 |
 |
|
|
|  PubMed
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
15 November 1997 | Volume 127 Issue 10 | Pages 866-874
Background: Interferon-
Objective: To compare clinical and economic outcomes after 6 months and 12 months of interferon-
Design: A Markov model depicting the natural progression of chronic hepatitis C. On the basis of this model, a simulated trial compared no therapy with 6 and 12 months of interferon-
Patients: Four age-specific cohorts (30, 40, 50, and 60 years of age) with chronic hepatitis C.
Measurements: Number of deaths from liver disease, total costs, and cumulative quality-adjusted life-years (QALYs).
Results: Six and 12 months of interferon-
Conclusion: From the standpoint of cost-effectiveness, interferon-
Despite an initial biochemical response in up to 76% of patients after 6 months of interferon-
Because of the low efficacy and high cost of interferon-
Previous analyses have suggested that 6 months of interferon-
We first used probabilities derived from an analysis of the current literature to construct a Markov model that describes the natural progression of liver disease from chronic hepatitis C in a cohort of patients. This model is described in detail in the Appendix. On the basis of this natural history model, we simulated a randomized treatment trial comparing no treatment, 6 months of interferon-
Natural History Model for Chronic Hepatitis C
Our Markov model consisted of six disease states: chronic hepatitis C, compensated cirrhosis, decompensated cirrhosis, orthotopic liver transplantation, hepatocellular carcinoma, and death (Figure 1). The entry point of our model was chronic hepatitis C without cirrhosis, as determined by liver biopsy. As shown in Figure 1, patients may progress from chronic hepatitis C to compensated and decompensated cirrhosis over time. Compensated cirrhosis is diagnosed when the patient has histologically progressed to cirrhosis but has neither developed any symptoms nor required ongoing medical treatment. Once a patient experiences symptoms related to cirrhosis, he or she is classified as having decompensated cirrhosis and incurs expenses for health care services. Some patients with decompensated cirrhosis may develop hepatocellular carcinoma or undergo liver transplantation. As the population ages, an increasing number of patients die of natural causes independent of liver disease. We modeled four age-specific cohorts (30, 40, 50, and 60 years of age) of 1000 patients each. ARTICLE
Cost-Effectiveness of 6 and 12 Months of Interferon-
Therapy for Chronic Hepatitis C
is effective in only a small number of patients with chronic hepatitis C, although prolonged treatment may increase the response rate. There is concern that the expense of interferon- therapy may not be justified by the low response rates and uncertain long-term benefit. therapy for chronic hepatitis C. therapy at standard doses (3 million U three times weekly). treatment gained 0.25 QALYs at an incremental cost of $1000 and 0.37 QALYs at an incremental cost of $1900, respectively. Thus, although 6 months of interferon- therapy was less efficacious than 12 months of therapy, it was more cost-effective ($4000 per QALY gained compared with $5000 per QALY gained). Nonetheless, in patients younger than 60 years of age, both 6 and 12 months of therapy compared favorably with other established medical interventions, such as screening mammography and cholesterol reduction programs. Important variables affecting the cost-effectiveness of interferon- treatment included the cost and efficacy of interferon-, the cost of treatment for decompensated cirrhosis, and quality of life in patients with chronic hepatitis C. therapy for 6 or 12 months may be justified in patients with chronic hepatitis C. The possible exception is patients older than 60 years of age.
Hepatitis C virus (HCV) is a major cause of liver-related illness and death in the United States. A recent report from the Centers for Disease Control and Prevention [1] estimated that 35 000 to 180 000 persons develop HCV infection and more than 8000 die of HCV-related illness each year. One reason that hepatitis C continues to be an important public health concern is the lack of effective therapy to eliminate HCV. therapy, only about 10% achieve a sustained response (defined as disappearance of biochemical, histologic, and virologic evidence of chronic hepatitis C) [2-5]. An additional 5% to 7% of patients may attain a sustained response when treatment is extended to 12 months [5, 6]. , the cost-effectiveness of the drug in the treatment of chronic hepatitis C has been questioned [7]. One of the difficulties in evaluating the cost-effectiveness of interferon- is lack of clinical data. The long-term effectiveness of interferon- remains undetermined because follow-up in most studies has lasted no more than 1 year. The effect of interferon- on the development of decompensated cirrhosis and hepatocellular carcinoma is also unknown. Moreover, our understanding of the natural history of chronic hepatitis C without treatment is incomplete. Investigators have therefore relied on computer-generated models to evaluate cost-effectiveness [8, 9]. treatment yields substantial health care cost savings [8, 9]. We analyzed the cost-effectiveness of 6 and 12 months of interferon- treatment for chronic hepatitis C by using a computer model that incorporated prognostic variables associated with the progression of liver disease and response to interferon-.
Methods
Top
Methods
Results
Discussion
Author & Article Info
References
Overview of Analysis treatment, and 12 months of interferon- treatment. The cost-effectiveness of interferon- treatment from the point of view of society was assessed by comparing the number of liver-related deaths, quality-adjusted survival, and costs among the treatment strategies. Simulations and analyses were performed and verified by using a statistical software package (SAS, SAS Institute, Cary, North Carolina) and spread-sheet software (Excel, Microsoft Corp., Redmond, Washington).
|
The rate at which simulated patients moved from one state to another was obtained by critically reviewing the literature. The reported rate of progression from chronic hepatitis C to cirrhosis varies from 1.1% to 10.8% [10-18]. We assumed that patients with chronic hepatitis C may be divided into two groups according to their rate of progression (Table 1). Patients in the indolent disease group would progress from chronic hepatitis to cirrhosis at the lower end of the range (1% per year) reported in the literature. In contrast, chronic hepatitis C in patients in the aggressive disease group would progress to cirrhosis at the higher end of the reported range (10% per year). The rates of progression from compensated to decompensated cirrhosis, from cirrhosis to hepatocellular carcinoma, and from decompensated cirrhosis to death were also obtained from the literature (Appendix Table) [19-24]. We assumed that once cirrhosis developed, the rate of occurrence of complications (that is, hepatic decompensation, hepatocellular carcinoma, and liver-related death) was the same in the indolent and aggressive disease groups. Age-related mortality rates from all causes were based on the 1990 U.S. Vital Statistics [25].
|
|
Interferon- Treatment
We simulated a randomized trial that compared the three study groups (no treatment, 6 months of interferon- treatment, and 12 months of interferon- treatment) in each of the four cohorts. Patients in the two treatment groups received 3 million U of interferon- three times a week by self-injection and were monitored every 3 months by clinical examination and laboratory tests. Interferon- therapy was discontinued at 12 weeks in patients in whom aminotransferase levels did not return to normal. Sustained response to treatment was defined as complete and continued disappearance of symptoms and normal liver biochemistry 6 months after discontinuation of treatment. Sustained biochemical response would be accompanied by histologic remission and disappearance of viral RNA from the blood. We assumed that patients who achieved sustained remission would follow the mortality pattern of the general population ("cure" state in the Markov model [Figure 1]). Patients who did not respond, had relapse, or were not treated would follow the clinical course prescribed by the natural history model.
With regard to the proportion of sustained response, we applied different response rates to the indolent and aggressive disease groups (Table 1). Many studies have shown that the factors associated with a more aggressive clinical course of chronic hepatitis C are also predictive of worse response to interferon- treatment [5, 26-28]. For example, multivariate analyses have shown that patients with HCV genotype 1b or high virus levels were up to 10 times less likely to have a sustained response to interferon- therapy than were patients with other genotypes or low virus levels [28]. This association must be considered in the analysis of cost-effectiveness of interferon- because the cost-effectiveness of the drug will otherwise be overestimated. Patients who attain a sustained response to interferon- may be those who would not have had progressive disease without treatment. Conversely, patients who are more likely to die of long-term complications of HCV infection are those who are less likely to respond to interferon- [7].
Costs
The costs of treating decompensated cirrhosis and hepatocellular carcinoma were based on a report from the National Institute of Diabetes and Digestive and Kidney Diseases after adjustment for inflation [29]. Costs of liver transplantation were also obtained from the literature and supplemented with institutional data [30, 31]. The cost of interferon- was the average wholesale price plus 20% for costs of injection supplies, clinical and biochemical monitoring, and treatment of side effects from interferon- [32]. These cost estimates are summarized in the Appendix Table. Monetary figures were discounted at an annual rate of 3%.
Assessment of Outcome and Sensitivity Analysis
Our main outcome measures were the number of deaths from liver disease and total costs. A third outcome, the effect on quality of life over time, was assessed as cumulative quality-adjusted life-years (QALYs) [33]. In computing QALYs, a panel of hepatologists and a nurse specialist used a generic instrument to estimate the utility weight for each disease state [34]. For example, we assigned a utility weight of 0.5 to decompensated cirrhosis, estimating that 1 year of life in a person with decompensated cirrhosis would be equivalent to 0.5 years of healthy life. The other utility weights assigned were 0.95 for chronic hepatitis, 0.8 for compensated cirrhosis, 0.8 for the time after liver transplantation, 0.25 for hepatocellular carcinoma, and 0 for death. We discounted the benefits of interferon- treatment (QALYs) at the same rate used for discounting costs (3%).
Incremental cost-effectiveness was assessed by computing cost per QALY gained; the three strategies were compared in a pairwise fashion. Sensitivity analyses were performed by varying the value of the variables used in the model to identify those that had the greatest effect on the conclusions. Variables associated with a more than twofold change in cost-effectiveness in this process were considered influential and are presented in the Results section. All cost figures were rounded to the nearest $100.
Results
|
|---|
|
TopMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
Figure 2 shows the results of the Markov model that describes the progression of liver disease in the cohort of a representative age group (40 years of age). At time zero, all patients have chronic hepatitis C. During the ensuing years, an increasing proportion of patients moves through subsequent stages of liver disease. Although most patients were relatively healthy (chronic hepatitis C or compensated cirrhosis) during most of their lives, 30% eventually died of liver-related causes. The proportion of patients who had hepatocellular carcinoma or underwent liver transplantation at any given time was small.
|
Among the four age-specific cohorts, the model's estimates of the length of time for disease progression from chronic hepatitis C to later stages of liver disease varied widely. This variation resulted from differences in the underlying mortality characteristics of the age-specific cohorts (that is, the rate at which the cohort size decreased as a result of deaths from natural causes). For example, the mean time to development of decompensated cirrhosis ranged from 24.8 years in the 30-year-old cohort to 14.8 years in the 60-year-old cohort. Similarly, the intervals to the development of hepatocellular carcinoma were 29.1 years for 30-year-old patients and 18.3 years for 60-year-old patients. The validity of our model was tested by reproducing long-term morbidity and mortality data in the literature, as shown in the Appendix.
Cost-Effectiveness of Interferon- Strategies
Our model estimated that the effect of both interferon- strategies (6 months and 12 months) on the outcome of chronic hepatitis was small. The average lifetime risk for decompensated cirrhosis was 34.5% without treatment, 32.5% after 6 months of interferon- treatment, and 31.5% after 12 months of interferon- treatment. Similarly, the proportion of patients who died of liver disease decreased from 26.5% without treatment to 25.0% with 6 months of treatment and 24.3% with 12 months of treatment. Cumulative QALYs increased from 18.00 years without treatment to 18.25 years with 6 months of treatment and 18.37 years with 12 months of treatment.
The effectiveness of interferon- in altering these clinical outcomes was affected by the patient's age. For example, the lifetime risks for decompensated cirrhosis in the 30-year-old cohort were 47.4% without treatment, 44.4% with 6 months of treatment, and 42.9% with 12 months of treatment. In the 60-year-old cohort, these values were 21.1%, 20.1%, and 19.6%, respectively.
Table 2 summarizes the effects of the three treatment strategies on costs and quality-adjusted survival based on our base-case scenario. When interferon- therapy was discontinued in nonresponders at 12 weeks, the average cost for interferon- treatment was $2300 for a 6-month course and $3800 for a 12-month course. The incremental cost-effectiveness of 6 months of interferon- therapy compared with no therapy and 12 months of therapy compared with no therapy was $4000 per QALY and $5000 per QALY, respectively. Results of the cost-effectiveness analysis for each cohort are shown in Table 3. Although 12 months of interferon- therapy was more efficacious (that is, fewer deaths from liver disease and more QALYs were seen), 6 months of interferon- therapy was slightly more cost-effective.
|
|
Sensitivity Analyses
Of the cost estimates, that of interferon- and that of therapy for decompensated cirrhosis had the greatest effect on the outcome of the analysis. Figure 3 shows results of a two-way sensitivity analysis of the effect of varying the cost of interferon- and the cost of therapy for decompensated cirrhosis on the cost-effectiveness (cost per QALY gained). The higher the cost associated with treatment of decompensated cirrhosis and the lower the cost of interferon-, the more cost-effective (lower cost per QALY gained) is interferon- treatment.
|
Not surprisingly, the rate of cure with interferon- therapy had a potentially notable impact on overall cost-effectiveness. Figure 4 shows how different estimates of the cure rate with interferon- influence cost-effectiveness. As the cure rate decreased toward zero, the cost per QALY increased dramatically. However, if the cure rate exceeded approximately 10%, the cost-effectiveness was stable over a relatively wide range of cure rates.
|
With regard to quality-of-life outcomes, the utility weight for the chronic hepatitis C state and the discount rate were influential variables. Our base-case scenario used discounted QALY calculations. When the morbidity associated with chronic liver disease secondary to chronic hepatitis C was ignored (that is, when no adjustment was made for quality of life), the cost-effectiveness of interferon- decreased almost threefold. In addition, not discounting the future benefit resulted in higher cost-effectiveness of interferon- (data not shown). In other words, interferon- treatment makes more sense the more the patient suffers from chronic hepatitis and the more the patient values health in the future.
We constructed the overall best- and worst-case scenarios on the basis of combinations of these influential variables (Table 4). When the most favorable set of variables was used, interferon- therapy resulted in net cost savings in all but the 60-year-old cohort. In the worst-case scenario, the cost per QALY gained increased dramatically compared with the base-case scenario. However, the cost-effectiveness of interferon- in the worst-case scenario was still within a reasonable range for younger cohorts; it was probably outside of the accepted range in the older cohorts.
|
Finally, we considered hypothetical situations in which all patients had either aggressive or indolent disease. Interferon- therapy was most cost-effective when all patients in the cohort had indolent disease (cost per QALY, $2300 for 6 months of treatment and $3700 for 12 months of treatment). Our analysis also suggested that 12 months of treatment may be more cost-effective than 6 months of treatment if all patients have an aggressive course (cost per QALY, $9800 for 6 months of treatment and $9400 for 12 months of treatment).
Discussion
|
|---|
|
TopMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
treatment. Our model is distinctive in that it incorporates some of the patient demographic and viral factors that are believed to influence disease progression and response to interferon-. It could also reproduce long-term follow-up data reported in the literature (Appendix). We therefore believe that this model is a reasonable approximation of long-term outcome in patients with chronic hepatitis C. However, our model is only one of many possible such models. For example, our model did not consider the effect of concomitant alcohol consumption, the route of infection, the possibility of recovery from decompensated cirrhosis, or retreatment with interferon-. One of the insights we gained from the model relates to the previous observation that older patients with HCV infection seem to have more rapid progression [35, 36]. We believe that this finding can be explained in part by the higher competing mortality in older patients. In other words, only patients who have rapidly progressive disease can reach more advanced stages of liver disease before they die of other causes. If these patients are retrospectively evaluated, they will have apparently short intervals before the development of cirrhosis or hepatocellular carcinoma. An example of high competing mortality is seen in the study by Seeff and colleagues [37], in which patients had serious comorbid conditions and high underlying mortality.
Our cost-effectiveness analysis showed that interferon- therapy for chronic hepatitis C ($4000 per QALY for 6 months of therapy and $5000 per QALY for 12 months of therapy) compares favorably to other medical interventions in the United States that have been considered reasonable, such as screening mammography ($20 000 per year of life) or cholesterol reduction for secondary cardiac prevention ($45 000 per year of life) [38, 39]. Under certain conditions, however, the cost-effectiveness of interferon- treatment in older patients may actually exceed the range that society has been willing to accept for other medical interventions, although there is no uniform agreement about where that range should lie. This finding is in contrast to those of previous analyses, which reported extremely favorable cost-effectiveness ratios.
The difference between our report and previous reports may be due to several factors. First, we restricted our definition of sustained response to patients who achieve complete biochemical, histologic, and virologic cure. Consequently, the estimates we used for the rate of response to interferon- (11.6% for 6-month therapy) were lower than those used in previous cost-effectiveness analyses (25% for 6 months). Moreover, trials conducted in the United States have reported sustained response rates [3, 4] that are lower than those reported in other parts of the world [40, 41]. Although the eventual outcome remains unknown in the subgroup of patients in whom liver biochemistry continues to be relatively normal but HCV is not eliminated after treatment, our assumption that interferon- achieves long-term benefit only in persons who attain viral clearance is probably reasonable [42].
Second, we modeled the fact that many patients who respond to interferon- may not have been at risk for future complications of chronic hepatitis C even if they had not responded. This reduced the estimates of the effectiveness of interferon-. Conversely, ignoring this factor can lead to gross overestimation of the effectiveness of interferon-. Finally, our study is based on cost estimates that may not include all of the indirect medical or nonmedical costs associated with complications of chronic liver disease. As our sensitivity analysis showed, the higher the costs assigned for the treatment of complications of chronic liver disease, the better the cost-effectiveness of interferon- treatment. We are not aware of any detailed study of the indirect medical and nonmedical costs related to HCV infection in the United States. Such efforts in other disease categories have been fraught with difficulties in obtaining accurate estimates [43, 44]. Overall, our results are far less favorable than those reported in previous analyses but still suggest that interferon- is as cost-effective as accepted medical treatments for other diseases.
Our model suggests that the cost-effectiveness of interferon- therapy for chronic hepatitis C is strongly influenced by the cost of interferon-. At least two ways are available to reduce the cost of interferon- treatment. The first and most obvious is to reduce the cost of the drug itself. If the monthly cost of interferon- could be reduced by 20%, the overall cost-effectiveness of interferon- therapy would improve by as much as 60% (Figure 4). Another way to reduce the cost of interferon- treatment is to identify treatment failure early and discontinue treatment. In our model, discontinuing treatment in nonresponders at 3 months decreased the cost of interferon- therapy by 25% for the 6-month strategy and 37.5% for the 12-month strategy. A recent analysis [45] suggested that a decision about treatment failure might be made as early as 4 weeks after the initiation of therapy.
The cost of treatment for complications of cirrhosis (decompensated cirrhosis, hepatocellular carcinoma, and liver transplantation) was another important determinant of the cost-effectiveness of interferon-. Although we based our model on the most recent data available, these data may not reflect the current standard of practice. For example, the introduction of resource-intensive procedures, such as transjugular intrahepatic portosystemic shunts, may have increased the overall cost of managing decompensated cirrhosis. Screening for hepatocellular carcinoma, if more widely accepted, may also have a great impact because of its added cost, making interferon- therapy more attractive. Liver transplantation is another expensive procedure to be considered, although the current shortage of donor livers is likely to preclude substantial increases in the number of transplantations and, therefore, the cost to society. Overall, as the cost of dying with advanced liver disease from HCV infection increases, interferon- will become a more attractive option [46].
With regard to the considerations of quality of life in our analysis, several limitations should be mentioned. Our utility estimates were based on an assessment by health care providers that may or may not accurately represent the quality of life perceived by patients. Quality-of-life data for patients with chronic viral hepatitis are limited [47]. In light of the recent emphasis on assessing outcomes of medical interventions from the perspective of the patient, more investigation is urgently needed in this area. Another issue is that of discounting for the value of life over time. For example, 1 year of life in a person 30 years of age may be more valuable than 1 year of life 50 years later. Moreover, 1 year of life in the present, with all of its tangible appeals, may be worth more than 1 year of life in an uncertain future. However, which method should be used to adjust for this time factor is controversial [48]. We discounted QALYs at the same rate that we used to discount costs [33]; this substantially decreased the cost-effectiveness of interferon- treatment. Despite these limitations, it is clear from our analysis that interferon- treatment may be more compelling when the patient is severely debilitated by the symptoms and effects of chronic hepatitis C. Because patients spend most of their time in the chronic hepatitis C state, even a slight decrease in the quality of life in that state would make a substantial difference in the cumulative QALY outcome.
Consideration of the best- and worst-case scenarios puts our analysis into a broader perspective [49]. We found that the cost-effectiveness of 12 months of interferon- therapy in patients younger than 40 to 50 years of age was within a reasonable range, even in the worst-case scenario. This finding strengthens our conclusion that interferon- therapy is an acceptable intervention for patients with chronic hepatitis C. Our incremental analysis comparing 6 and 12 months of interferon- treatment indicated that, in most cases, the additional cost associated with extending treatment from 6 to 12 months can be tolerated from the standpoint of cost-effectiveness. Moreover, for patients with aggressive disease who show an initial treatment response, 12 months of interferon- therapy may be a more cost-effective strategy than 6 months of therapy. Continuing treatment for 12 months for the relatively small number of responders in the aggressive disease group constitutes a relatively small incremental absolute cost.
On the basis of available data, we have shown that although interferon- may not be an ideal treatment for chronic hepatitis C, its cost-effectiveness compares favorably with that of other widely used medical interventions. The cost-effectiveness of interferon- therapy may be improved by reducing drug costs and by identifying treatment failures early. The development of further resource-intensive procedures for patients with advanced liver disease will continue to increase the cost-effectiveness of interferon-. In summary, although it is subject to the limitations and uncertainties of all decision analyses, our model suggests that interferon- therapy is cost-effective in patients with chronic hepatitis C and that continuing treatment for 12 months in patients who achieve an initial response, particularly those with aggressive disease, is justified.
Appendix
|
|---|
In Markov models, the natural history of a disease in a cohort of patients is represented as a repetitive sequence of several health states [33]. Health events (transitions between the health states) are assumed to occur at a constant rate. In our model, for example, the natural progression of chronic hepatitis C was described by the six disease states: chronic hepatitis C, compensated cirrhosis, decompensated cirrhosis, orthotopic liver transplantation, hepatocellular carcinoma, and death. All patients in the simulated cohort start from the chronic hepatitis C state. Over time, patients may progress to subsequent stages of liver diseases by given probabilities (transition probabilities) until they die of liver disease or natural causes.
Our simulation cohort consisted of 4000 persons who were 30, 40, 50, or 60 years of age (1000 persons in each cohort). Each cohort consisted of 500 men and 500 women. Each sex group was then divided into aggressive and indolent disease groups, as described in the text.
For each patient, we determined a value for the expected natural life span by using age- and sex-specific mortality tables, such that the patient's lifetime represents that of a random patient drawn from the population. We then computed an interval to the development of compensated cirrhosis on the basis of the estimated transition probability by random selection from the appropriate exponential distribution. Similar steps were used to compute a duration for each subsequent disease state in each patient. The durations of disease in each person were lined up sequentially until death occurred either from natural causes, as determined in the first step, or from liver-related causes (hepatic decompensation, hepatocellular carcinoma, or liver transplantation). Thus, for each individual cohort member, we assigned the age at death, cause of death, and time spent in each disease state. After the data set was created, such important summary statistics as time to death and QALYs were tabulated. This simulation process was repeated 30 times; at that point, means and CIs were obtained.
Validation of the Natural History Model
We tested the validity of our model by attempting to reproduce long-term morbidity and mortality data already in the literature. We chose two studies that seemed to have widely different outcomes: the study by Seeff and colleagues [37] and the study by Tong and associates [36]. Neither of these studies was used to create our model. We assumed that chronic hepatitis C occurred in 70% of patients with acute non-A, non-B hepatitis [35]. The starting point of our model (chronic hepatitis C) was 3.5 years after acquisition of HCV [4]. We judged that the model would be acceptable if the 95% CIs generated by the model included the point estimates described in the respective studies.
Seeff and colleagues described the survival of patients who developed non-A, non-B post-transfusion hepatitis at the time of cardiac surgery. Using the general demographic data presented in the report (n = 568; all-cause mortality rate, 51% over 18 years), we simulated two cohorts of 568 patients with and without chronic hepatitis C who were 50 years of age and had an annual mortality rate of 3.5%. We computed the number of deaths attributable to chronic hepatitis C. Our model predicted that the number of liver-related deaths (deaths resulting from decompensated cirrhosis or hepatocellular carcinoma or after liver transplantation) would be 11.5 (95% CI, 3.7 to 19.4), or 2.0% of the cohort. This correlated with the excess mortality of 1.8% from liver disease in patients with HCV infection reported by Seeff and colleagues.
In Tong and associates' study, the presumed duration of HCV infection was retrospectively determined in patients with cirrhosis and hepatocellular carcinoma. Patients were divided into two groups according to age at the time of acquisition of HCV (mean, 29 years and 59 years). We modeled two cohorts of 1000 patients each; in one, patients were 29 years of age, and in the other patients were 59 years of age. We used our model to determine the mean duration of infection in patients with hepatitis C cirrhosis (82% of Tong and associates' patients had decompensated cirrhosis and 18% had compensated cirrhosis) and hepatocellular carcinoma. The intervals to the development of cirrhosis and hepatocellular carcinoma predicted by our model were 20.0 years (CI, 19.0 to 21.0 years) and 27.2 years (CI, 24.5 to 30.0 years), respectively; these values are similar to Tong and associates' reported intervals of 20.6 and 28.3 years.
Mr. Hermans and Dr. Therneau: Section of Biostatistics (Harwick 7), Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905.
Dr. Evans: Section of Health Services Evaluation (Harwick 8), Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905.
Author and Article Information
|
|---|
|
TopMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
References
|
|---|
|
TopMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
1. Hepatitis Branch, Centers for Disease Control and Prevention. 1997 Hepatitis C Fact Sheet. Atlanta, GA: Centers for Disease Control and Prevention; 1997.
2. Hoofnagle JH, Lau D. Chronic viral hepatitis-benefits of current therapies [Editorial]. N Engl J Med. 1996; 334; 1470-1.
3. Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC Jr, Perrilo RP, et al. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. Hepatitis Interventional Therapy Group. N Engl J Med. 1989; 321:1501-6.
4. Di Bisceglie AM, Martin P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J, et al. Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. N Engl J Med. 1989; 321:1506-10.[Abstract]
5. Chemello L, Bonetti P, Cavalletto L, Talato F, Donadon V, Casarin P, et al. Randomized trial comparing three different regimens of -2a-interferon in chronic hepatitis C. The TriVento Viral Hepatitis Group. Hepatology. 1995; 22:700-6.
6. Poynard T, Bedossa P, Chevallier M, Mathurin P, Lemonnier C, Trepo C, et al. A comparison of three interferon alfa-2b regimens for the long-term treatment of chronic non-A, non-B hepatitis. Multicenter Study Group. N Engl J Med 1995; 332:1457-62.
7. Koretz RL. Interferon and chronic non-A, non-B hepatitis: whom are we treating? Hepatology. 1990; 12:613-5.
8. Dusheiko GM, Roberts JA. Treatment of chronic type B and C hepatitis with interferon alfa: an economic appraisal. Hepatology. 1995; 22:1863-73.
9. Bennett WG, Inoue Y, Beck JR, Paulker SG, Davis GL. Justification of a single 6-month course of interferon for histologically mild chronic hepatitis C [Abstract]. Hepatology. 1995; 22(S):290A.
10. Yousuf M, Nakano Y, Tanaka E, Sodeyama T, Kiyosawa K. Persistence of viremia in patients with type-C chronic hepatitis during long-term follow-up. Scand J Gastroenterol. 1992; 27:812-6.
11. Tremolada F, Casarin C, Alberti A, Drago C, Tagger A, Ribero ML, et al. Long-term follow-up of non-A, non-B (type C) post-transfusion hepatitis. 1992; 16:273-81.
12. Vaquer P, Canet R, Llompart A, Riera J, Ovrador A, Gaya J. Histological evolution of chronic hepatitis C: factors related to progression. Liver. 1994; 14:265-9.
13. Kiyosawa K, Sodeyama T, Tanaka E, Gibo Y, Yoshizawa K, Nakano Y, et al. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology. 1990; 12:671-5.
14. Wejstal R, Hermodsson S, Norkrans G. Long-term follow-up of chronic hepatitis non-A, non-B-with special reference to hepatitis C. Liver. 1991; 11:143-8.
15. Yano M, Yatsuhashi H, Inoue O, Inokuchi K, Koga M. Epidemiology and long term prognosis of hepatitis C virus infection in Japan. Gut. 1993; (2 Suppl):S13-6.
16. Kiyosawa K, Tanaka E, Sodeyama T, Furuta S. Natural history of hepatitis C. Intervirology. 1994; 37:101-7.
17. Di Bisceglie AM, Goodman ZD, Ishak KG, Hoofnagle JH, Melpolder JJ, Alter HJ. Long-term clinical and histopathological follow-up of chronic post-transfusion hepatitis. Hepatology. 1991; 14:969-74.[Medline]
18. Takahashi M, Yamada G, Miyamoto R, Doi T, Endo H, Tsuji T. Natural course of chronic hepatitis C. Am J Gastroenterol. 1993; 88:240-3.
19. Gines P, Quintero E, Arroyo V, Teres J, Bruguera M, Rimola A, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology. 1987; 7:122-8.
20. Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology. 1997; 112:463-72.
21. Colombo M, de Franchis R, Del Ninno E, Sangiovanni A, De Fazio C, Tommasini M, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med. 1991; 325:675-80.
22. Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med. 1993; 328:1797-801.
23. Belle SH, Beringer KC, Detre KM. An update on liver transplantation in the United States: recipient characteristics and outcome. In; Terasaki Pl, Cecka JM, eds. Clinical Transplants 1995. Los Angeles: UCLA Tissue Typing Laboratory; 1995:19-33.
24. Gane EJ, Portmann BC, Naoumov NV, Smith HM, Underhill JA, Donaldson PT, et al. Long-term outcome of hepatitis C infection after liver transplantation. N Engl J Med. 1996; 334:815-20.
25. National Center for Health Statistics. Vital Statistics of the United States, 1990. v II, Mortality, Part A. Washington, DC: Public Health Service; 1994.
26. Silini E, Bono F, Cividini A, Cerino A, Bruno S, Rossi S, et al. Differential distribution of hepatitis C virus genotypes in patients with and without liver function abnormalities, Hepatology. 1995; 21:285-90.
27. Zein NN, Rakela J, Krawitt EL, Reddy KR, Tominaga T, Persing DH. Hepatitis C virus genotypes in the United States: epidemiology, pathogenicity, and response to interferon therapy. Collaborative Study Group. Ann Intern Med. 1996; 125:634-9.
28. Marcellin P, Pouteau M, Martino-Peignoux M, Degos F, Duchatelle V, Boyer N, et al. Lack of benefit of escalating dosage of interferon alfa in patients with chronic hepatitis C. Gastroenteroloy. 1995; 109:156-65.
29. Brown DM, Everhart JE. Cost of digestive diseases in the United States. In: Everhart JE, ed. Digestive Diseases in the United States: Epidemiology and Impact. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1994.
30. Evens RW. Liver transplantation in a managed care environment. Liver Transplantation and Surgery. 1995; 1:61-75.
31. Kim WR, Therneau TM, Dickson ER, Evans RW. Preoperative predictors of resource utilization in liver transplantation. In: Terasaki PI, Cecka JM, eds. Clinical Transplants 1995. Los Angeles: UCLA Tissue Typing Laboratory; 1995:315-22.
32. Drug Topics Red Book. Montvale, NJ: Medical Economics; 1995.
33. Petitti DB. Meta-Analysis, Decision-Analysis and Cost-Effectiveness Analysis: Methods for Quantitative Synthesis in Medicine. New York: Oxford Univ Pr; 1994:119-24.
34. Drummond MF, Stoddart GL, Torrance GW. Methods for the Economic Evaluation of Health Care Programmes. Oxford: Oxford Medical Publications; 1987.
35. Alter MJ, Margolis HS, Krawczynski K, Judson FN, Mares A, Alexander WJ, et al. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study. N Engl J Med. 1992; 327:1899-905.
36. Tong MJ, el-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med. 1995; 332:1463-6.
37. Seeff LB, Buskell-Bales Z, Wright EC, Durako SJ, Alter HJ, Iber FL, et al. Long-term mortality after transfusion-associated non-A non-B hepatitis. The National Heart, Lung, and Blood Institute Study. N Engl J Med. 1992; 327:1906-11.
38. Lindfors KK, Rosenquist CJ. The cost-effectiveness of mammographic screening strategies. JAMA. 1995; 274:881-4.
39. Kinosian BP, Eisenberg JM. Cutting into cholesterol. Cost-effective alternatives for treating hypercholesterolemia. JAMA. 1988; 259:2249-54.
40. Marcellin P, Boyer N, Giostra E, Degott C, Courouce AM, Degos F, et al. Recombinant human -interferon in patients with chronic non-A, non-B hepatitis: a multicenter randomized controlled trial from France. Hepatology. 1991; 13:393-7.
41. Saez-Royuela F, Porres JC, Moreno A, Castillo I, Martinez G, Galiana F, et al. High doses of recombinant -interferon or 
-interferon for chronic hepatitis C: a randomized, controlled trial. Hepatology. 1991; 13:327-31.
42. Friedlander L, van Thiel DH, Faruki H, Molly PJ, Kania RJ, Hassanein T. New approach to HCV treatment. Recognition of disease process as systemic viral infection rather than as liver disease. Dig Dis Sci. 1996; 41:1678-81.
43. Eisenberg JM. Clinical economics. A guide to the economic analysis of clinical practices. JAMA. 1989; 262:2879-86.
44. Avorn J. Benefit and cost analysis in geriatric care; turning age discrimination into health policy. N Engl J Med. 1984; 310:1294-301.
45. Ampurdanes S, Olmedo E, Maluenda MD, Forns X, Lopez-Labrador FX, Costa J, et al. Permanent response to -interferon therapy in chronic hepatitis C is preceded by rapid clearance of HCV-RNA from serum. J Hepatol. 1996; 25:827-32.
46. Wong LL, McFall P, Wong LM. The cost of dying of end-stage liver disease. Arch Intern Med. 1997; 157:1429-32.
47. Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC Jr, Perrillo RP, et al. Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile. Clin Ther. 1994; 16:334-43.
48. La Puma J, Lawler EF. Quality-adjusted life-years. Ethical implications for physicians and policymakers. JAMA. 1990; 263:2917-21.
49. Siegel JE, Weinstein MC, Russell LB, Gold MR. Recommendations for reporting cost-effectiveness analyses. Panel on Cost-Effectiveness in Health and Medicine. JAMA. 1996; 276:1339-41.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
Related articles in Annals:
2b in Patients with Histologically Mild Chronic Hepatitis C Therapy for Chronic Hepatitis C: Reducing the UncertaintiesThis article has been cited by other articles:
|
|
 |
|
  S. Deuffic-Burban, P. Mathurin, and A.-J. Valleron Modelling the past, current and future HCV burden in France: detailed analysis and perspectives Statistical Methods in Medical Research, June 1, 2009; 18(3): 233 - 252. [Abstract] [PDF]
|
|
|
|
 |
|
 D. J. McLernon, J. Dillon, and P. T. Donnan Systematic Review: Health-State Utilities in Liver Disease: A Systematic Review Med Decis Making, July 1, 2008; 28(4): 582 - 592. [Abstract] [PDF]
|
|
|
|
 |
|
 D. W. Hutton, D. Tan, S. K. So, and M. L. Brandeau Cost-Effectiveness of Screening and Vaccinating Asian and Pacific Islander Adults for Hepatitis B Ann Intern Med, October 2, 2007; 147(7): 460 - 469. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. Sherman, S. N. Sherman, T. Chenier, and J. Tsevat Health Values of Patients With Chronic Hepatitis C Infection Arch Intern Med, November 22, 2004; 164(21): 2377 - 2382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Krahn, J. B. Wong, J. Heathcote, L. Scully, and L. Seeff Estimating the Prognosis of Hepatitis C Patients Infected by Transfusion in Canada between 1986 and 1990 Med Decis Making, January 1, 2004; 24(1): 20 - 29. [Abstract] [PDF]
|
|
|
|
 |
|
 J. A. Salomon, M. C. Weinstein, J. K. Hammitt, and S. J. Goldie Cost-effectiveness of Treatment for Chronic Hepatitis C Infection in an Evolving Patient Population JAMA, July 9, 2003; 290(2): 228 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Colli, M. Fraquelli, M. Andreoletti, B. Marino, E. Zuccoli, and D. Conte Severe Liver Fibrosis or Cirrhosis: Accuracy of US for Detection--Analysis of 300 Cases Radiology, April 1, 2003; 227(1): 89 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. C. Kuehne, U. Bethe, K. Freedberg, and S. J. Goldie Treatment for Hepatitis C Virus in Human Immunodeficiency Virus-Infected Patients: Clinical Benefits and Cost-effectiveness Arch Intern Med, December 9, 2002; 162(22): 2545 - 2556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Wong and R. S. Koff Watchful Waiting with Periodic Liver Biopsy versus Immediate Empirical Therapy for Histologically Mild Chronic Hepatitis C: A Cost-Effectiveness Analysis Ann Intern Med, November 7, 2000; 133(9): 665 - 675. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Henley, D. J. van Leeuwen, J. B. Wong, R. S. Koff, and S. G. Pauker Cost-effectiveness of Interferon Treatment for Hepatitis C JAMA, June 9, 1999; 281(22): 2083 - 2084. [Full Text] [PDF]
|
|
|
|
|
|
J. B. Wong, W. G. Bennett, R. S. Koff, and S. G. Pauker Pretreatment Evaluation of Chronic Hepatitis C: Risks, Benefits, and Costs JAMA, December 23, 1998; 280(24): 2088 - 2093. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 INTERFERON-ALPHA FOR HEPATITIS C: IS IT WORTH IT? Journal Watch (General), December 12, 1997; 1997(1212): 1 - 1. [Full Text]
|
|
