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

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• 作者：Prof Eric Lawitz ; MD ; ^a ; ^{lawitz@txliver.com} ; Jay P Lalezari ; MD^b ; Prof Tarek Hassanein ; MD^c ; Prof Kris V Kowdley ; MD^d ; Prof Fred F Poordad ; MD^e ; Aasim M Sheikh ; MBBS^f ; Prof Nezam H Afdhal ; MD^g ; Prof David E Bernstein ; MD^h ; Edwin DeJesus ; MDⁱ ; Bradley Freilich ; MD^j ; Prof David R Nelson ; MD^k ; Prof Douglas T Dieterich ; MD^l ; Prof Ira M Jacobson ; MD^m ; Prof Donald Jensen ; MDⁿ ; Gary A Abrams ; MD^o ; Jama M Darling ; MD^p ; Maribel Rodriguez-Torres ; MD^q ; Prof K Rajender Reddy ; MD^r ; Prof Mark S Sulkowski ; MD^s ; Natalie H Bzowej ; MD^t ; Robert H Hyland ; DPhil^u ; ^* ; Hongmei Mo ; PhD^u ; Ming Lin ; PhD^u ; Michael Mader ; MS^v ; ^* ; Robert Hindes ; MD^&dagger ; ; ^w ; ^* ; Efsevia Albanis ; MD^l ; ^* ; William T Symonds ; PharmD^u ; ^* ; Michelle M Berrey ; MD^x ; ^* ; Prof Andrew Muir ; MD^y
• 刊名：The Lancet Infectious Diseases
• 出版年：2013
• 出版时间：May, 2013
• 年：2013
• 卷：13
• 期：5
• 页码：401-408
• 全文大小：276 K

文摘

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Summary

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 ¦Ìg 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 , number .

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¡ªfatigue, headache, nausea, and chills¡ªwere 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.