Tuesday, February 25, 2014

Sofosbuvir Provides Strong Offense Against Hepatitis C

Sofosbuvir Provides Strong Offense Against Hepatitis C

Posted by: Maureen Newman

February 25, 2014

What was once a mere hope for a hepatitis C cure now appears to be a reality, thanks to a collection of clinical trials from a number of institutions, including the University of Texas Health Science Center in San Antonio. Unlike other forms of hepatitis, hepatitis C has no vaccine, which has allowed it to emerge as a common chronic viral liver disease–there are over 170 million cases of hepatitis C globally. The standard of care in the United States consists of pegylated interferon alpha and ribavirin, which have increased sustained virological response (SVR) rates from 50% to 80%. These response rates are now being further increased by the introduction of Sofosbuvir (Solvaldi, from Gilead Sciences), a nucleotide analogue inhibitor of HCV NS5B polymerase. Sofosbuvir was approved by the FDA in 2013 for the treatment of adults infected with genotypes 1 and 4 in combination with pegylated interferon alpha and ribavirin and for the treatment of adults infected with genotypes 2 and 3 in combination with ribavirin only.

“It’s a drug that has no resistance or incremental adverse effects. It is very well tolerated, very safe, very efficacious and there are no significant drug interactions with it. I think it is going to revolutionize the way we treat hepatitis in this country and around the world,” said Sammy Saab, MD, MPH, from the David Geffen School of Medicine in UCLA, at The Liver Meeting 2013. What makes sofosbuvir so revolutionary is that it is effective in treating a wide variety of patients. Four Phase III clinical trials (FISSION, POSITRON, FUSION, and NEUTRINO) found that many factors traditionally associated with poor outcomes in hepatitis C patients (including age, interleukin-28 B genotype, body mass index, and viral load) had no effect on the efficacy of sofosbuvir–only male gender and the presence of cirrhosis were predictive of a worse outcome. Yet results from LONESTAR-2 showed that sofosbuvir is highly efficacious in patients with cirrhosis: after twelve weeks of treatment, patients with HCV genotype 2 and cirrhosis had an SVR of 93%, compared to 100% of noncirrhotics, and there was no difference in outcome for patients with HCV genotype 3. According to Eric Lawitz, MD, of the Texas Liver Institute and UTHealth, “Sofosbuvir plus pegylated IFN/ribavirin for 12 weeks demonstrated high efficacy in treatment-experienced genotype 2/3 patients who have historically low response rates and limited treatment options. SVR rates were similar in patients with and without cirrhosis.”

Genotype 3 patients from LONESTAR-2 achieved an SVR of 83%, which is lower than that of the genotype 2 patients (93%/100%)–this difference may be due to a difference in response among HCV genotypes (though one genotype does not necessarily indicate a worse outcome). “The FDA did an elegant analysis of the effect of treatment duration with sofosbuvir–ribavirin in genotype 3–infected patients,” said Mark Sulkowski, MD, medical director of the Viral Hepatitis Center in the Divisions of Infectious Disease and Gastroenterology & Hepatology. “[They] presented very convincing data that a 24-week duration of sofosbuvir–ribavirin should be the standard for all genotype 3–infected patients.” The analysis looked at data from FISSION, POSITRON, FUSION, and VALENCE, and the findings prompted the FDA to approve sofosbuvir in December. A 12-week treatment was approved for genotype 2, and a 24-week treatment was approved for genotype 3. A treatment consisting of sofosbuvir, ribavirin, and interferon was approved for patients with genotypes 1 and 4.

In addition, sofosbuvir, when used in combination with ribavirin, is effective for patients who are coinfected with HIV and is less toxic than interferon-based regimens. In the PHOTON-1 trial, “The IFN-free regimen of sofosbuvir plus ribavirin resulted in high SVR 12 rates in HCV treatment-naive, HIV-infected patients with HCV genotype 1, 2 or 3 coinfection,” said Dr. Sulkowski, who presented the study. “SVR 12 rates were similar to those observed in patients with HCV mono-infection.”

To treat non-responding patients, sofosbuvir can be used in conjuction with simeprevir, rather than ribavirin, according to data from the Phase II COSMOS trial. “The findings in this interim analysis suggest that the addition of ribavirin to simeprevir plus sofosbuvir may not be needed to achieve high rates of SVR in this patient population,” said Ira Jacobson, MD, chief of the Division of Gastroenterology and Hepatology at Weill Cornell Medical College. “[Complications] were predominantly limited to the ribavirin-containing treatment arms.”

Results such as these prompt much excitement among clinicians. Said Dr. Saab, “I think sofosbuvir is the cat’s meow.”


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