Hepatitis B

Hepatitis B
Last Updated: August 24, 2005
Synonyms and related keywords: HBV, hepatitis B infection, viral hepatitis, hepatitis B virus,
chronic hepatitis, acute hepatitis, cirrhosis, fulminant hepatitis, hepatocellular carcinoma, HCC,
extrahepatic manifestations, hepatitis D virus, HDV, delta virus, hepatitis C virus, HCV, hepatitis
B surface antigen, HBsAg, Australia antigen, hepatitis B surface antibody, HBsAb
AUTHOR INFORMATION

Author: Nikolaos T Pyrsopoulos, MD, PhD, Assistant Professor, Department of Medicine,

Division of Hepatology and Liver/GI Transplant, University of Miami School of Medicine and
Jackson Memorial Hospital
Editor(s): George Y Wu, MD, PhD, Chief, Division of Gastroenterology-Hepatology, Herman
Lopata Chair in Hepatitis Research; Professor, Department of Medicine, University of
Connecticut Health Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor,
eMedicine; Oscar S Brann, MD, FACP, Associate Clinical Professor, Department of Medicine,
University of California at San Diego; Consulting Staff, Mecklenburg Medical Group; Alex J
Mechaber, MD, FACP, Associate Professor, Department of Internal Medicine, Division of
General Internal Medicine, University of Miami School of Medicine; and Julian Katz, MD,
Professor, Department of Internal Medicine, Division of Gastroenterology, Drexel University
College of Medicine

INTRODUCTION

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. Since then, considerable progress has been
made regarding the epidemiology, virology, natural history, and treatment of this
hepatotropic virus.

Hepatitis B is a worldwide health care problem, especially in developing areas. An

estimated one third of the global population has been infected with this virus.
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 this disease.

HBV is transmitted hematogenously and sexually. The outcome of this infection is a

complicated viral-host interaction resulting in either an acute symptomatic disease
or an asymptomatic disease. Patients may become immune to HBV or may
develop a chronic carrier state. Later consequences are cirrhosis and the
development of hepatocellular carcinoma (HCC). 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 this disease.

Pathophysiology: HBV is a Hepadna virus. It is an extremely resistant strain

capable of withstanding extreme temperatures and humidity. It can survive when
stored for 15 years at -20°C, for 24 months at -80°C, for 6 months at room

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 Hepatitis B

temperatures, and for 7 days at 44°C. The viral genome consists of a partially
double-stranded circular DNA of 3.2 kilobase 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 and C genes has been found, named pre-S and pre-
C, respectively. 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:
a, common to all HBsAg and d, y, w, and r, which are epidemiologically important.
The core antigen, HBcAg, is the protein that encloses the viral DNA. It also can 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 aiding viral replication. Evidence strongly suggests that these
transactivators may be involved in carcinogenesis.

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, immunoglobulin M (IgM) subtype,
is indicative of acute infection or reactivation, while the immunoglobulin G (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 the antigen has been cleared.

With the newest PCR techniques, scientists are able to identify variations in the
HBV genome (variant strains). A mutation at the 1896 nucleotide (precore/core
region) processing the production of the HBeAg was identified first. The prevalence
of this mutant virus varies among different areas. Estimates indicate that 50-60% of
the patients from southern Europe, the Middle East, Asia, and Africa and 10-30% of
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 Hepatitis B

patients in the United States and Europe who have chronic HBV infection have
been infected by this strain.

The pathogenesis and clinical manifestations are due to the interaction of the virus
and the host immune system. The latter attacks the 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 relatively
tolerant immune status results in chronic hepatitis. In particular, a restricted T cell–
mediated lymphocytic response occurs against the HBV-infected hepatocytes.

The final state of the disease is cirrhosis. Patients with cirrhosis and HBV infection
are likely to develop HCC. In the United States, the most common presentation is
that of patients of Asian origin who acquired the disease as newborns (vertical
transmission). Four different stages have been identified in the viral life cycle.

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 often is decades. Active viral replication is known to continue
despite little or no elevation in the aminotransferase levels and no symptoms of
illness.

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.

In the third stage, the host can target the infected hepatocytes and the 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.

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 co-
infection with other viruses.

Eight different genotypes A through H representing a divergence of the viral DNA at

around 8% have been identified. 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 antivirals is less favorable for patients infected
by genotype C compared with those infected by genotype B.

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 Hepatitis B

Frequency:

 In the US: An estimated 200,000 new cases of HBV occur annually, and 1-
1.25 million people are carriers. The prevalence of the disease is higher
among African Americans 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
accounts for 5-10% of cases of chronic end-stage liver disease and 10-15%
of cases of HCC.

HBV is blamed for 5000 deaths annually. Prevalence is low in persons

younger than 12 years, but it increases in those older than 12 years. The
increased prevalence in persons older than 12 years is associated 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 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 is expected to decline further.

 Internationally: The HBV carrier rate variation is 1-20% worldwide. This

variation is related to differences in the mode of transmission and age at
infection. The prevalence of the disease in different geographical areas can
be characterized as follows:
o Low-prevalence areas (rate of 0.1-2%) include Canada, western
Europe, Australia, and New Zealand. In the areas of low prevalence,
sexual and percutaneous transmission during adulthood are the main
modes of transmission.
o 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 routes.
o 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 during early childhood vertically 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, seroprevalence declined from 10% in 1984 (before
vaccination programs) to less than 1% in 1994 and the incidence of

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 Hepatitis B
HCC declined from 0.52% to 0.13%.

Mortality/Morbidity: An estimated 250,000 persons per year globally and 5000

persons per year in the United States die from chronic HBV infection.

Race: African Americans have a higher prevalence of the disease than persons of
Hispanic origin or white persons.

Sex: More cases occur in males than in females.

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

CLINICAL

History: The spectrum of the symptomatology 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
HCC during the chronic phase.
 Acute phase

o The incubation period is 1-6 months.

o Anicteric hepatitis is the predominant form of expression for this

disease. The majority of the patients are asymptomatic. Patients with
symptomatology have the same symptoms as patients who develop
icteric hepatitis. Patients with anicteric hepatitis have a greater
tendency to develop chronic hepatitis.

o Icteric hepatitis is associated with the 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)

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 Hepatitis B
o Patients with hyperacute, acute, and subacute hepatitis may present
with the following:
 Hepatic encephalopathy
 Somnolence
 Disturbances in sleep pattern
 Mental confusion
 Coma

 Chronic phase

o Patients with chronic hepatitis can be healthy carriers without any

evidence of active disease, and they also are asymptomatic.

o 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: The physical examination findings 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:

o Low-grade fever

o Jaundice (10 d after the appearance of constitutional symptomatology

and lasting for 1-3 mo)

o Hepatomegaly (mildly enlarged soft liver)

o Splenomegaly (5-15%)

o Palmar erythema (rarely)

o Spider nevi (rarely)

 The physical examination of patients with chronic hepatitis B can reveal

stigmata of chronic liver disease such as the following:

o Hepatomegaly

o Palmar erythema

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 Hepatitis B
o Spider angioma

 Patients with cirrhosis may have the following symptoms:

o Ascites

o Jaundice

o History of variceal bleeding

o Peripheral edema

o Gynecomastia

o Testicular atrophy

o Abdominal collateral veins (caput medusa)

DIFFERENTIALS

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

Other Problems to be Considered:

Drug hepatotoxicity
Congestive heart failure

WORKUP
Lab Studies:

 Acute hepatitis B

o High levels of alanine aminotransferase (ALT) and aspartate

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 Hepatitis B
aminotransferase (AST), at a range of 1000-2000 IU/mL, is the hallmark of
the disease, although values 100 times more than the upper limit of normal
can be identified. Higher values are found in patients with icteric hepatitis.
ALT levels usually are higher than AST levels.

o Alkaline phosphatase levels may be elevated, but usually they are not
more than 3 times the upper limit of normal.

o 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
sedimentation rate.

o Anemia due to a shortened red blood survival period is an infrequent

finding, although hemolysis may be noted. Thrombocytopenia is a rare
finding.

o Patients with severe hepatitis experience a prolongation of the prothrombin

time.

o Several viral markers can be identified in the serum and the liver. HBsAg
(Australian antigen) and HBeAg (marker of infectivity) are the first markers
that can be identified in the serum. HBcAb (IgM) follows.

o For patients who recover, seroconversion to HBsAb and HBeAb is

observed, and the HBcAb is of the IgG class. Patients with persistent
HBsAg for longer than 6 months develop chronic hepatitis.

 Chronic inactive hepatitis B

o Healthy carriers have normal AST and ALT levels, and the markers of
infectivity (ie, HBeAg, HBV DNA) may be negative.

o HBsAg, HBcAb of IgG type, and HBeAb also are present in the serum.

 Chronic active hepatitis B

o Patients have mild-to-moderate elevation of the aminotransferases (<5

times the upper limit of normal). The ALT levels usually are higher than the
AST levels. Extremely high levels of ALT can be observed during
exacerbation or reactivation of the disease and can be accompanied by
impaired synthetic function of the liver (ie, decreased albumin levels,
increased bilirubin levels, and prolonged prothrombin time). 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.

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 Hepatitis B
o 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 (20-25%) or antinuclear antibodies (10-
20%), can be identified. Tissue-specific antibodies, such as antibodies
against the thyroid gland (10-20%), also can be found. Mildly elevated
levels of rheumatoid factor usually are present.

 Cirrhosis

o In early stages, findings of chronic viral hepatitis can be found.

o Later on as the disease progresses, low albumin levels, hyperbilirubinemia,

prolonged prothrombin time, low platelet count and white blood cell count,
and AST levels higher than ALT levels can be identified.

o Alkaline phosphatase levels and gamma-glutamyl transpeptidase can be

slightly elevated.

Imaging Studies:

 Acute hepatitis B

o Performing abdominal ultrasonography, CT scan, or MRI is important to

help exclude biliary obstruction.

o Nonspecific findings include increased echogenicity of the liver

parenchyma.

 Chronic hepatitis B: Nonspecific findings may include increased echogenicity of

the liver parenchyma.

 Cirrhosis

o 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]).

o Lesions can be detected and may be very difficult to evaluate because they
can be mistaken for regenerating nodules. For these 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.

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 Hepatitis B

Procedures:

 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 HBV DNA).

Histologic Findings: Although liver biopsy is not indicated for patients with acute
hepatitis B, the findings are predominantly lobular, with degenerative and regenerative
hepatocellular changes and 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 HBsAg (see Image 1). Immunohistochemical
staining of the specimen can help identify the presence of HBsAg or HBcAg (ie,
chronic infection).

Staging:

 Liver damage grading according to the inflammatory component is described as

follows:

o Grade 0 - Portal inflammation only, no activity

o Grade 1 - Minimal portal inflammation and patchy lymphocytic necrosis
with minimal lobular inflammation and spotty necrosis
o Grade 2 - Mild portal inflammation and lymphocytic necrosis involving
some or all portal tracts, with mild hepatocellular damage
o Grade 3 - Moderate portal inflammation and lymphocytic necrosis involving
all portal tracts, with noticeable lobular inflammation and hepatocellular
change
o 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:

o Stage 0 - No fibrosis

o Stage 1 - Portal fibrosis

o Stage 2 - Periportal fibrosis

o Stage 3 - Septal, bridging fibrosis (see Image 2)

o Stage 4 - Cirrhosis (see Image 3)

TREATMENT

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 Hepatitis B

Medical Care: Therapy is currently recommended for patients with evidence of chronic
active disease (ie, high levels of the aminotransferases, positive HBV DNA findings,
HBeAg). See the Medication section. Currently, interferon alfa (IFN-a), lamivudine, and
adefovir dipivoxil are the main drugs approved globally, although ongoing trials are
investigating new types of medications such as entecavir, tenofovir disoproxil,
emtricitabine, BL-thymidine (L-dT), DAPD, clevudine (l-FMAU), thymosin, and
therapeutic vaccines. No clearcut guidelines are available as to which medication
should be chosen.

Patients who have lost HBeAg and in whom HBV DNA is undetectable have an
improved clinical outcome (ie, slower rate of progression, prolonged survival without
complications, reduced rate of HCC, and clinical and biochemical improvement after
decompensation).

Special attention must be given to patients on transplantation lists. Initiation of

treatment with lamivudine or adefovir is of cardinal importance before and after liver
transplantation in order to achieve viral suppression and prevent recurrence of the
disease after the procedure.

 Interferon alfa

o Published reports indicate that after IFN-a treatment with 5 million U/d or
10 million U 3 times per week subcutaneously for 4 months, the HBV DNA
levels and HBeAg become undetectable in 30-40% of patients. In addition,
10% of patients seroconvert from HBsAg to HBsAb. Unfortunately, 5-10%
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.
o High levels of aminotransferases, a low viral load, and infection with the
wild type are good prognostic factors for response to IFN-a treatment.
o Asian patients and patients with the precore mutant virus tend to not
respond to IFN-a treatment.
o 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 respond, they also can
deteriorate further.
o The adverse effects of IFN-a sometimes can 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.

 Lamivudine

o A nucleoside analogue inhibiting the viral polymerase, lamivudine has been

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 Hepatitis B
associated with a 4-log reduction of the viral load. Lamivudine treatment
(100 mg/d) has been associated with a 16-18% seroconversion rate from
HBeAg to 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.
o Histologic improvement (ie, reduction of histologic activity index of >2
points) has been noticed in approximately 50% of patients taking this
medication. The adverse effects are negligible.

Lamivudine appears to be effective for patients who do not respond to IFN-

a treatment (eg, patients infected by the precore mutant virus). A transient
elevation of aminotransferases can be noticed shortly after starting
treatment.

o The duration of treatment is 12 months, but 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 also has been shown to dramatically improve the

condition of patients with decompensated disease due to HBV reactivation.

o The emergence of viral variants is the major complication. 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. Discontinuation of treatment for these patients is
accompanied by a reversion to a wild type of HBV and a flare of the
disease.

 Adefovir dipivoxil

o This agent is a nucleoside analogue, a potent inhibitor of the viral

polymerase. The efficacy of this drug has been tested in HbeAg-positive,
HbeAg-negative, and lamivudine-resistant patients with encouraging
results.
o The estimated rate of resistance to adefovir and the development of
mutations (rtN236T and rtA181V) is approximately 4-6% after 3 years of
treatment.
o The optimal dose seems to be 10 mg/d. Higher doses are nephrotoxic.
o The results of 2 multicenter trials using adefovir for 48 weeks were
published recently.
 In HBeAg-positive subjects who received 10 mg of adefovir daily, a
median 3.52 log reduction of the viral load (HBV DNA) level was

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 Hepatitis B
noted. In 48% of the subjects, normalization of the aminotransferases
level was reported. Histologic improvement was noticed in 53% of the
subjects who received this regimen. The HBeAg seroconversion rate
was 12%.
 Sixty-four percent of the HbeAg-negative population 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 (Hadziyannis,
2003; Marcellin, 2003). The outcomes are maintained if treatment is
continued for 144 weeks, but the benefits are lost if treatment is
discontinued at 44 weeks. The development of resistant mutations
(rtN236T and rtA181V) has been estimated around 6% (Hadziyannis,
2005).

Surgical Care: 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 post-OLT period, and of lamivudine or adefovir in the pre-OLT period and post-
OLT period, dramatically improves the recurrence rate of HBV infection.

Diet:

 Acute and chronic hepatitis (patients without cirrhosis) - No restrictions

 Decompensated cirrhosis (prominent signs of portal hypertension or

encephalopathy) - 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)

MEDICATION

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Antivirals -- Interfere with replication; weaken or abolish viral activity.

Drug Name Interferon alfa-2b (Intron A) or alfa-2a (Roferon-A) -- Protein

product manufactured by recombinant DNA technology.
Mechanism of antiviral activity is not clearly understood. However,
modulation of host immune responses enhances cytolytic T-cell
activity; stimulates natural killer cell activity and amplifies HLA
class I protein on infected cells. Direct antiviral activity activates
viral ribonucleases, inhibits viral entry to cells, and inhibits viral
replication. Direct antifibrotic effect has been postulated. Prior to
initiation of therapy, perform tests to quantitate peripheral blood
hemoglobin, platelets, granulocytes, hairy cells, and bone marrow
hairy cells; monitor periodically (eg, monthly) during treatment to
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 Hepatitis B
determine response to treatment; if patient does not respond
within 4 mo, discontinue treatment. If a response occurs, continue
treatment until no further improvement is observed. Whether
continued treatment after that time is beneficial remains unknown.
5 million U IM/SC qd for 16 wk; alternatively, 10 million U IM/SC 3
times per wk for 16 wk
Adult Dose Reduce dose by 50% if severe reactions occur or temporarily
discontinue therapy until symptoms from adverse reactions
improve
Pediatric Dose Not established
Documented hypersensitivity; autoimmune hepatitis, other
Contraindications
autoimmune disorders
Theophylline may increase toxicity; cimetidine may increase
Interactions
antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy C - Safety for use during pregnancy has not been established.
Caution in brain metastases, severe hepatic or renal
insufficiencies, seizure disorders, multiple sclerosis, or
Precautions
compromised CNS; associated with depression and suicidal
ideation and severe or fatal GI hemorrhage
Lamivudine (Epivir) -- Thymidine analog that blocks viral replication
Drug Name by competitive inhibition of viral reverse transcriptase. Evidence
that an indirect immunomodulatory effect can be observed.
Adult Dose 100 mg PO qd
Pediatric Dose Not established
Contraindications Documented hypersensitivity
TMP-SMZ increases bioavailability; increases concentration of
Interactions
zidovudine when administered concurrently
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Adjust dose in renal impairment; caution in history of pancreatitis
Adefovir dipivoxil (Hepsera) -- Used to treat chronic hepatitis B.
This agent is a prodrug that is converted to the diphosphate salt.
The active drug is classified as an antiviral nucleotide reverse
Drug Name transcriptase inhibitor. It inhibits 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.
CrCl >50 mL/min: 10 mg PO qd
CrCl 20-49 mL/min: 10 mg PO q48h
Adult Dose
CrCl 10-19 mL/min: 10 mg PO q72h
Hemodialysis: 10 mg PO qwk following hemodialysis

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 Hepatitis B
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Coadministration with ibuprofen increases bioavailability of
Interactions adefovir; drugs that alter renal tubular secretion may affect adefovir
renal elimination
Pregnancy C - Safety for use during pregnancy has not been established.
Hepatitis exacerbation may occur following drug discontinuation;
may increase risk of renal dysfunction; HIV resistance may emerge
Precautions in patients with untreated or unrecognized HIV; lactic acidosis and
hepatomegaly with steatosis have been reported with other
nucleoside analogs
Entecavir (Baraclude) -- Guanosine nucleoside analogue with
activity against HBV polymerase. Competes with natural
substrate deoxyguanosine triphosphate to inhibit HBV
Drug Name polymerase activity (ie, reverse transcriptase). Less effective for
lamivudine-refractory HBV infection. Indicated for treatment of
chronic HBV infection. Available as tab and as oral solution (0.05
mg/mL; 0.5 mg = 10 mL).
Treatment for nucleoside naive: 0.5 mg PO qd 2 h ac or 2 h pc
CrCl 30-49 mL/min: 0.25 mg PO qd
CrCl 10-29 mL/min: 0.15 mg PO qd
CrCl <10 mL/min: 0.05 mg PO qd
Adult Dose Receiving lamivudine or lamivudine resistance: 1 mg PO qd 2 h
ac or 2 h pc
CrCl 30-49 mL/min: 0.5 mg PO qd
CrCl 10-29 mL/min: 0.3 mg PO qd
CrCl <10 mL/min: 0.1 mg PO qd
<16 years: Not established
Pediatric Dose
>16 years: Administer as in adults
Contraindications Documented hypersensitivity
Not a substrate, inhibitor, or inducer of cytochrome P450;
coadministration with drugs that reduce renal function (eg,
aminoglycosides, cidofovir, cyclosporine) or that compete for
Interactions
active tubular secretion (eg, probenecid, salicylates) may
increase serum concentration of either entecavir or
coadministered drug
Pregnancy C - Safety for use during pregnancy has not been established.
Reduce dose with renal impairment; if on hemodialysis,
administer afterward; common adverse effects include headache,
Precautions fatigue, dizziness, and nausea; may elevate liver enzyme levels;
may cause lactic acidosis; severe acute exacerbations of HBV
infection may occur in patients who discontinue anti-HBV therapy
15
 Hepatitis B
FOLLOW-UP

Further Inpatient Care:

 Fulminant hepatic failure: Patients should be hospitalized in the intensive care

unit and should be enrolled for liver transplantation in case they do not recover.

 Acute hepatitis: Patients should be monitored with blood tests in order to

document biochemical improvement.

Further Outpatient Care:

 Healthy carriers should have routine blood tests annually to check

aminotransferase levels.

 Patients with chronic active hepatitis should have blood tests (ie, to evaluate
aminotransferase levels, antigen-antibody HBV profile, and viral load), liver
biopsy, and treatment.

 Patients with cirrhosis must be checked every 3-6 months with alpha-fetoprotein
measurements and abdominal ultrasound for HCC surveillance.

Deterrence/Prevention:

 Universal vaccination programs are ongoing in endemic areas, with encouraging

results. This vaccine consists of recombinant HBsAg produced in yeast. A series
of 3 injections may achieve HBsAb levels of greater than 10 million IU/mL in
approximately 95% of people vaccinated.

o Low response rates have been associated with obesity, smoking,

immunosuppression, and advanced age.

o The HBV vaccine seems to be safe, although some questions exist

regarding neurological complications.

o Approximately 25-50% of persons who initially do not respond to the

vaccine will respond to one additional vaccine dose, and 50-75% of
persons will respond to a second 3-dose series.

o Vaccination with a single dose must be repeated every 5-10 years.

o All newborns must be vaccinated. For infants born to mothers with active
HBV infection, a passive-active (immunoglobulin and vaccination)
approach is recommended.

o A combined hepatitis A and B vaccine is licensed in many countries and

offers the advantage of protection against both of these diseases at the

16
 Hepatitis B
same time.

o Health care workers or people who have had a needle-stick accident from
a patient with active HBV infection must receive the active-passive
immunization approach (HBIG and the first dose of the vaccine at the same
time) and must be monitored with blood tests.

Complications:

 Hepatocellular carcinoma

o Even the presence of HBsAb in the absence of HBsAg or HBV DNA is

significantly related to an increased risk for HCC. The annual incidence of
this malignancy in patients with HBV infection and cirrhosis reported in
Taiwan is 2.8%. The estimated US 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 HBV in Africa, the Far East,
and Alaska.
o The prevalence of hepatitis D virus (HDV) co-infection among patients
infected with 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.
o The prevalence of HCC among patients with HBV and hepatitis C virus
(HCV) co-infection is higher than in those with single infection alone. The
rate of development of HCC per 100 person years of follow-up is 2% in
patients with cirrhosis and HBV infection, 3.7% in patients with HCV, and
6.4% in patients with dual infection. This points to a probable synergistic
effect on the risk of HCC.
o The mechanism by which chronic HBV 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.
o 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. Although the
cellular targets of carcinogenesis have not been identified, some evidence
resulting from experimental animal models suggests that oval cell
17
 Hepatitis B
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.
o 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.
o Transactivation of the function of genes controlling transcriptional factors
(ie, insulinlike growth factor II, transforming growth factor-alpha (TGF-a),
transforming growth factor-beta, cyclin-a [a protein that controls cell
division], epidermal growth factor-r, retinoic acid receptor) and oncogenes
such as c-myc, fos, ras (activating the internal signal transduction cascade
up-regulating ras/mitogen–activated kinase, c-Jun N terminal kinase,
nuclear factor – kB, Jak-1-STAT, src-dependent pathways) influence the
normal hepatocyte differentiation or cell cycle progression.

o Furthermore, the integrated part of the HBV controlling the production of

the HBxAg 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 and ATF-2, which alters their DNA-binding specificity. Thus, the
ability of pX 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.
o 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 HBV infection, thus
altering its function.
o Tumor necrosis factor-alpha (TNF-alpha, a proinflammatory cytokine)
levels also are up-regulated. The transcriptional transactivation of nitric
oxide (NO) synthetase II by pX and the elevated levels of TNF-alpha 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
18
 Hepatitis B
region of the HBV genome, stimulating the expression of the human proto-
oncogenes c-fos and c-myc, and this up-regulates the expression of TGF-a
by transactivation.

 Glomerulonephritis

o The most common type of glomerulonephritis (GN) described is

membranous GN (MGN), mainly in children. However,
membranoproliferative GN (MPGN) and, even more rarely, immunoglobulin
A (IgA) nephropathy, have been identified. The prevalence rate of GN
among patients with chronic HBV infection is not well known, although
observations have been made in children that suggest a range of 11-
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.
o 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 often are evident, and complement
activation is suggested by low levels of C3 and C4.
o Generally, the most prominent finding among 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 also
has been described.
o The mechanism by which patients with chronic HBV infection develop GN
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 epithelial cells of renal tubules.
o INF-a therapy has been successful in treating HBV-related GN. A regimen
of 5 million units of IFN-a subcutaneously daily for 4 months has achieved
HBsAg seroconversion with improvement of GN. It also has been reported
that IFN-a given at a dose of 3 million units 3 times per week led to
improvement of proteinuria only in patients with mesangial proliferative GN
but not in patients with MPGN. Finally, a single case report described the
resolution of this complication after liver transplantation.
o The prognosis of the disease is related to several factors such as age and
response to therapy. Children with MGN respond more favorably than
adults. White persons respond better than Asians and African Americans.
Approximately 30-60% of patients with MGN undergo spontaneous
19
 Hepatitis B
remission. However, the course of HBV-related membranous nephropathy
in adults in areas in which HBV is endemic is not benign. Regardless of
treatment, the 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
o An association between HBV 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 disease, 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 the disease. However, whether
these represent the primary etiology of the disease remains unclear.
o The clinical manifestations of the disease include cardiovascular (eg,
hypertension [sometimes severe], pericarditis, heart failure), renal (eg,
hematuria, proteinuria, renal insufficiency), gastrointestinal (eg, abdominal
pain, mesenteric vasculitis), musculoskeletal (eg, arthralgias, arthritis),
neurological (eg, mononeuritis), and dermatological (eg, rashes)
involvement. Significant proteinuria (>1 g/d), renal insufficiency (serum
creatinine >1.58 mg/dL), gastrointestinal involvement, cardiomyopathy, and
CNS involvement are associated with increased mortality. The course of
PAN is independent of the severity and the progression of 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 those with PAN who are seronegative.
o Small and medium-sized arteries and arterioles are affected. Although
corticosteroids and immunosuppressive agents may be beneficial for
treating vasculitis, they potentially may have a deleterious effect on the
course of HBV 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. Because of the fact that this is a rare complication, to
date no reports have been published on the use of the newer therapies for
HBV that include the nucleoside analogue, lamivudine.

 Skin manifestations
o A variety of cutaneous manifestations already have been recognized,
among which are hives and fleeting maculopapular rash, during the early
course of viral hepatitis. Women are more prone to developing cutaneous
manifestations.
20
 Hepatitis B
o 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.
o Papular acrodermatitis, also recognized as Gianotti-Crosti syndrome, has
been associated with hepatitis B, more commonly with acute infection in
children.

 Cardiopulmonary manifestations
o Pleural effusion, hepatopulmonary, and portopulmonary syndrome may
occur in patients with cirrhosis.
o Myocarditis, pericarditis, and arrhythmia occur primarily in patients with
fulminant hepatitis.
 Joint and neurologic manifestations
o Guillain-Barré syndrome, encephalitis, aseptic meningitis, and
mononeuritis multiplex may occur in patients with acute hepatitis.
o Arthralgias and arthritis (serum sickness) subcutaneous nodules also may
occur but are rare.

 Hematologic and gastrointestinal tract manifestations

o Patients may develop pancreatitis.

o Aplastic anemia is uncommon, and agranulocytosis is extremely
uncommon.
o Diffuse intravascular coagulation may occur in patients with fulminant
hepatitis.

Prognosis:

 Approximately 9% of patients in western Europe who have cirrhosis develop

HCC due to HBV 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 HBsAb in the absence of HBsAg or
HBV DNA is significantly related to an increased risk for HCC. The annual
incidence of this malignancy in patients with HBV 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 HBV in Africa, the Far East, and Alaska.
The cumulative probability of survival is 84% and 68% at 5 years and 10 years,
respectively.

 Cox's regression analysis identified 6 variables that independently correlate with

survival. These include age, albumin level, platelet count, splenomegaly, bilirubin
level, and HBeAg positivity at the time of diagnosis. According to the contribution
21
 Hepatitis B
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 HDV infection compared to
those who are not infected.

 The prevalence of HDV co-infection among patients infected with HBV varies
worldwide from 0-20%. 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.

Patient Education:

 For excellent patient education resources, visit eMedicine's Hepatitis Center and
Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient
education article Hepatitis B.

MISCELLANEOUS

Medical/Legal Pitfalls:

 Failure to identify hyperacute fulminant hepatic failure cases and list the patient
as a liver transplant candidate

 Failure to monitor healthy carriers for probable reactivation

 Failure to inform the spouses and sexual partners about the infectivity of the
disease and their possible need for vaccination

 Failure to monitor patients with cirrhosis and perform HCC surveillance studies
(ie, alpha-fetoprotein level and liver ultrasound) every 3-6 months

 Failure to put patients with cirrhosis in liver transplant lists when needed

 Failure to identify HDV superinfection

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