title: Ribavirin plus interferon versus interferon for chronic hepatitis C.
abstract: 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.
  
  
  OBJECTIVE
  To assess the beneficial and harmful effects of ribavirin and interferon combination therapy versus interferon monotherapy for chronic hepatitis C.
  
  
  METHODS
  We identified trials through electronic databases, manual searches of bibliographies and journals, approaching authors of trials, and pharmaceutical companies until March 2009.
  
  
  METHODS
  We included randomised trials, irrespective of blinding, language, or publication status, comparing ribavirin plus interferon versus interferon for treatment of chronic hepatitis C.
  
  
  METHODS
  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.
  
  
  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.
  
  
  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.
authors.affiliation: Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, Denmark, DK-2100.
authors.forename: Jesper
authors.initials: J
authors.lastname: Brok
authors.forename: Lise Lotte
authors.initials: LL
authors.lastname: Gluud
authors.forename: Christian
authors.initials: C
authors.lastname: Gluud
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination / Q000379:methods; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012254:Ribavirin / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin; D007372:Interferons