Relatively few patients (≤20%) with chronic hepatitis C achieve a sustained virological response after interferon-α monotherapy. Hence, alternative treatment strategies such as the addition of the broad spectrum antiviral agent ribavirin to interferon-a-2b have been investigated.

Combination therapy with subcutaneous interferon-α-2b [3 million units (MU) three times per week] plus oral ribavirin (1000 to 1200 mg/day) has proven effective in several well designed trials of 24 to 48 weeks’ duration in adult patients with compensated chronic hepatitis C. Compared with interferon-α-2b (3 or 6MU three times per week) with or without placebo, combination treatment with interferon-α-2b plus ribavirin significantly enhanced end-of-treatment and sustained virological and biochemical response rates in treatment-naive and treatment-experienced patients [sustained virological response rates in treatmentnaive recipients (6 to 19% vs 31 to 43% of patients); sustained overall (virological plus biochemical) response rates in nonresponders to (1 vs 14%) or relapsers (4 to 5% vs 30 to 44%) after previous interferon-a monotherapy]. Forty-eight weeks of combination therapy was superior to 24 weeks in treatment-naive patients infected with hepatitis virus C (HCV) genotype 1, whereas response rates were similar at 24 and 48 weeks in those infected with other HCV genotypes. Furthermore, there were marked improvements in histological inflammatory scores in patients who responded to treatment with either interferon-α-2b plus ribavirin or interferon-α-2b alone.

Although adverse events associated with either drug during combination therapy occurred frequently, these were generally mild to moderate in intensity and were consistent with those reported for each individual agent. Twenty-six percent of patients required dosage modifications of one or both drugs during combination therapy.

Conclusions: Interferon-α-2b plus ribavirin is an efficacious first- and second-line therapy in adult patients with compensated chronic hepatitis C, significantly improving sustained virological and biochemical responses versus interferon-α-2b monotherapy. The tolerability profile of interferon-α-2b plus ribavirin therapy is consistent with the individual profiles of these agents with no evidence of additive effects. The place of interferon-α-2b plus ribavirin combination therapy in relation to newer agents, including pegylated interferons-a and other multidrug regimens, remains to be determined in this rapidly evolving area of therapeutic management. Currently, combination therapy with interferon-α-2b plus ribavirin is recommended as first-line therapy for patients with chronic hepatitis C and compensated liver disease, and is an option for use as second-line therapy in those who have relapsed after, or failed to respond to, previous treatment with interferon-α.

Interferon-α-2b Plus Ribavirin

BACKGROUND Hepatitis C is a major cause of liver-related morbidity and mortality. Standard therapy is ribavirin plus pegylated interferon to achieve undetectable level of virus in the blood, but the effect on clinical outcomes is controversial. 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 March 2009. SELECTION CRITERIA We included randomised trials, irrespective of blinding, language, or publication status, comparing ribavirin plus interferon versus interferon for treatment of chronic hepatitis C. DATA COLLECTION AND ANALYSIS The primary outcome measures were serum sustained loss of hepatitis C virus, liver-related morbidity plus all-cause mortality, and adverse events. We performed subgroup analyses of patients who were naive, relapsers, or non-responders to previous antiviral treatment. All outcomes were analysed with the random-effects model. 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). We used trial sequential analyses to examine the robustness of our findings. MAIN RESULTS We included 83 randomised trials with 12,707 patients. Most trials had unclear or high risk of bias. We did not find any significant influence of bias on our results but cannot exclude outcome measure reporting bias as many trials did not report on the primary outcomes of this review. Compared with interferon, ribavirin plus interferon had a significant beneficial effect on sustained virological response in subgroups of naive patients (RR 0.72, 95% confidence interval (CI) 0.68 to 0.75), relapsers (RR 0.62, 95% CI 0.54 to 0.70), non-responders (RR 0.89, 95% CI 0.84 to 0.93), and in all patients (RR 0.75, 95% CI 0.71 to 0.79). Combination therapy significantly reduced morbidity plus mortality in all patients (Peto OR, 0.43, 95% CI 0.23 to 0.79), but not in naive, relapsers, or non-responders individually. Combination therapy significantly increased the risk of haematological, dermatological, gastrointestinal, infectious, and miscellaneous (cough, dyspnoea, fatigue) adverse reactions. Accordingly, combination therapy significantly increased the risk of treatment discontinuation and dose reductions. Trial sequential analyses confirmed our findings regarding virological effects, but not regarding liver-related morbidity and all-cause mortality. AUTHORS' CONCLUSIONS Compared with interferon alone, ribavirin plus interferon is more effective in clearing hepatitis C virus from the blood. Combination therapy may reduce liver-related morbidity and all-cause mortality, but we need more evidence. The number needed to treat to obtain a beneficial effect is considerable considering the increased risk of several severe adverse reactions and costs.

Ribavirin plus interferon versus interferon for chronic hepatitis C.

Background Hepatitis C is a major cause of liver-related morbidity and mortality. Ribavirin plus interferon combination therapy is presently considered the optimal treatment of interferon naive patients with chronic hepatitis C, but its role in relapsers and non-responders to previous interferon therapy is not established. Objectives To assess the efficacy and safety of ribavirin alone or in combination with alpha interferon in interferon naive patients, relapsers, and non-responders with chronic hepatitis C. Search strategy Eligible trials were identified through searches on electronic databases: The Cochrane Hepato-Biliary Group Controlled Trials Register (August 2001), The Cochrane Controlled Trials Register on The Cochrane Library Issue 3, 2001, MEDLINE (1966 - August 2001), and EMBASE (1985 - August 2001). Manual searches of bibliographies and journals were done as well as authors of trials and pharmaceutical companies producing ribavirin or interferon were contacted. Selection criteria We included all randomised trials comparing ribavirin with or without alpha interferon versus no intervention, placebo, or alpha interferon for chronic hepatitis C. Data collection and analysis The primary outcome measures were the 'sustained' (six months after treatment) virological response, and morbidity plus mortality. The secondary outcome measures were the 'end of treatment' and 'sustained' biochemical response, the 'end of treatment' virologic response, histology, quality of life, and adverse events. Main results We included eight trials in which 271 patients were randomised to ribavirin versus placebo or no intervention and 48 trials in which 6585 patients were randomised to interferon with or without ribavirin. Compared with placebo or no intervention, ribavirin monotherapy had no significant effect on the virological response or histology and only a transient effect on the biochemical response. Compared with interferon, combination therapy reduced the risk of not having a sustained virological response by 26% in naive patients (relative risk (RR) 0.74; 95% confidence interval (CI) 0.70-0.78), 33% in relapsers (RR 0.67; 95% CI 0.57-0.78), and 11% in non-responders (RR 0.89; 95% CI 0.83-0.96). There was no significant effect on morbidity plus mortality (Peto odds ratio 0.45; 95% CI 0.19-1.06). Irrespective of previous therapy, combination therapy significantly reduced the risk of not having a sustained biochemical response (RR 0.76; 95% CI 0.59-0.84) or improved histology (RR 0.67; 95% CI 0.56-0.81). Combination therapy also significantly increased the risk of treatment discontinuation (RR 1.28; 95% CI 1.07-1.52) and several types of adverse events. Reviewer's conclusions Combination therapy increased the number of naive patients, relapsers, and non-responders with a sustained virological, biochemical, or histological response, but also the occurrence of adverse events.

Ribavirin with or without alpha interferon for chronic hepatitis C.

Background Hepatitis C is a major cause of liver-related morbidity and mortality. Ribavirin plus interferon combination therapy is presently considered the optimal treatment of interferon naive patients with chronic hepatitis C, but its role in relapsers and non-responders to previous interferon therapy is not established. Objectives To assess the efficacy and safety of ribavirin alone or in combination with alpha interferon in interferon naive patients, relapsers, and non-responders with chronic hepatitis C. Search strategy Eligible trials were identified through searches on electronic databases: The Cochrane Hepato-Biliary Group Controlled Trials Register (August 2001), The Cochrane Controlled Trials Register on The Cochrane Library Issue 3, 2001, MEDLINE (1966 - August 2001), and EMBASE (1985 - August 2001). Manual searches of bibliographies and journals were done as well as authors of trials and pharmaceutical companies producing ribavirin or interferon were contacted. Selection criteria We included all randomised trials comparing ribavirin with or without alpha interferon versus no intervention, placebo, or alpha interferon for chronic hepatitis C. Data collection and analysis The primary outcome measures were the 'sustained' (six months after treatment) virological response, and morbidity plus mortality. The secondary outcome measures were the 'end of treatment' and 'sustained' biochemical response, the 'end of treatment' virologic response, histology, quality of life, and adverse events. Main results We included eight trials in which 271 patients were randomised to ribavirin versus placebo or no intervention and 48 trials in which 6585 patients were randomised to interferon with or without ribavirin. Compared with placebo or no intervention, ribavirin monotherapy had no significant effect on the virological response or histology and only a transient effect on the biochemical response. Compared with interferon, combination therapy reduced the risk of not having a sustained virological response by 26% in naive patients (relative risk (RR) 0.74; 95% confidence interval (CI) 0.70-0.78), 33% in relapsers (RR 0.67; 95% CI 0.57-0.78), and 11% in non-responders (RR 0.89; 95% CI 0.83-0.96). There was no significant effect on morbidity plus mortality (Peto odds ratio 0.45; 95% CI 0.19-1.06). Irrespective of previous therapy, combination therapy significantly reduced the risk of not having a sustained biochemical response (RR 0.76; 95% CI 0.59-0.84) or improved histology (RR 0.67; 95% CI 0.56-0.81). Combination therapy also significantly increased the risk of treatment discontinuation (RR 1.28; 95% CI 1.07-1.52) and several types of adverse events. Authors' conclusions Combination therapy increased the number of naive patients, relapsers, and non-responders with a sustained virological, biochemical, or histological response, but also the occurrence of adverse events.

WITHDRAWN: Ribavirin with or without alpha interferon for chronic hepatitis C.

Interferon-α-2b Plus Ribavirin A Review of its Use in the Management of Chronic Hepatitis C

Interferon-α (IFN) induction dosing and ribavirin (R) in IFN non-responders (NR) with chronic hepatitis C (CHC): Interim analysis of an ongoing study (SASL 10)

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Interferon-α (IFN) induction dosing and ribavirin (R) in IFN non-responders (NR) with chronic hepatitis C (CHC): Interim analysis of an ongoing study (SASL 10)