|
Effect of recombinant or lymphoblastoid interferon-alpha on alanine aminotransferase in patients with chronic hepatitis C or chronic non-A non-B hepatitis: a meta-analysis |
Bardelli F, Messori A, Rampazzo R, Alberti A, Martini N |
|
|
Authors' objectives To determine the efficacy of recombinant and lymphoblastoid interferon-alpha (IFN-alpha) in the induction and maintenance of remission (first and second meta-analyses, respectively) in patients with chronic C or non-A non-B hepatitis.
Searching MEDLINE, Current Contents, Cambridge Scientific Abstracts, IDIS, reviews, references of identified studies, and textbooks were searched. Experts in the field were also contacted.
Study selection Study designs of evaluations included in the reviewRandomised studies that evaluated the efficacy of IFN-alpha at weekly dosages of 4.5 to 45 MU for at least 4 months, in comparison with a control group receiving either a placebo or no treatment, were included. Where treatment efficacy was assessed in terms of the rates of 'stable' normalisation, the follow-up period after IFN-alpha withdrawal had to be of at least 2 months and be specifically aimed at detecting disease relapse (defined in terms of ALT elevation).
Specific interventions included in the reviewRecombinant and lymphoblastoid IFN-alpha, placebo, or no treatment.
Participants included in the reviewPatients with chronic C or non-A non-B hepatitis who had not been treated previously with IFN-alpha, who had elevated alanine aminotransferase (ALT) levels (greater than 88 IU/L or more than 1.5 times the upper normal limit) of more than 4 months' duration, and who had no history of other risk factors for liver disease. The total number of patients treated with IFN-alpha was 514 (controls, n=456).
Outcomes assessed in the reviewThe rate of remission during treatment, and the relapse-free remission after a follow-up period of 12 to 60 weeks, were assessed.
How were decisions on the relevance of primary studies made?The authors do not state how the papers were selected for the review, or how many of the authors performed the selection.
Assessment of study quality The authors do not state that they assessed validity.
Data extraction The first meta-analysis used relapse-free actuarial survival for the end points of the trials studied. For trials that reported rate of achievement of remission against time, the method of Fine et al. (see Other Publications of Related Interest no.1) was used to estimate study-specific data. Most trials failed to report this, so estimates of the number of normalised patients in each arm (stratified over time) were derived from indications in the text and from nonactuarial figures. When the remission timing was unclear, it was taken as the longest value compatible with the information in the study.
For the second meta-analysis, data were extracted from subgroups of patients who received IFN-alpha. Information derived from each study included the total number of normalised patients at the end of IFN-alpha treatment, the total number of relapses after drug withdrawal and the duration of follow-up.
Methods of synthesis How were the studies combined?The studies were combined using a meta-analysis. A 'survival' meta-analysis, originally described by Peto (see Other Publications of Related Interest no.2) and developed into a microcomputer program (META-EXE, Version 4.33), was used for the first analysis. For the second meta-analysis, Greenwood's formula, as described by Messori and Rampazzo (see Other Publications of Related Interest no.3), was used to calculate the pooled rate of maintenance of remission.
How were differences between studies investigated?The meta-analysis used equations described by Collins et al. (see Other Publications of Related Interest no.4) and Messori and Rampazzo (see Other Publications of Related Interest no.5) to assess heterogeneity, based on the chi-squared statistic.
Results of the review Twenty-one studies were included.
First meta-analysis: IFN-alpha significantly increased the rate of remission. The log-rank odds ratio during the interval from 0 to 48 weeks was 8.2 (95% confidence interval, CI: 6.2, 10.9, p<0.001). At 24 weeks, 42% of patients were normalised after IFN-alpha treatment, compared with 5% of controls; at 48 weeks this figure had increased to 50% for the treated group versus 6% of controls.
At 48 weeks, the pooled rates for ALT normalisation for the two types of IFN-alpha studied were nearly identical. There was no significant heterogeneity between the studies.
Second meta-analysis: the pooled relapse-free rate after drug discontinuation was 47%. The relapse-free rate for the 16 trials which used recombinant IFN-alpha was 43%, while for the 5 trials which used lymphoblastoid IFN-alpha it was 59%.
The global rates of success were 16 and 25% for recombinant and lymphoblastoid IFN-alpha, respectively.
The assessment for publication bias found that a total of 181 null studies would be required to alter the findings of the first meta-analysis to a non significant result.
Authors' conclusions IFN-alpha was highly effective at inducing ALT normalisation. The probability of achieving remission with treatment and maintaining remission after drug discontinuation was 17.4% at 24 weeks after IFN-alpha therapy.
CRD commentary The importance of this study is unclear. The authors admit that the clinical relevance of the end point used (ALT normalisation) is uncertain. In addition, the issue of adverse effects of IFN-alpha treatment was not addressed, nor was it systematically reported in the trials analysed. The long-term outcomes of treatment were also ignored. In view of the fact that less than 25% of the patients appeared to benefit from this treatment (according to the criterion used by the authors), while most potentially suffer adverse effects, further assessment of the long-term clinical value of this treatment and its cost-effectiveness should be carried out prior to its use outside of clinical trials.
Bibliographic details Bardelli F, Messori A, Rampazzo R, Alberti A, Martini N. Effect of recombinant or lymphoblastoid interferon-alpha on alanine aminotransferase in patients with chronic hepatitis C or chronic non-A non-B hepatitis: a meta-analysis. Drug Investigation 1995; 9(5): 239-254 Other publications of related interest 1. Fine MJ, Smith MA, Carson CA, Meffe F, Sankey SS, Weissfeld LA, et al. Efficacy of pneumococcal vaccination in adults. A meta-analysis of randomized controlled trials. Arch Intern Med 1994;154:2666-77. 2. Peto R. Why do we need systematic overviews of randomised trials. Stat Med 1987;6:233-9. 3. Messori A, Rampazzo R. Meta-analysis of clinical trials based on censored end-points: simplified theory and implementation of the statistical algorithms on a microcomputer. Comput Methods Programs Biomed 1993;40:261-7. 4. Collins R, Yusuf S, Peto R. Overview of randomised trials of diuretics in pregnancy. BMJ;290:17-25. 5. Malaguarnera P, Restuccia S, Trovato G, Siciliano R, Motta M, Trovato BA. Interferon-alpha treatment in patients with chronic hepatitis-C: a meta-analytic investigation. Clin Drug Invest 1995;9:141-9.
Indexing Status Subject indexing assigned by CRD MeSH Alanine Transaminase; Hepatitis C; Hepatitis, Chronic; Interferon Type I, Recombinant; Interferons AccessionNumber 11995001286 Date bibliographic record published 31/08/1996 Date abstract record published 31/08/1996 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
|
|
|