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Cost effectiveness of interferon A or peginterferon A with ribavirin for histologically mild chronic hepatitis C |
Grieve R, Roberts J, Wright M, Sweeting M, DeAngelis D, Rosenberg W, Bassendine M, Main J, Thomas H |
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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 study compared two management options, the provision and non provision of antiviral therapy, for patients with mild chronic hepatitis C.
Provision of antiviral therapy: interferon (IFN) alpha-2b (3 million units thrice weekly), or a combination of pegIFN alpha and ribavirin (1,000 or 1,200 mg/day), were administered for a maximum of 52 weeks.
No provision of antiviral therapy: patients wait and antiviral treatment is administered only to patients who progress to moderate disease.
Study population As this was a modelling study, the population comprised two hypothetical cohorts with the characteristics of UK patients with mild hepatitis C. (Wright et al. 2006, see 'Other Publications or Related Interest' below for bibliographic details). Patients were assumed to be aged 40 years, 60% were men and half of the target population was genotype 1. No further exclusion or inclusion criteria were reported.
Setting As this was a modelling study, the setting was not explicitly stated at the outset. However, it was reported that transition probabilities were retrieved from a secondary care setting. The economic study was carried out in the UK.
Dates to which data relate The effectiveness data were retrieved from studies published between 1997 and 2006. The resource use data were retrieved from a study published in 2005, while resources used for patients with moderate disease, cirrhosis and decompensated cirrhosis were retrieved from an observational study published in 2006. The costs were obtained from official sources published in 2002 and 2003; further relevant costs were directly obtained from health centres included in the study, although the dates were not reported. All costs were reported for the price year 2002/03.
Source of effectiveness data The effectiveness data were derived from a review and synthesis of published data.
Modelling The authors constructed a Markov model to estimate the lifetime cost-effectiveness of the two management options. Patients with mild chronic hepatitis C who entered the model could enter one of ten possible health states. These health states were antiviral treatment, sustained virological response (SVR), mild disease, moderate disease, cirrhosis, hepatocellular carcinoma (HCC), decompensated cirrhosis, liver transplant, post liver transplant and liver-related death. Details of the model were given in a published study (Grieve et al. 2002, see 'Other Publications of Related Interest' below for bibliographic details). The time horizon of the model was 50 years.
Outcomes assessed in the review The following input parameters were used in the model:
the annual transition probability from mild to moderate disease, from moderate disease to cirrhosis, from cirrhosis to decompensated cirrhosis, from cirrhosis or decompensated cirrhosis to HCC, and from decompensated cirrhosis to death;
the annual probability of all-cause death;
the duration of treatment; and
for patients with mild or moderate disease, the proportion of patients having SVR after receiving treatment.
Study designs and other criteria for inclusion in the review No inclusion or exclusion criteria for the review were reported. Randomised controlled trials (RCTs) and observational studies were included in the review.
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 Overall, the authors used 6 primary studies as sources of effectiveness evidence.
Methods of combining primary studies It appears that the results from individual primary studies have not been combined.
Investigation of differences between primary studies It appears that differences between the primary studies have not been investigated.
Results of the review The annual transition probabilities were expressed as the mean value with standard error (in brackets).
The annual transition probabilities were:
from mild to moderate disease, 0.025 (0.004);
from moderate disease to cirrhosis, 0.037 (0.007);
from cirrhosis to decompensated cirrhosis, 0.039 (0.01);
from cirrhosis or decompensated cirrhosis to HCC, 0.014(0.01);
from decompensated cirrhosis to death, 0.13 (0.01);
from HCC to death, 0.43 (0.03); and
all-cause death, 0 to 0.19.
The mean duration of IFN alpha-2b and ribavirin treatment was 37.8 (standard deviation, SD=15.6) weeks. The maximum duration was 52 weeks.
The proportions of mild hepatitis C patients having SVR when receiving combination of IFN alpha-2b and ribavirin were 33% overall, 18% for patients with genotype 1 and 49% for patients with genotype non-1.
Measure of benefits used in the economic analysis The authors used both quality-adjusted life-years (QALYs) and HRQOL as the measures of benefit in the economic analysis. Data on HRQOL were obtained using values for patients with mild hepatitis (n=196) from a UK-based RCT (Wright et al. 2005, see 'Other Publications of Related Interest' below for bibliographic details). The patient's HRQOL was assessed using the EQ-5D questionnaire at each patient's visit during the trial. Each patient's health state description was valued using tariffs from a general population survey. A separate observational study was used to evaluate HRQOL for patients with moderate disease (n=175), as well as patients with decompensated cirrhosis and hepatitis-related HCC (n=64). HRQOL for these patients was retrospectively evaluated using a postal questionnaire. Details were reported in another study (Wright et al. 2006). HRQOL was subsequently weighted by life expectancy to derive QALYs. All outcomes were appropriately discounted.
Direct costs Summary health service costs were reported for each strategy. These comprised the summary cost of mild disease, the treatment of mild and moderate disease, post-SVR costs, the cost of moderate disease, cirrhosis, decompensated disease, HCC and the cost of liver transplantation. The unit costs were not reported. Resource use was based on actual data and was derived from a sub-population analysis on patients who were included in the UK RCT (Wright et al. 2005). Resource use data were collected for each patient with mild disease who attended centres included in the study that were located in London, Newcastle-upon-Tyne and Southampton. Additional resources use data were derived from the observational study (Wright et al. 2006). The costs were based on actual data and were derived either from official published sources (e.g. the British National Formulary) or directly from the finance departments of the centres located in London, Newcastle-upon-Tyne and Southampton. As the time horizon of the model was 50 years, the costs were appropriately discounted. All costs were reported for the price year 2002/03.
Statistical analysis of costs Each annual summary cost category was reported as a mean with SD. However, no further statistical analysis of the costs was conducted.
Indirect Costs Inline with the perspective adopted, the indirect costs were not included in the analysis.
Currency UK pounds sterling (). The costs were also appropriately converted to US dollars ($) but the exchange rate was not reported.
Sensitivity analysis Multivariate Monte Carlo sensitivity analyses were conducted to investigate the robustness of the cost-effectiveness results to variability in the model input parameters, and also to estimate cost-effectiveness acceptability curves (CEACs). To estimate the cost-effectiveness of the interventions, a threshold of 30,000 per QALY gained was used. Further sensitivity analyses were conducted to investigate variability in the input parameters. Treatment duration was reduced from a maximum of 52 weeks to a maximum of 24 weeks for patients with genotype non-1 and to 12 weeks for patients documented as having insufficient change in viral load at week 12. The time horizon for estimates of HRQOL was reduced to 30 years. The proportion of patients experiencing SVR after treatment with IFN alpha-2b and ribavirin was increased to 28% for genotype 1 patients and to 66% for patients with genotype non-1. Finally, variability in the transition probabilities was also investigated. The ranges used in the sensitivity analyses were mainly derived from the literature.
The authors also tested the use of a combination of pegIFN alpha-2b and ribavirin (instead of IFN alpha-2b) by simply altering the effectiveness and the price of the treatment option, keeping all other base-case analysis parameters constant.
Estimated benefits used in the economic analysis Mean HRQOL was 0.77 for mild cases at baseline, 0.66 during treatment, 0.82 after SVR, 0.66 for moderate disease, 0.55 for cirrhosis and 0.45 for decompensated disease, HCC and liver transplantation.
For a mild disease genotype 1 patient aged 40 years, treatment with IFN alpha-2b and ribavirin resulted in a mean increase in QALYs of 0.17 compared with patients without treatment. For patients with genotype non-1, combination treatment resulted in a gain of 0.61 QALYs compared with patients without treatment.
Cost results The total costs were reported for a mild stage patient aged 40 years. All costs were appropriately discounted at an annual rate of 3.5%.
In the combination treatment group (IFN alpha-2b and ribavirin), the mean cost for a genotype 1 patient was 14,833 while the equivalent cost in the no treatment group was 10,472. The difference was 4,361.
For genotype non-1 patients, the mean cost was 11,343 in the treatment group and 8,561 in the no treatment group. The difference was 2,782.
Synthesis of costs and benefits An incremental cost-effectiveness analysis was conducted.
IFN alpha-2b and ribavirin resulted in mean incremental lifetime costs of 3,647 ($5,716) and a mean additional cost per QALY gained of 9,535 ($14,946) in comparison with no treatment. For patients with genotype 1, treatment at mild stage resulted in a cost per QALY gained of 25,188 ($39,480), while for patients with genotype non-1 the cost per QALY gained was 4,533 ($7,108).
The CEACs demonstrated that, at a threshold of 30,000 per QALY, the probability that IFN alpha-2b and ribavirin at mild stage was cost-effective was 0.86 for patients (40 years) with genotype non-1 and 0.52 for patients with genotype 1. Treatment appears to have been cost-effective for patients aged between 20 and 40 years in either genotype group, while it was not cost-effective for patients aged 65 years with genotype 1 (probability 0.28 and a cost of 53,017 ($83,099) per QALY).
The sensitivity analyses demonstrated that the results were robust for patients with genotype non-1. However, for patients with genotype 1, the results were sensitive to changes in health utility gain. Namely, treatment resulted in a cost per QALY gained greater than 30,000 if the gain in HRQOL was assumed to be zero or relatively small. Accordingly, the results were sensitive to changes in transition probabilities. Finally, it was demonstrated that the lowering of treatment duration to a maximum of 24 weeks for patients with genotype non-1, or the use of viral kinetics to adjust treatment to early response for either genotype group, resulted in a decreased cost per QALY gained.
The use of pegIFN alpha-2b and ribavirin proved to be a more cost-effective treatment at a mild stage compared with a moderate stage of the disease.
Authors' conclusions For patients with chronic hepatitis C, it is more cost-effective to provide antiviral treatment at a mild rather than a moderate stage. However, antiviral treatment is more cost-effective for mild patients with genotype non-1 than with genotype 1. In particularly, treatment is not cost-effective for patients aged 65 years or older with genotype 1. Finally, it was reported "the cost effectiveness of treating mild hepatitis C with peginterferon (IFN) alpha rather than interferon alpha in combination with ribavirin depends on the threshold willingness to pay for a QALY (quality-adjusted life-year) gained".
CRD COMMENTARY - Selection of comparators The selection of the comparators was justified with reference to the documented effectiveness in patients with chronic hepatitis C. The specific antiviral therapy was also recommended by the National Institute of Clinical Excellence as a treatment option for patients with moderate disease. You should decide if this is a widely used technology in your own setting.
Validity of estimate of measure of effectiveness No systematic review of the literature was undertaken. Although this is common practice with models, it does not always ensure that the best data available are used in the model. The authors appear to have used data from the available studies selectively and the impact of differences between the primary studies was not investigated. However, the authors carried out several sensitivity analyses relating to the efficacy estimates. These analyses help to improve both the internal validity and the generalisability of the study by demonstrating the robustness of the results to changes in the base-case estimates.
Validity of estimate of measure of benefit The authors used health utility (QALYs) as the measure of benefit in the economic analysis. Patient values were elicited using the EQ-5D questionnaire.
Validity of estimate of costs The cost analysis was conducted from the perspective of the health service. It appears that all the relevant cost categories have been included in the analysis. The quantities of resources used seem to have been recorded appropriately. However, the authors only reported summary annual costs, making it impossible to determine which cost items and equivalent unit costs were included in the analysis. This means that it would be difficult to rework the analysis in other settings. The statistical analysis of the costs and resources was restricted, and no sensitivity analysis of the costs or quantities was conducted to assess the robustness of the estimates used. This may introduce some uncertainty into the results. The price year was reported and discounting was appropriately conducted.
Other issues The authors compared their findings with those from other studies. Differences between them were mainly attributed to different study populations and different outcomes assessed. To enhance the generalisability of the results to other settings, the study findings were presented in a systematic way and separate results were reported according to genotype and age. The study enrolled patients with mild chronic hepatitis C and this was reflected in the authors' conclusions. The authors reported, as a limitation to their study, that HRQOL improvements after SVR were measured over a short time (6 to 12 months) and this might have resulted in an underestimation of the cost-effectiveness estimates.
Implications of the study The authors did not make explicit recommendations for changes in policy or practice, but they did recommend that future research should evaluate the cost-effectiveness of antiviral therapy in more general populations of patients with chronic hepatitis C.
Source of funding Funded by the UK NHS R&D National Coordinating Centre for Health Technology Assessment.
Bibliographic details Grieve R, Roberts J, Wright M, Sweeting M, DeAngelis D, Rosenberg W, Bassendine M, Main J, Thomas H. Cost effectiveness of interferon A or peginterferon A with ribavirin for histologically mild chronic hepatitis C. Gut 2006; 55(9): 1332-1338 Other publications of related interest Because readers are likely to encounter and assess individual publications, NHS EED abstracts reflect the original publication as it is written, as a stand-alone paper. Where NHS EED abstractors are able to identify positively that a publication is significantly linked to or informed by other publications, these will be referenced in the text of the abstract and their bibliographic details recorded here for information
Grieve R, Roberts J. Economic evaluation for hepatitis C. Acta Gastroenterol Belg 2002;65:104-9.
Wright M, Forton D, Main J, et al. Treatment of histologically mild hepatitis C virus infection with interferon and ribavirin: a multicentre randomized controlled trial. J Viral Hepat 2005;12:58-66.
Wright M, Grieve R, Roberts J, et al. Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation. Health Technol Assess 2006;10(21):1-130.
Indexing Status Subject indexing assigned by NLM MeSH Adult; Aged; Antiviral Agents /economics /therapeutic use; Cost-Benefit Analysis; Disease Progression; Drug Costs; Drug Therapy, Combination; Great Britain; Health Care Costs; Hepatitis C, Chronic /drug therapy /economics; Humans; Interferon-alpha /economics /therapeutic use; Middle Aged; Models, Econometric; Polyethylene Glycols; Quality of Life; Quality-Adjusted Life Years; Recombinant Proteins; Ribavirin /economics /therapeutic use; Severity of Illness Index AccessionNumber 22006001734 Date bibliographic record published 28/02/2007 Date abstract record published 28/02/2007 |
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