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From Hepatology Sept 2002, Vol 36, Number 3
  Recent large, randomized, controlled trials of therapies for chronic hepatitis C have reported sustained eradication of hepatitis C virus (HCV) and remission in disease in over half of treated patients. In two separate studies enrolling more than 1,000 patients each, the combination of peginterferon and ribavirin was found to be superior to standard interferon and ribavirin and to achieve sustained virological response rates of 54% (Lancet 2001;358:958-965) and 56% (Gastroenterology 2001;120:A55). These excellent response rates provide justification for treating patients with hepatitis C who have histologic and/or clinical evidence of progressive disease.
Unfortunately, therapies that are proven to be safe and effective in well-designed, multicenter, randomized trials may not prove to be as safe or as effective when applied in clinical practice. Perhaps the major reason for this discrepancy is that the average patient enrolled in a clinical trial that satisfies all inclusion and exclusion criteria may not be representative of the average patient with hepatitis C in practice. Several groups of patients with hepatitis C are underrepresented in the registration trials of new therapies for this disease-some intentionally and some by chance. Such understudied groups include children; the elderly; minority individuals; patients with comorbidities of human immunodeficiency virus infection, neuropsychiatric disease, or renal disease; persons in institutions or who are incarcerated; patients with advanced hepatitis C; and patients who have had a solid organ transplantation.
Quite striking in many of the initial large, randomized, controlled trials of interferon-based therapy of hepatitis C has been the underrepresentation of African Americans. In a combined analysis of studies of standard interferon monotherapy and combination therapy, less than 5% of patients enrolled were black, despite the fact that African Americans have a higher rate of hepatitis C than non-Hispanic white Americans and probably account for more than 20% of cases of chronic hepatitis C in the United States (Gastroenterology 2000;119:1385-1396). Also striking has been a lower response rate to interferon-based therapies among African Americans compared with whites. In several studies, the sustained response rate among African Americans was one third to one half of that in whites. In the recent multinational studies of peginterferon and ribavirin, blacks represented less than 5% of patients enrolled and had response rates that were less than the average, even after controlling for genotype. The numbers of African Americans in these studies, however, were not adequate to provide an accurate estimate of response rate.
For these reasons, the Division of Digestive Diseases and Nutrition of NIDDK published a request for applications (RFA) to conduct a multicenter clinical trial of peginterferon and ribavirin therapy in a cohort of patients that would include an adequate number of African Americans to establish an accurate estimation of the response rate in this group and to initiate basic research studies of the reasons for nonresponse and antiviral resistance. The RFA "Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep-C)" was published in September 2000; applications were received in December and reviewed by a special study section in March 2001. In July 2001, eight clinical centers and a data coordinating center were awarded. In addition, four ancillary studies were funded, which were to focus on analyses of the basis for antiviral resistance. The participants are shown below:
Beth Israel Deaconess Medical Center, Dr. Nezam Afdhal
New York-Presbyterian Medical Center, Drs. Robert Brown and Lorna Dove
University of Michigan, Drs. Hari Conjeevaram and Robert Fontana
University of North Carolina, Chapel Hill, Drs. Michael Fried and Scott Smith
University of Maryland, Dr. Charles Howell
University of Miami, Drs. Lennox Jeffers and Shvawn Baker
University of California, San Francisco, Dr. Norah Terrault
University of Illinois, Chicago, Drs. Thelma Wiley and Thomas Layden
Ancilliary Studies:
Cedar-Sinai Medical Center, Los Angeles, Dr. Huiying Yang: Host genetics
Indiana University, Dr. Milton Taylor: Interferon signaling
St. Louis University, Dr. John Tavis: Virology
Portland Veterans Aministration Medical Center, Dr. Hugo Rosen: Immunology
NIH Staff:
Dr. Patricia Robuck, Project Officer
Dr. David Kleiner, Pathologist
The protocol and manual of operations for Virahep-C have now been completed. A Web site describing the trial will be available at http://www.edc.gsph.pitt.edu/virahepc. The study will enroll 400 adult patients with chronic hepatitis C of genotype 1 who have never been treated with interferon. Of the total, 200 patients will be African Americans and 200 will be white Americans. All will receive a course of the combination of peginterferon alfa-2a (Pegasys) and ribavirin and be followed rigorously for symptoms, side effects, compliance, serum biochemical markers of liver disease, and HCV-RNA levels. Special blood samples will be taken at specified intervals for studies of immune function, interferon signaling, and genetic analyses. The study is being conducted under a clinical research and development agreement with Hoffmann LaRoche to provide the study medications and support for virologic and other measurements. The initial patients are scheduled to start enrollment in August 2002 and the full enrollment is expected within 12 months.
The elucidation of the nature and determinants of a response to antiviral therapy and a more clear delineation of the efficacy of combination therapy in all groups of patients with hepatitis C are areas of high priority for the National Institutes of Health in the long-term initiative on prevention and control of hepatitis C.
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