Hepatitis B Virus

Huamin Wang


Department of Microbiology & Immunology
Hainan Medical College
2007
Statistics on HBV
Most healthy adults (90%) who are
infected will recover and develop
protective antibodies against future
hepatitis B infections
90% of infants and up to 50% of young
children infected with hepatitis B will
develop chronic infections.
Hepatitis B In the World
2 billion people have been infected (1 out
of 3 people).
400 million people are chronically infected.
10-30 million will become infected each
year.
An estimated 1 million people die each
year from hepatitis B and its complications.
Approximately 2 people die each minute
from hepatitis B.

Hepatitis B In the United States
12 million Americans have been infected (1 out
of 20 people).
More than one million people are chronically
infected .
Up to 100,000 new people will become infected
each year.
5,000 people will die each year from hepatitis B
and its complications.
Approximately 1 health care worker dies each
day from hepatitis B.

Hepatitis B in China
1.3 billion people
the world's largest population of hepatitis B
patients, with nearly half a million people
dieing of the liver disease every year
120 million Chinese have tested positive
for hepatitis B, which has become a
severe public health problem in the
country
General Concepts
Hepatitis = 'inflammation of the liver'.
six medically important viruses are commonly
described as hepatitis viruses:
HAV,HBV,HCV,HDV,HEV,HGV.


Definitions for Hepatitises
Acute: Short term and/or severe.
Chronic: Lingering or lasting - may or may not be
severe
Fulminant: Developing quickly and lasting a
short time, high mortality rate.
Cirrhosis: Hardening: may be the result of infection
or toxins (e.g. alcohol)
Jaundice: Yellowing of the skin, eyes, etc due to
raised levels of bilirubin in the blood due to liver damage.
Hepatocellular carcinoma is closely
associated with hepatitis B, and at least in some regions of
the world with hepatitis C virus.

A
Infectious
Serum
Viral hepatitis
Enterically
transmitted
Parenterally
transmitted
F, G, TTV
? other
E
NANB
B D C
Viral Hepatitis - Historical Perspectives
Table 24.12
Hepatitis B Virus
1 Properties of HBV
a member of the hepadnavirus group
Circular partially double-stranded DNA
viruses
Replication involves a reverse transcriptase.
endemic in the human population and
hyperendemic in many parts of the world.
a number of variants
It has not yet been possible to propogate the
virus in cell culture
HBV : Structure
HBV : Structure

Virion also referred to as Dane particle (ds-tranded DNA)
42nm enveloped virus
Core antigens located in the center (nucleocapsid)
* Core antigen (HBcAg)
* e antigen (HBeAg)- an indicator of transmissibility
(minor component of the core- antigenically distinct from
HBcAg)
22nm spheres and filaments other forms- no DNA in
these forms so they are not infectious (composed of
surface antigen)- these forms outnumber the actual
virions
HBV Structure & Antigens
Dane particle
HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr)
HBcAg = inner core protein (a single serotype)
HBeAg = secreted protein; function unknown
decoy particles
HBsAg-containing
particles are released into
the serum of infected
people and outnumber the
actual virions.
Spherical or filamentous
They are immunogenic and
were processed into the
first commercial vaccine
against HBV.
G
E
N
O
M
E

There are 4 open reading frames derived from the same strand (the
incomplete + strand)
S - the 3 polypeptides of the surface antigen (preS1, preS2 and
S - produced from alternative translation start sites.
C - the core protein
P - the polymerase
X - a transactivator of viral transcription (and cellular genes?).
HBx is conserved in all mammalian (but not avian)
hepadnaviruses. Though not essential in transfected cells, it is
required for infection in vivo.

Open Reading Frames
2 HBV: Replication

Reverse transcription: one of the mRNAs is
replicated with a reverse transcriptase making the
DNA that will eventually be the core of the
progeny virion
RNA intermediate: HBV replicates through an
RNA intermediate and produces and release
antigenic decoy particles.
Integration: Some DNA integrates into host
genome causing carrier state

Replication of HBV
Parenteral - IV drug abusers, health workers are
at increased risk.

Sexual - sex workers and homosexuals are
particular at risk.

Perinatal(Vertical) - mother(HBeAg+) infant.

3HBV: Modes of Transmission
High (>8%): 45% of global population
lifetime risk of infection >60%
early childhood infections common
Intermediate (2%-7%): 43% of global
population
lifetime risk of infection 20%-60%
infections occur in all age groups
Low (<2%): 12% of global population
lifetime risk of infection <20%
most infections occur in adult risk groups
Global Patterns of Chronic HBV Infection
4 Epidemiology
350,000,000 carriers worldwide
120,000,000 carriers in China
- the carrier rate can exceed 10%
-15 to 25% of chronically infected patients will die
from chronic liver disease
500,000 deaths/year in China
982,297 liver disease in China 2005
50% of children born to mothers with chronic HBV in
the US are Asian American

High Moderate
Low/Not
Detectable
blood semen urine
serum vaginal fluid feces
wound exudates saliva sweat
tears
breastmilk
Concentration of Hepatitis B Virus
in Various Body Fluids




High-risk groups for HBV infection
People from endemic regions
Babies of mothers with chronic HBV
Intravenous drug abusers
People with multiple sex partners
Hemophiliacs and other patients requiting blood
and blood product treatments
Health care personnel who have contact with
blood
Residents and staff members of institutions for
the mentally retarded
Symptomatic Infection
Chronic Infection
Age at Infection
Chronic Infection (%)
S
y
m
p
t
o
m
a
t
i
c

I
n
f
e
c
t
i
o
n

(
%
)

Birth 1-6 months 7-12 months 1-4 years Older Children
and Adults
0
20
40
60
80
100 100
80
60
40
20
0
Outcome of Hepatitis B Virus Infection
by Age at Infection
C
h
r
o
n
i
c

I
n
f
e
c
t
i
o
n

(
%
)

5 Pathogenesis & Immunity
Virus enters hepatocytes via blood
Immune response (cytotoxic T cell) to viral
antigens expressed on hepatocyte cell surface
responsible for clinical syndrome
5 % become chronic carriers (HBsAg> 6 months)
Higher rate of hepatocellular ca in chronic
carriers, especially those who are e antigen
positive
Hepatitis B surface antibody likely confers
lifelong immunity (IgG anti-HBs)
Hepatitis B e Ab indicates low transmissibility
6 Clinical Features
Incubation period: Average 60-90 days
Range 45-180 days
Insidious onset of symptoms.
Tends to cause a more severe disease than Hepatitis A.
Clinical illness (jaundice): <5 yrs, <10%
5 yrs, 30%-50%
1/3 adults-no symptoms
Clinical Illness at presentation 10 - 15%

Acute case-fatality rate: 0.5%-1%
Chronic infection: < 5 yrs, 30%-90%
5 yrs, 2%-10%
More likely in ansymptomatic
infections
Premature mortality from
chronic liver disease: 15%-25%
Possible Outcomes of HBV Infection
Acute hepatitis B infection
Chronic HBV infection
3-5% of adult-
acquired infections
95% of infant-
acquired infections
Cirrhosis
Chronic hepatitis
12-25% in 5 years
Liver failure Hepatocellular
carcinoma
Liver transplant
6-15% in 5 years
20-23% in 5 years
Death
Death
Symptoms
HBeAg
anti-HBe
Total anti-HBc
IgM anti-HBc
anti-HBs
HBsAg
0 4 8 12 16 20 24 28 32 36 52 100
Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Weeks after Exposure
Titre
IgM anti-HBc
Total anti-HBc
HBsAg
Acute
(6 months)
HBeAg
Chronic
(Years)
Anti-HBe
0 4 8 12 16 20 24 28 32 36 52 Years
Weeks after Exposure
Acute HBV Infection with Progression to
Chronic Infection: Typical Serologic Course
7 Laboratory Diagnosis
8-1 Current Treatment Options

Interferon alfa (Intron A)
Response rate is 30 to 40%.
Lamivudine (Epivir HBV)
(relapse ,drug resistance)
Adefovir dipivoxil (Hepsera)
8-2 Prevention
Vaccination
- highly effective recombinant vaccines
Hepatitis B Immunoglobulin (HBIG)
-exposed within 48 hours of the incident/ neonates
whose mothers are HBsAg and HBeAg positive.
Other measures
-screening of blood donors, blood and body fluid
precautions.



Hepatitis B Vaccine
Infants: several options that depend on status of
the mother
If mother HBsAg negative: birth, 1-2m,6-18m
If mother HBsAg positive: vaccine and Hep B immune
globulin within 12 hours of birth, 1-2m, <6m
Adults
* 0,1, 6 months
Vaccine recommended in
All those aged 0-18
Those at high risk
summary
General concepts for hepatitis
Types of hepatitis
Properties of HBV : Structure\ ORF\Replication
Transmission \Epidemiology
Pathogenesis & Immunity
Clinical Features
Laboratory Diagnosis
Treatment \Prevention

Questions
What is hepatitis B?
What are the properties of HBV?
How many ORFs of HBV?
How is HBV spread?
How does the HBV curse the liver diseases?
How do you interpret serological lab results
for HBV?
How to treat and prevent hepatitis B?


Review Quiz
Following transmission of HBV from mother to
infant, which of the following is the most
common medical problem for the infant?
A. Liver failure.
B. Chronic HBV carrier state
C. Development of lymphoma.
D. Opportunistic infections.
E. Development of CNS disease.
Why are the Chinese at greater
risk than Westerners?
Because there are more Asian people already
infected with hepatitis B than Westerners.
Although hepatitis B is not an "Asian disease", it
affects hundreds of millions of Asians. Since the
Asian community starts with such a large
number of infected people, there are more
people who can pass the hepatitis B virus on to
others. This increases the risk that you could get
infected. Since there is a smaller number of
Westerners who are infected, this group has a
lower risk of infection
How is hepatitis B spread
differently among the Chinese?

Asians and Westerners can both get hepatitis B through contact with
blood, unprotected sex, shared needles, and from an infected
mother to newborn baby during delivery.
Jobs and lifestyle choices can create an equal risk for both groups.
However, hepatitis B is often spread differently among Asians.
Asians are most commonly infected as newborns - from a mother
who unknowingly passes the virus on during delivery.
Young children are also at risk if they live in close daily contact with
an infected family member.
Babies and children are more likely to develop a chronic hepatitis B
infection because their young immune systems have trouble getting
rid of the virus.
Westerners are most commonly infected as young adults through
unprotected sex. As adults, their immune systems can usually get
rid of the virus and they "recover" from an infection.
What does it mean to be a
"chronic carrier" of hepatitis B?
People who are unable to get rid of the hepatitis B
virus are diagnosed as being a "chronic carrier".
The virus can stay in their blood and liver for a
long time.
They can unknowingly pass the virus on to other
people.
Chronic hepatitis B can also lead to serious liver
diseases, such as cirrhosis or liver cancer. Not
every chronic carrier will develop serious liver
disease.
However, they have a greater chance than
someone who is not infected.
Why should Chinese people be
worried about chronic hepatitis B
infections?

Because chronic hepatitis B can lead to cirrhosis or liver
cancer.
It's important to get tested because early diagnosis can
lead to early treatment which can save your life.
Also, chronic carriers can spread the virus to others.
Since most chronic carriers don't know they are infected,
they are unknowingly spreading it to many other people.
If people are not tested, hepatitis B can pass through
several generations in one family and throughout the
community.
How can I stop the spread of
hepatitis B?
The good news is that you can break the cycle of
infection in your family and in the Chinese
community.
Get tested for hepatitis B.
Make sure everyone in your family is vaccinated
against hepatitis B.
Get the vaccine yourself.
Look for good medical care.
Discuss treatment options with your family doctor
or a liver specialist if you already have chronic
hepatitis B.
Are there any treatments if I have
chronic hepatitis B?

Currently, there are five approved drugs in the
United States for people who have chronic hepatitis
B infections. These drugs are also available in China:
1Epivir-HBV or Zeffix (lamivudine) is a pill that is
taken orally
2Hepsera (adefovir dipivoxil) is a pill that is taken
orally
3Baraclude (entecavir) is a pill that is taken orally
4Intron A (interferon alpha) is a drug given by
injection
5Pegasys (pegylated interferon) is a drug that is
give by injection

Are there any treatments if I have
chronic hepatitis B?
It is important to know, not every chronic hepatitis B
patient needs to be on medication.
Some patients only need to be monitored by their doctor
on a regular basis (at least once a year, or more).
Other patients with active signs of liver disease may
benefit the most from treatment.
Be sure to talk to your doctor about whether you could
benefit from treatment and discuss the treatment options.
In addition, there are promising new drugs in clinical
trials and in the research pipeline.
However, it is vital that all people with chronic
hepatitis B visit their doctor on a regular basis,
whether they receive treatment or not!