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Healthcare
Hepatitis C: an economic evaluation of extended treatment with
interferon
Alan Shiell, Sue Brown and Geoff C Farrell
MJA 1999; 171: 189-193
Abstract -
Introduction -
Methods -
Results -
Discussion -
References -
Authors' details
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Abstract |
Objectives: To re-evaluate the cost effectiveness
of treating hepatitis C virus (HCV) infection with interferon alfa
(IF ) in Australia, taking into account changes in clinical
practice.
Design: A decision-analytic method (Markov model) was
used to simulate the costs and effects of 6 months and 12 months of
treatment with IF versus no treatment (conventional management).
Both costs and effects were modelled over 30 years.
Data sources: Published meta-analysis of the
effectiveness of treatment, professional judgement about
treatment protocols, scheduled medical fees, diagnosis-related
costs for hospital admission, and a literature search for
quality-of-life weights.
Patients: A hypothetical cohort of 1000 patients with
chronic HCV infection aged 40 years at the start of treatment.
Main outcome measures: Incremental costs per life-year
gained and per quality-adjusted life-year (QALY) gained.
Results: Compared with no treatment, IF treatment for 6
months results in an extra 94.2 life-years or 320.1 QALYs at an extra
cost of $1.8 million (after discounting at 3%) in a cohort of 1000
patients. Discounted cost per life-year gained is $19 110, which is
about a quarter of the cost reported in 1994. The discounted cost per
QALY gained is $5625. Extended treatment for another 6 months results
in an additional 89.0 life-years saved or 170.8 QALYs gained at an
incremental discounted cost of $15 835 per life-year gained and $8250
per QALY gained.
Conclusions: The cost effectiveness of IF treatment for
HCV infection has improved as a result of better patient selection,
cost reductions and enhanced effectiveness of extended treatment.
The results are sensitive to assumptions made about quality of life
and the discount rate.
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| | Introduction |
Infection with the hepatitis C virus (HCV) is an important public
health problem in Australia. It is estimated that there are at least
100 000 people carrying the virus and that up to 10 000 new cases are
diagnosed each year.1 As many as 85% of those with
acute HCV infection will develop chronic infection, and, of these, a
significant proportion will develop cirrhosis and hepatocellular
carcinoma (HCC). The only approved treatment for chronic HCV
infection, interferon alfa (IF), is expensive, has significant
adverse effects and is effective in only 10%-35% of patients. The cost
effectiveness of treatment is uncertain.
Decision-analytic techniques have been used to simulate the
expected costs and effects of treatment, and several economic
evaluations of IF have been published.2-7 The only Australian study
(published in 1994)3 estimated the cost per
life-year gained by treatment with IF to be $33 000 in patients with
cirrhosis at the start of treatment and $71 000 for patients without
cirrhosis. These figures are substantially higher than those
reported elsewhere, reflecting a more cautious view of the long term
effectiveness of IF and the exclusion of the broader benefits of
therapy, such as its assumed effects on employment and production
capacity.
The impact that IF has on the natural history of HCV infection is now
better known. Treatment is discontinued in patients who fail to show a
response after 12 weeks, with no reduction in effectiveness but with
substantial cost savings. Further, several studies have shown
benefits of extended treatment over 12 months rather than 6 months,
and this has become the recommended treatment period in most
countries including Australia. The effect that this has on cost
effectiveness is not clear, as both costs and benefits are likely to
increase.
Our aim is to update our previous estimate of the cost effectiveness of
IF in the treatment of chronic HCV infection.3 Under section 100 of the
Health Act 1953 (Cwlth) (Highly Specialised Drugs Program),
subsidised treatment is restricted to patients with no signs of
cirrhosis at start of treatment and we have restricted our analysis to
such patients.
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Methods |
The costs and effects of IF treatment were simulated by a
decision-analytic method (the Markov model) in a hypothetical
cohort of 1000 patients with chronic HCV infection aged 40 years at
start of treatment (the mean age at diagnosis is 42 years). Both costs
and effects were modelled over 30 years. The cost effectiveness of
treatment with IF over 6 months versus no treatment (ie,
conventional management only) was re-evaluated, incorporating
changes in clinical practice, treatment costs and the price of IF.
The incremental costs and effects of moving from 6 months to 12 months'
treatment were then estimated. The software used was Microsoft Excel
97.
The assumptions and methods for the decision analytic technique are
shown in the Box.
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Results |
The net cost of 6 months' treatment with IF for chronic HCV infection
(ie, the cost of treatment minus the cost of conventional management
of the disease) was estimated to be $1800 per patient after
discounting at 3%. Treatment with IF results in an extra 94.2
discounted life-years saved or 320.1 additional (discounted) QALYs
(Table 2). The incremental cost per life-year
saved was $19 110, which is about a quarter of the cost reported in our
previous study.3 The incremental cost per
QALY gained was $5625.
Extending treatment from 6 to 12 months results in an additional 89.0
discounted life-years gained or 170.8 discounted QALYs at
incremental costs of $15 835 per life-year gained and $8250 per QALY
gained. Average cost per unit of outcome increases as the duration of
the model is reduced. As duration of the model acts as a proxy for age at
the start of treatment, this finding suggests that treatment is less
cost effective in older age groups.
The sensitivity analysis (Table 3)
suggests that the results for 6 months' treatment are robust with
respect to assumptions made about rates of disease progression, the
long term effectiveness of IF, the price of IF and the exclusion of
patients not responding after 12 weeks. The most important variables
are the choice of discount rate and the adjustment for quality of life
(Table 3). Relatively minor adjustments to
the quality-of-life weight for treatment have a large effect on cost
per QALY gained. In the extreme, the adverse effects of treatment
offset any gains in quality of life brought about by disease
resolution. The effect of 12 months' treatment over 6 months'
treatment is also sensitive to changes in the discount rate and the
duration of the model and, in addition, is more sensitive to
assumptions made about disease progression and treatment
effectiveness.
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Discussion |
Our results suggest that the cost per life-year gained from 6 months'
treatment with IF is lower than when it was first evaluated in an
Australian context in 1994.3 This change is attributable
to three main factors: a reduction in the cost of treating people with
IF; a reduction in the price of IF itself; and cessation of treatment
at 12 weeks in those who fail to show a reduction in serum alanine
aminotransferase levels. The latter has been clinical policy in
Australia since IF was first listed for public subsidy in 1994, but
our initial evaluation preceded this.3
Quality adjustment of the outcomes also has a substantial effect on
the cost-effectiveness ratios, suggesting that the major impact of
IF treatment is on improving quality of life rather than increasing
life expectancy through the prevention of cirrhosis. There is also
the relief offered to those in whom the infection is resolved.
However, the sensitivity of the results to changing assumptions
about the effect of the disease and its treatment on quality of life
reinforces the need for further research into the subjective impact
of HCV infection.
Only one other study has considered the cost effectiveness of 12
months' versus 6 months' therapy.7 Consistent with our
results, it concluded that treatment over 12 months may be cost
effective, except in patients older than 60 years of age.
The cost-effectiveness ratios reported here compare favourably
with many other public health interventions, such as screening for
breast and cervical cancer.20,21 However, there are
problems in comparing the results of economic evaluations,
particularly when different methods have been used.22 Furthermore,
if the benefits of extended treatment with IF are to be realised
within a limited healthcare budget, then some other program or
activity must be dropped or reduced in scale to accommodate the
increase in expenditure. Thus, before drawing conclusions about
cost effectiveness, one should compare the benefits of IF treatment
with the benefits of the other program or activity
affected.23
See Box for summary points.
Caution is especially warranted when, as in this case, a
decision-analytic model has been employed, as it is often difficult
to assess the validity of the assumptions made. The protracted nature
of HCV infection, however, makes it difficult to assess the cost
effectiveness of treatment by another means.24,25 Decisions on when and
how to use IF have to be made with available data. However, our
comprehensive sensitivity analysis showed that, for most of the
assumptions made, the results appear to be robust.
The exceptions are the two subjective variables -- the utility
attached to different disease endpoints and the rate at which future
costs and benefits are discounted. HCV infection is not the benign
disease it was once believed to be, but little is known about the impact
it has on people's lives or the lengths to which they might go for
relief. Our results are particularly sensitive to assumptions made
about the relative effect of living with chronic infection, and its
associated risks of long term sequelae versus the known risks and the
uncertain effectiveness of treatment. Individual attitudes to risk
and time preference will affect the perceived cost effectiveness of
treatment. Further research is needed to examine the personal and
social impact of HCV infection and the utility of its
treatment.26
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| |
References |
- Australian Health Ministers' Advisory Council. National
Hepatitis C Action Plan, October 1994. Canberra; AGPS, 1994.
-
2. Garcia de Ancos JL, Roberts JA, Dusheiko GM. An economic
evaluation of the costs of a-interferon treatment for chronic active
hepatitis due to hepatitis B or C virus. J Hepatol 1990; 11:
S11-S18.
-
Shiell A, Briggs A, Farrell G. The cost-effectiveness of alpha
interferon in the treatment of chronic active hepatitis C. Med J
Aust 1994; 160: 268-272.
-
Dusheiko GM, Roberts JA. Treatment of chronic type B and C hepatitis
with interferon alfa: an economic appraisal. Hepatology
1995; 22: 1863-1873.
-
Joliet E, Vanlemmens C, Kerleau M, et al. Cost-effectiveness
analysis of the treatment of chronic hepatitis C. Gastroenterol
Clin Biol 1997; 21: 336-338.
-
Bennet WG, Inoue Y, Beck R, et al. Estimates of the
cost-effectiveness of a single course of interferon-a 2b in patients
with histologically mild hepatitis C. Ann Intern Med 1997;
127: 855-865.
-
Kim WR, Poterucha JJ, Hermans JE, et al. Cost-effectiveness of 6 and
12 months of interferon-a therapy for chronic hepatitis C. Ann
Intern Med 1997; 127: 866-874.
-
National Institutes of Health Consensus Development Panel
statement: management of hepatitis C. Hepatology 1997; 26(3
Suppl 1): 2S-10S.
-
Fattovitch G, Giustina G, Degos F, et al. Morbidity and mortality in
compensated cirrhosis type C: a retrospective follow-up study of 384
patients. Gastroenterology 1997; 112: 463-472.
-
Australian Bureau of Statistics. Deaths: Australia 1994.
Canberra: ABS, 1994. (Catalogue No. 3302.0.)
-
Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon
randomized trials in the treatment of viral hepatitis C: effects of
dose and duration. Hepatology 1996; 24: 778-789.
-
Carithers RL Jr, Sugano D, Bayliss M. Health assessment for
chronic HCV infection: results of quality of life. Dig Dis Sci
1996; 41: 75S-80S.
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Davis GL, Balart LA, Schiff ER, et al. Assessing health-related
quality of life in chronic hepatitis C using the Sickness Impact
Profile. Clin Ther 1994; 16: 334-343.
-
Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C virus
infection causes a significant reduction in quality of life in the
absence of cirrhosis. Hepatology 1998; 27: 209-212.
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National Health and Medical Research Council. A strategy for the
detection and management of hepatitis C in Australia. Canberra:
NHMRC/AGPS, 1997.
-
Commonwealth Department of Health and Family Services. Medical
Benefits Schedule. Nov 1996. Canberra; AGPS, 1996.
-
Commonwealth Department of Health, Housing, Local Government
and Community Services. Manual of Resource Items and their
Associated Costs. Canberra: AGPS, November 1993.
-
Drummond MF, Brandt A, Luce B, Rovira J. Standardising
methodologies for economic evaluation in health care. Int J
Technol Assess Health Care 1993; 9: 26-36.
-
Gold MR, Siegel JE, Russell LB, Weinstein MC, editors.
Cost-effectiveness in health and medicine. New York: Oxford
University Press, 1996: 230.
-
AHMAC Breast Cancer Screening Evaluation Committee. Breast
screening in Australia: future directions. Canberra: Australian
Institute of Health and Welfare, 1990.
-
AHMAC Cervical Cancer Screening Evaluation Committee. Cervical
Screening in Australia: options for change. Canberra: Australian
Institute of Health and Welfare, 1991.
-
Salkeld G, Davey PD, Arnolda G. A critical review of
health-related economic evaluations in Australia: implications
for health policy. Health Policy 1995; 31: 111-125.
-
Birch S, Donaldson C. Cost-benefit analysis: dealing with the
problems of indivisible projects and fixed budgets. Health
Policy 1987; 7: 61-72.
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Bennet WG, Pauker SG, Davis GL, Wong JB. Modeling therapeutic
benefit in the midst of uncertainty: therapy for hepatitis C. Dig
Dis Sci 1996; 41: 56S-62S.
-
Koff RS, Seeff LB. Economic modeling of treatment of chronic
hepatitis B and chronic hepatitis C: promises and limitations.
Hepatology 1995; 22: 1880-1885.
-
Owens DK. In the eye of the beholder: assessment of health-related
quality of life. Hepatology 1998; 27: 292-293.
(Received 20 Nov 1998, accepted 3 May 1999)
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| | Authors' details |
Social and Public Health Economics Research Group (SPHERe),
Department of Public Health and Community Medicine, University of
Sydney, Sydney, NSW.
Alan Shiell, MSc(Econ), Honorary Research Associate.
Medical Benefits Fund of Australia, Sydney, NSW.
Sue Brown, MPH, BPharm, Pharmacy Manager, Provider
Relations.
Department of Medicine, Westmead Hospital, University of Sydney,
NSW.
Geoff C Farrell, MD, FRACP, Storr Professor of Medicine.
Reprints will not be available from the authors.
Correspondence: Mr A
Shiell, Social and Public Health Economics Research Group (SPHERe),
Department of Public Health and Community Medicine, University of
Sydney (A27), NSW 2006.
Email: alansATpub.health.usyd.edu.au
©MJA 1999
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Assumptions and methods for the decision analytic technique
Natural history of hepatitis C (HCV)
- Chronic HCV infection to cirrhosis: The rate of progression was assumed to be 20% at 20 years,8 consistent with experience in patients attending liver clinics, but is higher than in a community sample.
- Cirrhosis to hepatocellular carcinoma (HCC): Rates of progression range from 1% to 4% per year and are higher in older age groups.8 We have assumed an annual rate of 1.4% (14% over 10 years), which is the lowest rate from more than 10 published studies from Europe and Japan.9 The small chance of HCC developing in patients without cirrhosis (< 0.25% per year)8 was ignored.
- Cirrhosis to advanced liver failure: We assumed that 20% of the cohort would progress to advanced liver failure over 10 years from the onset of cirrhosis.8
- Death: All patients developing HCC or advanced liver failure were assumed to die within 2 years of diagnosis. Deaths from other causes were estimated from Australian life tables.10
Effectiveness of IF treatment
- Previous evaluation: In our previous evaluation,3 we assumed that 6 months' treatment with IF would be effective in 20% of cases overall and 26% of cases without cirrhosis at the start of treatment.
- A recent meta-analysis by Poynard et al11 suggests that a sustained response is achieved in 14%-22% of cases treated with 3 million international units (miu) of IF over 6 months, and in 28%-38% of patients treated with the same dose for 12 months or longer.
- Our estimates of the effectiveness of treatment were based on the assumption
of an 18% sustained response rate after
IF treatment for 6 months and a 35% sustained response rate after 12 months' treatment, with both rates subject to sensitivity analysis.
Quality of life
- Chronic HCV infection has been described as largely asymptomatic, with
less than 20% of patients developing non-specific symptoms such as fatigue.8 However, recent studies suggest that it has an impact on quality of life.12-14 People with chronic HCV infection scored significantly lower than a comparable but healthy population on various generic health measures, such as the 36-item short-form health survey (SF-36).12
- Side effects of treatment: Mild side effects of IF are common and most patients will experience flu-like symptoms which diminish over time. Less transient effects
-- fatigue, irritability, depression, thyroid disease and skin disorders -- are more troublesome and cause some patients to discontinue treatment. Less than 2% of patients will experience severe side effects.8
- Quality-adjusted life-years (QALYs): The impact of the disease (including its sequelae and treatment with IF) on quality of life can be incorporated into the analysis by weighting the life-years gained according to their quality, thus generating an estimate of quality-adjusted life-years,
or QALYs. These weights are usually calibrated on a scale of 0 to 1, where 0 is equivalent to death and 1 to a year of life
in full health.
- Subjective impact of the disease: A major shortcoming is a lack of understanding of the subjective impact of the disease. In the absence of patient-generated weights, other authors have used quality-of-life weights based on clinical judgement or small scale surveys.4,6,7 The weights are 0.8-0.95 for chronic hepatitis, 0.7-0.8 for compensated cirrhosis, 0.28-0.5 for decompensated cirrhosis, and 0.1-0.25 for hepatocellular carcinoma.
- The weights we used were adapted from those derived by Kim et al,7 as these were the only ones based on patient judgement (Table 1). In the baseline case, it was assumed that treatment had no additional adverse effect on quality of life -- an assumption relaxed in the sensitivity analysis.
Costs of treatment
- Estimates of the treatment costs for each
of the main clinical endpoints were based on clinical protocols as specified by the National Health and Medical Research Council (NHMRC)15 and the clinical opinion of one of the authors (G C F). The protocols were costed using the Medicare Benefits Schedule for medical services,16 and Australian national diagnosis-related groups (AN-DRG-3.1) for hospital admissions (Table 1).17 Click here for details. All costs are in Australian dollars at 1996 prices.
- Cirrhosis: A weighted cost was computed on the basis of specified treatment protocols for each of the main clinical manifestations of cirrhosis. The weights reflect the estimated proportion of patients likely to experience each state.6 It was further assumed that 2% of patients experiencing cirrhosis would undergo a liver transplant each year and that 25%
of cirrhotic patients would experience at least one episode of septicaemia requiring hospital admission.
- IF: The unit cost of IF reflected its price to the healthcare system. It was assumed that treatment would be given
at a rate of 3 miu three times a week for either 24 or 48 weeks and would be discontinued in people who did not show
a reduction in serum alanine aminotransferase (ALT) levels after 12 weeks. Experience in Australia suggests that 26% of people will fail to respond in this period and will discontinue treatment (R G Batey, Deputy Dean, and Professor of Gastroenterology, Faculty of Medicine and Health Sciences, University of Newcastle, Newcastle, NSW, personal communication).
- Other costs: Lost production capacity caused by morbidity and premature mortality associated with HCV infection was not considered.18 Other patient costs, such as the use of community services and alternative medicine, were also omitted. This biases the findings against treatment with IF.
Cost effectiveness of IF treatment
Sensitivity analysis
- The robustness of the results was
examined by sensitivity analysis (given
the uncertainties inherent in the modelling approach).
- Key variables included in the sensitivity analysis were response rates, rates of disease progression, time to develop sequelae, costs of treatment, percentage
of patients excluded at 12 weeks, age groups, the discount rate, and the adjustment for quality of life.
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| 1: Baseline assumptions: values and costs used in the Markov model |
| Value | Range |
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| Disease transition probabilities |
| From chronic infection to cirrhosis | 20% | 10%-30% |
| From cirrhosis to advanced liver failure | 20% | 10%-30% |
| From cirrhosis to hepatocellular carcinoma | 14% | 7%-21% |
| Effectiveness of treatment |
| Long term response after 6 months | 18% | 14%-24% |
| Long term response after 12 months | 35% | 26%-38% |
| Discontinue treatment after 12 weeks because of lack of response | 26% | 13%-39% |
| Health state (quality of life) weights |
| Chronic infection | 0.95 | 0.80-1.00 |
| Cirrhosis | 0.75 | 0.50-0.90 |
| Advanced liver failure | 0.25 | 0.10-0.40 |
| Hepatocellular carcinoma | 0.25 | 0.10-0.40 |
| Treatment with interferon alfa (IF) | 0.95 | 0.80-0.95 |
| Resolved infection | 1.00 | 1.00-1.00 |
| Treatment episode costs* | $ | $ |
|
| Medical management of chronic infection | 405 | 200-600 |
| Treatment with IF |
| 6 months' treatment including discontinuing treatment | 2 800 | 1 975-3 630 |
| 12 months' treatment including discontinuing treatment | 5 150 | 3 620-6 670 |
| Cirrhosis (weighted average) | 2 825 | 1 400-4 200 |
| Management of compensated cirrhosis | 660 | 330-990 |
| Diuretic-sensitive ascites | 1 880 | 940-2 820 |
| Refractory ascites | 13 640 | 6 820-20 460 |
| Variceal haemorrhage (Year 1) | 5 850 | 2 925-8 775 |
| Hepatic encephalopathy (Year 1) |
6 375 | 3 190-9 565 |
| Hepatocellular carcinoma (Year 1) | 8 865 | 4 435-13 290 |
| Liver transplant (Year 1) | 92 525 | 46 265-138 790 |
| Septicaemia | 5 300 | 2 650-7 950 |
| Terminal care | 28 400 | 14 200-42 600 |
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2: Summary of costs and outcomes of interferon treatment for chronic hepatitis C infection in a hypothetical cohort of 1000 patients |
| Treatment duration | Net costs ($) | Lives saved |
Life-years saved | QALYs gained |
|
| Undiscounted |
| (a) 6 months | 1 185 555 | 12.0 | 176.3 |
531.4 |
| (b) 12 months | 2 013 845 | 23.4 |
342.7 | 830.7 |
| (c) Increment | 828 290 | 11.3 | 166.5 | 299.3 |
| Discounted (3%) |
| (a) 6 months | 1 800 380 | 7.6 | 94.2 | 320.1 |
| (b) 12 months | 3 209 345 | 14.7 | 183.2 | 490.9 |
| (c) Increment | 1 408 965 | 7.1 | 89.0 | 170.8 |
| Discounted (5%) |
| (a) 6 months | 2 049 645 | 5.7 | 63.9 | 237.7 |
| (b) 12 months | 3 694 020 | 11.1 | 124.2 | 359.5 |
| (c) Increment | 1 644 375 | 5.4 | 60.3 | 121.8 |
|
| Treatment Duration | | Cost/life saved ($) | Cost/ life-year saved ($) | Cost/ QALY gained ($) |
|
| Undiscounted |
| (a) 6 months | | 98 710 | 6 720 | 2 230 |
| (b) 12 months | | 86 235 | 5 875 |
2 425 |
| (c) Increment | | 73 020 | 4 975 | 2 765 |
| Discounted (3%) |
| (a) 6 months | | 238 525 | 19 110 | 5 625 |
| (b) 12 months | | 218 670 | 17 520 |
6 540 |
| (c) Increment | | 197 645 | 15 835 |
8 250 |
| Discounted (5%) |
| (a) 6 months | | 360 370 | 32 095 |
8 620 |
| (b) 12 months | | 334 020 | 29 750 |
10 275 |
| (c) Increment | | 306 120
| 27 265 |
13 505 |
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Incremental cost and outcomes
(a) 6 months' treatment with interferon v. no treatment; (b) 12 months' treatment with interferon v. no treatment; (c) 12 months' treatment with interferon v. 6 months' treatment.
Net costs = costs of treatment minus costs of conventional management of the disease.
QALY = quality-adjusted life-year.
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