Cost-effectiveness of Interferon-2b Treatment for Hepatitis B e Antigen-Positive Chronic Hepatitis B

Chronic hepatitis B virus (HBV) infection affects more than 5% of the world population, an estimated 300 to 350 million people [1-5]. In the United States, more than 1 million persons are persistently infected [3, 6]. The 270 000 to 300 000 cases of acute hepatitis B that occur annually in the United States contribute 5000 to 30 000 new cases of chronic infection [2, 7, 8] because 2% to 10% of infected adults develop chronic hepatitis [9-14]. Despite the availability of a vaccine and a declining incidence among homosexual men and health care workers, the incidence of hepatitis B has remained constant or has even increased in the United States because the incidence in heterosexual persons and intravenous drug users is increasing [12, 15]. Chronic hepatitis B causes significant morbidity and mortality, induces substantial direct and indirect costs [16-18], can lead to cirrhosis, and increases the risk for hepatocellular carcinoma approximately 300-fold compared with the general population [19]. Recombinant interferon-2b was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic hepatitis B [20], but clinical trials show that only a proportion of treated patients lose viral serologic markers (such as HBV DNA, hepatitis B virus e antigen [HBeAg], or eventually hepatitis B virus surface antigen [HBsAg]) [21-23]. Information on more definitive clinical end points, such as a decline in the incidence and mortality of cirrhosis or hepatocellular carcinoma, must await the results of long-term follow-up during the next 20 to 30 years. Interferon therapy is now available for persons with chronic hepatitis B but is expensive and commonly associated with short-term adverse effects. In our study, we projected the expected clinical and economic outcomes of patients with chronic hepatitis B and estimated the cost-effectiveness of interferon therapy. Methods Decision Analytic Model We determined whether interferon should be given to patients with HBeAg-positive chronic hepatitis B who did not have cirrhosis (as determined by biopsy specimens) by using a decision analytic model to predict the likely clinical and economic outcomes for two cohorts of patients with chronic hepatitis. One cohort received a 16-week course of interferon and the other received standard care (treatment for cirrhosis-related signs and symptoms using diuretics, lactulose, and prophylactic antibiotics). Using a decision analysis software program, Decision Maker 7.0 (Pratt Medical Group, Boston, Massachusetts), we did a Markov computer simulation [24, 25] to estimate prognosis in a hypothetical cohort of patients. The Markov simulation is a modeling technique in which hypothetical patients are followed over time as they move among states of health. We defined each state by serologic viral markers and clinical descriptors (Figure 1). The likelihood and timing of adverse or beneficial events determine prognosis. All patients began the simulation having chronic hepatitis and both HBeAg and HBsAg. After each simulated year, some patients remained in the same state of health, whereas others improved (for example, became HBeAg negative) or developed complications (such as compensated cirrhosis). The likelihood of an improved or worsened state of health was specified by a set of probabilities (Table 1). The simulation continued until no patient remained alive. To estimate the average survival or life expectancy of each cohort, we recorded the number of patients in each state of health at the end of each simulated year; each member of the cohort who remained alive contributed 1 person-year to the total survival of the cohort. Table 1. Baseline Values* Figure 1. States of health in the decision model. Because the quality of life in some states of health may be preferable to that in other states (for example, having asymptomatic chronic hepatitis may be preferable to having decompensated cirrhosis), we calculated the quality-adjusted life expectancy for each cohort by adding less than 1 full person-year for members in these less desirable states. As explained below, we based these adjustments on the judgments of senior clinicians familiar with both liver disease and interferon therapy. For example, we diminished the quality of life for patients with hepatocellular carcinoma by approximately 50%; in other words, in each year in which they were alive and had hepatocellular carcinoma, they contributed only 6 quality-adjusted months to the cohort's quality-adjusted survival. We also diminished the quality of life during the 16-week course of interferon therapy by approximately 13%. Because techniques for quality adjustment remain controversial and are not standardized, we report both life expectancy and quality-adjusted life expectancy for each strategy. We based our economic projections on the costs associated with caring for patients in each state of health each year. In accordance with standard principles of economic analyses [26-28], we discounted both future costs and future life-years by 5% per year to reflect the higher value of spending a dollar now as opposed to a year from now. Although we recognized the importance of other clinical descriptors of disease activity (such as serum enzyme levels [29, 30] and histologic evidence of inflammatory activity [31, 32]) in patients with chronic hepatitis, sufficiently detailed data about prognosis based on combinations of these descriptors along with serologic viral markers and liver function do not currently exist. Consequently, we modeled only the nine states of health shown in Figure 1. The serologic viral marker events we modeled included loss of HBeAg or HBsAg and relapse or reactivation of HBeAg. Clinical events included the progression of chronic hepatitis to compensated and then to decompensated cirrhosis; the development of hepatocellular carcinoma; and death. Data Sources Probabilities and Utilities We did a MEDLINE search and examined the bibliographies of all identified articles. For studies in which data were sparse or missing, we obtained a consensus opinion from an expert panel (see Acknowledgments), using a modified Delphi method. Costs We obtained actual variable hospital costs (the cost to treat one additional patient with the same disease) from the Clinical Cost Manager (Transition Systems I, Boston, Massachusetts) accounting system at New England Medical Center. We approximated physician fees for inpatient and outpatient care by multiplying physician charges by the mean reimbursement-to-charge ratio for internal medicine services (0.51). Laboratory costs were obtained from actual variable costs. Drug costs reflect the wholesale drug price. The expert panel estimated the frequency of hospitalizations, outpatient visits, and laboratory tests, as well as which drugs would probably be used for each health state. Assumptions 1. We considered the prognosis of patients who did not lose HBeAg within 1 year despite receiving interferon therapy to be identical to that of untreated patients. 2. We considered loss of HBsAg to be permanent [33]. Although HBV DNA may persist (as measured by the polymerase chain reaction assay in serum or liver after the loss of HBsAg [34, 35]), we considered patients with chronic hepatitis who lose both HBeAg and HBsAg to be effectively cured, reflecting the natural extension of the asymptomatic healthy carrier who has become HBsAg negative [36]. On the basis of the expert panel's recommendations, we assumed that these patients have a risk for developing compensated cirrhosis and hepatocellular carcinoma that is one hundredth that of patients who remain HBsAg positive. 3. We did not consider unusual complications from chronic hepatitis B (such as glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, or vasculitis [37]), some of which may be ameliorated by interferon therapy [38]. 4. We did not include screening for hepatocellular carcinoma in our analysis [39]. Although one study [40] in Asian persons suggested that screening might be advantageous, the benefits may not apply to other groups [41]. An Italian study [42] failed to find any benefit from ultrasonography or -fetoprotein screening tests. 5. We did not consider a second course of interferon therapy in nonresponders or patients who became positive again (reactivation or relapse) for HBeAg (although such patients often respond to a second course of interferon therapy [20]) or in patients with cirrhosis [37, 43-45] because few studies have been done for these settings and no consensus has been reached [43, 46]. 6. We estimated the benefit of interferon from studies with interferon-2b, which appears to be more effective than interferon- [47-49]. Two studies [50] suggest that interferon-2a results in a higher prevalence of anti-interferon antibody than interferon-2b. Other therapies, including combination or sequential therapy with interferon or priming with steroid therapy, have not improved response rates [51, 52]. 7. We considered loss of HBeAg as equivalent to loss of HBV DNA as a marker of viral replication. We did not consider the presence of the precore mutant (HBeAg negative) HBV, which is more likely to be resistant to therapy but is rare in the United States [53-55]. 8. We did not consider liver transplantation because of the frequent recurrence of HBV infection and progressive hepatitis in persons who receive transplanted livers [56-59] and because only a small proportion of patients with decompensated cirrhosis could be served by the currently limited supply of donor organs [60]. 9. We did not consider concomitant infection with hepatitis C virus or hepatitis D (delta) virus. 10. We used age-specific standard life-tables to reflect the underlying background likelihood of dying from causes occurring in the general population [61]. In the base-case analysis, the age at inception was assumed to be 35 years. Sensitivity Analysis Published studies and expert opinion vary in th