A recent study conducted at the Keck School of Medicine and nine other clinical centers around the country found that treating patients who have chronic hepatitis C and advanced liver disease with long-term pegylated interferon significantly decreased their liver enzymes, viral levels and liver inflammation, but the treatment did not slow or prevent the progression of serious liver disease.

These findings come from the clinical trial, Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) and were reported in the New England Journal of Medicine in December.

"An important aspect of the results of the HALT-C study is that this is obviously a very difficult population to treat because of the resistance of their viral infection to the currently available treatment," said Karen L. Lindsay, professor of medicine at the Keck School and the principal investigator from USC on the study. "One in three patients in the study developed advanced problems with liver function over a three-year period clearly demonstrating that patients with hepatitis C and liver fibrosis are at high risk for developing severe problems with liver function."

Current standard of care therapy for chronic hepatitis C viral infection is a course of pegylated interferon injections and oral ribavirin therapy for up to 48 to 72 weeks, with a goal of eradicating the infection when treatment is discontinued. But patients who do not have a sustained response to initial therapy have been given peginterferon alone over a longer time. Small studies have shown that this approach suppresses viral and enzyme levels, even if the virus is not completely eliminated. However, it was not known if long-term therapy would improve important clinical outcomes such as liver damage and death.

"The results from HALT- C show without question that maintenance therapy with pegylated interferon does not prevent progression of liver disease among patients who have failed prior treatments," said James Everhart, project scientist for HALT-C in the Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the principal sponsor of HALT-C at the National Insitutes of Health (NIH). "These findings heighten the incentive to develop more effective drugs for patients with severe liver disease due to hepatitis C."

HALT-C, a randomized multicenter trial of 1,050 patients with chronic hepatitis C who had failed prior treatment to eradicate the infection, tested whether long-term treatment with pegylated interferon alfa-2a would reduce the development of cirrhosis, liver cancer or liver failure.

The 517 patients randomized to the treatment arm received 90 micrograms of pegylated interferon in weekly injections for 3.5 years. The 533 patients in the control arm underwent the same follow-up and care as the treated patients including liver biopsies, quarterly clinic visits and blood tests. All patients had advanced liver fibrosis, a gradual scarring of the liver that puts patients at risk for progressive liver disease and liver failure.

The outcomes studied in HALT-C were death, liver cancer or liver failure, and for those who did not have cirrhosis initially, the development of cirrhosis.

At the end of the study, 34.1 percent of the treated group and 33.8 percent of the control group had experienced at least one of the studied outcomes. Patients in the treated group had significantly lower blood levels of the hepatitis C virus and improvement in liver inflammation. However, there was no major difference in rates of any of the primary outcomes between the groups.

Among treated patients, 17 percent stopped pegylated interferon after 18 months and 30 percent stopped the drug after two years. Known interferon side effects were the most common reason for stopping the drug.

"The study was highly productive and important because it was the first long-term prospective study of patients with advanced hepatitis C," Lindsay said. "Numerous ancillary studies were included as part of the overall project, which is currently in its tenth year. The results of these data analyses have already led to more than 30 publications on this patient population and many of these results have changed the standard of clinical care for such patients."

The hepatitis C virus infects more than 170 million persons worldwide and as many as four million in the United States. Hepatitis C ranks with alcohol abuse as the most common cause of chronic liver disease and is the leading cause for liver transplantation in the United States.

The best current antiviral therapy of pegylated interferon given by injection in combination with oral ribavirin for about 6 months to a year eliminates the virus in about 50 percent of infected patients.

The magnitude of the HALT-C study demonstrates the importance of collaboration in clinical research, Lindsay noted.

Of the clinical centers that participated, USC was third in the number of patients enrolled and numerous Keck School faculty and their staff provided key support for the study.

HALT-C was funded by the NIH with additional support from Hoffmann-La Roche Inc.