HBV Viral Kinetics and Clinical Management: Key Issues and Current Perspectives

The management of hepatitis B virus (HBV) infection is changing rapidly as new discoveries and insights continue to expand our understanding of the disease and its treatment with antiviral agents. Affecting nearly 400 million people worldwide, chronic hepatitis B occurs most frequently in residents of Asian countries and in immigrants to the United States from these regions. In addition to the morbidity of chronic liver disease, chronic HBV infection places affected individuals at risk for the development of liver failure resulting from decompensated cirrhosis and hepatocellular carcinoma (HCC). To discuss the latest research on hepatitis B, a panel of 13 internationally recognized experts convened in October 2003. This supplement captures the highlights of their presentations, ranging from a discussion of viral kinetics and the natural history of HBV infection to reports of new data emerging from clinical trials with established and investigative therapies.

Persistence of hepatitis B surface antigen (HBsAg) signifies the presence of chronic HBV infection, whereas detectable HBV DNA reflects active viral replication. In the first article, Dr. Stephen Locarnini describes the viral life cycle in HBV infection and reviews the status of HBV replicative activity during the various stages of HBV-associated liver disease. In addition, he focuses on naturally occurring escape mutants and precore/core-promoter mutations as well as on mutations that can emerge as a result of the selective pressure of antiviral therapy and lead to drug resistance.

Mathematical modeling, which provides a better interpretation of viral kinetics and the patterns of response observed during therapy for chronic hepatitis B, also yields additional insight into the mechanisms of action of antiviral agents. Dr. Alan Perelson compares and contrasts various models that have been applied to HBV infection, explaining their mathematical derivation, underlying assumptions, and uncertainties. Among the factors included in these models and useful in establishing the efficacy of treatment are rates of viral production and mutation, viral decay profiles, and virion clearance rates. Simple, two-stage kinetic models, he points out, are insufficient to account for changes in viral decay profiles in all treated patients.

Dr. Brian McMahon provides an overview of the classification of the stages of chronic HBV infection proposed by some to explain differences in disease activity and the interaction between the host immune system and HBV-infected hepatocytes-the “immune tolerant” phase, the phase of chronic hepatitis B, and the inactive HBsAg carrier phase. Although far too simplistic to account for the complexity of host-virus interactions that characterize different clinical manifestations of chronic HBV infection, this classification focuses attention on differences between populations infected at birth whose clinical course is indolent, spans decades, and results in fatal complications and those infected in adulthood whose clinical course is more easily recognized clinically but less likely to culminate in the dreaded outcomes of HBV infection. In his article, Dr. McMahon reviews guidelines for monitoring and treatment of patients within each phase of infection; geographic distribution of specific HBV genotypes and the emerging recognition of their clinical impact; the importance of HBeAg-negative chronic hepatitis B, which is common among persons from the Mediterranean region and Asia; and risk factors for progressive liver damage and HCC in persons with chronic HBV infection.

Dr. Robert Perrillo discusses the pros and cons of therapy with nucleoside analogues and interferon. A noteworthy difficulty encountered during lamivudine monotherapy is resistance, which increases with the duration of therapy. Resistance is not unique to this drug, however. Theoretically, the use of nucleoside analogues in combination with interferon should provide an advantage over monotherapy, but studies to date of such combinations have been disappointing. Renewed interest has developed in interferon, especially pegylated interferons, for the treatment of chronic hepatitis B. In two large multicenter trials, one each in HBeAg-positive and HBeAg-negative chronic hepatitis B, groups of international investigators have evaluated combination therapy with lamivudine and pegylated interferon. Although combinations of lamivudine plus pegylated interferon show no benefit over pegylated interferon monotherapy, preliminary data on the efficacy of pegylated interferon are promising (see later).

Updates on the most recent efficacy and safety data from clinical trials with lamivudine, adefovir, and interferon/pegylated interferon (and their combinations) will be of interest to clinicians. These data are presented by Drs. Teresa Wright, Myron Tong and Stanley Tu, and Graham Cooksley, respectively. In addition, Dr. Wright highlights the evolution of changing end points used in clinical trials of patients with chronic HBV infection and discusses the importance of proper patient selection. The results of adefovir therapy cited by Drs. Tong and Tu in patients with lamivudine-resistant mutants are particularly relevant. In his review of the studies of pegylated interferon, Dr. Cooksley summarizes recent data on the safety and efficacy of pegylated interferon, with and without lamivudine, in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. Although oral nucleoside analogues may be better tolerated than injected pegylated interferons, Dr. Cooksley marshals evidence in favor of pegylated interferons as primary therapy. More detailed, and eagerly awaited, results of recent pegylated interferon clinical trials will be required before current recommendations are amended.

Until recently, the presence of chronic HBV infection was considered a contraindication to liver transplantation, because of the high likelihood, morbidity, and mortality of recurrent infection. As Dr. Didier Samuel reviews, however, prophylaxis with hepatitis B immune globulin and nucleoside analogues has improved transplantation outcomes and survival rates so substantially that the success of liver transplantation for hepatitis B is indistinguishable from that achieved after liver transplantation for nonviral causes of end-stage liver disease. As a result, liver transplantation is now accepted universally as a therapeutic intervention for patients with acute fulminant or end-stage liver disease associated with HBV infection.

The management of HBV infection in patients undergoing hemodialysis for end-stage renal disease is the subject of the discussion by Dr. Fabrizio Fabrizi and colleagues. They review the clinical presentation of HBV infection and associated liver disease in this population and the measures that have been established to control the spread of HBV infection within dialysis units. Limited experience with lamivudine following renal transplantation is encouraging and appears to improve survival.

Despite substantial advances in the treatment of chronic HBV infection over the past several years, patient selection for and applicability of therapy remain poorly defined. In his overview of these issues, Dr. Naoky Tsai focuses on the proper identification, evaluation, monitoring, and counseling of persons with chronic HBV infection. He presents practical guidelines for initial evaluation of persons with HBeAg-positive and HBeAg-negative chronic hepatitis B and of inactive HBsAg carriers. Among the three approved treatments-interferon, lamivudine, and adefovir-Dr. Tsai cites recommendations that they all may be used as first-line therapy (except in patients with decompensated cirrhosis), albeit each with specific advantages and disadvantages.

For the final presentation, Dr. Anna Lok examines future prospects in the treatment of chronic HBV infection. The need for new therapies that can overcome the limitations of current options is indisputable. Dr. Lok reviews the results thus far with antiviral agents being evaluated in clinical trials, specifically, entecavir, emtricitabine, clevudine, β-L nucleosides, ACH 126-443, and tenofovir. The evidence to date, she acknowledges, suggests that future research should focus on combination therapy, which appears to be the strategy most likely to achieve sustained viral suppression and optimal patient outcomes.

During the first decade of the 21st century, advances in the treatment of chronic hepatitis B are likely to eclipse even the rapid progress of the last decade of the 20th century. We live in exciting times!

DISCLOSURE OF COMMERCIAL FINANCIAL SUPPORT Dr. Keeffe receives grant support from Amgen and Roche; serves on advisory boards for Amgen, Gilead, GlaxoSmithKline, and Roche; and is a member of the speakers' bureau of Gilead, GlaxoSmithKline, InterMune, Roche, and Schering. Dr. Dienstag receives grant support from the National Institutes of Health (NIDDK) and Idenix; serves on advisory boards for Achillion, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Idenix, Metabasis, Rigel, SciClone, Syntonix, and Vertex; and is a member of the speakers' bureau of Gilead.