Drug therapy offers high cure rate for 2 hepatitis C subtypes

The drug, called sofosbuvir, offers more effective treatment for most patients studied in a Phase 3 clinical trial who had no other treatment options, report researchers in The New England Journal of Medicine. After three months of combined therapy with sofosbuvir and the antiviral drug ribavirin, the patient response rate for those with genotype 2 was 93 percent, and 61 percent in patients with genotype 3.

This new study is one of several testing new hepatitis C drugs that were published April 23 in an online edition of NEJM. The journal publication coincides with the International Liver Congress 2013 in Amsterdam, the Netherlands, where the results also will be presented.

"The new sofosbuvir therapy offers a much-needed alternative to standard therapy with interferon, which can cause significant side effects for hepatitis C patients," says the study's lead investigator, Dr. Ira Jacobson, chief of the Division of Gastroenterology and Hepatology and Vincent Astor Distinguished Professor of Medicine at Weill Cornell Medical College.

"We have dreamed for years of being able to eliminate interferon from our hepatitis C regimens and this study is one of several that are finally bringing us very close to realizing that goal," says Dr. Jacobson, who is also a gastroenterologist at the Center for Advanced Digestive Care at New York-Presbyterian Hospital/Weill Cornell Medical Center and medical director of the Center for the Study of Hepatitis C, a collaboration between Weill Cornell, NewYork-Presbyterian/Weill Cornell and The Rockefeller University.

The 207 patients enrolled in the clinical trial, known as POSITRON, either did not respond to interferon, could not tolerate it or were unwilling to use it, despite the fact that there were no other treatment options available to them.

"This new treatment represents a paradigm shift in the way that hepatitis C is going to be treated," says Dr. Jacobson. "We are achieving the same or higher cure rates in many patients with sofosbuvir, compared to interferon, and we are doing it in half the time with a drug that has a remarkable safety profile."

Dr. Jacobson estimates that up to half of patients with hepatitis C infection either can't use interferon or don't want to use it. "Sofosbuvir is an extremely promising treatment for this population. It is widely hoped that combinations of potent antiviral drugs will eventually replace the use of interferon, in general, for most hepatitis C patients."

The drug sofosbuvir works by interfering with the ability of the hepatitis C virus to replicate. The drug also confers a high barrier to developing the complication of drug resistance. The U.S. Food and Drug Administration (FDA) has not yet approved sofosbuvir. However, results of the four clinical trials published in the NEJM were used to support the regulatory filing submitted to the FDA by the drug's developer, Gilead Sciences, Inc.

No Treatment Options for Many Patients

Approximately 170 million people are infected with hepatitis C worldwide and 350,000 people die each year from the disease. According to federal statistics, there are an estimated four million people in the U.S. infected with hepatitis C. As there are often no symptoms, most people with hepatitis C are unaware that they are infected.

When left untreated, hepatitis C virus can cause progressive liver disease such as cirrhosis, liver cancer and liver failure. The virus is spread by contact with infected blood, such as through blood transfusions, injection drug use or sexual contact.

There are seven major genotypes of hepatitis C, but most cases are 1, 2 or 3. Genotype 1 is the most common subtype in the U.S. Genotypes 2 and 3 are more common in Europe than in the U.S. and genotype 3 is very prevalent on the Indian subcontinent.

In the study, three-fourths of participants (207) were randomized to treatment with sofosbuvir and ribavirin while one-fourth (71) of participants were randomized to a placebo treatment. All of the patients either did not respond to interferon, or did not want to use it. "This mirrors what happens frequently in the clinic," says Dr. Jacobson. "Between 15 and 30 percent of patients with hepatitis C genotype 2 or 3 infections do not have a response to interferon therapy and do not have alternate treatment options."

Patients were enrolled internationally at 63 sites in the United States, Canada, Australia and New Zealand.

Study results show the response rate for all treated patients with sofosbuvir was 78 percent compared to 0 percent in participants treated with placebo agents. Patients with genotype 2 had a higher cure rate (93 percent) than those with genotype 3 (61 percent), and patients without cirrhosis had a higher response rate (81 percent) compared with participants diagnosed with cirrhosis (61 percent).

The results of another clinical trial, led by Dr. David R. Nelson of the University of Florida at Gainesville, were incorporated into this NEJM manuscript publication. This clinical trial study, called FUSION, was designed to test sofosbuvir and ribavirin in hepatitis C patients with genotype 2 or 3 who had failed interferon therapy.

In FUSION, the drug regimen was tested for both 12 and 16 weeks in patients with genotype 2 or 3. The findings showed that extended use of sofosbuvir resulted in a higher cure rate in both genotypes, but that the difference seen in genotype 3 was highly significant. For genotype 2, 12 versus 16 weeks of treatment resulted in response rates of 86 percent compared to 94 percent; and for genotype 3, the response rates were 30 percent versus 62 percent, respectively.

"Given the absence to date of alternative therapies for patients with genotype 2 or 3 who have failed interferon therapy or for whom it is not an option, treatment with the new sofosbuvir regimen offers a vast improvement," Dr. Jacobson says. "But the optimal duration of treatment for genotype 3 patients, in order to maximize their chance of cure, remains undefined. It could be longer than 16 weeks." Dr. Jacobson adds that future clinical studies will continue to define the optimal length of treatment duration for patients with genotype 3, and that other antiviral drugs in combination with sofosbuvir might shorten the duration of treatment needed to maximize the rates of response.

Both the POSITRON and FUSION studies were funded by Gilead Sciences. Another paper in the same edition of the NEJM reports two additional studies of sofosbuvir-containing therapy, one evaluating a 12 week regimen of peginterferon, ribavirin and sofosbuvir in patients with genotypes 1, 4, 5 and 6 who have never been treated before; the other reporting results of a trial comparing 24 weeks of peginterferon and ribavin with 12 weeks of sofosbuvir and ribavirin in treatment naïve patients with genotypes 2 and 3.

Dr. Jacobson is a consultant, lecturer and a funded research investigator for Gilead Sciences.