A Cochrane review [Abstract] 1 included 83 studies, with a total of 12 707 subjects, published from 1995 to May 2004. Most trials had low methodological quality but any significant influence of quality on the results was not found.
Compared with interferon, combination therapy had a significant beneficial effect on sustained virological response (RR 0.75, 95% CI 0.71 to 0.79) and in subgroups of naive patients (RR 0.72, 95% CI 0.68 to 0.75), relapsers (RR 0.62, 95% CI 0.54 to 0.70), and non-responders (RR 0.89, 95% CI 0.84 to 0.93) individually. Combination therapy significantly reduced morbidity plus mortality (Peto OR 0.43, 95% CI 0.23 to 0.79), 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 9.45, 95% CI 7.42 to 12.05), which occurred in 16% of patients on combination therapy. It also increased the risk of leukopenia, but not neutropenia or thrombocytopenia. Combination therapy 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 1.13, 95% CI 1.02 to 1.26) and dose reductions. Trial sequential analyses confirmed the findings regarding virological effects, but not regarding liver-related morbidity and all-cause mortality.
A systematic review 2 including 19 RCTs and 2 meta-analyses with a total of more than 5 000 subjects was abstracted in DARE. Combination therapy produced larger sustained response rates than monotherapy. The authors conclude that it is appropriate to offer 6 months of combination therapy as a first-line treatment to both patients who have not previously been treated with interferon, and to those who have relapsed after a previous course of intervention. At 6 months, the decision on whether to continue treating patients should depend on factors that may predict a good sustained response. For treatment-naive patients these are: genotype two or three; baseline viral load less than 3.5 million copies/ml; no or portal fibrosis; female gender; age younger than 40 years.
A technology assessment report 3 abstracted in the Health Technology Assessment Database confirms the conclusion that the combination treatment with IFN and ribavirin can permanently eliminate HCV from the blood and thus cure and prevent a liver disease in approx. 40% of all treated patients. The proportion of patients experiencing a permanent effect of the combination treatment is larger than the respective proportion with IFN alone. Six months after the end of the treatment, 37% of the naive patients were still clear of HCV. Amongst the relapsing patients and the non-responder patients 43% and 15% respectively were clear of HCV. The combination treatment causes more side effects, some of which can be serious or permanent, such as interference with thyroid function. Approx. 30% of the patients developed anaemia. The follow-up times in the studies have been too short to assess the influence of the combination treatment on morbidity and mortality. However, there is a trend towards a reduction of the total morbidity and mortality in patients receiving the combination treatment as opposed to those receiving treatment with IFN alone.
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