ArticlesSofosbuvir 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
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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Employed by Pharmasset Inc (Princeton, NJ, USA) at the time the study was initiated
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No longer employed by Gilead Sciences