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CHRONIC VIRAL

HEPATITIS
Guide : Dr. Anjali Metgudmath
co guide : Dr. Dnyanesh
morkar
Dr. Santosh hazare
Presenter :Dr Yeshavanth G

Scheme of presentation

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.

Introduction
Epidemiology
Chronic Hepatitis B
Epidemiology
Definitions
Diagnostic criteria
mode of transmission
Symptoms and signs
Extrahepatic manifestations
Natural history
diagnosis
Complications and sequelae
Vaccination.
Treatment.

Chronic Hepatitis C

1.

Epidemiology

2.

Definitions

3.

mode of transmission

4.

Symptoms and signs

5.

Extrahepatic manifestations

6.

Natural history

7.

diagnosis

8.

Complications and sequelae

9.

Treatment.

Introduction

Chronic hepatitisis a clinicopathological


syndrome, defined clinically by evidence of
liver disease for at least 6 consecutive
months and characterized by varying
degrees of hepatocellular necrosis and
inflammation.
Chronic viral hepatitis is caused by
hepatitis C
hepatitis B and hepatitis D(now almost
obsolete)

Etiology of newly diagnosed


cases of chronic liver
disease

Hepatitis B virus infection

The no of cases has decreased markedly


due to universal vaccination, better
screening of blood and blood products,
increased awareness of stds.
identified in almost every body fluid.
sexual contact and perinatal transmission
The likelihood of perinatal transmission of
HBV correlates with the presence of HBeAg
and high-level viral replication
The >350400 million HBsAg carriers in the world
constitute the main reservoir of hepatitis B in
human beings

High-Risk Populations for Which HBVInfection Screening Is Recommended

Household and sexual contacts of persons with hepatitis B


Persons who have used injection drugs
Persons with multiple sexual contacts or a history of sexually
transmitted disease
Men who have sex with men
Inmates of correctional facilities
Persons with elevated alanine or aspartate aminotransferase
levels
Persons with HCV or HIV infection
Hemodialysis patients
Pregnant women
Persons who require immunosuppressive or cytotoxic therapy
Persons born in countries/regions with a high (>8%) and
intermediate (>2%) prevalence of HBV infection

Epidemiological patterns of
HEP B infection
Prevalenc
e

High

Intermedi
ate

Low

Carrier rate 8-20 %

3-7%

0.1-2%

Geography

Southeast
asia

Mediterrane Usa and


an, latin
canada
america,ind
ian

Predominan
t age at
infection

perinatal

Mode of
Maternal
transmissio infant
n

early
childhood

adult

sexual
percutaneo
us

Few important definitions

Chronic hepatitis B
Chronic necroinflammatory disease of the liver caused by
persistent infection with hepatitis B virus. Chronic hepatitis B
can be subdivided into HBeAg positive and HBeAg negative
chronic hepatitis B.

Inactive HBsAg carrier state


Persistent HBV infection of the liver without significant,
ongoing necroinflammatory disease.

Resolved hepatitis B
Previous HBV infection without further virological, biochemical
or histologic evidence of active virus infection or disease.

Acute exacerbation or flare of hepatitis B


Intermittent elevations of aminotransferase activity to more
than ten times the upper limit of normal and more than twice
the baseline value.

Reactivation of hepatitis B: Reappearance of


active necroinflammatory disease of the liver in a
person known to have the inactive HBsAg carrier
state or resolved hepatitis B.
HBeAg clearance :Loss of HBeAg in a person
who was previously HBeAg positive.
HBeAg seroconversion:Loss of HBeAg and
detection of anti-HBe in a person who was
previously HBeAg positive and anti-HBe negative,
associated with decrease in serum HBV DNA to
<105 copies/mL.
HBeAg reversion :Reappearance of HBeAg in a
person who was previously HBeAg negative, antiHBe positive.

Diagnostic criteria for chronic


hepatitis

1. HBsAg+ >6 m
2. Serum HBV DNA >105 IU/mL (may be
lower for HBeAg negative patients)
3. Persistent or intermittent elevation in
ALT/AST levels
4. Liver biopsy showing chronic hepatitis
(necroinflammatory score 4)

Inactive HBsAg carrier


state

1. HBsAg+ >6 m
2. HBeAg, anti-HBe+
3. Serum HBV DNA <105 Iu/ml (usually
<1000 IU/mL)
4. Persistently normal ALT/AST levels
5. Liver biopsy confirms absence of
significant hepatitis (necroinflammatory
score <4)

RESOLVED HEPATITIS B

1. Previous known history of acute or


chronic hepatitis B or the presence of
anti-HBc anti-HBs
2. HBsAg
3. Undetectable serum HBV DNAb
4. Normal ALT levels

Mode of transmission

Parenteral mode of transmission.


Blood and blood products.
Percutaneous transmission.
Sexual transmission.
Perinatal transmission.
unlikely to occur at HBV DNA levels
below 107 copies/mL

Symptoms and signs

30% to 50% of patients with chronic HBV


infection have h/o classical acute hepatitis
that progressed to chronic infection.
Most of them ASYMPTOMATIC.
During exacerbations it may mimic acute
hepatitis with fatigue, nausea, anorexia and
jaundice.
Physical examination of limited value.
Stigmata of chronic liver disease spider
angioma, palmar erythema and mild
hepatomegaly, splenomegaly may be seen.

Extrahepatic
Manifestations

1.

Associated with both acute and chronic.


(acute>chronic)
10 to 20 % of chronic HBV infection.
Mediated by circulating immune complexes.
Polyarteritis nodosa: immune complexes cause
vasculitis causing multisystem involvement.
-CVS,GI, CNS are involved and sometimes can
be fatal.
-IFN ,steroids,nucleoside analogs are used in
treatment.

2)GLOMERULONEPHRITIS:
-more in children.
-membranous most common.
-children usually undergo spontaneous
remission.
-30% adults progress to renal failure.
-steroids are ineffective.
-IFN can be tried as rx.

3) essential mixed cryoglobulinemia: GN,


arthritis, purpura.
4) papular acrodermatitis: more in
children. symmetrical, erythematous,
maculopapular, nonitchy eruptions over
the face, buttocks, limbs with
lymphadenopathy.
5)aplastic anemia.

NATURAL HISTORY

overall rate of progression from acute to


chronic HBV infection has been
estimated to be 5% to 10%.
Risk inversely proportional to age at
infection.
Hepatitis B Virus Infection is a LifeLong Infection.

80

60

40

Chronic Infection
Chronic Infection (%)

20

100
80

60

40

20

Symptomatic Infection (%)

Chronic Infection
(%)

100

Outcome of Hepatitis B Virus


Infection
by Age at Infection

Symptomatic Infection
0
Birth

0
1-6 months 7-12 months 1-4 yearsOlder Children
and Adults

Age at
Infection

Natural history of chronic HBV


infection in adults

Natural history of chronic HBV


infection in perinatal infection

Diagnosis serologic
markers

Hepatitis B surface
antigen

HBV infection: acute or


chronic

Hepatitis B e antigen

High levels of HBV


replication and infectivity

Anti-HBe

Low levels of HBV


replication and infectivity

Anti-HBc (IgM)

Recent HBV infection

Anti-HBc (IgG)

Recovered or chronic HBV


infection

Anti-HBs

Immunity to HBV infection

Anti-HBc (IgG) + anti-HBs

Past HBV infection

Anti-HBc (IgG) + HBsAg

Chronic HBV infection

Diagnosis of Hepatitis B
Virus
(HBV)
Infection
Chr HBs HBeA IgM IgG
Anti
Anti HBV
Interpreta
oni
c
HB
V

Ag

anti anti
HBc
HBc

HBs

Hbe

Dna

tion

Infe
ctio
n

+++

HBeAG+
chronic
hepatitis

Inactive
carrier
state

++

HBeAgchronic
hepatitis

++

Exacerbatio
ns of
chronic

Possible Outcomes of HBV Infection


Acute hepatitis B infection
3-5% of adultacquired
infections

95% of infantacquired
infections
Chronic HBV infection

Chronic hepatitis
12-25% in 5
years
Cirrhosis
20-23% in 5
6-15% in 5 years
years
Hepatocellular
Liver failure
carcinoma
Deat
h

Liver transplant

Death

Sequelae of Chronic
Hepatitis B Virus Infection

Range from inactive carrier state to


chronic hepatitis, cirrhosis, hepatic
decompensation, HCC and death.
Depends on severity of liver damage prior
to sustained sero conversion and
durability of inactive carrier phase.
rate of progression from chronic hepatitis
to cirrhosis: 2-6% in HBeAg-positive and
8-9% in HBeAg-negative patients.

Annual rate of progression from compensated


cirrhosis to hepatic decompensation has been
estimated to be 4% to 6%.
lifetime risk of a liver-related death was
estimated to be 40% to 50% for men and 15%
for women.
Annual rate of HCC development has been
estimated to be 0.5% to 1.0% for noncirrhotic
carriers and 2.5% to 3% for patients with
cirrhosis

Factors associated with worse


outcome

Host(older age, men),


virus (persistent high levels of HBV
replication, HBV genotype [C > B],
coinfection with HCV, HDV, and HIV),
environment (alcohol and more recently
obesity)

Hepatitis B Vaccines and


Dosage Recommendations

infants born to HBsAg-negative mothers and


unvaccinated children/adolescents up to 19
years of age, 3 doses (0, 1 and 6 months) of
vaccine at half strength ( 10 micrograms) to
be given.
For adults >20 years of age full dose (20
micrograms) is given.
newborns of HBsAg carrier mothers, HBIG 0.5
mL and the first dose of vaccine should be
administered at birth, using different sites.
For patients on hemodialysis or
immunocompromised patients, higher doses
of vaccine are needed (40 g)

Indications for Hepatitis


B Vaccine
1. All newborns
2. All children and adolescents not vaccinated at birth
3. High-risk adults:
a. Health care workers
b. Men who have sex with men
c. Persons with multiple sexual partners
d. Injection drug users
e. Patients on hemodialysis
f. Institutionalized patients
g. Health care workers and public safety workers
h. Spouse, sexual partners and household
members of HBV carriers

Vaccination contd

1.

2.

A protective response defined as an anti-HBs titer


more than 10 IU/L.
2.5% to 10% of vaccine recipients fail to respond
with adequate anti-HBs titers.
BOOSTER DOSE: NOT recommended routinely
considered in those who are immunocompromised
or at a high risk of exposure.
recommended booster vaccination approximately
10 to 15 years after primary vaccination
First vaccine to prevent cancer in humans.(HCC)
Extremely safe vaccine.
Newer combination vaccines are available(easy 5)

CHRONIC VIRAL
HEPATITIS
Guide : Dr. Anjali Metgudmath
co guide : Dr. Dnyanesh
morkar
Dr. Santosh hazare
Presenter :Dr Yeshavanth G

Post exposure prophylaxis

unvaccinated persons : HBIG + hepatitis B vaccine


Perinatal (HBsAg-positive mothers) :
HBIG, 0.5 mL,(immediately after birth) + complete
course of 3 injections of recomb hep B vaccine
started within the first 12 hours of life.
Direct percutaneous inoculation or transmucosal
exposure to HBsAg-positive blood or body fluids
HBIG, 0.06 mL/kg, administered as soon after
exposure as possible, is followed by a complete
course of hepatitis B vaccine to begin within the
first week.

Treatment of Chronic
Hepatitis B

APPROVED TREATMENTS IN THE UNITED STATES


Standard Interferon- 2b
Pegylated Interferon- 2a
Lamivudine
Adefovir dipivoxil
Entecavir
TREATMENTS APPROVED FOR HUMAN
IMMUNODEFICIENCY VIRUS WITH EFFICACY
AGAINST HEPATITIS B VIRUS
Emtricitabine
Tenofovir
Emtricitabine + Tenofovir

Definition of Response to
Antiviral Therapy of
Biochemi
Decrease
in serum ALTB
to within the
Chronic
Hepatitis
cal

normal range

Virologica Decrease in serum HBV DNA to <105


l
IU/mL and loss of HBeAg in patients who
were initially HBeAg positive;
undetectable serum HBV DNA (<102
IU/mL) in
patients who were initially HBeAg
negative
Histologic Decrease in histologic activity index by
at least two points compared to
pretreatment liver biopsy
Complete Fulfill criteria of biochemical and

Comparison of Percentages of Patients


with Antiviral Responses to Approved
Treatments of Hepatitis B

Interferons

antiviral, antiproliferative and


immunomodulatory effects.
IFN- and - bind to the same receptor
and have predominantly antiviral effects.
IFN- binds to a separate receptor and has
more marked immunoregulatory action.
Pegylation reduces rate of
absorption,renal clearance, decreases
immunogenecity and increases half life.

The recommended dose is 180 g weekly for 48


weeks.
pegIFN-2a monotherapy was superior to
lamivudine monotherapy in inducing HBeAg
seroconversion.
a/e include initial flu like illness, fever, chills,
headache, malaise, myalgia, emotional liability.
The strongest predictor of response in HBeAg+
patients is pretreatment ALT level. other
being histologic activity, low HBV dna level,HBV
genotypes.

Lamivudine

A nucleoside analogue causes chain


termination.
effective in suppressing HBV replication and in
ameliorating liver disease.
One-year treatment with lamivudine results in
similar rate of HBeAg seroconversion as 16
week of standard IFN-, but is inferior to a 1year course of pegIFN-.
recommended dose for adults with normal renal
function (creatinine clearance >50 mL/min) and
no HIV infection is 100 mg daily PO

Patients with HIV coinfection should be


treated with 150 mg b.i.d. doses.
minimum of 6 months after confirmed
HBeAg seroconversion.
longer duration of treatment is
recommended.
criteria for discontinuation of treatment
and the optimal duration of therapy have
not been established.

Famciclovir :
1)oral prodrug of penciclovir, an acyclic
deoxyguanosine analog.
2) low efficacy, need for administration thrice
daily, and potential for crossresistance with
lamivudine.
Adefovir Dipivoxil
1)inhibit reverse transcriptase
2) effective in suppressing wild type as well as
lamivudine-resistant HBV
3) 10 mg daily PO

Entecavir: orally administered


cyclopentyl guanosine analog.
Emtricitabine
Tenofovir
Telbivudine (sebivo)

Recommended Strategies for Patients


with Chronic Hepatitis B

Chronic Hepatitis C
infection

most common cause of chronic liver


disease accounting for 40 to 60% of cases.
Progression to cirrhosis mainly depends on
duration of the disease.
MC risk factor for new infection,
accounting (60%), is intravenous drug use.
50% to 80% of users became anti-HCV
positive within 12 months

Etiology of chronic hepatitis


c

Health care workers

needle-stick injuries probably account for


a large proportion of cases.
Skin exposure to blood is NOT a risk
factor.
anti-HCV seroconversion after accidental
needle-stick/sharp exposures averaged
only1.8%(greater than HIV or HBV).

Transfusion associated

risk of acquiring post-transfusion hepatitis has


declined dramatically(0.01% to 0.001% per unit
transfused sera).
Hemodialysis: approximately 8% of cases.
The improved safety of the blood supply, availability
of recombinant erythropoietin, phasing out of
pretransplant immune conditioning transfusion
protocols have significantly reduced the risk of
hepatitis C in these patients.
Transplantation and sexual transmission although
reported the data supporting is less.
Perinatal transmission.

Natural History

Approximately 80% of acutely infected


patients develop chronic infection (viremia)
and most of these (80% to 90%) have chronic
hepatitis with elevated ALT levels.
Alcohol and other factors accelerate the
progress of the disease.
asymptomatic elevations of serum
aminotransferase levels(mild) .
Fatigue, dull right upper quadrant pain,
anorexia, nausea, myalgia are the symptoms.

Although most of them developed chronic


liver disease, ALL CAUSE MORTALITY
remained the same in general populaton.
HCV-related HCC rarely occurs in the
absence of cirrhosis.(1.4 to 3.3%)
1. Mean duration 30 years.
2. Risk increase wit longer duration, cytopenia,
male gender, alcohol use, HBV coinfection,
3. AFP level is elevated
4. Diagnosed by imaging.

Extrahepatic manifestations
1. Mixed cryoglobulinemia
2. Chronic glomerulonephritis
these respond to interferons.

Risk of developing
Survival in patients
decompensated liver
with cirrhosis due to
disease among
chronic hepatitis C.
patients with stable
Effect of complications
cirrhosis due to chronic
and decompensation
hepatitis

Prevention and
Treatment
Public health guidelines have been issued for HCV-INFECTED

PERSONS

Consider all anti-HCV or HCV RNApositive persons to be


potentially infectious

Do not donate blood, organs, tissues, or semen

Avoid sharing of household items such as toothbrushes and razors

Changes in sexual practices are not required within a


monogamous relationship (however, a low potential for sexual
HCV transmission exists; anti-HCVpositive persons and their
partners should be informed of the potential risk of sexual
transmission and an informed decision regarding the need for
precautions should be made)

Vaccinate against hepatitis A and B

Avoid exposure to risk factors for transmission to others

Avoid alcohol consumption

The role IVIg is being studied.(not yet


proved)
Post exposure care:persons with
percutaneous exposure to HCV should be
closely monitored for infection(serial
testing of serum ALT and anti-HCV levels
at baseline and 4 to 6 months
postexposure)
No vaccine as yet available now.

Treatment
Major goal is to prevent the development
of decompensated liver disease and
death.
In chronic infection, goal
1. eradicate or prolonged suppression of
viral replication,
2. reduction of hepatic inflammation,
3. slowing the rate of progressive liver
injury

Peg IFN + Ribavirin >>>>> IFN/


Ribavirin monorx.
Viral genotype has an important effect
on response to treatment.
Std rx consist of Peg IFN a-2b
(1.5g/KBW) or pegylated IFN -2a s/c
once per week and 13 to 15 mg/kg of
oral ribavirin per day.

Interferon and Ribavirin


Dosing According to Viral
Genotype

Dosing Guidelines for


Combination Therapy with
Pegylated Interferon and
Ribavirin

Definitions of Treatment
Responses

In typical cases of acute hepatitis C, recovery is


rare, progression to chronic hepatitis is rule, and
meta-analyses of small clinical trials suggest that
antiviral therapy with interferon alfa monotherapy
(3 million units SC three times a week) is beneficial,
reducing rate of chronicity considerably by inducing
sustained responses in 3070% of patients
Although treatment of acute hepatitis C is
recommended, optimum regimen, duration of
therapy, and time to initiate therapy remain to be
determined.
Many authorities now opt for a 24-week course
(beginning within 23 months after onset) of the
best regimen identified for the treatment of chronic
hepatitis C, long-acting pegylated interferon plus
the nucleoside analogue ribavirin, although value of
adding ribavirin has not been demonstrated

Hepatitis D

HDV can either infect a person


simultaneously with HBV (co-infection) or
superinfect a person already infected
with HBV (super-infection)
Obsolete now.
Only drug used in treating was IFN-a

Hepatitis G

asymptomatic course
Role in liver disease not yet proven
co infection with HGV and HIV has been
shown to improve mortality and
morbidity for the HIV-infected individuals
and slow the progression to AIDS.
Herpes viruses also cause hepatitis.

Take home messages

Chronic viral hepatitis is definitely TREATABLE and


also CURABLE in many cases.
Early identification and initiation of rx.
Many patients ARE being treated and good responses
have been obtained.
HBeAg negativity does not always mean good
prognosis(it can be an indicator of resistant mutants)
Universal vaccination for hep b.
Post exposure prophylaxis.
Avoidance of additional hepatotoxic
factors(ALCOHOL)

Treatment is not very cumbersome and


quite patient friendly.
Active research is going on in this field
and lot of new treatment and guidelines
are coming up.

REFERENCES

Schiff's Diseases of the Liver, 10th Edition


CHRONIC VIRAL HEPATITIS DIAGNOSIS AND
THERAPEUTICS by RAYMOND S. KOFF, MD and
GEORGE Y. WU, MD, PhD.
Diseases of the Liver and Biliary System by sheila
sherlock
Sleisenger & Fordtran's Gastrointestinal and Liver
Disease, 8th ed.
Harrisons principles of internal medicine 18 th edition
Internet
International conference on viral hepatitis.

Thank you