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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.

Publication ,  Journal Article
Lawitz, E; Lalezari, JP; Hassanein, T; Kowdley, KV; Poordad, FF; Sheikh, AM; Afdhal, NH; Bernstein, DE; Dejesus, E; Freilich, B; Nelson, DR ...
Published in: Lancet Infect Dis
May 2013

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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Gilead Sciences.

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Published In

Lancet Infect Dis

DOI

EISSN

1474-4457

Publication Date

May 2013

Volume

13

Issue

5

Start / End Page

401 / 408

Location

United States

Related Subject Headings

  • Young Adult
  • Uridine Monophosphate
  • Treatment Outcome
  • Time Factors
  • Sofosbuvir
  • Secondary Prevention
  • Ribavirin
  • Recombinant Proteins
  • RNA, Viral
  • Polyethylene Glycols
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lawitz, E., Lalezari, J. P., Hassanein, T., Kowdley, K. V., Poordad, F. F., Sheikh, A. M., … Muir, A. (2013). 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. Lancet Infect Dis, 13(5), 401–408. https://doi.org/10.1016/S1473-3099(13)70033-1
Lawitz, Eric, Jay P. Lalezari, Tarek Hassanein, Kris V. Kowdley, Fred F. Poordad, Aasim M. Sheikh, Nezam H. Afdhal, et al. “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.Lancet Infect Dis 13, no. 5 (May 2013): 401–8. https://doi.org/10.1016/S1473-3099(13)70033-1.
Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, Afdhal NH, Bernstein DE, Dejesus E, Freilich B, Nelson DR, Dieterich DT, Jacobson IM, Jensen D, Abrams GA, Darling JM, Rodriguez-Torres M, Reddy KR, Sulkowski MS, Bzowej NH, Hyland RH, Mo H, Lin M, Mader M, Hindes R, Albanis E, Symonds WT, Berrey MM, Muir A. 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. Lancet Infect Dis. 2013 May;13(5):401–408.
Journal cover image

Published In

Lancet Infect Dis

DOI

EISSN

1474-4457

Publication Date

May 2013

Volume

13

Issue

5

Start / End Page

401 / 408

Location

United States

Related Subject Headings

  • Young Adult
  • Uridine Monophosphate
  • Treatment Outcome
  • Time Factors
  • Sofosbuvir
  • Secondary Prevention
  • Ribavirin
  • Recombinant Proteins
  • RNA, Viral
  • Polyethylene Glycols