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Ribavirin as Therapy for Chronic Hepatitis C: A Randomized, Double-Blind, Placebo-Controlled Trial

Adrian M. Di Bisceglie, MD; Hari S. Conjeevaram, MD; Michael W. Fried, MD; Richard Sallie, MD; Yoon Park, RN; Cihan Yurdaydin, MD; Mark Swain, MD; David E. Kleiner, MD, PhD; Kevin Mahaney, MD; and Jay H. Hoofnagle, MD*
[+] Article and Author Information

From the Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. *David Wright, PhD, was also an author on this paper. Acknowledgments: The authors thank Drs. Humberto Fernandez and Gordana Kosutic from ICN Pharmaceuticals for their advice and assistance and the nursing staff of the Clinical Center, National Institutes of Health, for invaluable patient care. Grant Support: In part by ICN Pharmaceuticals, who provided the ribavirin capsules, placebo capsules, serologic testing reagents, and fellowship support for Dr. Mahaney; and by Innogenetics, who provided reagents for the genotyping of hepatitis C virus RNA. Requests for Reprints: Jay H. Hoofnagle, MD, Building 31, Room 9A 23, National Institutes of Health, Bethesda, MD 20892. Current Author Addresses: Dr. Di Bisceglie: Department of Internal Medicine, St. Louis University Health Sciences Center, 1402 South Grand Boulevard, St. Louis, MO 63104. Dr. Conjeevaram: Liver Study Unit, Section of Gastroenterology, M454C, University Hospital and Clinics, 5841 South Maryland Avenue, Chicago, IL 60627. Dr. Fried: Division of Digestive Diseases, Emory University School of Medicine, P.O. Drawer AL, Atlanta, GA 30322. Drs. Sallie and Park: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Liver Diseases Section, Center Drive, Building 10, 9C306, Bethesda, MD 20892. Dr. Yurdaydin: Ankara Universitesi, Tip Fakultesi, Cebeci Hastanesi, Cebeci, Ankara, Turkey. Dr. Swain: Department of Medicine, Faculty of Medicine, Health Sciences Centre, 3330 Hospital Drive N.W., Calgary, Alberta, T2N 1N4, Canada. Dr. Kleiner: Division of Cancer Biology, Diagnosis and Centers, National Cancer Institute, Center Drive, Building 10, Room 2N206, Bethesda, MD 20892. Dr. Mahaney: Department of Medicine, Georgetown University Hospital, 3800 Reservoir Road, N.W., Washington, DC 20007. Dr. Hoofnagle: Building 31, Room 9A 23, National Institutes of Health, Bethesda, MD 20892. Dr. Wright: Westat, 1650 Research Boulevard, Rockville, MD 20850.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1995;123(12):897-903. doi:10.7326/0003-4819-123-12-199512150-00001
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Objective: To evaluate ribavirin, an oral antiviral agent, as therapy for chronic hepatitis C.

Design: Randomized, double-blind, placebo-controlled study.

Setting: Clinical Center of the National Institutes of Health, a tertiary referral research hospital.

Patients: 29 patients with chronic hepatitis C who received oral ribavirin (600 mg twice daily) for 12 months and 29 controls with chronic hepatitis C who received placebo for 12 months.

Measurements: Effects of therapy were evaluated by measuring serum aminotransferase and hepatitis C virus (HCV) RNA levels before, during, and for 6 months after therapy and by histologic examination of liver specimens before and at the end of treatment.

Results: Patients treated with ribavirin had a prompt decrease in serum aminotransferase levels (54% overall) compared with levels before treatment and levels in controls (5% decrease). Serum aminotransferase levels became normal or nearly normal in 10 patients treated with ribavirin (35% [95% CI, 18% to 54%]) but in no controls (0% [CI, 0% to 12%]). Aminotransferase levels remained normal in only 2 patients after ribavirin therapy was discontinued (7% [CI, 1% to 23%]). Serum HCV RNA levels did not change during or after therapy. Liver biopsy specimens showed a decrease in hepatic inflammation and necrosis among ribavirin-treated patients whose aminotransferase levels became normal.

Conclusions: Ribavirin has beneficial effects on serum aminotransferase levels and histologic findings in the liver in patients with chronic hepatitis C, but these effects are not accompanied by changes in HCV RNA levels and are not sustained when ribavirin therapy is discontinued. Thus, ribavirin alone for periods as long as 12 months is unlikely to be of value as therapy for chronic hepatitis C.

Figures

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Figure 1.
Mean serum alanine aminotransferase levels in 29 patients with chronic hepatitis C who were treated with ribavirin (solid line) and 29 patients with chronic hepatitis C who were treated with placebo (dashed line).

Levels decreased significantly among ribavirin-treated patients but not among placebo recipients (repeated-measures analysis of variance). To convert U/L to µkat/L, multiply by 0.01667.

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Figure 2.
Mean serum hepatitis C virus RNA levels as measured by branched DNA signal amplification assay in 29 patients with chronic hepatitis C who were treated with ribavirin (solid line) and 29 patients with chronic hepatitis C who received placebo (dashed line).
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Figure 3.
Total histology activity index scores for the initial and final liver biopsy specimens from 10 patients who responded (left) and 19 patients who did not respond (right) to ribavirin therapy.PP

In the left panel, closed circles denote complete responders and open circles denote partial responders. Among responders, the mean histology activity index score decreased by 4.3 ( = 0.0039, Wilcoxon signed-rank test). Among nonresponders, the mean histology activity index score decreased by 0.3 ( = 0.64).

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