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Background

In 1965, Blumberg et al reported the discovery of the hepatitis B surface antigen (HBsAg), also known as Australia antigen, and its antibody, hepatitis B surface antibody (HBsAb). A few years later, in 1970, Dane visualized the hepatitis B virus (HBV) virion. [1] Since then, considerable progress has been made regarding the epidemiology, virology, natural history, and treatment of this hepatotropic virus. The image below depicts a liver biopsy specimen.

Liver biopsy specimen showing the ground-glass appearance of hepatocytes in a patient with hepatitis B.

Hepatitis B is a worldwide healthcare problem, especially in developing areas. An estimated one third of the global population has been infected with the hepatitis B virus (HBV). Approximately 350 million people are lifelong carriers, and only 2% spontaneously seroconvert annually. Ongoing vaccination programs appear to be promising in the attempt to decrease the prevalence of HBV disease. The hepatitis B virus (HBV) is transmitted hematogenously and sexually. The outcome of this infection is a complicated viral-host interaction that results in either an acute symptomatic disease or an asymptomatic disease. Patients may become immune to HBV, or they may develop a chronic carrier state. Later consequences are cirrhosis and the development of hepatocellular carcinoma (HCC).[2, 3, 4, 5] Antiviral treatment may be effective in approximately one third of the patients who receive it, and for selected candidates, liver transplantation currently seems to be the only viable treatment for the latest stages of hepatitis B. See also Liver Disease in Pregnancy, Hepatitis A, Hepatitis C, Hepatitis D, andHepatitis E, and Viral Hepatitis.

Pathophysiology
Hepatitis B virus (HBV) is a hepadnavirus.[6, 7, 8, 9, 10] It is an extremely resistant strain capable of withstanding extreme temperatures and humidity. HBV can survive when stored for 15 years at 20C, for 24 months at 80C, for 6 months at room temperatures, and for 7 days at 44C.

Viral genome
The viral genome consists of a partially double-stranded, circular DNA of 3.2 kilobase (kb) pairs that encodes 4 overlapping open reading frames, as follows:

S for the surface or envelope gene encoding the pre-S1, pre-S2, and the S protein C for the core gene, encoding for the core nucleocapsid protein and the e antigen X for the X gene encoding the X protein

P for the polymerase gene encoding a large protein promoting priming RNA-dependent and DNA-dependent DNA polymerase and RNase H activities An upstream region for the S (pre-S) and C (pre-C,) genes has been found. The structure of this virion is a 42-nm spherical, double-shelled particle consisting of small spheres and rods, with an average width of 22 nm. The S gene encodes the viral envelope. There are 5 mainly antigenic determinants: (1) a, common to all hepatitis B surface antigen (HBsAg), and (2-5) d, y, w, and r, which are epidemiologically important. The core antigen, HBcAg, is the protein that encloses the viral DNA. It can also be expressed on the surface of the hepatocytes, initiating a cellular immune response. The e antigen, HBeAg, comes from the core gene and is a marker of active viral replication. Usually, HBeAg can be detected in patients with circulating serum HBV DNA. The best indication of active viral replication is the presence of HBV DNA in the serum. Hybridization or more sensitive polymerase chain reaction (PCR) techniques are used to detect the viral genome in the serum. The role of the X gene is to encode proteins that act as transcriptional transactivators that aid viral replication. Evidence strongly suggests that these transactivators may be involved in carcinogenesis.

Antibody production
The production of antibodies against HBsAg confers protective immunity and can be detected in patients who have recovered from HBV infection or in those who have been vaccinated. Antibody to HBcAg is detected in almost every patient with previous exposure to HBV. The immunoglobulin M (IgM) subtype is indicative of acute infection or reactivation, whereas the IgG subtype is indicative of chronic infection. With this marker alone, one cannot understand the activity of the disease. Antibody to HBeAg is suggestive of a nonreplicative state and one in which the antigen has been cleared.

Variant strains
With the newest PCR techniques, scientists are able to identify variations in the HBV genome (variant strains). Mutations of various nucleotides such as the 1896 (precore/core region) processing the production of the HBeAg have been identified (HBeAg negative strain). The prevalence of the HBeAg negative virus varies among different areas. Estimates indicate that 50-60% of the patients from Southern Europe, the Middle East, Asia, and Africa as well as 10-30% of patients in the United States and Europe who have chronic HBV infection have been infected by this strain.

Immune response
The pathogenesis and clinical manifestations of hepatitis B are due to the interaction of the virus and the host immune system. The immune system attacks HBV and causes liver injury. Activated CD4+ and CD8+ lymphocytes recognize various HBV-derived peptides located on the surface of the hepatocytes, and an immunologic reaction occurs. Impaired immune reactions (eg, cytokine release, antibody production) or a relatively tolerant immune status result in chronic hepatitis. In particular, a restricted T cellmediated lymphocytic response occurs against the HBV-infected hepatocytes.[11, 12]

The final state of HBV disease is cirrhosis. Patients with cirrhosis and HBV infection are likely to develop hepatocellular carcinoma (HCC).[2, 3, 4] In the United States, the most common presentation is that of patients of Asian origin who acquired the disease as newborns (vertical transmission).

Viral life cycle


Four different stages have been identified in the viral life cycle of hepatitis B and are briefly discussed below. Stage 1 The first stage is immune tolerance. The duration of this stage for healthy adults is approximately 2-4 weeks and represents the incubation period. For newborns, the duration of this period is often decades. Active viral replication is known to continue despite little or no elevation in the aminotransferase levels and no symptoms of illness. Stage 2 In the second stage, an inflammatory reaction with a cytopathic effect occurs. HBeAg can be identified in the sera, and a decline of the levels of HBV DNA is seen. The duration of this stage for patients with acute infection is approximately 3-4 weeks (symptomatic period). For patients with chronic infection, 10 years or more may elapse before cirrhosis develops. Stage 3 In the third stage, the host can target the infected hepatocytes and HBV. Viral replication no longer occurs, and HBeAb can be detected. The HBV DNA levels are lower or undetectable, and aminotransferase levels are within the reference range. In this stage, an integration of the viral genome into the host's hepatocyte genome takes place. HBsAg still is present. Stage 4 In the fourth stage, the virus cannot be detected and antibodies to various viral antigens have been produced. Different factors have been postulated to influence the evolution of these stages, including age, sex, immunosuppression, and coinfection with other viruses. Genotypes and disease progression Eight different genotypes (A through H) representing a divergence of the viral DNA at around 8% have been identified.[7] The prevalence of the genotypes varies in different countries. The progression of the disease seems to be more accelerated, and the response to treatment with antiviral agents is less favorable for patients infected by genotype C compared with those infected by genotype B. It is reported that the risk of HCC might be higher with an increasing level of HBV viral load and the presence of genotype C and common variants in the precore and basal core promoter regions. Dong et al developed a novel in vitro 1.5X HBV replication system that was capable of consistently generating a high level of HBV. Although the investigators believed this system

would help compare the replication capacity among the virus strains associated with high and low risk of HCC, there was no significant difference in the replication capacities among these strains in vitro.[13] The investigators concluded that the HBV-1.5X system may be a useful platform in helping to establish stable cell lines and transgenic mice for the investigation of viral pathogenesis, particularly for the various strains of HBV. [13]

Epidemiology
An estimated 200,000 new cases of hepatitis B virus (HBV) infection occur annually in the United States, and 1-1.25 million people are carriers. The prevalence of the disease is higher among blacks and persons of Hispanic or Asian origin. In addition, a higher carrier rate exists among certain subpopulations such as the Alaskan Eskimos, Asian Pacific islanders, and Australian aborigines. HBV disease accounts for 5-10% of cases of chronic end-stage liver disease and 10-15% of cases of hepatocellular carcinoma (HCC). HBV is blamed for 5000 US deaths annually. The prevalence is low in persons younger than 12 years, but it increases in those older than 12 yearsassociated with the initiation of sexual contact (the major mode of transmission), the number of sexual partners, and an early age of first intercourse. Additional risk factors identified in the National Health and Nutrition Examination Survey (NHANES) III survey are non-Hispanic black ethnicity, cocaine use, high number of sexual partners, divorced or separated marital status, foreign birth, and low educational level. Because of the implementation of routine vaccinations of infants in 1992 and adolescents in 1995, the prevalence of HBV infection is expected to decline further.

International statistics
The HBV carrier rate variation is 1-20% worldwide. This variation is related to differences in the mode of transmission and the patient's age at infection. The prevalence of the disease in different geographic areas can be characterized as follows:

Low-prevalence areas (rate of 0.1-2%) include Canada, Western Europe, Australia, and New Zealand; in the areas of low prevalence, sexual transmission and percutaneous transmission during adulthood are the main modes of transmission Intermediate-prevalence areas (rate of 3-5%) include Eastern and Northern Europe, Japan, the Mediterranean basin, the Middle East, Latin and South America, and Central Asia; in areas of intermediate prevalence, sexual and percutaneous transmission and transmission during delivery are the major transmission routes High-prevalence areas (rate of 10-20%) include China, Indonesia, sub-Saharan Africa, the Pacific Islands, and Southeast Asia; in areas of high prevalence, the predominant mode of transmission is perinatal, and the disease is transmitted vertically during early childhood from the mother to the infant; vaccination programs implemented in highly endemic areas such as Taiwan seem to change the prevalence of HBV infection: In Taiwan, HBV seroprevalence declined from 10% in 1984 (before vaccination programs) to less than 1% in 1994 after the implementation of vaccination programs, and the incidence of HCC declined from 0.52% to 0.13% during the same period[3] Racial, sexual, and age-related differences in incidence Black individuals have a higher prevalence of HBV disease than persons of Hispanic origin or white persons. More cases of HBV disease occur in males than in females.

The earlier the disease is acquired, the greater the chance of developing chronic hepatitis B infection. Infants (mainly infected through vertical transmission) have a 90% chance, children have a 25-50% chance, adults have an approximately 5% chance, and elderly persons have an approximately 20-30% chance of developing chronic disease.

Prognosis
Approximately 9% of patients in Western Europe who have cirrhosis develop hepatocellular carcinoma (HCC) due to hepatitis B infection at a mean follow-up of 73 months. The probability of HCC developing 5 years after the diagnosis of cirrhosis is established is 6%, and the probability of decompensation is 23%. Significant risk factors for carcinogenesis include older age, liver firmness, and thrombocytopenia. Even the presence of hepatitis B surface antibody (HBsAb) in the absence of hepatitis B surface antigen (HBsAg) or hepatitis B virus (HBV) DNA is significantly related to an increased risk for HCC. The annual incidence of this malignancy in patients with hepatitis B infection and cirrhosis reported in Taiwan is 2.8%. The US estimates for the annual incidence of HCC in patients infected with HBV is 818 cases per 100,000 persons. Familiar clustering of HCC has been described among families with hepatitis B infection in Africa, the Far East, and Alaska. The cumulative probability of survival is 84% at 5 years and 68% at 10 years. Cox regression analysis has identified 6 variables that independently correlate with survival. These include age, albumin level, platelet count, splenomegaly, bilirubin level, and hepatitis B e antigen (HBeAg) positivity at the time of hepatitis B diagnosis. According to the contribution of each of these factors to the final model, a prognostic index has been constructed that allows calculation of the estimated survival probability. No difference in survival is observed in patients with hepatitis D (delta) virus (HDV) infection compared with those who are not infected. The prevalence of HDV coinfection among patients infected with hepatitis B virus (HBV) varies worldwide from 0% to 20%. The speculation that HDV might promote hepatocarcinogenesis in these patients has been investigated, with controversial results. The prevalence of anti-delta among patients with cirrhosis with and without HCC is not significantly different, although HDV infection has been reported to increase the risk for HCC 3-fold and mortality rates 2-fold in patients with HBV cirrhosis. An estimated 250,000 persons per year globally and 5000 persons per year in the United States die from chronic HBV disease. The United States currently screens foreign-born residents for HBV infection if their country of origin has an HBV prevalence of 2% or greater. According to a model developed by Eckman et al, although this threshold for screening is cost-effective, a broader screening program with a threshold of 1.3% or even 0.3% country-of-origin prevalence would be costeffective as well, suggesting a reconsideration of current policy.[14]

Patient Education
Patients with acute and chronic HBV infections should be advised that this is a blood-borne disease that can be transmitted during sexual intercourse or at the time of childbirth.

Prophylaxis is strongly advised. Family members born by the same parents should also be checked for HBV infection. The best preventative measurement is vaccination. [15] For patient education information, see Hepatitis A; Hepatitis B; Hepatitis C;Cirrhosis; Liver Cancer; Hepatitis in Pregnancy; Immunization Schedule, Adults; and Immunization Schedule, Children. Proceed to Clinical Presentation

History
The spectrum of the symptomatology of hepatitis B disease varies from subclinical hepatitis to icteric hepatitis to hyperacute, acute, and subacute hepatitis during the acute phase, and from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) during the chronic phase.

Acute phase
The incubation period is 1-6 months in the acute phase. Anicteric hepatitis is the predominant form of expression for this disease. The majority of the patients are asymptomatic, but patients with anicteric hepatitis have a greater tendency to develop chronic hepatitis. Patients with symptomatology have the same symptoms as patients who develop icteric hepatitis. Icteric hepatitis is associated with a prodromal period, during which a serum sickness like syndrome can occur. The symptomatology is more constitutional and includes the following:

Anorexia Nausea Vomiting Low-grade fever Myalgia Fatigability Disordered gustatory acuity and smell sensations (aversion to food and cigarettes) Right upper quadrant and epigastric pain (intermittent, mild to moderate) Patients with hyperacute, acute, and subacute hepatitis may present with the following: Hepatic encephalopathy Somnolence Disturbances in sleep pattern Mental confusion Coma Chronic phase Patients with chronic hepatitis B disease can be healthy carriers without any evidence of active disease, and they also are asymptomatic. Patients with chronic active hepatitis, especially during the replicative state, may complain of symptomatology such as the following:

Symptoms similar to those of acute hepatitis

Fatigue Anorexia Nausea Mild upper quadrant pain or discomfort Hepatic decompensation

Physical Examination
The physical examination findings in hepatitis B disease vary from minimal to impressive (patients with hepatic decompensation) according to the stage of disease. Patients with acute hepatitis usually do not have any clinical findings, but the physical examination can reveal the following:

Low-grade fever Jaundice (10 d after the appearance of constitutional symptomatology and lasting for 1-3 mo) Hepatomegaly (mildly enlarged soft liver) Splenomegaly (5-15%) Palmar erythema (rarely) Spider nevi (rarely) The physical examination of patients with chronic hepatitis B virus (HBV) infection can reveal stigmata of chronic liver disease such as the following: Hepatomegaly Palmar erythema Spider angioma Patients with cirrhosis may have the following symptoms: Ascites Jaundice History of variceal bleeding Peripheral edema Gynecomastia Testicular atrophy Abdominal collateral veins (caput medusa)

Staging
Liver damage is graded according to the inflammatory component and is described as follows: Grade 0 Portal inflammation only, no activity Grade 1 Minimal portal inflammation and patchy lymphocytic necrosis, with minimal lobular inflammation and spotty necrosis Grade 2 Mild portal inflammation and lymphocytic necrosis involving some or all portal tracts, with mild hepatocellular damage Grade 3 Moderate portal inflammation and lymphocytic necrosis involving all portal tracts, with noticeable lobular inflammation and hepatocellular change Grade 4 Severe portal inflammation and severe lymphocytic bridging necrosis, with severe lobular inflammation and prominent diffuse hepatocellular damage Liver damage staging (ie, fibrosis) is described as follows:

Stage 0 No fibrosis Stage 1 Portal fibrosis Stage 2 Periportal fibrosis

Stage 3 Septal, bridging fibrosis (see the image below)


Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.

Stage 4 Cirrhosis (see the following image)


hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.

Liver biopsy with

Diagnostic Considerations
When evaluating a patient with suspected infection with hepatitis B virus (HBV), also consider the other viral hepatitides and etiologies that can lead to cirrhosis and liver failure, such as drug hepatotoxicity. In addition, because a major mode of transmission of this disease is sexual, also consider the possibility of infection with human immunodeficiency virus (HIV) or other sexually transmitted diseases. Congestive heart failure, Wilson disease, and cholangitis are other conditions included in the differential diagnosis.

Differential Diagnoses

Alcoholic Hepatitis Autoimmune Hepatitis Cholangitis Cirrhosis Hemochromatosis Hepatic Carcinoma, Primary Hepatitis A Hepatitis C Hepatitis D Hepatitis E Hepatitis, Viral

Approach Considerations
Laboratory evaluation for hepatitis B disease generally consists liver function tests (LFTs), including levels of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), alkaline phosphatase (ALP), total and direct serum

bilirubin, and urine bilirubin and urobilinogen. Hematologic and coagulation studies include prothrombin time (PT), total protein level, albumin level, complete blood cell (CBC) count. In severe cases, serum ammonia levels may be obtained.

Diagnostic Tests
Laboratory studies will be discussed according to the stage of disease. Acute hepatitis B disease High levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), at a range of 1000-2000 IU/mL, is the hallmark of this disease, although values 100 times more than the upper limit of normal (ULN) can be identified. Higher values are found in patients with icteric hepatitis. ALT levels are usually higher than AST levels. Alkaline phosphatase (ALP) levels may be elevated, but they are usually not more than 3 times the upper limit of normal. Albumin levels can be slightly low, and serum iron levels may be elevated. In the preicteric period (ie, before the appearance of jaundice), leukopenia (ie,granulocytopenia) and lymphocytosis are the most common hematologic abnormalities and are accompanied by an increase in the erythrocyte sedimentation rate (ESR). Anemia due to a shortened red blood cell survival period is an infrequent finding, although hemolysis may be noted. Thrombocytopenia is a rare finding. Patients with severe hepatitis experience a prolongation of the prothrombin time (PT). Several viral markers can be identified in the serum and the liver. Hepatitis B surface antigen (HBsAg) (Australian antigen) and hepatitis B e antigen (HBeAg) (marker of infectivity) are the first markers that can be identified in the serum. Hepatitis B core antibody (HBcAb) (immunoglobulin M [IgM]) follows. For patients who recover, seroconversion to hepatitis B surface antibody (HBsAb) and hepatitis B e antibody (HBeAb) is observed. The HBcAb is of the IgG class. Patients with persistent HBsAg for longer than 6 months develop chronic hepatitis. Chronic inactive hepatitis B disease Healthy carriers have normal AST and ALT levels, and the markers of infectivity (ie, HBeAg, HBV DNA) may be negative. HBsAg, HBcAb of IgG type, and HBeAb are also present in the serum. Chronic active hepatitis B disease Patients have mild to moderate elevation of the aminotransferases (5 times the ULN). The ALT levels are usually higher than the AST levels. Extremely high levels of ALT can be observed during exacerbation or reactivation of the disease, and they can be accompanied by impaired synthetic function of the liver (ie, decreased albumin levels, increased bilirubin levels, and prolonged PT). Hepatitis B virus (HBV) DNA levels are high during this phase. HBsAg and HBcAb of IgG or IgM type (in case of reactivation) are identified in the serum. If the AST levels are higher than the ALT levels, the diagnosis of cirrhosis must be excluded. Hyperglobulinemia is another finding, predominantly with an elevation of the IgG globulins. Tissue-nonspecific antibodies, such as antismooth muscle antibodies (ASMAs) (20-25%) or antinuclear antibodies (ANAs) (10-20%), can be identified. Tissue-specific antibodies, such as antibodies against the thyroid gland (10-20%), can also be found. Mildly elevated levels of rheumatoid factor (RF) are usually present.

Cirrhosis In early stages of cirrhosis, findings of chronic viral hepatitis can be found. Later on, as the disease progresses, low albumin levels, hyperbilirubinemia, prolonged PT, low platelet count and white blood cell count, and AST levels higher than ALT levels can be identified. ALP levels and gamma-glutamyl transpeptidase (GGT) can be slightly elevated.

Radiologic Studies
Findings on imaging studies are briefly reviewed according to the disease stage. Acute and chronic hepatitis B disease Performing abdominal ultrasonography, computed tomography (CT) scanning, or magnetic resonance imaging (MRI) is important to help exclude biliary obstruction. Nonspecific findings include increased echogenicity of the liver parenchyma. Cirrhosis Imaging findings include coarse echogenicity of the liver, with a nodular appearance, and findings compatible with portal hypertension (eg, varices,splenomegaly, ascites, pleural effusion [ie, hepatic hydrothorax]). Lesions can be detected and may be very difficult to evaluate, because they can be mistaken for regenerating nodules. In such cases, highly sophisticated techniques, such as MRI with superparamagnetic iron oxide (ferumoxides), should be considered. Ferumoxides (negative contrast material) are phagocytosed by the reticuloendothelial cells of the normal liver, producing predominant T2 imaging on MRI. Therefore, a marked decrease of the signal in the normal liver parenchyma occurs, effectively permitting the identification of tumors.

Liver Biopsy and Histologic Features


Liver biopsy, percutaneous or laparoscopic, is the standard procedure to assess the severity of disease for patients with features of chronic active liver disease (ie, abnormal aminotransferase levels and detectable levels of hepatitis B virus [HBV] DNA). Although liver biopsy is not indicated for patients with acute hepatitis B disease, the findings are predominantly lobular, with degenerative and regenerative hepatocellular changes as well as accompanying inflammation. Necrosis may be predominantly centrilobular. Ground-glass cells are seen in approximately 50-75% of livers affected by chronic HBV infection, and they stain positive for hepatitis surface B antigen (HBsAg) (see the image below). Immunohistochemical staining of the specimen can help identify the presence of HBsAg or hepatitis B core antigen (HBcAg) (ie, chronic infection).

Liver biopsy specimen showing the ground-glass appearance of

hepatocytes in a patient with hepatitis B. trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.

Liver biopsy with

Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.

Approach Considerations
Therapy is currently recommended for patients with evidence of chronic active hepatitis B disease (ie, high aminotransferase levels, positive hepatitis B virus [HBV] DNA findings, hepatitis B e antigen [HBeAg]). Various algorithms have been proposed, such as that by Keeffe and colleagues[16] and the American Association for the Study of Liver Diseases (AASLD).[17] In general, for the HBeAg-positive patient population that is identified with evidence of chronic HBV disease, treatment is advised to be administered when the HBV DNA level is 20,000 IU/mL (105 copies/mL) and when serum alanine aminotransferase (ALT) is elevated for 3-6 months. For the HBeAg-negative chronic population with hepatitis B disease, treatment can be administered when the HBV DNA is 2000 IU/mL (104 copies/mL) and serum ALT is elevated (ALT levels >20 U/L for females; 30 U/L for males) for 3-6 months.

Inpatient care
Patients with hepatitis B disease and fulminant hepatic failure should be hospitalized in the intensive care unit (ICU), and these individuals should be considered as liver transplant candidates in the event they do not recover.

Patients with acute hepatitis should be monitored with blood tests in order to document biochemical improvement (see Workup).

Dietary limitations
For individuals with decompensated cirrhosis (prominent signs of portal hypertension or encephalopathy), a low-sodium diet (1.5 g/d), high-protein diet (ie, white-meat protein [eg, pork, turkey, fish]), and, in cases of hyponatremia, fluid restriction (1.5 L/d) are indicated. Patients with acute and chronic hepatitis without cirrhosis have no dietary restrictions.

Pharmacologic Management
Currently, interferon alfa (IFN-a), lamivudine, telbivudine, adefovir, entecavir, and tenofovir are the main treatment drugs approved globally for hepatitis B disease, although ongoing trials are investigating new types of medications, such as tenofovir disoproxil in combination with emtricitabine, clevudine (l-FMAU), and therapeutic vaccines. It appears that lamivudine and telbivudine are not recommended as first-line agents in the treatment of hepatitis B disease.[18] Patients who have lost hepatitis B e antigen (HBeAg) and in whom hepatitis B virus (HBV) DNA is undetectable have an improved clinical outcome (ie, slower rate of disease progression, prolonged survival without complications, reduced rate of hepatocellular carcinoma [HCC], and clinical and biochemical improvement after decompensation). Special attention must be given to patients on liver transplantation lists. Initiation of treatment with adefovir or entecavir or tenofovir or in combination with lamivudine is of cardinal importance before and after liver transplantation to achieve viral suppression and to prevent recurrence of the disease after the procedure.

Interferon alfa
Published reports indicate that after IFN-a[19] treatment with 5 million U/d or 10 million U 3 times per week subcutaneously (SC) for 4 months, the HBV DNA levels and HBeAg become undetectable in 30-40% of patients. In addition, 10% of patients seroconvert from hepatitis B surface antigen (HBsAg) to hepatitis B surface antibody (HBsAb). Unfortunately, 5-10% of patients relapse after completion of treatment. A transient "flare" (ie, increased aminotransferase levels during the beginning of treatment) can be identified, and this represents the impact of the activated cytolytic T cells on the infected hepatocytes. High levels of aminotransferases, a low viral load, and infection with the wild type are good prognostic factors for response to IFN-a treatment. However, Asian patients and patients with the precore mutant virus tend to not have a clinical response to IFN-a treatment. Loss of hepatitis B surface antigen (HBsAg) indicates resolution of the HBV infection, acute or chronic, but is rare in chronic infection. A study by Tseng et al followed Taiwanese patients with chronic hepatitis B infection who developed spontaneous HBeAg loss (seroconversion). Patients with low levels of HBsAg a year after their seroconversion had a higher probability of loss of HBsAg.[20]

Special attention must be given to patients with HBV-decompensated cirrhosis (eg, ascites, encephalopathy) who are taking IFN-a because of the fact that, although they occasionally may have a treatment response, these individuals can also deteriorate further. The adverse effects of IFN-a treatment can sometimes be severe, even devastating. Some patients cannot complete treatment. A flulike syndrome, myelosuppression (eg, leukopenia, thrombocytopenia), nausea, diarrhea, fatigue, irritability, depression, thyroid dysfunction, and alopecia are among the adverse effects that may occur.

Pegylated IFN-a 2a
A 48-week regimen of pegylated IFN-a 2a (PEG-IFN-a 2a) might induce a 27% rate of HBeAg seroconversion and a 25% rate of loss of HBV DNA.[21] Extension to treatment for 48 weeks resulted in an HBeAg seroconversion of 32%. Placing patients that have HBeAg-negative chronic hepatitis B disease on 48 weeks of a PEG-IFN-a 2a regimen resulted in a significantly greater percentage of patients with a viral load that was nondetectable 24 weeks after the end of treatment (19%) compared with lamivudine monotherapy (7%).[18] It appears that patients infected by HBV genotype A or B have a better response to IFN treatment compared with patients infected by genotype C or D, and this kind of treatment appears to be more appealing, especially for patients with increased alanine aminotransferase (ALT) levels.

Lamivudine
A nucleoside analogue that inhibits the viral polymerase, lamivudine[18, 22, 23, 24]has been associated with a 4-log reduction of the viral load. Lamivudine treatment (100 mg/d) has also been associated with a 16-18% seroconversion rate from hepatitis B e antigen (HBeAg) to hepatitis B e antibody (HBeAb), a 30-33% rate of HBeAg loss, a 40-50% normalization of the value of the aminotransferases, and a 1-2% HBsAg seroconversion rate. Histologic improvement (ie, reduction of histologic activity index of >2 points) has been noticed in approximately 50% of patients taking lamivudine. The adverse effects are negligible. Lamivudine appears to be effective for patients who do not have a treatment response to IFN-a (eg, patients infected by the precore mutant virus). A transient elevation of aminotransferases can be noticed shortly after starting treatment. The HBeAg seroconversion rate has been shown to possibly increase to 27% after 2 years, 40% after 3 years, and 47% after 4 years of treatment in patients with a viral load of less than 104 pg/mL. Lamivudine treatment has also been shown to dramatically improve the condition of patients with decompensated disease due to HBV reactivation. The emergence of viral variants is the major complication in hepatitis B disease. [25, 26] Approximately 15-30% of patients develop a mutation of the viral polymerase gene (the

YMDD variants) after 12 months of treatment, and approximately 50% develop a mutation after 3 years of treatment. However, continued treatment after the breakthrough with the variant type has been associated with lower HBV DNA levels, less aminotransferase activity, and histologic improvement. For these patients, discontinuation of treatment is accompanied by a reversion to a wild type of HBV and a flare of the disease.

Adefovir dipivoxil
Adefovir is a nucleoside analogue, a potent inhibitor of the viral polymerase. The efficacy of adefovir dipivoxil has been tested in HBeAg-positive, HBeAg-negative, and lamivudineresistant patients with encouraging results. The estimated rate of resistance to adefovir and the development of mutations (rtN236T and rtA181V) are approximately 4-6% after 3 years and approximately 30% after 5 years of treatment.[27, 28, 29, 30] The optimal dose seems to be 10 mg/d.[31, 32] Higher doses are nephrotoxic. The results of 2 multicenter trials that used adefovir for 48 weeks[31, 32] noted that in HBeAgpositive patients who received 10 mg of adefovir daily, there was a median 3.52 log reduction of the viral load (HBV DNA) level. In 48% of the patients, normalized aminotransferase levels were reported, and histologic improvement was seen in 53% of the patients who received this regimen.[31] The HBeAg seroconversion rate was 12%. Furthermore, of the HBeAg-negative population, 64% experienced histologic improvement after receiving 10 mg of adefovir for 48 weeks, and 72% had normalized aminotransferase levels. The serum HBV DNA level was decreased in 51% of subjects.[31, 32] The outcomes were maintained if treatment was continued for 144 weeks, but the benefits were lost if treatment was discontinued at 44 weeks. The development of resistant mutations (rtN236T and rtA181V) has been estimated to be around 6%.[32]

Entecavir
Entecavir is a potent guanosine analogue inhibitor of the viral polymerase with 1.2% resistance in patients who have no history of previous treatment with nucleostide/nucleoside analogues and almost 56 % in lamivudine-resistant patients during a 6-year treatment period.[33] HBeAg-positive patients With regard to the HBeAg-positive population, administration of 0.5 mg of entecavir in patients who are naive to nucleoside analogues relative to patients who received 100 mg of lamivudine for a duration of 48 weeks resulted in histologic improvement in 72% of the entecavir group compared with 62% of the lamivudine group.[34]Undetectable serum HBV DNA levels were reported in 67% of entecavir-treated patients compared with 36% of lamivudine-treated patients. Normalized ALT levels were achieved in 68% of the entecavir group versus 60% of the lamivudine group.[34] The mean reduction in serum HBV DNA from baseline to week 48 was 6.9 log copies/mL (on a base-10 scale) in the entecavir-treated patients relative to 5.4 log

copies/mL in the lamivudine-treated patients. HBeAg seroconversion occurred in 21% of patients treated with entecavir and 18% of patients treated with lamivudine. [34] HBeAg-negative patients With regard to the HBeAg-negative population, administration of 0.5 mg of entecavir in patients who are naive to nucleoside analogues compared with patients who received 100 mg of lamivudine for a duration of 48 weeks resulted in histologic improvement in 71% of the entecavir group versus 61% of the lamivudine group.[33] Undetectable serum HBV DNA levels were found in 90% of the entecavir-treated patients versus 72% of the lamivudinetreated patients. Normalized ALT levels were achieved in 78% of the entecavir group compared with 71% of the lamivudine group.[33] The mean reduction in serum HBV DNA levels from baseline to week 48 was 5.0 log copies/mL (on a base-10 scale) in the entecavir-treated patients versus 4.5 log copies/mL in the lamivudine-treated patients.[33]

Telbivudine
Telbivudine, a cytosine nucleoside analogue, is a potent inhibitor of the HBV DNA polymerase. HBeAg-positive patients The results of the GLOBE Trial, a phase III study, that tested the administration of 600 mg of telbivudine versus 100 mg of lamivudine over a 2-year period reported that in the HBeAgpositive population, therapeutic response (defined as HBV DNA < 10,000 copies/mL, with either ALT normalization or HBeAg loss) was 75% for the patients treated with telbivudine compared with 67% for the patients treated with lamivudine.[35, 36] Of the patients receiving telbivudine, 26% lost the e antigen versus 23% of the patients receiving lamivudine.[35, 36] In addition, a 6.5 log reduction of the HBV DNA was noted for the patients receiving telbivudine versus a 5.5 log reduction for the patients receiving lamivudine. HBeAg-negative patients In the HBeAg-negative patients, the response rates at 1 year were 75% for the telbivudine group and 77% in the lamivudine group, whereas 88% of the telbivudine-treated patients versus 71% of the lamivudine-treated patients were HBV DNA nondetectable. The HBV DNA log reduction was 5.2 (telbivudine group) versus 4.4 (lamivudine group). [35, 36] Because resistance is a major issue, the reported rates at 1 year were 2.6% of patients on telbivudine and 8.2% of patients on lamivudine.[35, 36]

Tenofovir
Tenofovir is a nucleotide analogue (adenosine monophosphate) reverse transcriptase and HBV polymerase inhibitor. HBeAg-positive nave patients

In a study that randomized patients in 2 arms to receive either tenofovir (300 mg once daily) or adefovir (10 mg once daily) for 48 weeks, with the adefovir-treated patients then switched to tenofovir, 79% of the patients who received tenofovir were found to have a viral load below 400 copies/mL, whereas in the adefovir group, 76% of patients receiving adefovir before switching to tenofovir were found to have a viral load below 400 copies/mL. [37] In addition, 72% of the patients in the adefovir arm that were found to have a viral load greater than 400 copies/mL achieved viral suppression after they were switched to tenovofir, whereas for those who had achieved viral suppression, the effect was maintained after they were switched to tenofovir.[37] Biochemical response was reported in 77% of patients in the tenofovir arm at week 72 and in 61% of those switching from adefovir to tenofovir. With regard to seroconversion, 26% of patients who received tenofovir seroconverted at week 64 relative to the adefovir arm, in which the observed seroconversion rate was reported as 21%.[37] It is noteworthy to mention that 5% of patients in the tenofovir arm experienced loss of the "s" antigen. HBeAg-negative patients In another report, of patients who were randomized receive either tenofovir (300 mg once daily) or adefovir (10 mg once daily), and then after 48 weeks when all eligible adefovirtreated patients were switched to tenofovir, 91% of patients receiving tenofovir at 72 weeks of treatment were found to have a viral load below 400 copies/mL. [38] In contrast, in the adefovir arm, of patients who switched to tenofovir after 48 weeks, 88% had a viral load below 400 copies/mL by week 72 of the study. All the adefovir-treated patients who had a viral load below 400 copies/mL at week 48 maintained a viral load below this level after switching to tenofovir.[38] For the patient population in the adefovir arm who did not achieve optimal viral response (viral load above 400 copies/mL) at the time of switch to tenofovir, 94% had a viral load below this level by week 72. Normal ALT levels at week 72 were observed in 79% of patients who initiated therapy with tenofovir and in 77% of patients who switched to tenofovir drug from adefovir. [38] HBeAg-negative or HBeAg-positive chronic HBV patients In 2 double-blind, phase 3 studies, in which patients with HBeAg-negative or HBeAgpositive chronic hepatitis B were randomized to receive tenofovir disoproxil fumarate (DF) (300 mg) or adefovir dipivoxil (10 mg) (ratio, 2:1) once daily for 48 weeks,[39] Marcellin et al concluded that among patients with chronic hepatitis B, tenofovir at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir at a daily dose of 10 mg through week 48.[39] At week 48 in both studies, a significantly higher proportion of patients receiving tenofovir than of those receiving adefovir had reached the primary end point (plasma HBV DNA level < 400 copies/mL [69 IU/mL]), and viral suppression occurred in more HBeAg-negative patients in the tenofovir group (93%) than patients in the adefovir group (63%), as well as in more HBeAg-positive patients receiving tenofovir (76%) than those receiving adefovir (13%).[39]

In addition, significantly more HBeAg-positive patients in the tenofovir group (68%) not only had normalized ALT levels relative to those in the adefovir group (54%) but also had loss of HBsAg (3% tenofovir group vs 0% adefovir group).[39] At the end of 48 weeks, none the patients had developed the amino acid substitutions within HBV DNA polymerase that are associated with phenotypic resistance to tenofovir or other drugs used to treat hepatitis B; tenofovir produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not; and the 2 treatments in both studies had similar safety profiles.[39]

Surgical Intervention
Orthotopic liver transplantation (OLT) is the treatment of choice for patients with fulminant hepatic failure who do not recover and for patients with end-stage liver disease. The implementation of hepatitis B immunoglobulin (HBIG) during and after the OLT period, and of lamivudine or adefovir in the pre- and post-OLT periods, dramatically improves the recurrence rate of hepatitis B.

Complications
Complications from hepatitis B include progression to hepatocellular carcinoma (HCC), glomerulonephritis, and polyarteritis nodosa, as well as various dermatologic, cardiopulmonary, joint, neurologic, hematologic, and gastrointestinal (GI) tract manifestations.

Hepatocellular carcinoma
Even the presence of hepatitis B surface antibody (HBsAb) in the absence of hepatitis B surface antigen (HBsAg) or hepatitis B virus (HBV) DNA is significantly related to an increased risk for HCC. The annual incidence of this malignancy in patients with hepatitis B and cirrhosis reported in Taiwan is 2.8%. The estimated US annual incidence of HCC in patients infected with hepatitis B is 818 cases per 100,000 persons. Familiar clustering of HCC has been described among families with hepatitis B in Africa, the Far East, and Alaska. HBV and HDV coinfection The prevalence of hepatitis D virus (HDV) coinfection among patients infected with hepatitis B virus (HBV) worldwide is 0-20%. The speculation that HDV might promote hepatocarcinogenesis in these patients has been investigated. The prevalence of anti-delta among patients with cirrhosis with and without HCC was not significantly different. Therefore, delta superinfection does not appear to increase the rate of HCC. HBV and HCV coinfection The prevalence of HCC among patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection is higher than in those with a single infection alone. The rate of development of HCC per 100 person years of follow-up is 2% in patients with cirrhosis and hepatitis B infection, 3.7% in patients with HCV infection, and 6.4% in patients with dual HBV and HCV infection. This points to a probable synergistic effect on the risk of HCC. Possible pathogenic mechanisms

The mechanism by which chronic hepatitis B infection predisposes to the development of HCC is not clear. Cirrhosis is a cardinal factor in carcinogenesis. Hepatocyte inflammation, necrosis, mitosis, and features of chronic hepatitis are major factors for nodular regeneration, fibrosis, and carcinoma. Liver cell dysplasia, defined as cellular enlargement, nuclear pleomorphism, and multinucleated cells affecting groups or whole nodules, may be an intermediate step. The high cell-proliferation rate increases the risk for HCC. The fact that facultative liver stem cells are capable of bipotent differentiation into hepatocytes or biliary epithelium, termed oval cells, may play an important role in the pathogenesis. These cells are small, with oval nuclei and scant pale cytoplasm. Oval cells are prominent in actively regenerating nodules and in liver tissue surrounding the cancer. They appear to be the principal producers of alpha-fetoprotein (AFP). Although the cellular targets of carcinogenesis have not been identified, some evidence resulting from experimental animal models suggests that oval cell proliferation is associated with an increased risk for the development of HCC. Although cirrhosis is found in the majority of these patients, it is not obligatory, because chronic carriers may develop HCC even without the evidence of cirrhosis. HBV has been speculated to have intrinsic hepatocarcinogenic activity, interacting with host DNA in different ways. After entering the hepatocyte, viral DNA is integrated within the genome. The site of integration is not constant but usually involves the terminal repeat sequences. Chromosomal deletions, translocations, rearrangements, inversions, or even duplications of normal DNA sequencing accompany integration. Transactivation of the function of genes controlling transcriptional factors (ie, insulinlike growth factor II [IGF-2], transforming growth factor-alpha [TGF-a], TGF-beta, cyclin-a [a protein that controls cell division], epidermal growth factor-r [EGFR], retinoic acid receptor [RAR]) and oncogenes such as c-myc, fos, ras(activating the internal signal transduction cascade upregulating ras/mitogenactivated kinase, c-Jun N terminal kinase, nuclear factorkB, Jak-1-STAT, src-dependent pathways) influence the normal hepatocyte differentiation or cell cycle progression. Furthermore, the integrated part of the hepatitis B virus (HBV) controlling the production of the HBxAg (antigen for the X gene of HBV) is overexpressed. These observations suggest the site of viral genomic integration into the host's DNA alone is not the factor. Most likely, the HBxAg produced by these sequences is the transactivating factor, because it has been found to bind to a variety of transcription factors such as CREB (cyclic adenosine monophosphate [cAMP]response element-binding protein) and ATF-2 (activating transcription factor 2), which alters their DNA-binding specificity. Thus, the ability of the HBV pX protein to interact with cellular factors broadens the DNA-binding specificity of these regulatory proteins and provides a mechanism for pX to participate in transcriptional regulation. This shifts the pattern of host gene expression relevant to the development of HCC. Additionally, HBxAg has been postulated to bind to the C-terminus and inactivate the product of the tumor suppressor gene TP53 and (1) sequester TP53 in the cytoplasm, resulting in the abrogation of TP53 -induced apoptosis (although controversy exists regarding this concept); (2) reduce the ability for nucleotide excision repair by directly acting

with proteins associated with DNA transcription and repair such as XPB and XPD; (3) reduce p21WAF1 expression, which is a cell cycle regulator; and (4) bind to protein p55sen, which is involved in the cell fate during embryogenesis and is found in the liver of patients with hepatitis B, thus altering its function. Tumor necrosis factor-alpha (TNF-a) (a proinflammatory cytokine) levels are also upregulated. The transcriptional transactivation of nitric oxide (NO) synthetase II by pX and the elevated levels of TNF-a are responsible for the high levels of NO found in these patients. NO is a putative mutagen through several mechanisms of functional modifications of TP53, DNA oxidation, deamination, and formation of the carcinogenic N-nitroso compounds. A second transactivator is encoded in the pre-S/S region of the HBV genome, stimulating the expression of the human proto-oncogenes c-fos and c-myc, and this upregulates the expression of TGF-a by transactivation.

Glomerulonephritis
The most common type of glomerulonephritis described in association with hepatitis B is membranous glomerulonephritis (MGN), mainly in children. However,membranoproliferative glomerulonephritis (MPGN) and, even more rarely, immunoglobulin (Ig) A nephropathy, have been identified. The prevalence rate of glomerulonephritis among patients with chronic hepatitis B is not well known, although observations have been made in children that suggest a range of 11% to 56.2%. However, such a high prevalence is not recognized in the United States, and this may be because of the differences in epidemiology of HBV, which might be predominantly perinatal in other geographic areas of the world (see Epidemiology). A previous history of chronic liver disease is not present in the majority of these patients at presentation, and most of them have no clinical or biochemical findings to suggest acute or chronic liver disease. However, liver biopsies often demonstrate features of chronic hepatitis. Serologic markers of an HBV replicative state are often evident, and complement activation is suggested by low levels of C3 and C4. Generally, the most prominent finding among affected children is MGN, primarily with capillary wall deposits of HBeAg. In contrast, adults present with features of MPGN with mesangial and capillary wall deposits of HBsAg. A rare overlap between membranous nephropathy and IgA nephropathy has also been described. Possible pathogenic mechanisms The mechanism by which patients with chronic hepatitis B develop glomerulonephritis is not completely understood. One possible explanation is that HBV antigens (ie, HBsAg, HBeAg) act as triggering factors, eliciting immunoglobulins and thus forming immune complexes, which are dense irregular deposits in the glomerular capillary basement membranes. HBV DNA has been identified by in situ hybridization in kidney specimens, distributed generally in the nucleus and cytoplasm of epithelial cells and mesangial cells of glomeruli and in the epithelial cells of renal tubules. IFN-a therapy

IFN-a therapy has been successful in treating HBV-related glomerulonephritis. A regimen of 5 million units of IFN-a subcutaneously (SC) daily for 4 months has achieved HBsAg seroconversion with improvement of glomerulonephritis. It has also been reported that IFNa given at a dose of 3 million units 3 times per week led to improvement of proteinuria only in patients with mesangial proliferative glomerulonephritis but not in patients with MPGN. Finally, a single case report described the resolution of this complication after liver transplantation. Prognosis The prognosis of renal disease in hepatitis B is related to several factors, such as age and response to therapy. Children with MGN have a more favorable response than adults. White persons have a better response than Asians and black patients. Approximately 30-60% of cases with MGN undergo spontaneous remission. However, the course of HBV-related membranous nephropathy in adults in areas in which the virus is endemic is not benign. Regardless of treatment, hepatitis B disease has a slow but relentlessly progressive clinical course in approximately one third of patients who have progressive renal failure, necessitating maintenance dialysis therapy.

Polyarteritis nodosa
An association between hepatitis B and arteritis has been described when HBsAg is present in serum and in vascular lesions. Evidence for a cause-and-effect relationship is further supported by a high prevalence (36-69%) of HBsAg in patients with polyarteritis nodosa (PAN). This very serious complication presents early during the course of hepatitis B, and the incidence is high among certain populations, such as Alaskan Eskimos. The pathogenesis of PAN is not clear. Circulating immune complexes containing HBsAg, immunoglobulins (IgG and IgM), and complement have been demonstrated by immunofluorescence in the walls of the affected vessels, which might trigger the onset of PAN. However, whether these represent the primary etiology of the disease remains unclear. The clinical manifestations of PAN include cardiovascular (eg, hypertension [sometimes severe], pericarditis, heart failure), renal (eg, hematuria, proteinuria, renal insufficiency), GI (eg, abdominal pain, mesenteric vasculitis), musculoskeletal (eg, arthralgias, arthritis), neurologic (eg, mononeuritis), and dermatologic (eg, rashes) involvement. Significant proteinuria (>1 g/d), renal insufficiency (serum creatinine >1.58 mg/dL), GI and central nervous system involvement, and cardiomyopathy, are associated with increased mortality. The course of PAN is independent of the severity and the progression of the liver disease. Of these patients, 20-45% die as a consequence of vasculitis in 5 years, despite treatment, and the mortality rate is similar for patients with PAN who are HBsAg seropositive and for those with PAN who are seronegative. Small and medium-sized arteries and arterioles are affected in PAN. Although corticosteroids and immunosuppressive agents may be beneficial for treating vasculitis, they potentially may have a deleterious effect on the course of hepatitis B liver disease because of viral reactivation, particularly after the withdrawal of treatment. Adenine arabinoside, an antiviral drug, and IFN-a, an immunomodulator and antiviral protein, have

been used in conjunction with plasmapheresis and a short course of corticosteroids, with promising results. The combination of short-term corticosteroids accompanied by plasmapheresis and lamivudine resulted in 100% clinical recovery and 66 % seroconversion, although the number of patients studied was relatively small.[40] .

Skin manifestations
A variety of cutaneous manifestations have already been recognized during the early course of viral hepatitis, among which are hives and a fleeting maculopapular rash. Women are more prone to developing cutaneous manifestations. The various cutaneous lesions are episodic, palpable, and, at times, pruritic. Although they are transient, a discoloration of the skin can be identified after the resolution of the exanthem, particularly on the lower extremities. Papular acrodermatitis, also recognized as Gianotti-Crosti syndrome, has been associated with hepatitis B, more commonly with acute infection in children.[41]

Cardiopulmonary, joint, neurologic, hematologic, and GI tract manifestations


The following multisystem manifestations may occur in HBV:

Pleural effusion, hepatopulmonary, and portopulmonary syndrome may occur in patients with cirrhosis Myocarditis, pericarditis, and arrhythmia occur primarily in patients with fulminant hepatitis Arthralgias and arthritis (serum sickness) subcutaneous nodules may also occur, but these are rare. Guillain-Barre syndrome, encephalitis, aseptic meningitis, and mononeuritis multiplex may occur in patients with acute hepatitis B Patients may develop pancreatitis Aplastic anemia is uncommon, and agranulocytosis is extremely uncommon Diffuse intravascular coagulation may occur in patients with fulminant hepatitis

Vaccination
Universal hepatitis B vaccination programs are ongoing in endemic areas, with encouraging results. The hepatitis B vaccine consists of recombinant hepatitis B surface antigen (HBsAg) produced in yeast. A series of 3 injections may achieve HBsAb levels greater than 10 million IU/mL in approximately 95% of people vaccinated. Vaccination with a single dose must be repeated every 5-10 years. All newborns must be vaccinated against hepatitis B. For infants born to mothers with active hepatitis B, a passive-active (immunoglobulin [HBIG] and vaccination) approach is recommended. Healthcare workers or people who have had a needle-stick accident from a patient with active hepatitis B infection must receive the active-passive immunization approach (HBIG and the first dose of the vaccine at the same time), and these individuals must be monitored with blood tests. Current guidelines recommend all previously unvaccinated adults aged 19 through 59 years with diabetes mellitus (type 1 and type 2) be vaccinated against hepatitis B as soon as

possible after a diagnosis of diabetes is made. Clinicians may use their discretion in determining whether to vaccinate elderly diabetic patients (60 years). [42] Low response rates have been associated with obesity, smoking, immunosuppression, and advanced age. Approximately 25-50% of persons who initially do not have a vaccine response will show a response to 1 additional vaccine dose, and 50-75% of persons will have a response to a second 3-dose series. A combined hepatitis A virus (HAV) and hepatitis B vaccine is licensed in many countries and offers the advantage of protection against both of these diseases at the same time. The HBV vaccine seems to be safe, although some questions exist regarding neurologic complications.

Long-Term Monitoring
Inactive carriers of the hepatitis B virus (HBV) should have routine blood tests annually to check their aminotransferase levels. Patients with chronic active hepatitis should undergo blood tests (ie, to evaluate aminotransferase levels, antigen-antibody HBV profile, and viral load), liver biopsy, and treatment. Current guidelines recommend monitoring of HBV DNA and alanine aminotransferase (ALT) levels at least annually; however, a study conducted by Juday et al suggests that adherence falls below recommendations.[43] Following the recommended guideline reduces the risk of disease progression. Patients with cirrhosis must be checked every 3-6 months with alpha-fetoprotein (AFP) measurements and abdominal ultrasonography for hepatocellular carcinoma (HCC) surveillance.

Precautions
Physicians should keep the following in mind when managing a patient with hepatitis B

Identify cases of hyperacute fulminant hepatic failure, and list the patient as a candidate for liver transplantation Monitor healthy carriers for probable disease reactivation Inform the patients' spouses and sexual partners about the infectivity of hepatitis B and their possible need for vaccination Monitor patients with cirrhosis and perform HCC surveillance studies (ie, AFP levels and liver ultrasonography) every 3-6 months Put patients with cirrhosis on liver transplantation lists when needed Identify hepatitis D virus (HDV) superinfection

Medication Summary

The goals of pharmacotherapy in patients with hepatitis B disease are to reduce morbidity and to prevent complications.

Antivirals
Class Summary
Antiviral agents interfere with viral replication and weaken or abolish viral activity.
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Tenofovir disoproxil fumarate (Viread)


Tenofovir is a nucleotide analogue (adenosine monophosphate) reverse transcriptase and hepatitis B virus (HBV) polymerase inhibitor.
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Lamivudine (Epivir, Epivir-HBV)


Lamivudine is a thymidine analogue that blocks viral replication by competitive inhibition of viral reverse transcriptase. There is evidence that an indirect immunomodulatory effect can be observed.
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Adefovir dipivoxil (Hepsera)


Adefovir is used to treat chronic hepatitis B disease. This agent is a prodrug that is converted to the diphosphate salt. The active drug is classified as an antiviral nucleotide reverse transcriptase inhibitor. It inhibits hepatitis B virus (HBV) DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate (dATP) and by causing DNA chain termination after its incorporation into viral DNA.
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Entecavir (Baraclude)
Entecavir is a guanosine nucleoside analogue with activity against hepatitis B virus (HBV) polymerase. This agent competes with the natural substrate deoxyguanosine triphosphate (dGTP) to inhibit HBV polymerase activity (ie, reverse transcriptase). Entecavir is less effective for lamivudine-refractory HBV infection. This drug is indicated for treatment of chronic HBV infection and is available as a tablet and as an oral solution (0.05 mg/mL; 0.5 mg = 10 mL).
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Telbivudine (Tyzeka)
Telbivudine is a nucleoside analogue approved by the US Food and Drug Administration (FDA) for chronic hepatitis B treatment. This drug inhibits hepatitis B viral DNA polymerase and is indicated for patients with evidence of ongoing hepatitis B viral replication and either persistent elevated aminotransferase activity or histologic evidence of active liver disease. Consider telbivudine for patients whose condition did not or is unlikely to respond to interferon or for patients who cannot tolerate interferon. Emergence of resistance is a major drawback of nucleoside analogue monotherapy.

Interferons
Class Summary
Interferon agents are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions.
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Peginterferon alfa 2a (Pegasys)


Peginterferon alfa 2a binds to cell surface receptors in a cascade of protein interactions, resulting in gene transcription. These stimulated genes inhibit viral replication in infected cells, cell proliferation, and immunomodulation. Peginterferon alfa 2a is indicated for adults with hepatitis B "e" antigen (HBeAg)positive and HBeAg-negative chronic hepatitis B disease with compensated liver disease and evidence of viral replication and liver inflammation.
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Interferon alfa-2b (Intron A)


This is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Its immunomodulatory effects include enhancement of cytolytic T-cell activity, stimulation of natural killer cell activity, amplification of human leukocyte antigen (HLA) class I protein on infected cells, and suppression of tumor cell proliferation. The direct antiviral activity of interferon alfa-2b activates viral ribonucleases, inhibits viral entry to cells, and inhibits viral replication. A direct antifibrotic effect has been postulated. Before initiation of therapy with Interferon alfa-2b, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells. Monitor periodically (eg, monthly) during treatment to determine the patient's response to treatment; if the patient's condition does not respond within 4 months, discontinue treatment. If a response occurs, continue treatment until no further improvement is observed. Whether continued treatment is beneficial after that time remains unknown.
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Peginterferon alfa-2b (Pegintron, Pegintron Redipen, Sylatron)


This is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood, but direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

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