Sofosbuvir Shows Promise in Difficult-To-Treat Hep C Patients
ISSUE: SEPTEMBER 2013 | VOLUME: 40
by George Ochoa
The experimental drug sofosbuvir (Gilead Sciences), in combination with ribavirin, showed promising results in a single-center, randomized open-label Phase II trial of 60 patients with hepatitis C virus (HCV) genotype 1.
The interferon-free, 24-week, oral regimen was safe and well tolerated, and resulted in a sustained virologic response (SVR) rate of 68% in patients who received a weight-based dose of ribavirin and 48% in patients who received low-dose ribavirin. The study was published in the Aug. 28 issue of the Journal of the American Medical Association (2013;310:804-811).
“There is a pressing need for hepatitis C virus treatments that are less burdensome to the patient, have fewer side effects and take less time to complete. Building on previous work, this trial provides compelling evidence that interferon-free regimens can be safe and effective,” said study coauthor Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, Bethesda, Md., in a press statement.
The patients included in the trial were treatment-naïve and had chronic HCV infection. Notably, there was a high prevalence of unfavorable traditional predictors of treatment response in this study population (e.g., black race, HCV genotype 1a, advanced fibrosis, body mass index greater than 30 kg/m2) compared with previous trials of other direct-acting antiviral agents. Thus, the patients were demographically representative of the HCV epidemic in the United States, the authors wrote.
The primary end point of the study was undetectable HCV viral load at 24 weeks after treatment completion. The trial was conducted in two parts. The first part was a proof-of-concept study in which 10 patients with early to moderate liver fibrosis were treated for 24 weeks with 400 mg per day of sofosbuvir and weight-based ribavirin (if <75 kg, 400 mg in the morning, 600
mg in the evening; if >75 kg, 600 mg twice daily). In this part of the study, nine patients (90%) achieved SVR at week 24 (95% confidence interval [CI], 55%-100%). In the second part of the study, 50 patients with all stages of liver fibrosis were randomized to receive 400 mg per day of sofosbuvir combined with either a weight-based dose of ribavirin or low-dose ribavirin (600 mg daily) for 24 weeks. By week 4, viral suppression was achieved by 24 of 25 patients (96%) in each of the dosage groups. However, some of these patients relapsed at treatment completion: Seven patients (28%) in the weight-based ribavirin group and 10 patients (40%) in the low-dose ribavirin group relapsed at week 24. SVR rates at week 24 were 68% in the weight-based treatment group and 48% in the low-dose treatment group (95% CI, 46%-85% and 28%-69%, respectively;
“Bivariable analysis of baseline factors showed that in all randomized patients who completed treatment, the odds of relapse were significantly higher in participants who were male (odds ratio [OR], 6.09; 95% CI, 1.17-31.6), had advanced fibrosis (OR, 4.27; 95% CI, 1.10-16.54) and had baseline HCV RNA greater than 800,000 IU/mL (OR, 5.74; 95% CI, 1.35-24.38),” the
Twenty patients were included in a pharmacokinetic–viral kinetic substudy, which showed that patients who relapsed had a slower loss rate of infectious HCV than those who achieved SVR (HCV rate clearance 3.57 vs. 5.60 per day, respectively; P=0.009.)
None of the study participants discontinued treatment due to adverse events. The most common side effects of treatment, ranging from mild to moderate in severity, were headache, anemia, fatigue and nausea. The authors acknowledged the small sample size as a limitation of the study.
“Due to the small size, associations described are preliminary in nature and require further evaluation in larger studies,” the