Sofosbuvir (GS-7977) plus peginterferon/ribavirin in treatment-naïve patients with HCV genotype 1: a randomized, 28-day, dose-ranging trial.

BACKGROUND & AIMS: Sofosbuvir (formerly GS-7977) is a pyrimidine nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B polymerase. We assessed the safety, tolerability, antiviral activity, and pharmacokinetics of sofosbuvir plus pegylated-interferon (PegIFN)/ribavirin (RBV) in a 28-day, dose-ranging trial in treatment-naïve patients infected with genotype 1 HCV. METHODS: In this double-blind study, 64 patients were randomized (1:1:1:1) to receive one of three once-daily doses of oral sofosbuvir (100, 200, or 400mg) or placebo plus PegIFN/RBV for 28 days, after which all patients continued to receive PegIFN/RBV alone for a further 44 weeks. RESULTS: Patients in the sofosbuvir/PegIFN/RBV groups experienced mean reductions in HCV RNA >5 log10 IU/ml (-5.3 for 100 mg, -5.1 for 200 mg and -5.3 for 400 mg) vs. -2.8 log10 IU/ml for placebo/PegIFN/RBV after 28 days. Rapid virologic response (RVR) rates were markedly higher after sofosbuvir treatment (88-94%) than placebo (21%), as were rates of sustained virologic response (SVR) at post-treatment Week 24 (56%, 83%, and 80% for sofosbuvir 100, 200, and 400 mg, respectively, vs. 43% for placebo). The number of patients experiencing virologic breakthrough and post-treatment relapse was higher in the sofosbuvir 100 mg group than sofosbuvir 200 and 400 mg groups. Sofosbuvir was well tolerated; the most frequent adverse events were fatigue and nausea. CONCLUSIONS: These results support further studies with sofosbuvir at 200 mg and 400 mg to determine the optimal dose and treatment duration of sofosbuvir in HCV genotype 1.

RG7128 alone or in combination with pegylated interferon-α2a and ribavirin prevents hepatitis C virus (HCV) Replication and selection of resistant variants in HCV-infected patients.

INTRODUCTION: RG7128 (prodrug of PSI-6130) shows potent antiviral efficacy in patients infected with hepatitis C virus (HCV) genotypes 1, 2, or 3, with mean viral load decreases of 2.7 and 5 log(10) IU/mL, respectively, associated with 1500-mg doses twice daily after monotherapy for 2 weeks and with 1000-mg and 1500-mg doses twice daily after treatment in combination with the standard of care (SOC) for 4 weeks. RESULTS: From 32 patients treated with RG7128 monotherapy for 2 weeks, marginal viral load rebound was observed in 3 HCV genotype 1-infected patients, whereas partial response was observed in 2 genotype 1-infected patients. From 85 patients receiving RG7128 in combination with SOC, 1 HCV genotype 1-infected patient experienced a viral rebound, and 2 genotype 3-infected patients experienced a transient rebound. Five genotype 1-infected patients had an HCV load of >1000 IU/mL at the end of 4-week treatment. No viral resistance was observed, per NS5B sequencing and phenotypic studies. PSI-6130 resistance substitution S282T needs to be present at levels of ≥90% within a patient's quasispecies to confer low-level resistance. No evidence of S282T was found by population or clonal sequence analyses. CONCLUSIONS: The requirement for a predominant S282T mutant quasispecies, its low replication capacity, and the low-level resistance it confers probably contribute to the lack of RG7128 resistance observed in HCV-infected patients.

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.

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.