Clinical Care Options Hepatitis B Review Jun 2014

CLINICAL CARE OPTIONS. ACTUALIZACION EN HEPATITIS B. JUNIO 2014..
Hepatitis B Epidemiology, Pathogenesis, Diagnosis, and Natural History
Author: Marc G. Ghany, MD (More Info)
Editors In Chief: Nezam H. Afdhal, MD, FRCPI; Stefan Zeuzem, MD
Last Reviewed: 6/18/14 (What's New)
Global Overview of Hepatitis B Virus

Infection
SUMMARY
More than one third of the worlds population has been exposed to HBV, and more than 240 million
persons are chronically infected
[WHO HBV]
Persons with chronic infection are at risk for the development of complications such as cirrhosis,
hepatic decompensation, and hepatocellular carcinoma
In the US, 2890 cases of acute HBV infection were reported in 2011
[CDC 2011a]
; the true figure is
estimated to be considerably higher
The prevalence of chronic hepatitis B in the US has remained stable for the last 2 decades
It is estimated that 40% to 70% of persons with chronic HBV infection in the US are foreign born
[Kowdley
2012]
Despite the availability of an effective vaccine for hepatitis B virus (HBV), more than one third of the worlds
population has been exposed to HBV, and more than 240 million persons are chronically infected.
HBV]
[WHO
Persons with chronic infection are at risk for the development of complications of chronic hepatitis B such
as cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Chronic hepatitis B accounts for more
than 600,000 deaths from decompensated cirrhosis or hepatocellular carcinoma each year, and cirrhosis is the
12th-leading cause of death worldwide.
[Goldstein 2005; Lavanchy 2004; Lozano 2012]
In the United States, 2890 cases of acute HBV infection were reported in 2011.
[CDC 2011a]
Because many
infections are never reported, however, the estimated number of acute clinical cases may be much higher.
Moreover, because many HBV infections are asymptomatic, the estimated number of actual new infections in
2011 is estimated to have been approximately 18,800 (7400-86,200).
The prevalence of chronic hepatitis B in the United States has remained stable for the last 2 decades. It is
estimated that 40% to 70% of persons with chronic hepatitis B infection in the United States are foreign
born.
[Kowdley 2012]
The Centers for Disease Control and Prevention reported that chronic HBV infection was listed
as the cause of death in 1792 cases in the United States in 2010.
[CDC 2011a]
Click here for a Journal Highlight discussing a study suggesting that mortality in the United States due to liver
diseaserelated complications has been underestimated by the Centers for Disease Control and Prevention
and has been relatively stable for the past 3 decades, not declining.
Keywords: Hepatitis B, Hepatitis B-Epidemiology, Hepatitis B-Pathogenesis and Natural History, Hepatitis BVaccination and Preventiion.
Epidemiology of Hepatitis B Virus: Current

Status and Trends
SUMMARY
HBV prevalence, routes of transmission, and genotype vary widely across geographic regions (Figure
1)
Areas with the highest prevalence ( 8%) are in west sub-Saharan Africa
Areas with high-intermediate prevalence (5% to 7%) include China, southeast Asia, and the
remainder of sub-Saharan Africa
Areas with low-intermediate prevalence (2% to 4%) include the Mediterranean region, India,
the Middle East, Australia, and Japan
Prevalence is lowest (< 2%) in North America and Western Europe
Routes of transmission vary geographically:
In regions of high endemicity, HBV is primarily transmitted vertically (perinatally) or

horizontally (household transmission between family members)
[Stevens 1975]
In regions of intermediate prevalence, multiple modes of transmission are important,

including vertical and horizontal transmission,
[Doganci 2005]
as well as sexual, injection-drug
use, and through medical care
In areas of low endemicity, transmission is mostly via high-risk behaviors such as injectiondrug use and unprotected sexual intercourse
[Alter 1990]
Age at exposure is inversely related to rate of chronicitythe younger an individual is at the time of
infection, the more likely they are to become chronic carriers of HBV
[McMahon 1985]
Hepatitis B Virus Epidemiologic Trends in the United States
The epidemiology of HBV in the US has changed in recent decades due to the introduction
of mandatory immunization, HBV screening in pregnant women, postexposure immunization
in at-risk infants, and changes in behavior
Between 1990 and 2007, the incidence of acute hepatitis B declined 82%, from 8.5
cases per 100,000 population to 1.5 cases per 100,000 population
[Daniels 2009]
and
declined a further 36% between 2007 and 2011 to 0.9 cases per 100,000
population (Figure 2)
[CDC 2013; CDC 2011a]
Acute infection rates are highest among adults, particularly persons 30-39 years of
age
Chronic HBV infection in the US is linked to race, ethnicity, and country of birth, with
prevalence higher in Asians and blacks, followed by non-Hispanic whites
The third NHANES estimated overall prevalence of chronic HBV infection at

approximately 700,000 persons,
[Ioannou 2011]
believed to be a considerable
underestimate (Table 1)
Geographical Distribution of Hepatitis B Virus Genotypes
8 different genotypes of HBV have been recognized and are designated by letters A-H
HBV genotypes differ among different geographic regions (Table 2)
Migration is changing the pattern of genotype distribution, particularly in the US, with an
increase in genotypes from countries with a high prevalence of HBV infection (predominantly
HBV genotypes B and C)
[Chu 2003]
Clinical Significance of Hepatitis B Virus Genotype
HBV genotype influences natural history, clinical outcomes, and response to therapy (Table
2)
Patients infected with genotype B achieve better clinical outcomes than patients
with genotype C
[Kao 2000; Chu 2002; Chu 2005;Chan 2004; Sumi 2003; Yu 2005; Kao 2011]
Patients with genotypes A or B may respond better to peginterferon than those with
genotypes C or D
[Cao 2009]
Genotype D infection has been associated with increased frequency of HBeAgnegative chronic hepatitis B
[Cao 2009; Carman 1989]
Effect of Immunization on Hepatitis B Virus Disease Burden
Immunization programs have reduced the rate of chronic HBV infection and liver cancer in
endemic regions
In 1984, universal newborn immunization and mass population screening and immunization
was introduced in the Alaska Native people,
and chronic HBV rates in the US
[McMahon 2011]
who have the highest rates of acute
[McMahon 1993]
Immunization has significantly reduced the prevalence of markers of HBV infection and
chronic infection among children in the US
[Wasley 2010]
Although hepatitis B virus (HBV) is distributed globally (Figure 1), local prevalence, routes of transmission, and
genotype vary widely across geographic regions. Regions of the world with high HBV prevalence, including
west sub-Saharan Africa with the highest prevalence ( 8%), and regions with high-intermediate prevalence
(5% to 7%)China, Southeast Asia, and the remainder of sub-Saharan Africainclude nearly one half of the
worlds population.
[Ott 2012]
Areas with low-intermediate prevalence (2% to 4%) include the Mediterranean
region, India, the Middle East, Australia, and Japan; another approximately 40% of the worlds population lives
in these regions. The prevalence is lowest (< 2%) in North America and Western Europe.
From 1990-2005, the prevalence of chronic HBV infection decreased in most regions. This was particularly
evident in central sub-Saharan Africa, tropical and Central America, southeast Asia, and central Europe.
2012]
[Ott
Immigration from countries with high and intermediate prevalence of chronic hepatitis B, constituting close
to 90% of the worlds population, represents a major source of imported chronic hepatitis into the United
States. It was estimated that during 2004-2008, 95% of new cases of chronic hepatitis B in the United States
were imported.
[Mitchell 2011]
Figure 1. Worldwide prevalence of chronic hepatitis B in adults aged 1949 years in 2005.[Ott 2012]
Routes of transmission vary by geographic prevalence. In regions of high endemicity, HBV is primarily
transmitted vertically (perinatally) or horizontally (household transmission from one family member to
another).
[Stevens 1975]
In regions of intermediate prevalence, multiple modes of transmission are important,
including vertical and horizontal transmission,
[Doganci 2005]
as well as sexual, injection drug use, and through
medical care. Conversely, in areas of low endemicity, transmission is mostly percutaneous, occurring primarily
in late adolescence or young adulthood via high-risk behaviors such as injection drug use and unprotected
[Alter 1990]
sexual intercourse.
The infection of younger individuals in high-endemic areas contributes to, and maintains, the reservoir of
chronically infected persons. Moreover, age at exposure is inversely related to rate of chronicitythe younger
an individual is at the time of infection, the more likely they are to become chronic carriers of hepatitis B.
1985]
Hepatitis B Virus Epidemiologic Trends in the United States
[McMahon
The epidemiology of acute and chronic hepatitis B in the United States has changed in the past 2 decades,
largely due to the introduction of a mandatory immunization program in 1992, the prevention of perinatal HBV
infection by screening all pregnant women, provision of postexposure immunization to at-risk infants of
chronically infected mothers, routine vaccination of adolescents and vaccination of adolescents and adults in
groups at increased risk of infection, behavioral changes in response to the HIV epidemic, and the introduction
of universal precautions to limit nosocomial and occupational exposure.
[Wasley 2008]
Overall, between 1990 and 2007, the incidence of acute hepatitis B in the United States declined 82%, from
8.5 cases per 100,000 population to 1.5 cases per 100,000 population
[Daniels 2009]
between 2007 and 2011 to 0.9 cases per 100,000 population (Figure 2).
with a further 36% decline
[CDC 2013; CDC 2011a]
During that time, the
incidence declined among all age groups, but the reduction was most pronounced among children younger
than 15 years of age, highlighting the significant impact of the mandatory immunization program. Native
Alaskan people, who had a prevalence of hepatitis B infection > 6% overall in the 1970s,
[Schreeder 1983]
have seen
a remarkable decline in hepatitis B virus (HBV) infection. Indeed, among children younger than 20 years of
age, the number of HBV-positive individuals declined from 657 in 1987 to 2 in 2008.
[McMahon 2011]
In the United
States, rates remain highest among adults, particularly among those 30-39 years of age who had an incidence
of 2.0 cases per 100,000 population in 2011.
[CDC 2013]
Figure 2. Annual US incidence of acute hepatitis B from 1980-2011.[CDC 2011a]
The most important epidemiologic correlates of chronic HBV infection in the United States are race, ethnicity,
and country of birth. As noted earlier, immigration from countries with high and intermediate prevalence of
chronic hepatitis B represents a major source of imported chronic hepatitis into the United States. It was
estimated that during 2004-2008, 95% of new cases of chronic hepatitis B in the United States were
imported.
[Mitchell 2011]
In an analysis of the third National Health and Nutrition Examination Survey (NHANES),
the overall prevalence of chronic HBV infection among persons 6 years of age and older was 0.27%,
[Ioannou 2011]
corresponding to approximately 700,000 persons nationwide.
The prevalence was highest among
persons of other races (presumably Asian race/ethnicity), followed by blacks and non-Hispanic whites, and
was lowest in Hispanics.
[Ioannou 2011]
The prevalence of chronic HBV infection was higher in men vs women and
increased with age, peaking between the ages of 50-59 years.
[Ioannou 2011]
However, high-risk groups, such as recent Asian immigrants, undocumented immigrants, institutionalized,
[IOM 2010; Cohen 2008]
incarcerated, military, and homeless persons were underrepresented in the NHANES survey
Table 1 shows the estimated prevalence of hepatitis B in some of these populations. Some estimates suggest
that this survey may not account for anywhere from 800,000 to as many as 1.32 million persons with chronic
HBV infection.
[Cohen 2008; Kowdley 2012]
Including these individuals would increase the estimated prevalence of
chronic hepatitis B in the United States to more than 2 million people.
Table 1. Estimated Prevalence of HBsAg-Positive Persons in the United

States by Population Segment[Weinbaum 2008; Cohen 2008]
Population Group
Chronic Hepatitis B Prevalence, %
US-born Asian-Pacific Islander
1.40
Foreign-born Asian-Pacific Islander
8.90
NonAsian Americans
0.42
Correctional institutions
2.00
Other group living quarters
0.50
Geographical Distribution of Hepatitis B Virus Genotypes

Eight different genotypes of hepatitis B virus (HBV), designated by the letters A through H, have been
recognized based on a sequence divergence of 8% of the complete genome among isolates.
[Kao 2011]
HBV
genotypes differ among different geographic regions and mirror the pattern of human migration (Table
2).
[Miyakawa 2003]
Increased global migration is changing the pattern of genotype distribution, particularly in the
United States, with an increase in genotypes from countries with a high prevalence of HBV infection
(predominantly HBV genotypes B and C).
[Chu 2003]
Table 2. HBV Genotypes: Geographic Distribution and Clinical

Significance[Kao 2011; Lok 2009]
Genotype Geographic Distribution
Clinical Significance
United States, sub-Saharan

Africa, northern Europe,
western Europe
Better response to interferon and

peginterferon vs all other genotypes
Japan, China, Indonesia,

Vietnam, Taiwan,
Philippines, Alaska, northern
Canada, Greenland
Lower disease activity, younger age at

HBeAg seroconversion, lower risk of
hepatocellular carcinoma, and better response
to peginterferon therapy compared with
genotype C
Korea, China, Taiwan, Japan,

Polynesia, Southeast Asia,
Australia, Philippines,
Vietnam
More severe disease and worse clinical

outcome, including a higher risk of
hepatocellular carcinoma
Mediterranean, Europe,
Africa, India
Associated with precore mutation
West Africa
Unknown
Central and South America
Unknown
United States, France,

Germany
Unknown
Central America
Unknown
Clinical Significance of Hepatitis B Virus Genotype

Numerous studies have reported differences in the natural history, clinical outcomes, and responses to therapy
based on hepatitis B virus (HBV) genotype (Table 2).
2011; Shiffman 2004; Heathcote 2011]
[Cao 2009; Kao 2000; Chu 2002; Chu 2005; Chan 2004; Sumi 2003; Yu 2005; Kao
Indeed, data show that patients infected with genotype B achieve better clinical
outcomes than patients infected with genotype C, including lower disease activity, a younger age at hepatitis B
e antigen (HBeAg) seroconversion (reflecting less active and lower risk for progressive liver disease), a higher
chance of sustained remission after HBeAg seroconversion, and a reduced risk of hepatocellular
carcinoma.
[Kao 2000; Chu 2002; Chu 2005; Chan 2004; Sumi 2003; Yu 2005; Kao 2011]
In addition, patients infected with HBV
genotypes A and B have been shown to have higher rates of HBeAg seroconversion when treated with
peginterferon vs patients with HBV genotypes C and D.
[Cao 2009]
HBV genotype does not appear to be
associated with hepatitis B e antigen seroconversion among patients treated with nucleos(t)ide
analogues.
[Westland 2003]
Finally, genotype D has been correlated with the precore mutation leading to HBeAg-
negative chronic hepatitis B.
[Cao 2009; Carman 1989]
Effect of Immunization on Hepatitis B Virus Disease Burden

The introduction of immunization programs in endemic regions has had a profound impact on the hepatitis B
virus (HBV) carrier rate and on the incidence of hepatocellular carcinoma (HCC). Taiwan was the first country
to introduce universal immunization against HBV in 1984.
estimated to be 15% to 20%.
[Hsu 1999]
[Ni 2010]
Before vaccination, the carrier rate was
In 2004, the seropositive rates for hepatitis B surface antigen (HBsAg),
antibody to HBsAg, and antibody to hepatitis B core antigen were 1.2%, 50.5%, and 3.7%, respectively, in
those born after the vaccination program.
[Ni 2010]
In addition, 2 decades after the introduction of the vaccination
program, the seroprevalence of HBsAg in children declined from 9.8% to 0.6%.
[Ni 2010]
The incidence of HCC in
children (6-9 years of age) decreased 4-fold from 1981-1994, from 0.52/100,000 for those born between 1974
and 1984 to 0.13/100,000 for those born between 1984 and 1986.
[Ni 2010]
A more recent report evaluating
outcomes 30 years after the vaccination program was introduced revealed a > 90% reduction in infant
fulminant hepatitis mortality from 1977-1980 to 2009-2011.
[Chiang 2013]
Likewise, age- and sex-adjusted rate
ratios for chronic liver disease and hepatocellular carcinoma mortality decreased by > 90% between 19771980 and 2001-2004 among persons aged 5-29 years. Similar results have been reported from other endemic
regions.
[Poovorawan 2009;Sangfelt 1995; Whittle 1995]
In 1984, a universal newborn immunization and mass population screening immunization program was initiated
in the Alaska Native people,
United States.
[McMahon 1993]
[McMahon 2011]
who have the highest rates of acute and chronic HBV rates in the
In this successful program, the incidence of acute symptomatic HBV infection in
persons younger than 20 years of age fell from 19/100,000 cases in 1981-1982 to 0 cases in 1993-1994, with
no new cases of acute HBV in children since 1992.
[McMahon 2011]
The incidence of HCC in persons younger than
20 years of age decreased from 3/100,000 in 1984-1988 to 0 in 1995-1999 and no cases thereafter.
2011]
[McMahon
Moreover, the number of identified HBsAg-positive children younger than 20 years of age in the Alaska
Native population declined from 657 in 1987 to 2 in 2008.
[McMahon 2011]
In addition, data from the National Health
and Nutrition Examination Survey conducted a decade after the introduction of the mandatory vaccination
program in the United States indicates a significant 68% reduction in the prevalence of markers of hepatitis B
infection and chronic infection among children born in the United States or elsewhere.
[Wasley 2010]
In 2005, the World Health Organization set forth an HBV control goal of reducing the seroprevalence of HBsAg
to less than 2% in children 5 years of age by 2012.
[WHO 2005]
As of July 2011, 179 countries reported that they
had included the hepatitis B vaccine into their national infant immunization programs.
Keywords: Hepatitis B, Hepatitis B-Epidemiology
[WHO 2011]
DR. CARLOS RODOLFO MEJIA VILLATORO
MY SUBSCRIPTIONS
QUICK TOUR
MY CE
MY FOLDER
LOGOUT
Specialty
Decision Tools
Drug Reference
Guidelines
PubMed
Trials
More
XGO
Specialty
Hepatology
HBV Epidemiology
Summary
Global Overview
Epidemiology: Current Status and Trends
US Epidemiologic Trends
Geographical Distribution of Genotypes
Genotype Clinical Significance
Effect of Immunization on HBV Disease Burden
Routes of HCV Transmission
Transmission Through Transfusion
Vertical Transmission
Horizontal Transmission
Sexual Transmission
Percutaneous Transmission
Transmission in Special Settings
Nosocomial Transmission
Organ Transplantation
Vaccination
Pre- and Postvaccination Testing
Postexposure Prophylaxis
Vaccine Booster
Vaccine Nonresponders
Pathogenesis
Natural History
Primary Infection and Acute Hepatitis
Video Insight: Prevention and Management of HBV Reactivation
Chronic Hepatitis and Its Sequelae
HBeAg-Positive Immune-Tolerant Chronic Hepatitis B
HBeAg-Positive Active Chronic Hepatitis B
Inactive HBsAg Carrier State
HBeAg-Negative Active Chronic Hepatitis B
Screening and Diagnosis
Overview
Serology
HBsAg and Anti-HBs
Anti-HBc
HBeAg and Anti-HBe
HBV DNA Assays
Diagnostic Algorithm
The Role of Liver Histology
Primary Care Essentials
Supporting Assets
References
Jointly Provided by USF Health and inPractice Resources, LLC
more information about our sponsors
Officially Endorsed By
Previous
Next
Save
Share
Print
Email
Editors In Chief: Nezam H. Afdhal, MD, FRCPI; Stefan

Zeuzem, MD
Routes of Hepatitis B Virus Transmission

SUMMARY
HBV is transmitted primarily by infected blood and

body fluids
Perinatal, percutaneous, and sexual transmission

account for most acute and chronic HBV cases
worldwide
[Mast 2005; Mast 2006]
Viral titers are highest in blood and serum;

intermediate in semen, vaginal fluid, and saliva; and
lowest in urine, feces, and breast milk
[Bancroft 1977; Alter
1977; Beasley 1975]
Transmission Through Transfusion of Blood or

Blood Products
The introduction of screening for HBsAg

and anti-HBc has virtually eliminated the
transmission of HBV through transfusion in
the US and developed world
Nucleic acid testing has been introduced

more recently, which identifies blood
donors who are HBV DNA positive but do
not yet have detectable HBsAg
This technique has further reduced the

estimated risk of HBV infection from blood
transfusion in the US to 1 in 830,0002,000,000 donations
[DHHS 2009]
Vertical Transmission of Hepatitis B Virus
HBV acquisition occurs in 70% to 90% of

infants born to HBeAg-positive mothers
with high HBV DNA levels (> 7.3
log10 IU/mL) at delivery
[Stevens 1975]
Transmission usually occurs at delivery

when the infant is exposed to maternal
blood; intrauterine transmission is
uncommon
[Zhu 2010]
Passive-active immunization at birth

significantly reduces (~ 95%) the rate of
perinatal transmission
[Mast 2005]
Failure of active-passive
immunization is more likely in
HBeAg-positive women with high
[Song
HBV DNA (> 7.3 log10 IU/mL)
2007;Singh 2011; Wiseman 2009; Shao 2011]
Use of nucleos(t)ide analogues in the third

trimester of pregnancy, with
immunoprophylaxis, may further reduce
perinatal transmission rates compared with
immunoprophylaxis alone, particularly in
mothers with high HBV DNA levels (> 7.3
[Xu 2009; Han 2011;Pan 2012]
log10 IU/mL)
Risk of transmission appears

negligible if maternal HBV DNA
level is < 6.3 log10 IU/mL
The drug with the most accumulated

experience and safety data during
pregnancy is lamivudine, rated pregnancy
category C,
althoughtelbivudine and tenofovir have also
been used in this setting and are rated
pregnancy category B
[Antiretroviral Pregnancy
Registry]
Vertical transmission is not an

approved indication for starting
HBV therapy; risk to the infant

should be balanced against
possible maternal HBV flares
following therapy discontinuation
Use of antiviral prophylaxis may

be best reserved for women with
high HBV DNA levels (>
8
10 IU/mL)
If used, treatment should

be initiated in the third
trimester, preferably 6-8
weeks before delivery
Therapy should be
continued for
approximately 4 weeks
after delivery
Mothers should be
monitored for an increase
in disease activity
following withdrawal of
antiviral therapy
Cesarean section has not been shown to

affect the rate of perinatal HBV
transmission
[Wang 2002]
Horizontal transmission refers to

transmission of HBV from person to
person, usually in the same age group
HBV-infected persons should be counseled

on precautions they should take to prevent
transmission (Table 3)
Sexual Transmission
[Lok 2009]
Sexual transmission is the major route of

HBV transmission in the US and Western
Europe
Sexual transmission accounts for

approximately 38% of acute HBV infections
in the US; 25% are estimated to occur via
sex between men
[Wasley 2008]
Risk of sexual transmission is related to

number of lifetime sexual partners, use of
paid sex, and a history of sexually
transmitted diseases
[Mast 2006]
Sexual partners of HBV-infected persons

should be vaccinated or advised to use
barrier protection (Table 3)
[Mast 2005; Lok 2009]
Estimates of the global prevalence of

HBsAg in injection-drug users range from
5% to 10%
[Nelson 2011]
Risk of HBV infection increases with the

number of years of drug use, with
frequency of injection, and with sharing of
drug-preparation equipment
[Hagan 1999; Bialek
2005]
HBV vaccination of injection-drug users is

recommended
[Mast 2006]
Hepatitis B Virus Transmission in Special

Settings
Transmission of HBV in hospital

settings may occur from patient to
patient, patient to healthcare
personnel via contaminated
instruments or accidental
needlestick, and, rarely, from

healthcare personnel to
patient
[Thompson 2009]
Healthcare professionals are

strongly advised to receive
immunization against HBV
Transmission of HBV has been

reported after transplantation of
solid organs such as kidneys and
livers
[Dickson 1997]
The CDC recommends screening

all potential organ donors for highrisk behavior and testing for
HBsAg prior to donation
[CDC 2011b]
Persons testing HBsAg

positive should not
donate organs (Table
3)
[Lok 2009]
Antiviral therapy should be

administered to recipients of
organs from people who are antiHBc positive
[Lok 2009]
6-12 months of therapy is

sufficient for people
receiving non-hepatic
transplants; lifelong
therapy is recommended
for those receiving liver
transplants
Hepatitis B Vaccination
Five vaccines are licensed in the US for

hepatitis B vaccination
[Mast 2005; Mast 2006]
Hepatitis B immune globulin contains antiHBs and provides temporary protection (for
~ 3-6 months); used with hepatitis B
vaccine for postexposure
immunoprophylaxis
The CDC recommends the following

groups for vaccination
[CDC 2012]
All newborns
Children and adolescents through

18 years of age who did not
receive the vaccination earlier
Adults at risk for HBV infection
Anyone who wants to be protected

against HBV
The hepatitis B pediatric

vaccine and hepatitis B immune
globulin should be administered to the
neonate of an HBsAg-positive mother
within 12 hours of birth
[Mast 2005]
The vaccine schedule after birth

and for other age groups is shown
in Table 4
The CDC recommends testing the

following groups for HBV infection
or immunity prior to HBV
vaccination
[CDC 2011c; CDC 2008b]
Hemodialysis patients
Pregnant women
Individuals with known or

suspected HBV
exposure, including:
Infants born to
HBV-infected
mothers
Household
contacts of
persons infected
with HBV
Individuals with
known
occupational or
other exposures
to infectious
blood or body
fluids
Foreign-born persons
from countries with high
HBV endemicity (HBsAg
prevalence > 2%)
US-born persons not

vaccinated as infants
whose parents were born
in regions with high HBV
endemicity (> 8%)
Individuals who are HIV

positive
Injection-drug users
Men who have sex with

men
Persons needing
immunosuppressive
therapy, including
chemotherapy,
immunosuppression
related to organ
transplantation, and
immunosuppression for
rheumatologic or
gastroenterologic
disorders
Persons with elevated

transaminases of
unknown etiology
Donors of blood, plasma,

organs, tissues, or
semen
Household, needlesharing, or sex contacts

of persons known to be
HBsAg positive
Postvaccination testing for

immunity is recommended only for
individuals whose clinical
management will depend on their
immune status
If needed,
postvaccination testing
for anti-HBs should be
conducted 1-2 months
following completion of
the vaccine series
Postvaccination testing of
infants born to HBsAgpositive mothers should
not be conducted within 4
weeks of the latest
vaccine dose or before 9
months of age
Follow-up management for

healthcare personnel who have
recently received complete HBV
vaccination series varies based on
postvaccination immune
[CDC HCP HBV Prevention]
response
Guidelines for postexposure

prophylaxis for adults with
occupational (Management
Guidelines)
and
nonoccupational (Management
Guidelines)
[Mast 2006]
exposures to
HBV are available
Postexposure prophylaxis is
recommended for anyone who is
exposed to HBV and is considered
susceptible to HBV infection
The effectiveness of
prophylaxis is dependent
on early administration of
the initial dose of vaccine
and diminishes with time
after exposure
[Mast 2006]
Ideally, persons without

contraindication to HBV
vaccination should
receive the first dose
within 24 hours and not
later than 7 days
following exposure
Hepatitis B Virus Vaccine Booster
The CDC recommend that booster

doses of the HBV vaccine be
administered to hemodialysis
patients and other
immunocompromised
individuals
[CDC 2011c]
Booster doses not recommended

for persons with normal immune
status
Hepatitis B Virus Vaccine

Nonresponders
Approximately 5% to 15% of
healthy individuals fail to respond
to the 3-dose HBV vaccine
series
[CDC 1991]
People with anti-HBs levels < 10

mIU/mL following the primary HBV
vaccine series should be
revaccinated with 3 doses
according to the appropriate
schedule and retested after the
third dose (Table 4)
Individuals with anti-HBs levels <

10 mIU/mL following revaccination
should be tested for HBsAg
Those who test negative

should be counseled on
preventive measures
Hepatitis B virus (HBV) is transmitted primarily by infected blood and body fluids. Perinatal, percutaneous, and
sexual transmission account for the majority of cases of acute and chronic HBV infection worldwide.
2005; Mast 2006]
[Mast
Viral titers are highest in blood and serum; they are intermediate in semen, vaginal fluid, and
saliva; and they are lowest in urine, feces, and breast milk.
[Bancroft 1977; Alter 1977; Beasley 1975]
Transmission Through Transfusion of Blood or Blood Products

Prior to the introduction of screening, the risk of transmitting hepatitis B virus (HBV) infection through
transfusion was as high as 50%.
the 1970s
[Schreiber 1996]
[MMWR 1991]
The introduction of hepatitis B surface antigen (HBsAg) screening in
and screening for anti-HBc in 1986 (to detect HBsAg negative, anti-HBc positive units
that were possibly infectious) has virtually eliminated the transmission of HBV through transfusion. After the
introduction of anti-HBc screening, the estimated risk of HBV infection from donations to the American Red
Cross was 1 in 280,000 to 1 in 357,000 donations.
[Zou 2009]
More recently, nucleic acid testing has been introduced, which identifies blood donors who are HBV DNA
positive but do not yet have detectable HBsAg. The technique, which uses a strategy of screening minipools of
6 -16 donations, has further reduced the estimated risk of HBV infection from blood transfusion to 1 in 830,0002,000,000 donations.
[DHHS 2009]
In a study highlighting the success of this strategy, 9 out of 3.7 million donations
tested positive for HBV DNA (1 in 410,540 donations), of which 6 samples were from vaccinated donors in
whom subclinical infection had developed and resolved.
[Stramer 2011]
Whether these units would have been
infectious is unknown.
Vertical Transmission of Hepatitis B Virus

Vertical (perinatal) transmission refers to the transmission of hepatitis B virus (HBV) from mother to infant
immediately before or after birth. Also called mother-to-infant transmission or perinatal transmission, vertical
transmission is very efficient and the most important mode of HBV transmission in highly endemic areas.
1975; Schweitzer 1972]
[Stevens
Among infants born to hepatitis B e antigen (HBeAg)positive mothers with high HBV DNA
levels (> 7.3 log10 IU/mL) at the time of delivery, 70% to 90% acquire HBV infection.
[Stevens 1975]
Transmission from mother to infant usually occurs at the time of delivery when the infant is exposed to
maternal blood; intrauterine transmission is uncommon.
[Zhu 2010]
Passive-active immunization at birth is
associated with a significant reduction (~ 95%) in the rate of perinatal transmission(Management

Guidelines).
[Mast 2005]
However, there is a 10% to 15% failure rate of this strategy; most failures of active[Song
passive immunizations occurred in HBeAg-positive women with high HBV DNA (> 7.3 log10 IU/mL).
2007; Singh 2011; Wiseman 2009; Shao 2011]
Several studies have reported that the use of nucleoside analogues in the third trimester of pregnancy together
with immunoprophylaxis may further reduce perinatal transmission rates over immunoprophylaxis alone. In one
study, lamivudine administered late in pregnancy reduced rates of HBsAg seropositivity over active-passive
immunization alone from 39% to 18% in women with serum HBV DNA levels > 1000 MEq/mL,
or approximately 8.3 log10 IU/mL.
[Xu 2009]
Similarly, telbivudine treatment administered at Weeks 20-32 of
gestation reduced perinatal transmission rates from 8% to 0% (P = .002) in women with HBeAg-positive HBV
7
and an HBV DNA level > 10 copies/mL, or approximately 6.3 log10 IU/mL.
[Han 2011]
Another study reported
that telbivudine administered for an average of 15 weeks at the end of pregnancy plus active-passive
immunization to neonates reduced vertical transmission rates to 0% compared with 8.6% in neonates who
received immunization alone.
[Pan 2012]
Tenofovir DF has also been evaluated in this setting.
[Celen 2013]
multicenter observational study compared outcomes among pregnant women with HBV DNA levels > 7 log
IU/mL who were treated with lamivudine 100 mg/day (n = 52; 2007-2010), tenofovir DF 300 mg/day (n = 58;
starting late 2010), or no antiviral therapy (n = 20) in addition to the use of passive active HBV
immunoprophylaxis for all infants.
[Greenup 2014]
Antiviral treatment was initiated at 32 weeks of gestation.
Perinatal HBV transmission rates were lower with antiviral therapy, at 0% withlamivudine and 2%
with tenofovir compared with 20% without antiviral treatment. Among women initially treated with tenofovir, 4
switched tolamivudine because of intolerance after < 1 week of treatment.
These studies also suggest that the transmission rate is negligible once the HBV DNA level is below 6.3
log10 IU/mL. Although any of the approved nucleoside analogues could be used in the third trimester of
pregnancy, lamivudine, telbivudine, and tenofovir are the most reasonable first choices because of experience
with the first and Category B classification for use in pregnancy with the later 2. The drug with the largest
experience in pregnancy is lamivudine. In vivo safety data on antiviral agents during pregnancy (any trimester)
from the Antiretroviral Pregnancy Registry reported birth defects in 3.1% (136 from 4360 live births) of women
receiving lamivudine and 2.3% (46 from 1982 live births) of women receiving tenofovir; these rates are similar
to those observed in normal pregnancy.
[Antiretroviral Pregnancy Registry]
It should be noted, however, that prevention of vertical transmission is not an approved indication for starting
HBV therapy, and prophylaxis is the best method to prevent mother-to-child transmission.
[Tran 2009]
This is
largely because of concerns of the long-term safety to the infant and reactivation of hepatitis after withdrawal of
antiviral agent in the mother.
[ter Borg 2008]
Thus, until further data become available, antiviral therapy to prevent

6
perinatal transmission should only be considered in women with high HBV DNA levels (> 10 copies/mL or ~
5.3 log10 IU/mL) (B).
[Wong 2014]
Treatment should be initiated in the third trimester, preferably 6-8 weeks before
delivery to allow sufficient time for the viral level to decline. Therapy should be continued for approximately 4
weeks after delivery. Mothers should be monitored for an increase in disease activity following withdrawal of
antiviral therapy. Cesarean section has not been shown to affect the rate of perinatal transmission and should
not be performed if HBV infection is the only indication for doing so.
[Wang 2002]
For additional information from inPractice on the management of HBV infection during pregnancy, click here.
Horizontal transmission refers to transmission of hepatitis B virus (HBV) from person to person, usually in the
same age group. In sub-Saharan Africa, horizontal transmission is a major route of transmission among
[Martinson 1998]
children.
This may result from contact with blood from scrapes, breaks in mucous membranes, or
interfamilial contact. To prevent horizontal transmission, HBV-infected persons should be counseled on

precautions they should take to prevent transmission. These include covering open cuts and scratches,
cleaning blood spills with detergent or bleach, and not sharing toothbrushes or razors (Table 3) (Management
Guidelines) (B).
[Lok 2009]
Table 3. Recommendations for Preventing Transmission of HBV[Lok 2009]

Hepatitis B surface antigenpositive patients should take the following precautions:
Have sexual contacts vaccinated

Use barrier protection during sexual intercourse if partner is not vaccinated or
naturally immune
Do not share toothbrushes or razors
Cover open cuts and scratches
Clean blood spills with detergent or bleach
Do not donate blood, organs, or sperm
Sexual Transmission
Sexual transmission is the major route of hepatitis B virus (HBV) transmission in the United States and
Western Europe, as well as other geographic areas where the prevalence of HBV infection is low.
1990]
[Alter
Indeed, sexual transmission accounts for approximately 38% of cases of acute HBV infection in the United
States, and 25% are estimated to occur among men who have sex with men.
[Wasley 2008]
The risk of sexual
transmission is directly related to number of lifetime sexual partners, use of paid sex, and a previous history of
sexually transmitted diseases(Management Guidelines).
[Mast 2006]
To prevent HBV transmission through sexual contact, steady sexual partners of HBV-infected persons should
be vaccinated (Table 3)(Management Guidelines) (C).
[Mast 2005]
To prevent transmission to persons who are not
vaccinated, including casual sexual partners, barrier protection is recommended (Management Guidelines).
[Lok
2009]
Percutaneous transmission is an important mode of transmission among injection drug users. Estimates of the
global prevalence of hepatitis B surface antigen (HBsAg) in injection drug users range from 5% to 10%.
2011]
[Nelson
Worldwide, it is estimated that 1.2 million injection drug users (range: 0.3 million-2.7 million) are HBsAg-
positive.
[Nelson 2011]
The risk for acquiring hepatitis B virus infection has been found to increase with the number
of years of drug use, with the frequency of injection, and with sharing of drug-preparation equipment.
1999; Bialek 2005]
Vaccination of all patients at high risk, including injection drug users, is
recommended (Management Guidelines) (C).
[Mast 2006]
[Hagan
Hepatitis B Virus Transmission in Special Settings

In the hospital setting, transmission of hepatitis B virus (HBV) generally occurs from patient to patient, patient
to healthcare personnel via contaminated instruments or accidental needlestick, and, rarely, from healthcare
personnel to patient due to tears in safety gloves, suturing accidents, or through use of contaminated multiuse
vials.
[Thompson 2009]
The risk of acquiring HBV infection after an accidental needlestick is related to the degree of
contact with blood and the hepatitis B e antigen (HBeAg) status of the source patient. The risk for clinical
hepatitis if the source patient is HBeAg-positive is 22% to 31% vs 1% to 6% if the source patient is HBeAgnegative (Management Guidelines).
[Mast 2006]
Therefore, healthcare professionals are strongly advised to receive
immunization against HBV (Management Guidelines).
A number of cases of acute hepatitis B that occurred outside of the hospital setting but were related to the use
of medical devices were reported to the US Centers of Disease Control and Prevention in 2012. Specifically,
these cases were due to improper use of blood glucosemonitoring devices in assisted living facilities.
2012]
[McIntosh
These cases serve to highlight the need for a comprehensive strategy to prevent HBV transmission in
assisted living facilities, including vaccination, improved infection control oversight, and appropriate training of
staff members performing assisted monitoring of blood glucose.
Transmission of hepatitis B virus (HBV) has been reported after transplantation of solid organs such as kidneys
and livers.
[Dickson 1997]
The Centers for Disease Control and Prevention recommends screening all potential
organ donors for high-risk behavior and testing for hepatitis B surface antigen (HBsAg) prior to
donation (Management Guidelines) (B).
[CDC 2011c]
To prevent transmission, persons testing HBsAg-positive
should not donate organs (Table 3) (Management Guidelines).
[Lok 2009]
There is some uncertainty about the role
of anti-HBc screening prior to organ donations because of false-positive results leading to loss of donors and
uncertainties regarding the true infectivity of anti-HBc positive donors. The risk of HBV transmission following
renal transplantation using a donor with isolated anti-HBc is low (0% to 2%),
[CDC 2011c; Ouseph 2010]
0% to 78% in liver transplantation, depending on the HBV serologic status of the recipient.
but ranges from
[Dickson 1997; Prieto 2001]
an organ of an anti-HBc-positive person is used, antiviral therapy should be administered to the recipient to
prevent HBV infection (C).
[Lok 2009]
Available data suggest that 6-12 months of therapy is sufficient for person
receiving non-hepatic transplants, while lifelong therapy is recommended for persons receiving liver
transplants.
[Lok 2009]
If
Five vaccines are licensed in the United States for hepatitis B vaccination2 of which are available as singleantigen formulations (available as either the hepatitis B adult vaccine and the hepatitis B pediatric vaccine) and
3 that are available as combinations (hepatitis A hepatitis B vaccine,haemophilus b hepatitis B vaccine, and
diphtheria/tetanus/pertussis (DTaP)) according to 2005 (Management Guidelines)
2006(Management Guidelines)
[Mast 2006]
[Mast 2005]
and
guidelines from the Centers for Disease Control and Prevention. All of
the vaccines use the hepatitis B surface antigen (HBsAg) to generate immunity against hepatitis B virus
(HBV). Hepatitis B immune globulin, which contains anti-HBs, provides temporary protection (for ~ 3-6 months)
and is used in addition to the hepatitis B vaccine for postexposure immunoprophylaxis to prevent HBV
infection.
[Mast 2005; Mast 2006]
The Centers for Disease Control and Prevention recommends the following groups for vaccination (C)
[CDC 2012]
All newborns
Children and adolescents through 18 years of age who did
not receive the vaccination earlier
Anyone who wants to be protected against HBV
The hepatitis B pediatric vaccine and hepatitis B immune globulin should be administered to the neonate of an
HBsAg-positive mother within 12 hours of birth, as efficacy of the vaccine declines with time after birth.
2005]
[Mast
The vaccine schedule after birth and for other age groups is shown in Table 4.
Table 4. Hepatitis B Vaccine Schedules for Children, Adolescents, and

Adults*[Mast 2005]
Age
Children (1-10 yrs)
Schedule
0, 1, and 6 mos
0, 1, and 4 mos
0, 1, 2, and 12 mos
Adolescents (11-19 yrs)
0, 1, and 6 mos
0, 1, and 4 mos
0, 2, and 4 mos
0, 12, and 24 mos
0 and 4-6 mos
0, 1, 2, and 12 mos
Adults ( 20 yrs)
0, 1, and 6 mos
0, 1, and 4 mos
0, 2, and 4 mos
0, 1, 2, and 12 mos
*Children, adolescents, and adults may be vaccinated according to any of the schedules indicated, except as
noted. Selection of a schedule should consider the need to optimize compliance with vaccination.
Pediatric/adolescent formulation.
A 2-dose schedule of Recombivax-HB adult formulation (10 g) is licensed for adolescents aged 11-15 years.
When scheduled to receive the second dose, adolescents aged older than 15 years should be switched to a 3dose series, with doses 2 and 3 consisting of the pediatric formulation administered on an appropriate
schedule.
A 4-dose schedule of Engerix B is licensed for all age groups.
Adult formulation.
Hepatitis A-hepatitis B vaccine may be administered to persons aged older than 18 years at 0, 1, and 6
months.

The US Centers for Disease Control and Prevention (CDC) currently recommend that certain groups be tested
for hepatitis B virus (HBV) infection or immunity using serologic assays for HBsAg and anti-HBs before being
vaccinated for HBV (B).
[CDC 2011b; CDC 2008b]
The reason for this recommendation is to identify chronic infection in
high-risk groups who may benefit from therapy. These groups include the following persons:
Pregnant women
Individuals with known or suspected HBV exposure,

including:
Infants born to HBV-infected mothers
Household contacts of persons infected with HBV
Individuals with known occupational or other exposures to

infectious blood or body fluids
Foreign-born persons from countries with high HBV

endemicity
Individuals who are HIV positive
A 2013 update of CDC guidelines for evaluating healthcare workers for HBV protection recommends that the
following groups of healthcare personnel receive prevaccination serologic testing for HBV
infection (Management Guidelines) (B)
Persons born in geographic regions with moderate or high

HBV endemicity
Certain indigenous populations from countries with low

overall HBV endemicity
Individuals with potential behavioral HBV exposures (eg, men

who have sex with men, past/current injection drug users)
Individuals receiving immunosuppressive or cytotoxic therapy
Persons with liver disease of unknown etiology
Postvaccination testing for immunity is recommended only for individuals whose clinical management will
depend on information regarding their immune status, including (C)
[CDC 2011b; CDC 2008b]
Infants born to hepatitis B surface antigenpositive mothers
Healthcare and public safety workers who are at high risk for
continued percutaneous or mucosal exposure to blood or
bodily fluids
HIV-infected individuals, patients undergoing chronic

hemodialysis, and other immunocompromised individuals
Sexual partners of individuals chronically infected with HBV
If needed, postvaccination testing for the presence of anti-HBs should be conducted 1-2 months following
completion of the vaccine series (B). Infants born to hepatitis B surface antigenpositive mothers should be
tested 1-2 months after 3 doses of a licensed HBV vaccine series have been administered. Postvaccination
testing in this setting should not be conducted within 4 weeks of the latest vaccine dose or before 9 months of
age to prevent detection of anti-HBs derived from hepatitis B immune globulin given during infancy and to
increase the likelihood of detecting late HBV infection.
Follow-up management strategies for healthcare personnel who have recently received a complete HBV
vaccination series vary depending on the postvaccination immune response
Anti-HBs 10 mIU/mL: considered hepatitis B immune; no

further action needed
Anti-HBs < 10 mIU/mL:
Administer an additional dose of hepatitis B vaccine; test for

anti-HBs 1-2 months later
If anti-HBs 10 mIU/mL: considered hepatitis B immune; no

If anti-HBs < 10 mIU/mL: administer 2 additional doses of

hepatitis B vaccine; test for anti-HBs 1-2 months later
Or, administer a second 3-dose series before retesting antiHBs 1-2 months after last dose
Healthcare workers who continue to demonstrate anti-HBs < 10 mIU/mL after 2 full courses of HBV vaccination
(6 doses total) should be tested for the presence of HBsAg and anti-HBc to determine their infection status. If
HBV infection is absent, these persons are considered vaccine nonresponders and should not receive
additional HBV vaccine doses.
Postexposure prophylaxis is recommended for all persons who are exposed to hepatitis B virus (HBV) and are
considered susceptible to HBV infection (eg, nonvaccinated, vaccine nonresponder). Both the hepatitis B
immune globulin plus the hepatitis B vaccine and the hepatitis B vaccine alone are highly effective in
[Andr 1994; Mitsui 1989]
preventing infection after exposure to HBV.
Recommended postexposure prophylaxis strategies for adults with nonoccupational exposure to

HBV (Management Guidelines)
[Mast 2006]
depend on the HBV status of the exposure source as well as the
vaccination status of the exposed individual (Table 5). For cases in which the exposure source individual is
known to be HBsAg positive, exposed persons who have documented receipt of a complete HBV vaccine
series but no postvaccination testing should receive a single booster dose of vaccine. Exposed persons who
have not been vaccinated should receive both hepatitis B vaccine and hepatitis B immune globulin as soon as
possible following exposure. If the HBsAg status of the exposure source individual is unknown, hepatitis B
immune globulin is not included in the postexposure prophylaxis recommendations. In these cases, exposed
persons who have a documented receipt of a complete HBV vaccine series require no further treatment,
whereas unvaccinated persons should receive a complete HBV vaccine series beginning as soon as possible
following exposure.
Table 5. Guidelines for HBV Postexposure Prophylaxis of Persons With

Nonoccupational Exposures to Blood or Bloody Body Fluids (C)[Mast 2006]
HBsAg Status of
Treatment for Exposed Individual*
Exposure Source
Individual
Positive
Unknown
Unvaccinated
Previously Vaccinated
HBV vaccine series

+ hepatitis B immune
globulin
HBV vaccine series
HBV vaccine booster dose
None
*If indicated, postexposure prophylaxis should be administered as soon as possible and preferably within 24
hours.
Persons in the process of receiving HBV vaccine series should complete the series and receive treatment
listed in table.
Documentation of receipt of complete HBV vaccination series without postvaccination serotesting.
In late 2013, the US Centers for Disease Control and Prevention published updated guidance on protecting
healthcare personnel (HCP) from HBV infection, including recommendations for postexposure
prophylaxis (Management Guidelines).
Postexposure prophylaxis in this setting is issued
based on the HBV status of the source individual, the vaccination status of the exposed person, and the
exposed individuals vaccine response (Table 6). For exposed individuals with documented response to a
complete HBV vaccination series, no action is needed. Exposed individuals who did not respond to 2 complete
HBV vaccination series for whom the HBsAg status of the source patient is positive or unknown should receive
2 doses of hepatitis B immune globulin beginning as soon as possible, with the 2 doses separated by 1 month.
Healthcare personnel with an unknown response to 3 doses of HBV vaccine should be tested for response
based on anti-HBs levels, and the subsequent postexposure prophylaxis strategy should be based on this antiHBs level as well as the HBsAg status of the source individual. Postvaccination serologic testing for anti-HBs
response is recommended for patients whose postexposure prophylaxis strategy includes completion or repeat
of HBV vaccination. Postvaccination anti-HBs assessment should take place 1-2 months after the last HBV
vaccine dose and 4-6 months after hepatitis B immune globulin administration (if indicated).
Table 6. Guidelines for HBV Postexposure Prophylaxis of Healthcare

Personnel With Occupational Percutaneous and Mucosal Exposure to
Blood and Body Fluids (C)[CDC HCP HBV Prevention]
HCP
Vaccination
Status
Documented
Postexposure Testing
Source Patient
HCP
(HBsAg)
(AntiHBs)
Postexposure Prophylaxis Postvaccination

Serologic
Hepatitis B
Vaccination
Testing*
Immune
Globulin 0.06
mL/kg via
Intramuscular
Injection
No action needed
response after
complete vaccine
series
Documented
Positive/unknown
nonresponse after
6 doses
Negative
Response
unknown after 3
doses
Unvaccinated,
incompletely
vaccinated, or
vaccine refused
--
Positive/unknown
< 10
mIU/mL
Negative
< 10
mIU/mL
Any result
10
mIU/mL
Positive/unknown
--
Negative
--
2 doses
-separated by 1
mo
No action needed
1 dose
Initiate
revaccination
No action needed
1 dose
None
Complete
vaccination
Complete
vaccination
immune globulin); use quantitative method.

Vaccine response: anti-HBs 10 mIU/mL after 3 vaccine doses; vaccine nonresponse: anti-HBs < 10
mIU/mL after 6 vaccine doses.
HCP without vaccination, with incomplete vaccination, or with nonresponse to vaccination who sustain
exposure to HBsAg-positive/unknown source should be tested for HBV infection as soon as possible after
exposure and ~ 6 mos later.
The effectiveness of postexposure prophylaxis is dependent on early administration of the initial dose of
vaccine and diminishes the longer after exposure it is initiated.
[Mast 2006]
Ideally, persons without contraindication
to HBV vaccination should receive the first dose within 24 hours and not later than 7 days following exposure.

Booster doses of the hepatitis B virus vaccine are not recommended for individuals with normal immune
status.
[CDC 2011b]
However, the Centers for Disease Control and Prevention recommend that booster doses be
administered in the following circumstances:
Yes
None
*Perform 1-2 mos after last dose of HBV vaccine series (and 4-6 mos after administration of hepatitis B
No
Hemodialysis patients: assess the need for booster doses by

annual anti-HBs testing; administer a booster dose when antiHBs levels decrease to < 10 mIU/mL
Yes
Yes
Other immunocompromised individuals: requirement for

booster doses is undetermined; when anti-HBs levels
decrease to < 10 mIU/mL, consider annual anti-HBs testing
and booster doses in persons with ongoing hepatitis B virus
exposure risk
Hepatitis B Virus Vaccine Nonresponders

Although the currently available hepatitis B virus (HBV) vaccines are highly effective, it is estimated that
approximately 5% to 15% of healthy individuals fail to respond to the 3-dose series.
US Centers for Disease Control and Prevention (Management Guidelines),
[Mast 2006]
[CDC 1991]
According to the
individuals who have anti-
HBs levels < 10 mIU/mL following the primary HBV vaccine series should be revaccinated with 3 doses
according to the appropriate schedule (Table 4) and should be retested for anti-HBs 1-2 months following the
third dose (B). Individuals with anti-HBs levels < 10 mIU/mL following revaccination should be tested for
hepatitis B surface antigen to determine if they are infected with HBV. If the test is negative, they should be
considered susceptible to HBV infection and should be counseled on precautions to avoid becoming infected
and the need for hepatitis B immune globulin postexposure prophylaxis in the event of any known or likely
parenteral exposure to hepatitis B surface antigenpositive blood.
SUMMARY
Transmission of HBV in hospital settings may occur from patient to patient, patient to healthcare
personnel via contaminated instruments or accidental needlestick, and, rarely, from healthcare
personnel to patient
[Thompson 2009]
Healthcare professionals are strongly advised to receive immunization against HBV
In the hospital setting, transmission of hepatitis B virus (HBV) generally occurs from patient to patient, patient
to healthcare personnel via contaminated instruments or accidental needlestick, and, rarely, from healthcare
personnel to patient due to tears in safety gloves, suturing accidents, or through use of contaminated multiuse
vials.
[Thompson 2009]
The risk of acquiring HBV infection after an accidental needlestick is related to the degree of
contact with blood and the hepatitis B e antigen (HBeAg) status of the source patient. The risk for clinical
hepatitis if the source patient is HBeAg-positive is 22% to 31% vs 1% to 6% if the source patient is HBeAgnegative (Management Guidelines).
[Mast 2006]
Therefore, healthcare professionals are strongly advised to receive
immunization against HBV (Management Guidelines).
A number of cases of acute hepatitis B that occurred outside of the hospital setting but were related to the use
of medical devices were reported to the US Centers of Disease Control and Prevention in 2012. Specifically,
these cases were due to improper use of blood glucosemonitoring devices in assisted living facilities.
2012]
[McIntosh
These cases serve to highlight the need for a comprehensive strategy to prevent HBV transmission in
assisted living facilities, including vaccination, improved infection control oversight, and appropriate training of
staff members performing assisted monitoring of blood glucose.
SUMMARY
Transmission of HBV has been reported after transplantation of solid organs such as kidneys and
livers
[Dickson 1997]
The CDC recommends screening all potential organ donors for high-risk behavior and testing for
HBsAg prior to donation
[CDC 2011b]
Persons testing HBsAg positive should not donate organs (Table 3)
[Lok 2009]
Antiviral therapy should be administered to recipients of organs from people who are anti-HBc
positive
[Lok 2009]
6-12 months of therapy is sufficient for people receiving non-hepatic transplants; lifelong
therapy is recommended for those receiving liver transplants
Transmission of hepatitis B virus (HBV) has been reported after transplantation of solid organs such as kidneys
and livers.
[Dickson 1997]
The Centers for Disease Control and Prevention recommends screening all potential
organ donors for high-risk behavior and testing for hepatitis B surface antigen (HBsAg) prior to
donation (Management Guidelines) (B).
[CDC 2011c]
To prevent transmission, persons testing HBsAg-positive
should not donate organs (Table 3) (Management Guidelines).
[Lok 2009]
There is some uncertainty about the role
of anti-HBc screening prior to organ donations because of false-positive results leading to loss of donors and
uncertainties regarding the true infectivity of anti-HBc positive donors. The risk of HBV transmission following
renal transplantation using a donor with isolated anti-HBc is low (0% to 2%),
[CDC 2011c; Ouseph 2010]
0% to 78% in liver transplantation, depending on the HBV serologic status of the recipient.
but ranges from
[Dickson 1997; Prieto 2001]
an organ of an anti-HBc-positive person is used, antiviral therapy should be administered to the recipient to
prevent HBV infection (C).
[Lok 2009]
Available data suggest that 6-12 months of therapy is sufficient for person
receiving non-hepatic transplants, while lifelong therapy is recommended for persons receiving liver
transplants.
[Lok 2009]
MY SUBSCRIPTIONS
QUICK TOUR
MY CE
MY FOLDER
LOGOUT
Specialty
If
Decision Tools
Drug Reference
Guidelines
PubMed
Trials
More
XGO
Specialty
Hepatology
HBV Epidemiology
Summary
Global Overview
Sexual Transmission
Vaccination
Vaccine Booster
Pathogenesis
Natural History
Overview
Serology
HBsAg and Anti-HBs
Anti-HBc
HBeAg and Anti-HBe
HBV DNA Assays
Supporting Assets
References
Previous
Next
Save
Share
Print
Email

Zeuzem, MD
SUMMARY
Five vaccines are licensed in the US for hepatitis B

vaccination
[Mast 2005; Mast 2006]
Hepatitis B immune globulin contains anti-HBs and

provides temporary protection (for ~ 3-6 months);
used with hepatitis B vaccine for postexposure
immunoprophylaxis
The CDC recommends the following groups for

vaccination
[CDC 2012]
All newborns
Children and adolescents through 18 years

of age who did not receive the vaccination
earlier
Anyone who wants to be protected against

HBV
The hepatitis B pediatric vaccine and hepatitis B

immune globulin should be administered to the
neonate of an HBsAg-positive mother within 12
hours of birth
[Mast 2005]
The vaccine schedule after birth and for

other age groups is shown in Table 4
The CDC recommends testing the following

groups for HBV infection or immunity prior
to HBV vaccination
[CDC 2011c; CDC 2008b]
Pregnant women
Individuals with known or
suspected HBV exposure,

including:
Infants born to HBVinfected mothers
Household contacts of
persons infected with
HBV
Individuals with known

occupational or other
exposures to infectious
blood or body fluids
Foreign-born persons from

countries with high HBV
endemicity (HBsAg prevalence >
2%)
US-born persons not vaccinated

as infants whose parents were
born in regions with high HBV
endemicity (> 8%)
Injection-drug users
Men who have sex with men
Persons needing
immunosuppressive therapy,
including chemotherapy,
immunosuppression related to
organ transplantation, and
immunosuppression for
rheumatologic or
gastroenterologic disorders
Persons with elevated

transaminases of unknown
etiology
Donors of blood, plasma, organs,

tissues, or semen
Household, needle-sharing, or sex

contacts of persons known to be
HBsAg positive
Postvaccination testing for immunity is

recommended only for individuals whose
clinical management will depend on their
immune status
If needed, postvaccination testing

for anti-HBs should be conducted
1-2 months following completion
of the vaccine series
Postvaccination testing of infants

born to HBsAg-positive mothers
should not be conducted within 4
weeks of the latest vaccine dose
or before 9 months of age
Follow-up management for healthcare

personnel who have recently received
complete HBV vaccination series varies
based on postvaccination immune
response
Guidelines for postexposure prophylaxis for

adults with occupational (Management
Guidelines)
and
nonoccupational (Management
Guidelines)
[Mast 2006]
exposures to HBV are
available
Postexposure prophylaxis is recommended

for anyone who is exposed to HBV and is
considered susceptible to HBV infection
The effectiveness of prophylaxis is

dependent on early administration
of the initial dose of vaccine and
diminishes with time after
exposure
[Mast 2006]
Ideally, persons without

contraindication to HBV
vaccination should receive the first
dose within 24 hours and not later
than 7 days following exposure
The CDC recommend that booster doses of

the HBV vaccine be administered to
hemodialysis patients and other
immunocompromised individuals
[CDC 2011c]
Booster doses not recommended for

persons with normal immune status
Approximately 5% to 15% of healthy

individuals fail to respond to the 3-dose
HBV vaccine series
[CDC 1991]
People with anti-HBs levels < 10 mIU/mL

following the primary HBV vaccine series
should be revaccinated with 3 doses
according to the appropriate schedule and
retested after the third dose (Table 4)
Individuals with anti-HBs levels < 10

mIU/mL following revaccination should be
tested for HBsAg
Those who test negative should

be counseled on preventive
measures
3 that are available as combinations (hepatitis A hepatitis B vaccine,haemophilus b hepatitis B vaccine, and
2006(Management Guidelines)
[Mast 2006]
[Mast 2005]
and
guidelines from the Centers for Disease Control and Prevention. All of
the vaccines use the hepatitis B surface antigen (HBsAg) to generate immunity against hepatitis B virus
(HBV). Hepatitis B immune globulin, which contains anti-HBs, provides temporary protection (for ~ 3-6 months)
and is used in addition to the hepatitis B vaccine for postexposure immunoprophylaxis to prevent HBV
infection.
[Mast 2005; Mast 2006]
The Centers for Disease Control and Prevention recommends the following groups for vaccination (C)
[CDC 2012]
All newborns

The hepatitis B pediatric vaccine and hepatitis B immune globulin should be administered to the neonate of an
HBsAg-positive mother within 12 hours of birth, as efficacy of the vaccine declines with time after birth.
2005]
[Mast
The vaccine schedule after birth and for other age groups is shown in Table 4.
Table 4. Hepatitis B Vaccine Schedules for Children, Adolescents, and

Adults*[Mast 2005]
Age
Schedule
0, 1, and 6 mos
Children (1-10 yrs)
0, 1, and 4 mos
0, 1, 2, and 12 mos
0, 1, and 6 mos
Adolescents (11-19 yrs)
0, 1, and 4 mos
0, 2, and 4 mos
0, 12, and 24 mos
0 and 4-6 mos
0, 1, 2, and 12 mos
Adults ( 20 yrs)
0, 1, and 6 mos
0, 1, and 4 mos
0, 2, and 4 mos
0, 1, 2, and 12 mos
*Children, adolescents, and adults may be vaccinated according to any of the schedules indicated, except as
noted. Selection of a schedule should consider the need to optimize compliance with vaccination.
Pediatric/adolescent formulation.
A 2-dose schedule of Recombivax-HB adult formulation (10 g) is licensed for adolescents aged 11-15 years.
When scheduled to receive the second dose, adolescents aged older than 15 years should be switched to a 3dose series, with doses 2 and 3 consisting of the pediatric formulation administered on an appropriate
schedule.
A 4-dose schedule of Engerix B is licensed for all age groups.
Adult formulation.
Hepatitis A-hepatitis B vaccine may be administered to persons aged older than 18 years at 0, 1, and 6
months.
The US Centers for Disease Control and Prevention (CDC) currently recommend that certain groups be tested
for hepatitis B virus (HBV) infection or immunity using serologic assays for HBsAg and anti-HBs before being
vaccinated for HBV (B).
[CDC 2011b; CDC 2008b]
The reason for this recommendation is to identify chronic infection in
high-risk groups who may benefit from therapy. These groups include the following persons:
Pregnant women

including:


endemicity
infection (Management Guidelines) (B)

HBV endemicity


depend on information regarding their immune status, including (C)
[CDC 2011b; CDC 2008b]
Infants born to hepatitis B surface antigenpositive mothers
bodily fluids

completion of the vaccine series (B). Infants born to hepatitis B surface antigenpositive mothers should be
tested 1-2 months after 3 doses of a licensed HBV vaccine series have been administered. Postvaccination
testing in this setting should not be conducted within 4 weeks of the latest vaccine dose or before 9 months of
age to prevent detection of anti-HBs derived from hepatitis B immune globulin given during infancy and to
increase the likelihood of detecting late HBV infection.
Follow-up management strategies for healthcare personnel who have recently received a complete HBV
vaccination series vary depending on the postvaccination immune response
Anti-HBs 10 mIU/mL: considered hepatitis B immune; no

Anti-HBs < 10 mIU/mL:
Administer an additional dose of hepatitis B vaccine; test for

anti-HBs 1-2 months later
If anti-HBs 10 mIU/mL: considered hepatitis B immune; no

If anti-HBs < 10 mIU/mL: administer 2 additional doses of

hepatitis B vaccine; test for anti-HBs 1-2 months later
Or, administer a second 3-dose series before retesting antiHBs 1-2 months after last dose
Healthcare workers who continue to demonstrate anti-HBs < 10 mIU/mL after 2 full courses of HBV vaccination
(6 doses total) should be tested for the presence of HBsAg and anti-HBc to determine their infection status. If
HBV infection is absent, these persons are considered vaccine nonresponders and should not receive
additional HBV vaccine doses.
Postexposure prophylaxis is recommended for all persons who are exposed to hepatitis B virus (HBV) and are
considered susceptible to HBV infection (eg, nonvaccinated, vaccine nonresponder). Both the hepatitis B
immune globulin plus the hepatitis B vaccine and the hepatitis B vaccine alone are highly effective in
preventing infection after exposure to HBV.
Recommended postexposure prophylaxis strategies for adults with nonoccupational exposure to

HBV (Management Guidelines)
[Mast 2006]
depend on the HBV status of the exposure source as well as the
vaccination status of the exposed individual (Table 5). For cases in which the exposure source individual is
known to be HBsAg positive, exposed persons who have documented receipt of a complete HBV vaccine
series but no postvaccination testing should receive a single booster dose of vaccine. Exposed persons who
have not been vaccinated should receive both hepatitis B vaccine and hepatitis B immune globulin as soon as
possible following exposure. If the HBsAg status of the exposure source individual is unknown, hepatitis B
immune globulin is not included in the postexposure prophylaxis recommendations. In these cases, exposed
persons who have a documented receipt of a complete HBV vaccine series require no further treatment,
whereas unvaccinated persons should receive a complete HBV vaccine series beginning as soon as possible
following exposure.
Table 5. Guidelines for HBV Postexposure Prophylaxis of Persons With

Nonoccupational Exposures to Blood or Bloody Body Fluids (C)[Mast 2006]
HBsAg Status of
Exposure Source
Individual
Positive
Treatment for Exposed Individual*

Unvaccinated
Previously Vaccinated
HBV vaccine series
+ hepatitis B immune
globulin
HBV vaccine series
Unknown
HBV vaccine booster dose
None
*If indicated, postexposure prophylaxis should be administered as soon as possible and preferably within 24
hours.
Persons in the process of receiving HBV vaccine series should complete the series and receive treatment
listed in table.
Documentation of receipt of complete HBV vaccination series without postvaccination serotesting.
In late 2013, the US Centers for Disease Control and Prevention published updated guidance on protecting
healthcare personnel (HCP) from HBV infection, including recommendations for postexposure
prophylaxis (Management Guidelines).
Postexposure prophylaxis in this setting is issued
based on the HBV status of the source individual, the vaccination status of the exposed person, and the
exposed individuals vaccine response (Table 6). For exposed individuals with documented response to a
complete HBV vaccination series, no action is needed. Exposed individuals who did not respond to 2 complete
HBV vaccination series for whom the HBsAg status of the source patient is positive or unknown should receive
2 doses of hepatitis B immune globulin beginning as soon as possible, with the 2 doses separated by 1 month.
Healthcare personnel with an unknown response to 3 doses of HBV vaccine should be tested for response
based on anti-HBs levels, and the subsequent postexposure prophylaxis strategy should be based on this antiHBs level as well as the HBsAg status of the source individual. Postvaccination serologic testing for anti-HBs
response is recommended for patients whose postexposure prophylaxis strategy includes completion or repeat
of HBV vaccination. Postvaccination anti-HBs assessment should take place 1-2 months after the last HBV
vaccine dose and 4-6 months after hepatitis B immune globulin administration (if indicated).
Table 6. Guidelines for HBV Postexposure Prophylaxis of Healthcare

Personnel With Occupational Percutaneous and Mucosal Exposure to
Blood and Body Fluids (C)[CDC HCP HBV Prevention]
HCP
Vaccination
Status
Postexposure Testing
Source Patient
HCP
(HBsAg)
(AntiHBs)
Documented
response after
complete vaccine
series
Documented
Positive/unknown
nonresponse after
6 doses
Negative
Response
unknown after 3
doses
Unvaccinated,
incompletely
vaccinated, or
vaccine refused
--
Positive/unknown
< 10
mIU/mL
Negative
< 10
mIU/mL
Any result
10
mIU/mL
Positive/unknown
--
Negative
--
Postexposure Prophylaxis Postvaccination

Serologic
Hepatitis B
Vaccination
Testing*
Immune
Globulin 0.06
mL/kg via
Intramuscular
Injection
No action needed
2 doses
-separated by 1
mo
No action needed
1 dose
Initiate
revaccination
No action needed
1 dose
None
Complete
vaccination
Complete
vaccination
immune globulin); use quantitative method.

Vaccine response: anti-HBs 10 mIU/mL after 3 vaccine doses; vaccine nonresponse: anti-HBs < 10
mIU/mL after 6 vaccine doses.
Yes
None
*Perform 1-2 mos after last dose of HBV vaccine series (and 4-6 mos after administration of hepatitis B
No
HCP without vaccination, with incomplete vaccination, or with nonresponse to vaccination who sustain
Yes
Yes
exposure to HBsAg-positive/unknown source should be tested for HBV infection as soon as possible after
exposure and ~ 6 mos later.
The effectiveness of postexposure prophylaxis is dependent on early administration of the initial dose of
vaccine and diminishes the longer after exposure it is initiated.
[Mast 2006]
Ideally, persons without contraindication
to HBV vaccination should receive the first dose within 24 hours and not later than 7 days following exposure.

Booster doses of the hepatitis B virus vaccine are not recommended for individuals with normal immune
status.
[CDC 2011b]
However, the Centers for Disease Control and Prevention recommend that booster doses be
administered in the following circumstances:
Hemodialysis patients: assess the need for booster doses by

annual anti-HBs testing; administer a booster dose when antiHBs levels decrease to < 10 mIU/mL
Other immunocompromised individuals: requirement for

booster doses is undetermined; when anti-HBs levels
decrease to < 10 mIU/mL, consider annual anti-HBs testing
and booster doses in persons with ongoing hepatitis B virus
exposure risk

Although the currently available hepatitis B virus (HBV) vaccines are highly effective, it is estimated that
approximately 5% to 15% of healthy individuals fail to respond to the 3-dose series.
US Centers for Disease Control and Prevention (Management Guidelines),
[Mast 2006]
[CDC 1991]
According to the
individuals who have anti-
HBs levels < 10 mIU/mL following the primary HBV vaccine series should be revaccinated with 3 doses
according to the appropriate schedule (Table 4) and should be retested for anti-HBs 1-2 months following the
third dose (B). Individuals with anti-HBs levels < 10 mIU/mL following revaccination should be tested for
hepatitis B surface antigen to determine if they are infected with HBV. If the test is negative, they should be
considered susceptible to HBV infection and should be counseled on precautions to avoid becoming infected
and the need for hepatitis B immune globulin postexposure prophylaxis in the event of any known or likely
parenteral exposure to hepatitis B surface antigenpositive blood.
Keywords: Hepatitis B, Hepatitis B-Epidemiology, Hepatitis B-Vaccination and Prevention
Pathogenesis of Hepatitis B Virus

SUMMARY
Nonspecific immune responses, including production of interferon, activation of natural killer cells and
Kupffer cells, may help to control viral replication during early HBV infection
[Wieland 2000; Tang 2003; Webster
2002]
Acute, self-limited HBV infection is characterized by a strong, polyclonal, multispecific cytotoxic and
helper T-cell response
[Ferrari 1990; Thimme 2003]
Clinical hepatitis is associated with an influx of inflammatory cells, including both HBV-specific and
nonHBV-specific T cells
Upon activation, HBV-specific CD8+ cytotoxic T cells secrete cytokines, including

interferons, that recruit nonspecific inflammatory cells in the liver, resulting in more extensive
liver injury
The CD4+ and CD8+ response in chronic carriers is negligible
[Rehermann 1995]
Successful control of hepatitis B virus (HBV) is dependent on the complex interplay between the innate,
cellular, and humoral responses to the infecting virus.
[Chang 2007; Chisari 2010]
At the same time, the immune
response may be responsible for mediating clinical hepatitis and disease progression. The exact role of the
innate response in acute HBV infection is unclear. The nonspecific innate immune response involves
production of interferon, activation of natural killer cells, and activation of Kupffer cells, all of which may help to
control viral replication and limit the spread of the virus during the early stages of infection.
[Boltjes 2014; Wieland
2000; Tang 2003; Webster 2002]
The roles of the cellular and humoral responses are better defined. The T-cell response during acute, selflimited HBV infection is characterized by a strong, polyclonal, multispecific cytotoxic and helper T-cell
response.
[Ferrari 1990; Thimme 2003]
Clinical hepatitis is associated with an influx of inflammatory cells, including both
HBV-specific and nonHBV-specific T cells.
[Thimme 2003]
In particular, CD8+ T cells that mediate cytolytic activity
against HBV-infected hepatocytes correlate with an increase in serum alanine aminotransferase level.
2003]
By contrast, the CD4+ and CD8+ response in chronic carriers is feeble or undetectable.
[Rehermann
[Thimme
1995]
However, their presence in the peripheral blood and liver of chronically infected persons with elevated
alanine aminotransferase levels suggest a pathogenic role for the cellular immune response. Therefore, the
cell-mediated immune response is a doubled-edged sword: a vigorous response leads to viral clearance,
whereas an ineffective response leads to hepatocellular injury.
HBV-specific CD8+ cytotoxic T cells appear to be important for initiating liver injury. Upon activation, they
secrete a number of cytokines, including interferons, that recruit a variety of nonspecific inflammatory cells in
the liver, resulting in more extensive liver injury. Infiltrating macrophages probably mediate most of the hepatic
damage.
[Chang 2007]
For additional information from inPractice on the pathogenesis of HBV infection, please click here.
Keywords: Hepatitis B, Hepatitis B-Pathogenesis and Natural History
MY SUBSCRIPTIONS
QUICK TOUR
MY CE
MY FOLDER
LOGOUT
Specialty
Decision Tools
Drug Reference
Guidelines
PubMed
Trials
More
XGO
Specialty
Hepatology
HBV Epidemiology
Summary
Global Overview
Sexual Transmission
Vaccination
Vaccine Booster
Pathogenesis
Natural History
Overview
Serology
HBsAg and Anti-HBs
Anti-HBc
HBeAg and Anti-HBe
HBV DNA Assays
Supporting Assets
References
Save
Previous
Next
Share
Print
Email

Zeuzem, MD
Natural History
SUMMARY
Following exposure to HBV, two thirds of

patients present with asymptomatic
infection and one third present with acute
hepatitis with jaundice; a minority (< 1%)
develop fulminant hepatitis (Figure 3)
[Kao
2008]
Acute infection is more likely to resolve in

patients who present with jaundice or who
are not immunosuppressed at time of
infection
Likelihood of progression to chronicity is

inversely linked to age at exposure
Low-level viral replication can be detected

in up to 15% to 20% of persons who
recover from acute HBV
[Yuki 2003]
These individuals are at risk of

reactivation of hepatitis B if they
become immunosuppressed, eg,
with use of chemotherapy
Video Insight: Prevention and Management of

HBV Reactivation
The outcome of chronic HBV infection is

variable; approximately one half of
individuals transition to an inactive carrier
state, 30% progress to cirrhosis, and the
remainder to chronic hepatitis (Figure 3)
[Kao
2008]
Chronic HBV infection consists of 4

phases: immune-tolerant, immune
clearance, inactive, and reactivation (Table
7)
Hepatitis B e AntigenPositive ImmuneTolerant Chronic Hepatitis B
HBeAg-positive immune-tolerant
chronic hepatitis B is
characterized by the presence of
HBeAg in serum, normal ALT
levels, and high HBV DNA levels
7
(> 10 IU/mL) in serum (Table

7)
[Chu 1985]
Generally associated
with acquisition of HBV
infection perinatally or in
early childhood
May last 10-30 years
Most patients have mild

liver disease on biopsy
Spontaneous clearance
of HBeAg is uncommon
Risk of disease
progression is low, and
treatment is not indicated
Hepatitis B e AntigenPositive Active

Chronic Hepatitis B
HBeAg-positive, active, chronic

hepatitis B is characterized by
HBeAg positivity, elevated ALT
levels, and high HBV DNA in
serum (Table 7)
Histology may range

from mild disease to
cirrhosis
Spontaneous HBeAg
loss occurs at a rate of
10% to 20% per year
Higher rates of
spontaneous HBeAg loss
are associated with older
age, higher ALT levels,
and HBV genotype B vs
C
Inactive Hepatitis B Surface Antigen

Carrier State
Inactive HBsAg carrier state

characterized by the presence of
anti-HBe, normal ALT levels, and

low or undetectable HBV DNA in
serum (< 2000 IU/mL) (Table 7)
Liver biopsy usually

shows minimal
necroinflammation and
varying degrees of
fibrosis
The rate of HBsAg

clearance is low, but
higher in women, older
patients, and those with
cirrhosis
Spontaneous HBeAg
loss may be followed by
reversion to HBeAg
positivity in some
patients
Lifelong follow-up of
these patients required
Hepatitis B e AntigenNegative Active

Chronic Hepatitis B
HBeAg-negative chronic HBV

infection is characterized by
presence of anti-HBe, raised ALT
levels, and HBV DNA in serum
(Table 7)
Patients in the immuneclearance and

reactivation phases
should be considered for
treatment
Monitoring is
recommended for those
in the immune-tolerant
and inactive phases,
according to activity of
liver disease
Approximately 30% of individuals

with chronic HBV infection will
develop cirrhosis (Figure 3)
The annual incidence of

cirrhosis is estimated to
be 8% to 10% for
HBeAg-negative
patients
[Fattovich 2003]
Risk factors include

advanced age, elevated
HBV DNA levels, HBV
genotype C infection,
chronic increased alcohol
intake, male sex, basal
core promoter mutations,
and HCV, HDV, or HIV
coinfection
High HBV DNA level is

associated with
increased risk of both
HCC and cirrhosis in
HBeAg-negative patients

Following exposure to hepatitis B virus (HBV), two thirds of patients present with an asymptomatic, subclinical
infection and one third present with an acute hepatitis with jaundice, of whom a minority (< 1%) develop
fulminant hepatitis (Figure 3).
[Kao 2008]
The outcome of acute infection is largely dependent on age at exposure:
90% to 95% of individuals who acquire the infection as infants progress to chronic infection compared with
25% of those infected during childhood, and 5% of those infected as adults (Figure 3).
Figure 3. Natural history of hepatitis B infection.
[Hyams 1995]
Acute hepatitis B infection is more likely to resolve in patients who present with jaundice or who are not
immunosuppressed at the time of infection compared with those who present with a subclinical infection or who
are immunosuppressed. With sensitive assays for hepatitis B virus (HBV) DNA, low-level viral replication can
be detected in up to 15% to 20% of persons who recover from acute HBV.
[Yuki 2003]
Indeed, it is now believed
that low-level viral replication probably occurs throughout an individuals lifetime and is held in check by the
immune system.
[Liang 2009]
This explains why reactivation of hepatitis B might occur if the immune system
becomes compromised by chemotherapy, bone marrow or stem cell transplantation, or HIV infection.
Click here to view a Video Insight in which Anna S. F. Lok, MD, discusses the importance of preventing
reactivation of hepatitis B and approaches for its management.

In this Video Insight, recorded in Boston, Massachusetts, during the 2012 annual meeting of the American
Association for the Study of Liver Diseases, Anna S. F. Lok, MD, Professor of Internal Medicine and Director of
Clinical Hepatology at the University of Michigan in Ann Arbor, discusses the importance for screening for HBV
in patients at risk for HBV reactivation, the potential consequences of HBV reactivation, and strategies to
management of HBV reactivation.
Preventing and Managing HBV Reactivation

The outcome of chronic hepatitis B is variable and dependent on a complex interplay between the level of viral
replication and the host immune response. Approximately one half of individuals transition to an inactive carrier
state, 30% progress to cirrhosis, and the remainder have varying degrees of chronic hepatitis (Figure 3).
2008]
[Kao
Although all patients with chronic hepatitis B are at risk for hepatocellular carcinoma, the rate is highest for
those with cirrhosis or persistently high viral replication.
[McClune 2010; Chen 2006]
In addition, an analysis of 1999-
2007 mortality data from the US National Center for Health Statistics demonstrated that being of Asian or
Pacific Islander descent was associated with an increased risk of hepatitis B virus (HBV)related death.
2012]
[Ly
Understanding the natural history of chronic HBV infection is crucial for determining who requires therapy,
when to initiate treatment, and establishing realistic therapeutic goals.
In general, chronic HBV infection consists of 4 phases: an immune-tolerant phase, an immune clearance
phase, an inactive phase, and a reactivation phase in a proportion of patients (Table 7). Serum HBV DNA,
alanine aminotransferase, and hepatitis B e antigen (HBeAg) status are used to define these different phases
of chronic infection.
Table 7. Phases of Chronic HBV Infection[Lok 2009]

Immune
Tolerance
Typical HBV
DNA, IU/mL
HBeAg
Alanine
aminotransferase
Other
observations
HBsAg,
log10IU/mL
Treatment
candidate?
> 107-9
Positive
Normal
Liver biopsy
typically
normal or
minimal
findings
~ 4.5
No
Immune
Active/
HBeAgPositive
Chronic
Hepatitis B
200,000 - 2 x
108
Positive
Elevated or
fluctuating
Active
inflammation
on liver biopsy
Nonreplicative
(Inactive
Carrier)
HBeAgNegative
Chronic
Hepatitis B
< 2000
2000 - 2 x 107
Negative
Normal
HBsAg may
become
undetectable
Negative
Elevated or
fluctuating
Active
inflammation
on liver biopsy
~ 4.0
~ 2.86
~ 3.35
Yes
No
Yes
Hepatitis B e AntigenPositive Immune-Tolerant Chronic Hepatitis B
Hepatitis B e antigen (HBeAg)positive immune-tolerant chronic hepatitis B is characterized by the presence of

HBeAg in serum, normal alanine aminotransferase levels, and high hepatitis B virus (HBV) DNA levels in
serum (Table 7).
[Chu 1985]
Most of these patients have mild liver disease on biopsy.
[Chu 1985]
This phase may last
for 10-30 years. Spontaneous clearance of HBeAg occurs at a very low rate in this phase of the disease (< 1%
per year).
[Liaw 1984; Lok 1987]
Despite the high HBV DNA levels, the risk of disease progression is low and
treatment is not indicated.Immune-tolerant hepatitis B is generally associated with acquisition of HBV infection
perinatally or in early childhood.
Hepatitis B e AntigenPositive Active Chronic Hepatitis B

Hepatitis B e antigen (HBeAg)positive active chronic hepatitis B is characterized by HBeAg positivity,
elevated alanine aminotransferase (ALT) levels, and high hepatitis B virus (HBV) DNA in serum (~ 1-2
log10 IU/mL lower compared with the immune-tolerant phase) (Table 7). These individuals have varying
degrees of histologic damage on liver biopsy ranging from mild hepatitis to cirrhosis. Spontaneous HBeAg loss
occurs at a rate of 10% to 20% per year and is frequently accompanied by a flare in hepatitis.
1987]
[Liaw 1984; Lok
Repeated, unsuccessful attempts to clear HBeAg may result in recurring exacerbations of hepatitis,
leading to more rapid progression to cirrhosis.
[Liaw 1983; Lok 1987]
Factors associated with higher rates of
spontaneous HBeAg seroconversion include older age, higher ALT levels, and HBV genotype B vs
C (Management Guidelines).
[Lok 2009]
A high ALT level is believed to be a surrogate marker for a vigorous host-
immune response, accounting for its strong correlation with spontaneous as well as treatment-related HBeAg
seroconversion. Some patients may clear HBeAg without an accompanying ALT flare. In adult-acquired
infection, the immune clearance phase represents the first phase of infection.
Inactive Hepatitis B Surface Antigen Carrier State

The third phase of infection of perinatally acquired chronic hepatitis B and second phase of adult-acquired
chronic hepatitis B is the inactive HBsAg carrier state characterized by the presence of anti-HBe, normal
alanine aminotransferase levels, and low or undetectable hepatitis B virus (HBV) DNA in serum (< 2000 IU/mL)
(Table 7). These patients usually have a liver biopsy that shows minimal necroinflammation and varying
degrees of fibrosis. The prognosis is generally good for true inactive carriers; hepatitis B surface antigen
(HBsAg) clearance occurs in these individuals at a rate of 0.5% to 2.0% per year.
[Alward 1985; Liaw 1991; Liu
2010]
Women, older patients, and those with cirrhosis have a higher chance of HBsAg clearance.
2010]
Following spontaneous hepatitis B e antigen (HBeAg) seroconversion, approximately 4% to 20% of
patients will experience 1 reversion back to HBeAg positivity,
[Hsu 2002; McMahon 2001]
[Chu
highlighting the dynamic
nature of chronic HBV infection and the need for lifelong follow-up of patients in the inactive carrier state to
ensure that the inactive state persists.
Hepatitis B e AntigenNegative Active Chronic Hepatitis B

A proportion of patients continue to have moderate levels of hepatitis B virus (HBV) replication and liver
damage, despite clearance of HBeAg, due to mutations in the precore or core promoter region of the viral
genome.
[Chan 2000; Okamoto 1994; Lok 1994; Carman 1989]
This scenario is termed hepatitis B e antigen (HBeAg)negative
chronic hepatitis B and is characterized by presence of anti-HBe, raised alanine aminotransferase levels, and
HBV DNA in serum (Table 7). Liver biopsy shows varying degrees of chronic hepatitis on biopsy. Thus,
patients in the immune-clearance and reactivation phases should be considered for treatment, whereas
monitoring is recommended for those in the immune-tolerant and inactive phases. Monitoring should be
lifelong because up to 30% of patients may transition between the active and inactive phases (Management
Guidelines).
[Lok 2009]
The frequency of monitoring should be determined by the activity of liver disease.
For additional information from inPractice on monitoring recommendations for patients who are not candidates
for therapy, click here.
Major complications of chronic hepatitis B include the development of cirrhosis, hepatic decompensation,
hepatocellular carcinoma, and death. These outcomes are variable and dependent on host, viral, and
environmental factors. Approximately 30% of individuals with chronic hepatitis B will develop cirrhosis (Figure
3). The annual incidence of cirrhosis is estimated to be 2% to 6% for hepatitis B e antigen (HBeAg)positive
[Fattovich 2003]
and 8% to 10% for HBeAg-negative patients.
The annual incidence of hepatocellular carcinoma has
been estimated to be 2% to 3% for carriers with cirrhosis and < 1% for carriers without cirrhosis (Figure 3).
Risk factors for progression to cirrhosis include advanced age, elevated HBV DNA levels, HBV genotype C
infection, chronic increased alcohol intake, male sex, basal core promoter mutations, and coinfections with
either hepatitis C virus, hepatitis D virus, or HIV.
[Yim 2006; Fattovich 2003; Chu 2009; Lin 2005]
A large prospective, population-based study conducted in Taiwanese patients, the majority of whom had
HBeAg-negative chronic hepatitis B, demonstrated that patients with high baseline HBV DNA level have an
increased risk for the development of cirrhosis and hepatocellular carcinoma (HCC).
2006]
[Iloeje 2006; Chen
Compared with patients with a baseline HBV DNA level < 300 copies/mL (approximately 60 IU/mL),
patients with a baseline HBV DNA level 1 million copies/mL (approximately 200,000 IU/mL) have an
approximately 10-fold higher risk of developing cirrhosis
2006]
[Iloeje 2006]
and an 11-fold increased risk for HCC.
[Chen
In the same study, a persistently high HBV DNA level was associated with an increased risk for HCC;
5
patients with an HBV DNA level persistently > 10 copies/mL (approximately 4.3 log10 IU/mL) had a 10-fold
4
higher risk of HCC vs those with a DNA level < 10 copies/mL (approximately 3.3 log10 IU/mL) at entry into the
study.
[Chen 2006]
Hepatitis B e AntigenPositive ImmuneTolerant Chronic Hepatitis B

SUMMARY
HBeAg-positive immune-tolerant chronic hepatitis B is characterized by the presence of HBeAg in

7
[Chu 1985]
serum, normal ALT levels, and high HBV DNA levels (> 10 IU/mL) in serum (Table 7)
Generally associated with acquisition of HBV infection perinatally or in early childhood
May last 10-30 years
Most patients have mild liver disease on biopsy
Spontaneous clearance of HBeAg is uncommon
Risk of disease progression is low, and treatment is not indicated
Hepatitis B e antigen (HBeAg)positive immune-tolerant chronic hepatitis B is characterized by the presence of

HBeAg in serum, normal alanine aminotransferase levels, and high hepatitis B virus (HBV) DNA levels in
serum (Table 7).
[Chu 1985]
Most of these patients have mild liver disease on biopsy.
[Chu 1985]
This phase may last
for 10-30 years. Spontaneous clearance of HBeAg occurs at a very low rate in this phase of the disease (< 1%
per year).
[Liaw 1984; Lok 1987]
Despite the high HBV DNA levels, the risk of disease progression is low and
treatment is not indicated.Immune-tolerant hepatitis B is generally associated with acquisition of HBV infection
perinatally or in early childhood.
Hepatitis B e AntigenPositive Active

Chronic Hepatitis B
SUMMARY
HBeAg-positive, active, chronic hepatitis B is characterized by HBeAg positivity, elevated ALT levels,
and high HBV DNA in serum (Table 7)
Histology may range from mild disease to cirrhosis
Spontaneous HBeAg loss occurs at a rate of 10% to 20% per year
Higher rates of spontaneous HBeAg loss are associated with older age, higher ALT levels,
and HBV genotype B vs C
Hepatitis B e antigen (HBeAg)positive active chronic hepatitis B is characterized by HBeAg positivity,

elevated alanine aminotransferase (ALT) levels, and high hepatitis B virus (HBV) DNA in serum (~ 1-2
log10 IU/mL lower compared with the immune-tolerant phase) (Table 7). These individuals have varying
degrees of histologic damage on liver biopsy ranging from mild hepatitis to cirrhosis. Spontaneous HBeAg loss
occurs at a rate of 10% to 20% per year and is frequently accompanied by a flare in hepatitis.
1987]
[Liaw 1984; Lok
Repeated, unsuccessful attempts to clear HBeAg may result in recurring exacerbations of hepatitis,
leading to more rapid progression to cirrhosis.
[Liaw 1983; Lok 1987]
Factors associated with higher rates of
spontaneous HBeAg seroconversion include older age, higher ALT levels, and HBV genotype B vs
C (Management Guidelines).
[Lok 2009]
A high ALT level is believed to be a surrogate marker for a vigorous host-
immune response, accounting for its strong correlation with spontaneous as well as treatment-related HBeAg
seroconversion. Some patients may clear HBeAg without an accompanying ALT flare. In adult-acquired
infection, the immune clearance phase represents the first phase of infection.
Inactive Hepatitis B Surface Antigen

Carrier State
SUMMARY
Inactive HBsAg carrier state characterized by the presence of anti-HBe, normal ALT levels, and low or
undetectable HBV DNA in serum (< 2000 IU/mL) (Table 7)
Liver biopsy usually shows minimal necroinflammation and varying degrees of fibrosis
The rate of HBsAg clearance is low, but higher in women, older patients, and those with
cirrhosis
Spontaneous HBeAg loss may be followed by reversion to HBeAg positivity in some patients
Lifelong follow-up of these patients required
The third phase of infection of perinatally acquired chronic hepatitis B and second phase of adult-acquired
chronic hepatitis B is the inactive HBsAg carrier state characterized by the presence of anti-HBe, normal
alanine aminotransferase levels, and low or undetectable hepatitis B virus (HBV) DNA in serum (< 2000 IU/mL)
(Table 7). These patients usually have a liver biopsy that shows minimal necroinflammation and varying
degrees of fibrosis. The prognosis is generally good for true inactive carriers; hepatitis B surface antigen
(HBsAg) clearance occurs in these individuals at a rate of 0.5% to 2.0% per year.
[Alward 1985; Liaw 1991; Liu
2010]
Women, older patients, and those with cirrhosis have a higher chance of HBsAg clearance.
2010]
Following spontaneous hepatitis B e antigen (HBeAg) seroconversion, approximately 4% to 20% of
patients will experience 1 reversion back to HBeAg positivity,
[Hsu 2002; McMahon 2001]
[Chu
highlighting the dynamic
nature of chronic HBV infection and the need for lifelong follow-up of patients in the inactive carrier state to
ensure that the inactive state persists.
Hepatitis B e AntigenNegative Active

Chronic Hepatitis B
SUMMARY
HBeAg-negative chronic HBV infection is characterized by presence of anti-HBe, raised ALT levels,
and HBV DNA in serum (Table 7)
Patients in the immune-clearance and reactivation phases should be considered for

treatment
Monitoring is recommended for those in the immune-tolerant and inactive phases, according
to activity of liver disease
Approximately 30% of individuals with chronic HBV infection will develop cirrhosis (Figure 3)
The annual incidence of cirrhosis is estimated to be 8% to 10% for HBeAg-negative

patients
[Fattovich 2003]
Risk factors include advanced age, elevated HBV DNA levels, HBV genotype C infection,
chronic increased alcohol intake, male sex, basal core promoter mutations, and HCV, HDV,
or HIV coinfection
High HBV DNA level is associated with increased risk of both HCC and cirrhosis in HBeAgnegative patients
A proportion of patients continue to have moderate levels of hepatitis B virus (HBV) replication and liver
damage, despite clearance of HBeAg, due to mutations in the precore or core promoter region of the viral
genome.
[Chan 2000; Okamoto 1994; Lok 1994; Carman 1989]
This scenario is termed hepatitis B e antigen (HBeAg)negative
chronic hepatitis B and is characterized by presence of anti-HBe, raised alanine aminotransferase levels, and
HBV DNA in serum (Table 7). Liver biopsy shows varying degrees of chronic hepatitis on biopsy. Thus,
patients in the immune-clearance and reactivation phases should be considered for treatment, whereas
monitoring is recommended for those in the immune-tolerant and inactive phases. Monitoring should be
lifelong because up to 30% of patients may transition between the active and inactive phases (Management
Guidelines).
[Lok 2009]
The frequency of monitoring should be determined by the activity of liver disease.
For additional information from inPractice on monitoring recommendations for patients who are not candidates
for therapy, click here.
Major complications of chronic hepatitis B include the development of cirrhosis, hepatic decompensation,
hepatocellular carcinoma, and death. These outcomes are variable and dependent on host, viral, and
environmental factors. Approximately 30% of individuals with chronic hepatitis B will develop cirrhosis (Figure
3). The annual incidence of cirrhosis is estimated to be 2% to 6% for hepatitis B e antigen (HBeAg)positive
[Fattovich 2003]
and 8% to 10% for HBeAg-negative patients.
The annual incidence of hepatocellular carcinoma has
been estimated to be 2% to 3% for carriers with cirrhosis and < 1% for carriers without cirrhosis (Figure 3).
Risk factors for progression to cirrhosis include advanced age, elevated HBV DNA levels, HBV genotype C
infection, chronic increased alcohol intake, male sex, basal core promoter mutations, and coinfections with
either hepatitis C virus, hepatitis D virus, or HIV.
[Yim 2006; Fattovich 2003; Chu 2009; Lin 2005]
A large prospective, population-based study conducted in Taiwanese patients, the majority of whom had
HBeAg-negative chronic hepatitis B, demonstrated that patients with high baseline HBV DNA level have an
increased risk for the development of cirrhosis and hepatocellular carcinoma (HCC).
2006]
[Iloeje 2006; Chen
Compared with patients with a baseline HBV DNA level < 300 copies/mL (approximately 60 IU/mL),
patients with a baseline HBV DNA level 1 million copies/mL (approximately 200,000 IU/mL) have an
approximately 10-fold higher risk of developing cirrhosis
2006]
[Iloeje 2006]
and an 11-fold increased risk for HCC.
[Chen
In the same study, a persistently high HBV DNA level was associated with an increased risk for HCC;
5
patients with an HBV DNA level persistently > 10 copies/mL (approximately 4.3 log10 IU/mL) had a 10-fold
4
higher risk of HCC vs those with a DNA level < 10 copies/mL (approximately 3.3 log10 IU/mL) at entry into the
study.
[Chen 2006]
MY SUBSCRIPTIONS
QUICK TOUR
MY CE
MY FOLDER
LOGOUT
Specialty
Decision Tools
Drug Reference
Guidelines
PubMed
Trials
More
XGO
Specialty
Hepatology
HBV Epidemiology
Summary
Global Overview
Sexual Transmission
Vaccination
Vaccine Booster
Pathogenesis
Natural History
Overview
Serology
HBsAg and Anti-HBs
Anti-HBc
HBeAg and Anti-HBe
HBV DNA Assays
Supporting Assets
References
Previous
Next
Save
Share
Print
Email

Zeuzem, MD
Screening and Diagnosis of Hepatitis B

Virus
SUMMARY
Overview of Screening and Diagnosis
Persons at high risk of HBV infection

should be screened for HBV (Management
Guidelines)
[CDC 2008a; CDC 2008b]
Persons testing negative should be

vaccinated, and persons testing positive
should be correctly diagnosed and
managed according to available guidelines
Serology
Acute and chronic HBV infections are

diagnosed using serologic assays for viral
antigens (hepatitis B surface and e
antigens) and antibodies (anti-HBc, antiHBs, and anti-HBe)
Hepatitis B Surface Antigen and AntiHBs
HBsAg is the serologic hallmark of

HBV infection
HBsAg usually appears

in serum 1-10 weeks
following exposure to
HBV and approximately
4-6 weeks before onset
of symptoms or elevation
of serum
aminotransferase
levels
[Krugman 1979; Holland
1975]
Resolution of infection is
characterized by loss of
HBsAg and detection of
anti-HBs, which confers
protection against HBV
infection and usually
persists for life
Persistence of HBsAg for

> 6 months indicates
chronic infection
Occasionally, HBsAg and

anti-HBs may coexist;
these individuals should
be regarded as
chronically infected
Quantifying HBsAg levels might

help distinguish active from
inactive HBeAg-negative chronic
hepatitis B
Monitoring HBsAg levels during

treatment may help identify
patients who are unlikely to
respond to peginterferon
The change in HBsAg levels

during nucleos(t)ide analogue
therapy is less predictable
Anti-HBc
Hepatitis B core antigen is an

intracellular viral antigen present
in infected hepatocytes
Anti-HBc, which is detectable in

serum, is present in acute and
chronic infection and persists after
recovery
Among populations with a high

HBV prevalence, an isolated antiHBc positive result is likely to
reflect a previous infection; among
groups with low HBV prevalence,
it is likely to reflect a false-positive
result (Management
Guidelines)
[Mast 2005]
Patients with an isolated anti-HBc

should be retested, preferably
using a radioimmunoassay test,
as well as being tested for HBsAg
and anti-HBs
Reactivation of hepatitis following

high-dose prednisone,
chemotherapy, bone marrow, or
stem cell transplant has also been
observed in anti-HBc positive
individuals
[Lubel 2010; Yeo 2006; Lok 1991]
Hepatitis B e Antigen and Anti-HBe
HBeAg is a secretory protein

derived from the precore protein
HBeAg levels correlate closely

with HBV DNA levels and are a
marker of viral replication and
[Alter 1976]
infectivity
During acute infection, HBeAg

appears shortly after the
appearance of HBsAg
During recovery, HBeAg

seroconversion usually precedes
HBsAg seroconversion and
signals the transition from a high
to a low replication state
[Krugman
1979]
Some patients who clear HBeAg

continue to have detectable HBV
DNA and active hepatitis due to
precore or double core promoter
mutations
[Kao 2008]
and are at risk
for progressive liver disease
HBeAg seroconversion to antiHBe is an important therapeutic

endpoint of anti-HBV
therapy (Management
Guidelines)
[Lok 2009]
HBV DNA Assays
HBV DNA is detectable within a few days

following acute infection, peaks with serum
ALT level, and then declines with resolution
of infection
[Fong 1994]
In chronic infection, HBV DNA levels are

highest in the immune-tolerant phase, high
in the immune-active phase, and very low
or undetectable in the inactive phase
(Table 7)
[Kao 2008]
HBV DNA quantification is used to estimate

phase of disease, prognosis, and the need
for therapy
HBV DNA level should be expressed in

IU/mL to permit comparisons between
different assays
Diagnosis of acute hepatitis B is based on

the detection of HBsAg and anti-HBc IgM in
serum (Table 8)
Diagnosis of chronic hepatitis B is based on

the detection and persistence of HBsAg in
serum for > 6 months (Table 8)
Patients diagnosed with chronic infection

require supplemental testing to stage
disease and inform treatment decision
making, eg, for HBeAg and HBV DNA
Liver biopsy is rarely necessary in patients

with acute hepatitis B
For patients with chronic hepatitis B, liver

biopsy is used to grade and stage the
severity of the liver disease and to

determine the need for therapy
Persons with moderate to severe

necroinflammation, or significant
fibrosis (Metavir stage > F2 or
Ishak stage 3) are candidates for
therapy, according to international
guidelines
[Lok 2009; EASL 2009; Liaw 2008]
Liver biopsy may also be used to

investigate abnormal radiologic findings
during screening for hepatocellular
carcinoma
Noninvasive tests have been evaluated for

the assessment of fibrosis severity in
chronic HBV infection (Table 9)
The use of these tests in

management algorithms has not
been well studied; use caution
when basing treatment decisions
on these tests
Overview of Screening and Diagnosis

Persons at high risk of hepatitis B virus (HBV) infection should be screened. Persons testing negative should
be vaccinated, and persons testing positive should be correctly diagnosed and managed according to available
[CDC 2008a; CDC
guidelines. HBV screening is indicated in the following situations(Management Guidelines) (B)

2008b]
Persons born in geographic regions with HBsAg prevalence

of 2%
US-born persons not vaccinated as infants whose parents

were born in geographic regions with hepatitis B surface
antigen (HBsAg) prevalence of 8%
Injection drug users
Persons with elevated alanine

transaminase/aspartate aminotransferase of unknown
etiology
Persons with selected medical conditions requiring or

resulting in an immunosuppressive state:
Chemotherapy
Organ transplantation
Rheumatologic disorders
Gastroenterologic disorders
Pregnant women
Infants born to HBsAg-positive mothers
Household contacts and sex partners of HBV-infected

persons
Persons who are the source of blood or body fluid exposures

that might warrant postexposure prophylaxis (eg, needlestick
injury to a healthcare worker)
Persons infected with HIV
In May 2014, the US Preventive Services Task Force published revised guidelines on HBV screening in
nonpregnant adults and adolescents that include recommendations for the screening of persons at high risk for
HBV infection. These high-risk groups are consistent with the Centers for Disease Control and Prevention
definitions and include the following populations (Management Guidelines)
[USPSTF HBV Screening]

of 2%

were born in geographic regions with hepatitis B surface
antigen prevalence of 8%

persons
Serology
Serologic assays for 2 viral antigens (hepatitis B surface and e antigens) and 3 antibodies (anti-HBc, anti-HBs,
and anti-HBe) form the basis of diagnosis of acute and chronic hepatitis B virus infection. Sensitive and
specific commercial assays that are US Food and Drug Administration approved or licensed are available for
their detection.
Hepatitis B Surface Antigen and Anti-HBs

Hepatitis B surface antigen (HBsAg), the serologic hallmark of hepatitis B virus (HBV) infection, usually
appears in serum 1-10 weeks following exposure to HBV and approximately 4-6 weeks before the onset of
symptoms or elevation of serum aminotransferase levels.
months indicates chronic infection.
[Kao 2008]
[Krugman 1979;Holland 1975]
Persistence of HBsAg for > 6
Conversely, resolution of infection is characterized by loss of HBsAg
and detection of anti-HBs, which usually persists for life.
[Bcher 1996]
induced by vaccination, confers protection against HBV infection.
Anti-HBs, the only neutralizing antibody
[Bcher 1996]
In rare circumstances, anti-HBs
may not be detectable for some weeks to months in an individual destined for recovery and in whom HBsAg
has already cleared.
[McMahon 1981]
During the window period in which neither HBsAg nor anti-HBs are
detectable in serum, the only serologic marker of infection is hepatitis B core antibody (anti-HBc) IgM.
[van
Ditzhuijsen 1985]
Occasionally, HBsAg and anti-HBs may coexist. It is believed in this situation that the anti-HBs is directed
against one of the subtypical determinants and not the common a determinant of the antibody; therefore, it is
[Chongsrisawat 2006]
not neutralizing.
These individuals should be regarded as chronically infected.
There has been interest in the clinical utility of HBsAg quantification. Three types of assays are available:
enzyme immunoassays (EIAs), microparticle EIAs, and chemiluminescence assays. These assays all have a
narrow dynamic range at the lower end of quantification and thus high titer samples must be diluted.
[Nguyen 2010]
Cross-sectional studies demonstrate a gradient in HBsAg levels during the course of chronic hepatitis B: they
are highest in the immune-tolerant phase (HBeAg positive), lower in the immune clearance phase (hepatitis B
e antigen [drug: HBeAg] positive), and lowest in the inactive phase (hepatitis e surface antigen negative)
(Table 7).
[Nguyen 2010]
The correlation between HBsAg and HBV DNA levels among different phases of chronic
hepatitis B infection is complex and variablethe best correlation is during the immune-clearance phase
where higher serum HBV DNA levels correlate with higher hepatitis B surface antigen (HBsAg) levels (r =
0.77; P = .0001).
[Nguyen 2010]
HBsAg levels have been shown to differ among genotypes; indeed, one study
reported that among patients with HBeAg-negative chronic hepatitis B, patients with genotype A tended to
have higher HBsAg levels compared with those with genotype D.
[Jaroszewicz 2010]
Quantifying HBsAg levels might help distinguish active from inactive HBeAg-negative CHB and, when
combined with HBV DNA measurement, may permit a more accurate assessment of the true inactive carrier in
patients with HBV genotype D infection.
[Chan 2010; Brunetto 2010]
HBsAg levels and serum alanine aminotransferase levels.
No correlation has been found to exist between
[Nguyen 2010; Jaroszewicz 2010]
The variable correlation
between HBsAg and HBV DNA levels, especially among different genotypes, may be a limitation to the clinical
applicability of HBsAg quantification.
[Thompson 2010]
Monitoring HBsAg levels during treatment may be useful in identifying patients who are unlikely to respond to
peginterferon early in the course of therapy and may lead to the development of early stopping rules that limit
exposure to therapy with numerous adverse effects.
2013]
[Martinot-Peignoux 2013; Hadziyannis 2014; Sonneveld 2010; Sonneveld
Conversely, it may have a role to identify patients who are responding to peginterferon and serve as
motivation for them to remain on therapy. The change in HBsAg levels during nucleos(t)ide analogue therapy
is less predictable compared with that with peginterferon and results are inconsistent across studies.
Peignoux 2013; Hadziyannis 2014; Jung 2010;Reijnders 2011]
[Martinot-
A study that followed 48 HBV-infected patients who were receiving
either lamivudine or entecavir monotherapy demonstrated that significant decreases in HBsAg levels from
baseline were only detectable after 5 years of treatment (P = .028).
[Kim 2013]
The results of another recent trial
suggested that HBsAg levels at the end of lamivudine treatment may be predictive of HBsAg loss and HBV
relapse following treatment discontinuation.
[Chen 2014]
In summary, numerous issues remain to be resolved before HBsAg quantification can be recommended in
routine clinical practice. The optimal HBsAg cutoff with the ideal positive and negative predictive values needs
to be defined. It is unclear whether HBsAg quantification is a better predictor of treatment outcome than HBV
DNA level alone. Finally, prediction models using HBsAg quantification with HBV DNA levels during antiviral
therapy need to be developed and prospectively validated.
Anti-HBc
Hepatitis B core antigen is an intracellular viral antigen that is present in infected hepatocytes but cannot be
detected in serum. Antibody to hepatitis B core antigen (anti-HBc), which is detectable in serum, is present in
acute and chronic infection and persists after recovery. Anti-HBc usually appears after hepatitis B surface
antigen (HBsAg) but before the rise in serum alanine aminotransferase. The presence of anti-HBc IgM typically
indicates acute infection, but the antibody is also occasionally detectable during exacerbation of chronic
hepatitis B; this can lead to confusion as to whether the presentation is acute or chronic.
[Kao 2008]
Anti-HBc IgGa nonneutralizing antibodypersists in persons with chronic hepatitis B virus (HBV) and in
those who recover from acute hepatitis. Anti-HBc IgG may be detected in the absence of other serologic
markers of infection (HBsAg and anti-HBs) in approximately 1% of blood donors in low-prevalence areas
[Chevrier
2007; Joller-Jemelka 1994; Hadler 1984]
and in 20% of blood donors from endemic areas.
[Kao 2002; Chung 1993]
Anti-HBc IgG
measurements are therefore useful for epidemiologic surveys of chronic hepatitis B prevalence.
Isolated detection of anti-HBc can occur in 4 settings: a false-positive test result; during the window period of
acute hepatitis B when the anti-HBc is predominantly IgM; many years after recovery from acute hepatitis B
when anti-HBs has fallen to undetectable levels; and after many years of chronic HBV infection when the
HBsAg titer has decreased below the cutoff level for detection.
[Hess 1980; Lok 1988; McMahon 1992]
Among populations
with a high HBV prevalence, an isolated anti-HBc positive result is likely to reflect a previous infection;
however, among groups with low HBV prevalence, isolated anti-HBc positivity is likely to reflect a false-positive
result (Management Guidelines).
[Mast 2005]
Most patients in the latter category exhibit a primary anti-HBs
response to HBV vaccination (3-dose series). HBV DNA is detectable in 0% to 20% of persons with isolated
anti-HBc.
[Douglas 1993; Mosley 1995]
Transmission of HBV infection can occur from anti-HBc positive blood or solid
organ donors; transmission rates range from 0.4% to 78%, with the highest rates observed in liver donors.
Reactivation of hepatitis following high-dose prednisone, chemotherapy, bone marrow, or stem cell transplant
has also been observed in anti-HBc positive individuals.
[Lubel 2010; Yeo 2006; Lok 1991]
The evaluation of patients with an isolated anti-HBc should include retesting, preferably by a
radioimmunoassay test. HBsAg and anti-HBs should be tested as well. Individuals who remain isolated antiHBc positive should be tested for anti-HBc IgM to exclude acute hepatitis B in the window period and HBV
DNA to exclude chronic HBV infection with low level viral replication (A). For patients with no risk factors for
hepatitis B, an isolated anti-HBc should be considered a false positive test and the patient considered
nonimmune. These patients should be offered the complete HBV immunization series.

Hepatitis B e antigen (HBeAg) is a secretory protein derived from the precore protein. HBeAg levels correlate
closely with hepatitis B virus (HBV) DNA levels; thus, it is a useful surrogate marker of viral replication and
infectivity.
[Alter 1976]
Consequently, rates of infection resulting from mother-to-infant transmission, occupational
exposure, and nosocomial exposure are all higher in HBeAg-positive individuals compared with persons who
have developed antibody toward HBeAg (anti-HBe) (Management Guidelines).
[Stevens 1975; Mast 2006]
During acute
infection, HBeAg appears shortly after the appearance of hepatitis B surface antigen (HBsAg). During
recovery, HBeAg seroconversion (loss of HBeAg and detection of anti-HBe) usually precedes HBsAg
seroconversion (loss of HBsAg and detection of anti-HBs) and signals the transition from a high replicative
state to a low replication state.
[Krugman 1979]
However, a proportion of patients who clear HBeAg and gain anti-
HBe continue to have detectable HBV DNA and active hepatitis due to the presence of precore or double core
promoter mutations that downregulate the production of HBeAg.
progressive liver disease.
[Kao 2008]
These latter individuals are at risk for
The detection of HBeAg is important for determining the phase of HBV infection, but its role in determining viral
activity has been largely superseded by sensitive assays for HBV DNA. However, HBeAg seroconversion to
anti-HBe remains an important therapeutic endpoint of anti-HBV therapies(Management Guidelines).
[Lok 2009]
HBV DNA Assays

Hepatitis B virus (HBV) DNA is detectable within a few days following acute infection, peaks just prior to the
peak serum alanine aminotransferase level, and then declines and becomes undetectable with resolution of
infection.
[Fong 1994]
In chronic infection, HBV DNA levels differ with each phase of infection.
[Kao 2008]
Levels are
highest in the immune-tolerant phase, high in the immune-active phase, and very low or undetectable in the
inactive phase (Table 7).
[Kao 2008]
In the reactivation (anti-HBe-positive) phase, HBV DNA levels are high but
lower than in the immune-active phase by approximately 2 logs. Thus, HBV DNA quantification is helpful for
estimating phase of disease, prognosis and determining the need for therapy.
Early assays for HBV DNA quantification were based on hybridization and/or signal amplification methods.
These assays had narrow dynamic ranges that spanned the upper ranges of HBV DNA quantification (4.3
log10 IU/mL to 5.3 log10 IU/mL), limiting their clinical utility. More recently, the introduction of polymerase chain
reaction technology has provided the accurate quantification over a broad range of HBV DNA levels, allowing
the accurate monitoring of both treated and untreated patients.
[Pawlotsky 2008]
The HBV DNA level should be
expressed in IU/mL to allow for standardized reporting and to permit comparisons between studies that use
different assays.
In clinical practice, HBV DNA measurement is used to assess the state of HBV infection, stratify risk of disease
progression to cirrhosis and hepatocellular carcinoma, aid in the decision to begin therapy, and monitor
treatment efficacy and failure. A serum HBV DNA level > 2000 IU/mL has been proposed as a cutoff level to
differentiate patients with HBeAg-negative chronic hepatitis from those in an inactive carrier state (ie, hepatitis
B e antigen negative, persistently normal alanine aminotransferase).
For persons in whom acute hepatitis B is suspected, the diagnosis is based on the detection of hepatitis B
surface antigen (HBsAg) and anti-HBc IgM in serum (Table 8). In the uncommon situation of a patient
presenting in the window period, anti-HBc IgM is the only serologic marker of infection. Fulminant hepatitis is
an example of a situation where only anti-HBc IgM may be present because of rapid viral clearance. Recovery
is diagnosed by the detection of anti-HBc IgG and anti-HBs (Table 8).
The diagnosis of chronic hepatitis B is based on the detection and persistence of HBsAg in serum for > 6
months (Table 8). To better characterize patients and provide information on prognosis and response to
treatment, supplemental testing for hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA should be
performed. If interferon therapy is being considered, testing for HBV genotype is helpful to predict response to
treatment.
[Cao 2009; Buster 2008; Buster 2009]
Table 8. Serologic Tests and Their Interpretation[Mast 2005]

HBsAg HBeAg AntiHBc
IgM
+
+
+
+
+
-
AntiHBc
IgG
+
AntiHBe
AntiHBs
Interpretation
+
+
+
-
+
+
Acute hepatitis B
HBeAg-positive chronic
hepatitis B
HBeAg-negative chronic
hepatitis B
Recovered
Chronic hepatitis B or passive
transfer to infant born to
HBsAg-positive mother or falsepositive
Vaccinated

Liver biopsy is rarely necessary in the setting of acute hepatitis B. For patients with chronic hepatitis B, the
purpose of the liver biopsy is to grade and stage the severity of the liver disease and to determine the need for
therapy; it is not required for diagnosis. Persons with moderate to severe necroinflammation and persons with
significant fibrosis (Metavir stage > F2 or Ishak stage 3) are candidates for therapy according to guidelines
from the American Association for the Study of Liver Diseases (AASLD) (Management Guidelines) (B),
2009]
the European Association for the Study of the Liver (Management Guidelines),
Pacific Association for the Study of the Liver (Management Guidelines).
[Liaw 2008]
[EASL 2009]
[Lok
and the Asian
Another role of liver biopsy is
to investigate abnormal radiologic findings during screening for hepatocellular carcinoma. Liver biopsy can
identify liver cell dysplasia, including large and small cell changes, and can differentiate macroregenerative
nodules from well-differentiated hepatocellular carcinoma.
According to the AASLD guidelines, if the decision to treat is clear-cut, such as for persons who are hepatitis B
e antigen (HBeAg)-positive or HBeAg-negative with elevated serum transaminases (> 2 upper limit of
normal), a liver biopsy is optional and patients may be initiated on therapy without a biopsy.
[Lok 2007]
On the
other hand, if the indication for treatment is unclear, then a biopsy should be performed to aid in the
management decision. As an example, liver biopsy should be considered in patients with mildly elevated
alanine transaminase (1-2 upper limit of normal) who have persistently elevated hepatitis B virus (HBV) DNA,
particularly if the patient is older than 40 years or has features suggestive of chronic liver disease. In all
instances, the indication and risks of the procedure should be discussed with the patient (C).
Numerous noninvasive tests have been evaluated for the assessment of fibrosis severity in chronic HBV
infection. These include transient elastography and several serum-based tests (Table 9). Despite extensive
research, no guidelines currently recommend routine clinical use of noninvasive methods for the evaluation of
fibrosis severity. In general, noninvasive tests can distinguish advanced fibrosis from no fibrosis with a high
degree of accuracy, but the performance of the test declines in persons with mild to moderate degrees of
fibrosis, in which there is considerable overlap in scores.
[Chan 2009; Marcellin 2009]
These tests are less accurate for
prediction of fibrosis in chronic hepatitis B compared with chronic hepatitis C.
[Degos 2010]
management algorithms for treatment has not been well studied and basing treatment decisions on the results
of these tests should be performed with caution.
Table 9. Noninvasive Serum-Based Tests for the Detection of Fibrosis

Test
Parameters Measured
FibroTest[Myers 2003; Ngo 2008]
2-macroglobulin, haptoglobin, gamma glutamyl

transferase, total bilirubin, and apolipoprotein A1
FibroSpect II[Jeffers 2007]
2-macroglobulin, hyaluronic acid, and tissue inhibitor of

metalloproteinase-1
FibroSURE[Poynard 2011]
2-macroglobulin, haptoglobin, apolipoprotein A1,

bilirubin, gamma glutamyl transferase, alanine
transaminase, aspartate aminotransferase, total
cholesterol, triglycerides, and fasting glucose
APRI[Wu 2010; Shin 2008]
Aspartate aminotransferase-to-platelets ratio index
Forns fibrosis index[Wu 2010; ref:Mart
Age, platelet count, gamma glutamyl transferase,

cholesterol
nez 2011]
FIB-4[Mallet 2009]
Platelets, alanine transaminase, aspartate

aminotransferase, and age
HepaScore[Raftopoulos 2011; Zhou 2010]
2-macroglobulin, gamma glutamyl transferase,

hyaluronic acid, and total bilirubin
Fibrometer[Zhou 2010]
Age, sex, 2-macroglobulin, hyaluronic acid, platelets,

prothrombin index, aspartate aminotransferase, and urea
Keywords: Hepatitis B, Hepatitis B-Diagnosis, Hepatitis B-Screening
Hepatitis B Surface Antigen and Anti-HBs

SUMMARY
HBsAg is the serologic hallmark of HBV infection
HBsAg usually appears in serum 1-10 weeks following exposure to HBV and approximately
4-6 weeks before onset of symptoms or elevation of serum aminotransferase levels
[Krugman
1979; Holland 1975]
Resolution of infection is characterized by loss of HBsAg and detection of anti-HBs, which

confers protection against HBV infection and usually persists for life
Persistence of HBsAg for > 6 months indicates chronic infection
Occasionally, HBsAg and anti-HBs may coexist; these individuals should be regarded as
chronically infected
Quantifying HBsAg levels might help distinguish active from inactive HBeAg-negative chronic hepatitis
B
Monitoring HBsAg levels during treatment may help identify patients who are unlikely to respond to
peginterferon
The change in HBsAg levels during nucleos(t)ide analogue therapy is less predictable
Hepatitis B surface antigen (HBsAg), the serologic hallmark of hepatitis B virus (HBV) infection, usually
appears in serum 1-10 weeks following exposure to HBV and approximately 4-6 weeks before the onset of
symptoms or elevation of serum aminotransferase levels.
months indicates chronic infection.
[Kao 2008]
[Krugman 1979;Holland 1975]
Persistence of HBsAg for > 6
Conversely, resolution of infection is characterized by loss of HBsAg
and detection of anti-HBs, which usually persists for life.
[Bcher 1996]
induced by vaccination, confers protection against HBV infection.
Anti-HBs, the only neutralizing antibody
[Bcher 1996]
In rare circumstances, anti-HBs
may not be detectable for some weeks to months in an individual destined for recovery and in whom HBsAg
has already cleared.
[McMahon 1981]
During the window period in which neither HBsAg nor anti-HBs are
detectable in serum, the only serologic marker of infection is hepatitis B core antibody (anti-HBc) IgM.
[van
Ditzhuijsen 1985]
Occasionally, HBsAg and anti-HBs may coexist. It is believed in this situation that the anti-HBs is directed
against one of the subtypical determinants and not the common a determinant of the antibody; therefore, it is
[Chongsrisawat 2006]
not neutralizing.
These individuals should be regarded as chronically infected.
There has been interest in the clinical utility of HBsAg quantification. Three types of assays are available:
enzyme immunoassays (EIAs), microparticle EIAs, and chemiluminescence assays. These assays all have a
narrow dynamic range at the lower end of quantification and thus high titer samples must be diluted.
[Nguyen 2010]
Cross-sectional studies demonstrate a gradient in HBsAg levels during the course of chronic hepatitis B: they
are highest in the immune-tolerant phase (HBeAg positive), lower in the immune clearance phase (hepatitis B
e antigen [drug: HBeAg] positive), and lowest in the inactive phase (hepatitis e surface antigen negative)
(Table 7).
[Nguyen 2010]
The correlation between HBsAg and HBV DNA levels among different phases of chronic
hepatitis B infection is complex and variablethe best correlation is during the immune-clearance phase
where higher serum HBV DNA levels correlate with higher hepatitis B surface antigen (HBsAg) levels (r =
0.77; P = .0001).
[Nguyen 2010]
HBsAg levels have been shown to differ among genotypes; indeed, one study
reported that among patients with HBeAg-negative chronic hepatitis B, patients with genotype A tended to
have higher HBsAg levels compared with those with genotype D.
[Jaroszewicz 2010]
Quantifying HBsAg levels might help distinguish active from inactive HBeAg-negative CHB and, when
combined with HBV DNA measurement, may permit a more accurate assessment of the true inactive carrier in
patients with HBV genotype D infection.
[Chan 2010; Brunetto 2010]
HBsAg levels and serum alanine aminotransferase levels.
No correlation has been found to exist between
[Nguyen 2010; Jaroszewicz 2010]
The variable correlation
between HBsAg and HBV DNA levels, especially among different genotypes, may be a limitation to the clinical
applicability of HBsAg quantification.
[Thompson 2010]
Monitoring HBsAg levels during treatment may be useful in identifying patients who are unlikely to respond to
peginterferon early in the course of therapy and may lead to the development of early stopping rules that limit
exposure to therapy with numerous adverse effects.
2013]
[Martinot-Peignoux 2013; Hadziyannis 2014; Sonneveld 2010; Sonneveld
Conversely, it may have a role to identify patients who are responding to peginterferon and serve as
motivation for them to remain on therapy. The change in HBsAg levels during nucleos(t)ide analogue therapy
is less predictable compared with that with peginterferon and results are inconsistent across studies.
Peignoux 2013; Hadziyannis 2014; Jung 2010;Reijnders 2011]
[Martinot-
A study that followed 48 HBV-infected patients who were receiving
either lamivudine or entecavir monotherapy demonstrated that significant decreases in HBsAg levels from
baseline were only detectable after 5 years of treatment (P = .028).
[Kim 2013]
The results of another recent trial
suggested that HBsAg levels at the end of lamivudine treatment may be predictive of HBsAg loss and HBV
relapse following treatment discontinuation.
[Chen 2014]
In summary, numerous issues remain to be resolved before HBsAg quantification can be recommended in
routine clinical practice. The optimal HBsAg cutoff with the ideal positive and negative predictive values needs
to be defined. It is unclear whether HBsAg quantification is a better predictor of treatment outcome than HBV
DNA level alone. Finally, prediction models using HBsAg quantification with HBV DNA levels during antiviral
therapy need to be developed and prospectively validated.
Anti-HBc
SUMMARY
Hepatitis B core antigen is an intracellular viral antigen present in infected hepatocytes
Anti-HBc, which is detectable in serum, is present in acute and chronic infection and persists after
recovery
Among populations with a high HBV prevalence, an isolated anti-HBc positive result is likely to reflect
a previous infection; among groups with low HBV prevalence, it is likely to reflect a false-positive
result (Management Guidelines)
[Mast 2005]
Patients with an isolated anti-HBc should be retested, preferably using a radioimmunoassay test, as
well as being tested for HBsAg and anti-HBs
Reactivation of hepatitis following high-dose prednisone, chemotherapy, bone marrow, or stem cell
transplant has also been observed in anti-HBc positive individuals
[Lubel 2010; Yeo 2006; Lok 1991]
Hepatitis B core antigen is an intracellular viral antigen that is present in infected hepatocytes but cannot be
detected in serum. Antibody to hepatitis B core antigen (anti-HBc), which is detectable in serum, is present in
acute and chronic infection and persists after recovery. Anti-HBc usually appears after hepatitis B surface
antigen (HBsAg) but before the rise in serum alanine aminotransferase. The presence of anti-HBc IgM typically
indicates acute infection, but the antibody is also occasionally detectable during exacerbation of chronic
hepatitis B; this can lead to confusion as to whether the presentation is acute or chronic.
[Kao 2008]
Anti-HBc IgGa nonneutralizing antibodypersists in persons with chronic hepatitis B virus (HBV) and in
those who recover from acute hepatitis. Anti-HBc IgG may be detected in the absence of other serologic
markers of infection (HBsAg and anti-HBs) in approximately 1% of blood donors in low-prevalence areas
2007; Joller-Jemelka 1994; Hadler 1984]
and in 20% of blood donors from endemic areas.
[Kao 2002; Chung 1993]
[Chevrier
Anti-HBc IgG
measurements are therefore useful for epidemiologic surveys of chronic hepatitis B prevalence.
Isolated detection of anti-HBc can occur in 4 settings: a false-positive test result; during the window period of
acute hepatitis B when the anti-HBc is predominantly IgM; many years after recovery from acute hepatitis B
when anti-HBs has fallen to undetectable levels; and after many years of chronic HBV infection when the
HBsAg titer has decreased below the cutoff level for detection.
[Hess 1980; Lok 1988; McMahon 1992]
Among populations
with a high HBV prevalence, an isolated anti-HBc positive result is likely to reflect a previous infection;
however, among groups with low HBV prevalence, isolated anti-HBc positivity is likely to reflect a false-positive
result (Management Guidelines).
[Mast 2005]
Most patients in the latter category exhibit a primary anti-HBs
response to HBV vaccination (3-dose series). HBV DNA is detectable in 0% to 20% of persons with isolated
anti-HBc.
[Douglas 1993; Mosley 1995]
Transmission of HBV infection can occur from anti-HBc positive blood or solid
organ donors; transmission rates range from 0.4% to 78%, with the highest rates observed in liver donors.
Reactivation of hepatitis following high-dose prednisone, chemotherapy, bone marrow, or stem cell transplant
has also been observed in anti-HBc positive individuals.
[Lubel 2010; Yeo 2006; Lok 1991]
The evaluation of patients with an isolated anti-HBc should include retesting, preferably by a
radioimmunoassay test. HBsAg and anti-HBs should be tested as well. Individuals who remain isolated antiHBc positive should be tested for anti-HBc IgM to exclude acute hepatitis B in the window period and HBV
DNA to exclude chronic HBV infection with low level viral replication (A). For patients with no risk factors for
hepatitis B, an isolated anti-HBc should be considered a false positive test and the patient considered
nonimmune. These patients should be offered the complete HBV immunization series.

SUMMARY
HBeAg is a secretory protein derived from the precore protein
HBeAg levels correlate closely with HBV DNA levels and are a marker of viral replication and
[Alter 1976]
infectivity
During acute infection, HBeAg appears shortly after the appearance of HBsAg
During recovery, HBeAg seroconversion usually precedes HBsAg seroconversion and signals the
transition from a high to a low replication state
Some patients who clear HBeAg continue to have detectable HBV DNA and active hepatitis due to
precore or double core promoter mutations
[Krugman 1979]
[Kao 2008]
and are at risk for progressive liver disease
HBeAg seroconversion to anti-HBe is an important therapeutic endpoint of anti-HBV

therapy (Management Guidelines)
[Lok 2009]
Hepatitis B e antigen (HBeAg) is a secretory protein derived from the precore protein. HBeAg levels correlate
closely with hepatitis B virus (HBV) DNA levels; thus, it is a useful surrogate marker of viral replication and
infectivity.
[Alter 1976]
Consequently, rates of infection resulting from mother-to-infant transmission, occupational
exposure, and nosocomial exposure are all higher in HBeAg-positive individuals compared with persons who
have developed antibody toward HBeAg (anti-HBe) (Management Guidelines).
[Stevens 1975; Mast 2006]
During acute
infection, HBeAg appears shortly after the appearance of hepatitis B surface antigen (HBsAg). During
recovery, HBeAg seroconversion (loss of HBeAg and detection of anti-HBe) usually precedes HBsAg
seroconversion (loss of HBsAg and detection of anti-HBs) and signals the transition from a high replicative
state to a low replication state.
[Krugman 1979]
However, a proportion of patients who clear HBeAg and gain anti-
HBe continue to have detectable HBV DNA and active hepatitis due to the presence of precore or double core
promoter mutations that downregulate the production of HBeAg.
[Kao 2008]
These latter individuals are at risk for
progressive liver disease.
The detection of HBeAg is important for determining the phase of HBV infection, but its role in determining viral
activity has been largely superseded by sensitive assays for HBV DNA. However, HBeAg seroconversion to
anti-HBe remains an important therapeutic endpoint of anti-HBV therapies(Management Guidelines).
[Lok 2009]
HBV DNA Assays

SUMMARY
HBV DNA is detectable within a few days following acute infection, peaks with serum ALT level, and
then declines with resolution of infection
[Fong 1994]
In chronic infection, HBV DNA levels are highest in the immune-tolerant phase, high in the immuneactive phase, and very low or undetectable in the inactive phase (Table 7)
[Kao 2008]
HBV DNA quantification is used to estimate phase of disease, prognosis, and the need for therapy
HBV DNA level should be expressed in IU/mL to permit comparisons between different assays
Hepatitis B virus (HBV) DNA is detectable within a few days following acute infection, peaks just prior to the
peak serum alanine aminotransferase level, and then declines and becomes undetectable with resolution of
infection.
[Fong 1994]
In chronic infection, HBV DNA levels differ with each phase of infection.
[Kao 2008]
Levels are
highest in the immune-tolerant phase, high in the immune-active phase, and very low or undetectable in the
inactive phase (Table 7).
[Kao 2008]
In the reactivation (anti-HBe-positive) phase, HBV DNA levels are high but
lower than in the immune-active phase by approximately 2 logs. Thus, HBV DNA quantification is helpful for
estimating phase of disease, prognosis and determining the need for therapy.
Early assays for HBV DNA quantification were based on hybridization and/or signal amplification methods.
These assays had narrow dynamic ranges that spanned the upper ranges of HBV DNA quantification (4.3
log10 IU/mL to 5.3 log10 IU/mL), limiting their clinical utility. More recently, the introduction of polymerase chain
reaction technology has provided the accurate quantification over a broad range of HBV DNA levels, allowing
the accurate monitoring of both treated and untreated patients.
[Pawlotsky 2008]
The HBV DNA level should be
expressed in IU/mL to allow for standardized reporting and to permit comparisons between studies that use
different assays.
In clinical practice, HBV DNA measurement is used to assess the state of HBV infection, stratify risk of disease
progression to cirrhosis and hepatocellular carcinoma, aid in the decision to begin therapy, and monitor
treatment efficacy and failure. A serum HBV DNA level > 2000 IU/mL has been proposed as a cutoff level to
differentiate patients with HBeAg-negative chronic hepatitis from those in an inactive carrier state (ie, hepatitis
B e antigen negative, persistently normal alanine aminotransferase).
SUMMARY
Diagnosis of acute hepatitis B is based on the detection of HBsAg and anti-HBc IgM in serum (Table
8)
Diagnosis of chronic hepatitis B is based on the detection and persistence of HBsAg in serum for > 6
months (Table 8)
Patients diagnosed with chronic infection require supplemental testing to stage disease and inform
treatment decision making, eg, for HBeAg and HBV DNA
For persons in whom acute hepatitis B is suspected, the diagnosis is based on the detection of hepatitis B
surface antigen (HBsAg) and anti-HBc IgM in serum (Table 8). In the uncommon situation of a patient
presenting in the window period, anti-HBc IgM is the only serologic marker of infection. Fulminant hepatitis is
an example of a situation where only anti-HBc IgM may be present because of rapid viral clearance. Recovery
is diagnosed by the detection of anti-HBc IgG and anti-HBs (Table 8).
The diagnosis of chronic hepatitis B is based on the detection and persistence of HBsAg in serum for > 6
months (Table 8). To better characterize patients and provide information on prognosis and response to
treatment, supplemental testing for hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA should be
performed. If interferon therapy is being considered, testing for HBV genotype is helpful to predict response to
treatment.
[Cao 2009; Buster 2008; Buster 2009]
Table 8. Serologic Tests and Their Interpretation[Mast 2005]

HBsAg HBeAg AntiHBc
IgM
+
+
+
+
+
-
AntiHBc
IgG
+
AntiHBe
AntiHBs
Interpretation
+
+
+
-
+
+
Acute hepatitis B
HBeAg-positive chronic
hepatitis B
HBeAg-negative chronic
hepatitis B
Recovered
Chronic hepatitis B or passive
transfer to infant born to
HBsAg-positive mother or falsepositive
Vaccinated

SUMMARY
Liver biopsy is rarely necessary in patients with acute hepatitis B
For patients with chronic hepatitis B, liver biopsy is used to grade and stage the severity of the liver
disease and to determine the need for therapy
Persons with moderate to severe necroinflammation, or significant fibrosis (Metavir stage >
F2 or Ishak stage 3) are candidates for therapy, according to international guidelines
[Lok
2009; EASL 2009; Liaw 2008]
Liver biopsy may also be used to investigate abnormal radiologic findings during screening for
hepatocellular carcinoma
Noninvasive tests have been evaluated for the assessment of fibrosis severity in chronic HBV
infection (Table 9)
The use of these tests in management algorithms has not been well studied; use caution
when basing treatment decisions on these tests
therapy; it is not required for diagnosis. Persons with moderate to severe necroinflammation and persons with
significant fibrosis (Metavir stage > F2 or Ishak stage 3) are candidates for therapy according to guidelines
from the American Association for the Study of Liver Diseases (AASLD) (Management Guidelines) (B),
2009]
the European Association for the Study of the Liver (Management Guidelines),
Pacific Association for the Study of the Liver (Management Guidelines).
[Liaw 2008]
[EASL 2009]
[Lok
and the Asian
Another role of liver biopsy is
to investigate abnormal radiologic findings during screening for hepatocellular carcinoma. Liver biopsy can
identify liver cell dysplasia, including large and small cell changes, and can differentiate macroregenerative
nodules from well-differentiated hepatocellular carcinoma.
According to the AASLD guidelines, if the decision to treat is clear-cut, such as for persons who are hepatitis B
e antigen (HBeAg)-positive or HBeAg-negative with elevated serum transaminases (> 2 upper limit of
normal), a liver biopsy is optional and patients may be initiated on therapy without a biopsy.
[Lok 2007]
On the
other hand, if the indication for treatment is unclear, then a biopsy should be performed to aid in the
management decision. As an example, liver biopsy should be considered in patients with mildly elevated
alanine transaminase (1-2 upper limit of normal) who have persistently elevated hepatitis B virus (HBV) DNA,
particularly if the patient is older than 40 years or has features suggestive of chronic liver disease. In all
instances, the indication and risks of the procedure should be discussed with the patient (C).
Numerous noninvasive tests have been evaluated for the assessment of fibrosis severity in chronic HBV
infection. These include transient elastography and several serum-based tests (Table 9). Despite extensive
research, no guidelines currently recommend routine clinical use of noninvasive methods for the evaluation of
fibrosis severity. In general, noninvasive tests can distinguish advanced fibrosis from no fibrosis with a high
degree of accuracy, but the performance of the test declines in persons with mild to moderate degrees of
fibrosis, in which there is considerable overlap in scores.
[Chan 2009; Marcellin 2009]
These tests are less accurate for
prediction of fibrosis in chronic hepatitis B compared with chronic hepatitis C.
[Degos 2010]
management algorithms for treatment has not been well studied and basing treatment decisions on the results
of these tests should be performed with caution.
Table 9. Noninvasive Serum-Based Tests for the Detection of Fibrosis

Test
Parameters Measured
FibroTest[Myers 2003; Ngo 2008]
2-macroglobulin, haptoglobin, gamma glutamyl

transferase, total bilirubin, and apolipoprotein A1
FibroSpect II[Jeffers 2007]
2-macroglobulin, hyaluronic acid, and tissue inhibitor of

metalloproteinase-1
FibroSURE[Poynard 2011]
2-macroglobulin, haptoglobin, apolipoprotein A1,

bilirubin, gamma glutamyl transferase, alanine
transaminase, aspartate aminotransferase, total
cholesterol, triglycerides, and fasting glucose
APRI[Wu 2010; Shin 2008]
Aspartate aminotransferase-to-platelets ratio index
Forns fibrosis index[Wu 2010; ref:Mart
Age, platelet count, gamma glutamyl transferase,

cholesterol
nez 2011]
FIB-4[Mallet 2009]
Platelets, alanine transaminase, aspartate

aminotransferase, and age
HepaScore[Raftopoulos 2011; Zhou 2010]
2-macroglobulin, gamma glutamyl transferase,

hyaluronic acid, and total bilirubin
Fibrometer[Zhou 2010]
Age, sex, 2-macroglobulin, hyaluronic acid, platelets,

prothrombin index, aspartate aminotransferase, and urea
MY SUBSCRIPTIONS
QUICK TOUR
MY CE
MY FOLDER
LOGOUT
Specialty
Decision Tools
Drug Reference
Guidelines
PubMed
Trials
More
XGO
Specialty
Hepatology
HBV Epidemiology
Summary
Global Overview
Sexual Transmission
Vaccination
Vaccine Booster
Pathogenesis
Natural History
Overview
Serology
HBsAg and Anti-HBs
Anti-HBc
HBeAg and Anti-HBe
HBV DNA Assays
Supporting Assets
References
Previous
Next
Save
Share
Print
Email

Zeuzem, MD

SUMMARY
Primary care physicians play a critical role in

reducing the risk of HBV infection among patients by
ensuring vaccination guidelines are followed and in
identifying those at risk for infection who should be

screened
HBV acquisition occurs in 70% to 90% of infants

born to HBeAg-positive mothers with high HBV DNA
levels (> 7.3 log10 IU/mL) at delivery
[Stevens 1975]
Passive-active immunization at birth

significantly reduces (~ 95%) the rate of
perinatal transmission
[Mast 2005]
The CDC recommends the following groups for HBV

vaccination
[CDC 2012]
All newborns
Children and adolescents through 18 years

of age who did not receive the vaccination
earlier
Anyone who wants to be protected against

HBV
The CDC currently recommend that certain groups

be tested for HBV infection or immunity using
serologic assays for HBsAg and anti-HBs before
being vaccinated for HBV
[CDC 2011b; CDC 2008b]
Postvaccination testing for immunity is

recommended only for individuals whose clinical
management will depend on information regarding
their immune status
[CDC 2011b; CDC 2008b]
Postexposure prophylaxis is recommended for all

persons who are exposed to HBV and are
considered susceptible to HBV infection (eg,
nonvaccinated, vaccine nonresponder)
HBV screening is indicated in the following

situations (Management Guidelines)
2008b]
[CDC 2008a; CDC
Persons born in geographic regions with

HBsAg prevalence of 2%
US-born persons not vaccinated as infants

whose parents were born in geographic
regions with HBsAg prevalence of 8%

transaminase/aspartate aminotransferase
of unknown etiology
Persons with selected medical conditions

requiring or resulting in an
immunosuppressive state:
Chemotherapy
Pregnant women
Household contacts and sex partners of

HBV-infected persons
Persons who are the source of blood or

body fluid exposures that might warrant
postexposure prophylaxis (eg, needlestick
Serologic assays for 2 viral antigens (hepatitis B

surface and e antigens) and 3 antibodies (anti-HBc,
anti-HBs, and anti-HBe) form the basis of diagnosis
of acute and chronic HBV infection; sensitive and
specific commercial assays that are FDA approved
or licensed are available for their detection
Liver biopsy is rarely necessary in the setting of

acute hepatitis B; for patients with chronic hepatitis
B, the purpose of the liver biopsy is to grade and
stage the severity of the liver disease and to
determine the need for therapy
Primary care physicians play a critical role in reducing the risk of hepatitis B virus (HBV) infection among
patients by ensuring vaccination guidelines are followed and in identifying those at risk for infection who should
be screened. Early diagnosis of infection is important because chronic HBV infection puts patients at risk for
the development of complications such as cirrhosis, hepatic decompensation, and hepatocellular carcinoma.
Although the introduction of mandatory immunization, HBV screening in pregnant women, postexposure
immunization in at-risk infants, and changes in behavior have dramatically reduced the incidence of HBV
infection in the United States,
[CDC 2013; CDC 2011a]
there is still a high burden of disease, and maintaining reduced
disease incidence requires continued vigilance and prevention practices. HBV is transmitted primarily by
infected blood and body fluids, with perinatal, percutaneous, and sexual transmission accounting for most
acute and chronic HBV infection cases worldwide.
[Mast 2005; Mast 2006]
In the United States, sexual
transmission accounts for approximately 38% of acute HBV infections; 25% are estimated to occur via sex
between men.
[Wasley 2008]
Immigration from countries with high and intermediate prevalence of chronic hepatitis
B represents a major source of imported chronic hepatitis into the United States. It was estimated that during
2004-2008, 95% of new cases of chronic hepatitis B in the United States were imported.
[Mitchell 2011]
Overall, it is
estimated that 40% to 70% of persons with chronic hepatitis B infection in the United States are foreign
born.
[Kowdley 2012]
Prevention of Vertical Transmission

Vertical (perinatal) transmission refers to the transmission of hepatitis B virus (HBV) from mother to infant
immediately before or after birth. Although HBV acquisition occurs in 70% to 90% of infants born to hepatitis B
e antigen (HBeAg)positive mothers with high HBV DNA levels (> 7.3 log10 IU/mL) at delivery,
[Stevens
1975]
passive-active immunization at birth significantly reduces (~ 95%) the rate of perinatal transmission.
[Mast
2005]
For passive-active immunization, the hepatitis B pediatric vaccine and hepatitis B immune globulin should
be administered to the neonate of an hepatitis B surface antigen (HBsAg)positive mother within 12 hours of
birth.
[Mast 2005]
Failure of passive-active immunization is more likely in HBeAg-positive women with high HBV
DNA (> 7.3 log10 IU/mL).
[Song 2007; Singh 2011; Wiseman 2009; Shao 2011]
Several studies have shown that the use of
nucleos(t)ide analogues in the third trimester of pregnancy, along with immunoprophylaxis, may further reduce
perinatal transmission rates compared with immunoprophylaxis alone, particularly in mothers with high HBV
DNA levels (> 7.3 log10IU/mL).
[Xu 2009; Han 2011; Pan 2012]
It should be noted, however, that prevention of vertical
transmission is not an approved indication for starting HBV therapy, and prophylaxis is the best method to
prevent mother-to-child transmission.
[Tran 2009]
This is largely because of concerns of the long-term safety to the
infant and reactivation of hepatitis after withdrawal of antiviral agent in the mother.
[ter Borg 2008]
Thus, until further
data become available, antiviral therapy to prevent perinatal transmission should only be considered in women
6
with high HBV DNA levels (> 10 copies/mL or ~ 5.3 log10 IU/mL).
[Wong 2014]
Treatment should be initiated in the
third trimester, preferably 6-8 weeks before delivery to allow sufficient time for the viral level to decline.
Therapy should be continued for approximately 4 weeks after delivery. Mothers should be monitored for an
increase in disease activity following withdrawal of antiviral therapy. Cesarean section has not been shown to
affect the rate of perinatal transmission and should not be performed if HBV infection is the only indication for
doing so.
[Wang 2002]
Vaccination
3 that are available as combinations (hepatitis A-hepatitis B vaccine, haemophilus b-hepatitis B vaccine, and
2006 (Management Guidelines)
[Mast 2006]
[Mast 2005]
and
guidelines from the Centers for Disease Control and Prevention
(CDC). All of the vaccines use the HBsAg to generate immunity against HBV. Hepatitis B immune globulin,
which contains anti-HBs, provides temporary protection (for ~ 3-6 months) and is used in addition to the
hepatitis B vaccine for postexposure immunoprophylaxis to prevent HBV infection.
The CDC recommend the following groups for HBV vaccination
[CDC 2012]
[Mast 2005; Mast 2006]
All newborns

The recommended vaccine schedule is shown in Table 4.
The CDC currently recommend that certain groups be tested for HBV infection or immunity using serologic
assays for HBsAg and anti-HBs before being vaccinated for HBV.
[CDC 2011b; CDC 2008b]
The reason for this
recommendation is to identify chronic infection in high-risk groups who may benefit from therapy. These groups
include the following persons:
Pregnant women

including:


endemicity
infection (Management Guidelines)

HBV endemicity


depend on information regarding their immune status, including
[CDC 2011b; CDC 2008b]
bodily fluids

completion of the vaccine series. Infants born to HBsAg-positive mothers should be tested 1-2 months after 3
doses of a licensed HBV vaccine series have been administered. Postvaccination testing in this setting should
not be conducted within 4 weeks of the latest vaccine dose or before 9 months of age to prevent detection of
anti-HBs derived from hepatitis B immune globulin given during infancy and to increase the likelihood of
detecting late HBV infection.
In addition to vaccinating uninfected persons, prevention of horizontal transmission also requires counseling
HBV-infected persons on precautions they should take to prevent exposing others to the virus. These include
covering open cuts and scratches, cleaning blood spills with detergent or bleach, and not sharing toothbrushes
or razors (Table 3) (Management Guidelines).
[Lok 2009]
Postexposure prophylaxis is recommended for all persons who are exposed to HBV and are considered
susceptible to HBV infection (eg, nonvaccinated, vaccine nonresponder). Both the hepatitis B immune
globulin plus the hepatitis B vaccine and the hepatitis B vaccine alone are highly effective in preventing
infection after exposure to HBV.
Guidelines for postexposure prophylaxis for adults with occupational (Management Guidelines)
Prevention]
and nonoccupational (Management Guidelines)
[Mast 2006]
[CDC HCP HBV
exposures to HBV are available. Ideally,
persons without contraindications to HBV vaccination should receive the first dose within 24 hours and not later
than 7 days following exposure. The CDC recommend that booster doses of the HBV vaccine be administered
to hemodialysis patients and other immunocompromised individuals, but not to persons with normal immune
status.
[CDC 2011c]
Although the currently available HBV vaccines are highly effective, it is estimated that approximately 5% to
15% of healthy individuals fail to respond to the 3-dose series.
Guidelines),
[Mast 2006]
[CDC 1991]
According to the CDC (Management
patients who have anti-HBs levels < 10 mIU/mL following the primary HBV vaccine series
should be revaccinated with 3 doses according to the appropriate schedule (Table 4) and should be retested
for anti-HBs 1-2 months following the third dose. Individuals with anti-HBs levels < 10 mIU/mL following
revaccination should be tested for HBsAg to determine if they are infected with HBV. If the test is negative,
they should be considered susceptible to HBV infection and should be counseled on precautions to avoid
becoming infected and the need for hepatitis B immune globulin postexposure prophylaxis in the event of any
known or likely parenteral exposure to HBsAg-positive blood.
Diagnosis
Persons at high risk of HBV infection should be screened. Persons testing negative should be vaccinated, and
persons testing positive should be correctly diagnosed and managed according to available guidelines. HBV
screening is indicated in the following situations (Management Guidelines)
[CDC 2008a; CDC 2008b]

of 2%

were born in geographic regions with HBsAg prevalence of
8%

transaminase/aspartate aminotransferase of unknown
etiology
Persons with selected medical conditions requiring or

resulting in an immunosuppressive state:
Chemotherapy
Pregnant women

persons
Persons who are the source of blood or body fluid exposures

that might warrant postexposure prophylaxis (eg, needlestick
Serologic assays for 2 viral antigens (HBsAg and HBeAg) and 3 antibodies (anti-HBc, anti-HBs, and anti-HBe)
form the basis of diagnosis of acute and chronic HBV infection. Sensitive and specific commercial assays that
are US Food and Drug Administration approved or licensed are available for their detection. Diagnosis of acute
hepatitis B is based on the detection of HBsAg and anti-HBc IgM in serum whereas diagnosis of chronic
hepatitis B is based on the detection and persistence of HBsAg in serum for longer than 6 months. Patients
with an isolated anti-HBc should be retested, preferably using a radioimmunoassay test, as well as being
tested for HBsAg and anti-HBs. Patients diagnosed with chronic infection require supplemental testing to stage
disease and inform treatment decision making, for example, for HBeAg and HBV DNA.
therapy; it is not required for diagnosis. Persons with moderate to severe necroinflammation, or significant
fibrosis (Metavir stage > F2 or Ishak stage 3) are candidates for therapy, according to international
guidelines.
[Lok 2009; EASL 2009; Liaw 2008]
Liver biopsy may also be used to investigate abnormal radiologic findings
during screening for hepatocellular carcinoma.
MY SUBSCRIPTIONS
QUICK TOUR
MY CE
MY FOLDER
LOGOUT
Specialty
Decision Tools
Drug Reference
Guidelines
PubMed
Trials
More
XGO
Specialty
Hepatology
HBV Epidemiology
Summary
Global Overview
Sexual Transmission
Vaccination
Vaccine Booster
Pathogenesis
Natural History
Overview
Serology
HBsAg and Anti-HBs
Anti-HBc
HBeAg and Anti-HBe
HBV DNA Assays
Supporting Assets
References
Save
Share
Print
Email
Previous

Zeuzem, MD
References
Alter HJ, Seeff LB, Kaplan PM, et al. Type B hepatitis: the infectivity of blood positive for e antigen and DNA
polymerase after accidental needlestick exposure. N Engl J Med. 1976;295:909-913.[Alter 1976]
Alter HJ, Purcell RH, Gerin JL, et al. Transmission of hepatitis B to chimpanzees by hepatitis B surface
antigen-positive saliva and semen. t Immun. 1977;16:928-933.[Alter 1977]
Alter MJ, Hadler SC, Margolis HS, et al. The changing epidemiology of hepatitis B in the United States. Need
for alternative vaccination strategies. JAMA. 1990;263:1218-1222.[Alter 1990]
Alward WL, McMahon BJ, Hall DB, et al. The long-term serological course of asymptomatic hepatitis B virus
carriers and the development of primary hepatocellular carcinoma. J Infect Dis. 1985;151:604-609.[Alward
1985]
Andr FE, Zuckerman AJ. Review: protective efficacy of hepatitis B vaccines in neonates. J Med Virol.
1994;44:144-151.[Andr 1994]
Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim
Report for 1 January 1989 through 31 July 2013. Wilmington, NC: Registry Coordinating Center; 2013.
Available at: http://www.apregistry.com/forms/interim_report.pdf. Accessed June 2, 2014.[Antiretroviral
Pregnancy Registry]
Bancroft WH, Snitbhan R, Scott RM, et al. Transmission of hepatitis B virus to gibbons by exposure to human
saliva containing hepatitis B surface antigen. J Infect Dis. 1977;135:79-85.[Bancroft 1977]
Beasley RP, Stevens CE, Shiao IS, Meng HC. Evidence against breast-feeding as a mechanism for vertical
transmission of hepatitis B. Lancet. 1975;2:740-741.[Beasley 1975]
Bialek SR, Bower WA, Mottram K, et al. Risk factors for hepatitis B in an outbreak of hepatitis B and D among
injection drug users. J Urban Health. 2005;82:468-478.[Bialek 2005]
Bcher WO, Herzog-Hauff S, Herr W, et al. Regulation of the neutralizing anti-hepatitis B surface (HBs)
antibody response in vitro in HBs vaccine recipients and patients with acute or chronic hepatitis B virus (HBV)
infection. Clin Exp Immunol. 1996;105:52-58.[Bcher 1996]
Boltjes A, Movita D, Boonstra A, Woltman AM. The role of Kupffer cells in hepatitis B and hepatitis C virus
infections. J Hepatol. 2014;[Epub ahead of print].[Boltjes 2014]
Brunetto MR, Oliveri F, Colombatto P, et al. Hepatitis B surface antigen serum levels help to distinguish active
from inactive hepatitis B Virus genotype D carriers. Gastroenterology. 2010;139:483-490.[Brunetto 2010]
Buster EH, Flink HJ, Cakaloglu Y, et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAgpositive patients treated with peginterferon alpha-2b. Gastroenterology. 2008;135:459-467.[Buster 2008]
Buster EH, Hansen BE, Lau GK, et al. Factors that predict response of patients with hepatitis B e antigenpositive chronic hepatitis B to peginterferon-alfa. Gastroenterology. 2009;137:2002-2009.[Buster 2009]
Cao GW. Clinical relevance and public health significance of hepatitis B virus genomic variations. World J
Gastroenterol. 2009;15:5761-5769.[Cao 2009]
Carman WF, Jacyna MR, Hadziyannis S, et al. Mutation preventing formation of hepatitis B e antigen in
patients with chronic hepatitis B infection. Lancet. 1989;2:588-591.[Carman 1989]
Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal
childhood vaccination. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR
Recomm Rep. 1991;40:1-25.[CDC 1991]
Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and public health management
of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57(RR-8):1-20.[CDC 2008a]
Centers for Disease Control and Prevention. Recommendations for routine testing and follow-up for chronic
hepatitis B virus (HBV) infection. Adapted from CDC/ Travellers Health; Yellow Book 2008. Available at:
http://www.cdc.gov/hepatitis/HBV/PDFs/ChronicHepBTestingFlwUp.pdf. Accessed June 2, 2014.[CDC 2008b]
Centers for Disease Control and Prevention. Viral hepatitis statistics and surveillance. 2011. Available at:
http://www.cdc.gov/hepatitis/Statistics/index.htm. Accessed June 2, 2014.[CDC 2011a]
Centers for Disease Control and Prevention. Hepatitis B FAQs for health professionals. 2011. Available at:
http://www.cdc.gov/hepatitis/hbv/hbvfaq.htm. Accessed June 2, 2014.[CDC 2011b]
Centers for Disease Control and Prevention. Draft 2011 Public Health Service guideline for reducing
transmission of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV)
through solid organ transplantation. 2011. Available at: http://www.regulations.gov/#!documentDetail;D=CDC2011-0011-0001. Accessed June 2, 2014.[CDC 2011c]
Centers for Disease Control and Prevention. Hepatitis B vaccine: what you need to know. February 2, 2012.
Available at: http://www.cdc.gov/vaccines/hcp/vis/vis-statements/hep-b.html. Accessed June 2, 2014.[CDC
2012]
Centers for Disease Control and Prevention. Surveillance for viral hepatitis: United States, 2011. Available at:
http://www.cdc.gov/hepatitis/Statistics/2011Surveillance/Commentary.htm. Accessed June 2, 2014.[CDC 2013]
Centers for Disease Control and Prevention. CDC guidance for evaluating health-care personnel for hepatitis B
virus protection and for administering postexposure management. MMWR Recomm Rep. 2013;62(RR-10):119.[CDC HCP HBV Prevention]
Celen MK, Mert D, Ay M, et al. Efficacy and safety of tenofovir disoproxil fumarate in pregnancy for the
prevention of vertical transmission of HBV infection. World J Gastroenterol. 2013;19:9377-9382.[Celen 2013]
Chan HL, Leung NW, Hussain M, Wong ML, Lok AS. Hepatitis B e antigen-negative chronic hepatitis B in
Hong Kong. Hepatology. 2000;31:763-768.[Chan 2000]
Chan HL, Hui AY, Wong ML, et al. Genotype C hepatitis B virus infection is associated with an increased risk
of hepatocellular carcinoma. Gut. 2004;53:1494-1498.[Chan 2004]
Chan HL, Wong GL, Choi PC, et al. Alanine aminotransferase-based algorithms of liver stiffness measurement
by transient elastography (FibroScan) for liver fibrosis in chronic hepatitis B. J Viral Hepat. 2009;16:3644.[Chan 2009]
Chan HL, Wong VW, Wong GL, Tse CH, Chan HY, Sung JJ. A longitudinal study on the natural history of
serum hepatitis B surface antigen changes in chronic hepatitis B. Hepatology. 2010;52:1232-1241.[Chan 2010]
Chang JJ, Lewin SR. Immunopathogenesis of hepatitis B virus infection. Immunol Cell Biol. 2007;85:1623.[Chang 2007]
Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis
B virus DNA level. JAMA. 2006;295:65-73.[Chen 2006]
Chen CH, Lu SN, Hung CH, et al. The role of hepatitis B surface antigen quantification in predicting HBsAg
loss and HBV relapse after discontinuation of lamivudine treatment. J Hepatol. 2014;[Epub ahead of
print].[Chen 2014]
Chevrier MC, St-Louis M, Perreault J, et al. Detection and characterization of hepatitis B virus of anti-hepatitis
B core antigen-reactive blood donors in Quebec with an in-house nucleic acid testing assay. Transfusion.
2007;47:1794-1802.[Chevrier 2007]
Chiang CJ, Yang YW, You SL, Lai MS, Chen CJ. Thirty-year outcomes of the national hepatitis B immunization
program in Taiwan. JAMA. 2013;310:974-976.[Chiang 2013]
Chisari FV, Isogawa M, Wieland SF. Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris).
2010;58:258-266.[Chisari 2010]
Chongsrisawat V, Thawornsuk N, Theamboonlers A, Louisirirotchanakul S, Poovorawan Y. Hepatitis B virus

DNA in unusual serological profiles of hepatitis B surface antigen-positive sera. Viral Immunol. 2006;19:623629.[Chongsrisawat 2006]
Chu CM, Karayiannis P, Fowler MJ, Monjardino J, Liaw YF, Thomas HC. Natural history of chronic hepatitis B
virus infection in Taiwan: studies of hepatitis B virus DNA in serum. Hepatology. 1985;5:431-434.[Chu 1985]
Chu CJ, Hussain M, Lok AS. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion
compared with hepatitis B virus genotype C. Gastroenterology. 2002;122:1756-1762.[Chu 2002]
Chu CJ, Keeffe EB, Han SH, et al. Hepatitis B virus genotypes in the United States: results of a nationwide
study. Gastroenterology. 2003;125:444-451.[Chu 2003]
Chu CM, Liaw YF. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of
hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive
patients with normal aminotransferase levels at baseline. J Hepatol. 2005;43:411-417.[Chu 2005]
Chu CM, Liaw YF. Incidence and risk factors of progression to cirrhosis in inactive carriers of hepatitis B virus.
Am J Gastroenterol. 2009;104:1693-1699.[Chu 2009]
Chu CM, Liaw YF. Hepatitis B surface antigen seroclearance during chronic HBV infection. Antivir Ther.
2010;15:133-143.[Chu 2010]
Chung HT, Lee JS, Lok AS. Prevention of posttransfusion hepatitis B and C by screening for antibody to
hepatitis C virus and antibody to HBcAg. Hepatology. 1993;18:1045-1049.[Chung 1993]
Cohen C, Evans AA, London WT, Block J, Conti M, Block T. Underestimation of chronic hepatitis B virus
infection in the United States of America. J Viral Hepat. 2008;15:12-13.[Cohen 2008]
Daniels D, Grytdal S, Wasley A; Centers for Disease Control and Prevention (CDC). Surveillance for acute
viral hepatitis - United States, 2007. MMWR Surveill Summ. 2009;58:1-27.[Daniels 2009]
Degos F, Perez P, Roche B, et al. Diagnostic accuracy of FibroScan and comparison to liver fibrosis
biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study). J Hepatol.
2010;53:1013-1021.[Degos 2010]
Department of Health and Human Services, US Food and Drug Administration, Center for Biologics Evaluation
and Research. Blood products advisory committee. 94th meeting. April 1, 2009. Available at:
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologi
cs/bloodproductsadvisorycommittee/ucm155530.pdf. Accessed June 2, 2014.[DHHS 2009]
Dickson RC, Everhart JE, Lake JR, et al. Transmission of hepatitis B by transplantation of livers from donors
positive for antibody to hepatitis B core antigen. The National Institute of Diabetes and Digestive and Kidney
Diseases Liver Transplantation Database. Gastroenterology. 1997;113:1668-1674.[Dickson 1997]
Doganci T, Uysal G, Kir T, Bakirtas A, Kuyucu N, Doganci L. Horizontal transmission of hepatitis B virus in
children with chronic hepatitis B. World J Gastroenterol. 2005;11:418-420.[Doganci 2005]
Douglas DD, Taswell HF, Rakela J, Rabe D. Absence of hepatitis B virus DNA detected by polymerase chain
reaction in blood donors who are hepatitis B surface antigen negative and antibody to hepatitis B core antigen
positive from a United States population with a low prevalence of hepatitis B serologic markers. Transfusion.
1993;33:212-216.[Douglas 1993]
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of chronic
hepatitis B. J Hepatol. 2009;50:227-242.[EASL 2009]
Fattovich G. Natural history of hepatitis B. J Hepatol. 2003;39(suppl 1):S50-S58.[Fattovich 2003]
Ferrari C, Penna A, Bertoletti A, et al. Cellular immune response to hepatitis B virus-encoded antigens in acute
and chronic hepatitis B virus infection. J Immunol. 1990;145:3442-3449.[Ferrari 1990]
Fong TL, Di Bisceglie AM, Biswas R, et al. High levels of viral replication during acute hepatitis B infection
predict progression to chronicity. J Med Virol. 1994;43:155-158.[Fong 1994]
Goldstein ST, Zhou F, Hadler SC, Bell BP, Mast EE, Margolis HS. A mathematical model to estimate global
hepatitis B disease burden and vaccination impact. Int J Epidemiol. 2005;34:1329-1339.[Goldstein 2005]
Greenup AJ, Tan PK, Nguyen V, et al. Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to
prevent perinatal transmission of Hepatitis B Virus. J Hepatol. 2014;[Epub ahead of print].[Greenup 2014]
Hadler SC, Murphy BL, Schable CA, et al. Epidemiological analysis of the significance of low-positive test
results for antibody to hepatitis B surface and core antigens. J Clin Microbiol. 1984;19:521-525.[Hadler 1984]
Hadziyannis E, Hadziyannis SJ. Hepatitis B surface antigen quantification in chronic hepatitis B and its clinical
utility. Expert Rev Gastroenterol Hepatol. 2014;8:185-195.[Hadziyannis 2014]
Hagan H, McGough JP, Thiede H, Weiss NS, Hopkins S, Alexander ER. Syringe exchange and risk of
infection with hepatitis B and C viruses. Am J Epidemiol. 1999;149:203-213.[Hagan 1999]
Han GR, Cao MK, Zhao W, et al. A prospective and open-label study for the efficacy and safety of telbivudine
in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection. J Hepatol.
2011;55:1215-1221.[Han 2011]
Heathcote J, Manns M, Mathurin P, et al. Baseline genotype and HBsAg were found to have significant
association with HBeAg seroconversion following up to 4 years of tenofovir disoproxil fumarate treatment.
Program and abstracts of the 46th Annual Meeting of the European Association for the Study of the Liver;
March 30 - April 3, 2011; Berlin, Germany. Abstract 715.[Heathcote 2011]
Hess G, Arnold W. The clinical relevance of the antibody to hepatitis B core antigen (anti-HBc): a review. J
Virol Methods. 1980;2:107-117.[Hess 1980]
Holland PV, Alter HJ. The clinical significance of hepatitis B virus antigens and antibodies. Med Clin North Am.
1975;59:849-855.[Holland 1975]
Hsu HM, Lu CF, Lee SC, Lin SR, Chen DS. Seroepidemiologic survey for hepatitis B virus infection in Taiwan:
the effect of hepatitis B mass immunization. J Infect Dis. 1999;179:367-370.[Hsu 1999]
Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients
with chronic hepatitis B. Hepatology. 2002;35:1522-1527.[Hsu 2002]
Hyams KC. Risks of chronicity following acute hepatitis B virus infection: a review. Clin Infect Dis. 1995;20:9921000.[Hyams 1995]
Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.
Gastroenterology. 2006;130:678-686.[Iloeje 2006]
Ioannou GN. Hepatitis B virus in the United States: infection, exposure, and immunity rates in a nationally
representative survey. Ann Intern Med. 2011;154:319-328.[Ioannou 2011]
Institute of Medicine. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and
C. Washington, DC: National Academies Press; 2010.[IOM 2010]
Jaroszewicz J, Calle Serrano B, Wursthorn K, et al. Hepatitis B surface antigen (HBsAg) levels in the natural
history of hepatitis B virus (HBV)-infection: a European perspective. J Hepatol. 2010;52:514-522.[Jaroszewicz
2010]
Jeffers LJ, Cortes RA, Bejarano PA, et al. Prospective evaluation of FIBROSpect II for fibrosis detection in
hepatitis C and B patients undergoing laparoscopic biopsy. Gastroenterol Hepatol (N Y). 2007;3:367376.[Jeffers 2007]
Joller-Jemelka HI, Wicki AN, Grob PJ. Detection of HBs antigen in anti-HBc alone positive sera. J Hepatol.
1994;21:269-272.[Joller-Jemelka 1994]
Jung YK, Kim JH, Lee YS, et al. Change in serum hepatitis B surface antigen level and its clinical significance
in treatment-naive, hepatitis B e antigen-positive patients receiving entecavir. J Clin Gastroenterol.
2010;44:653-657.[Jung 2010]
Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with
chronic hepatitis B. Gastroenterology. 2000;118:554-559.[Kao 2000]
Kao JH, Chen PJ, Lai MY, Chen DS. Occult hepatitis B virus infection and clinical outcomes of patients with
chronic hepatitis C. J Clin Microbiol. 2002;40:4068-4071.[Kao 2002]
Kao JH. Diagnosis of hepatitis B virus infection through serological and virological markers. Expert Rev
Gastroenterol Hepatol. 2008;2:553-562.[Kao 2008]
Kao JH. Molecular epidemiology of hepatitis B virus. Korean J Intern Med. 2011;26:255-261.[Kao 2011]
Kim JH, Choi YJ, Moon HW, Ko SY, Choe WH, Kwon SY. HBsAg level and clinical course in patients with
chronic hepatitis B treated with nucleoside analogue: five years of follow-up data. Clin Mol Hepatol.
2013;19:409-416.[Kim 2013]
Kowdley KV, Wang CC, Welch S, Roberts H, Brosgart CL. Prevalence of chronic hepatitis B among foreignborn persons living in the United States by country of origin. Hepatology. 2012;56:422-433.[Kowdley 2012]
Krugman S, Overby LR, Mushahwar IK, Ling CM, Frsner GG, Deinhardt F. Viral hepatitis, type B. Studies on
natural history and prevention re-examined. N Engl J Med. 1979;300:101-106.[Krugman 1979]
Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention
and control measures. J Viral Hepat. 2004;11:97-107.[Lavanchy 2004]
Liang TJ. Hepatitis B: the virus and disease. Hepatology. 2009;49(5 suppl):S13-S21.[Liang 2009]
Liaw YF, Chu CM, Su IJ, et al. Clinical and histological events preceding hepatitis B e antigen seroconversion
in chronic type B hepatitis. Gastroenterology. 1983;84:216-219.[Liaw 1983]
Liaw YF, Chu CM, Lin DY, Sheen IS, Yang CY, Huang MJ. Age-specific prevalence and significance of
hepatitis B e antigen and antibody in chronic hepatitis B virus infection in Taiwan: a comparison among
asymptomatic carriers, chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. J Med Virol.
1984;13:385-391.[Liaw 1984]
Liaw YF, Sheen IS, Chen TJ, Chu CM, Pao CC. Incidence, determinants and significance of delayed clearance
of serum HBsAg in chronic hepatitis B virus infection: a prospective study. Hepatology. 1991;13:627-631.[Liaw
1991]
Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis
B: a 2008 update. Hepatol Int. 2008;2:263-283.[Liaw 2008]
Lin CL, Liao LY, Wang CS, et al. Basal core-promoter mutant of hepatitis B virus and progression of liver
disease in hepatitis B e antigen-negative chronic hepatitis B. Liver Int. 2005;25:564-570.[Lin 2005]
Liu J, Yang HI, Lee MH, et al. Incidence and determinants of spontaneous hepatitis B surface antigen
seroclearance: a community-based follow-up study. Gastroenterology. 2010;139:474-482.[Liu 2010]
Lok AS, Lai CL, Wu PC, Leung EK, Lam TS. Spontaneous hepatitis B e antigen to antibody seroconversion
and reversion in Chinese patients with chronic hepatitis B virus infection. Gastroenterology. 1987;92:18391843.[Lok 1987]
Lok AS, Lai CL, Wu PC. Prevalence of isolated antibody to hepatitis B core antigen in an area endemic for
hepatitis B virus infection: implications in hepatitis B vaccination programs. Hepatology. 1988;8:766-770.[Lok
1988]
Lok AS, Liang RH, Chiu EK, et al. Reactivation of hepatitis B virus replication in patients receiving cytotoxic
therapy. Report of a prospective study. Gastroenterology. 1991;100:182-188.[Lok 1991]
Lok AS, Akarca U, Greene S. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability
of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci U S A. 1994;91:40774081.[Lok 1994]
Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-539.[Lok 2007]
Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-662.[Lok 2009]
Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age
groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet.
2012;380:2095-2128.[Lozano 2012]
Lubel JS, Angus PW. Hepatitis B reactivation in patients receiving cytotoxic chemotherapy: diagnosis and
management.J Gastroenterol Hepatol. 2010;25:864-871.[Lubel 2010]
Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of mortality from viral
hepatitis in the United States between 1999 and 2007. Ann Intern Med. 2012;156:271-278.[Ly 2012]
Mallet V, Dhalluin-Venier V, Roussin C, et al. The accuracy of the FIB-4 index for the diagnosis of mild fibrosis
in chronic hepatitis B. Aliment Pharmacol Ther. 2009;29:409-415.[Mallet 2009]
Marcellin P, Ziol M, Bedossa P, et al. Non-invasive assessment of liver fibrosis by stiffness measurement in
patients with chronic hepatitis B. Liver Int. 2009;29:242-247.[Marcellin 2009]
Martnez SM, Crespo G, Navasa M, Forns X. Noninvasive assessment of liver fibrosis. Hepatology.
2011;53:325-335.[Martnez 2011]
Martinot-Peignoux M, Asselah T, Marcellin P. HBsAg quantification to predict natural history and treatment
outcome in chronic hepatitis B patients. Clin Liver Dis. 2013;17:399-412.[Martinot-Peignoux 2013]
Martinson FE, Weigle KA, Royce RA, Weber DJ, Suchindran CM, Lemon SM. Risk factors for horizontal
transmission of hepatitis B virus in a rural district in Ghana. Am J Epidemiol. 1998;147:478-487.[Martinson
1998]
Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of
hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization
Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR Recomm Rep. 2005;54:131.[Mast 2005]
Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of
hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization
Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep. 2006;55:1-33.[Mast 2006]
McClune AC, Tong MJ. Chronic hepatitis B and hepatocellular carcinoma. Clin Liver Dis. 2010;14:461476.[McClune 2010]
McIntosh YG, Powell TA, Tipple M, et al. Multiple outbreaks of hepatitis B virus infection related to assisted
monitoring of blood glucose among residents of assisted living facilitiesVirginia, 2009-2011. MMWR.
2012;61;339-343.[McIntosh 2012]
McMahon BJ, Bender TR, Berquist KR, Schreeder MT, Harpster AP. Delayed development of antibody to
hepatitis B surface antigen after symptomatic infection with hepatitis B virus. J Clin Microbiol. 1981;14:130134.[McMahon 1981]
McMahon BJ, Alward WL, Hall DB, et al. Acute hepatitis B virus infection: relation of age to the clinical
expression of disease and subsequent development of the carrier state. J Infect Dis. 1985;151:599603.[McMahon 1985]
McMahon BJ, Parkinson AJ, Helminiak C, et al. Response to hepatitis B vaccine of persons positive for
antibody to hepatitis B core antigen. Gastroenterology. 1992;103:590-594.[McMahon 1992]
McMahon BJ, Schoenberg S, Bulkow L, et al. Seroprevalence of hepatitis B viral markers in 52,000 Alaska
Natives. Am J Epidemiol. 1993;138:544-549.[McMahon 1993]
McMahon BJ, Holck P, Bulkow L, Snowball M. Serologic and clinical outcomes of 1536 Alaska Natives
chronically infected with hepatitis B virus. Ann Intern Med. 2001;135:759-768.[McMahon 2001]
McMahon BJ, Bulkow LR, Singleton RJ, et al. Elimination of hepatocellular carcinoma and acute hepatitis B in
children 25 years after a hepatitis B newborn and catch-up immunization program. Hepatology. 2011;54:801807.[McMahon 2011]
Mitchell T, Armstrong GL, Hu DJ, Wasley, Painter JA. The increasing burden of imported chronic hepatitis B
United States, 1974-2008. PLoS One. 2011; 6:e27717.[Mitchell 2011]
Mitsui T, Iwano K, Suzuki S, et al. Combined hepatitis B immune globulin and vaccine for postexposure
prophylaxis of accidental hepatitis B virus infection in hemodialysis staff members: comparison with immune
globulin without vaccine in historical controls. Hepatology. 1989;10:324-327.[Mitsui 1989]
Miyakawa Y, Mizokami M. Classifying hepatitis B virus genotypes. Intervirology. 2003;46:329-338.[Miyakawa

2003]
Public Health Service inter-agency guidelines for screening donors of blood, plasma, organs, tissues, and
semen for evidence of hepatitis B and hepatitis C. MMWR Recomm Rep. 1991;40:1-17.[MMWR 1991]
Mosley JW, Stevens CE, Aach RD, et al. Donor screening for antibody to hepatitis B core antigen and hepatitis
B virus infection in transfusion recipients. Transfusion. 1995;35:5-12.[Mosley 1995]
Myers RP, Tainturier MH, Ratziu V, et al. Prediction of liver histological lesions with biochemical markers in
patients with chronic hepatitis B. J Hepatol. 2003;39:222-230.[Myers 2003]
Nelson PK, Mathers BM, Cowie B, et al. Global epidemiology of hepatitis B and hepatitis C in people who inject
drugs: results of systematic reviews. Lancet. 2011;378:571-583.[Nelson 2011]
Ngo Y, Benhamou Y, Thibault V, et al. An accurate definition of the status of inactive hepatitis B virus carrier by
a combination of biomarkers (FibroTest-ActiTest) and viral load. PLoS One. 2008;3:e2573.[Ngo 2008]
Nguyen T, Thompson AJ, Bowden S, et al. Hepatitis B surface antigen levels during the natural history of
chronic hepatitis B: a perspective on Asia. J Hepatol. 2010;52:508-513.[Nguyen 2010]
Ni YH, Chen DS. Hepatitis B vaccination in children: the Taiwan experience. Pathol Biol (Paris). 2010;58:296300.[Ni 2010]
Okamoto H, Tsuda F, Akahane Y, et al. Hepatitis B virus with mutations in the core promoter for an e antigennegative phenotype in carriers with antibody to e antigen. J Virol. 1994;68:8102-8110.[Okamoto 1994]
Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates
of age-specific HBsAg seroprevalence and endemicity. Vaccine. 2012;30:2212-2219.[Ott 2012]
Ouseph R, Eng M, Ravindra K, Brock GN, Buell JF, Marvin MR. Review of the use of hepatitis B core antibodypositive kidney donors. Transplant Rev (Orlando). 2010;24:167-171.[Ouseph 2010]
Pan CQ, Han GR, Jiang HX, et al. Telbivudine prevents vertical transmission from HBeAg-positive women with
chronic hepatitis B. Clin Gastroenterol Hepatol. 2012;10:520-526.[Pan 2012]
Pawlotsky JM, Dusheiko G, Hatzakis A, et al. Virologic monitoring of hepatitis B virus therapy in clinical trials
and practice: recommendations for a standardized approach. Gastroenterology. 2008;134:405-415.[Pawlotsky
2008]
Poovorawan Y, Chongsrisawat V, Theamboonlers A, et al. Long-term benefit of hepatitis B vaccination among

children in Thailand with transient hepatitis B virus infection who were born to hepatitis B surface antigenpositive mothers. J Infect Dis. 2009;200:33-38.[Poovorawan 2009]
Poynard T, Ngo Y, Munteanu M, Thabut D, Ratziu V. Noninvasive markers of hepatic fibrosis in chronic
hepatitis B. Curr Hepat Rep. 2011;10:87-97.[Poynard 2011]
Prieto M, Gmez MD, Berenguer M, et al. De novo hepatitis B after liver transplantation from hepatitis B core
antibody-positive donors in an area with high prevalence of anti-HBc positivity in the donor population. Liver
Transpl. 2001;7:51-58.[Prieto 2001]
Raftopoulos SC, George J, Bourliere M, et al. Comparison of noninvasive models of fibrosis in chronic hepatitis
B. Hepatol Int. 2011;[Epub ahead of print].[Raftopoulos 2011]
Rehermann B, Fowler P, Sidney J, et al. The cytotoxic T lymphocyte response to multiple hepatitis B virus
polymerase epitopes during and after acute viral hepatitis. J Exp Med. 1995;181:1047-1058.[Rehermann 1995]
Reijnders JG, Rijckborst V, Sonneveld MJ, et al. Kinetics of hepatitis B surface antigen differ between
treatment with peginterferon and entecavir. J Hepatol. 2011;54:449-454.[Reijnders 2011]
Sangfelt P, Reichard O, Lidman K, von Sydow M, Forsgren M. Prevention of hepatitis B by immunization of the
newborn infant--a long-term follow-up study in Stockholm, Sweden Scand. J Infect Dis. 1995;27:3-7.[Sangfelt
1995]
Schreeder MT, Bender TR, McMahon BJ, et al. Prevalence of hepatitis B in selected Alaskan Eskimo villages.
Am J Epidemiol. 1983;118:543-549.[Schreeder 1983]
Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted viral infections. The
Retrovirus Epidemiology Donor Study. N Engl J Med. 1996;334:1685-1690.[Schreiber 1996]
Schweitzer IL, Wing A, McPeak C, Spears RL. Hepatitis and hepatitis-associated antigen in 56 mother-infant
pairs. JAMA. 1972;220:1092-1095.[Schweitzer 1972]
Shao ZJ, Zhang L, Xu JQ, et al. Mother-to-infant transmission of hepatitis B virus: a Chinese experience. J
Med Virol. 2011;83:791-795.[Shao 2011]
Shiffman M, Marcellin P, Jeffers L, et al. HBsAg seroconversion in adefovir dipivoxil (ADV) treated chronic
hepatitis B (CHB) patients. Program and abstracts of the 39th Annual Meeting of The European Association for
the Study of the Liver; April 14-18, 2004; Berlin, Germany. Abstract 45.[Shiffman 2004]
Shin WG, Park SH, Jang MK, et al. Aspartate aminotransferase to platelet ratio index (APRI) can predict liver
fibrosis in chronic hepatitis B. Dig Liver Dis. 2008;40:267-274.[Shin 2008]
Singh AE, Plitt SS, Osiowy C, et al. Factors associated with vaccine failure and vertical transmission of
hepatitis B among a cohort of Canadian mothers and infants. J Viral Hepat. 2011;18:468-473.[Singh 2011]
Song YM, Sung J, Yang S, Choe YH, Chang YS, Park WS. Factors associated with immunoprophylaxis failure
against vertical transmission of hepatitis B virus. Eur J Pediatr. 2007;166:813-818.[Song 2007]
Sonneveld MJ, Rijckborst V, Boucher CA, Hansen BE, Janssen HL. Prediction of sustained response to
peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B
surface antigen decline. Hepatology. 2010;52:1251-1257.[Sonneveld 2010]
Sonneveld MJ, Hansen BE, Piratvisuth T, et al. Response-guided peginterferon therapy in hepatitis B e
antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels. Hepatology. 2013;58:872880.[Sonneveld 2013]
Stevens CE, Beasley RP, Tsui J, Lee WC. Vertical transmission of hepatitis B antigen in Taiwan. N Engl J
Med. 1975;292:771-774.[Stevens 1975]
Stramer SL, Wend U, Candotti D, et al. Nucleic acid testing to detect HBV infection in blood donors. N Engl J
Med. 2011;364:236-247.[Stramer 2011]
Sumi H, Yokosuka O, Seki N, et al. Influence of hepatitis B virus genotypes on the progression of chronic type
B liver disease. Hepatology. 2003;37:19-26.[Sumi 2003]
Tang TJ, Kwekkeboom J, Laman JD, et al. The role of intrahepatic immune effector cells in inflammatory liver
injury and viral control during chronic hepatitis B infection. J Viral Hepat. 2003;10:159-167.[Tang 2003]
ter Borg MJ, Leemans WF, de Man RA, Janssen HL. Exacerbation of chronic hepatitis B infection after
delivery. J Viral Hepat. 2008;15:37-41.[ter Borg 2008]
Thimme R, Wieland S, Steiger C, et al. CD8(+) T cells mediate viral clearance and disease pathogenesis
during acute hepatitis B virus infection. J Virol. 2003;77:68-76.[Thimme 2003]
Thompson ND, Perz JF, Moorman AC, Holmberg SD. Nonhospital health care-associated hepatitis B and C
virus transmission: United States, 1998-2008. Ann Intern Med. 2009;150:33-39.[Thompson 2009]
Thompson AJ, Nguyen T, Iser D, et al. Serum hepatitis B surface antigen and hepatitis B e antigen titers:
disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers. Hepatology.
2010;51:1933-1944.[Thompson 2010]
Tran TT. Management of hepatitis B in pregnancy: weighing the options. Cleve Clin J Med. 2009;(76 suppl
3):S25-S29.[Tran 2009]
US Preventive Services Task Force. Screening for hepatitis B virus infection in nonpregnant adolescents and
adults. Available at: http://www.uspreventiveservicestaskforce.org/uspstf12/hepb/hepbfinalrs.htm#summary.
Accessed June 2, 2014.[USPSTF HBV Screening]
van Ditzhuijsen TJ, Selten GC, van Loon AM, et al. Detection of hepatitis B virus DNA in serum and relation
with the IgM class anti-HBc titers in hepatitis B virus infection. J Med Virol. 1985;15:49-56.[van Ditzhuijsen
1985]
Wang J, Zhu Q, Zhang X. Effect of delivery mode on maternal-infant transmission of hepatitis B virus by
immunoprophylaxis. Chin Med J (Engl). 2002;115:1510-1512.[Wang 2002]
Wasley A, Grytdal S, Gallagher K; Centers for Disease Control and Prevention (CDC). Surveillance for acute
viral hepatitis--United States, 2006. MMWR Surveill Summ. 2008;57:1-24.[Wasley 2008]
Wasley A, Kruszon-Moran D, Kuhnert W, et al. The prevalence of hepatitis B virus infection in the United
States in the era of vaccination. J Infect Dis. 2010;202:192-201.[Wasley 2010]
Webster GJ, Bertoletti A. Control or persistence of hepatitis B virus: the critical role of initial host-virus
interactions.[Webster 2002]
Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and public health management
of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57:1-20.[Weinbaum 2008]
Westland C, Delaney W 4th, Yang H, et al. Hepatitis B virus genotypes and virologic response in 694 patients
in phase III studies of adefovir dipivoxil. Gastroenterology. 2003;125:107-116.[Westland 2003]
Whittle HC, Maine N, Pilkington J, et al. Long-term efficacy of continuing hepatitis B vaccination in infancy in
two Gambian villages. Lancet. 1995;345:1089-1092.[Whittle 1995]
World Health Organization. Regional Committee for the Western Pacific. Resolutions: measles elimination,
hepatitis B control and poliomyelitis eradication. September 23, 2005. Available at:
http://www2.wpro.who.int/rcm/en/archives/rc56/rc_resolutions/wpr_rc56_r08.htm. Accessed June 2,
2014.[WHO 2005]
World Health Organization. Immunization, vaccines and biologicals: Hepatitis B. Available at:
http://www.who.int/immunization/topics/hepatitis_b/en/index.html. Accessed June 2, 2014.[WHO 2011]
World Health Organization. Hepatitis B fact sheet 204 (updated July 2013). Available
at:http://www.who.int/mediacentre/factsheets/fs204/en/index.html. Accessed June 2, 2014.[WHO HBV]
Wieland SF, Guidotti LG, Chisari FV. Intrahepatic induction of alpha/beta interferon eliminates viral RNAcontaining capsids in hepatitis B virus transgenic mice. J Virol. 2000;74:4165-4173.[Wieland 2000]
Wiseman E, Fraser MA, Holden S, et al. Perinatal transmission of hepatitis B virus: an Australian experience.
Med J Aust. 2009;190:489-492.[Wiseman 2009]
Wong F, Pai R, Van Schalkwyk J, Yoshida EM. Hepatitis B in pregnancy: a concise review of neonatal vertical
transmission and antiviral prophylaxis. Ann Hepatol. 2014;13187-13195.[Wong 2014]
Wu SD, Wang JY, Li L. Staging of liver fibrosis in chronic hepatitis B patients with a composite predictive
model: a comparative study. World J Gastroenterol. 2010;16:501-507.[Wu 2010]
Xu WM, Cui YT, Wang L, et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B
virus infection: a multicentre, randomized, double-blind, placebo-controlled study. J Viral Hepat. 2009;16:94103.[Xu 2009]
Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer
therapy. Hepatology. 2006;43:209-220.[Yeo 2006]
Yim HJ, Lok AS. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know
in 2005. Hepatology. 2006;43:S173-S181.[Yim 2006]
Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a
prospective study in men. J Natl Cancer Inst. 2005;97:265-272.[Yu 2005]
Yuki N, Nagaoka T, Yamashiro M, et al. Long-term histologic and virologic outcomes of acute self-limited
hepatitis B. Hepatology. 2003;37:1172-1179.[Yuki 2003]
Zhou K, Gao CF, Zhao YP, Liu HL, et al. Simpler score of routine laboratory tests predicts liver fibrosis in
patients with chronic hepatitis B. J Gastroenterol Hepatol. 2010;25:1569-1577.[Zhou 2010]
Zhu YY, Mao YZ, Wu WL, Cai QX, Lin XH. Does hepatitis B virus prenatal transmission result in postnatal
immunoprophylaxis failure? Clin Vaccine Immunol. 2010;17:1836-1841.[Zhu 2010]
Zou S, Stramer SL, Notari EP, et al. Current incidence and residual risk of hepatitis B infection among blood
donors in the United States. Transfusion. 2009;49:1609-1620.[Zou 2009]

Clinical Care Options Hepatitis B Review Jun 2014

Caricato da

Informazioni sul documento

Titolo originale

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

Clinical Care Options Hepatitis B Review Jun 2014

Caricato da

Copyright:

Formati disponibili

CLINICAL CARE OPTIONS. ACTUALIZACION EN HEPATITIS B. JUNIO 2014..

Hepatitis B Epidemiology, Pathogenesis, Diagnosis, and Natural History

Author: Marc G. Ghany, MD (More Info)

Editors In Chief: Nezam H. Afdhal, MD, FRCPI; Stefan Zeuzem, MD

Last Reviewed: 6/18/14 (What's New)

Global Overview of Hepatitis B Virus

; the true figure is

estimated to be considerably higher

[Goldstein 2005; Lavanchy 2004; Lozano 2012]

as the cause of death in 1792 cases in the United States in 2010.

Hepatitis B Epidemiology, Pathogenesis, Diagnosis, and Natural History

Author: Marc G. Ghany, MD (More Info)

Editors In Chief: Nezam H. Afdhal, MD, FRCPI; Stefan Zeuzem, MD

Last Reviewed: 6/18/14 (What's New)

Epidemiology of Hepatitis B Virus: Current

Prevalence is lowest (< 2%) in North America and Western Europe

Routes of transmission vary geographically:

In regions of high endemicity, HBV is primarily transmitted vertically (perinatally) or

In regions of intermediate prevalence, multiple modes of transmission are important,

as well as sexual, injection-drug

use, and through medical care

Hepatitis B Virus Epidemiologic Trends in the United States

[CDC 2013; CDC 2011a]

The third NHANES estimated overall prevalence of chronic HBV infection at

Geographical Distribution of Hepatitis B Virus Genotypes

HBV genotypes differ among different geographic regions (Table 2)

Clinical Significance of Hepatitis B Virus Genotype

[Cao 2009; Carman 1989]

Effect of Immunization on Hepatitis B Virus Disease Burden

who have the highest rates of acute

Areas with low-intermediate prevalence (2% to 4%) include the Mediterranean

In regions of intermediate prevalence, multiple modes of transmission are important,

including vertical and horizontal transmission,

as well as sexual, injection drug use, and through

Hepatitis B Virus Epidemiologic Trends in the United States

with a further 36% decline

[CDC 2013; CDC 2011a]

During that time, the

Figure 2. Annual US incidence of acute hepatitis B from 1980-2011.[CDC 2011a]

corresponding to approximately 700,000 persons nationwide.

The prevalence was highest among

increased with age, peaking between the ages of 50-59 years.

[Cohen 2008; Kowdley 2012]

Including these individuals would increase the estimated prevalence of

chronic hepatitis B in the United States to more than 2 million people.

Table 1. Estimated Prevalence of HBsAg-Positive Persons in the United

Chronic Hepatitis B Prevalence, %

US-born Asian-Pacific Islander

Foreign-born Asian-Pacific Islander

Other group living quarters

Geographical Distribution of Hepatitis B Virus Genotypes

Table 2. HBV Genotypes: Geographic Distribution and Clinical

United States, sub-Saharan

Better response to interferon and

Japan, China, Indonesia,

Lower disease activity, younger age at

Korea, China, Taiwan, Japan,

More severe disease and worse clinical

Associated with precore mutation

Central and South America

United States, France,

Clinical Significance of Hepatitis B Virus Genotype

In addition, patients infected with HBV