Assessing the Benefits and Costs of New Therapies for Hepatitis B Virus Infection

In recent years, hepatitis B has taken a backseat to hepatitis C because of the increased prevalence of hepatitis C in the United States and western Europe. However, hepatitis B has reclaimed the attention of gastroenterologists and other health care professionals because of 3 developments: the introduction of polymerase chain reaction (PCR)based hepatitis B virus (HBV) DNA testing; the improved understanding of the nature of HBV-related disease; and the introduction of potent, orally administered new antiviral agents. In our editorial, we discuss the treatment of HBV, which has evolved rapidly, and then comment on the cost-effectiveness of HBV therapies. The renewed interest in hepatitis B has led to the publication of 2 treatment guidelines authored by 2 expert groups of hepatologists (1, 2). While differing slightly in criteria for offering treatment, both guidelines emphasize that treatment with current antiviral regimens can achieve 2 long-term goals. First, treatment can reverse decompensated cirrhosis (thereby allowing many patients with seemingly end-stage disease to be removed from transplantation lists). Second, treatment reduces the risk for developing hepatocellular carcinoma. Although some clinical issues relating to HBV therapy are still unsettled, enough evidence exists to justify antiviral therapy for a substantial proportion of chronically infected individuals. However, treatment is usually prolonged, and some of the drugs are expensive. Placed in this context, the contribution of Kanwal and colleagues' analysis in this issue (3) is timely. During the early days of HBV treatment when interferon was the only available therapy, the most frequently used criterion for treatment was the presence of hepatitis B e antigen (HBeAg) in the serum. Introduction of PCR-based assay methods (4) for measuring HBV DNA demonstrated that many HBeAg-negative patients had substantial serum levels of HBV DNA. Thus, HBV DNA levels have replaced HBeAg as a criterion for offering treatment. Increasingly, physicians are treating HBeAg-negative patients with high HBV DNA levels (called precore mutant and core promoter infections) (5). Whether a patient is HBeAg-positive or -negative, the short-term goal of treatment is to lower HBV DNA levels. Lamivudine and adefovir accomplish this goal readily; interferon treatment is less consistently successful. If treatment of the HBeAg-positive patient eliminates HBeAg from the serum (which it does in 20% to 50% of patients depending on the antiviral regimen), serum HBV DNA usually remains negative after stopping the antiviral therapy (called a durable response). In contrast, the HBeAg-negative patient is likely to require antiviral therapy indefinitely because serum HBV DNA typically rebounds after stopping antiviral therapy. The increasing complexity and cost of treatment, which may be lifelong in some patients, provides the rationale for Kanwal and colleagues' analysis (3). A major concern with lamivudine therapy is the frequent occurrence of drug-resistant mutations (in the tyrosine, methionine, aspartate, aspartate [YMDD] locus of the HBV DNA polymerase). Drug resistance is present in approximately 25% of patients at the end of 1 year of therapy, increasing to 67% after 4 years. Initially, physicians tried to manage patients with drug-resistant mutations by continuing lamivudine treatment, reasoning that while serum HBV DNA returned to pretreatment levels, the mutated virus was less pathogenic. Eventually, they recognized that liver disease progressed with this approach (6). The solution to the problem of lamuvidine-resistant mutants was learning that adefovir is active against the mutant virus (7, 8), as are several newer agents being investigated as HBV treatments. The effectiveness of adefovir against a drug-resistant virus has allowed treating physicians to use lamivudine as initial therapy and switch to adefovir once lamivudine resistance occurs. However, physicians remain uneasy about a therapeutic strategy that promotes emergence of the mutant virus, and some physicians (9) suggest initial treatment with combination therapy to avoid selecting for lamivudine-resistant HBV. Kanwal and colleagues (3) evaluate the cost-effectiveness of monotherapy with interferon-2b, lamivudine, adefovir, and a crossover salvage strategy in which the physician switches from the initial lamivudine therapy to adefovir if resistance develops (adefovir salvage). Treatment options for HBV may broaden beyond the drugs included in their analysis. Although the pegylated interferon derivatives of interferon-2b (PEG INTRON, Schering Corp., Kenilworth, New Jersey) and interferon-2a (Pegasys, Hoffmann-La Roche, Nutley, New Jersey) are not currently approved for hepatitis B treatment, they are active against HBV as well as hepatitis C virus (10, 11). Another active drug is tenofovir (Viread, Gilead Sciences, Inc., Foster City, California), which the U.S. Food and Drug Administration (FDA) has approved for HIV treatment but not for HBV infection. Entecavir (Baraclude, Bristol-Myers Squibb, New York, New York) is under review by the FDA and should be released soon. Cost-effectiveness analysis provides a method to determine which interventions provide the most health benefit for a given investment of resources. The most important principle of cost-effectiveness analysis is that a particular strategy is always assessed relative to another strategy (for example, salvage therapy compared with lamivudine monotherapy). If 1 strategy provides more health benefit and costs less than another strategy, the superior strategy dominates the inferior strategy. In HBeAg-positive patients, Kanwal and colleagues found that adefovir salvage therapy dominated all other therapies. Adefovir monotherapy provided almost as much benefit but at a substantially greater cost. In HBeAg-negative patients, Kanwal and colleagues foundas is more typical in cost-effectiveness analysesthat the more effective strategies were also more expensive, and so they estimated the cost-effectiveness ratio. The ratio is the difference in costs of 1 strategy (for example, adefovir salvage) and the comparison strategy (for example, interferon monotherapy) divided by the difference in health benefit between the 2 strategies. They found that the cost-effectiveness ratio of adefovir salvage therapy relative to interferon monotherapy is $16593 per quality-adjusted life-year (QALY) in HBeAg-negative patients. Understanding the meaning of the cost-effectiveness ratio is critical: It indicates the additional cost, per QALY gained, of using adefovir salvage rather than interferon. Does the adefovir salvage strategy represent a good value? The highest cost-effectiveness ratio at which a decision maker is willing to pay for an intervention is called the cost-effectiveness threshold. The cost-effectiveness threshold represents a decision maker's willingness to pay for health benefits. The threshold depends on how the decision maker values health, money, and risk (12, 13). The literature contains many references to a threshold of $50000 per QALY, but this number is arbitrary. As a practical matter, however, most observers would consider interventions that cost less than $50000 per QALY gained to be a good value, partly because many commonly accepted interventions meet this criterion. In HBeAg-negative patients, adefovir salvage therapy, at $16593 per QALY gained, easily falls within the range generally accepted as cost-effective. In contrast, adefovir monotherapy costs about $91000 per QALY gained, which is relatively expensive compared with other interventions that most people accept as providing good value. The conclusion that adefovir salvage is a dominant (HBeAg-positive patients) or cost-effective (HBeAg-negative patients) strategy may change if newer drugs, or combinations of current drugs, are more effective, cheaper, or both. Thus, if new drug therapies become available for HBV (or if emergence of the YMDD mutation proves to have a greater downside), Kanwal and colleagues' analysis should be revisited. Fortunately, bringing a decision model up to date can be as easy as inserting a new value in a spreadsheet. As health care becomes increasingly expensive, payers, employers, and patients are asking whether their dollars are being well spent. Cost-effectiveness analyses can help us understand whether expensive treatments are worth the cost.