symonds
authors.forename: M Michelle
authors.initials: MM
authors.lastname: Berrey
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011647:Puerto Rico; D011994:Recombinant Proteins / Q000008:administration & dosage; D012254:Ribavirin / Q000008:administration & dosage*; D000069474:Sofosbuvir; D016896:Treatment Outcome; D014481:United States; D014542:Uridine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D014542:Uridine Monophosphate; C100416:peginterferon alfa-2a; D000069474:Sofosbuvir