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Cost-effectiveness of 24 or 48 weeks of interferon alpha-2b alone or with ribavirin as initial treatment of chronic hepatitis C |
Wong J B, Poynard T, Ling M H, Albrecht J K, Pauker S G |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology The use of 24 or 48 weeks' interferon (IFN) alpha-2b, either alone or with ribavirin, as initial treatment for chronic hepatitis C. The doses for each treatment were not reported.
Study population The study population comprised patients with histologically chronic hepatitis C virus (HCV).
Setting The setting was secondary care. The economic analysis was carried out in the USA.
Dates to which data relate The effectiveness data were gathered from studies published between 1997 and 1998. The resource data were gathered from studies published between 1995 and 1999. The price year was 1999.
Source of effectiveness data The effectiveness data were derived from a review of the literature review plus authors' estimates.
Modelling A Markov-based decision analytic model was created using Decision Maker 7.0 software to simulate the costs and health outcomes assigned to each treatment strategy. Hypothetical patients were extrapolated from 1,744 patients enrolled in two large clinical trials, and were matched for age and initial liver history. Sub-group analyses were conducted according to the gender, site (USA or International), initial histology, viral load (<=2 million or > 2 million), genotype (1 or 2&3) and frequency of favourable response characteristics (0 or 1; 2 or 3; 4 or 5). The four health states described were mild hepatitis, moderate hepatitis, cirrhosis and death. The lifetime horizon was used. Annual cycles were used.
Outcomes assessed in the review The outcomes assessed in the review and used as model inputs were
the sustained viral response rate with antiviral therapies,
the lifetime incidence of decompensated cirrhosis or hepatocellular carcinoma, and
the relative risk of liver-related death.
Study designs and other criteria for inclusion in the review The two large clinical trials were randomised placebo-controlled trials that compared 48 weeks (and 24 weeks in the US trial) of IFN alone and a placebo with the combination of ribavirin and IFN. The natural history of HCV infection was derived from published computer simulation models.
Sources searched to identify primary studies Criteria used to ensure the validity of primary studies Methods used to judge relevance and validity, and for extracting data Number of primary studies included Two primary studies were included in the analysis of treatment efficacy. Two published studies were used to model the natural history of HCV infection.
Methods of combining primary studies The authors combined data for 1,744 patients enrolled in the two clinical trials. Data on characteristics and sustained viral response rates were presented as mean values, along with chi-squared or Kruskall-Wallis tests for statistical significance.
Investigation of differences between primary studies Results of the review The data about the natural history of HCV infection were not reported.
The sustained viral response rate (24 weeks after treatment) was:
40.6% for patients receiving 48 weeks' combination therapy,
33.1% for patients receiving 24 weeks' combination therapy,
16.3% for patients receiving 48 weeks' IFN alone, and
5.6% for patients receiving 24 weeks' IFN alone, (p=0.001).
Combination therapy compared with IFN alone for 48 weeks should decrease the relative risk of liver-related death and the lifetime incidence of decompensated cirrhosis or hepatocellular by 15 to 28%. It should also decrease the absolute risk of these complications by 2 to 10%.
Methods used to derive estimates of effectiveness The authors made several assumptions when estimating the outcomes.
Estimates of effectiveness and key assumptions The authors made the following assumptions:
a sustained viral response indicated no further progression of liver disease caused by HCV;
patients who lose HCV either spontaneously or from treatment would have a greatly reduced likelihood of developing progressive liver disease;
combination therapy had twice the negative impact on quality of life than did IFN alone;
patients who relapsed after initial treatment would receive no further treatment;
there would be no further benefit to patients who did not complete the 12 months of IFN alone or 24 weeks of combination therapy, and then the treatment would be discontinued; and
the likelihood of pregnancy was 11% when using condoms for contraception.
The authors also assumed a more benign prognosis for patients with bridging fibrosis than most likely occurs. The authors did not consider liver transplantation for hepatocellular carcinoma.
Measure of benefits used in the economic analysis The benefit measures used were the number of life-years saved and the number of discounted quality-adjusted life-years (QALYs) gained. An expert panel familiar with liver disease and IFN treatment assessed utilities using the time trade-off and standard reference gamble techniques. The benefits were discounted at a rate of 3%.
Direct costs Although a societal perspective was adopted, only the direct costs were included. The direct costs were for antiviral therapies, office visits, laboratory testing, reproduction services and post-treatment costs. The costs of office visits and laboratory testing covered office visits and laboratory testing for routine visits and adverse events. The cost of reproduction services included pregnancy tests, condoms, pregnancy and elective abortions. The authors determined the frequency of clinic visits using product labelling rather than the visit frequency that occurred in the trial. The drug costs were based on average wholesale costs. The post-treatment costs were derived from published variable treatment costs and health resource use frequencies from an expert panel. All non drug costs were expressed in 1995 dollars and were inflated to 1999 dollars using the medical care component of the Consumer Price Index. The resource quantities and the costs were not reported separately. The lifetime horizon was used. The costs were discounted at an annual rate of 3%.
Statistical analysis of costs No statistical analysis of the costs was performed.
Indirect Costs The indirect costs were not included in the analysis.
Sensitivity analysis One-way sensitivity analyses were performed for each parameter over a wide range (the results were not shown). In the sensitivity analysis, the incremental cost-effectiveness ration (ICER) was calculated for combination therapy compared with no antiviral therapy.
Estimated benefits used in the economic analysis The unadjusted life expectancy was 26.6 years with 24 weeks' IFN alone, 28.2 years with 48 weeks' IFN alone, 29.3 years with 24 weeks' combination therapy, and 30.0 years with 48 weeks' combination therapy.
The IFN alone therapy for 24 (or 48) weeks resulted in 14.5 (or 15.4) discounted QALYs. The combination therapy for 24 (or 48) weeks resulted in 16.0 (or 16.4) discounted QALYs.
On average, combination therapy should increase life expectancy by 1.4 to 2.0 years. It should increase quality-adjusted life expectancy by 1.7 to 2.5 QALYs.
Cost results The total costs (discounted) of therapy with IFN alone were $16,700 for 24 weeks and $15,000 for 48 weeks. The total costs (discounted) of combination therapy were $18,300 for 24 weeks and $20,900 for 48 weeks.
Synthesis of costs and benefits IFN alone for 24 weeks was always dominated, costing more and yielding a lower life expectancy.
Compared with IFN alone for 48 weeks, 24 (or 48) weeks' combination therapy had a marginal cost-effectiveness ratio of $5,400 (or $7,700) per discounted QALY gained (not shown).
Compared with 24 weeks' combination therapy, 48 weeks' combination therapy should prolong life expectancy by 0.6 years at an ICER of $7,700 per discounted QALY gained.
The results were robust in the sensitivity analysis.
When discounting at 5%, the ICER of 24 (or 48) weeks' combination therapy versus 48 weeks' IFN alone rose to $8,300 (or $9,900) per discounted QALY gained (not shown).
For each univariate sub-group, 24 weeks' combination therapy remained cost-effective at under $7,300 per discounted QALY gained when compared with 48 weeks' IFN alone.
Combination therapy for 48 weeks was cost-effective when compared with 24 weeks' combination therapy for all univariate sub-groups, except for genotype 2 or 3.
Compared with no antiviral therapy, 48 weeks' combination therapy should increase life expectancy by 3 years at an ICER of $3,200 per discounted QALY gained.
Authors' conclusions For patients with chronic hepatitis C virus (HCV) infection, 24 or 48 weeks' ribavirin and interferon (IFN) should prolong life and be cost-effective when compared with 48 weeks' IFN alone.
CRD COMMENTARY - Selection of comparators A justification was given for the comparator used (IFN), which referred to the standard treatment strategy for HCV infection. You should consider whether this is a widely used practice in your own setting.
Validity of estimate of measure of effectiveness The authors reported that two randomised placebo-controlled trials were used as the primary studies. They did not report whether a systematic review of the literature was conducted, but it is likely that few other randomised controlled trials on combination therapy for HCV infection were available. The authors used estimates from published computer simulation models to estimate transition probabilities for the natural history of HCV infection. The validity of those models was not reported. Data on transition probabilities (natural history) were not reported in the "Results of the Review" section. Strong assumptions, such as no retreatment and no benefit from uncompleted treatment, were made. However, most of the assumptions were tested in the sensitivity analyses. The adherence to HCV treatment was not evaluated. This parameter might have influenced the effectiveness results.
Validity of estimate of measure of benefit The estimation of benefits was modelled. The decision analysis model used to derive a measure of heath benefit was appropriate, even though the authors made several model assumptions. The method used to derive the life expectancy was also appropriate. On the other hand, utility weights were derived from experts' opinion. A more appropriate approach would have been to derive the utilities directly from patients' preferences. This fact may limit the relevance of the QALY measurements.
Validity of estimate of costs The authors reported that they adopted a societal perspective, but they did not include the indirect costs. The exclusion of such costs might have biased the results in favour of the combination therapy (important psychological costs relative to pregnancy or abortion). The resource quantities and the unit costs were not reported separately. Other costs were also excluded from the analysis. For example, the costs of future liver biopsies, surveillance for hepatocellular carcinoma, and further therapy for non-responders. Hence, the disease-related costs were underestimated. Health resource use was not based on actual data but on published sources. These facts would hinder the replication of the analysis in other settings. A sensitivity analysis was performed on the costs, but the ranges used and results were not reported in detail. Discounting was, however, performed.
Other issues The generalisability of the results was not discussed in detail. The authors did not compare their findings with those from other studies. The authors highlighted some limitations of their study and do not appear to have reported their results selectively.
Implications of the study In the absence of a randomised controlled study based on long-term follow-up, cost-effectiveness analyses based on decision models are required. This study suffered from limitations essentially due to uncertainties. However, this was an interesting and relevant evaluation of the cost-effectiveness of combination therapy of HCV infection. This study should be re-analysed when new data are available (see Other Publications of Related Interest).
Source of funding Supported by a grant from Schering-Plough Corporation, Kenilworth (NJ), USA.
Bibliographic details Wong J B, Poynard T, Ling M H, Albrecht J K, Pauker S G. Cost-effectiveness of 24 or 48 weeks of interferon alpha-2b alone or with ribavirin as initial treatment of chronic hepatitis C. American Journal of Gastroenterology 2000; 95(6): 1524-1530 Other publications of related interest Sagmeister M, et al. A pragmatic and cost-effective strategy of a combination therapy of interferon alpha-2b and ribavirin for the treatment of chronic hepatitis C. European Journal of Gastroenterology and Hepatology 2001;13:483-8.
Buti M, et al. Cost-effectiveness of combination therapy for naive patients with chronic hepatitis C. Journal of Hepatology 2000;33:651-8.
Younossi ZM, et al. Cost effectiveness of interferon alpha 2b combined with ribavirin for the treatment of chronic hepatitis C. Hepatology 1999;30:1318-24.
Indexing Status Subject indexing assigned by NLM MeSH Adult; Antiviral Agents /administration & Cost-Benefit Analysis; Drug Therapy, Combination; Female; Hepatitis C, Chronic /drug therapy; Humans; Interferon-alpha /administration & Life Expectancy; Male; Middle Aged; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Recombinant Proteins; Ribavirin /therapeutic use; Sensitivity and Specificity; Time Factors; dosage /economics /therapeutic use; dosage /economics /therapeutic use AccessionNumber 22000001071 Date bibliographic record published 31/08/2004 Date abstract record published 31/08/2004 |
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