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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

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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 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.

Introduction

The 2011 approval of the NS3/4A protease inhibitors telaprevir and boceprevir for the treatment of patients with hepatitis C virus (HCV) genotype-1 has substantially improved rates of sustained virological response (SVR) compared with use of peginterferon alfa-2a (peginterferon) and ribavirin alone. In registration studies, the protease inhibitors in combination with peginterferon and ribavirin gave SVR rates between 66% and 75% in treatment-naive patients with chronic HCV genotype-1 infection.1, 2 However, several features of regimens based on these protease inhibitors—eg, three-times-a-day dosing, high pill burdens, complicated dosing strategies, low barrier to resistance, and many drug interactions and side-effects—restrict their use.3, 4, 5, 6 Moreover, safety and effectiveness of these drugs have not been established in patients with chronic viral genotypes 2 and 3.

Sofosbuvir (formerly known as GS-7977; Gilead Sciences, Foster City, CA, USA) is a nucleotide analogue that is a potent and selective inhibitor of NS5B-directed HCV RNA replication in vitro.7 Sofosbuvir is a prodrug of 2′-deoxy-2′-fluoro-2′-C-methyluridine monophosphate that is converted within hepatocytes to its active uridine triphosphate form, causing chain termination during replication of the viral genome.8 In vitro, the active triphosphate inhibits recombinant NS5B polymerases from HCV genotypes 1–4 with similar half maximum inhibitory concentration values for each genotype, indicating broad activity across HCV genotypes.9 Also, compared with non-nucleoside inhibitors, nucleoside and nucleotide inhibitors in general have a higher resistance barrier.10, 11 Findings from phase 1 and 2 studies suggest that sofosbuvir is well tolerated and has potent antiviral effects.12, 13

In this phase 2 trial, we aimed to assess the safety and tolerability of two different doses of sofosbuvir (200 mg and 400 mg) in combination with peginterferon and ribavirin in patients with HCV genotype-1, and also assessed sofosbuvir 400 mg with peginterferon and ribavirin in a separate, open-label cohort of patients with HCV genotypes 2 and 3.

Section snippets

Study design and participants

For this two-cohort study, we recruited previously untreated patients (aged 18–70 years) with chronic HCV genotypes 1–3 infection from 22 sites in the USA. We enrolled patients between Aug 16, 2010, and Dec 13, 2010, with the last follow-up visit on May 11, 2012. We enrolled patients with HCV genotype-1 into a randomised cohort (cohort A), patients with genotypes 2 or 3 were enrolled into a separate non-randomised, open-label cohort (cohort B).

To be eligible for enrolment, patients with HCV

Results

We randomly allocated 122 patients to treatment in cohort A and enrolled 25 patients into cohort B (figure 1; see appendix for details of those not enrolled). Baseline characteristics were much the same across treatment groups in cohort A: the mean age of patients was about 50 years and most patients were men, white, non-Hispanic, had the IL28B CC or CT genotype, and had portal fibrosis (table 1). Most patients had genotype-1a HCV with baseline HCV RNA concentrations of about 6·5 log10 IU/mL (

Discussion

In this phase 2 trial, patients receiving sofosbuvir plus peginterferon and ribavirin had adverse events that were similar in both type and severity to those seen in patients receiving placebo plus peginterferon and ribavirin, with an adverse event profile broadly consistent with that seen elsewhere during treatment with peginterferon and ribavirin.14, 15, 16 The most common events—fatigue, headache, nausea, and chills—are well known side-effects of interferon. We detected no additional or new

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  • Cited by (0)

    *

    Employed by Pharmasset Inc (Princeton, NJ, USA) at the time the study was initiated

    No longer employed by Gilead Sciences

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