Download Causative agents of viral hepatites

Chair of Medical biology, Microbiology, Virology, and
Immunology
Causative agents of viral
hepatites
Lecturer Prof. S.I. Klymnyuk
Although hepatitis (inflammation of the liver) was first
described in the fifth century BC, it is only recently (1940 to
1950) that the viral etiology of man cases of this disease has
been established. More than 50,000 cases of viral hepatitis
are reported annually in the United States.
Human hepatitis is caused by at least six genetically and
structurally distinct viruses (Table 1). The diseases caused
by each of these viruses are distinguished in part by the
length of their incubation periods and the epidemiology of
the infection.
Table 1
Characteristics of Human Hepatitis Viruses
Virus
Family/
Genus
Size/
Genome
Length of
Incubation
Source of
Infection
Vaccine
HAV
Picornaviridae /
enterovirus 72
27-30 nm,
singlestranged
RNA
15-40 days
Mostly oralfecal
No
HBV
Hepadnaviridae /
hepadnavirus
142 nm,
circular
doublestranged
DNA
50-180
days
Parenteral
Recombinant
subunit
vaccine
HCV
Flavivirida
e
30-50 nm
singlestranged
RNA
14-28 days
Parenteral,
likely other
sources
No
Table 1
Characteristics of Human Hepatitis Viruses
Virus
Family/
Genus
Size/
Genome
Length of
Incubation
Source of
Infection
Vaccine
HDV
Unclassified
35-40 nm
singlestranged
RNA
50 180
days*
Parenteral
transmission
No
HEV
Calicivirid
ae
27 34 nm
singlestranged
RNA
6 weeks
Oral-fecal
No
* Length of incubation will vary depending on the HBV status
of the infected individual. HDV infection requires either
coinfection with HBV or prior infection with HBV
HEPATITIS A VIRUS
Much of the initial information about HAV resulted from the
use of human volunteers to determine the epidemiology of
the disease, its incubation period, and the role of the immune
response in controlling it. HAV also can be transmitted to
several species of marmoset monkeys and chimpanzees, and
can be grown in cell cultures of some primate and human
cells.
Global Prevalence of Hepatitis A
Infection
HAV Prevalence
High
Intermediate
Low
Very Low
STRUCTURE AND REPLICATION OF HEPATITIS A
VIRUS. Hepatitis A virus, now classified as a member of
the Picornaviridae, is a spherical, RNA containing particle,
27 to 32 nm in diameter. Biochemical analysis has shown
that the virus possesses a single stranded RNA of about
7500 nucleotides. The mature virus particle contains three
major polypeptides (VP1, VP2, and VP3) with molecular
weights ranging from 14,000 to 33,000 daltons. The
particle also can contain a small VP4 protein.
HEPATITIS A VIRUS
Virus
Hepatitis A
Family
Picornaviri-dae
Genus
Hepatovirus
Virion
27 nm icosahedral
Envelope
No
Genome
ssRNA
Genome size
7,5kb
Stability
Heat- and acid-stable
Transmission
Fecal-oral
Prevalence
High
Fulminant disease
Rare
Chronic disease
Never
Oncogenic
No
Hepatitis A virus particles found in fecal extracts by
immunoelectron microscopy. Both full and empty particles
are present. The virus is 27 to 29 nm in diameter. (X
125,000.)
HAV is one of most stable viruses infecting humans. It is
resistant to treatment with diethyl ether, can withstand
heating at 56 C for 30 minutes, and is remarkably resistant
to many disinfectants. Electron microscopy of fecal extracts
mixed with antibody to HAV has revealed clumps of virus
particles about 27 nm in diameter with icosahedral
symmetry. Although minor biochemical differences have
been reported among HAV strains isolated in different
studies, there appears to be no evidence for major antigenic
differences among HAV strains isolated in various parts or
the world.
Genome organisation of HAV
EPIDEMIOLOGY OF HEPATITIS A VIRUS INFECTIONS.
The spread of hepatitis A is most often from person to person by a
fecal-oral route, hence, the older term for the disease was infectious
hepatitis. An average of 25,000 cases of hepatitis A are reported
each year in the United States. However, these cases represent only
a small percentage or actual infections, because many HAV
infections remain undiagnosed. This is particularly true for children,
in whom infections frequently are subclinical and the characteristic
jaundice rarely is seen. As public health standards increase, the
overall prevalence of HAV usually decreases. However, especially
in developing countries, this can lead paradoxically to more disease,
because it often postpones exposure to the virus until an age at
which infection is more likely to produce clinical symptoms.
The most common source of infection is close person to person
contact.
Outbreaks of hepatitis A have been reported in day-care
centres and institutions for the mentally retarded. In some
cities in the United States, 9% to 12% of reported cases of
hepatitis A occur in children in day-care centres, their
parents, or staff members. Epidemics also have resulted from
drinking fecally contaminated water; however, such water
borne epidemics are rare. Eating food prepared by an infected
person or ingesting raw oysters, clams, or mussels harvested
from fecally contaminated water is the source of many HAV
infections. Because there is no persistent infection with
continuous viremia (as in HBV infections), HAV
transmission by blood products is rare. Although the
incidence of HAV infections in intravenous drug abusers is
high, it has not been proven that this is due to blood borne
transmission
Hepatitis A Transmission
Close personal contact
Household or sexual contact
Daycare centers
Fecal-oral contamination of food or water
Food handlers
Raw shellfish
Travel to endemic areas
Blood-borne (rare)
Injecting drug users
PATHOGENESIS OF HEPATITIS A VIRUS
INFECTIONS. Hepatitis A is an acute, usually self limiting
disease with an asymptomatic incubation period of 15 to 40
days. During this time, the liver is infected and large amounts
of virus can be shed in the feces. Symptoms usually begin
abruptly with fever, nausea, and vomiting.The major area of
cell necrosis occurs in the liver, and the resulting enlargement
of the liver frequently causes blockage of the biliary
excretions, resulting in jaundice, dark urine, and clay colored
stool. A fulminant form of hepatitis A occurs in only 1% to 4%
of patients. Complete recovery can require 8 to 12 weeks,
especially in adults.
During convalescence, patients frequently remain weak and
occasionally mentally depressed.
In humans, the severity of the disease varies considerably
with age, most cases occurring in young children are mild
and undiagnosed, resolving without sequelae. In contrast to
HBV, HAV infections result in no extrahepatic manifestations
of acute infection and no long term carrier state, and they are
not associated with either cirrhosis or primary hepatocellular
carcinoma.
Hepatitis A - Clinical
Features
• Incubation period:
• Jaundice by
age group:
• Complications:
Average 30 days
Range 15-50 days
<6 yrs,
<10%
6-14 yrs, 40%-50%
>14 yrs, 70%-80%
Fulminant hepatitis
Cholestatic
hepatitis
• Chronic sequelae:
Relapsing hepatitis
None
Body Fluid
Concentration of Hepatitis A Virus
in Various Body Fluids
Feces
Serum
Saliva
Urine
100
102
104
106
108
Infectious Doses per ml
1010
Clinical Variants of
HAV
Hepatitis A Infection
Asymptomatic (anicteric) disease
Children under 6 years of age, > 90%
Children from 6-14 years old, 40-50%
Symptomatic (icteric) disease
Adults and children over 14, 70-80%
DIAGNOSIS OF HEPATITIS A VIRUS INFECTIONS. The
diagnosis of individual cases of hepatitis A usually is not possible
without supporting laboratory findings. However, a tentative
diagnosis of hepatitis A is appropriate if there is the simultaneous
occurrence of several cases in which the epidemiology and
incubation period are consistent with that of HAV disease Such
situations have been known to arise in day-care centres, summer
camps, and military installations.
Virus particles frequently can be detected in fecal extracts by use of
immune electron microscopy, in which the fecal extract is mixed
with antibodies to HAV. Standard radioimmunoassays also can be
used to detect the presence of HAV antigens in fecal extracts. An
enzymelinked immunosorbent assay using anti HAV linked to either
horseradish peroxidase or alkaline phosphatase also is used to detect
fecal HAV.
In addition, a specific diagnosis of hepatitis A can be made by
demonstrating at least a four fold rise in anti-HAV antibody levels in
serum.
Typical Serologic Course of Acute
Hepatitis A Virus Infection
Symptoms
ALT
Total anti-HAV
Fecal
HAV
0
1
IgM anti-HAV
2
3
4
5
6
Months after exposure
12
24
Nomenclature and definition of hepatitis A
viruses, antigens, and antibodies
Disease
Hepatitis A
Component
of system
Definition
HAV
Hepatitis A virus. Etiologic agent of infectious
hepatitis. A picornavirus the prototype of a
new genus Hepatovirus
Anti HAV
Antibody to HAV. Detectable at onset of
symptoms; lifetime persistence
IgM antiHAV
IgM class antibody to HAV. Indicates recent
infection with hepatitis A; positive up to 4-6
months after infection
CONTROL OF HEPATITIS A VIRUS INFECTIONS. Proper
sanitation to prevent fecal contamination of water and food is the
most effective way to interrupt the fecal-oral transmission of
hepatitis A.
Pooled immune serum globulin from a large number of individuals
can be used to treat potentially exposed poisons, and its
effectiveness has been well established. Immune serum globulin
normally contains a substantial titer of neutralizing antibodies to
HAV. Studies indicate that large amounts of immune serum globulin
can effectively prevent hepatitis A infection, whereas smaller
amounts (0 01 mg/kg) modify the severity of the disease, resulting in
a mild or asymptomatic infection Such infections can produce a
long-lasting active immunity.
Formalin inactivated HAV vaccines have been developed and some
have been licensed. Additional approaches using recombinant DNA
techniques also are being used to generate subunit vaccines or novel
recombinant vaccine strains
Hepatitis A Vaccine Efficacy
Studies
Vaccine
Site/Age
Group
N
Vaccine
Efficacy
(95% CI)
HAVRIX
(SKB)
2 doses
360 EL.U.
Thailand
1-16 yrs
38,157
94%
(79%-99%)
VAQTA
(Merck)
1 dose
25 units
New York
2-16 yrs
1,037
100%
(85%-100%)
HEPATITIS B VIRUS
About 300 million people world-wide are thought to be carriers of
HBV, and many carriers eventually die of resultant liver disease.
HBV causes acute hepatitis that can vary from a mild and self
limiting form to an aggressive and destructive disease leading to
postnecrotic cirrhosis. Many HBV infections are asymptomatic
(especially in children). However, many infections become
persistent, leading to a chronic carrier state. This can lead to
chronic active hepatitis and cirrhosis later in life. The HBV carrier
state also is strongly associated with one of the most common
visceral malignancies world-wide, primary hepatocellular
carcinoma. Much of our early knowledge concerning HBV
infections stems from studies with human volunteers, because the
virus does not readily infect cell cultures More recently, the
application of molecular biologic techniques, especially
recombinant DNA technology, has yielded significant insights into
the structure and replication of HBV.
HBV - Epidemiology
Prevalence of HBsAg Carrier State
>8%
28%
<2%
WHO
STRUCTURE OF THE HEPATITIS B VIRION
In spite of our inability to grow HBV in cell cultures, several
details have been learned about the structure of the hepatitis B
virion through studies of new antigens appearing in the blood of
infected persons Such information indicates that HBV is unlike
any known group of human viruses. Interestingly, similar
viruses have been identified in other species Woodchucks,
Beechy ground squirrels, and Peking ducks all harbour viruses
that are similar in structure and in biologic properties to human
HBV.
In 1964, it was discovered that numerous virus-like particles
were present in the blood of both patients with HBV hepatitis
and asymptomatic carriers of HBV. These virus-like particles,
first discovered in the serum of an Australian aborigine,
originally were referred to as Australia antigen or hepatitisassociated antigen.
HEPATITIS B VIRUS
Virus
Hepatitis B
Family
Hepadnaviridae
Genus
Orthohepadnavirus
Virion
42 nm, spherical
Envelope
Yes (HBsAg)
Genome
dsDNA
Genome size
3,2kb
Stability
Acid-sensitive
Transmission
Parenteral
Prevalence
High
Fulminant disease
Rare
Chronic disease
Often
Oncogenic
Yes
The particles are uniformly 22 nm in diameter, existing as both
spherical particles and filaments (Fig. 1). Treatment with ether
removes a 2-nm envelope, leaving a 20-nm particle. However,
these particles do not contain nucleic acid and since have been
shown to represent incomplete virus particles containing HRV
envelope protein but lacking nucleocapsids. The standard
terminology for these particles is HBsAg to designate that they
contain the surface antigens of HBV.
In 1970, another particle, 42 nm in diameter, was found in the
serum of patients with hepatitis B. These larger particles
(named Dane particles after their discoverer) occurred in much
lower concentrations than did the HBsAg particles. Dane
particles were shown to contain the double-stranded, circular
viral DNA genome. It has now been demonstrated that the 42nm Dane particle represents the intact, infectious HBV
particle.
FIGURE 1. Fraction of the blood scrum from a patient
with a severe ease of hepatitis. The larger spherical
particles, or Dane particles, are 42 nm in diameter and are
the complete hepatitis B virus. Also evident are filaments of
capsid protein (HBsAg).
HEPATITIS B VIRUS:
Treatment of the Dane particles with a non-ionic detergent
dissociates the HBsAg and liberates a 27-nm inner core. This
inner core contains a core protein, defined serologically as the
HBcAg, as well as viral DNA. It also contains two virally
encoded enzymes (a DNA polymerase and a protein kinase).
Another HBV antigen, designated HBcAg, is often found in
the serum of patients during the early stages of infection and
in patients with chronic active hepatitis. HBcAg is structurally
related to the HBV core protein and is encoded by the C gene.
It can be detected in preparations of Dane particles and,
therefore, appears to be an integral part of the infectious
virion. Its presence in serum is believed to reflect active
replication of HBV and is a marker for active disease. The
appearance of anti-HBc antibodies generally correlates with a
good prognosis and a decline in virus replication.
REPLICATION OF HEPATITIS B VIRUS. Studies on the
replication of HBV and HBV-related viruses (ie, woodchuck,
ground squirrel, and duck hepatitis viruses) have suggested a
unique mode of replication for HBV. This replication involves
reverse transcription, indicating that HBV is phylogenetically
related to the retrovirus family. The viral genome of HBV is
about 3000 to3300 nucleotides in length, and molecular
cloning and DNA sequencing experiments have established
the relative organization of the genes for the various structural
proteins (Fig. 2). In addition, an open reading frame encoding
a putative DNA polymerase has been identified.
Although the viral DNA is circular, both strands of the
duplex are linear, and the circular conformation is
maintained solely by extensive base pairing between the two
gapped DNA strands. Within the virus particle, the negative
strand appears to be uniform in length, about 3200
nucleotides. In contrast, the positive strand is shorter and
varies in length between different virions, due to singlestranded gaps of variable size. On infection, the DNA
polymerase in the nucleocapsid core is activated and
completes the synthesis of the positive strand, using the
negative strand as a template.
After the conversion of gapped double-stranded viral DNA to
fully double-stranded DNA, a full-length positive-strand
RNA (a "pre-genome") is transcribed from the HBV DNA
template. This RNA serves as the mRNA for the translation
of the HBcAg. Evidence suggests that this form of RNA also
is packaged with viral core proteins and the viral DNA
polymerase within the cell to form an "immature core". A
DNA strand of negative polarity then is synthesized through
reverse transcription. This step is followed by the synthesis
of a partial positive strand and the full maturation of the virus
particle containing a gapped DNA genome.
HOW THE VIRUS REPRODUCES ??
First the virus attached to a liver cell membrane.
The virus is then transported into the liver cell
The core particle then releases it’s contents of DNA and
DNA polymerase into the liver cell nucleus.
 Once within the cell
nucleus the hepatitis B
DNA causes the liver
cell to produce, via
messenger RNA ; HBs
protein , HBc protein ,
DNA polymerase, the
HBe protein , and other
undetected protein and
enzymes.
 DNA polymerase
causes the liver cell to
make copies of hepatitis
B DNA from messenger
RNA.
The cell then assembles ’live’ copies of virus.
However because of the excess numbers of surface
proteins produced many of these stick together to form
small spheres and chains. These can give a characteristic “
ground glass” appearance to blood samples seen under a
microscope.
The copies of the virus and excess surface antigen are
released from the liver cell membrane into blood stream
and from there can infect other liver cells .
Organization of the genes in hepatitis B virus (HBV). The dashed line represents the
variable single- stranded region. The EcoRI site denotes the point of origin for the physical
map. The broad arrows define the four large open reading frames of the L strand transcript.
The four coding regions arc designated S(made up of pre-S and S genes), P (polymerise),
X (regulatory gene), and C. The two regions encoding the S (surface antigen) and C (core
antigen) proteins are represented by stippling.
Genome of HBV virus
Genome: 3.200 nucleotídes
S
P
C
X
HBV Genome
AgHBs
Pré S1
Pré S2
DNA Polimerase
gene P
AgHBc
gene C
AgHBe
Pré C
gene S
Hepatitis B Virus
Gene Products and Functions
Polymerase
Terminal protein (priming)
Reverse transcriptase, RNAse H
Surface
Envelope proteins
Receptor binding,
Regulation of cccDNA, viral
Pre - S1
assembly
Pre - S2
S
Core
HBX
HBeAg
Core
Viral assembly, fusion sequence
Primary structural component,
major antigenic determinants
Secreted, immunomodulatory function
Nucleocapsid component
Pleiotropic effects
ANTIGEN OF HEPATITIS B VIRUS:
HBe
In HBsAg there are some determinants, which
are responsible for 10 subtypes of this antigen.
“а” determinat is general.
There are d and y, and two additional - w and
r.
So, there are foe main subtypes: adw, ayw,
adr, ayr.
Other determinants - f, g, j, n, t, x.
EPIDEMIOLOGY
OF
HEPATITIS
B
VIRUS
INFECTIONS. Early volunteer studies failed to show a
normal portal of exit for HBV and, for years, it was believed
that a person could become infected only by the injection of
blood or serum from an infected person or by the use of
contaminated needles or syringes. As a result, the older name
for this disease was serum hepatitis. It has now been shown
that this supposition is not true. Using serologic techniques,
HBsAg has been found in feces, urine, saliva, vaginal
secretions, semen, and breast milk. Undoubtedly, the
mechanical transmission of infected blood or blood products is
one of the most efficient methods of viral transmission, and
infections have been traced to tattooing, ear piercing,
acupuncture, and drug abuse. About5% to 10% of intravenous
drug abusers are HBV carriers, and as many as 60% show
evidence of previous HBV infections.
Neonatal transmission also appears to occur during
childbirth. The incidence is increased significantly if the
mother's blood contains HBcAg. For example, in a study
from Taiwan, a 32% transmission rate was observed, and the
transmission could be correlated with HBcAg-positive cord
blood. The presence of HBsAg in breast milk also suggests
an additional vehicle for the transmission of HBV to the
newborn. The demonstration of infectious virus in semen
presents the possibility that virus can be sexually transmitted.
In hospitals, HBV infections are a risk for both hospital
personnel and patients because of constant exposure to blood
and blood products.
HBV SPREAD MAINLY BY
PARENTERAL ROUTE
 DIRECT PERCUTANEOUS INOCULATION OF
INFECTED SERUM OR PLASMA
 INDIRECTLY THROUGH CUTS OR ABRASIONS
 ABSORPTION THROUGH MUCOSAL SURFACES
 ABSORPTION OF OTHER INFECTIOUS
SECRETIONS (SALIVA OR SEMEN DURING SEX)
HBV SPREAD MAINLY BY
PARENTERAL ROUTE
 POSSIBLE TRANSFER VIA INANIMATE
ENVIRONMENTAL SURFACES
 VERTICAL TRANSMISSION SOON AFTER
CHILDBIRTH (TRANSPLACENTAL TRANSFER
RARE)
 CLOSE, INTIMATE CONTACT WITH AN
INFECTED PERSON
WHO IS AT GREATEST RISK FOR
HBV INFECTION?
 DRUG ABUSERS
 BLOOD PRODUCT RECIPIENTS
 ACCOUNTS FOR 5-10% POSTRANSFUSION
HEPATITIS
 HEMODIALYSIS PATIENTS
 PEOPLE FROM SOUTHEAST ASIAN
COUNTRIES (70-80%)
WHO IS AT GREATEST RISK FOR
HBV INFECTION?
 LAB PERSONNEL WORKING WITH
BLOOD PRODUCTS
 SEXUALLY ACTIVE HOMOSEXUALS
 PERSONS WITH MULTIPLE AND
FREQUENT SEX CONTACTS
 MEDICAL/DENTAL PERSONNEL
HBV
 300,000 NEW CASES IN U.S. PER YEAR
 LIFETIME RISK FOR AVERAGE PERSON
IS 5%
 SEXUAL PROMISCUITY > RISK
 LIFETIME RISK FOR DENTIST IS 13-28%
PATHOGENESIS OF HEPATITIS B VIRUS
INFECTIONS.
Acute hepatitis caused by HBV cannot be clinically
distinguished from hepatitis caused by HAV. However, several
characteristics differentiate the infections caused by these
viruses (see Table 2). HBV infections are characterized by a
long incubation period, ranging from 50 to 180 days.
Symptoms such as fever, rash, and arthritis begin insidiously,
and the severity of the infection varies widely. Mild cases that
do not result in jaundice are termed anicteric. In more severe
cases, characterized by headache, mild fever, nausea, and loss
of appetite, icterus (jaundice) occurs 3 to 5 days after the
initial symptoms. The duration and severity of the disease vary
from clinically inapparent to fatal fulminating hepatitis. The
overall fatality rate is estimated to be 1% to 2%, with most
deaths occurring in adults older than 30 years of age.
The duration of uncomplicated hepatitis rarely is more than 8
to 10 weeks, but mild symptoms can persist for more than 1
year. The mechanism of hepatic damage of HBV is not
established, but considerable data support the notion that
most of the liver damage that occurs during acute or chronic
hepatitis is mediated by a cellular immune response directed
toward the new antigens deposited in the cell membrane of
the infected cell.
Based on the ultimate pattern of the disease, this disease can
be divided into two categories: self- limiting acute infections
and chronic infections.
CHARACTERISTICS OF HBV
INFECTION
 INFECTION IS USUALLY SELF LIMITING,
COMPLETE RESOLUTION IN 6 MONTHS
 HOWEVER, WHEN INFECTED



5% ADULTS CHRONIC CARRIERS
20% CHILDREN CHRONIC CARRIERS
80-90% NEONATES AND INFANTS
BECOME CHRONIC CARRIERS
Table 2
Differential Characteristics of Hepatitis A and Hepatitis B
Characteristic
Hepatitis A
Hepatitis B
Length of incubation
period
15-40 days
50-180 days
Host range
Humans and possibly
nonhuman primates
Humans and some
nonhuman primates
Seasonal occurrence
Higher in fall and winter Year round
Age incidence
Much higher in children
All ages
Occurrence of jaundice
Much higher in adults
Higher in adults
Virus in blood
2-3 weeks before
illness to 1-2 weeks
after recovery
Several weeks before
illness to months or
years after recovery
Table 2
Differential Characteristics of Hepatitis A and Hepatitis B
Characteristic
Hepatitis A
Hepatitis B
Virus in feces
2-3 weeks before
illness to 1-2 weeks
after recovery
Rarely present, or
present in very small
amounts
Size of virus
27-32 nm
42 nm
Diagnosis based on
Liver function tests,
clinical symptoms, and
history
Liver function tests,
clinical symptoms,
history, and presence
of HBsAg in blood
Effective vaccine
No
Yes
Self-Limiting Hepatitis B Virus Infections.
Self limiting infections can be inapparent or can result in a
clinical hepatitis with jaundice lasting 4 to 5 weeks. HBsAg
may or may not be present in the blood, but, if present, it
usually disappears as the symptoms of hepatitis subside and
the jaundice clears. Antibodies to HBcAg, HBeAg, and
HBsAg arise at different periods during the infection and can
remain detectable for years after recovery. There seems to be
a good immune response to groupspecific determinants,
because recover)' appears to provide immunity to different
subtypes of the virus.
Chronic Hepatitis B Virus Infections. Between 6% and 10%
of clinically diagnosed patients with hepatitis B become
chronically infected and continue to have HBsAg in their
blood for at least 6 months, and sometimes for life. Chronic
infections can be subdivided into two general categories:
chronic persistent hepatitis and chronic active hepatitis. The
latter is the most severe and often eventually leads to cirrhosis
or the development of primary hepatocellular carcinoma.
Worldwide, it has been estimated that there are more than 200
million permanently infected carriers of HBV, of which about
1million reside in the United States. The prevalence of
chronic carriers varies widely in different parts of the world,
from 0.1% to 0.5% in the United States to up to 20% in
China, Southeast Asia, and some African countries.
The perinatal infection of newborn infants born to chronically
infected mothers results in a high incidence of chronic infection
(90%), which often is lifelong. This is particularly disquieting in
the developing countries of Asia and Africa, where carrier rates
are high. It has been estimated that HBV is the most common
single cause of liver disease in the world.
All carriers have antibodies to HBcAg, and some have antibodies
to HBeAg. Those who do not possess antiHBe may have
circulating HBeAg. Carriers with high concentrations of Dane
particles and circulating HBeAg appear to be more likely to suffer
liver damage than those in whom only HBsAg can be detected,
but the validity of this proposal is yet to be established. However,
such persons are much more likely to be transmitters of the
disease than are those who have solely HBsAg in their blood.
Several cases of membranous glomeulonephritis have been
described in HBsAg-positive children, and it has been reported
that the glomerulonephritis results from the deposition of
immune complexes consisting of anti-HBe IgG and HBeAg.
The mechanism by which carriers can remain persistently
infected and yet be asymptomatic is unknown. However,
prolonged carrier status is seen in association with chronic
hepatitis in patients with lowered immunity and in those
infected during the neonatal period or early childhood.
Virus-Host Immune Reactions. Currently there is evidence for at
least 3 hepatitis viruses—type A (short incubation hepatitis virus), type
B (long incubation hepatitis virus), and the agent or agents of non-A,
non-B hepatitis. A single infection with any confers homologous but
not heterologous protection against reinfection. Infection with HBV of
a specific subtype, eg, HBsAg/adw, appears to confer immunity to
other HBsAg subtypes, probably because of their common group a
specificity.
Most cases of hepatitis type A presumably occur without jaundice
during childhood, and by late adulthood there is a widespread
resistance to reinfection. However, serologic studies in this country
indicate that the incidence of infection among certain populations may
be declining as a result of improvements in sanitation commensurate
with arise in the standard of living. It has been estimated that as many
as 50-75% of young middle to upper income adults in the USA may be
susceptible to type A hepatitis. Younger people who live in poorer
circumstances or crowded institutions (eg, the armed forces) are at
increased risk.
The immunopathogenetic mechanisms that result in viral persistence
and hepatocellular injury in type B hepatitis remain to be elucidated.
An imbalance between suppressive and cytopathic immune
responses of the host has been hypothesized to account for the
various pathologic manifestations of this disease. It is postulated that
antibody-dependent, complement-mediated cytolysis or cellular
effector mechanisms are responsible for the hepatic injury observed,
whereas noncytopathic synthesis of viral components, surface
expression of viral antigens or liver-specific neoantigens, and
shedding of virus are primarily modulated by the humoral immune
response.
Various host responses, immunologic and genetic, have been
proposed to account for the higher frequency of HBsAg
persistence observed in infants or children compared to adults
and in certain disease states, eg, Down's syndrome, leukemia
(acute and chronic lymphocytic), leprosy, thalassemia, and
chronic renal insufficiency. Patients with Down's syndrome
are particularly prone to persistent antigenemia (but low
antibody frequency) and inapparent infections, and they show
a significantly greater prevalence of these disorders than is
found in other mentally retarded patients. This does not imply
that these patients have an increased susceptibility to HBV. On
the contrary, among other equally exposed patients who are
residents within the same institution, the total serologic
evidence of HBV infection is similar except that the antigen
carrier rate is low whereas the antibody prevalence is high. An
immunologic difference in the host response to the virus is
apparently responsible for this serologic dichotomy.
Persistent antigenemia and mild or subclinical infections are
more frequently observed in individuals who have been
infected with low doses of virus. Correspondingly, a direct
relationship between virus dose and time of appearance of
HBsAg or an abnormal ALT value has been reported; i.e., the
incubation period becomes longer as the dose of virus
diminishes.
The frequency of the chronic HBsAg carrier state following
acute icteric type B hepatitis is not known but is probably
under 10%. More than half of these patients continue to
exhibit biochemical and histologic evidence of chronic liver
disease, i.e., chronic persistent or chronic active hepatitis.
Primary Hepatocellular Carcinoma. A considerable amount of
evidence has documented the close association between HBV
infection and the development of primary hepatocellular
carcinoma. Hepatocellular carcinoma is the most common cancer
in the world, with at least 250,000 new cases reported annually.
Patients with hepatocellular carcinoma often have high levels of
HBsAg, and the carcinoma cells often contain integrated HBV
DNA. Further evidence for the link between persistent HBV
infections and hepatocellular carcinoma comes from
epidemiologic data showing that the risk of developing primary
hepatocellular carcinoma is more than 200 times higher in HBV
carriers than in noncarriers. Within some populations, the risk of
developing primary hepatocellular carcinoma is as high as 50% in
male chronic carriers.
However, HBV infection is not solely responsible for tumor
development, because the carrier state often exists for a lengthy period
(often 40 years or more) before the onset of liver cancer In addition, the
predominance of hepatocellular carcinoma in men indicates that other
factors, including sex related factors, contribute to the development of
this cancer. Nonetheless, an important component of chronic liver
disease is the continual regeneration of damaged or destroyed
hepatocytes, which, coupled with HBV replication and exposure to
environmental carcinogens, likely contributes in a significant fashion to
tumor development and progression. The relationships between
oncogene activation, loss of tumor suppressor genes, and the HBV are
under active investigation.
Because of the close egidemiologic link between chronic HBV infection
and hepatocellular carcinoma, it is hoped that mass vaccination of
susceptible individuals in such countries as China and Taiwan will
reduce the overall incidence of HBV infection, and that this eventually
will reduce dramatically the incidence of hepatocarcinoma.
DIAGNOSIS OF HEPATITIS B VIRUS INFECTIONS.
As in all cases of viral hepatitis, abnormal liver function is
indicated by increased levels of liver enzymes such as serum
glutamic
oxaloacetic
transaminase
and
alanine
aminotransferase (ALT). The presence of HBsAg confirms a
diagnosis of hepatitis B, and its serologic detection is
routinely carried out in diagnostic laboratories and blood
banks using radioimmunoassays or enzyme-linked
immunosorbent assay's.
HBV - Diagnosis
Acute Infection
HBV DNA
HBeAg
Anti-HBe
Anti-HBs
AntiHBc
HBsAg
0
Anti-HBc
IgM
2
Months
4
6
Years
HBV - Diagnosis
Chronic Infection
HBV DNA
HBeAg
Anti-HBe
HBsAg
Anti-HBc
IgG
Anti-HBc IgM
Month
s
Years
Nomenclature and definition of hepatitis B viruses,
antigens, and antibodies
Hepatitis B
HBV
Hepatitis B virus. Etiologic agent of serum hepatitis.
A hepadnavirus
HBsAg
Hepatitis B surface antigen. Surface antigen(s) of HBV
detectable in large quantity in serum;
several subtypes identified
HBeAg
Hepatitis B e antigen. Soluble antigen associated with HBV
replication, with high liters of HBV in serum, and with
infectivity of serum
HBcAg
Hepatitis B core antigen
Anti-HBs
Antibody to HBsAg. Indicates past infection with and
immunity to HBV, presence of passive antibody from HBIG
or immune response from HBV vaccine
Anti-HBe
Antibody to HBeAg. Presence in serum of HBsAg carrier
suggests lower liter of HBV
Anti-HBc
Antibody to HBcAg. Indicates infection with HBV at some
undefined time in the past
IgM anti-HBc
IgM class antibody to HBcAg. Indicates recent infection with
HBV; positive for 4-6 months after infection
PRACTICE
 HBsAg
 HBcAB (TOTAL)
 HBsAB
 HAV-IGM
 HCV
N.
N.
N.
N.
N.
 NO evidence of viral hepatitis viruses.
PRACTICE
 HBsAG
 HBcAB (TOTAL)
 HBsAB
 HAV-IGM
 HCV
 PAST INFECTION.
N.
P.
P.
N.
N.
PRACTICE
 HBsAg
 HBcAB (total)
 HBsAB
 HAV-IGM
 HCV
 IMMUNIZATION.
N.
N.
P.
N.
N.
PRACTICE
 HBsAg
P.
 HBcAB (Total)
P.
 HBsAB
N.
 HAV-IGM
N.
 HCV
N.
 MAY BE ACUTE OR CHRONIC.
 Order Hep. B Core IgM to clarify.
 The IgM will be positive , If Acute.
PRACTICE
 HBsAg
 HBcAB (TOTAL)
 HBsAB
 HAV-IGM
 HCV
P.
P.
N.
P.
P.
 Co infection with HBV, HAV, and HCV
PRACTICE
 HBsAG
P.
 HBcAB (total)
P.
 HBsAB
P.
 HAV-IGM
N.
 HCV
N.
 Past infection with recovery, and then reinfection that has become chronic, this is very
rare but does happen.
CONTROL OF HEPATITIS B VIRUS INFECTIONS. The
examination of all donor blood for the presence of HBsAg is
now routine, and this practice has done much to control the
occurrence of posttransfusion hepatitis B infections.
Passive immunization of human volunteers with hepatitis B
immune globulin (HBIG) has been shown to prevent disease
when the volunteers were challenged with infectious material,
but the use of immune globulin is not effective for the
treatment of active disease. One important and effective use
for HBIG, however, is the prevention of active hepatitis B
infections in neonates born to mothers who are chronic
carriers of HBsAg. HBIG also can be given to nonimmune
individuals known to have been exposed to HBV.
Active immunization with HBsAg promises to provide a
vehicle for the control of hepatitis B.
Clinical trials in high-risk populations have shown that the
incidence of hepatitis B in persons actively immunized with
HBsAg is decreased by about 95%. Moreover, immunization even
during the long incubation period may be efficacious in
preventing HBV infections. Because HBV has not been grown in
cell cultures, the first vaccine consisted of highly purified,
formalin-inactivated HBsAg particles obtained from the plasma of
persistently infected carriers. This vaccine has now been
superseded by a recombinant vaccine, in which the gene for
HBsAg has been cloned in yeast, enabling the production of
polypeptides carrying the antigenic determinants of HBsAg in
large amounts. The yeast-produced vaccine has been licensed for
use and has been given to more than 2 million people in the
United States.
The vaccine is considered safe and provides effective
protection. Administration of the HBV vaccine world-wide
has the potential to reduce drastically the incidence of HBV
infection. Early studies have shown that its use in HBVpositive pregnant women reduces the percentage of infants
who become carriers from 90% to 23%. In addition, if HBIG
is used in conjunction with the vaccine, the newborn carrier
incidence can be reduced to less than 5%. Taking note of the
fact that many chronic HBV carriers eventually die of liver
disease, tills vaccine represents the first prophylactic
measure to substantially reduce or prevent cirrhosis and
human cancer.
HBV - Vaccine
Vaccine
Engerix-B
Age Group
Dose
Volume
(ug)
(ml)
0-19 yr
 20 yr
Adults on
hemodialysis
10
20
0.5
1.0
0-19 yr
 20 yr
11-15 yr
Adults on
hemodialysis
5
10
10
0.5
1.0
1.0
3 (mo 0,1,6)
3 (mo 0,1,6)
2 (mo 0, 4-6)
40
1.0*
3 (mo 0,1,6)
40
# Doses
3 (mo 0,1,6)
3 (mo 0,1,6)
2.0
4
(mo 0,1,2,6)
Recombivax HB
(Optional 2-dose)
Combined HAV and HBV - Vaccine
Bivalent HAV and HBV vaccine
1ml contains 720 ELISA Units of
inactivated
HAV and 20 ug of
recombinant HBsAg protein
Dosage: 1 ml at 0, 1, 6 months
Recommended for all susceptible persons 
18 years at risk of exposure to both HAV
and HBV,
including travelers to
areas of
high/intermediate endemicity for both
viruses
HBV - Therapy
Therapeutic Agents
Immune Modulators
analog
Nucleo(s)tide
Interferon
Lamivudine
Thymosin
Adefovir dipivoxil
Therapeutic vaccines
Emtricitabine
Entecavir
L-dT/ L-dC
Clevudine
Famciclovir
HEPATITIS C VIRUS. When it became clear that most
cases of transfusion-associated hepatitis probably were
caused by a hitherto unknown virus, molecular genetic and
recombinant DNA techniques were used to identify, clone,
and sequence putative agents. This led to the isolation of a
new RNA virus, HCV. Sequence analysis has revealed that
HCV is organized in a manner similar to the flaviviruses and
that it shares biologic characteristics with this family.
Characteristics of hepatitis C viruses
Virus
Hepatitis C
Family
Flaviviridae
Genus
Hepacivirus
Virion
60 nm spherical
Envelope
Yes
Genome
ssRNA
Genome size
9,4 kb
Stability
Ether-sensitive, acid-sensitive
Transmission
Parenteral
Prevalence
Moderate
Fulminant disease
Rare
Chronic disease
Often
Oncogenic
Yes
Structural model of the Hepatitis C virus.
Model of Human Hepatitis C Virus
Lipid Envelope
Capsid Protein
Nucleic Acid
Envelope Glycoprotein E2
Envelope Glycoprotein E1
This has led to a classification of HCV as a genus within the
flavivirus family. About 80% of patients with chronic, posttransfusion NANB hepatitis in Italy and Japan have been
shown to have antibodies to HCV, and 58% of patients with
NANB hepatitis in the United States, with no known
parenteral exposure to the virus, have HCV antibodies.
Based on these data, it seems likely that HCV is a major
contributor to NANB hepatitis throughout the world. Most
infected individuals become chronic carriers of the virus,
and many develop chronic hepatitis. Studies in several urban
areas have shown that as many as 80% of intravenous drug
abusers have been infected with HCV. The development of
commercial antibody tests to detect HCV infection has
markedly reduced the number of cases of NANB hepatitis
acquired from transfusions and blood products.
HCV RNA Structure
Transcription, Replication
IRES, Translation
Structural
Non-Structural
5' UTR
3' UTR
Structure
C
E1
E2
Nucleocapsid,
Assembly
Processing
p7
NS2
Protease
Calcium
Envelope Proteins, Channel?
Assembly and Entry
NS3
Replication
NS4A NS4B
NS3 cofactor
Serine Protease,
Helicase
NS5A
Phosphoprotein,
Replication
Replication?
IRES = internal ribosomal entry site; UTR = untranslated region;
C = nucleocapsid core; E1 = envelope protein 1; E2 = envelope protein 2;
NS = non-structural
NS5B
RNA-dependent
RNA polymerase
Hepatitis C: A Global Health Problem
170-200 Million (M) Carriers Worldwide
United
States
3-4 M
Americas
12-15 M
Western
Europe
5M
Eastern
Europe
10 M
Far East Asia
60 M
Southeast Asia
30-35 M
Africa
30-40 M
Australia
0.2 M
HCV - Epidemiology
Prevalence In Groups at Risk
Recipients of clotting factors before 1987 75 90%
Injection drug users
70 - 85%
Long-term hemodialysis patients
10%
Individuals with > 50 sexual partners
10%
Recipients of blood prior to 1990
5%
Infants born to infected mothers
5%
Long-term sexual partners of HCV positive 1 - 5%
Health workers after random needlesticks 1 - 2%
Current Likelihood of
Transmission
Transfusion
1,000,000
~ 1 in
Maternal-Infant
Mother HIV-negative
Mother HIV-positive
~ 5%
15 - 20%
Heterosexual partner ~1 in 1,000 per yr
Needlestick injury
HCV-positive source
HCV status unknown
~ 5%
~ 1%
HCV
 ACCOUNTS FOR 90-95% OF POST
TRANSFUSION HEPATITIS
 RISK OF SEXUAL TRANSMISSION
LOWER THAN FOR HBV
 RISK THROUGH CASUAL CONTACT LOW
HCV
 VERTICAL TRANSMISSION POSSIBLE


RISK INCREASED IF MOTHER IS
POSITIVE FOR HCV RNA
RISK INCREASED IF MOTHER IS HIV
POSITIVE
 OVERALL PREVALENCE ESTIMATED
AT 1.4%
WHO IS AT GREATEST RISK FOR
HCV INFECTION?
 DRUG ABUSERS
 BLOOD PRODUCT RECIPIENTS (ANTI-HCV
SCREENING HAS GREATLY REDUCED
RISK)
 HEMODIALYSIS PATIENTS
 LAB PERSONNEL WORKING WITH BLOOD
PRODUCTS
WHO IS AT GREATEST RISK FOR
HCV INFECTION?
 SEXUALLY ACTIVE HOMOSEXUALS
 PERSONS WITH MULTIPLE AND
FREQUENT SEXUAL CONTACTS
 MEDICAL/DENTAL PERSONNEL (3-10%
VIA NEEDLESTICK FROM INFECTED
PATIENT)
HCV - Diagnosis
Diagnostic Tests
Hepatitis C antibody tests
Qualitative HCV RNA tests
Quantitative HCV RNA tests
Genotyping
HCV - Diagnosis
Acute
HCV
Infection
1000
HCV RNA positive
800
Anti-HCV
ALT
600
(IU/L)
Symptoms
400
200
Normal
ALT
0
0
2
4
6
8
10 12 24
Weeks
1
2
3
4
Months
Time After Exposure
Hoofnagle JH, Hepatology 1997; 26:15S
5
6
7
HCV - Diagnosis
HCV Antibody Test
Indicates past or present infection
Inexpensive, sensitive and specific
Poor positive predictive value in low
prevalence populations
Low sensitivity in immunosuppressed
patients
HCV - Diagnosis
Qualitative HCV RNA (PCR)
Confirms diagnosis of HCV infection
Useful in the early diagnosis of acute
hepatitis C
Demonstrates the presence of active
infection
“Gold standard” for documenting
response to treatment
Potential HCV Therapies
Phase I
R803
Rigel
HCV/MF59
Chiron
SCH-6
Schering
ANA245
ANADYS
Phase II
Phase III
Albuferon
VX-950
Human Genome
Vertex
Sciences
JTK 003
AKROS
Oral IFN alpha
Pharma
Amarillo
Biosciences
NM283
Idenix
HepX-C
XTL
Ceplene
Maxim
Multiferon
IDN-6556
Viragen
ISIS 14803
Idun
VX-497
Isis
Vertex
Infergen/gamma IFN
Civacir
InterMune
E-1
Omega IFN
NABI
Innogenetics
Biomedicine
Viramidine
Valeant
Amantadine
Endo Labs
Solvay
IP-501
Indevus
Zadaxin
SciClone
REBIF
Ares-Serono
Time to Market
HCV-086
ViroPharma/
Wyeth
HEPATITIS DELTA VIRUS. Hepatitis delta virus was first
described in 1977 as a novel antigen-antibody complex
detected by immunofluorescence in hepatocyte nuclei of
patients with chronic HBV infection and chronic hepatitis.
Although HDV antigen was initially observed in Italy, it has
been detected world-wide, primarily in HBV carriers who
have had multiple exposures to blood and blood products
(Table 3).
Characteristics of hepatitis D viruses
Virus
Hepatitis D
Family
Unclassi-fied
Genus
Deltavirus
Virion
35 nm spherical
Envelope
Yes (HBsAg)
Genome
ssRNA
Genome size
1,7 kb
Stability
Acid-sensitive
Transmission
Parenteral
Prevalence
Low, regional
Fulminant disease
Frequent
Chronic disease
Often
Oncogenic
?
Vírus da Hepatite Delta (HDV)
Vírus da Hepatite B
Vírus da Hepatite Delta
Envelope
AgHBs
Envelope
AgHBs
DNA
polimerase
RNA
42 nm
DNA
Core (27 nm)
AgHBc
AgHBe
Vírus Delta
Core (27 nm)
Virus Delta
Table 3.
Prevalence of Delta Infection in Hepatitis B Virus (HBV)
Carriers and Persons With HBsAg-Positive Acute and
Chronic Hepatitis in North America
Group
Number of
Groups
Studied
Delta
Prevalence
(%)
HBV carriers (blood donors)
15
14-80
Acute hepatitis
6
15-72
Fulminant hepatitis
2
16-34
Chronic hepatitis
4
13-41
Cirrhosis
1
25
Primary hepatocellular carcinoma
3
0-3
Transmission experiments in chimpanzees and other studies
have shown that HDV is a transmissible and pathogenic
agent that requires concomitant replication of HBV to
provide certain helper functions. The HDV virion is a
spherical, 36-nm enveloped particle with a chimeric
structure; the genome consists of a 1.7-kilobase RNA
molecule specific for HDV, whereas the envelope contains
HBV encoded HBsAg. The HDV genomic RNA is a
circular, single stranded RNA similar in structure to certain
pathogenic RNAs or plants (viroids), and its replication
requires the concomitant expression of HBV gene products
Two principal modes of HDV infection have been described (1)
coinfection (the simultaneous introduction of both HBV and HDV into
a susceptible host), and(2) superinfection (the infection of an HBV
carrier with HDV). Simultaneous exposure to HBV and HDV leads to
a typical pattern of HBV disease, with the duration of HBV infection
being the limiting factor to the expression of HDV. The outcome of
such HBV/HDV coinfections usually is similar to that of infection
with HBV alone, and chronic infections seem to be established with
the same frequency.
The clinical outcome from HDV superinfection of an HBV carrier is
markedly different In this case, the persistent HBV infection promotes
the efficient replication of the defective HDV and leads to a fulminant
HBsAg-positive hepatitis with a significant mortality rate (5% to
15%). In addition, the chronic infection with HBV potentiates the
continued replication of HDV, establishing a chronic HDV infection.
There are few data to support a role for HDV in the development of
primary hepatocellular carcinoma.
HDV transmission is linked closely to that of its helper, HBV.
Parenteral inoculation accounts for the world-wide distribution of HDV
among drug addicts. In parts of the world with a low incidence of HBV,
HDV infections are found mostly in drug addicts and other individuals
at risk for being HBV carriers HDV infection of newborns occurs only
in babies born to HBcAg-positive, HDV infected mothers. Although
HDV is found worldwide, an interesting anomaly exists in that HDV
infection is endemic in South America, resulting in severe outbreaks of
fulminant hepatitis. In contrast, HDV infections are rare in Asia,
although the prevalence of HBsAg carriers is similar to that in South
America. Overall, it has been estimated that about 5% of chronic HBV
carriers also are infected with HDV.
Because no HDV vaccine is available, controlling the transmission of
HBV is the only approach to controlling the spread of HDV.
Unfortunately for the estimated 200 million HBsAg carriers in the
world, there is no effective measure to prevent HDV infection per se
HDV INFECTION PATTERNS
 COINFECTION



ACUTE SIMULTANEOUS INFECTION WITH
HBV AND HDV
OFTEN RESULTS IN FULMINANT
INFECTION (70% CIRRHOSIS)
SURVIVORS RARELY DEVELOP CHRONIC
INFECTION (< 5%)
HDV INFECTION PATTERNS
 SUPERINFECTION



RESULTS IN HDV SUPERINFECTION IN AN
HBsAg CARRIER (CHRONIC HBV)
CAN OCCUR ANYTIME DURING CHRONIC
DISEASE
USUALLY RESULTS IN RAPIDLY
PROGRESSIVE SUBACUTE OR CHRONIC
HEPATITIS
HDV
HDV - Coinfection
ALT
HDV RNA
IgM anti-HDV
HDA
g
IgM antiHBc
HBsAg
Months
IgG anti-HDV
IgG anti-HBc
anti-HBs
HDV
HDV - Superinfection
ALT
HDV RNA
IgM antiHDV
HDAg
IgG anti-HDV
HBV DNA
HBsAg, IgG anti-HBc
Years
Nomenclature and definition of hepatitis viruses,
antigens, and antibodies
Hepatitis D
HDV
Hepatitis D virus. Etiologic agent of delta
hepatitis; causes infection only in presence of
HBV
HDAg
Delta antigen (delta-Ag). Detectable in early
acute HDV infection
Anti-HDV
Antibody to delta-Ag (anti-delta); indicates past
or present infection with HDV
HDV
Transmission
Oral
No
Percutaneous
Sexual
Perinatal
Incubation period
Clinical Illness at
presentation
Jaundice
Common
Yes, rare
No
21 - 45 (days)
10%, higher with
superinfection
Unknown
Fulminant
2 – 7.5%
Diagnostic tests
Acute infection
IgM anti-HDV
Chronic infection
IgG anti-HDV, HBsAg +
Immunity
Not applicable
Case-fatality rate
1 – 2%
Chronic infection
Superinfection – 80%
Coinfection < 5%
HEPATITIS E VIRUS. Many cases of acute viral hepatitis
in Asia and Africa are caused by a virus that is transmitted
through the fecal-oral route but is unrelated to HAV.
Outbreaks of this disease also have been confirmed in other
parts of the world, including the Middle East and Mexico.
The disease usually is caused by the ingestion of fecally
contaminated water. The virus causing this kind of hepatitis
has been named HEV. The first verified hepatitis E outbreak
was documented in New Delhi, India, in 1955 In this
epidemic, 29,000 cases of icteric hepatitis were reported after
fecal contamination of the city's drinking water. Several other
outbreaks have been linked to HEV since then HEV is a
small, nonenveloped RNA virus. Recent information about
the genomic organization and other properties of the virus
strongly suggests that it is a calicivirus and should be placed
in a new genus within this family.
HEPATITIS E VIRUSE
Virus
Hepatitis E
Family
Caliciviridae
Genus
Unnamed
Virion
30-32 nm, icosahedral
Envelope
No
Genome
ssRNA
Genome size
7,6kb
Stability
Heat-stable
Transmission
Fecal-oral
Prevalence
Regional
Fulminant disease
In pregnancy
Chronic disease
Never
Oncogenic
No
FIGURE 7. Structural model of the Hepatitis E virus
Hepatitis E
Epidemiology
Suspected from study of waterborne
hepatitis in India in 1980
Confirmed by transmission to chimp
and
human in 1983
Probably accounts for many historical
outbreaks of hepatitis
Endemic mainly in Asia, Middle East,
North Africa
Hepatitis E
Epidemiology
Fecal-oral transmission (human to
human)
Contaminated water supplies in tropical
or
subtropical developing
countries
Mainly young adults
Can infect primates, swine, sheep, rats
Swine may be reservoir of infection in
North
America (attenuated virus)
Maternal-infant transmission occurs and
Hepatitis E
Clinical Characteristics
Similar to hepatitis A
Can cause severe acute hepatitis
Subclinical infection is common
Attenuated virus from animal reservoirs
Low-dose infections often asymptomatic
No chronic infection
Up to 20% mortality among pregnant
(esp. third trimester)
women
Hepatitis E
Course of Acute Infection
Viral Replication
IgM Antibody
IgG Antibody
Viremia
ALT
Symptoms
Virus in Stool
0
10
20
30
40
50
Time After Infection (days)
60
1
2
(years)
Hepatitis E
Prevention
Passive (Immune serum globulin)
Does not prevent infection
May ameliorate hepatitis
Active (Vaccine)
Anti-ORF2 prevents infection in chimps and
humans
Clinical trials in progress
HEV
Transmission
Oral
Percutaneous
Sexual
Perinatal
Incubation period
(days)
Clinical Illness at
presentation
Jaundice
Fulminant
30%
Diagnostic tests
Acute infection
Chronic infection
Immunity
Case-fatality rate
Chronic infection
Common
Unknown
No
Yes, unknown frequency
15 - 60
70 – 80% in adults
Common
<1%, in pregnancy up to
IgG anti-HEV (seroconversion)
Not applicable
Not applicable
0.5 – 4%
1.5 – 21% in pregnant women
None
HEPATITIS G VIRUS
Virus
Hepatitis G
Family
Flaviviridae
Genus
Unnamed
Virion
60 nm, spherical
Envelope
Yes
Genome
ssRNA
Genome size
9,4 kb
Stability
Ether-sensitive
Transmission
Parenteral
Prevalence
Moderate
Fulminant disease
?
Chronic disease
?
Oncogenic
?
HGV AND GVB-C
 SHARE 95% AMINO ACID IDENTITY
 THUS REPRESENT DIFFERENT
ISOLATES OF THE SAME HUMAN VIRUS
HGV
 “HEPATITIS C-LIKE VIRUS”
 CLASSIFIED IN THE FLAVIVIRIDAE FAMILY
 SAME AS HCV
 GENETIC ORGANIZATION


SIMILAR TO HCV
GENONE CONSISTS OF SINGLE-STRANDED
RNA MOLECULE OF POSITIVE POLARITY
HGV - EPIDEMIOLOGY

TRANSMISSABLE BY BLOOD AND BLOOD PRODUCTS
 PRESENT IN ASYMPTOMATIC BLOOD DONORS
WITH
NORMAL ALT LEVELS
 FOUND IN:
GENERAL POPULATION
1-2 %
HEMOPHILIA PATIENTS
18 %
IV DRUG USERS
33 %
Patients with chronic Hepatitis B
10 %
Patients with chronic Hepatitis C
20%
HGV - CLINICAL SIGNIFICANCE
 RECENT DATA SUGGESTS:
 HGV INFECTION DOES NOT CAUSE ACUTE



HEPATITIS
HGV MAY ESTABLISH CHRONIC INFECTIONS
FREQUENTLY OCCURS WITH HBC AND HCV
INFECTIONS
MAY NOTQUALIFY AS A TRUE HEPATITIS
VIRUS