Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial.

BACKGROUND: The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. METHODS: For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978. RESULTS: We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. INTERPRETATION: Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. FUNDING: Gilead Sciences.

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.

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.