January 10, 2001

Interferon and Ribavirin vs Interferon Alone in the Re-treatment of Chronic Hepatitis C Previously Nonresponsive to InterferonA Meta-analysis of Randomized Trials

Author Affiliations

Author Affiliations: Departments of International Health (Dr Cummings), Epidemiology (Ms West and Drs Fein and Goodman), Health Policy and Management, Health Services Research and Development Center (Dr Cid-Ruzafa), and Environmental Health Sciences (Mr Aoki), Johns Hopkins University School of Hygiene and Public Health; and Departments of Oncology (Ms Lee and Dr Goodman) and Medicine, Division of Infectious Diseases (Dr Sulkowski), Johns Hopkins University School of Medicine, Baltimore, Md. Dr Cummings is now with the Department of Medicine, Stanford University Medical Center, Stanford, Calif, and Dr Fein is now with the Department of Medicine, Duke University Medical Center, Durham, NC.

JAMA. 2001;285(2):193-199. doi:10.1001/jama.285.2.193

Context Hepatitis C is the leading cause of chronic liver disease in the United States. Several trials have found that interferon and ribavirin combination therapy is more efficacious than interferon monotherapy for previously untreated patients and those who relapsed after prior interferon monotherapy, but its effectiveness for nonresponders to prior interferon monotherapy is unclear.

Objective To assess the efficacy and safety of interferon and ribavirin vs interferon alone for treatment of patients with chronic hepatitis C who previously did not respond to interferon monotherapy.

Data Sources A systematic search was performed using MEDLINE and the Science Citation Index for publications from 1966 to December 1999. A manual reference search and a manual review of relevant specialty journals also were performed, and input from clinical hepatology experts was sought.

Study Selection Included studies were randomized, controlled clinical trials comparing interferon and ribavirin with interferon alone and reporting virological and biochemical outcomes after a follow-up period. Of 50 identified studies, 12 trials (941 patients) were included in the analysis.

Data Extraction Two investigators reviewed trials independently for methods, inclusion and exclusion criteria, and outcomes. Disagreements were resolved by discussion. Abstracted data included study and patient characteristics and virological, biochemical, and histological outcomes. A quality evaluation questionnaire was used to score studies.

Data Synthesis The pooled virological response rate for combination therapy was 14% (95% confidence interval [CI], 11%-17%), with a risk difference favoring combination therapy of 7% (95% CI, 2%-13%). Use of interferon alfa-2a/2b and ribavirin, 1000 to 1200 mg/d, was associated with a pooled virological response rate of 18% and a risk difference of 16% (95% CI, 11%-21%). When interferon alfa-n/n3 and a lower dosage of ribavirin (600-800 mg/d) were used, the risk difference was 0% (95% CI, –7% to 7%). Combination therapy was associated with more adverse effects and an increased rate of discontinuation of treatment compared with interferon monotherapy.

Conclusions For chronic hepatitis C that is nonresponsive to prior interferon monotherapy, combination therapy is more effective than re-treatment with interferon alone. Response rates remain less than 20% even in the most responsive subgroups, demonstrating a need for better therapeutic options.