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Cost-effectiveness of combination therapy for naive patients with chronic hepatitis C |
Buti M, Casado M A, Fosbrook L, Wong J B, Esteban R |
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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 a combination therapy comprising interferon (IFN) and ribavirin, for the treatment of patients with chronic hepatitis C.
Economic study type Cost-effectiveness and cost-utility analyses.
Study population The study population comprised patients with moderate and mild chronic hepatitis C. Patients from the age classes of 30, 45 and 60 years, were considered.
Setting The setting was a hospital. The economic study was carried out in Spain.
Dates to which data relate The effectiveness and resource used data were obtained from studies published between 1989 and 1998. The price year was 1998.
Source of effectiveness data The effectiveness evidence was derived from a review of published studies and experts' assumptions.
Modelling A Markov model was used to estimate the clinical and economic benefits and the costs. The model simulated the natural history of the disease in different cohorts of patients with (mild or moderate) chronic hepatitis C. The simulation was conducted throughout the patient's lifetime until death due to liver-related or other causes. The transitional probabilities from histologically mild to moderate chronic hepatitis, cirrhosis, decompensated liver disease, and finally death, were used. The model was populated with data derived from the literature.
Outcomes assessed in the review The outcomes assessed in the review were the transitional probabilities among health states, the related utility values, and the treatment response data.
Study designs and other criteria for inclusion in the review Not reported. However, the authors indicated that one of the studies was a large, placebo-controlled, multicentre, randomised trial.
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 The effectiveness evidence were derived from twelve primary studies.
Methods of combining primary studies Investigation of differences between primary studies Results of the review The probability of moving from mild to moderate chronic hepatitis was 4.1%.
The probability of moving from moderate hepatitis to cirrhosis was 7.3%.
The probability of moving from cirrhosis to hepatocellular carcinoma was 1.5%, to hepatic encephalopathy 0.4%, to variceal bleeding 1.1%, and to ascites 2.5%.
The probability of moving from hepatocellular carcinoma to death was 85%, from hepatic encephalopathy to death in the first year 68%, to death in subsequent years 40%, and to liver transplantation 3.1%.
The probability of moving from variceal bleeding to death in the first year was 40%, to death in subsequent years 13%, and to liver transplantation 3.1%.
The probability of moving from ascites to death in the first year was 11%, to death in subsequent years 33%, and to liver transplantation 3.1%.
The probability of moving from liver transplantation to death in the first year was 21%, and to death in subsequent years 4.7%.
With respect to health states, the utility values were:
1 for a viral negative state;,
0.82 for mild chronic hepatitis and 0.78 for moderate chronic hepatitis;
0.7 for cirrhosis;
0.5 for liver transplantation in the first year, and 0.7 for liver transplantation in subsequent years;
0.35 for ascites;
0.3 for hepatic encephalopathy;
0.28 for variceal bleeding;
0.1 for hepatocellular carcinoma; and
0 for death.
Finally, a sustained viral response occurred in 19% of patients treated with IFN alone, 35% of those treated with the combination therapy for 6 months, and 43% of those treated with the combination therapy for 12 months.
Methods used to derive estimates of effectiveness A panel of hepatologists was consulted to support the utility data obtained from the literature. The authors made assumptions that were also used in the decision model.
Estimates of effectiveness and key assumptions The final utility values were reported in the 'Results' section. The authors assumed a constant rate of disease progression over time. Further, they assumed that a sustained response at 6 months' follow-up was equivalent to a prolonged response, and subsequently a cure. Finally, when there was no significant response, it was assumed that the monotherapy was stopped at week 4 whereas combination therapy was not stopped until week 24.
Measure of benefits used in the economic analysis The benefit measures used in the effectiveness analysis were the number of life-years saved (LYSs) and the quality-adjusted life years (QALYs) gained with each treatment. The utility values for the health states were obtained from the effectiveness analysis. Both the LYSs and QALYs were calculated for various combinations of the patient's age (30, 45 and 60 years) and the degree of hepatic lesion (mild or moderate chronic hepatitis). Compared with a healthy individual, the life expectancy of a 30-year-old patient was diminished by 7.1 years in the case of mild hepatitis, and by 16.9 years in the case of moderate hepatitis. No discount rate was applied to the future benefits.
Direct costs The future costs were discounted at a rate of 3%. The cost/quantity boundary adopted was that of the payer. The quantities of the resources used and the unit costs were not reported. The cost analysis included the costs of screening, diagnostic and laboratory testing, drugs, monitoring during therapy, follow-up, and hospitalisation. The costs were estimated from a Spanish database, and the total treatment costs were then derived using modelling. The resources used were estimated from studies published between 1989 and 1998. The price year was 1998.
Statistical analysis of costs No statistical analysis of the costs was reported.
Indirect Costs No indirect costs were included.
Currency Euros. 1 euro = 166.386 pesetas.
Sensitivity analysis Sensitivity analyses were carried out to assess the effect of variations in the following on the incremental cost-effectiveness ratios: transition probabilities (range not given), discount rate (5%), sustained response rate (various), and price of ribavirin (doubled). Further analyses aimed to identify the best- and worst- case scenarios. In the best-case scenario, the typical patient was a female aged younger than 40 years, of genotype 2 or 3, with favourable hepatitis C virus-ribonucleic acid (HCV-RNA) levels (less than or equal to 2xE06 copies/mL), and without fibrosis. The typical patient in the worst-case scenario was a male aged older than 40 years, of genotype 1, 4 or 5, with unfavourable HCV-RNA levels (greater than 2x10E06 copies/mL) and fibrosis.
Estimated benefits used in the economic analysis For patients with moderate hepatitis, the extra LYSs associated with the 12-month combined treatment were:
1.4 over the 6-month combined treatment and 4.1 over monotherapy, in a 30-year-old patient;
0.7 over the 6-month combined treatment and 2 over monotherapy, in a 45-year-old patient; and
0.2 over the 6-month combined treatment and 0.7 over monotherapy, in a 60-year-old patient.
For patients with mild hepatitis, the extra LYSs associated with the 12-month combined treatment were:
0.6 over the 6-month combined treatment and 1.7 over monotherapy, in a 30-year-old patient;
0.2 over the 6-month combined treatment and 0.7 over monotherapy, in a 45-year-old patient; and
0.1 over the 6-month combined treatment and 0.2 over monotherapy, in a 60-year-old patient.
The estimated QALYs were not reported.
Cost results The total cost of the 12-month IFN monotherapy was 3,440 euros. This included the cost of visits, laboratory tests, HCV-RNA, thyroid-stimulating hormone, pre- and post-treatment biopsies, and IFN.
The total cost of the 6-month combination therapy was 6,602 euros, whilst the total cost for the 12-month combination therapy was 10,643 euros. Both included the costs of visits, laboratory tests, haemogram, thyroid-stimulating hormone, HCV-RNA, pre- and post-treatment biopsies, pregnancy test, electrocardiogram, eye examination, IFN, and ribavirin.
The costs of the clinical states were:
172 euros for either mild or moderate chronic hepatitis C;
308 euros for cirrhosis;
1,007 euros for ascites and 7,676 euros for refractory ascites;
3,513 euros for variceal bleeding in the first year, and 1,069 euros in subsequent years;
4,268 euros for hepatic encephalopathy in the first year, and 1,089 euros in subsequent years;
4,817 euros for hepatocarcinoma;
98,584 euros for liver transplantation in the first year, and 10,887 euros in subsequent years; and
5,031 euros for death.
Synthesis of costs and benefits The costs and the benefits were combined using incremental cost-effectiveness and cost-utility analyses. A treatment was considered cost-effective when it was below the threshold of 25,000 to 28,000 euros per LYS.
Incremental cost-effectiveness analysis.
In the case of moderate chronic hepatitis C, the incremental costs per LYS of 12-month combination therapy over 6-month combination therapy 2,093 euros in a 30-year-old patient, 4,648 euros in a 45-year-old patient, and 14,551 euros in a 60-year-old patient.
The corresponding incremental costs per LYS of 12-month combination therapy over monotherapy were 880 euros in a 30-year-old patient, 2,172 euros in a 45-year-old patient, and 7,575 euros in a 60-year-old patient.
In the case of mild chronic hepatitis C, the incremental costs per LYS of 12-month combination therapy over 6-month combination therapy were 5,862 euros in a 30-year-old patient, 15,891 euros in a 45-year-old patient, and 64,421 euros in a 60-year-old patient.
The corresponding incremental costs per LYS of 12-month combination therapy over monotherapy were 2,984 euros in a 30-year-old patient, 8,515 euros in a 45-year-old patient, and 36,171 euros in a 60-year-old patient.
Incremental cost-utility analysis.
In the case of moderate chronic hepatitis C, the incremental costs per QALY with 12-month combination therapy over 6-month combination therapy were 1,374 euros in a 30-year-old patient, 2,508 euros in a 45-year-old patient, and 5,542 euros in a 60-year-old patient.
The corresponding incremental costs per QALY of 12-month combination therapy over monotherapy were 578 euros in a 30-year-old patient, 1,172 euros in a 45-year-old patient, and 2,885 euros in a 60-year-old patient.
In the case of mild chronic hepatitis C, the incremental costs per QALY of 12-month combination therapy over 6-month combination therapy were 2,603 euros in a 30-year-old patient, 4,774 euros in a 45-year-old patient, and 9,939 euros in a 60-year-old patient.
The corresponding incremental costs per QALY of 12-month combination therapy over monotherapy were 1,325 euros in a 30-year-old patient, 2,558 euros in a 45-year-old patient, and 5,581 euros in a 60-year-old patient.
It was stated that the sensitivity analyses showed that, at a discount rate of 5% and with moderate disease, the 12-month combination therapy remained cost-effective. If the price of ribavirin were doubled, it was stated that the 12-month combination therapy remained cost-effective for patients under 59 years old with moderate chronic hepatitis, and for those under 43 years old with mild hepatitis. Analyses of the worst- and best-case scenarios indicated that the 12-month combination therapy became, at best, cost-saving.
Authors' conclusions The 12-month combination therapy was the most cost-effective strategy for patients with moderate hepatic lesions, regardless of their age. However, for patients with milder disease, the 12-month combination therapy was only the most cost-effective strategy for patients under 50 years of age. In older patients with mild disease, the 6-month combination therapy was the preferred option.
CRD COMMENTARY - Selection of comparators The comparator was selected from those therapies available for the treatment of patients with moderate or mild hepatitis C. Monotherapy using IFN represented the routine therapy, while combined therapy (both 12 and 6 months) was the recently introduced technology. You should consider whether they represent widely used interventions in your own setting.
Validity of estimate of measure of effectiveness The effectiveness evidence was derived from a review of the literature. No information was provided on how the studies were identified, or the criteria on which they were selected and assessed. In addition, details of the design of the primary studies were not reported. Further, many estimates were obtained from several studies, but the method used to combine them was not reported. It was unclear whether the authors considered the impact of differences between the primary studies. It is worth highlighting that, in order to take into account subgroup populations, the analysis was conducted for patients with different disease severity grades (mild and moderate) and different ages.
Validity of estimate of measure of benefit Two benefit measures (life-years gained and QALYs) were used in the analysis. Both were derived from the decision model, which appears to have been appropriate for evaluating the treatment of patients with hepatitis C. With respect to QALYs, the utility values were obtained from final estimates assigned by a panel of hepatologists on the basis of published studies. To take into account potential uncertainty around these estimations, several sensitivity analyses were carried out. The model appeared quite robust to any variation.
A proper incremental analysis was not performed. Such an analysis involves measuring the incremental gain in benefit (LYSs or QALYs) for the increase in cost when moving from one technology to the next most expensive one. Therefore, the 12-month combination therapy should have been compared with the 6-month combination therapy, which it was. However, the 6-month combination therapy should have also been compared with monotherapy, which it was not. There are several assumptions required for this kind of analysis, but there is insufficient space here to describe them in detail. Assuming that, within a fixed budget, more benefit could be gained per unit cost increase by adopting the 6-month combination therapy instead of monotherapy, than by moving from the 6- to the 12-month combination therapy, one would prefer the 6-month to the 12-month option. It can be shown in this paper that this is the case, at least in some scenarios. In particular, for a patient who is 30 years old with moderate disease, for which the authors recommend the 12-month combination therapy.
Validity of estimate of costs The costs were mainly estimated using actual data derived from Spanish databases. Therefore, the cost estimates were quite specific to the study setting. In addition, the costs were treated deterministically and sensitivity analyses were only conducted on the price of ribavirin. Finally, the unit costs were not reported separately from the resources used, thus hindering the generalisability of the results.
Other issues The issue of generalisability to other settings was not explicitly discussed. It was, however, implicitly addressed by performing some sensitivity analyses and simulating the best and worst scenarios. The authors made few comparisons of their findings with those from others studies. However, the 12-month combination therapy compared favourable with the cost-effectiveness of other widely accepted medical interventions. The results were reported selectively in the sensitivity analysis and, as explained above, the claim regarding cost-effectiveness in the authors' conclusions is not entirely supported.
Implications of the study The authors pointed out that although the 12-month combination therapy was highly cost-effective, several factors need to be taken into account. First, several adverse effects were associated with the treatment. Second, the positive response to the therapy decreases as the age of the patient increases. Again, the claim regarding the cost-effectiveness was not entirely supported, and the 6-month therapy might be preferred in more scenarios.
Bibliographic details Buti M, Casado M A, Fosbrook L, Wong J B, Esteban R. Cost-effectiveness of combination therapy for naive patients with chronic hepatitis C. Journal of Hepatology 2000; 33(4): 651-658 Other publications of related interest Comment In: Journal of Hepatology 2000;33(4):664-6.
Indexing Status Subject indexing assigned by NLM MeSH Adult; Age Factors; Antiviral Agents /economics /therapeutic use; Computer Simulation; Cost-Benefit Analysis; Disease Progression; Drug Therapy, Combination; Hepatitis C, Chronic /drug therapy /economics /physiopathology; Humans; Life Expectancy; Markov Chains; Middle Aged; Spain AccessionNumber 22000001626 Date bibliographic record published 31/07/2002 Date abstract record published 31/07/2002 |
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