Hepatitis B Virus ::HBV
This is caused by a double stranded DNA Virus which is one of the most common causes of chronic liver disease and hepatocellular carcinoma worldwide.
Epidemiology
• The hepatitis B virus (HBV) carriers are
360 million worldwide.
• Approximately one-third of the world's
population have serological evidence of
past or current infection with hepatitis B.
• In Bangladesh it is estimated that about
5% of the population are HBS +ve.
TRANSMISSION
• Vertical transmission (from mother to
child in utero) is the usual means of
transmission worldwide (90%)
• HBV is not transmitted by breast-
feeding.
• Horizontal transmission (1 0%) occurs
mostly by-
o Injection drug use
o Unscreened blood transfusion
o Tattoos/acupuncture needles
o Sexual (homosexual and
heterosexual)
Pathophysiology
Hepatitis B virus (HBV) contains
• an inner core formed of core protein
• an outer envelope of surface protein
(HBCAg) surrounded by
• a Pre-core protein Hepatitis Be antigen
(HBSAg) &(HBeAg) is part of the HBCAg that can be found in the blood and indicatesi infectivity.
Hepatitis B mutants
=>Mutations occur in the various reading
frames of the HBV genome. These
mutants can emerge in patients with
chronic HBV infection (escape mutants)
or can be acquired by infection.
=>A mutation in the pre-core region
prevents the production of HBeAg, To
detect infectivity in this case, HBV DNA
must always be measured as no eAg will
be present.
Clinical features
Symptoms
The clinical picture is the same as that found in
HAV infection like -
• Nausea, Vomiting, jaundice & others
resembling a viral illness
> However, in many, the infection is
subclinical
> The virus is cleared in approximately
99% of patients as there is a good immune reaction.
In addition a serum sickness-like
immunological syndrome may be seen. This consists of
a. Rashes (e.g. urticaria or a
maculopapular rash)
b. Polyarthritis affecting small joints
occurring in up to 25% of cases in the
prodromal period.
c. Fever is usual.
d. Vasculitis
e. Glomerulonephritis are seen as
extrahepatic immune complex-mediated
conditions.
Investigations
A. LFT:
(may be normal in chronic cases)
otherwise- SGPT &, Bilirubin (in acute
hepatitis)
B. Viral Marker:
a. HBsAg
• it is an indicator of active infection,
• A negative test for HBsAg makes HBV
infection very unlikely.
• The persistence of HBsAg for longer
than 6 months indicates chronic
infection or carrier state.
b. HBeAg
• indicates continued active replication of
the virus in the liver.
• In acute hepatitis B it may appear only
transiently at the outset of the illness
• Its appearance is followed by the
production of antibody. (anti-HBe).
c. HBV-DNA:
• Can be measured by PCR in the blood.
Usually >10 copies/mL is considered
as high viral load indicating active viral
replication (HBeAg also positive)
• The exception is 'Pre-core mutant'
infection where high viral load is
associated with negative HBeAg. Here
anti-HBe-positive is +ve.
• Low Viral replication said when viral loads
<10 copies/mL.
d. Anti-HBelndicating Seroconversion
e. Anti-HBc lgM (not always required)
found in
In Acute hepatitis B (high titre)
In Chronic hepatitis B (low titre)
f. Anti-HBc lgGNot needed usually -
indiacating previous exposure to
hepatitis B (here HBsAg-negative)
Other tests
1. USG of Abdomen to detect cirrhosis and
hepatocellular Ca (HCC).
2. Liver biopsy: done when SGPT <2 times
upper limit, HBeAg negative and HBV
DNA 10°- 10 iu/ml.
3. Upper Gl endoscopy: If Cirrhosis in USG.
Management
Treatment of acute hepatitis B
> Treatment is supportive, with monitoring
for acute liver failure (occurs in less than
1% of cases).
> There is no definitive evidence that
antiviral therapy reduces the severity or
duration of acute hepatitis B.
Prognosis of Ac. HBV infection
• Full recovery occurs in 90-95% of adults
within 6 months.
• The remaining 5-10% develop a chronic
hepatitis B infection that usually
continues for life (although later
recovery occasionally occurs.)
• Infection passing from mother to child at
birth leads to chronic infection in the
child in 90% of cases and recovery is
rare.
Chronic HBV infection
Following an acute HBV infection which may be
subclinical-
approximately 1-10% of patients will not clear
the virus and will develop a chronic HBV
infection.
Chronic HBV Occurs with-
neonatal (90%)
childhood (20-50% below the age of 5
years)
in adult (<10%).
immune tolerant chronic HBV infection
(Most have been infected perinatally )
Asymptomatic
HBSAg +ve
HBeAg +ve with
Very high levels of serum HBV DNA, but
Normal liver function tests.
> They do not require treatment, but
>often in the third to fifth decade in life
there is a change in host immunity leads
to acute hepatitis followed by chronic
hepatitis.
Inactive carrier with chronic HBV infection
Usually discovered incidentally by blood tests,such screened for donating blood.
or when attending medical check ups for other purposes.
Patients have-
• HBSAg +ve
• HBeAg -ve,
• Anti HBe positive
• HBV DNA below 400 iu/L
• Normal ALT.
Prognosis:
There is an annual spontaneous clearance rate of HBsAg of 1-2%.
Treatment of Active chronic HBV infection
> no drug is consistently able to eradicate
hepatitis B infection completely (i.e.
render the patient HBSAg-negative).
=>The goals of treatment are
• HBeAg seroConversion,
• reduction in HBV-DNA and
• normalisation of the LFTS
=>Three criteria are used for commencing
treatment:
serunm HBV DNA levels,
serum ALT levels and
histological grade and stage
The indication tor treatment is
a high viral load+active hepatitis)
(evidenced by
• elevated serum transaminases
and/or
• histological evidence of
inflammation and fibrosis.
Choice of treatment:
1. One of the potent oral drugs with a high
barrier to resistance (Entecavir or
Tenofovir Disoproxil Fumarate) or
Peginterferon Alfa-2a or
Peginterferon Alfa-2b can be used as
first-line therapy.
2. These oral agents, (but not PEG IFN),
should be used for interferon-
refractory/intolerant and
immunocompromised patients.
3. The oral agents are administered daily
for at least a year and continued
indefinitely or until at least 6 months
after HBeAg seroconversion.
4. Compensated cirrhosis and low HBV
DNA level, even with normal ALT; should
be treated indefinitely, even in HBeAg-
positive disease after HBeAg
seroconversion.
.
5. Cirrhosis decompensated:
a low-resistance regimen is
recommended (Therapy should be
instituted Urgently)-
• Entecavir / Tenofovir
monotherapy or
• combination therapy with
Lamivudine / Telbivudine) plus
Adefovir Dipivoxil.
6. HBeAg negative chronic hepatitis:
PEG IFN is administered by subcutaneous injection weekly for a year;
Oral agents, entecavir or tenofovir, are
administered daily, usually indefinitely
(or, until as very rarely occurs, virologic
and biochemical responses are
accompanied by HBSAg
seroconversion.)
==>The duration of all treatment is probably
lifelong (still being assessed) & should be
under specialist supervision.
1. Oral agents
The available drugs are given below. But
nterferon, entecavir and tenofovir are the most
commonly used drugs.
a. Lamivudine. 100 mg/day
Advantage- is well tolerated.
Caution/Disadvantage-
by 4 years, 80% develop viral resistance
Lamivudine monotherapy is no longer
recommended.
b. Telbivudine:
Advantage- more potent
Disadvantage- but it is also susceptible
to viral resistance.
c. Adefovir Dipivoxil: Adult with good
renal function 10 mg once daily.
Advantage- Well tolerated;
Disadvantage- Viral resistance None @1
yr but 18% after 3 years & 29% at 5 yrs
creatinine monitoring recommended
Hepatitis B Virus (HBV)
Contraindicated in renal failure.
d. Tenofovir Disoproxil Fumarate dose:
Adult- 300 mg once daily.
Advantage- reduces DNA <400
copies/ml (76-93%). HBeAg
seroconversion 21% (@ 1yr. & 27% @ 2
yrs ALT normalization at the end of 1 yr.
68-76% used for HIV patients with HBV
infection. It can also be used in patients
with lamivudine mutations, Viral
resistance 0% @ yr 1 0% through yr 3
Caution/Disadvantage- creatinine
monitoring reconmmended
e. Entecavir : (Adult over 18 years), not
previously treated with nucleoside
analogues) - 0.5 mg once daily; in
lamivudine-resistant chronic hepatitis B,
1 mg once daily Counseling: To be taken
at least 2 hours before or 2 hours after
food
Advantage-
• No creatinine monitoring
recommended.
• reduces HBV DNA [<400
copies/ml ]67%-91 % @ 4yrs.,
• HBe seroconversion 21% (@ 1yr
Hepatitis B Virus (HBV) 39% @ 3yr.
• ALT normalization at the end of
yr. 68-78% anti-HIV action.
Disadvantage-
Viral resistance None @ 1 yr 29% at 5 yrs
It should not be used in patients with
lamivudine-induced mutants
( but can be used if adefovir mutations
have occurred.)
II..injectables agents:
Contraindicated in Cirrhosis
(Compensated or Decompensated)
a. Interferon Alfa-2a:
it acts by
augmenting a native immune response
Advantage:
• most effective in patients with a low vira
load and serum transaminases greater
than twice the upper limit of normal.
• 33% loss of eAg after 4-6 months
treatment in HBe +ve patients.
Disadvantage:
Response rates are lower in
HBeAg-negative chronic hepatitis
Hepatitis B Virus (HBV)
b. Pegylated interferon:
(180 Hg once a week
subcutaneously for 6 months
Advantage:
• reduces DNA <400 copies/ml in 63% if
HBeAg-negative but 10-25% if HBeAg
+ve
• HBeAg seroconversion in 18-20%
• ALT normalization at the end of 1 yr.
~35%
• Viral resistance is none LFT 25%.,
>respond is best in Patients with higher
ALT (3x the upper limit of normal) who
are younger, with viral loads<107 IU/mL.
Disadvantage:
>Poorly toleratedhH
> common Side-effects are-
> acute flu-like illness occurring 6-8 h
after the first injection.
> fatigue,
> depression,
irritability,
> bone marrow Suppression
(platelet
count should be monitored)
>the triagering of autoimmune thyroid
Hepatitis B Virus (HBV)
disease
IIl. Liver transplantation:
considered when
decompensated cirrhosis and HBV DNA
undetectable.
Precaution
Prevention depends on avoiding risk factors
1. Not sharing needles and
2. Having safe sex.
3. Avoid HBSAg positive blood and blood
products.
4. Standard safety Precautions in
laboratories and hospitals must be
enforced strictly to avoid accidental
needle punctures and contact with
infected body fluids.Infectivity is highest in those with the e antigen and/or HBV DNA in their blood. These patient should be counselled about their infection.
Passive and active immunization
Hepatitis B Vaccination is obligatory in most developed countries as well as countries with high endemicity.
Hepatitis B Vaccine should be given to groups at high rÃsk:
• All healthcare personnel;
• Members of emergency and rescue
teams;
• People with haemophilia;
• Patients with chronic kidney disease/
on dialysis units;
• Long-term travellers;
• Men who have sex with men (MSM),
• Bisexual men and sex workers;
• Intravenous drug users.
Combined prophylaxis (i.e. vaccination &
Immunoglobulin) should be given to:
• Staff with accidental needle-stick
injury, contamination of cuts or mucous
membranes,
• All newborn babies of HBsAg-positive mothers
• Regular sexual partners of HBsAg-
positive patients, who have been found
to be HBV-negative.
This should be given within 24 hours, or at most a week,
For adults a dose of 500 IU of specific hepatitis B immunoglobulin (HBIG) (200 IU to newborns) and
the vaccine (i.m.) is given at another site.
Hepatitis B serology should be checked at 12
months of age of babies of HBSAg-positive
mothers.
Active immunization
This is with a recombinant yeast vaccine
produced by insertion of a plasmid containing
the gene of HBSAg into a yeast.
Dosage regimen.
Three injections (at 0, 1 and 6 months) are given
into the deltoid muscle;
This gives short-term protection in over 90% of
patients.
More frequent and larger doses are required
for
• People who are over 50 years of age or
• clinically ill and/or
• Immunocompromised (including those
with HIV infection or AIDS) have a poor
antibody response
Antibody levels should be measured at 7-9
months after the initial dose in all at-risk groups.
Antibody levels fall steadily after vaccination
and booster doses may be required after
approximately 3-5 years.
The vaccine is ineffective in those already
infected by HBV.
It is not cost-effective to check antibody levels
prior to active immunization.
There are few side-effects from the vaccine.
Complication
1.chronic carrier.
2.Hepatocellular carcinoma
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