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WIN-R Study Demonstrates Efficacy of Shorter PEG-Intron and Rebetol Regimen in Hepatitis C Patients with Genotype 2 or 3 Virus

24 Weeks of Therapy More Tolerable for Patients, with Low Risk of Relapse

VIENNA, AUSTRIA -- April 28, 2006 -- For patients infected with hepatitis C virus (HCV) genotype 2 or 3, a shorter, 24-week course of therapy with PEG-Intron(R) (peginterferon alfa-2b) in combination with Rebetol(R) (ribavirin, USP) was as effective as a 48-week course, and was better tolerated by patients, according to findings(1) presented today at the 41^st annual meeting of the European Association for the Study of the Liver (EASL).

Importantly, the shorter 24-week regimen was also associated with a low rate of relapse -- only 6% in genotype 2 patients and 10% in genotype 3 patients, which was consistent with a finding of 5% and 12%, respectively, in the longer 48-week regimen. Relapse is defined as patients with undetectable hepatitis C virus levels at the end of treatment who subsequently have detectable virus 24 weeks after treatment.

The results are from a genotype 2/3 sub-study within the larger WIN-R (Weight-Based Dosing of PEG-Intron and Rebetol) trial, a community-based access trial and the largest clinical study in hepatitis C ever conducted in the United States.

"These findings are important because they confirm the effectiveness of a shorter course of peginterferon alfa-2b and ribavirin combination therapy for genotype 2 and 3 patients in a real-world community setting and reinforce current treatment practice," said Robert S. Brown Jr., MD, MPH, lead investigator of the WIN-R genotype 2/3 sub-study, associate professor of medicine and surgery at Columbia University College of Physicians and Surgeons, and chief of clinical hepatology and medical director of the Center of Liver Disease and Transplantation at NewYork-Presbyterian Hospital/Columbia University Medical Center.

Lessening treatment duration can benefit patients in a number of ways, including by limiting side effects, which can be significant with hepatitis C therapy. However, the risk of relapse is a concern when shortening treatment of the hepatitis C virus.

"No physician wants to tell a patient the devastating news that after completing a difficult course of HCV therapy and thinking it has been successful, they have relapsed. The low rate of relapse seen in WIN-R can give physicians added confidence that 24 weeks of peginterferon alfa-2b and ribavirin combination therapy is sufficient to optimize the chance of cure in their genotype 2 and 3 patients," said Ira M. Jacobson, MD, principal investigator of the WIN-R study and coauthor of the genotype 2/3 sub-study, Vincent Astor Professor of Clinical Medicine at Weill Medical College of Cornell University, and chief of the division of gastroenterology and hepatology at NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City. Drs. Jacobson and Brown are also co-directors of NewYork- Presbyterian Healthcare System's Liver Clinical Trials Network (LCTN).

WIN-R Study Findings in HCV Genotype 2/3 Patients
In the WIN-R study, 4,913 patients were randomized to receive weight-based PEG-Intron (1.5 mcg/kg weekly) in combination with Rebetol given either as a flat dose (800 mg daily) or a weight-based dose (800 mg, 1,000 mg, 1,200 mg or 1,400 mg daily for body weights of less than 65 kg, 65 to 85 kg, 86 to 105 kg, or 106 to 125 kg, respectively).

Patients were treated for 48 weeks (genotype 1) or 24 weeks (genotype 2 or 3). Patients in the treatment arms were evenly matched for gender, age, body weight, genotype, viral load and stage of liver fibrosis. A total of 1,829 genotype 2 and 3 patients were enrolled and randomized in the study.

Investigators found that in genotype 2 and 3 patients the 24-week course of therapy was as effective as 48 weeks and better tolerated. In the weight- based Rebetol dosing arms, the rate of sustained virologic response (SVR)(2) was 68% for the 24-week course compared to 60% for the 48-week course, with the lower percentage attributable to more missing follow-up data.

In the 24-week arm, patients with genotype 2 had a higher SVR and lower relapse rate than those with genotype 3 (72% vs. 60% and 6% vs. 10%, respectively). Investigators concluded that higher, weight-based doses of ribavirin appear to be necessary to achieve similar SVR rates in genotype 3 patients. Multivariate analyses showed that genotype 2, less advanced fibrosis and 24 weeks of therapy were significant predictors of SVR. Safety and rates of drug discontinuation were similar between the treatment groups.

A short-coming in conducting large community-based HCV studies such as WIN-R, as opposed to registration trials with their more intensive monitoring capabilities, is the tendency for a high rate of patients to miss their follow-up viral testing (PCR) visit 24 weeks after treatment ends due to the limited ability of many sites to conduct rigorous monitoring of patients once they have received their final treatment dose. In the WIN-R study overall, 13.1% (164/1,256) of patients in the weight-based dose group and 13.7% (163/1,193) of patients in the fixed-dose group who were responders at the end of treatment were lost to follow up and subsequently counted as treatment failures under a strict intent-to-treat (ITT) analysis.

WIN-R was an investigator-initiated clinical study supported by Schering-Plough Corporation and monitored by Schering-Plough Research Institute as part of a post-marketing commitment to the U.S. Food and Drug Administration (FDA). PEG-Intron and Rebetol are registered trademarks of Schering-Plough.

About Hepatitis C
Hepatitis C is the most common blood-borne infection in America, affecting approximately 4 million people or about one in every 50 adults. Chronic hepatitis C can cause cirrhosis, liver failure and liver cancer. It has been estimated that at least 20% of patients with chronic hepatitis C develop cirrhosis, and a smaller percentage of patients with chronic disease develop liver cancer. Patients with chronic hepatitis C and related cirrhosis are 100 times more likely to develop liver cancer than uninfected persons(3). About half of all cases of primary liver cancer in the developed world are caused by hepatitis C, and hepatitis C related liver disease is now the leading cause for liver transplants(4).


REFERENCES:
1. Brown Jr. RS, Jacobson IM, Afdahl N, Freilich B, Pauly MP, Regenstein F, Flamm S, Kwo P, Griffel LH, Brass CA, the WIN-R Study Group. Differences in treatment outcome to antiviral therapy based on genotype and viral load in hepatitis C genotypes 2 and 3 in the WIN-R trial. Oral presentation 41 at: 41^st Annual Meeting of the European Association for the Study of the Liver, Vienna, Austria, April 26-30, 2006.
2. SVR is defined as undetectable virus (HCV RNA) levels 24 weeks after the end of treatment.
3. Ince N, Wands JR. The increasing incidence of hepatocellular carcinoma. N Engl J Med 1999 March 11;340:10.
4. Centers for Disease Control and Prevention. Recommendations for prevention and treatment of hepatitis C virus (HCV) and HCV-related chronic disease. MMWR Weekly Report 1998 Oct. 16;1.


SOURCE: NewYork-Presbyterian Hospital/Columbia

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