Presented by principal investigator Nezam Afdhal, M.D., Chief of Hepatology at Beth Israel Deaconess Medical Center (BIDMC) and Associate Professor of Medicine at Harvard Medical School, the new findings provide researchers with sufficient evidence to demonstrate promising results for hepatitis C patients who have not responded to existing therapies.
A viral infection, hepatitis C is transmitted through exposure to infected blood. The virus, which affects an estimated 4 million individuals nationwide, is able to survive and flourish inside the body by taking up residence in the liver cells, and subsequently using the cells' inner machinery to make more copies of the virus. These in turn, infect other healthy cells.
The standard treatment for hepatitis C is a combination of interferon alfa and ribavirin, which act as anti-viral agents to eradicate the virus. According to Afdhal, the most recent advance in treatment has been the pegylation of interferon, which enables a once- a- week administration of the protein by injection and improves the ability to clear the virus. Combination therapy with pegylated interferon plus ribavirin for 24 to 48 weeks can result in eradication of the virus in about 50 percent of patients, he adds.
"When the hepatitis C virus doesn't respond - as occurs in about half of all patients who are treated - those patients who already have cirrhosis are at a far greater risk for developing liver cancer or suffering liver failure," notes Afdhal. In fact, he says, hepatitis C is the leading cause of liver transplants in the U.S. Until now, no treatment has been available for these patients.
In his first presentation, Afdhal will describe results from the COPILOT [Colchicine versus PEG-INTRON Long-Term] study, which was designed by Afdhal and colleagues at BIDMC to test the long-term use of low-dose interferon among hepatitis C patients. Conducted at 40 sites nationwide, the findings are the first to demonstrate that the progression of hepatitis C can be prevented or delayed through long-term maintenance therapy with peginterferon alfa-2b.
According to Afdhal, researchers found that peginterferon alfa-2B reduced by 50 percent the risk of patients reaching a clinical endpoint (variceal bleeding, liver failure, liver transplantation, hepatocellular carcinoma or death) and reported the results as part of a planned two-year interim analysis of the data.
"This is a new treatment paradigm, showing for the first time that we can prevent the serious complications of liver disease," he explains. "The results found that when used in this way, the therapy reduced by half the risk of the virus advancing to cause liver damage."
The COPILOT study tested weight-based low-dose peginterferon alfa-2b (0.5 mcg/kg/wk, injected subcutaneously) against colchicine (0.6 mg orally, twice daily), an anti-inflammatory and antifibrotic medication, in 550 chronic hepatitis C patients with advanced fibrosis who had previously failed interferon-based therapies. A total of 59 patients reached a clinical verified endpoint: 39 in the colchicine group versus 20 in the peginterferon alfa-2b group (p=0.003). The annual clinical event rate was approximately five percent (7.0 percent vs. 3.5 percent for colchicine and peginterferon alfa-2b, respectively), underscoring the need for better treatments to prevent disease progression.
Afdhal noted that the low 0.5 mcg/kg weekly dose of peginterferon alfa-2b used in the study - one-third the dose used in standard combination therapy - was well tolerated by patients and spared them the side effect of developing hemolytic anemia, which is often associated with ribavirin use.
"Patient adherence to their prescribed regimen is critical to success in hepatitis treatment and is an important consideration for long-term maintenance therapy," he said.
The COPILOT study was supported by Schering-Plough Corporation, manufacturer of peginterferon alfa-2b.
Afdhal's second presentation will describe results from a Phase II clinical trial of a new antiviral agent, NM283, being tested in humans for the first time.
The new drug shows activity against hepatitis C genotype 1 (HCV). One of six genotypes in existence, genotype 1 is the most predominant strain in the U.S., Japan and Western Europe, and is particularly difficult to treat.
Unlike existing therapies, which are administered by injection, NM283 is taken orally, says Afdhal, adding that it also has fewer side effects than existing agents. NM283 is the first in a new class of designer drugs, a polymerase inhibitor, specifically designed to block a step in HCV viral replication.
"This drug is a new class of treatment for HCV and represents significant hope for future therapies," he noted. "Data from these clinical trials are encouraging and suggest that NM283 may prove to be another treatment option [for hepatitis C patients]." NM283 was shown to have direct and significant antiviral activity against HCV as a single agent in both Phase I and Phase II clinical trials. Combining NM283 with interferon also showed promising activity, according to Afdhal.
NM283 was developed by Idenix Pharmaceuticals, Inc., which sponsored the Phase II clinical trial.
Beth Israel Deaconess Medical Center is a major patient care, teaching and research affiliate of Harvard Medical School, and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information visit www.bidmc.harvard.edu.