Adding ribavirin to interferon increases the number of patients who clear hepatitis C virus but also leads to several adverse reactions

Brok J, Gluud LL, Gluud C

Published Online:

January 20, 2010

Globally about 170 million people are chronically infected with hepatitis C virus. Hepatitis C is a blood-borne virus and routes of transmission include intravenous drug use, mother-to-infant transmission, unsafe medical practices, high-risk sexual behavior, and blood transfusion. Chronic hepatitis C is in most patients a benign viral infection, but a minority of patients develop liver cirrhosis and may suffer from complications due to cirrhosis or die.

It is known that treatment with the drug interferon clears hepatitis C virus from the blood in about 15% of patients. This review identified studies comparing ribavirin plus interferon with interferon alone in patients with chronic hepatitis C. This review shows, by combining the results from all trials, that adding ribavirin to interferon increases the number of patients who clear the hepatitis C virus to about 40% as well as the number of patients who demonstrate improved liver histology. Ribavirin and interferon may also reduce the risk of liver-related morbidity or all-cause mortality. However, the number needed to treat to prevent one patient developing morbidity or dying seems very large. Furthermore, combination therapy was associated with increased risk of anaemia and several other adverse reactions.

The results gives rise to a dilemma - should we, by adding ribavirin to interferon, increase the risk of haematological, dermatological, gastrointestinal, infectious, and miscellaneous adverse reactions in a situation where it has not yet been clearly demonstrated that the antiviral effect of the intervention is directly linked to the reduction of all-cause mortality? We, therefore, suggest that the combination intervention is applied only with stringent emphasis on the individual patients' well-being. Furthermore, we suggest that all future trials within the area should focus more on adverse reactions and long-term clinical outcomes.

Abstract (click to read)

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.

This record should be cited as:

Brok J, Gluud LL, Gluud C. Ribavirin plus interferon versus interferon for chronic hepatitis C. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD005445. DOI: 10.1002/14651858.CD005445.pub2

Assessed as up to date:

April 1, 2009

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Primary Review Group:

Hepato-Biliary Group

Health topics:

Gastroenterology > Liver diseases > Hepatitis C

Infectious disease > Liver diseases > Hepatitis C

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Adding ribavirin to interferon increases the number of patients who clear hepatitis C virus but also leads to several adverse reactions

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