J Brok1, L L Gluud, C Gluud. 1. Centre for Clinical Intervention Research, Copenhagen University Hospital, Copenhagen Trial Unit, Department 7102, H:S Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark, 2100 Ø. jbrok@ctu.rh.dk
Abstract
BACKGROUND: Hepatitis C is a major cause of liver-related morbidity and mortality. The disease progresses without symptoms for several decades and most patients are diagnosed based on the presence of hepatitis C virus ribonucleic acid and elevated transaminases. OBJECTIVES: To assess the beneficial and harmful effects of ribavirin and interferon combination therapy versus interferon monotherapy for chronic hepatitis C. SEARCH STRATEGY: We identified trials through electronic databases, manual searches of bibliographies and journals, approaching authors of trials and pharmaceutical companies, until May 2004. SELECTION CRITERIA: We included randomised trials, irrespective of blinding, language, or publication status, comparing ribavirin plus interferon versus interferon alone for treatment of chronic hepatitis C. DATA COLLECTION AND ANALYSIS: The primary outcome measures were the sustained loss of hepatitis C virus and liver-related morbidity plus all-cause mortality. We separately analysed patients who were naive, relapsers, or non-responders to previous antiviral treatment. Random-effects and fixed-effect model meta-analyses were performed for all outcomes. We used Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of morbidity plus mortality. The remaining outcomes were presented as relative risks (RR). MAIN RESULTS: We included 72 randomised trials with 9991 patients. Most trials had low methodological quality but we did not find any significant influence of quality on our results. Compared with interferon, combination therapy had a significant beneficial effect on sustained virological response (RR 0.73, 95% CI 0.71 to 0.75) and in subgroups of naive patients (RR 0.72, 95% CI 0.68 to 0.76), relapsers (RR 0.63, 95% CI 0.54 to 0.73), and non-responders (RR 0.89, 95% CI 0.84 to 0.94) individually. Combination therapy significantly reduced morbidity plus mortality (Peto OR 0.46, 95% CI 0.22 to 0.96), but not in naive, relapsers, or non-responders individually. Combination therapy also had a significant beneficial effect on the histological response. Combination therapy significantly increased the risk of anaemia (RR 10.48, 95% CI 5.34 to 20.55), which occurred in 22% of patients on combination therapy. Combination therapy also significantly increased the risk of dermatological, gastrointestinal, infectious, and miscellaneous (cough, dyspnea, fatigue) adverse events. Accordingly, combination therapy significantly increased the risk of treatment discontinuation (RR 1.19, 95% CI 1.01 to 1.39). AUTHORS' CONCLUSIONS: Compared with interferon alone, ribavirin plus interferon is more effective in clearing hepatitis C virus and improving liver histology. This may lead to reduced morbidity and mortality. However, combination therapy significantly increased the risk of several adverse events.
BACKGROUND: Hepatitis C is a major cause of liver-related morbidity and mortality. The disease progresses without symptoms for several decades and most patients are diagnosed based on the presence of hepatitis C virus ribonucleic acid and elevated transaminases. OBJECTIVES: To assess the beneficial and harmful effects of ribavirin and interferon combination therapy versus interferon monotherapy for chronic hepatitis C. SEARCH STRATEGY: We identified trials through electronic databases, manual searches of bibliographies and journals, approaching authors of trials and pharmaceutical companies, until May 2004. SELECTION CRITERIA: We included randomised trials, irrespective of blinding, language, or publication status, comparing ribavirin plus interferon versus interferon alone for treatment of chronic hepatitis C. DATA COLLECTION AND ANALYSIS: The primary outcome measures were the sustained loss of hepatitis C virus and liver-related morbidity plus all-cause mortality. We separately analysed patients who were naive, relapsers, or non-responders to previous antiviral treatment. Random-effects and fixed-effect model meta-analyses were performed for all outcomes. We used Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of morbidity plus mortality. The remaining outcomes were presented as relative risks (RR). MAIN RESULTS: We included 72 randomised trials with 9991 patients. Most trials had low methodological quality but we did not find any significant influence of quality on our results. Compared with interferon, combination therapy had a significant beneficial effect on sustained virological response (RR 0.73, 95% CI 0.71 to 0.75) and in subgroups of naive patients (RR 0.72, 95% CI 0.68 to 0.76), relapsers (RR 0.63, 95% CI 0.54 to 0.73), and non-responders (RR 0.89, 95% CI 0.84 to 0.94) individually. Combination therapy significantly reduced morbidity plus mortality (Peto OR 0.46, 95% CI 0.22 to 0.96), but not in naive, relapsers, or non-responders individually. Combination therapy also had a significant beneficial effect on the histological response. Combination therapy significantly increased the risk of anaemia (RR 10.48, 95% CI 5.34 to 20.55), which occurred in 22% of patients on combination therapy. Combination therapy also significantly increased the risk of dermatological, gastrointestinal, infectious, and miscellaneous (cough, dyspnea, fatigue) adverse events. Accordingly, combination therapy significantly increased the risk of treatment discontinuation (RR 1.19, 95% CI 1.01 to 1.39). AUTHORS' CONCLUSIONS: Compared with interferon alone, ribavirin plus interferon is more effective in clearing hepatitis C virus and improving liver histology. This may lead to reduced morbidity and mortality. However, combination therapy significantly increased the risk of several adverse events.