Estimates of the Cost-Effectiveness of a Single Course of Interferon-2b in Patients with Histologically Mild Chronic Hepatitis C

It is currently estimated that the hepatitis C virus (HCV) chronically infects 3.9 million persons in the United States and is the most common cause of chronic liver disease [1]. Although chronic hepatitis C usually progresses slowly and usually leads to cirrhosis and major illness only after decades [2], it results in approximately 8300 deaths each year and accounts for 20% of the 3650 liver transplantations performed in the United States annually [1, 3]. 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 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. Figure 1. Schematic of the Markov model with health states and annual probabilities (expressed as percentages) of disease progression. 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. 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 als