HCV Maintenance Therapy From Hep C Advocate
In most trials of new treatments for hepatitis C, researchers have looked at the "gold standard" endpoint of undetectable HCV RNA viral load six months after the end of therapy-sustained viral response, or SVR. Most studies have looked at results after 24 or 48 weeks of combination therapy with interferon plus ribavirin.
However, several studies have suggested that even people who do not achieve a sustained undetectable viral load-so called "non-responders," partial responders, and relapsers-may still benefit from treatment, and that long-term, low-dose interferon maintenance therapy may be effective in delaying disease progression and liver damage. For example, Dr. Mitch Shiffman and colleagues reported in the November 1999 issue of Gastroenterology that in a small study "maintenance interferon may prevent histological progression of chronic HCV in patients who remain viremic." In this study, those receiving ongoing interferon therapy had lower HCV viral loads, decreased ALT levels, and reduced liver inflammation and fibrosis as determined by biopsy; when interferon was discontinued, fibrosis scores increased in one-third of the patients.
It makes good sense that even less-than-perfect antiviral treatment should help reduce liver disease progression. Because HCV multiplies in and destroys liver cells, any substantial reduction in virus replication should have a protective effect. In HIV disease-which in many ways has proved to be a model for HCV treatment-it has been shown that therapy that decreases viral load is beneficial, even if HIV RNA is not reduced to an undetectable level.
Although HCV maintenance therapy appears promising, it is not known whether the benefits of long-term interferon will outweigh the often-daunting side effects of treatment. Two large, currently enrolling studies-HALT-C and COPILOT-are designed to shed light on this question. Both studies will attempt to determine whether long-term treatment with low-dose pegylated interferon can help delay the development of fibrosis and cirrhosis, slow the progression from compensated to decompensated cirrhosis, and reduce the chances of developing liver cancer (hepatocellular carcinoma). Ultimately, researchers want to know whether maintenance therapy can reduce the need for liver transplants and keep people with chronic HCV alive longer-hopefully until more effective HCV treatments are developed.
The HALT-C study will test Roche's Pegasys brand of pegylated interferon-alpha (currently undergoing priority approval review), while the COPILOT study will use Shering-Plough's Peg-Intron brand of pegylated interferon-alpha (currently on the market). Both studies are for participants with existing fibrosis or cirrhosis who have not achieved a sustained, undetectable viral load using current interferon or interferon plus ribavirin regimens. Both trials will continue for four years.
HALT-C (the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis study), conducted by the National Institutes of Health, will include over 1,000 participants who have not achieved an SVR after at least twelve weeks of treatment with any type of interferon or interferon plus ribavirin. Participants will begin receiving full-dose Pegasys plus ribavirin once weekly for six months. Those who still have detectable HCV viral load at the end of six months will be randomized to received either half-dose Pegasys for an additional 3.5 years, or no treatment at all (the current standard of care for non-responders). People coinfected with HIV or HBV are not eligible for this study.
COPILOT (the Colchicine versus Peg-Intron Long-Term study), which is already well underway, will include about 1,000 participants who have not achieved an SVR after more than one treatment attempt using current regimens. Participants will be randomized to receive either low-dose maintenance Peg-Intron once weekly or an oral drug called colchecine twice daily; colchecine is an antifibrotic drug that has been shown to benefit people with liver damage related to heavy alcohol use. People with decompensated cirrhosis, liver failure, and HIV coinfection are not eligible. At the Digestive Disease Week meeting in May 2002 researchers presented preliminary COPILOT results for 250 participants who had received maintenance therapy for one year. Early data show that those receiving maintenance Peg-Intron had a reduction in HCV RNA, while the viral loads of those taking colchicine remained the same.
In both HALT-C and COPILOT, HCV viral load and biochemical markers such as ALT will be measured throughout the study. Blood tests and ultrasound scans will be used to detect liver cancer. Biopsies will be performed at baseline (unless a recent biopsy result is available) and later during the course of the study to assess the degree of liver disease progression.
HALT-C is being conducted at eleven research sites across the United States: Worcester, MA; Boston; Farmington, CT; Dallas; St. Louis; Los Angeles; Long Beach, CA; Ann Arbor; Denver; Richmond, VA; and Bethesda, MD. There is no study site in the San Francisco Bay Area. For contact information, see the web site at www.haltctrial.org.
COPILOT has some 100 study sites throughout the country, including San Francisco, Oakland, Boston, New York City, Chicago, Detroit, Dallas, Denver, Seattle, Pittsburgh, and Baltimore. For the site nearest you, contact study coordinator Jocelyn Leone at 617-632-1071.
A third new, currently recruiting maintenance trial called AEGIS aims to look at the safety and effectiveness of interferon-gamma (InterMune) in reducing fibrosis in people with chronic HCV who are at risk of developing complications of advanced liver disease. Participants will be randomized to receive one of two doses of InterMune or a placebo. There are over fifty AEGIS study sites in the U.S. and Canada including San Francisco, Los Angeles, Seattle, Houston, Minneapolis, Cincinnati, New York City, New Orleans, Atlanta, Miami, and Ontario, Canada. For the site near you call 866-618-4634 (toll free).
Clinical trials are the best way to advance the state of the art of HCV treatment. As these trials proceed, it should become clear whether interferon maintenance therapy can help reduce the long-term negative effects of HCV infection and improve patients' quality of life.
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