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Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review |
Shepherd J, Waugh N, Hewitson P |
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Authors' objectives To review the clinical effectiveness and cost-effectiveness of combination therapy (interferon alpha and ribavirin) compared with monotherapy (interferon alpha alone) in patients with chronic hepatitis C.
Searching The Cochrane Controlled Trials Register, the Cochrane Database of Systematic Reviews, DARE, MEDLINE and EMBASE were searched from 1996 (Cochrane Controlled Trials Register from 1993) to the end of 1999. A detailed search strategy was reported in Appendix 1 of the review. The bibliography of studies identified from a previous review on combination therapy (see Other Publications of Related Interest nos.1 and 2) were examined, as were company submissions made to the National Institute of Clinical Excellence by Schering-Plough and Roche.
Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs) and systematic reviews of primary studies were included.
Specific interventions included in the reviewStudies were included if they compared interferon alpha (monotherapy) with interferon alfa plus ribavirin (combination therapy). The dosing regimens used in the studies included in the review were 3, 4.5 or 6 mU interferon alpha (3 times weekly), and 800 to 1,200 mg/day ribavirin. The duration of the included studies ranged from 24 weeks to 14 months.
Participants included in the reviewStudies of participants with chronic hepatitis C were included. The participants in the included studies were previously untreated patients, patients not treated previously with interferon, treatment relapsers, and nonresponders.
Outcomes assessed in the reviewThe authors did not specify any inclusion or exclusion criteria with respect to outcome measures. The outcome measures used in the included studies were: hepatitis C viral RNA, as determined by polymerase chain reaction; liver enzymes indicative of inflammation, i.e. serum alanine aminotransferase; histology in terms of the Hepatitis Activity Index; adverse events; compliance, according to a pill count; and haemoglobin concentration.
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 reviewers performed the selection.
Assessment of study quality The included RCTs were quality assessed according to the UK Critical Appraisal Skills Programme guidelines (see Other Publications of Related Interest no.3), and the scoring checklist of Jadad et al. (see Other Publications of Related Interest no.4). The quality assessment was performed by one reviewer and checked by a second. Any disagreements were resolved through discussion.
Data extraction Data on study design, participants, outcome measures and results were extracted using a standard template, and were reported in Appendix 2 of the review. The authors do not state how many reviewers were involved in this process.
Methods of synthesis How were the studies combined?A narrative synthesis was undertaken initially. Subsequently, a meta-analysis of 15 RCTs was conducted using a random-effects model. Subgroup analysis was conducted according to patient group, i.e. interferon-naive, relapsers, and nonresponders to previous interferon treatment.
How were differences between studies investigated?For the purposes of the meta-analysis, heterogeneity was investigated using the chi-squared test.
Results of the review The authors stated that a total of 19 RCTs and 2 meta-analyses were included in the review. The total numbers of participants for each of the 2 meta-analyses were 1,744 and 344. It was unclear how many participants were included in the RCTs; the extracted data were only reported for 12 RCTs with a total of 3,367 participants.
The results of the included RCTs and meta-analyses indicated that combination therapy produced larger sustained response rates than monotherapy.
Following submission of the review, a meta-analysis was conducted based upon 24 weeks of treatment and an outcome measure of sustained complete response, as indicated by the disappearance of viral RNA at 6 months post-treatment. The results were as follows.
The odds ratio (OR) was 4.90 (95% confidence interval, CI: 2.63, 9.13) for interferon-naive patients, 5.81 (95% CI: 1.77, 19.06) for relapsers and 9.14 (95% CI: 3.42, 10.59) for nonresponders, all of which were statistically significant. The overall OR was 6.10 (95% CI: 3.52, 10.59). A funnel plot suggested no publication bias.
The proportions of interferon-naive participants achieving a sustained virological response after 24 weeks of treatment were 32% (95% CI: 27, 37) with combination therapy and 8% (95% CI: 5, 11) with interferon monotherapy. The corresponding values in those patients who had relapsed after previous monotherapy were 40% (95% CI: 35, 45) and 6% (95% CI: 3, 9), respectively. In those who did not respond to a first course of interferon (nonresponders), combination therapy was less effective than monotherapy, with rates of 15% (95% CI: 12, 19) and 0.8% (95% CI: 0.3, 2), respectively.
Cost information A 4-week cycle of interferon alfa at 3 mU (3 times weekly) cost £194, whilst for ribavirin (at an average of the recommended dose range) the cost was £543, excluding monitoring costs.
Cost-effectiveness and cost-utility analyses were conducted.
Cost-utility.
For interferon-naive patients, the additional discounted cost per quality-adjusted life-year (QALY) gained from treatment with combination therapy for 6 months, compared with interferon monotherapy for 12 months, was £6,839. If providing 6 months of combination therapy as a first-line treatment, the marginal cost per QALY was £7,578. A move from 6 to 12 months of combination therapy incurred a marginal discounted cost per QALY of £36.971. For patients who had relapsed following a previous course of interferon alfa, the additional discounted cost per QALY gained from treatment with combination therapy for 6 months, compared with monotherapy for 6 months, was £3,503.
Cost-effectiveness.
For interferon-naive patients, the cost information were based on the results obtained from the synthesis of two trials. The additional figures presented in brackets were based on results from only one of these trials; these indicate the sensitivity of the cost per life-year gained (LYG) to slight changes in response.
The additional discounted cost per LYG from treatment with interferon monotherapy for 12 months, compared with no active treatment, was £12,369 (£10,060). The additional discounted cost per LYG gained from treatment with combination therapy for 6 months, compared with interferon monotherapy for 12 months, was £10,086 (£5,638). The additional discounted cost per LYG from treatment with interferon plus ribavirin (combination therapy) for 6 months, compared with combination therapy for 12 months, was £53,213 (£26,307). The additional discounted cost per LYG from treatment with combination therapy for 6 months, compared with no active treatment, was £19,392 (£18,385).
For patients who have relapsed after monotherapy, the additional discounted cost per LYG gained from treatment with combination therapy for 6 months, compared with monotherapy for 12 months, was £5,173. Authors' conclusions The results of this review showed that there was a benefit associated with combination therapy, and that it could be a cost-effective treatment option. 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 further 6 months of treatment was recommended in the literature for those who have fewer than four favourable factors. However, for those with three to four factors, further treatment is unlikely to derive any additional benefit and should thus cease. The most cost-effective option is to treat those with one to two favourable factors for a further 6 months.
The re-treatment of nonresponders to interferon monotherapy with combination therapy is unlikely to be cost-effective. As combination therapy is becoming increasingly accepted as first-line therapy, it is unlikely that there will be many monotherapy nonresponders or relapsers seeking re-treatment in the future. Interferon monotherapy should only be prescribed to patients in whom combination therapy is contraindicated.
CRD commentary The review question was defined clearly, and appropriate inclusion criteria were specified in terms of intervention, participant characteristics and study design. No outcome measures were specified in the inclusion criteria; however, included studies used similar measures.
The search strategy was comprehensive and there were no restrictions on publication language. However, there was no specific attempt to identify unpublished data or (in the main review) to check for publication bias. The funnel plot, reported as part of a subsequent meta-analysis, did not suggest the presence of publication bias.
The methodological quality of included studies was rigorously assessed using a published, validated scoring system, and the results of this assessment were reported in Appendix 4 of the review. It was not unclear whether the quality scores had been used either to exclude or to give differential weight to studies.
Limited details of the characteristics of the participants were reported. There were no details of either the gender or age mix of the participants, and the exclusions for co-morbid conditions were detailed for only three of the included studies. It is, therefore, difficult to make any judgement about the generalisability of the findings of this review to the population of patients with chronic hepatitis C.
The narrative synthesis was clear and concise, and the results were also presented in a tabular format. The meta-analysis was appropriate and rigorously conducted, though it is unclear why a meta-analysis should only have been conducted as an adjunct to the initial report. The sustained response rates as determined in the meta-analysis (Appendix 5) do not agree with those reported in the 'Executive summary' of the original review.
The authors' conclusions follow readily from the results, as reported in the review.
Implications of the review for practice and research Practice: The authors state that it is recommended that all treatment-naive patients receive 6 months of combination therapy as a first-line treatment, with those who have fewer than four factors predictive of a good response receiving a further 6 months.
Interferon monotherapy should only be prescribed to patients in whom combination therapy is contraindicated.
It is appropriate to offer 6 months of combination therapy to patients who have relapsed after a previous course of interferon.
Re-treatment of nonresponders to interferon monotherapy with combination therapy is unlikely to be cost-effective.
Research: The authors do not state any implications for further research, but ongoing trials of potential interest are highlighted.
A longer acting version of interferon alfa, pegylated interferon, is currently being evaluated in dose-ranging studies with ribavirin.
A review of pegylated interferon in chronic hepatitis C patients is planned by the Cochrane Hepato-Biliary Group.
There have been some trials of combination treatment with amantadine versus combination treatment with ribavirin. A trial of combination therapy in mild hepatitis C patients has been funded by the UK NHS Health Technology Assessment programme; this is due to report in 2003.
Funding NHS R&D Health Technology Assessment (HTA) Programme, project number 00/09/01.
Bibliographic details Shepherd J, Waugh N, Hewitson P. Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review. Health Technology Assessment 2000; 4(33): 1-67 Other publications of related interest 1. Scottish Health Purchasing Centre (SHPIC). Ribavirin and interferon alfa in the treatment of chronic hepatitis C. Aberdeen: SHPIC; 1998. 2. Scottish Health Purchasing Centre (SHPIC). Ribavirin and interferon alfa in the treatment of chronic hepatitis C - an update. Aberdeen: SHPIC; 1999. 3. Critical Appraisal Skills Programme. Making sense of evidence about effective healthcare. Oxford: CASP; 1999. 4. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12.
Indexing Status Subject indexing assigned by NLM MeSH Antiviral Agents /therapeutic use; Drug Therapy, Combination; Female; Great Britain; Hepatitis C, Chronic /diagnosis /drug therapy /economics; Humans; Interferon-alpha /therapeutic use; Male; Prognosis; Randomized Controlled Trials as Topic; Ribavirin /therapeutic use; Treatment Outcome AccessionNumber 12001008013 Date bibliographic record published 30/04/2002 Date abstract record published 30/04/2002 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. |
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