Special report
A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States: 2008 Update

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Chronic HBV infection is an important public health problem worldwide and in the United States. A treatment algorithm for the management of this disease, published previously by a panel of U.S. hepatologists, has been revised on the basis of new developments in the understanding of the disorder, the availability of more sensitive molecular diagnostic tests, and the licensure of new therapies. In addition, a better understanding of the advantages and disadvantages of new treatments has led to the development of strategies for reducing the rate of resistance associated with oral agents and optimizing treatment outcomes. This updated algorithm was based primarily on available evidence by using a systematic review of the literature. Where data were lacking, the panel relied on clinical experience and consensus expert opinion. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to low or undetectable levels. Assays can now detect serum HBV DNA at levels as low as 10 IU/mL and should be used to establish a baseline level, monitor response to antiviral therapy, and survey for the development of drug resistance. Interferon alfa-2b, lamivudine, adefovir, entecavir, peginterferon alfa-2a, telbivudine, and tenofovir are approved as initial therapy for chronic hepatitis B and have certain advantages and disadvantages. Although all of these agents can be used in selected patients, the preferred first-line treatment choices are entecavir, peginterferon alfa-2a, and tenofovir. Issues for consideration for therapy include efficacy, safety, rate of resistance, method of administration, and cost.

Section snippets

Natural History of Chronic Hepatitis B Virus Infection

The accurate and early diagnosis of chronic HBV infection is an important step in patient management. An understanding of the natural history of CHB is fundamental to the evaluation and management of CHB, playing a critical role in the assessment of patient status and in guiding decisions regarding candidacy for treatment and treatment end points. The natural course of HBV infection is a dynamic interplay of complex interactions involving the virus, the hepatocyte, and the host immune response,

Hepatitis B Virus DNA and Disease Progression

Large, long-term population-based studies of HBsAg-positive individuals have demonstrated a strong relationship between the risk of progression to cirrhosis, HCC, or both and ongoing HBV replication.12, 35, 36, 37 In both natural history and therapeutic studies, patients with cirrhosis who are seropositive for HBeAg, HBV DNA, or both have an approximately 4-fold higher risk of further disease progression to decompensation, HCC, and death than do patients who are HBeAg seronegative.15, 38, 39, 40

Risk Factors for Disease Progression

Viral and host factors have been shown to influence disease progression to cirrhosis or HCC.15 In large, long-term, natural history studies of HBsAg-positive individuals, viral and disease factors that were predictive of HCC included the presence of HBeAg (hazard ratio [HR], 4.2), HBV DNA levels >104 copies/mL (HR, 2.7), and HBV DNA levels >105 copies/mL (HR, 8.9–10.7).12 Host factors included male gender (HR, 3.0), advanced age (HR, 3.6–8.3), alcohol consumption (HR, 2.6), and cigarette

Candidates for Hepatitis B Virus Screening and Vaccination

During the last 2 years, the guidelines for the screening and vaccination of individuals with HBV infection have been revised by the Centers for Disease Control and Prevention (CDC).42, 43 All persons in high-risk groups for hepatitis B should be screened for serum HBsAg (Table 3).40, 42, 43 Testing for hepatitis B should be performed on any person with risk factors for acquiring HBV infection and in persons with elevated liver enzymes or evidence of active liver disease without an identified

Fibrosis Screening

After initial serologic testing and HBV DNA quantification, it might also helpful to establish the baseline liver histology before the initiation of therapy and to exclude other causes of liver disease. Liver biopsy is currently the gold standard for this assessment, but its use is limited because of its invasiveness, and it only samples a small portion of the liver; in addition, it has limited interobserver and intraobserver concordance. Although significant progress has been made during the

Candidates for Therapy

Although there is general agreement on the tests that should be ordered in the initial evaluation of patients with chronic HBV infection (Table 4), controversy remains regarding the identification of candidates for therapy and how to follow patients who are not initially considered for therapy, particularly HBeAg-positive patients with high HBV DNA levels and normal ALT levels.

Goals of Therapy

The goal of therapy for CHB is to eliminate or significantly suppress the replication of HBV and prevent the progression of liver disease to cirrhosis, with culmination in liver failure, or HCC, eventually leading to death or transplantation. Hence, the primary aim of treatment should be to reduce and maintain serum HBV DNA at the lowest possible levels (ie, achieve durable HBV DNA suppression). This, in turn, will promote the other aims of therapy, including histologic improvement and ALT

Hepatitis B Therapies

Currently, 7 drugs are available for the management of chronic HBV infection in the United States: interferon alfa-2b, lamivudine, adefovir, entecavir, peginterferon alfa-2a, telbivudine, and tenofovir. At present, the preferred first-line treatment choices are entecavir, peginterferon alfa-2a, and tenofovir because of their superior efficacy, tolerability, and favorable resistance profiles in HBeAg-positive (Table 5) and HBeAg-negative (Table 6) CHB over comparable drugs in pivotal clinical

Peginterferon alfa-2a

The efficacy of peginterferon alfa-2a has been demonstrated in a large phase III randomized study that compared peginterferon alfa-2a 180 μg/wk, lamivudine 100 mg/day, and both drugs in combination for 48 weeks in patients with HBeAg-positive CHB.63 At the end of treatment, therapy with peginterferon alfa-2a, with or without lamivudine, resulted in significantly greater rates of HBeAg seroconversion, HBV DNA undetectability, and ALT normalization, compared with treatment with lamivudine alone (

Hepatitis B e Antigen–Positive Patients

The recommendations for the treatment of HBeAg-positive patients are summarized in Table 7. The panel recommends an HBV DNA level of ≥20,000 IU/mL as a reasonable threshold for determining candidates for treatment, in combination with elevated ALT levels. HBeAg-positive patients who have HBV DNA levels of <20,000 IU/mL are atypical and are not recommended routinely for treatment because the majority of these individuals have inactive disease. However, because these individuals might be at risk

Monitoring Virologic Response and Management of Resistance to Oral Antiviral Therapy

Prolonged antiviral therapy with the oral nucleosides and nucleotides is associated with the development of antiviral resistance.146 The rate of resistance depends on a number of factors, including pretreatment HBV DNA levels, potency of the antiviral agent, prior exposure to oral nucleoside or nucleotide antiviral therapy, duration of treatment, and the degree of genetic barriers to resistance to the individual drug. The long-term rates of resistance are highest for lamivudine (65%–70% at 4–5

Patients With Cirrhosis

Before the advent of effective antiviral therapy, the 5-year survival rate was 84% for patients with compensated cirrhosis and 14%–35% for patients with decompensated cirrhosis.38, 155, 156 Various clinical parameters such as bilirubin level and older age were shown to predict survival. In addition, patients with compensated cirrhosis who lost HBeAg had 97% survival at 5 years, compared with 72% in HBeAg-positive patients; such findings implicated viral replication in adverse outcomes.38, 40,

Conclusion

For patients with chronic HBV infection, the primary goal of treatment is to prevent progression of liver disease to liver failure or HCC and prevent premature death or need for transplantation. On the basis of clinical and epidemiologic data, durable HBV DNA suppression is now considered the primary determinant of treatment outcomes, along with avoidance of resistance. The threshold level of HBV DNA for initiation of therapy remains unchanged at ≥20,000 IU/mL for patients with HBeAg-positive

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    The authors wish to thank Kathy Covino, PhD, for her editorial contributions and assistance in the preparation of the manuscript.

    The authors disclose the following: This algorithm was developed with support by an unrestricted educational grant from Gilead Sciences.

    Dr Keeffe is an employee of Romark Laboratories and has been a consultant for and served on advisory boards for Bristol-Myers Squibb, Gilead, Idenix, Novartis, and Roche. Dr Dieterich has received grant or research support and honoraria from Bristol-Myers Squibb, Gilead, Idenix, and Roche. Dr Han has received grant or research support, served on the advisory boards, and been a member of speakers' bureaus for Bristol-Myers Squibb, Gilead, and Roche. Dr Jacobson has received grant or research support from Coley, Gilead, Globelmmune, InterMune, Ribozyme, Valeant, and Schering-Plough; is a consultant for Anadys, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Coley, Gilead, Globelmmune, Idenix, InterMune, Novartis, Pfizer, Schering-Plough, Valeant, and Vertex; and is on speakers' bureaus for Bristol-Myers Squibb, Gilead, GlaxoSmithKline, and Schering-Plough. Dr Martin has been a consultant, speaker, and investigator for Gilead, Bristol-Myers Squibb, Idenix, Novartis, Roche, and Schering. Dr Schiff has been a consultant to Abbott, Achillion, Bayer, Bristol-Myers Squibb, Cadence, Gilead, GlobeImmune, Idenix, Maxim, National Genetics Institute, Novartis, Ortho-Biotech, Pharmasset, Pfizer, PowerMed Limited, Prometheus, Roche Molecular, Salix, Sankyo Pharma, Schering-Plough, and SciClone; he has research grants and support including clinical trials from Abbott, Bayer, Bristol-Myers Squibb, Coley, Gilead, GlaxoSmithKline, Idenix, Ortho-Biotech, Prometheus, Roche Diagnostics, Roche Molecular, Roche Pharmaceutical, Schering-Plough, SciClone, and Vertex; and he has served on the speakers' bureau or received honoraria from Abbott, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Idenix, Ortho-Biotech, and Schering-Plough. Dr Tobias has served as a consultant and/or is on speakers' bureaus for Bristol-Myers Squibb, Gilead, Novartis and Roche.

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