Cost-effective pharmacologic therapies to treat chronic hepatitis B: how far have we really come?

of lamivudine with entecavir appears impractical. According to American Association for the Study of Liver Disease (AASLD) guidelines, lamivudine is preferred for short (undefined) courses of treatment.8 In addition, this pharmacoeconomic (PE) model proposed by Yuan et al. begins with a hypothetical population of lamivudine treatment-naïve individuals in the base-case model, and conclusions are drawn from the sensitivity analysis in which more than half of the patient population develops resistance to lamivudine within 10 years. This population is quite different from that of the Benefits of Entecavir for Hepatitis B Liver Disease (BEHoLD) study in which 2% of patients in the entecavir study group and 18% of patients in the lamivudine study group experienced virologic rebound during the first year of therapy. In the BEHoLD study, virologic rebound was used as a determinant to identify if resistance, defined as an increase in HBV DNA by at least 1 log 10 copies per mL from the nadir, occurred during the treatment period.2 The continued use of lamivudine in treating lamivudine-resistant individuals has been associated with a diminished treatment response (i.e., higher pretreatment HBV DNA and ALT levels).10 The clinical significance of this observation, however, has not been fully elucidated.11 The incidence and clinical course of CHB are different in developing countries than in the United States. In the United States, the risk of adults developing CHB from acute exposure to HBV is < 5% while the incidence of CHB in endemic areas (e.g., Southeast Asia) can range from 25% to 30% in infants and children under the age of 5 years to as high as 90% in newborns of HBeAg-positive mothers.12-16 Cohorts in studies describing the natural history of CHB can be categorized into 2 basic groups: (1) patients born in areas with high and intermediate prevalence rates for HBV and (2) patients in high-risk groups (e.g., intravenous drug users, homosexual men, inmates of correctional institutions, and individuals coinfected with hepatitis C virus or human immunodeficiency virus). This is an important consideration when evaluating drug therapy. Those who develop CHB early in life (i.e., acquired at birth from an infected mother or during early childhood) from an acute exposure experience disease progression and develop serious liver complications (i.e., compensated and decompensated cirrhosis and hepato cellular carcinoma) by the fourth decade of life due to the prolonged immune tolerance phase that is characterized by persistence of HBeAg, persistence of viremia for a longer duration, and normal ALT/aspartate aminiotransferase (AST) levels. The prolonged immune tolerance phase is followed by a prolonged immune clearance phase (i.e., longer time to Six products are approved in the United States for the treatment of chronic hepatitis B (CHB) viral infection: interferon alfa-2b, recombinant (Intron-A); peginterferon alfa-2a (Pegasys); lamivudine (Epivir HBV); adefovir dipivoxil (Hepsera); entecavir (Baraclude); and telbivudine (Tyzeka).1 In clinical trials, oral products administered up to 1 year to treat this chronic condition have demonstrated similar rates of hepatitis B e antigen (HBeAg) seroconversion from HBeAgpositive to HBeAg-negative status with the detection of hepatitis B e antibody (anti-HBe) ranging from 17% to 27% in adults.2-5 Costs, however, can vary widely. Factors affecting costs include the direct cost of the drug, length of treatment, and complications associated with continued therapy (e.g., development of resistance, intolerable adverse events). In addition, predictors and durability of response (pretreatment alanine aminotransferase [ALT] levels and serum hepatitis B virus [HBV] deoxyribonucleic acid [DNA] levels) may affect overall costs.6 In this issue of JMCP, Yuan and colleagues attempt to estimate the long-term health and economic impact of treating patients with CHB from an overall cost perspective. The authors conclude that entecavir is more cost-effective than lamivudine in the long-term treatment of HBeAg-positive CHB virus patients.7 We applaud the efforts of the authors for the development and refinement of such a complicated and sophisticated model. However, the assumptions used for model development in this disease state (i.e., 10-year time horizon, difference in study populations, and epidemiology of the disease) create a doubleedged sword. On one edge, using multiple variables allows an opportunity for greater accuracy for predictive modeling, and 10 years is an appropriate period to measure outcomes in a disease such as CHB since it typically takes 10 years or longer for the disease to manifest as adverse clinical outcomes. However, in a hypothetical population, if any of the assumptions used in creating the model are incorrect, the overor underestimation of clinical utility will be magnified in proportion to the length of the time frame used in the model. Lamivudine was the first oral nucleoside analog approved for the treatment of CHB and is now joined by 3 other oral agents. Since lamivudine’s entry into the marketplace, evidence of drug resistance to HBV has emerged, suggesting reduced susceptibility to lamivudine. Reported lamivudine resistance rates in CHB patients are 14% after 1 year of treatment and may increase to as high as 69% after 5 years of treatment.8,9 In light of lamivudine’s reported resistance patterns and the overall conclusion that entecavir given for up to 10 years is more cost-effective, the 10-year time horizon utilized in Yuan et al.’s comparison CoMMENTARY