Treatment Alternatives for Chronic Hepatitis B Virus Infection: A Cost-Effectiveness Analysis

Context Because current treatment options for chronic hepatitis B virus (HBV) infection have varying effects and costs, choosing among them is often difficult. Contribution Using a third-party payer perspective and lifetime horizon, this costutility analysis found that monotherapy with interferon but not lamivudine or adefovir was cost-effective. A salvage strategy that used adefovir only in case of lamivudine-associated viral resistance also seemed cost-effective. Cautions The findings apply only to patients with persistently elevated aminotransferase levels and no cirrhosis. The authors did not model the cost-effectiveness of nucleoside analogue salvage after interferon therapy failure. The Editors Chronic hepatitis B virus (HBV) infection is a prevalent and expensive condition, affecting 350 million people worldwide and 1.25 million people in the United States (1) at a cost of more than $700 million annually (2). Chronic HBV infection can progress to cirrhosis, liver failure, and hepatocellular carcinoma and is a major cause of morbidity and mortality (1, 3). Traditional therapy for chronic HBV infection with either interferon-2b (interferon) or lamivudine is difficult and has limited long-term efficacy (4). Interferon has clinically significant side effects and results in durable virologic response in only 15% to 30% of patients (5-8). Lamivudine is easy to administer and is associated with minimal side effects (9-11), but it has a higher rate of viral resistance (12), lower durable response rate (9-11), and greater need for prolonged therapy (9, 11) compared with interferon. The efficacy of both interferon and lamivudine is even more limited in patients with hepatitis B e antigennegative (HBeAg-negative) disease (4). This burgeoning population now accounts for more than half of patients with HBV in the United States (13) and up to 80% of patients with HBV in Asia (14, 15). Data from 2 randomized, controlled trials indicate that adefovir is efficacious in HBeAg-positive and HBeAg-negative patients (16, 17). Adefovir has a low risk for side effects and viral resistance (18) compared with interferon and lamivudine, but it is more expensive (19). Therefore, the improved therapeutic benefits of adefovir in chronic HBV infection may offset its increased cost compared with interferon and lamivudine, therapies that are less effective yet less expensive. The most effective and cost-effective therapeutic approach to chronic HBV infection must be established. Given the uncertainty on how best to initiate therapy in HBV, this information may assist clinicians in everyday clinical decision making. We therefore performed an economic analysis to estimate the cost-effectiveness of 5 competing strategies for managing chronic HBV infection in patients with elevated liver enzyme levels and no evidence of cirrhosisthe most prevalent and clinically relevant presentation of chronic HBV infection in the primary care setting. We sought to determine whether and under what circumstances the improved therapeutic benefits of adefovir offset its increased cost compared with lamivudine or interferon in managing chronic HBV infection. Methods Decision Model Framework Model Overview Using decision analysis software (DATA, version 4.0, TreeAge Software, Inc., Williamstown, Massachusetts), we evaluated a hypothetical cohort of patients 40 years of age with chronic HBV infection, elevated aminotransferase levels, and no clinical or histologic evidence of cirrhosis. To emulate the case mix in clinical practice in the United States (13), we assumed that 55% of the cohort was HBeAg-negative. We subsequently varied this estimate between 0% and 100% in our sensitivity analysis. Patients entered the hypothetical model without previous treatment for HBV infection and received 1 of 5 competing strategies for managing chronic HBV infection: 1) no pharmacologic treatment of chronic HBV infection (do nothing strategy), 2) interferon monotherapy, 3) lamivudine monotherapy, 4) adefovir monotherapy, or 5) lamivudine with crossover to adefovir upon development of viral resistance (adefovir salvage strategy). Because the clinical course, prognosis, and response to therapy vary in patients with HBeAg-positive and HBeAg-negative HBV (4), we stratified our analysis by HBeAg status and assigned separate probability estimates for each group. Patients entering the model received either no treatment (do nothing strategy) or active treatment for chronic HBV infection. We then followed the cohort over a lifetime horizon through a series of Markov cycles governing patient transitions between relevant health states. The Appendix describes the model structure in detail. Competing Strategies Do Nothing Strategy. In this strategy, which served as the referent case for our analysis, we assumed that patients were followed clinically but did not receive pharmacologic therapy for chronic HBV infection. Patients followed the natural history of chronic HBV infection according to their HBeAg status. We further assumed that all patients received regular ongoing care, including hepatocellular cancer screening, and that patients developing cirrhosis were managed for complications, as outlined by published management guidelines (4, 20). We assumed that a proportion of patients with cirrhosis became eligible for liver transplantation and that a subgroup of these patients subsequently underwent liver transplantation at the rate reported by the United Network for Organ Sharing (21). Interferon Monotherapy Strategy. Patients in this strategy received up-front active therapy with interferon, 10 million units subcutaneously 3 times per week. We assumed that HBeAg-positive and HBeAg-negative patients received 4 and 12 months of treatment, respectively, as suggested by published guidelines (4, 20). Patients without virologic response did not receive additional HBV therapy and followed the natural history of chronic HBV infection. Lamivudine Monotherapy Strategy. Patients in this strategy received up-front lamivudine, 100 mg orally once daily. Lamivudine therapy was discontinued 6 months after a virologic response. Patients without virologic response, including those developing viral resistance, continued to receive long-term lamivudine therapy as recommended by published guidelines (4, 20). We then assigned patients to receive lifetime lamivudine therapy and discontinued therapy if patients developed a subsequent virologic response. Adefovir Monotherapy Strategy. Patients in this strategy received up-front adefovir, 10 mg orally once daily. Adefovir therapy was discontinued 6 months after a virologic response. Patients without virologic response, including those developing viral resistance, continued to receive long-term adefovir therapy as recommended by published guidelines (20). We then assigned patients to receive lifetime adefovir therapy and discontinued therapy if patients developed a subsequent virologic response. Adefovir Salvage Strategy (Lamivudine to Adefovir Crossover). A relevant therapeutic alternative available to clinicians is a hybrid strategy of up-front lamivudine followed by adefovir salvage if lamivudine-related viral resistance develops. We assumed that patients in this strategy initially received lamivudine as described in the lamivudine monotherapy strategy. We then crossed patients over to adefovir when they developed viral resistance, and we subsequently managed patients as described in the adefovir monotherapy strategy. Patients without viral resistance continued to receive lamivudine. Therefore, we reserved adefovir therapy only for patients developing viral resistance while they were receiving lamivudine therapy. Tables 1 and 2 and the Appendix describe the probability estimates governing all 5 strategies. Table 1. Base-Case Probability Estimates Table 2. Base-Case Treatment-Related Probability Estimates Model Assumptions The Appendix contains information about our key model assumptions, including base-case patient characteristics, survival assumptions, definition of virologic response, relationship between virologic response or resistance and subsequent health, and effect of treatment-related adverse events. Clinical Probability Estimates Our base-case model incorporated a wide range of estimates governing relevant clinical probabilities in the management and natural history of chronic HBV infection (Tables 1 and 2). To derive these estimates, we systematically reviewed MEDLINE to identify relevant English-language studies published from January 1970 to February 2005. The Appendix describes our systematic review methods. Outcomes Because the main objective of cost-effectiveness analysis is to permit comparisons among different interventions in medicine, and because quality-adjusted life-years (QALYs) are the exchange currency that allows these comparisons to be made, we adopted QALYs as our main outcome (120). Our analysis reports the incremental cost per QALY gained among the competing strategies, along with the respective 2.5th and 97.5th percentiles around the point estimates as generated by a Monte Carlo analysis of 1000 trials (see Sensitivity Analyses section for details). Utilities We incorporated a wide range of relevant health state utilities in our model. Table 1 contains the specific utility estimates, and the Appendix describes these estimates in detail. Cost Estimates We conducted our analysis from the perspective of a third-party payer and incorporated the direct health care costs for many therapies, physician visits, diagnostic tests, and complications of chronic liver disease (Table 3). We obtained costs for physician services and procedures from the 2004 American Medical Association Current Procedural Terminology codebook and the 2004 Medicare Fee Schedule (121) and derived our base-case pharmaceutical costs from the average wholesale prices listed in the 2004 Red Book (19). Because large buying consortiums can often obtain prices lower th