Recombinant interferon remains the only agent approved by the U.S. Food and Drug Administration for the treatment of chronic hepatitis C and is usually administered at a dosage of 3 million U three times per week for 6 months. However, although more than 40% of patients overall initially respond with normalization of the serum alanine aminotransferase (ALT) level and loss of detectable HCV RNA during treatment, most patients relapse [4, 5]. Only 10% to 15% of patients achieve a sustained long-term response to a single 6-month course of interferon therapy [4, 5].

Patients with histologically less advanced liver disease have a greater long-term response to interferon, but treatment of these patients remains controversial because interferon is expensive and can be associated with side effects, most patients with chronic hepatitis C relapse and need to be retreated, and histologically mild disease progresses relatively slowly [6].

Given the lack of controlled clinical trials on the effect of interferon therapy in patients with mild chronic hepatitis C, the modest long-term response rate to interferon, and the many years usually required before disease complications arise, we developed a decision analytic model [7] to project the immediate responses to treatment and predict the long-term outcomes on the basis of current natural history data. We sought to determine whether treatment of histologically mild chronic hepatitis C with a single 6-month course of interferon-2b would affect life expectancy and lifelong costs.

Methods

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Decision Analytic Model

To determine the expected consequences of interferon therapy in patients with mild chronic hepatitis C, we developed a decision analytic model to simulate disease progression and compare standard care with interferon-2b treatment. The natural history of chronic hepatitis C was modeled by using a Markov simulation in which hypothetical cohorts of identical patients with histologically mild chronic hepatitis move through states of health defined by clinical and histologic descriptors (Figure 1). Time is represented by annual cycles during which patients may remain in the same histologic or clinical state; progress or regress to another histologic or clinical state; die of liver disease; or die of other causes as a function of sex, race, and attained age. The simulation was carried out in each cohort until all patients died of liver-related or other causes.

View larger version (26K): [in this window] [in a new window]   Figure 1. Schematic of the Markov model with health states and annual probabilities (expressed as percentages) of disease progression. The annual probability for liver transplantation from any liver failure state is 3.1%. The two health states for both variceal bleeding and hepatic encephalopathy refer to the rates of progression for the first and subsequent years. HCC = hepatocellular carcinoma; HCV = hepatitis C virus.

By recording the proportion of the cohort remaining alive and treatment costs for each year, the simulation estimated the life expectancy and lifetime cost associated with each treatment intervention. Calculations were done by using DecisionMaker 7.0 (Pratt Medical Group, Boston, Massachusetts) [8]. Because the quality of life associated with some health states may be less desirable than that associated with other states, we also adjusted life expectancy for quality of life on a scale from 0 (dead) to 1 (perfect health). Using a modified Delphi approach, an expert panel of hepatologists estimated the quality of life for each health state [9]. In these analyses, patients who were alive but in less desirable health states were not given full credit for each year lived but instead received only partial credit (for example, 0.7 years for 1 year of life with cirrhosis). At the end of the simulation, the quality-adjusted life-years were summed, yielding the quality-adjusted life expectancy.

Data Sources

Likelihood of Events

The natural history of hepatitis C was estimated from published studies. When the sample size was small or follow-up was short, several studies were pooled. All likelihood estimates were reviewed by an expert panel of hepatologists and statisticians and, after extensive discussion, were modified where appropriate.

Treatment Response

Treatment responses were determined according to baseline histologic findings by reanalysis of the pooled data from five clinical trials involving 287 patients with chronic hepatitis C [4, 10-13]. These studies were selected because they all used the same treatment regimen (recombinant interferon-2b at a fixed dose of 3 million U administered three times weekly for 6 months), had systematic follow-up after treatment, and had liver biopsy slides and study databases available for review (provided courtesy of Schering-Plough Research Institute with the consent of the studies' principal investigators). All patients were positive for antibody to HCV and had no evidence of coexisting liver diseases. A single pathologist who was blinded to liver enzyme levels, clinical history, and response to therapy reviewed the 221 available pretreatment liver biopsy specimens and established the correlation of histologic findings and response. We used the histologic activity index of Knodell [14] and a modification of the classification of Desmet and coworkers [15]. In the absence of cirrhosis or bridging fibrosis, mild chronic hepatitis required a Knodell periportal inflammation score of 0 or 1 and moderate chronic hepatitis required a score of 3 to 10. Regardless of the Knodell inflammation score, chronic hepatitis with fibrosis required a Knodell fibrosis score of 3 (bridging fibrosis), and chronic hepatitis with cirrhosis required a score of 4 (cirrhosis). These categories approximated previously used histologic definitions of chronic persistent hepatitis or mild chronic active hepatitis, moderate chronic active hepatitis, chronic active hepatitis with bridging, and cirrhosis, respectively.

We used traditional definitions of response [4]: Persons with no response had ALT levels that did not return to normal by the end of treatment, persons with an end-of-treatment response had an unsustained normalization of the serum ALT level, and persons with a sustained response had a persistently normal serum ALT level for at least 6 months after completion of therapy.

An end-of-treatment response occurred in 64% of patients with mild or moderate chronic hepatitis without fibrosis, 42% of those with chronic hepatitis with fibrosis, and 28% of those with cirrhosis. A sustained response occurred in 31% of those with mild or moderate hepatitis, 11% of those with chronic hepatitis with fibrosis, and 9% of those with cirrhosis. Table 1 lists similar rates in studies that used the same dose and duration of interferon-2b treatment [4, 11, 13, 16-18]. Because approximately 14% of persons who had a sustained response have either persistent viremia or virologic relapse despite a persistently normal serum ALT level [19], we reduced the 31% sustained response rate by 14% to estimate a durable long-term viral-negative response rate of 27% in patients with mild to moderate chronic hepatitis.

View this table: [in this window] [in a new window]   Table 1. Estimates of Sustained Response to Interferon-2b, 3 Million U Three Times Weekly for 24 Weeks

Costs

Because charges often vary among providers and can be artificially inflated because of payer mix and institutional costs, the use of charges tends to bias an economic analysis in favor of treatment by increasing the cost of disease. Thus, we used costs or adjusted charges, not full charges, to make the model more widely applicable and to remove a potential bias in favor of interferon-2b treatment. We used a managed care perspective and variable cost estimates (the amount spent by the hospital to care for one additional patient with the illness) based on inpatient variable cost estimates for actual patients with hepatitis C-related hospitalizations, including hospital and physician costs at the University of Florida. Because variable cost data were not available for outpatient medical care, charges for outpatient physician visits, outpatient laboratory evaluations, and radiography were summed and adjusted by a 50% cost-to-charge ratio to estimate complete outpatient costs. The wholesale cost of outpatient medications was obtained from the 1995 Red Book [20]. A panel of hepatologists estimated the frequencies of outpatient visits and laboratory tests and the amount of each medication used for each health state per year. Finally, we did not consider the cost of adverse reactions to interferon-2b because severe complications are unusual and typically resolve with discontinuation of treatment, rarely incurring additional cost [4].

Assumptions of the Model

We assumed that patients with relapse are not re-treated and that their subsequent prognosis is identical to that of patients with no response (that is, a short-term response to interferon-2b conveys no long-term benefit). We also assumed that patients who lose HCV either spontaneously or as a result of treatment will not develop progressive liver disease [21-23]. Indeed, long-term histologic follow-up of patients with sustained response has found that inflammation resolves and fibrosis regresses after 2 years [23].

Because data on the effect of extrahepatic complications of HCV infection on disease progression, morbidity, mortality, and response to treatment are insufficient, we could not model the impact of these data.

We could not determine with certainty the age-dependent rate of liver disease progression from published studies, although some reports suggest that histologic progression may be accelerated in patients older than 55 years of age [2, 24]. Thus, we excluded age from the model. Because this exclusion may cause the model to underestimate progression in older patients, we would also underestimate disease complications, death, and cost. This, in turn, would reduce the apparent cost of untreated disease and make any treatment effect on cost more difficult to detect. Thus, exclusion of age-dependent disease progression from the model biases against interferon-2b in older patients.

We did not consider serial liver biopsies. Because we assumed that no re-treatment would be given, biopsy would not affect treatment and would only add cost and morbidity. Thus, although our model contains other histologic states, these states remain unobserved clinically until patients develop decompensated liver disease. The cost of follow-up then equals the cost for patients with mild chronic hepatitis until patients are found to be viral negative or until they present with decompensated liver disease. This is a bias against interferon-2b.

Although the model permits liver transplantation for cirrhosis, it does not consider liver transplantation for hepatocellular carcinoma, which, although performed in some centers, generally remains an investigational therapy. After patients undergo liver transplantation, we did not consider decreased survival from recurrent hepatitis C or hepatocellular carcinoma because of inadequate data. This is a bias against interferon-2b.

We could not consider viral factors, such as genotype, pretreatment level of viremia, or presumed source of infection, in this model. Although these factors may affect response to interferon-2b treatment, they were not available for most patients, and retrospective analysis of stored serum samples for measurement of viral levels may be unreliable [25].

Data

Natural History of Chronic Hepatitis C

Because HCV has only recently been described [26] and the progression of chronic HCV infection is slow [2], data on the natural progression of this disease are limited. We estimated the natural history of hepatitis C from three retrospective observational studies that included serial liver biopsies of patients with non-A, non-B chronic hepatitis. These studies comprised 47 patients with mild chronic hepatitis (mean duration of follow-up ±SD, 8.9 ± 9 years) and 79 patients with moderate chronic hepatitis (mean duration of follow-up, 6.6 ± 6 years) [8, 27, 28] (Table 2).

We estimated the probability of spontaneous resolution of hepatitis C to be 0.2% on the basis of a study in which 2 of 111 patients who were positive for antibody to HCV and had chronic hepatitis developed persistently normal ALT levels, spontaneous clearance of HCV RNA (as measured by polymerase chain reaction), and normal liver histologic findings over a mean follow-up of 8.8 years [29].

We used the only published natural history study of patients with compensated cirrhosis and hepatitis C [30] to determine the likelihood of development of hepatocellular carcinoma and decompensated cirrhosis (Table 2). Because the literature suggests that the mortality rate from decompensated liver disease (12% to 68%) depends on the presenting mode of decompensation, we stratified decompensation into diuretic-sensitive ascites, diuretic-refractory ascites, variceal hemorrhage, and hepatic encephalopathy. Salerno and colleagues' study [31] of 110 patients with diuretic-sensitive ascites (excluding patients who developed refractory ascites) had an annual excess mortality rate of 11% over the 3-year follow-up. Among patients with refractory ascites, the annual excess mortality increased to 33% [31]. The Veterans Affairs Cooperative Sclerotherapy trial [32] of 253 patients with initial variceal hemorrhage yielded a first-year excess mortality rate of 40%, which is similar to the rates reported in other published studies [33, 37]. Among the 111 patients who survived the first year, the subsequent annual excess mortality rate was 13% over a 3-year follow-up [32]; this is similar to the 12% rate in Christensen and colleagues' study after variceal hemorrhage [33]. This study also found that 108 patients presenting with hepatic encephalopathy without variceal hemorrhage had an annual excess mortality rate of 68% for the first year and 40% for subsequent years.

Because the natural history of decompensated liver disease may be altered by liver transplantation, we had to estimate the number of patients with chronic hepatitis C who were eligible for liver transplantation in the United States. The Centers for Disease Control and Prevention estimates that approximately 8300 persons die of complications of chronic hepatitis C each year [38]. Given that the median duration of survival is 1.6 years for patients with decompensated liver disease, 35% of them die each year [39]. From these data, it appears that each year, 23 700 (8300 ÷ 0.35) persons have decompensated liver disease related to chronic hepatitis C. The United Network of Organ Sharing (UNOS) reported that 730 (20%) of the 3650 liver transplantations performed in the United States in 1994 were done for complications of chronic hepatitis C [40]. Thus, the annual probability of liver transplantation for patients with decompensated hepatitis C is approximately 3.1% (730 ÷ 23 700). We assumed that, on average, the probability of liver transplantation was equal across all degrees of liver decompensation because more severely ill patients are also more likely to die or become ineligible before receiving a liver transplant.

On the basis of three studies involving 2166 patients undergoing liver transplantation for chronic hepatitis [34-36], we estimated the annual excess mortality rate to be 21% for the first year after liver transplantation and 5.7% for all subsequent years.

Sensitivity Analysis

Because of the variation in published data and expert estimates, we examined the effect of varying all values over a wide range to assess their effect on the results. We used a range identified by using the 95% CIs, halved and doubled cost and data estimates, or used the range from the literature (whichever was greatest) (Table 2). Wherever appropriate, we used estimates that biased against interferon-2b therapy.

Quality of Life

Although chronic hepatitis C has documented effects on quality of life [41], estimates for the various stages of the disease and for treatment remain unknown. Ideally, these estimates should be obtained from patient surveys, but no surveys are available. Instead, we asked a panel of hepatologists to use linear scaling and time trade-off methods to estimate the quality of life or utility for each health state listed in Table 3 on a scale of 0 (death) to 10 (perfect health). We used the median values in the base case and the extreme low or high utility estimate in the sensitivity analysis.

Costs and Discounting

Discounting assumes that money saved or spent and years saved or lost in the future are not worth as much as they are today. This process reduces future costs and future life-years by a fixed percentage each year [7] so that up-front costs, such as the cost of interferon-2b treatment, weigh more than the projected future costs of potential late complications from the disease. Because discounting, particularly of survival benefits, is somewhat controversial, we also calculated costs and life expectancy without discounting (Table 4). Costs, wholesale prices, or charges adjusted by a cost-to-charge ratio were used for all calculations. The cost of a 6-month course of interferon-2b at 3 million U three times weekly was $2150 [20]; this cost increased to $2511 after the addition of drug-induced costs for counseling patients, additional follow-up laboratory evaluations, and visits. However, for patients who were unresponsive to interferon-2b and had treatment discontinued after 3 months, the cost was reduced to $1253. Such patients have almost no chance of subsequent response even with continued treatment [1, 4].

Industry Role

This study was funded in part by an unrestricted grant from Schering-Plough to the investigators' institutions. The grant sponsor had no input into study design, data analysis, manuscript preparation, or the decision to submit the paper for publication. The Schering-Plough Research Institute (the branch of the company that conducts clinical trials) facilitated access to clinical trial databases, including the original liver biopsy slides. However, this information was provided as raw data and the authors performed all analyses.

None of the authors owns stock or has any other relationship with Schering-Plough that would represent a conflict of interest. One of the authors (GLD) has grant support from the Schering-Plough Research Institute for clinical research studies.

Results

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Model Validation

Because data on the natural history of hepatitis C are recent and somewhat uncertain, we tested the validity of our analysis by comparing model predictions with findings from published studies. Most hepatologists believe that Seeff and colleagues' long-term follow-up study of 568 patients with acute post-transfusion hepatitis [2] represents a very conservative view of disease progression, supporting a "benign" natural history of chronic hepatitis C. This study included patients with acute post-transfusion hepatitis, but an unknown proportion developed chronic hepatitis. Assuming that 80% of these patients with post-transfusion hepatitis developed chronic hepatitis and considering a cohort that matches the age and mortality rates from nonliver disease of Seeff and colleagues' study, our Markov model predicted that 2.3% of patients would die of liver disease after 18 years compared with the 3.3% observed in Seeff and colleagues' study. We also compared the prognosis for patients with compensated cirrhosis predicted by our model to that observed in the sole study examining this outcome [30]. Our model predicted a 5-year survival rate of 55%; the rate in Fattovich and colleagues' study [30] was 50%. Thus, our model seems to provide relatively conservative estimates of disease progression, biasing our results against interferon-2b.

Base-Case Analysis

Our base-case analysis considers a 35-year-old person presenting with histologically mild chronic hepatitis C. When undiscounted costs are used, interferon-2b would save $3500 by reducing long-term medical costs in responding patients and would increase the cohort's life expectancy by 1.5 years (Table 5). Discounting at a 5% annual rate decreases the economic impact of future medical expenditures and reduces the benefit of future improved survival associated with interferon-2b so that interferon-2b costs $490 (discounted) more than standard care while adding 0.26 discounted life-years, yielding a discounted marginal cost-effective ratio of $1900 per life-year gained (Figure 2).

View larger version (14K): [in this window] [in a new window]   Figure 2. The effect of discounting on the marginal cost-effectiveness ratio. The y-axis values that exceed zero represent an excess cost of interferon-2b; values less than zero represent a net cost savings from interferon-2b. The x-axis represents the probability of a sustained viral-negative response to treatment with the 27% base-case value for patients with histologically mild chronic hepatitis C (arrow).

As expected, the survival benefit and cost-effectiveness of interferon-2b for mild chronic hepatitis C decreased with advancing age Figure 3 and Figure 4). For patients 20 to 50 years of age, the increase in life expectancy ranged from 3.1 to 0.5 years and the discounted marginal cost-effectiveness ratios ranged from $530 to $7100. For 60- and 70-year-old patients, life expectancy increased by 2 and 0.7 months, respectively, and the discounted marginal cost-effectiveness ratios increased to $19 000 and $62 000, respectively.

View larger version (18K): [in this window] [in a new window]   Figure 3. The effect of age at the time of interferon-2b treatment for histologically mild chronic hepatitis C on the estimated gain in life expectancy.

View larger version (19K): [in this window] [in a new window]   Figure 4. The effect of age at the time of interferon-2b treatment for histologically mild chronic hepatitis C on the discounted marginal cost-effectiveness ratio.

Sensitivity Analysis

We varied each model variable over a wide range of possible values (Table 2). When quality-of-life adjustments were used (Table 3), interferon-2b increased life expectancy by 3.7 quality-adjusted years at a discounted marginal cost-effectiveness ratio of $430. Although our analysis used the traditional 5% discount rate, it was recently suggested that a 3% discount rate might be more appropriate [42]. If the analysis were to use a 3% discount rate instead of the traditional 5% rate that we report here, interferon-2b treatment becomes cost saving (by prolonging life and reducing lifetime expenditures).

Only four variables (cost of interferon-2b, response to interferon-2b, rate of transition from mild chronic hepatitis to moderate chronic hepatitis, and rate of transition from moderate chronic hepatitis to cirrhosis) changed the results significantly. Table 6 shows the impact on marginal cost-effectiveness of varying each of these variables over a wide range and compares these with the base-case analysis. Although altering the cost of interferon-2b in the model significantly increases the marginal cost-effectiveness ratio, drug cost is unlikely to be higher than the value we used in the base-case analysis. Indeed, the true cost (not charge) is probably overestimated by the baseline value because bulk buying significantly reduces the cost of the drug. A worst-case scenario was defined in which all four of these variables (values in Table 6 marked by a ) were biased against interferon-to the limits of what was considered plausible (by halving histologic progression rates, reducing the response to interferon-to the viral-negative response observed in patients with fibrosis and cirrhosis, and increasing the cost of interferon-fourfold). When this worst-case scenario is used, treatment increased life expectancy by a range of 5 months for a 20-year-old patient to 2 days for a 70-year-old patient at discounted marginal cost-effectiveness ratios of $67 000 to $1.3 million, respectively. Leaving the cost of interferon-at $2511 but changing the other variables resulted in a discounted marginal cost-effectiveness ratio that ranged from $31 000 for a 20-year-old patient to $640 000 for a 70-year-old patient. If these latter three values (response to interferon-and progression rates) were changed to the limits shown for the sensitivity analysis, our model would have predicted that Seeff and colleagues' study should have found only 0.8% liver-related deaths after 18 years rather than the 3.3% that they did find.

Because we derived variable cost estimates from actual patients with hepatitis C from just one institution, we also estimated costs based on diagnosis-related groups (DRGs), as developed by the Health Care Financing Administration [43, 44]. According to 50th-percentile DRG reimbursements, interferon-therapy was cost saving for 20- to 35-year-old patients; discounted marginal cost-effectiveness ratios were less than $30 000 for patients younger than 65 years of age but increased to $58 000 for 70-year-old patients.

Finally, some may believe that response to interferon may occur only in patients who would spontaneously become viral negative. Thus, to explore whether earlier loss of virus resulted from interferon, we modified the model to assume a 6.2% annual probability of spontaneously becoming viral negative in the standard therapy strategy (>30 times the rate used in the model) so that over a 5-year period, 27% of this group becomes viral negative. In the interferon-group, we assumed that all patients who do not become viral negative after treatment will never become viral negative. In this analysis, interferon-increased life expectancy by 0.3 years at a marginal cost-effectiveness ratio of $22 000 per discounted quality-adjusted life-year gained. Earlier conversion to a viral-negative state protected some patients from developing complications.

Our base-case analysis biased against interferon-by excluding quality-of-life adjustments and using conservative discounted variable costs. When both quality-of-life adjustments and DRG reimbursements were used, interferon-was cost saving for 20- and 35-year-old patients and had a discounted marginal cost-effectiveness ratio less than $5000 for all patients 45 to 70 years of age.

Discussion

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Chronic hepatitis C usually has a slow rate of progression; only a minority of patients develop cirrhosis with hepatic failure. The rate of progression to cirrhosis depends on the amount of inflammation seen on liver biopsy: Patients with mild hepatitis have a slow rate of progression over decades, whereas those with severe inflammation or fibrosis usually develop cirrhosis within 10 years [6]. Interferon-treatment achieves a sustained viral-negative response in only a minority of patients [4, 5]. Although the indication for interferon-treatment is unequivocal in patients with moderately severe inflammation or early fibrosis [45], the benefits of treatment in those with histologically mild disease is less certain. Long-term placebo-controlled trials might establish the benefit of interferon-in this group; such a study would be extremely expensive, however, and the slow rate of spontaneous progression would mandate decades of follow-up in thousands of patients in order to observe a treatment effect. Because treatment decisions must be made now, we turned to decision analysis to assess long-term clinical outcomes and the cost-effectiveness of interferon-in treating chronic hepatitis C on the basis of the best available, albeit imperfect, information.

Our decision model differs from other published models [46, 47] in that it focused on patients with mild chronic hepatitis C who have a good long-term prognosis and a greater likelihood of response to interferon-treatment compared with patients who have fibrosis or cirrhosis. Previously published models have not distinguished patients with fibrosis or cirrhosis from those with mild hepatitis. Second, in estimating the natural history of hepatitis C, we based our progression and decompensation rates on literature estimates for non-A, non-B or C hepatitis. In contrast, Shiell and colleagues [46] and Dusheiko and coworkers [47] based several of their progression estimations on studies of patients with liver diseases other than chronic hepatitis C. Shiell and colleagues' 1.1% annual rate of progression to cirrhosis may be an underestimate. Tong and associates [24] reported that 52% of 130 patients with post-transfusion hepatitis C developed cirrhosis after 22 years, and Kiyosawa and colleagues [48] observed that the mean duration of disease from HCV exposure to cirrhosis may be 21 years. Together, these reports suggest that the risk for cirrhosis may be as high as 50% after 20 years of disease. Nonetheless, we based our model on conservative estimates of disease progression, projecting the risk for compensated cirrhosis to be 28% after 20 years. We used an annual risk for developing decompensated cirrhosis from compensated cirrhosis of 4.0% based on the only published data for hepatitis C. This study was unavailable when Shiell and colleagues (who used a risk of 1.9%) and Dusheiko and associates published their studies. Our model also separated patients with hepatic decompensation into different modes to allow more precise modeling of clinical outcomes and costs.

We estimated costs and survival over a lifetime, whereas the other studies estimated costs and effects over only 20 to 30 years [46, 47]. Costs of therapy in Shiell and colleagues' study were higher because patients received a full 24 weeks of interferon-alpha2b. In contrast, we assumed that interferon-therapy was stopped after the first 12 weeks if patients did not respond, thus reducing treatment cost by half in the 46% who did not respond (or by one fourth overall).

Our use of variable costs and cost-adjusted charges instead of total charges biases our results against interferon-by reducing the apparent savings achieved from successful treatment. Variable costs (the cost of treating one additional patient, rather than the first patient) are lower than average costs (total cost ÷ number of patients), which may include fixed costs such as buildings, maintenance, and administrative personnel. Variable costs consist primarily of personnel time and additional materials consumed. The use of variable costs assumes that sufficient excess capacity exists within the established system to accommodate one more patient without the need for further capital investment [42]. By using variable costs (which were less than one fourth of total charges and less than half of total estimated costs) and excluding any induced fixed costs, our baseline costs should underestimate the potential financial benefits of interferon-alpha2b.

When the recently recommended 3% discount rate was used, interferon- for hepatitis C is cost saving, just as it is for patients with chronic hepatitis B [49]. Using the traditional 5% rate biases our results against interferon- because its cost is incurred up front, whereas savings are in the future; in this context, interferon- is more expensive (in discounted dollars) than standard care. Nonetheless, its discounted marginal cost-effectiveness ratio of $1900 per year of life gained compares favorably with cost-effectiveness ratios for well-accepted medical practices (Table 7) [49-55].

View this table: [in this window] [in a new window]   Table 7. Comparison of Cost-Effectiveness Ratios for Interferon-2b Treatment, Other Therapies, and Screening

These results should be interpreted within the limitations of the model and data on which they are based. First, because no long-term studies have followed the histologic course of hepatitis C from the time of infection to its natural conclusion, estimations of the natural history of the infection are necessarily based on the piecing together of observations and studies of patients at different points in their disease course. Although the progression rates used in our model represent the most recent estimates from the literature, they may need to be adjusted as we learn more about this disease. Second, our results were primarily developed from U.S. and European studies and may not be generalizable to East Asia, Africa, the Middle East, and Australia, where HCV disease progression and response to interferon-2b may differ. Finally, these results apply to mild chronic hepatitis alone, not other histologic stages. Nonetheless, in the absence of a long-term clinical trial, our analysis suggests that a single 6-month course of interferon-2b for mild chronic hepatitis should increase life expectancy at an economically reasonable cost that falls below that of many well-accepted health care interventions, particularly for younger patients.

Dr. Inoue: Yamaguchi University Hospital, 1144 Kogushi, Ube, Yamaguchi 755, Japan.

Dr. Beck: Information Technology Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.

Drs. Wong and Pauker: New England Medical Center, 750 Washington Street, Box 302, Boston, MA 02111.

Dr. Davis: PO Box 100214, University of Florida, Gainesville, FL 32610-0214.