Hepatitis A-E Viruses

An Overview

Viral Hepatitis - Historical

Perspectives
Infectious
Viral hepatitis

Serum

Enterically
E
transmitted

A
NANB

Parenterall
B D
C y
transmitted
F, G, TTV
? other

Type of Hepatitis

A
Source of
virus
Route of
transmission
Chronic
infection
Prevention

feces

blood/
blood/
blood/
blood-derived blood-derived blood-derived
body fluids
body fluids
body fluids

feces

fecal-oral

percutaneous percutaneous percutaneous

permucosal
permucosal
permucosal

fecal-oral

no

yes

pre/postexposure
immunization

pre/postexposure
immunization

yes

yes

blood donor
pre/postscreening;
exposure
risk behavior immunization;
modification risk behavior
modification

no

ensure safe
drinking
water

Hepatitis A Virus

Hepatitis A - Clinical
Features
Incubation period:




Jaundice by

<10%
age group:

40%-50%




Complications:
hepatitis




hepatitis

Average 30 days
Range 15-50 days

<6 yrs,

6-14 yrs,

>14 yrs, 70%-80%

Fulminant

Cholestatic

Relapsing

Hepatitis A Infection
Typical Serological Course
Symptoms

Titre

Total anti-HAV

ALT

Fecal
HAV

IgM anti-HAV

Months after

12

24

Hepatitis A Virus
Transmission
Close personal contact
(e.g., household contact, sex contact, child day
care centers)
Contaminated food, water
(e.g., infected food handlers, raw shellfish)
Blood exposure (rare)
(e.g., injecting drug use, transfusion)

Global Patterns of
Hepatitis A Virus Transmission
Disease Peak Age
Endemicity Rate of Infection Transmission Patterns
High

Low to
High

Moderate

High

Low

Low

Very low

Early
childhood

Person to person;
outbreaks uncommon

Late
Person to person;
childhood/ food and waterborne
young adults outbreaks

Young adults Person to person;

food and waterborne
outbreaks
Very low Adults
Travelers; outbreaks
uncommon

Laboratory Diagnosis

Acute infection is diagnosed by the detection of

HAV-IgM in serum by EIA.
Past Infection i.e. immunity is determined by the
detection of HAV-IgG by EIA.

Hepatitis A Vaccination Strategies

Epidemiologic Considerations
Many cases occur in community-wide
outbreaks

no risk factor identified for most cases

highest attack rates in 5-14 year olds
children serve as reservoir of infection

Persons at increased risk of infection

travelers
homosexual men
injecting drug users

Hepatitis A Prevention - Immune

Globulin
Pre-exposure
travelers to intermediate and high
HAV-endemic regions

Post-exposure (within 14 days)

Routine
household and other intimate contacts
Selected situations
institutions (e.g., day care centers)
common source exposure (e.g., food prepared
by infected food handler)

Hepatitis B Virus

Hepatitis B - Clinical

Features
Incubation period:






Clinical illness (jaundice):





Acute case-fatality rate:

Average 60-90 days

Range 45-180 days

<5 yrs, <10%
5 yrs, 30%-50%
0.5%-1%

Chronic infection:






Premature mortality from
chronic liver disease:

<5 yrs, 30%-90%

5 yrs, 2%-10%

15%-25%

Spectrum of Chronic Hepatitis B

Diseases

1. Chronic Persistent Hepatitis - asymptomatic

2. Chronic Active Hepatitis - symptomatic
exacerbations of hepatitis
3. Cirrhosis of Liver
4. Hepatocellular Carcinoma

Acute Hepatitis B Virus Infection with

Recovery Typical Serologic Course
Symptoms
HBeAg

anti-HBe
Total anti-HBc

Titre

anti-HBs

IgM anti-HBc

HBsAg

12 16 20 24 28 32 36

Weeks after Exposure

52

100

Progression to Chronic Hepatitis B Virus

Infection
Typical Serologic Course
Acute
(6 months)

Chronic
(Years)
HBeAg

anti-HBe
HBsAg
Total anti-HBc

Titre

IgM anti-HBc

0 4 8 12 16 20 24 28 32 36

52

Weeks after Exposure

Years

Outcome of Hepatitis B Virus Infection

by Age at Infection
100

80

on
ic
Inf
ec
tio
n
(%
)

60

Chronic Infection

60

40

Chronic Infection (%)

20

Symptomatic Infection (%)

80

40

100

20
Symptomatic Infection

0
Birth

1-6 months

7-12 months

Age at Infection

1-4 years

0
Older Children
and Adults

Global Patterns of Chronic HBV

Infection
High (>8%): 45% of global population
lifetime risk of infection >60%
early childhood infections common

Intermediate (2%-7%): 43% of global

population
lifetime risk of infection 20%-60%
infections occur in all age groups

Low (<2%): 12% of global population

lifetime risk of infection <20%
most infections occur in adult risk groups

Concentration of Hepatitis B
Virus in Various Body Fluids
High

Moderate

blood
semen
serum
vaginal fluid
wound exudates
saliva

Low/Not
Detectable
urine
feces
sweat
tears
breastmilk

Hepatitis B Virus
Modes of Transmission
Sexual - sex workers and homosexuals are
particular
at
risk.


Parenteral - IVDA, Health Workers are at
increased
risk.


Perinatal - Mothers who are HBeAg positive
are much more likely to transmit to their
offspring than those who are not. Perinatal
transmission is the main means of
transmission in high prevalence populations.

Diagnosis
A battery of serological tests are used for the diagnosis of
acute and chronic hepatitis B infection.
HBsAg - used as a general marker of infection.
HBsAb - used to document recovery and/or immunity to HBV
infection.
anti-HBc IgM - marker of acute infection.
anti-HBcIgG - past or chronic infection.
HBeAg - indicates active replication of virus and therefore
infectiveness.
Anti-Hbe - virus no longer replicating. However, the patient can
still be positive for HBsAg which is made by integrated HBV.
HBV-DNA - indicates active replication of virus, more accurate
than HBeAg especially in cases of escape mutants. Used
mainly for monitoring response to therapy.

Treatment
Interferon - for HBeAg +ve carriers with chronic active
hepatitis. Response rate is 30 to 40%.
Lamivudine - a nucleoside analogue reverse
transcriptase inhibitor. Well tolerated, most patients will
respond favorably. However, tendency to relapse on
cessation of treatment. Another problem is the rapid
emergence of drug resistance.
Successful response to treatment will result in the
d i s a p p e a r a n c e o f H B s A g , H B V- D N A , a n d
seroconversion to HBeAg.

Prevention
Vaccination - highly effective recombinant vaccines are now
available. Vaccine can be given to those who are at increased
risk of HBV infection such as health care workers. It is also
given routinely to neonates as universal vaccination in many
countries.
Hepatitis B Immunoglobulin - HBIG may be used to protect
persons who are exposed to hepatitis B. It is particular
efficacious within 48 hours of the incident. It may also be given
to neonates who are at increased risk of contracting hepatitis
B i.e. whose mothers are HBsAg and HBeAg positive.
Other measures - screening of blood donors, blood and body
fluid precautions.

Hepatitis C Virus
capsid envelope
protein

protease/
helicase

c22

33c

RNA-dependent
RNA polymerase
c-100

3
cor E1
e

E2

hypervariable
region

NS
2

NS
3

NS
4

NS
5

Hepatitis C - Clinical
Features
Incubation period:






Clinical illness (jaundice):
(20-30%)
Chronic hepatitis:

Persistent infection:
Immunity:













identified

Average 6-7 wks

Range 2-26 wks
30-40%

70%

85-100%
No protective
antibody
response

Chronic Hepatitis C Infection

The spectrum of chronic hepatitis C infection is

essentially the same as chronic hepatitis B
infection.

All the manifestations of chronic hepatitis B

infection may be seen, albeit with a lower
frequency i.e. chronic persistent hepatitis, chronic
active hepatitis, cirrhosis, and hepatocellular
carcinoma.

Hepatitis C Virus Infection

Typical Serologic Course
anti-HCV
Symptoms

Titre

ALT

Normal
0

3
4
Months

Time after Exposure

2
3
Years

Risk Factors Associated

with Transmission of HCV

Transfusion or transplant from infected donor

Injecting drug use
Hemodialysis (yrs on treatment)
Accidental injuries with needles/sharps
Sexual/household exposure to anti-HCVpositive contact
Multiple sex partners
Birth to HCV-infected mother

Laboratory Diagnosis

HCV antibody - generally used to diagnose hepatitis C

infection. Not useful in the acute phase as it takes at
least 4 weeks after infection before antibody appears.
HCV-RNA - various techniques are available e.g. PCR
and branched DNA. May be used to diagnose HCV
infection in the acute phase. However, its main use is
in monitoring the response to antiviral therapy.
HCV-antigen - an EIA for HCV antigen is available. It
is used in the same capacity as HCV-RNA tests but is
much easier to carry out.

Treatment

Interferon - may be considered for patients

with chronic active hepatitis. The response
rate is around 50% but 50% of responders
will relapse upon withdrawal of treatment.
Ribavirin - there is less experience with
ribavirin than interferon. However, recent
studies suggest that a combination of
interferon and ribavirin is more effective than
interferon alone.

Prevention of Hepatitis C
Screening of blood, organ, tissue
donors
High-risk behavior modification
Blood and body fluid precautions

Hepatitis D (Delta) Virus

d antigen

HBsAg

RNA

Hepatitis D - Clinical Features

Coinfection
severe acute disease.
low risk of chronic infection.
Superinfection
usually develop chronic HDV infection.
high risk of severe chronic liver disease.
may present as an acute hepatitis.

Hepatitis D Virus Modes

of Transmission
Percutanous exposures
injecting drug use
Permucosal exposures
sex contact

Typical Serologic
HBV - HDV Coinfection Course
Symptoms
ALT Elevated

Titre

anti-HBs
IgM anti-HDV

HDV RNA
HBsAg
Total anti-HDV

Time after Exposure

HBV HDV Coinfection

Typical Serologic Course
Symptoms
ALT Elevated

Titre

anti-HBs
IgM anti-HDV

HDV RNA
HBsAg
Total anti-HDV

Time after Exposure

HBV - HDV Superinfection

Typical Serologic Course
Jaundice
Symptoms

Titre

Total anti-HDV

ALT

HDV RNA
HBsAg
IgM anti-HDV

Time after Exposure

Hepatitis D - Prevention

HBV-HDV Coinfection
Pre or postexposure prophylaxis to prevent
HBV infection.
HBV-HDV Superinfection
Education to reduce risk behaviors among
persons with chronic HBV infection.

Hepatitis E Virus

Hepatitis E - Clinical
Features
Incubation period:





Case-fatality rate:










Illness severity:

age
Chronic sequelae:

Average 40 days
Range 15-60 days
Overall, 1%-3%
Pregnant women,

15%-25%

Increased with
None identified

Hepatitis E Virus Infection

Typical Serologic Course
Symptoms
IgG anti-HEV

ALT

Titer

IgM anti-HEV
Virus in stool

Weeks after Exposure

1
0

11

1
2

1
3

Hepatitis E -
Epidemiologic Features

Most outbreaks associated with faecally contaminated

drinking water.
Several other large epidemics have occurred since in the
Indian subcontinent and the USSR, China, Africa and
Mexico.
In the United States and other nonendemic areas, where
outbreaks of hepatitis E have not been documented to
occur, a low prevalence of anti-HEV (<2%) has been found
in healthy populations. The source of infection for these
persons is unknown.
Minimal person-to-person transmission.

Prevention and Control Measures for

Travelers to HEV-Endemic Regions

Avoid drinking water (and beverages with ice)

of unknown purity, uncooked shellfish, and
uncooked fruit/vegetables not peeled or
prepared by traveler.
IG prepared from donors in Western countries
does not prevent infection.
Unknown efficacy of IG prepared from donors
in endemic areas.
Vaccine?