A Decade of Trials of Interferon-Alpha for Chronic Hepatitis C. A Meta-Regression Analysis

Abstract

The most relevant randomized controlled trials of interferon-alpha (IFN) for naive patients with chronic hepatitis C (CHC) published in a decade, just before appearance of pegylated IFN trials in 2000, were included in this paper. Its purpose is to review the relationship between sustained biochemical response in active versus control group versus usual clinical variables as IFN regimens, cirrhosis, genotype and versus less frequently addressed variables as funding, methodological quality or location of principal author. Meta-analysis estimates of global treatment effect varied according to trial design: group 1=IFN versus placebo/no treatment, 32 RCTs, 2499 pts, OR 9.5 (6.3-14.2); group 2a=comparison of IFN schedules, 43 RCTs, 7454 pts, OR 1.6 (1.4-1.9); group 2b=IFN+other drugs versus standard IFN, 30 RCTs, 4737 pts, OR 2.0 (1.6-2.6). Fixed effects (arm-level) meta-regression on the complete data set (171 arms, 10,580 pts) revealed that sustained response was most likely in experimental arms of IFN+ribavirin or other drugs (OR 2.4), arms using yearly schedule (OR 2.0), trial principal author from Asia (OR 1.7), trial sample size >200 (OR 1.4) and arms enrolling less than 50% of cirrhotics (OR 1.3). Moreover, focus was on some significant interactions too, as the effect of trial''s quality interacting to the recorded funding (more benefit if no-profit, less if for-profit) and the effect of trial funding interacting to the location of first author (more benefit if from Asia). Three main effects (experimental arm, cirrhosis, funding) and one interaction (funding*location of principal author) explained 31% of between study variability in a random-effect meta-regression. In a subgroup analysis on a data set including available information on HCV genotype (93 arms, around 7000 pts), meta-regression revealed that genotype 1 or 4 less than 50% per arm and specialistic journal were significant predictors of either biochemical (transaminases) or virological (HCV-RNA) sustained response, in a model including the same main effects identified in the complete data set analysis. Finally, although mostly captured by different IFN regimens along time, heterogeneity of effect in a large set of (not-pegylated) IFN trials was also explained by HCV genotype and variables of quality and reporting, such as trial''s principal author from Asia.