Hepatitis B

Steve Hart

Electron
micrograph of
serum
containing
hepatitis B virus
after negative
staining.
Overview

Discussion Hepatitis B
Epidemiology
Serologies
Clinical course
Prevention
Treatment options
Herbs
 Hepatitis B
Hepadnaviridae family Diagrammatic
representation
DNA virus of the hepatitis B
virion and the
Double-shelled particles surface antigen
components
Outer lipoprotein
envelope (surface Ag)
Inner viral nucleocapsid
(core)
seven genotypes
four major subtypes. EM of Hepatitis
B viron
All HBV subtypes share one
common antigenic
determinant - "a.
Thus, antibodies to the "a"
determinant confer protection
to all HBV subtypes
 Hep B epidemiology
1/3 of worlds
population has
been infected
350 million with
chronic disease
15-25% of these
die due to liver
related diseases
1 million deaths
annually
United States
1.25 million
chronic carriers
5000 deaths
annually
Hep B surface Ag prevalence, 2002 Source: CDC website
 Hepatitis B transmission
Dominant mode of transmission related to
prevalence
Low prevalence (.1 to <2%) adults
unprotected sexual intercourse
intravenous drug use
Moderate (3-5%) - children
Horizontal transmission
High prevalence (>10-20%) - infants
Maternal infant
Percutaneous
Other
Occupational exposure
Blood transfusions
Increasingly rare
Hepatitis B primary
infection
Symptoms
Malaise, fatigue,
anorexia, nausea, low
grade fever after 45-
160 day incubation
Can be asymptomatic
More common in
children
Usually self limited in adults
Viral clearance from blood and liver
Lasting immunity
Can result in fulminate hepatic failure
Hepatitis B primary
infection
HBsAg 4-10 wks
Anti-HBc
antibody follows
+/- HBeAg
Viral load very
high
109 to 1010
Highly contagious
at this time
Hepatitis B primary
infection
Decrease in HBsAg
correlates with onset of
T-cell mediated
immune response
Also, when present,
correlates with onset of
elevated liver enzymes
Traditionally,
conversion to anti-HBs
antibodies signals cure
Viral DNA may persist for
years to lifetime
Significance unknown
 Hep B - Persistent Infection
Definition:
Persistence of HBsAg for greater
than 6 months
 Hepatitis B persistent
infection
Persistent viral load that
declines over time
HBeAg declines overtime,
converting eventually to
anti-HBe antibody
Seroconversion correlates
with rise in LFTs and 5
order of magnitude
decline in viral load.
Classically, to Anti-HBe
antibody = no viral DNA
circulating, which is
incorrect
0.5% clear HBsAg
annually
 Persistent Hepatitis B
Two clinical patterns
Chronic liver disease
Elevated LFTS
Abnormal hepatic histology
20% develop cirrhosis
Asymptomatic carrier
Normal LFTs
Asymptomatic
Near normal liver histology
Both risk development of Hepatocellular
Carcinoma
 Persistent Hepatitis B
HBV replication
extensive and
continuous in chronic
carriers
Replication is not
cytotoxic
Host immune
response to viral
antigens expressed
on infected
hepatocytes
Hepatocellular carcinoma
100 times the risk in persistently
infected patients
Risk is greater if HBeAg positive

Twice a year screening is recommended

in persistent carriers
Alpha fetoprotein and/or hepatic U/S
When to start screening is unclear
Who gets chronic disease?

Rule of thumb, the younger the age,

the more likely to become chronic
Neonates 95% chronic, most
asymptomatic
Infant to 6 yo 30% chronic

Older children to adults 3-5% chronic

 Hepatitis B - Serology
Surface Antigen (HBsAg)
Hep B surface antigen Outer surface
lipoprotein, appears early
Hallmark of infection
Surface antigen antibody (anti-HBs)
signifies cure

Hep B core antigen (HBcAg)

intracellular antigen
expressed in infected hepatocytes
not detectable in serum
Core antibody appear early in
infection (Anti-HBc)
Predominately IGM early in infection
detection of IgM anti-HBc usually
regarded as an indication of acute
HBV infection
Traditionally, the sole marker of HBV
infection during the window period
between the disappearance of HBsAg
and the appearance of anti-HBs
Hep B e antigen
secretory protein that is processed from the
precore protein
Elevated early in infection and usually coverts
to antibody early on.
Traditionally used as a marker for viral load as
viral load was undetectable with early assays
when Ag was absent.
However, certain variants of the Hep B virus do not
create the HBeAg as it has no known function.
When present, it does correlate with elevated
viral load and seroconversion the antibody
usually correlates with a decrease in viral load
by a magnitude of 4-5.
 Hep B serology
interpretation
Acute infection
HBsAg positive and anti-HBcAg
IGM
Rarely, IgM anti-HBc only marker
Usually seen in acute fulminate
Hep B
Chronic infection
HBsAg positive and anti-HBcAg
Previous Infection
HBsAg negative
anti-HBs positive
IgG anti-HBc positive
Screening Who?
Who
Persons born in hyperendemic areas
Men who have sex with men
Injection drug users
Patients on dialysis
HIV infected patients
Pregnant women
Family and household contacts and sexual
contacts of HBV-infected persons.
Testing should be performed by obtaining
an HBsAg and anti-HBs.
Hepatitis B Treatments
Prevention
Neonates
Vaccine

Prophylaxis
Possible exposure
Chronic infection
Prevention
In 1991, US started routine
vaccination
Since then incidence of acute HBV
infection has declined by 67%
However, incidence has continued to
increase in adults
Offer vaccine to high risk individuals
Prophylaxis
Hepatitis B immune globulin (HBIG) and
vaccine
Indications
Patients with no history of vaccine and
Percutaneous exposure (needle sticks)
Household contacts exposed to blood
Perinatal exposure prevents transmission in
95% of mothers HBsAg positive when given
within 12 hours of birth
Breast feeding ok if baby received prophylaxis
 Treatment of persistent infection-
Who to treat?
Treat: HBeAg
HBeAg positive with Pos Neg
persistent infection
Chronic Probably
treat
No treatment: dz treat

HBeAg negative and

carrier (nl LFTs, viral load Carrier treat
Probably
less than 105 and not treat
asymptomatic)

Probably treat:
HBeAg negative with
chronic infection (high
viral load, abnormal LFTs)
Treatment options
FDA approved
Interferon Alfa
Lamivudine reverse transcriptase inhibitor
Adefovir nucleotide analogue that inhibits
viral polymerase
Investigational
Tenofovir adenine nucleotide analogue
Approved for HIV
Entecavir guanosine analogue, highly
selective for the HBV polymerase
Interferon alfa
Had been mainstay for therapy
Subcutaneous injection three times per
week for 3 months or longer
30% of patients who could tolerated
regime had a successful response
Seroconverted to HBe antibodies
Normalization of LFTs
Multiple side effects
Fever, myalgia, thrombocytopenia, depression
Interferon alfa
Contraindicated in very advanced
liver disease
Flairs or bump in LFTs occur at time of
seroconversion to anti-Hbe due to
increased immune response
may precipiate overt liver failure
Lamivudine
Oral medication
Usually given for year or longer
Found to inhibit HIV reverse
transcriptase.
Noted that patients with both HIV and chronic
Hep B had large declines in Hep B viral load
This phenomenon was then noted in patients
with only chronic Hep B
By itself, results in a 3 to 4 log decrease
serum viral load
Increased rate of seroconversion to HBe-
antibodies and normalization of LFTs
Lamivudine
Those who respond best are those with
elevated LFTs
>5 times normal -> 65% response rate
2-5 times normal -> 26% response
<2 times normal -> 5% response
Remember, liver damage is caused by
immune response
So higher LFTs likely correlates to a most
robust host immune response
By inhibiting viral reproduction, the immune
system is able to clear the virus more
effectively.
Lamivudine
Use limited by resistance
At one year of treatment 15-20% of patients
develop resistance
40% at two years
67% at four years
However, the resistant virus is less hearty
than the native virus resulting is lower
replication rates than pretreatment
Resistant variants also convert to anti-
HBe antibodies at higher rates.
Lamivudine
Resistance
No clear evidence regarding
continuation of treatment
Prior to new meds, many continued.

Discontinuing medication is
associated with flairs
Overlapping with another medication
recommended
Adefovir
Initially, devoloped for HIV
Nucleotide analogue
Prodrug phosphorylated
intracellularly to yield active drug
Inhibits viral polymerase
Has been evaluated for primary
monotherapy and in patients with
resistance to Lamivudine
Adefovir
Efficacy
Reduces viral load by 3 to 4 log
Enhances HBeAg seroconversion
Results in histological improvement of liver
Improved LFTs
Effective even in Lamivudine resistant patients
Much lower rate of resistance than
Lamivudine
Approach to treatment
Unfortunately, studies are lacking to
define what is the best approach
Presently, alpa interferon, Adefovir and
Lamivudine are all considered first line
therapy
Considerations
Adefovir less resistance, possibly nephrotoxic
Lamivudine good side effect profile
Interferon difficult course
All provided about the same results
Unknown if benefit to using combination
therapy.
Hepatitis B/C Alternative Therapy:
What your patient might read about on the
internet

MTH-68/B. vaccine strain of Both studies

investigated
Newcastle disease, virus that the use in
causes a bird infection both Hepatitis
B and C.
Controlled study - conventional
txment vs vaccine in acute phase
n=42, showed more progressed
to chronic infection with
conventional txmt.
Case reports of benefit to pts
given this vaccines after
progressing to decompensated
liver failure.
 Hepatitis B and Herbs
Cochrane review
Asymptomatic carries
Very few quality studies
Three randomised clinical trials of carriers (307 patients) three
months or more of follow identified.
The methodological quality was poor overall, only one significant
trial
'Jianpi Wenshen recipe'
significant effects on viral markers compared to interferon serum:
HBsAg,HBeAg, and seroconversion of HBeAg to anti-HBe.
Poor long term f/u

Chronic carriers
Fuzheng Jiedu Tang (compound of herbs)
positive effects on clearance of serum HBsAg, HBeAg, and HBV DNA
Polyporus umbellatus polysaccharide vs interferon
Positive effects on serum HBeAg and HBV DNA
Phyllanthus amarus vs interferon
Improvement in serum HBeAg
Hepatitis B Alternative Therapies
One small retrospective study showed patients in
fulminent hepatic failure who took dietary or herbal
supplements often did worse than those who did not. Arch
Surg. 2003 Aug;138(8):852-8.
Thought to be due to heptotoxic effects of componds in these
supplements.

Basically
No firm evidence supporting medicinal herbs
follow-up randomized trials seem justified for some
Would not recommend due to potential hepatotoxic effects
References

Images:
http://www.cdc.gov/ncidod/diseases/hepatitis/
http://gsbs.utmb.edu/microbook/ch070.htm
http://web.uct.ac.za/depts/mmi/jmoodie/dihep.html
http://www.aids-hepatitisc.org/healthinsurance/maps-graphs/figure7-infectious-hepatitis.gif

Am J Gastroenterol. 2003 Mar;98(3):538-44

Arch Surg. 2003 Aug;138(8):852-8
N Engl J Med Mar 11,2004;
Pediatrics in Review, Vol 24, No.12 Dec 2003