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
DNA virus
Double-shelled particles
Outer lipoprotein
envelope (surface Ag)
Inner viral nucleocapsid
(core)
seven genotypes
four major subtypes.
All HBV subtypes share one
common antigenic
determinant - "a.
Thus, antibodies to the "a"
determinant confer protection
to all HBV subtypes

Diagrammatic
representation
of the hepatitis B
virion and the
surface antigen
components

EM of Hepatitis
B viron

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

Can be asymptomatic

More common in children

Usually self limited in adults

Malaise, fatigue, anorexia,

nausea, low grade fever
after 45-160 day incubation

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 infectionWho to treat?

Treat:

HBeAg positive with

persistent infection

No treatment:

HBeAg negative and carrier

(nl LFTs, viral load less than
105 and asymptomatic)

Probably treat:

HBeAg

HBeAg negative with

chronic infection (high viral
load, abnormal LFTs)

Pos

Neg

Chronic
dz

treat

Probably
treat

Carrier

treat

Probably
not treat

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 HBeantibodies 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 antiHBe 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

Newcastle disease, virus that
causes a bird infection

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.

Both studies
investigated
the use in both
Hepatitis B
and C.

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.
Surg. 2003 Aug;138(8):852-8.

Thought to be due to heptotoxic effects of componds in these

supplements.

Basically

Arch

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