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Table of Contents

Revised November 16, 2005

Robert S. O'Shea, MD, MScE

Robert S. O'Shea, MD, MScE

Department of
Gastroenterology
and Hepatology

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Copyright 2005
The Cleveland Clinic Foundation



RELATED CME

Viral Hepitatis Summit
 August 24-26
  
To provide education & guidance regarding advances in Hepatitis Management.

 

   Viral liver disease has become a highly visible public health concern, particularly with the growing awareness of the hepatitis C epidemic. It also presents a challenging and frequently encountered problem for practicing physicians. The literature on this subject is vast and rapidly expanding as new and promising therapies are studied and made available to patients. This chapter covers hepatitis B, which remains one of the most common hepatitis infections in the world. The other hepatitis viruses are discussed in separate chapters and can be viewed by clicking on the hyperlinks on the right-hand side of this page.

 

Chapter Outline

Epidemiology

Natural History

Diagnosis

Clinical Course

Therapy and
Immunization

References

National Guidelines

A Comprehensive Strategy for Eliminating Transmission in the United States Through Universal Childhood Vaccination: Recommendations of the Immunization Practices Advisory Committee (ACIP)

AASLD Practice Gudielines for Chronic Hepatitis B

 

RELATED
CHAPTERS

Hepatitis A

Hepatitis C

Hepatitis D

Hepatitis E
and Hepatitis G/GBV-C

Related Material from The Cleveland Clinic Guidelines for Antimicrobial Usage

  • Recommended Schedule for Active Immunization of Normal Infants and Children

 

 
EPIDEMIOLOGY

Hepatitis B is found throughout the world, but its prevalence varies greatly; it is especially high in Asia, sub-Saharan Africa, the south Pacific, as well as within specific populations in South America, the Mid-East, and the Arctic.1 Prevalence in the United States varies, partially based on the population makeup, including the extent of the immigrant population from endemic areas, or based upon risk factors and behaviors, such as the prevalence of injection drug use or homosexual practices. In the United States, the Centers for Disease Control and Prevention (CDC) estimates that there are about 1.25 million people infected;2 the World Health Organization (WHO), however, estimates that 2 billion people are infected worldwide, with approximately 5% of the world's population (or 350 million people) being carriers of chronic hepatitis B.3

Figure 1, based on data from the WHO, illustrates the prevalence of hepatitis B throughout the world.

Hepatitis B was first discovered in 1963 by Dr. Baruch Blumberg and colleagues, who identified a protein (the "Australia antigen") that reacted to antibodies from patients with hemophilia and leukemia. The association of this protein with infectious hepatitis was discovered 3 years later by several investigators, and the virus was specifically seen by electron microscopy in 1970.4

 
Figure 2

The hepatitis B virus (HBV) is a double-stranded hepatotropic DNA virus belonging to the family Hepadnaviridae. It is a 42 nm spherical particle with a 27nm diameter, electron-dense, nucleocapsid core and a 7nm thickness outer lipoprotein envelope (Figure 2). The viral genome is 3.2 kb in length, and possesses four partially overlapping open-reading frames that encode various antigens.5 The virus infects only humans and some other non-human primates. Viral replication takes place predominantly in hepatocytes and to a lesser extent in the kidney, pancreas, bone marrow, and spleen. The intact virion is a double-shelled particle with an envelope of hepatitis B surface antigen (HBsAg), an inner nucleocapsid of core antigen (HBcAg), and an active polymerase enzyme that is linked to a single molecule of double-stranded HBV DNA. Significant variability of the nucleotide sequence exists as in hepatitis C, and the virus can be subdivided into 8 different genotypes, based on the degree of variation. The clinical importance of these is still uncertain, however.6

NATURAL HISTORY

Although HBV can survive outside the body for up to 1 week (and therefore, might be transmitted via indirect contact, e.g., from open sores), hepatitis B is spread predominantly parenterally, through intimate personal contact, and perinatally. Individuals at risk are intravenous drug users, children of mothers with HBV, men who have sex with men, patients on hemodialysis and those exposed to blood or blood products.2,7

The incubation period of HBV ranges from 45 to 160 days (mean = 100 days). The acute illness is usually mild, particularly in children. In adults, as many as 30% to 50% will present with jaundice, and hepatitis may be fulminant in 0.1% to 0.5% of adults patients with acute hepatitis B infection8,9 Symptoms therefore range widely in severity, from asymptomatic, subclinical infection to fulminant, fatal disease. An insidious onset of nausea, anorexia, malaise and fatigue, or flu-like symptoms, such as pharyngitis, cough, coryza, photophobia, headache, and myalgias may precede the onset of jaundice. Fever is uncommon, unlike hepatitis A infection. Symptoms abate or disappear with the onset of jaundice, although anorexia, malaise, and weakness may persist. Physical examination features are nonspecific, but may include mild enlargement and slight tenderness of the liver, mild splenomegaly, and posterior cervical lymphadenopathy in 15% to 20% of patients. Fulminant disease (acute liver failure) presents as a change in mental status (encephalopathy) and coagulopathy.10

Patients with chronic hepatitis B may develop extra-hepatic manifestations, including arthralgias, mucocutaneous vasculitis, glomerulonephritis, and polyarteritis nodosa. The glomerulonephritis of hepatitis B occurs more commonly in children than in adults and is usually characterized by nephrotic syndrome with little decrease in renal function. Polyarteritis nodosa occurs primarily in adults and is marked by a sudden and severe onset of hypertension, renal disease, and systemic vasculitis with arteritis in the vessels of the kidney, gallbladder, intestine, or brain. Other rare extrahepatic manifestations are mixed essential cryoglobulinemia, pericarditis and pancreatitis.11

The risk of developing chronic infection (or the carrier state), defined as the persistence of HBsAg in the blood for more than 6 months, is dependent on the age and immune function of the patient at the time of initial infection. Ninety percent of infected newborns, 30% of children under the age of 5 years, and 10% of adults progress to chronic infection. Fifteen percent to 40% of these carriers may develop hepatitis B-related sequelae in their lifetimes. Patients with chronic infection will spontaneously clear surface antigen at a rate of 0.5% a year.12

DIAGNOSIS

Viral and immune markers are detectable in blood, and characteristic antigen-antibody patterns evolve over time that allow us to characterize hepatitis B infection (Figure 3,Table 1). The first detectable viral marker is HBsAg followed by hepatitis B e antigen (HBeAg) and HBV DNA. Titers may be high during the incubation period, but HBV DNA and HBeAg levels begin to fall at the onset of illness and may be undetectable at the time of peak clinical illness.13 Core antigen does not appear in blood, but antibody to this antigen (anti-HBc) is detectable with the onset of clinical symptoms. The immunoglobulin M (IgM) fraction is used in an important diagnostic assay for acute hepatitis B infection. Before current molecular assays were available, it was the only marker detectable at the time between when HBsAg disappears and anti-HBs appears (Figure 3), the "window period".14,15 Patients who clear the virus lose HBsAg and develop anti-HBsAb. Anti-HBsAb is a long-lasting antibody and is associated with immunity. The presence of anti-HBsAb and anti-HBcAb (IgG) indicates recovery and immunity in a previously infected individual, whereas a successful vaccination response produces antibody only to HBsAg.

HBeAg is another viral marker detectable in blood and correlates with active viral replication, and therefore high viral load and infectivity (Figure 3). The antigen is synthesized from a strand of DNA immediately preceding the area that codes for the core antigen.16 A mutation in this area can occur, preventing the production of the HBeAg. Such affected viruses are present throughout the world, particularly in Asia and the Mediterranean, and are known as "precore mutants."17,18 The presence of a precore mutant, causing hepatitis B e antigen-negative chronic hepatitis, has a number of implications regarding the natural history, as well as treatment options and outcomes.19

The hepatitis B virus is not cytopathic, and therefore liver injury in chronic hepatitis B is believed to be immunologically mediated. Thus, the severity and course of disease do not correlate well with the level of virus in serum or the amount of antigen expressed in the liver. Antigen-specific cytotoxic T cells are believed to play a role in the cell injury in hepatitis B, but account for ultimate viral clearance. Specific cytokines produced by cytotoxic and other T cells also have antiviral effects on the hepatitis B virus, contributing to viral clearance without cell death. The lack of a vigorous and specific CD8+ cytotoxic T-cell and CD4+ T helper cell response may allow chronic infection to develop. Recruitment of nonspecific T cells then results in low-level, chronic inflammation and liver damage.20,21 Similarly, spontaneous seroconversion from HBeAg to anti-HBeAb during chronic hepatitis B may also be immunologically mediated, as is suggested from the transient flare of disease that often immediately precedes clearance of HBeAg.13
CLINICAL COURSE

In the appropriate clinical context, acute hepatitis B is diagnosed by detecting HBsAg and IgM core antibody, or core antibody alone, in the window period.22,23 IgM core antibodies are lost within 6 to 12 months of the onset of illness. Biochemically, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels increase to between 500 to 5000 U/L and fall after the acute phase of infection. Serum bilirubin level seldom increases above 10 mg/dL, alkaline phosphatase and prothrombin time are usually normal or mildly elevated (1-3 seconds), and serum albumin is normal or minimally depressed. Peripheral blood counts may show mild leukopenia with or without relative lymphocytosis. Loss of HBsAg and the development of HBsAb denotes recovery from the acute infection and the development of immunity.24

Chronic hepatitis B is defined as the persistence of HBsAg in the serum of a patient for at least six months. Patients with chronic infection may be divided into those with evidence of active replication, typically associated with abnormal transaminases and higher viral loads, and those in the nonreplicative state, which is associated with decreased markers of liver inflammation and damage, and lower viral loads. Transaminases may be normal, or increased anywhere from 1 to 10 times the upper limit of normal in chronic infection. Levels of HBV DNA are usually in the range of 105 genome copies/mL, which are readily detectable by hybridization techniques, but the absolute level may fluctuate.25 Hepatitis B e antigen (HBeAg) in serum reflects active viral replication, and the clinical outcome of infection is correlated with e Ag status. Conversion to e antigen negative, e Ab-positive in patients with chronic hepatitis B typically leads to decreased inflammation, with normalizing transaminases and decreased levels of HBV DNA in serum — "the inactive carrier" state. The e-antigen marker is absent in patients with precore mutants. Using conventional hybridization assays, HbsAg carriers do not have detectable HBV DNA in serum. Testing for HBV DNA with more sensitive techniques, such as polymerase chain reaction (PCR), however, usually demonstrates low levels of viral DNA in serum in these carriers.26

Spontaneous loss of HBeAg occurs at a rate of 8% to 12% per year, associated with a decrease in HBV DNA below levels detected by hybridization techniques.27 Loss of HBsAg occurs less frequently (1% per year).

The course of chronic hepatitis B is variable. Chronically infected patients without active liver disease or viral replication (inactive carriers) generally have a benign course with very little chance of progressing to cirrhosis. Patients who continue to have active viral replication with high levels of HBV DNA and HBeAg in serum have progressive liver injury, and cirrhosis and end-stage liver disease may develop. A transient flare of disease often precedes remission. Loss of HBeAg is not always followed by permanent resolution of disease and disease flares may occur, particularly if a patient is treated with steroids or other immunosuppressive medications. Patients who revert to chronic hepatitis B e antigen-positive status tend to develop cirrhosis at a substantially increased rate compared to those who remain hepatitis B e antigen-negative.28

Patients who continue to have high DNA levels and evidence of ongoing hepatic inflammation - despite a positive hepatitis B e Ab and loss of hepatitis B e Ag - are likely infected with a mutant strain. Specific mutations in the pre-core and core promoter genes can be found, which typically have developed in the course of natural infection. These mutants, however, tend to be associated with more significant disease than in patients who are e Ag-positive.29

Chronic HBV infection is associated with a 10-fold increase in the risk of developing hepatocellular carcinoma (HCC). This risk is further magnified in the setting of ongoing inflammation: in patients with both hepatitis B s Ag and e Ag, the risk increases to 60-fold compared with the general population.30 Older men with cirrhosis and those co-infected with hepatitis C are at greatest risk. In regions where HBV is endemic, HCC is the leading cause of cancer-related deaths.31,32 It is therefore recommended that HBV carriers, particularly those at highest risk (men over age 45, patients with cirrhosis, and those with a family history of liver cancer) should be screened with ultrasound and alpha-fetoprotein for HCC, probably every 6 months.33

THERAPY AND IMMUNIZATION

Effective vaccines for HBV (defined as inducing better than 90% protection against HBV) have been available in the United States since 1982. Early strategies targeted high- risk groups, but were not successful in materially decreasing incidence rates.34 Therefore, universal vaccination for HBV has been recommended for infants by the American Academy of Pediatrics since 1991. Guidelines for the prevention of hepatitis B are comprehensively outlined by the CDC and can be accessed at www.cdc.gov.35 Post-exposure prophylaxis consists of a single dose of hepatitis B immune globulin (HBIG) injected intra-muscularly followed immediately by HBV vaccination. Two recombinant hepatitis B vaccines are available in the United States. For adults, the recommended regimen is three injections (10 µg of Engerix-B or 20 µg of Recombivax HB) intramuscularly in the deltoid muscle at 0, 1, and 6 months. The seroconversion rate is greater than 90% in adults but may be lower, based on particular comorbid diseases or genetic factors,36 as well as in smokers, the obese, or the elderly, or in patients who are immunocompromised. These patients may require higher doses and more injections.37,38

Pre-vaccination screening for anti-HBs is not recommended except for adult patients who are likely to have been previously exposed, including those in high-risk groups (injection drug users or male homosexuals).39 Post-vaccination testing for anti-HBs to document seroconversion is not routinely recommended except for persons who are at risk for lack of response or continued exposure.40 Booster doses may be appropriate for high-risk individuals if titers of anti-HBs fall below what is considered protective (10 IU/mL). The vaccine should be routinely administered to all those younger than age 18, as well as those adults at risk of exposure. It should be given to neonates of HBV-infected mothers together with HBIG.41,42

In acute hepatitis B, treatment is supportive. Although several case series have been published, there is no clear evidence that early therapy with antiviral agents for acute hepatitis B decreases the risk of chronicity or speeds recovery.43-45 Most patients with acute, icteric hepatitis B recover without residual injury or chronic hepatitis. Patients should be followed with repeat testing for HBsAg and ALT levels to determine whether seroconversion and clearance of surface antigen occurs.46

In chronic hepatitis B, therapy is administered to suppress viral replication and prevent progression of liver disease. Therapy is not routinely recommended for patients with normal enzymes whether they are chronic inactive carriers or based on their e antigen status.47 Therapy is recommended for patients with evidence of active damage to the liver, eg, those with abnormal levels of aminotransferases (ie, an ALT level more than twice the upper limit of normal). A liver biopsy before therapy is the gold standard to assess the degree of necroinflammatory activity and fibrosis.

Although the data are still evolving, the most recent recommendations of the American Association for the Study of Liver Diseases (AASLD) also include treatment of patients with compensated and decompensated cirrhosis and measurable HBV DNA regardless of e Ag status, or degree of elevation of ALT. Support for this approach is lent by several studies that have shown a decreased rate of development of progressive liver disease in treated patients.48 Because the likelihood of developing anti-HBs — and therefore recovery with long-term protection from hepatitis B — is fairly small, measured outcomes of treatment focus on rates of normalization of liver enzymes, decreases in viral DNA levels, or seroconversion: i.e., the conversion of a patient from e Ag-positive to E Ag-negative, with a positive e Ab.

Five agents have been approved by the US Food and Drug Administration (FDA) to treat hepatitis B. Interferon alpha, available since 1992 and injected subcutaneously at a dose of 5 MU daily, has direct antiviral activity as well as effects on the host immune system.49,50 The major side effects of interferon include fatigue, muscle aches, fever, depression, and irritability. Uncommon severe side effects include exacerbation of depression, psychosis, renal and cardiac failure, bacterial infections, and induction of autoimmunity.

The FDA approved the use of long-acting interferon (peginterferon alfa 2a, at a dose of 180µg for 48 weeks) in 2005 for treatment of patients with chronic hepatitis B; the side effect profile of peginterferon alfa 2a is very similar to that of shorter acting interferon.

The other drugs available are nucleoside or nucleotide analogs, which interfere with the replication of the virus but unfortunately have no effect on the immune clearance of viral DNA. Lamivudine, approved by the FDA in 1998, is the negative enantiomer of 2'3' dideoxy-3'-thiacytidine, and inhibits HBV DNA synthesis at a dose of 100 mg daily.51 The most recent oral drugs available for treatment of HBV are adefovir, which was approved by the FDA in September, 2002, and entecavir, approved in March 2005.

Patients who are HBeAg-positive and have evidence of liver disease should be treated. The longest follow-up data on treatment outcomes are available for interferon and lamivudine, given the length of time they have been used by physicians. Each treatment option has been approved for use in this patient population, and the choice between them is dictated by considerations of the likelihood of response, cost, length of treatment, and side-effect profile. There are some data regarding likelihood of treatment response in patients treated with interferon, with a higher chance of success in patients with high ALT levels, but low HBV DNA levels. Analogously, lamivudine is more likely to be effective in patients with increased ALT levels or inflammation on liver biopsy.52 Comparable predictors of response for the other antivirals have not been established.

Treatment options for patients with e antigen-positive chronic hepatitis B include either 16 weeks of interferon therapy, or a minimum of 1 year of lamivudine therapy, with an additional 3 to 6 months after seroconversion, or 1 year of adefovir or entecavir treatment.47 The response rate for these different therapies in this population, defined as seroconversion (from e Ag-positive to e Ag-negative, with a positive e Ab) is variable; published rates range from 12% (with adefovir), 16% to 18% with lamivudine, 21% with entecavir,53 to 32% to 33% with pegylated alfa 2a or interferon.54,55,63 Other endpoints (normalization of liver enzymes or improvement in liver histology) are seen in 50% to 70% of treated patients, regardless of therapy.

Patients with a beneficial response to interferon therapy often develop a flare of disease with elevations of serum ALT to levels 2 to 3 times the baseline before normalization occurs. Because of this, the use of interferon in cirrhotic patients is not recommended. Disease flares, by comparison, are not typically seen in patients treated with lamivudine or adefovir. Preliminary data suggest that entecavir may also be safe in cirrhotic patients.

Whether combination therapy using two or more agents, or others, either sequentially or simultaneously, will translate into increased response rates is still not yet clear.

Treatment for patients with hepatitis B e Ag-negative disease is also possible. Multiple studies have shown efficacy with each of the various approved therapies, in terms of loss of hepatitis B viral DNA or normalization of liver enzymes (on the order of 60% to 70%). Unfortunately, the response rates are often not sustained, with very high relapse rates after therapy is stopped. As a result, the optimal duration of therapy is not defined in this population. An important consideration in patients on lamivudine becomes the possibility of emergence of mutants resistant to treatment, which increases with increasing duration of treatment. Rates of resistance range from 24% at 1 year, to 42% by year 2 of continued therapy. Lamivudine resistance is manifested by the re-appearance of HBV DNA in serum, most commonly with the so-called YMDD mutant, characterized by an amino acid substitution in HBV DNA polymerase. The outcomes in these patients are variable, but they should be considered for treatment with another antiviral.56-58 In this situation, multiple studies have shown a beneficial role for the use of adefovir, which is associated with a much lower rate of resistance.

Thus, although the introduction of nucleotide or nucleoside analogs represents a significant advance in the management of chronic hepatitis B, many questions remain regarding optimal dosing, duration and possible combinations to prevent resistance, to increase long-term suppression or to promote eventual clearance. A number of other drugs, including emtricitabine, clevudine, famciclovir, telbivudine, and tenofovir have shown some efficacy, often in patients coinfected with HIV, and are therefore being further studied in a number of clinical trials.59-62 The above recommendations are based in part on the AASLD Practice Guidelines for Chronic Hepatitis B, which can be accessed at www.aasld.org.

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