See article in J. Gastroenterol. Hepatol. 2002; 17: 153–64
The development of potent new orally active anti-hepatitis B virus (HBV) agents has revolutionized the treatment of chronic hepatitis B. Until recently, the mainstay of therapy for this disease has been α- interferon. However, use of this agent has been limited by a number of problems including a significant side-effect profile, high cost, and the need for parenteral administration. Lamivudine, the first of the new antiviral agents to enter widespread clinical use has several advantages over interferon therapy, including oral administration, significantly lower cost and a remarkable lack of side-effects that allows it to be administered to a wider group of patients and for more prolonged periods. Recent data have also clearly shown that, in contrast to interferon, lamivudine can be safely administered to patients with decompensated HBV cirrhosis, and that it can produce significant improvements in hepatic function by inhibiting viral replication and reducing disease activity.1 Lamivudine used alone, or in combination with hepatitis B immune globulin, has also had a major impact on liver transplant outcomes in HBV-infected patients by greatly reducing the risk of post-transplant recurrence of HBV infection.2
Despite these advantages, lamivudine or other new antivirals will not necessarily completely supplant interferon as first-line therapy for active hepatitis B in hepatitis B e antigen (HBeAg)-positive patients. In this group, the rates of seroconversion achieved with the two drugs are similar, and while the convenience of oral administration and lack of side-effects of lamivudine are undeniable, the relatively short and defined course of therapy with interferon (4–6 months) may still be preferred to the need for more prolonged therapy with lamivudine (1 year or more) and the risks of the development of antiviral resistance (approximately 20% per year of treatment).3 However, perhaps a more important issue is whether the introduction of lamivudine will allow the potential benefits of treatment to be extended to the very substantial proportion of HBV-infected patients who are either unwilling or unable to be treated with interferon.
In the current era of increasing health costs, assessment of the potential benefits of any new therapy must take into account cost-effectiveness compared with other treatments, including long-term effects on clinical outcomes and total health-care costs. The article published in the Journal by Crowley et al. is a welcome attempt to address these very important issues as they relate to the introduction of lamivudine.4 The authors have used the technique of Markov modeling to analyze the potential clinical and economic effects of the introduction of lamivudine for hepatitis B treatment in the group of patients for whom the role of interferon and lamivudine therapy is most clearly established (i.e. HBeAg antigen-positive patient with an ALT of greater than two times the upper limit of normal). The current situation in Australia, in which both interferon and lamivudine therapy are now available for treatment of these patients, is compared with the period when interferon was the only available therapy, and with no treatment. A key assumption is that only 20% of these prime candidates for treatment previously received therapy because of the presence of contraindications to interferon therapy or an unwillingness to be treated, but that the introduction of lamivudine would boost treatment rates in this group to 77% (65% lamivudine; 12% interferon). Perhaps the most important message from this paper is that, if this proves to be the case, there would be major benefits in terms of reduction in progression to cirrhosis and improved life expectancy for a relatively modest lifetime increase in the total cost of HBV treatment.4
There are a number of important caveats. It is assumed that continuation of lamivudine therapy beyond 2 years leads to further significant gains in seroconversion, compared to a background seroconversion rate in untreated patients of 9% per year. This assumption is based on data from a small number of long-term studies involving relatively few patients3,4 and needs to be confirmed in larger studies. Modeling of the short-term (1 year) results of therapy is based on solid data from a number of controlled clinical studies and, in this model, the benefits of extending treatment to a larger proportion of HBeAg-positive patients can be clearly identified.4 Long-term modeling of the benefits of treatment for a disease such as hepatitis B, which has an unpredictable course and highly variable prognosis in different patient populations, is much more difficult. The long-term model outlined in this study allows for lifelong treatment with lamivudine in those who do not achieve HBeAg seroconversion with short-term therapy. The development of mutations within the YMDD motif of the HBV genome occurs in 14–32% of patients after 1 year of therapy, and the prevalence of these mutants increases with time, so that after 4 years of continuous treatment approximately two-thirds of patients will have a drug-resistant virus.5,6 Whether this cumulative increase in resistance rates will have long-term impacts on the cost of patient management and health outcomes is as yet unknown. The study also assumes that reactivation to HBeAg positivity following seroconversion to HBeAg negativity occurs in only 15% of patients and that such relapses only occur in the first 12 months following lamivudine withdrawal. However, recent studies involving Asian patients have reported significantly higher cummulative reactivation rates at 2 years after treatment, and this would clearly impact on the long-term costs and efficacy of treatment in this population.7
By assuming a very low background rate of interferon use, the impact of interferon therapy in Australia may have been underestimated in this study. Nevertheless, despite the above concerns, the benefits of lamivudine treatment compared to no therapy are convincing, in terms of life-years and quality adjusted life-years gained. Costs also compare very favorably with other widely accepted medical therapies. As the authors point out, this economic evaluation is limited to a selected subgroup of patients with chronic hepatitis B in whom treatment outcomes are most favorable. Further data will be required to determine whether similar cost-effectiveness can be demonstrated for use of the drug in other patient groups, such as those with HBeAg- negative chronic hepatitis B and patients with HBV cirrhosis.
Finally, the potential impact of treatment with lamivudine or other antiviral agents on the total costs and clinical outcomes of HBV infection in the community as a whole will largely depend on the proportion of HBV-infected individuals who are treated. Chronic hepatitis B is a disease that is often clinically silent, and in many patients the presence of infection is not identified until late complications such as cirrhosis and liver cancer have developed. In order to maximize the benefits gained from the development of more effective anti-HBV therapies, a key issue for the future will be to facilitate the identification of greater numbers of patients during the early asymptomatic phases of the disease when treatment is likely to be most beneficial.