brand logo

Am Fam Physician. 2009;80(8):884-888

Guideline source: National Institutes of Health

Literature search described? No

Evidence rating system used? No

Published source:Annals of Internal Medicine, January 20, 2009

Hepatitis B is a significant cause of liver disease worldwide, including cirrhosis and hepatocellular carcinoma. The development of a hepatitis B virus (HBV) vaccine has reduced the number of new cases of acute hepatitis B in the United States; however, acute and chronic HBV infections remain a global health problem. The National Institutes of Health (NIH) Consensus Development Panel has produced a report on the management of HBV created by independent panels of health professionals and public representatives using a systematic literature review. The literature review was prepared under contract with the Agency for Healthcare Research and Quality, along with input from investigators and conference attendees. The panel addressed six questions concerning the economic burden, history, treatment, and future research opportunities of HBV.

What Is the Current Burden of Hepatitis B?

An estimated 400 million persons worldwide are living with chronic HBV infection. Approximately 500,000 persons die of cirrhosis and hepatocellular carcinoma from chronic HBV each year, and another 40,000 persons die of acute hepatitis B. Although the incidence of acute HBV infection in the United States has decreased since the mid-1980s, there are an estimated 1 million U.S. residents with chronic infection, leading to approximately 2,000 to 4,000 deaths annually. National surveys suggest that 0.3 to 0.5 percent of U.S. residents have chronic HBV infection, and 47 to 70 percent of these persons were born outside the United States. There is an increased prevalence of HBV infection among persons born in countries with a high prevalence of HBV, and among subpopulations who engage in behaviors that carry a risk of HBV transmission, such as persons who use injectable drugs and men who have sex with men.

The public health burden of HBV stems primarily from its long-term effects on liver function. More than $1 billion is spent annually on HBV-related hospitalizations. Indirect costs of chronic HBV infection include reduced physical and emotional quality of life, reduced economic productivity, long-term disability, and premature death.

What Is the Natural History of Hepatitis B?


HBV is transmitted through infected blood or body fluids entering the body through mucous membranes or open wounds. It may also be passed by injection through shared needles or syringes; by sexual contact with an infected person; or by perinatal exposure to an infected mother. It is more common for adults to experience symptoms than newborns and young children. The hepatitis B surface antigen (HBsAg) can be detected in the blood four to 10 weeks after infection, but it may be up to six months before symptoms develop. In adults, most acute HBV infections are self-limited, and patients recover by developing antibodies and clearing HBsAg from the blood. A small proportion of patients may develop severe acute hepatitis B. Persons who are infected with hepatitis C virus (HCV) or hepatitis D virus (HDV) are at increased risk of severe acute HBV infection.


Chronic HBV infection occurs in most children infected with HBV in the perinatal period, and in about one half of children infected between one and five years of age. Less than 5 percent of adults develop HBV infection with ongoing viral replication in the liver.

There are three phases of chronic HBV infection: immune tolerant, immune active, and inactive carrier. The immune-tolerant phase may last for decades in children who are infected in the perinatal period. It consists of active viral replication in the liver with little or no evidence of disease activity; a liver biopsy will show normal or minimal inflammation. Liver disease generally does not progress in this phase.

The immune-active phase usually follows the immune-tolerant phase. During this phase, the immune response to HBV is more pronounced. A liver biopsy will show inflammation with or without scarring. Patients in the immune-tolerant or immune-active phases usually have a detectable level of hepatitis B e antigen (HBeAg), which indicates high levels of HBV DNA in the blood.

Most patients with chronic HBV will eventually enter the inactive-carrier phase where HBeAg is cleared from the body as anti-HBe (HBeAg seroconversion) develops. Levels of HBV DNA are low or undetectable. In this phase, patients have a low risk of hepatocellular carcinoma and do not usually progress to severe disease, although immunosuppression can reactivate the disease.

The long-term progression of chronic HBV varies. Patients infected with HBV in adolescence or later typically enter the inactive-carrier phase after clearing HBeAg, whereas patients infected at birth or in early childhood may have a longer immune-tolerant phase.


Chronic HBV infection is a strong risk factor for hepatocellular carcinoma, although the mechanisms are not well understood. Every 10 years, approximately 5 percent of adults with chronic HBV infection acquired during the perinatal period will develop hepatocellular carcinoma. The mortality rate for hepatocellular carcinoma is high, except in persons who undergo liver resection or transplantation.

Patients who remain in the immune-active phase of HBV infection have the highest risk of cirrhosis and hepatocellular carcinoma. Predictors of these conditions include a prolonged elevation of HBV DNA in the blood, an elevated level of alanine transaminase (ALT), and the presence of HBeAg. Persons who are coinfected with HCV are also at increased risk. Other risk factors for hepatocellular carcinoma include male sex, older age, and family history of hepatocellular carcinoma.

What Are the Benefits and Risks of the Current Therapeutic Options for Hepatitis B?

The U.S. Food and Drug Administration has approved seven agents for treating HBV infection in adults. These are categorized as interferons (interferon alfa-2b or pegylated interferon alfa-2a [Pegasys]), or nucleoside or nucleotide analogues (lamivudine [Epivir], adefovir dipivoxil [Hepsera], entecavir [Baraclude], telbivudine [Tyzeca], and tenofovir [Viread]). These may be used as monotherapy or in combination. Interferon agents have a self-limited, defined course (16 to 48 weeks), and are not associated with the development of antiviral resistance. However, they require subcutaneous injections and may cause side effects, such as headache, nausea, influenza-like symptoms, depression, and some hematologic abnormalities.

Nucleoside or nucleotide analogues are long-term, indefinite treatments that are administered orally. They are associated with a more profound suppression of HBV DNA, and are safe in patients who do not respond to interferons. However, if nucleoside or nucleotide analogue therapy is discontinued prematurely, HBV DNA levels may increase and hepatitis may reactivate. Long-term use of these agents may lead to resistance. Nucleoside and nucleotide analogues are also associated with renal toxicity, myopathy, and mitochondrial toxicity.

There is limited evidence to demonstrate the effects of these therapies on long-term clinical outcomes. Because cirrhosis, hepatocellular carcinoma, and death usually do not occur for many years after HBV infection, most studies use short-term changes in virologic, biochemical, and histologic measures to predict long-term outcomes. In the absence of long-term randomized controlled trials (RCTs), biomarkers such as loss of HBsAg, HBV DNA level, HBeAg or antibody status, ALT level normalization, and improvement in liver histology may be used to predict clinical benefit or harm. Because the available evidence does not favor one therapeutic course, physicians should discuss the risks and benefits of both options with patients.

Who Should Be Treated?


Therapy is indicated in patients with rapid deterioration of liver function and in patients with decompensated cirrhosis (Table 1). In clinical experience, nucleoside or nucleotide analogues have shown a reduction in adverse clinical outcomes. Interferons are contraindicated because of the risk of liver failure. Although patients with compensated cirrhosis are at increased risk of clinically important complications, one RCT demonstrated a relevant improvement in the stage of cirrhosis and a borderline-significant reduction in the incidence of hepatocellular carcinoma with therapy.

IndicationsTherapy indicated?
Patients with acute liver failure; cirrhosis and clinical complications; cirrhosis or advanced fibrosis and HBV DNA in serum; or reactivation of chronic HBV after chemotherapy or immunosuppressionYes
Infants born to women who are HBsAg-positive (immunoglobulin and vaccination)
Patients in the immune-active phase who do not have advanced fibrosis or cirrhosisPossibly
Patients with chronic hepatitis B in the immune-tolerant phase (with high levels of serum HBV DNA but normal levels of serum ALT or little activity on liver biopsy)No
Patients in the inactive-carrier or low-replicative phase (with low levels of or no detectable HBV DNA in serum, and normal serum ALT levels)
Patients with latent HBV infection (HBV DNA without HBsAg)

Patients with HBV who receive immunosuppressive or cancer chemotherapy are at increased risk of developing exacerbated hepatitis. These patients should begin antiviral therapy for hepatitis B before beginning immunosuppressive therapy, and should continue antiviral therapy throughout the duration of treatment.

Infants of women who are HBsAg positive should receive hepatitis B immunoglobulin and hepatitis B vaccination within 12 hours of birth to reduce the risk of perinatal transmission.


Patients with chronic HBV who have active liver inflammation, as reflected by elevated ALT levels or histology, may receive treatment depending on the progression of the disease in the absence of therapy (Table 1). Therapy may decrease HBV DNA levels and improve ALT levels in patients in the immune-active phase of chronic HBV. Because patients younger than 40 years may undergo spontaneous HBeAg seroconversion, they may be monitored without therapy unless progressive liver disease begins. Therapy may be indicated if spontaneous seroconversion has not occurred in patients by their late 30s or early 40s and active inflammation is present.

Patients in the reactivation phase of chronic HBV, characterized by elevated HBV DNA levels and evidence of liver inflammation, usually should receive therapy. Other factors that may influence the decision to treat include male sex, genotype C, a family history of hepatocellular carcinoma, and ongoing alcohol abuse. Coinfection with human immunodeficiency virus (HIV), HCV, or HDV increases the risk of adverse outcomes. Patients with HBV and HIV should receive combination therapy with nucleoside or nucleotide analogues to avoid resistance and reduce the replication of both viruses.


Therapy is not indicated in younger patients in the immune-tolerant phase, those in the inactive-carrier phase, and those who have latent HBV infection (Table 1). These patients are at lower risk of adverse outcomes. Therapy is not recommended in patients with concurrent serious conditions in whom complications from HBV-associated liver disease are unlikely to contribute to morbidity and mortality. Patients who are nonadherent to a therapy regimen are unlikely to benefit from therapy. If therapy is not initiated, ALT levels should still be monitored at regular intervals. Elevated ALT levels may warrant consideration of therapy.

What Measures Are Appropriate to Monitor Therapy and Assess Outcomes?

Response to treatment is measured with biochemical, virologic, serologic, or histologic indices. Virologic activity is typically measured using quantitation of HBV DNA with an assay that provides a wide dynamic range. The loss of HBsAg and seroconversion are associated with durable suppression of HBV DNA, although this is not usually achieved in the short term with current therapy.

Measuring HBV DNA and ALT levels every 12 weeks, and HBeAg or anti-HBe levels every 24 weeks is one proposed management strategy for patients who are HBeAg-positive. Seroconversion to anti-HBe may allow patients who are HBeAg-positive with undetectable HBV DNA levels to discontinue therapy after six to 12 months. Periodic monitoring of HBV DNA and HBeAg status is advised because relapse is possible. Patients with cirrhosis should continue therapy. The benefits and harms of screening for hepatocellular carcinoma are unknown.

What Are the Greatest Needs and Opportunities for Future Research on Hepatitis B?

Because of the long duration of illness, research on HBV infection is challenging. Clinical trials should use extended follow-up to measure outcomes in populations with high levels of infection. More RCTs, including placebo-controlled studies, are needed to eliminate reliance on results from observational studies. These trials should be conducted with standardized protocols, regimens, clinical definitions, diagnostic methods, follow-up intervals, and outcome measures.

Coverage of guidelines from other organizations does not imply endorsement by AFP or the AAFP.

This series is coordinated by Michael J. Arnold, MD, Assistant Medical Editor.

A collection of Practice Guidelines published in AFP is available at

Continue Reading

More in AFP

Copyright © 2009 by the American Academy of Family Physicians.

This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP.  See permissions for copyright questions and/or permission requests.