Genotype

Sofosbuvir Works for Patients Who Cannot Take Peginterferon.

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Two phase III studies confirm the efficacy of a sofosbuvir and ribavirin therapy in patients with HCV genotype 2 or 3 infection for whom peginterferon is not an option.

In patients infected with hepatitis C virus (HCV) genotype 2 or 3, treatment with peginterferon plus ribavirin has a sustained virologic response (SVR) of 70% to 85%. However, adverse effects of peginterferon are a barrier to treatment for many patients. Now, two industry-funded, phase III trials have evaluated the efficacy of sofosbuvir (400 mg daily) plus ribavirin (1000 mg–1200 mg daily) in these patients.

In a blinded, placebo-controlled trial, investigators randomized 280 patients for whom peginterferon therapy was not an option (e.g., adverse effects, contraindications for interferons, and patient refusal) to receive sofosbuvir/ribavirin or matching placebo for 12 weeks. In a blinded, active-control trial, researchers randomized 202 patients with prior nonresponse to peginterferon therapy to receive 12 or 16 weeks of sofosbuvir/ribavirin. The primary endpoint in both studies was SVR at 12 weeks after therapy ended.

In patients for whom peginterferon therapy was not an option, SVR was 78% for treatment with sofosbuvir/ribavirin compared with 0% for placebo (P<0.001). In previously treated patients, SVR was 50% for 12 weeks of therapy versus 73% for 16 weeks (P<0.001). SVR rates were lower for patients with genotype 3 versus genotype 2 in both treatment-naive patients (61% vs. 93%) and treatment-experienced patients who received therapy for 12 weeks (30% vs. 86%) or 16 weeks (62% vs. 94%).

SVR rates were lower in patients with cirrhosis than without, both in treatment-naive patients (overall, 61% vs. 81%; genotype 3 vs. 2, 21% vs. 94%) and treatment-experienced patients (overall, 66% vs. 76%; genotype 3 vs. 2 in 16-week group, 61% vs. 78%). In both studies, investigators found no evidence of resistance development, and discontinuation rates were low (1%–2%).

Comment: Oral sofosbuvir plus ribavirin is effective in patients with HCV genotypes 2 or 3 for whom peginterferon-based therapy is not an option or was previously ineffective. Of note, these sustained virologic response rates for sofosbuvir plus ribavirin are comparable to or higher than those previously reported for therapy with peginterferon plus ribavirin in this population.

Source: Journal Watch Gastroenterology

 

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.

Source: Lancet

Sofosbuvir for Hepatitis C Genotype 2 or 3 in Patients without Treatment Options..

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Background Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection. Methods We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin (207 patients) or matching placebo (71) for 12 weeks. In a second trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks (103 patients) or 16 weeks (98). The primary end point was a sustained virologic response at 12 weeks after therapy. Results Among patients for whom treatment with peginterferon was not an option, the rate of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, -23 percentage points; 95% CI, -35 to -11; P<0.001). In both studies, response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and, among patients with genotype 3 infection, lower among those with cirrhosis than among those without cirrhosis. The most common adverse events were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation of sofosbuvir was low (1 to 2%). Conclusions In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option, 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective. Efficacy was increased among patients with HCV genotype 2 infection and those without cirrhosis. In previously treated patients with genotype 3 infection, 16 weeks of therapy was significantly more effective than 12 weeks.

Source: NEJM