Hepatitis B Articles (HBV)

Epidemiology, Natural History, Impact of Therapy of Hepatitis B

- Epidemiology of Hepatitis B
- Candidates for Screening
- Diagnostic Tests for Screening and Evaluation in Hepatitis B
- Further Evaluation for HBsAG+ Patients
- Warning Signs of Serious Liver Disease
- Vaccination
- natural history
- chronic HBV
- impact of therapy on natural history
.....Hepatitis B virus (HBV) is transmitted via parenteral or mucosal exposure to
body fluids (semen) of individuals who are acutely infected with or are chronic
carriers of HBV. The highest viral concentrations are found in the blood and
serous fluids....
......Chronic infection has been observed to evolve in up to 90% of infected
infants of HBeAg positive mothers, in about 30% of children infected at <6
years of age, and probably in <5% of infected older children and adults....
www.projectsinknowledge.com/HBV
Robert G. Gish, md
Medical Director
Liver Transplant Program
Chief, Division of Hepatology and Complex GI
California Pacific Medical Center
San Francisco, California
Conclusions
Hepatitis B is a common and potentially serious infection. Worldwide, there are
more than 4 million acute cases each year, and approximately 350 million people
are chronic carriers.1 In areas of high endemicity- southeast Asia and the
Pacific Basin (except for Japan, Australia, and New Zealand), sub-Saharan
Africa, the Amazon Basin, parts of the Middle East, the central Asian republics,
and some eastern European countries-up to 90% of the population becomes
infected with hepatitis B virus (HBV) by age 40 years, 8% to 20% of whom
become carriers.1 Areas of low endemicity, where infection rates are <20% and
carrier rates are <2%, include North America, western and eastern Europe,
Australia, and parts of South America.1
Hepatitis B is a common and potentially serious infection. Worldwide, there are more

than 4 million acute cases each year, and approximately 350 million people are
chronic carriers.1 In areas of high endemicity southeast Asia and the Pacific Basin
(except for Japan, Australia, and New Zealand), sub-Saharan Africa, the Amazon
Basin, parts of the Middle East, the central Asian republics, and some eastern
European countriesup to 90% of the population becomes infected with hepatitis B
virus (HBV) by age 40 years, 8% to 20% of whom become carriers.1 Areas of low
endemicity, where infection rates are <20% and carrier rates are <2%, include North
America, western and eastern Europe, Australia, and parts of South America.1
In the United States, reported cases of acute hepatitis B peaked at 26,000 per year in
th mid-1980s and have since declined steadily to about 7526 reported cases in
2003.2-4 This decline is largely attributable to HIV prevention efforts that reduced
transmission among homosexual men and injection drug users, and to vaccination of
children.2,3 The Centers for Disease Control and Prevention (CDC) estimates that in
the early 2000s, there have been about 73,000 to 80,000 new infections each year,
which have led to about 21,000 to 23,000 new acute clinical infections annually
(only about 75008000 of which are reported),4 and that there are 5000 to 8000 new
chronic infections each year.2 Currently, 1 to 1.25 million persons in the United
States are chronically infected.2,4 Thus, identification and treatment of hepatitis B
remain important concerns, even in areas of "low" endemicity, like the United States.
HBV is transmitted through parenteral or mucosal exposure to body fluids of carriers
or acutely infected individuals.2 In areas of high endemicity, hepatitis B is most
commonly transmitted perinatally from the mother or through infection in early
childhood. Due to their more immature immune systems, children are much more
likely to develop chronic infection than adults.5 Since mother to- child transmission
accounts for the majority of hepatitis B cases in areas of high endemicity, these areas
have higher rates of chronicity than low-endemicity areas.5 Moreover, the higher
prevalence of chronic infection also translates into higher rates of cirrhosis and
cancer in these areas. In the United States, hepatitis B is mostly an adult-acquired
disease associated with high-risk behavior, including sexual contact and injection
drug use.2 However, it is important to consider that the United States is a country of
immigrants, many of whom arrive from areas of high endemicity. For example,
although the prevalence of HBV infection is only 0.3% in the general US population,
it is as high as 15% among Asians and Pacific Islanders, who comprise 1.3 to 1.5
million known carriers of hepatitis B in the United States.6
The need for concern about hepatitis B stems not only from its prevalence but also
from its potentially serious sequelae. Persons with chronic HBV infection are at risk
for cirrhosis and hepatocellular carcinoma (HCC), which occur in about 20% of
cases (annual incidence: 5.9%).7 At 5 years after diagnosis of compensated cirrhosis,
the cumulative probability of HCC is 6% and that of decompensation is 23%.8 It
should also be noted that hepatitis B is a systemic disease and can, in rare cases,
result in nonhepatic end-organ injury, including vasculitis, kidney failure,
pancreatitis, nerve damage, and other forms of tissue injury.

Candidates for Screening

Screening for hepatitis B is routinely performed in persons who have elevated liver
enzyme levels, jaundice, or other evidence of acute liver disease. In
addition, screening is warranted for anyone with risk factors for HBV infection,
and at-risk persons who are found to be susceptible to hepatitis B should receive
vaccination against HBV.
At-risk individuals include 2,9:
- Those who have engaged in high-risk sexual behaviors (men who have sex with
men, anyone with multiple heterosexual sex partners, and persons recently
diagnosed with a sexually transmitted disease)
- Injection drug users
- Immigrants, refugees, or adoptees/orphans from areas of high endemicity
- Those who are immunosuppressed (eg, transplant recipients, those on
immunosuppressive therapies, those with autoimmune diseases or HIV infection, and
patients receiving chemotherapy)
- Dialysis patients
- Household members or sexual partners of known HBV carriers
- Those who have had occupational exposure through needle sticks
- Recipients of certain blood products (eg, clotting factors for hemophilia) - Inmates
in long-term correctional facilities or residents in an institution for the
developmentally disabled
The risk of hepatitis B through blood transfusion varies throughout the world. In
countries with similar blood-screening systemsthe United States, Europe, and
Australiathe risk for HBV can range from 1 in 63,000 blood units to 1 in
398,499.10,11
Diagnostic Tests for Screening and Evaluation in Hepatitis B
An initial screen for hepatitis B should consist of hepatitis B surface antigen
(HBsAg), hepatitis B core antibody (anti-HBc), and hepatitis B surface antibody
(anti-HBs). HBsAg positivity is a general marker of acute or chronic infection. It is
the first marker......

to appear, and its persistence for >6 months indicates chronic infection. Anti-HBc is
a marker of exposure that persists for life.
Anti-HBs documents recovery and/or immunity to HBV and is detectable after
immunity conferred by hepatitis B vaccination or previous infection. There is some
controversy regarding the need for, and the cost-effectiveness of inclusion of, all
three tests in the initial screen. Some healthcare authorities have advocated that only
the HBsAg test, or only the anti-HBc test, be used; however, the full panel appears to
be the most effective means of screening an individual for the presence of infection,
exposure, or immunity.
Further Evaluation for HBsAg+ Patients
Individuals with HBsAg positivity should undergo further workup that includes
hepatitis B e antigen (HBeAg), hepatitis B e antibody (anti-HBe), and HBV DNA
quantification by nucleic acid testing.
An optional test is the anti-HBc IgM, which is the best test to document an acute
infection; if positive in a person known to have chronic infection, it imparts a worse
prognosis.12,13 Another optional test in patients with adult-acquired HBV infection
is a test for hepatitis delta antibody. Interpretation of these tests is described in Table
1.14,15 Liver biopsy is useful in deciding which patients with chronic infection to
treat and when to initiate therapy.
Precore mutant chronic hepatitis B is found in about 10% to 40% of cases in
northern Europe and the United States and 30% to 80% in southern Europe and
Asia.16 Patients with precore mutant chronic hepatitis B are HBsAg+, are HBeAg ,
generally have HBV DNA levels 30,000 to >100,000 copies/mL, and typically have
elevated alanine aminotransferase (ALT) levels. This variant of chronic hepatitis B is
suspected, but not proven, to be associated with a high risk of cirrhosis,16 and it is
more difficult to treat,17 though response may be better with peginterferon than with

nucleoside analogs like lamivudine.18

Serologic findings also vary over time with the stage of infection (See Figure 1).19
In the first stage of viral replication, patients generally are asymptomatic and have
normal ALT levels. In the second phase of replication, an immunologic response
develops or increases and ALT levels tend to become elevated as HBV DNA levels
decline. Replication ends as the virus is cleared, but this is followed by a phase of
integration of HBV into the hepatocyte genome. This is a quiescent phase with low
HBV DNA levels and normal or slightly abnormal ALT levels. The final phase is
clearance of HBsAg and HBV DNA, which can occur naturally or through
therapeutic intervention. HBV is not considered a curable disease, because even
when viral replication is stopped, the virus persists in an inactive form. Persons who
are HBsAg may still have tiny amounts of HBV DNA in their liver tissue.
However, though "not cured," most patients with previous exposure who are not
chronically infected and lack HBsAg have minimal longterm risk from HBV.

Additional tests are currently available to some practitioners in the United States,
including tests for hepatitis B genotype, and direct tests for precore and core
promoter mutations. It has been proposed that these tests may provide further
information regarding prognosis, likelihood of treatment response, risk of developing
treatment resistance, and risk of cancer.
Nucleic Acid Testing
As noted above, every patient who is HBsAg+ should have HBV DNA testing. In
acute HBV infection, a high HBV DNA level indicates a low probability of
clearance, whereas clearance is more likely among those with low HBV DNA
levels.
In chronic infections, serum HBV DNA level has been found to correlate with
histologic grading as well as biochemical and serologic response to treatment.20,21

The test should be repeated every 6 months for those not on therapy in order to
identify any changes in replication status. In addition, for those on therapy, HBV
DNA testing is used every 3 to 6 months, or immediately after stopping therapy, to
monitor treatment response. It can be useful in evaluating the rare patient who is
HBsAg but has active viral replication.
A number of nucleic acid tests measure HBV DNA, including polymerase chain
reaction (PCR), branched-chain (bDNA) assay, transcription-mediated amplification
(TMA), hybrid capture, and column hybridization. The latter two are of historical
value but are now rarely used.
The PCR assay copies the viral DNA to another DNA molecule, and is the standard
test used for almost all licensing trials since it denotes the most profound level of
viral suppression. The test with the lowest range of detection is the COBAS
Amplicor HBV Monitor PCR assay, which can detect as few as 200 copies/mL.
Taqman, a new PCR test currently in development, is anticipated to have a higher
level of sensitivity and the widest dynamic range, but it is not yet fully developed for
broad-based clinical use.
The bDNA assay has a dynamic range of 2000 to 100 million copies/mL. Dilution
extends its range to 5 billion copies/mL. This test was used in some licensing studies,
including studies of emtricitabine and entecavir.
A new qualitative PCR test, the COBAS AmpliScreenTM, can detect as few as 15
copies/mL, and the Procleix UltrioTM TMA assay can detect down to 25 copies/mL.
In the future, these qualitative tests may be able to be converted to quantitative tests.
Warning Signs of Serious Liver Disease
Hepatitis B potentially has serious clinical consequences including cirrhosis, liver
failure, and HCC.2 In the United States, HBV-related cirrhosis kills about 3000 to
4000 persons each year, and another 1000 to 1500 die of HBV-related liver cancer.2
It is important to recognize the warning signs of advanced liver disease. In acute
liver disease, ALT > 500 IU/L, encephalopathy, and jaundice are signs of serious
liver disease. The presence of encephalopathy indicates fulminant hepatic
failure. In chronic infections, warning signs of serious liver disease include
prolonged prothrombin time or institutional normalized ratio (INR), bilirubin >
2 mg/dL, albumin < 3.5 g/dL, cholesterol < 100 mg/dL, ammonia > 65 mmol/L,
and platelets < 100,000 mm3.
Signs/symptoms of serious liver disease found on physical examination include
swollen feet or abdomen, confusion, progressive memory loss, sleep difficulties,
vomiting blood/blood in the stool, bleeding/hemorrhages (including gastrointestinal
bleeding and skin bleeding), jaundice, flapping of hands when arms are extended,
and muscle wasting. Such patients should be referred to specialists who manage

advanced liver disease or to liver transplant centers.

Vaccination
The only way to eliminate hepatitis B globally is through vaccination. All infants,
children, and adolescents should now be vaccinated routinely.2 All pregnant women
should be screened, and vaccination and immunoprophylaxis provided to their
infants if appropriate.2 All susceptible adults with any of the risk factors described
earlier in this newsletter should be vaccinated.2 An anti-HBs level > 10 mIU/mL
indicates vaccine immune response, which is achieved in 95% of children and 90%
of adults.2
Factors associated with reduced immune response to vaccine include older age
(~90% seroprotection for persons >40 years and ~75% for persons >60 years),2
chronic medical disease, buttock injection site, smoking, obesity, and male gender.2
Postvaccination serologic testing is not routinely performed, but there are some
exceptions.
Serologic testing at 1 to 2 months following completion of vaccination is
recommended if knowledge of immune status would affect management,2 as might
be the case, for example, for dialysis patients, immunocompromised persons at
continued risk, sexual partners of patients with chronic HBV infection, and people
with occupational risk of blood exposure.
Postvaccination testing at 9 to 15 months of age is also recommended for infants
born to HBsAg+ mothers.2 Nonresponders (ie, anti-HBs < 10 mIU/mL) at high risk
for infection should be revaccinated by repeating a three-dose vaccine series, which
produces response in 30% to 50% of adults.2
NATURAL HISTORY: From Exposure to Acute Infection
Hepatitis B virus (HBV) is transmitted via parenteral or mucosal exposure to body
fluids of individuals who are acutely infected with or are chronic carriers of HBV.
The highest viral concentrations are found in the blood and serous fluids.1 In the
Western World, HBV infection is most commonly acquired in adulthood via
percutaneous exposure or sexual contact. In contrast, in endemic areas such as subSaharan Africa and the Far East, HBV infection is most commonly acquired from an
infected mother at birth or during early childhood.
Initial exposure to the virus is followed by an incubation period of 6 weeks to 6
months.1 Most children and about half of all adults who have acute infections are
asymptomatic. A preicteric/prodromal phase lasts approximately 3 to 10 days, from
initial symptoms to onset of jaundice. Symptoms of acute infection are nonspecific
and include nausea/ vomiting, anorexia, fatigue, malaise, pain in the right upper
abdominal quadrant, fever, headache, myalgia, arthralgia, arthritis, skin rash, and
dark urine. The preicteric phase is succeeded by the icteric phase, lasting 1 to 3
weeks. During this phase, patients may have jaundice, light or gray stools, hepatic

tenderness, and hepatomegaly. Malaise and fatigue may last for weeks or months
during convalescence, while other symptoms disappear. Fulminant hepatitis develops
in 1% to 2% of cases and is associated with a mortality rate of 63% to 93%.1
Children who are acutely infected are more likely to develop chronic disease than
those who acquired HBV in adulthood. Chronic infection has been observed to
evolve in up to 90% of infected infants of HBeAg positive mothers, in about 30% of
children infected at <6 years of age, and probably in <5% of infected older children
and adults.2 Viral clearance in the acute phase is most common among those who
mount a vigorous immune response, as characterized by elevated ALT levels and
jaundice, and this is more likely among those who are exposed to HBV in adulthood.
Chronic HBV Infection
When the virus is not cleared in the acute phase and continues to replicate, there is a
potential for clinical disease. Persistence of HBsAg for >6 months, often high serum
HBV DNA > 105 copies/mL (100,000), persistent or intermittent elevations in
ALT/AST levels, and liver biopsy showing chronic hepatitis indicate chronic
infection.
Prognosis of Chronic Hepatitis B
Over time, a minority of patients with chronic infection spontaneously clears the
virus. Although most patients lose HBeAg (up to 80% at 10 years), few (about 5%)
lose HBsAg.6 Patients who remain HBsAg positive are still at risk for reactivation of
viral replication.
Without treatment, chronic active infection can be progressive. About 30% of those
with chronic HBV infection progress to cirrhosis.2 Within 5 years, cirrhosis
progresses to liver failure in about 23% and to HCC in about 6%.7 About 5% to 10%
of chronically infected individuals develop HCC in the absence of cirrhosis.2 Risk
factors for HCC among those with chronic infection include cirrhosis, residence in
an area of high endemicity, older age, male gender, sustained activity of liver
disease, coinfection with hepatitis C virus, HBeAg positivity, high HBV DNA levels,
alcohol abuse, family history of liver cancer, smoking, and aflatoxin exposure.8-10
Some patients also experience an acute flare-up of chronic infection, which can
mimic acute hepatitis. This phenomenon can have serious consequences, particularly
for those with cirrhosis. These flares can be spontaneous, can result from treatment
interruption, can occur with the use of immunosuppressant drugs for any reason, or
can occur following the development of treatment-resistant viral mutations.
Five-year survival is 55% to 84% for those with compensated cirrhosis and 14% for
those with decompensated cirrhosis.11,12 Risk factors for mortality related to HBV
infection include HBeAg positivity, older age, race other than white or black, male
gender, bilirubin 1.5 mg/dL, ascites, and the presence of spider nevi.11,12
Impact of Treatment on Natural History

Although direct evidence from long-term prospective trials is lacking (recently at

hepatitis conferences--DDW, EASL 2005study data has been presented showing
HBV DNA levels were associated with improved outcomes), indirect evidence
supports the belief that treating chronic hepatitis B would favorably impact on the
natural history and improve survival. Viral replication/HBV viremia is associated
with progressive disease; therefore, it is logical that suppression of viral replication
and loss of HBeAg would improve long-term outcomes.
Treatment, however, would have to consider several factors apart from viral
replication, and these include the natural history of liver disease in the various
clinical profiles, the probability of response to therapy in a given situation, the
histologic severity of liver disease, and the cost of the therapy, as these are likely to
influence the risk/benefit ratio. High levels of HBV DNA have been shown in
longitudinal studies to correlate with histologic activity, progression of disease to
cirrhosis, increased risk of HCC, and mortality from liver disease.13-19 In contrast,
inactive carriers with undetectable HBV DNA, normal ALT levels, and loss of
HBeAg rarely show signs of progression or histologic abnormality, as mentioned
above.
Histologic improvement has also been documented in studies of antiviral therapy for
chronic hepatitis B. For example, studies have shown histologic improvement in
53% to 64% of patients treated with adefovir.20,21 In randomized studies, histologic
improvement was observed in 70% to 72% of those treated with entecavir and 61%
to 62% of those treated with lamivudine.22,23 In recent studies, histologic
improvement was reported in 41% to 48% of patients treated with peginterferon alfa2a and 40% to 41% of those treated with lamivudine.24
Dienstag et al25 also provided important evidence of histologic improvement with
treatment in an evaluation of patients on longterm lamivudine. In this study, 63
patients underwent three sets of liver biopsies: one pretreatment, one after 1 year of
lamivudine therapy, and another after an additional 2 years of lamivudine. After 3
years of treatment, necroinflammatory activity was reduced in 56% of patients.
Another third showed no change, and only 11% showed worsening. Those who
developed YMDD variants, which is associated with treatment resistance, were least
likely to improve.
Importantly, bridging fibrosis improved by 1 level in 63% and cirrhosis improved
in 73%. Only 2% progressed to cirrhosis and 9% (all with YMDD variants)
progressed to bridging fibrosis (See Table 1). This important study provides some of
the best available evidence that treatment does affect natural history and can even
reverse fibrosis and cirrhosis in many patients.
In addition to histologic improvement, treatment has also been shown to improve
clinical outcomes. For example, in 23 patients with severely decompensated HBVrelated cirrhosis, lamivudine treatment was associated with clinical response (ie, 3-

point decrease in Child-Turcotte-Pugh score) in 60.9% versus none of 23 historical

controls (P < .0001).
Lamivudine-treated patients also had significantly fewer transplants, experienced
longer time to transplantation, and exhibited a survival advantage.26 One could
assume that similar results will be seen with effective therapy with other agents. One
may also speculate that with the lower incidence of resistance with adefovir and
entecavir, the improvement histologically and clinically may be even better, but time
will tell.

Treatment needs to be tailored for different subgroups of patients in order to

maximize its effect on long-term outcomes. Patients with wild-type HBV (HBeAg
positive patients) can have a durable response to therapy of finite duration with
suppression of HBV DNA and HBeAg seroconversion. In contrast, those with
precore mutant virus have a high rate of relapse after treatment discontinuation and
therefore require indefinite therapy to maximize treatment benefits. The optimal
duration of therapy in patients with cirrhosis is controversial, but Dr. Reddy believes
that treatment should be indefinite for this population as well, since reactivation can
lead to worsening liver function and decompensation.
Case Study
A 46-year-old man presented with complaints of fatigue. Physical examination
showed him to be anicteric with occasional spider angiomata, a liver span of 16 cm,
and no splenomegaly. Laboratory analysis showed ALT 78 IU/L, AST 89 IU/L,
alkaline phosphatase 133 IU/L, albumin 3.6 g/dL, total bilirubin 1.2 mg/dL, INR 1.1,
and platelets 138,000/_L. His viral hepatitis tests indicated that he was positive for
HBsAg and HBeAg, and negative for anti-HBe, anti-HCV [hepatitis C virus], and
anti-delta.
His HBV DNA level was 85,000 copies/mL. Abdominal ultrasound showed no
masses in the liver and no ascites. He had no evidence of encephalopathy or variceal

bleeding. Although there was no evidence of cirrhosis, the patient was worried about
a "missed diagnosis" and requested a liver biopsy, which showed histologic evidence
of cirrhosis. The patients physician recommended treatment with a nucleoside or
nucleotide analog, but he was reluctant due to concerns regarding side effects and
resistance rates with oral agents. The patient returned in 6 months with mild ascites
and requested to be considered for HBV therapy to prevent further progression and
liver transplantation.
Workup showed no evidence of HCC. At that time he was positive for HBeAg and
anti-HBe, and had an HBV DNA level of 94,000 copies/mL. His model for end-stage
liver disease (MELD) score was 9. The patient refused lamivudine due to the risk of
developing early resistance. His physician prescribed adefovir, and his ascites was
well controlled with spironolactone. In a situation such as this, entecavir, the more
recently approved nucleoside analog, would be another option.
Four months later, the patient felt well. His MELD score decreased to 7, and he was
HBV DNA negative by polymerase chain reaction; however, he remained HBeAg
positive. One year later, he continues to feel well and is negative for both HBV DNA
and HBeAg. He is anti-HBe positive and HBsAg positive. He has so far avoided the
need for liver transplantation. His physician recommended that he continue therapy
indefinitely to reduce the long-term risk of decompensation and HCC.
Conclusion
As the case study illustrates, untreated chronic HBV infection can be progressive
with serious clinical consequences. However, treatment has the potential to alter the
natural progression of the disease and, in some cases, reverse even advanced fibrosis
and cirrhosis.

Hepatitis B laboratory tests

Overview
Diagnosis of hepatitis is made by biochemical assessment of liver function. Initial
laboratory evaluation usually reveals: increased bilirubin levels;
increased ALT, AST, alkaline phosphatase and decreased protein. Prothrombin
time may be prolonged in cases of hepatocellular necrosis and hemoglobin may be low.
Initial lymphopenia andneutropenia may be followed
by lymphocytosis. Serologic markers, such as Hepatitis B surface antigen (HBsAg);
anti-HBsAg; anti-HBc IgM and anti-HBc IgG; hepatitis B e antigen and anti-HBeAg
confirm the diagnosis of hepatitis B. These levels fluctuate throughout the course of
the disease.
Laboratory Findings
Diagnosis of hepatitis is made by biochemical assessment of liver function. Initial
laboratory evaluation should include:[1][2]

Total and direct bilirubin (increased)

Severe disease is often associated with persistent bilirubin levels >340 mol/L

ALT and AST (increased)

Alkaline phosphatase (normal or mildly elevated)

Prothrombin time (prolonged from synthetic defect, caused by hepatocellular

necrosis)

Total protein (decreased)

Globulin (mildly elevated)

Complete blood count

Initial lymphopenia and neutropenia, followed by relative lymphocytosis

Low hemoglobin

Diagnosis is confirmed by demonstration in sera of specific antigens and/or antibodies.

Three clinical useful antigen-antibody systems have been identified for hepatitis B:

Hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs)

Antibody (anti-HBc IgM and anti-HBc IgG) to hepatitis B core antigen

(HBcAg)

Hepatitis B e antigen (HBeAg) and antibody to HBeAg (anti-HBe)

Antigens

Description

HBsAg

Hepatitis B surface antigen is the earliest indicator of acute infection

and is also indicative of chronic infection if its presence persists for
more than 6 months. It is useful for the diagnosis of HBV infection
and for screening of blood. Its specific antibody is antiHBs. HBsAg indicates that the person is potentially infectious.

HBcAg

Hepatitis B core antigen is derived from the protein envelope that

encloses the viral DNA, and it is not detectable in the bloodstream.
When HBcAg peptides are expressed on the surface of hepatocytes,
they induce an immune response that is crucial for killing infected
cells. The HBcAg is a marker of the infectious viral material and it is
the most accurate index of viral replication. Its specific antibody is
anti-HBc.

HBeAg

Hepatitis B e antigen appearing during weeks 3 to 6 indicates an acute

active infection at its most infectious period, and means that the
patient is infectious. Persistence of this virological marker beyond 10
weeks shows progression to chronic infection and infectiousness.

Continuous presence of anti-HBe indicates chronic or chronic active

liver disease. HBeAg is not incorporated into virions, but is instead
secreted into the serum. Mutant strains of HBV exist that replicate
without producing HBeAg. HBeAgs function is uncertain. Its
specific antibody is anti-HBe.

HBxAg

Hepatitis B x antigen is detected in HBeAg positive blood in patients

with both acute and chronic hepatitis. HBxAg is a transcriptional
activator. It does not bind toDNA. Its specific antibody is anti-HBx.

HBV DNA

HBV DNA is detectable by PCR as soon as 1 week after initial

infection, but the test is generally only performed for research
purposes or to detect mutants that escape detection by current
methods.

HBV DNA
Polymerase

Tests for the presence of HBV DNA polymerase, detectable within 1

week of initial infection, are only performed for research purposes.

Antibodies Description
This is the specific antibody to hepatitis B surface antigen. Its
appearance 1 to 4 months after onset of symptoms indicates clinical
Anti-HBs
recovery and subsequent immunity to HBV. Anti-HBs can neutralize
HBV and provide protection against HBV infection.
This is the specific antibody to hepatitis B core antigen. Antibodies to
HBc are of class IgM and IgG. They do not neutralize the virus. The
presence of IgM identifies an early acute infection. In the absence
Anti-HBc of HBsAg and anti-HBs, it shows recent infection. IgG with no IgM may
be present in chronic and resolved infections. Anti-HBc testing identifies
all previously infected persons, including HBV carriers, but does not
differentiate carriers and non-carriers.
This is the specific antibody to hepatitis B e antigen. During the acute
stage of infection the seroconversion from e antigen to e antibody
Anti-HBe is prognostic for resolution ofinfection. Its presence in the patients
blood along with anti-HBc and in the absence of HBsAg and anti-HBs
indicates low contagiousness and convalescence.
Anti-HBx

This is the specific antibody to hepatitis B x antigen. It appears when

other virological markers are becoming undetectable.

Serological Markers

Hepatitis B viral antigens and antibodies detectable in the blood following acute
infection.

Hepatitis B viral antigens and antibodies detectable in the blood of a chronically

infected person
Serological markers may vary throughout the course of the disease:[3]

Pre-S1 and pre-S2 antigens are present early in the incubation period. They are
never detected in the absence of HBsAg.

Hepatitis B virions, HBV DNA, DNA polymerase, and HBeAg are then also
detected.

The presence of HBeAg is associated with relatively high infectivity and

severity of disease.

Anti-HBc is the first antibody to appear. Demonstration of anti-HBc

in serum indicates HBV infection, current or past.

IgM anti-HBc is present in high titre during acute infection and usually

disappears within 6 months, although it can persist in some cases of chronic

hepatitis. This test may therefore reliably diagnose acute HBV infection.

IgG anti-HBc generally remains detectable for a lifetime.

Anti-HBe appears after anti-HBc and its presence correlates to a

decreased infectivity. Anti-HBe replaces HBeAg in the resolution of the
disease.

Anti-HBs replaces HBsAg as the acute HBV infection is resolving. Anti-HBs

generally persists for a lifetime in over 80% of patients and indicates
immunity. Acute hepatitis patients who maintain a constant
serum HBsAg concentration, or whose serum HBeAg persists 8 to 10 weeks
after symptoms have resolved, are likely to become carriers and at risk of
developing chronic liver disease.

Diagnostic Studies
The following studies are used to examine pathological specimens for the presence
of HBV-associatedantigens or particles. They provide information about the
relationship between HBV DNA replication and HBV gene expression:

Immunofluorescence studies

In situ hybridization

Immunohistochemistry

Thin-section electron microscopy

PCR
More recently, PCR tests have been developed to detect and measure the amount of
viral nucleic acid in clinical specimens. These tests are called viral loads and are used
to assess a person's infection status and to monitor treatment.[4]
Recommendations for Monitoring Patients with Chronic HBV Infection: AASLD
Practice Guidelines 2009[5]
Class I
"1. HBeAg-positive and HBeAg-negative patients who meet criteria
for chronic hepatitis B should be evaluated for treatment."
Class III
"2. HBeAg-positive patients:

HBeAg-positive patients with persistently normal ALT

should be tested for ALT at 3-6 month intervals. ALT along
with HBV DNA should be tested more often when ALT
levels become elevated. HBeAg status should be checked

every 6-12 months.

Patients who remain HBeAg positive with HBV DNA levels

>20,000 IU/mL after a 3-6 month period of elevated ALT
levels between 1-2 ULN, or who remain HBeAg positive
with HBV DNA levels >20,000 IU/mL and are >40 years
old, should be considered for liver biopsy, and treatment
should be considered if biopsy shows moderate/severe
inammation or signicant brosis. Patients who remain
HBeAg positive with HBV DNA levels >20,000 IU/mL after
a 3-6 month period of elevated ALT levels >2 ULN should
be considered for treatment."

Class III
"3. HBeAg-negative patients:

HBeAg-negative patients with normal ALT and HBV DNA

<2,000 IU/mL should be tested for ALT every 3 months
during the rst year to verify that they are truly in the
"inactive carrier state" and then every 6-12 months.

Tests for HBV DNA and more frequent monitoring should be

performed if ALT or AST increases above the normal limit."

References
1. Jump up Hepatitis B.
2. Jump up Fields, Bernard (2007). Fields virology. Philadelphia: Wolters
Kluwer Health/Lippincott Williams & Wilkins. ISBN 0781760607.
3. Jump up Hepatitis B.
4. Jump up Zoulim F (2006). "New nucleic acid diagnostic tests in viral
hepatitis". Semin. Liver Dis. 26 (4): 30917.doi:10.1055/s-2006-951602. PMID
17051445.
5. Jump up Lok AS, McMahon BJ (June 2004). "[AASLD Practice Guidelines.
Chronic hepatitis B: update of therapeutic guidelines]". Romanian Journal of
Gastroenterology 13 (2): 1504. PMID 15229781. Retrieved on 2012-02-10.