Viral Hepatitis - Historical Perspectives

“Infectious” A Enterically
E
transmitted

Viral NANB
hepatitis

Parenterall
“Serum” B D C y
transmitted
F, G, TTV
? other
 Type of
Hepatitis
A B C D E

Source of feces blood/ blood/ blood/ feces

virus blood-derived blood-derived blood-derived
body fluids body fluids body fluids

Route of fecal-oral percutaneous percutaneous percutaneous fecal-oral

transmission permucosal permucosal permucosal

Chronic no yes yes yes no

infection

Prevention pre/post- pre/post- blood donor pre/post- ensure safe

exposure exposure screening; exposure drinking
immunization immunization risk behavior immunization; water
modification risk behavior
modification
Hepatitis A Virus
 Hepatitis A virus
 HAV is a single stranded RNA picornavirus.
 One stable serotype only.
 Difficult to grow in cell culture.
 Viral antigen is found in serum, stool and liver
only during acute infection.
 IgM antibody appear early in the disease but
diminishes within several weeks, followed by
the development of protective IgG antibody,
which persist usually for life.
Epidemiology
 Hepatitis A is the most common type of
viral hepatitis occurring world wide, often
in epidemics.
 The disease is commonly seen in autumn
and affects children and young adults.
 Overcrowding and poor sanitation facilitate
spread.
 There is no carrier state.
Transmission
 Spread of infection is mainly by the faecal-
oral route and arises from the ingestion of
contaminated water or food.
 Infected persons excrete viruses in the
faeces for about 2-3 weeks before the onset
of the illness and for up to 2 weeks thereafter.
 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)
 Hepatitis A Virus Transmission

Disease Peak Age

Endemicity Rate of Infection Transmission Patterns

High Low to Early Person to person;

High childhood outbreaks uncommon
Moderate High Late Person to person;
childhood/ food and waterborne
young adults outbreaks
Low Low Young adults Person to person;
food and waterborne
outbreaks
Very low Very low Adults Travelers; outbreaks
uncommon
 Hepatitis A - Clinical
Features
 Non-specific symptoms:
Nausea.
Anorexia.
 Jaundice after 1 or 2 weeks.
 Urine become dark.
 Stool become pale.
 The liver is moderately enlarged.
 Hepatitis A - Clinical
Features
 Spleen is palpable in about 10% of patients.
 Occasionally , tender lymphadenopathy is
seen.
 Transient rash in some cases.
 Hepatitis A - Clinical
Features
 Incubation period: Average 30 days
Range 15-50 days
 Jaundice by <6 yrs, <10%
age group: 6-14 yrs, 40%-50%
>14 yrs, 70%-80%
 Complications: Fulminant hepatitis
Cholestatic hepatitis
Relapsing hepatitis
 Chronic sequelae: None
Complications
 Fulminant hepatitis with liver coma and death.
 Extra hepatic complications include:
 Arthritis.
 Vasculitis.
 Myocarditis.
 Renal failure.
 Hepatitis A Infection
Typical Serological Course
Symptom Total anti-
s
HAV

Titre ALT

Fecal
HAV
IgM anti-HAV

0 1 2 3 4 5 6 1 2
2 4
Months after exposure
Laboratory Diagnosis

 Acute infection is diagnosed by the detection of HAV-IgM in

serum.
 Past Infection i.e. immunity is determined by the detection of
HAV-IgG.
 Cell culture – difficult and take up to 4 weeks, not routinely
performed
 Direct Detection– PCR of faeces. Can detect illness
earlier than serology but rarely performed.
 Hepatitis A Vaccination.

 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 Virus -
Virology
Hepatitis B virus (HBV) is a member of the
Hepadnavirus family-”hepatotropic DNA viruses”
• large DNA virus with a circular chromosome
with an RNA stage in the host cell during its
replicative cycle
• Replicative RNA subsequently produces viral
DNA that leads to synthesis of the viral
proteins. (retrovirus-like reverse transcription)
Hepatitis B Virus - Virology
• The major proteins involved in HBV infection
are the surface antigen (HBsAg), core
antigen (HBcAg) and the e antigen (HBeAg).
– HBsAg is an element of the outer surface of the
virus
– HBcAg and HBeAg are different forms of the same
polyprotein
– HBcAg is made up of subunit proteins to form the
genomic core of the full virus
– HBeAg is a truncated form thought to play a role in
signaling for viral replication
 Hepatitis B Virus - Virology
 Double stranded DNA virus,the + strand not complete
 Replication involves a reverse transcriptase.
 Complete Dane particle 42 nm, 28 nm electron dense core,
containing HBcAg and HBeAg. The coat and the 22 nm free
particles contain HBsAg
 At least 4 phenotypes of HBsAg are recognized.
 The HBcAg is of a single serotype
 Hepatitis B virus (HBV) has been classified into 8 genotypes (A-
H).
 It has not yet been possible to propagate the virus
in cell culture.
 Epidemiology.

• HBV is a worldwide public health concern

– It is estimated that 350 million people are carriers of
the virus
– prevalence rates in Africa and Asia of greater than
8%
– In developing nations, the major route of acquisition
of HBV is vertical transmission
– in the Western Hemisphere, most acquire HBV in
adolescence and adulthood via sexual or parenteral
routes
 Epidemiology.
 2 billion with positive serology
 300 million HBV carriers
 500,000 deaths globally
 High Prevalence= SE Asia, China, Africa
 USA = 1.2 million chronic Hep B patients
 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.
MODES OF TRANSMISSION

 Perinatal infection
 Blood Transfusion
 Horizontal transmission
 Sexual transmission
 Intravenous drug use / percutaneous
inoculation.
 Nosocomial
 Organ transplantation-Anti-HBc screening
HBV Clinical features

 Incubation of HBV after exposure averages

60-90 days Range 45-180 days before the
onset of symptoms.
• Acute HBV infection is subtle in most cases
– may be symptomatic in about 30% of patients.
 Symptoms of Hep B
 Early symptoms include:
-general discomfort, fatigue, lack of appetite,
skin rash, nausea, vomit, flu-like symptoms
 Relatively few cases : JAUNDICE follows

with yellow skin and dark urine

 Jaundice and other symptoms usually

resolve in 3-4 weeks

 HBV Clinical features
 Symptoms include:
– Fever
– Jaundice
– Malaise
– abdominal pain
– clinical course identical to HAV.
• Symptoms appear after the peak period of
Hepatitis B surface antigen (HBsAg) levels
have peaked in the bloodstream
 HBV Clinical features

• 90% of patients with acute HBV infection will

resolve their illness spontaneously
• very small percentage of patients develop
fulminant hepatic failure
• 2-6% of older children and adults develop a
chronic carrier state where the virus remains
active at a low level-30% of 1-5 yr olds
 HBV Clinical features
• HBV carriers are at high risk for end stage
liver disease and ultimately hepatocellular
carcinoma-25% mortality in children who
acquire chronic infection at birth
• Patients with chronic HBV infection may also
present with glomerulonephritis secondary to
immune complex deposition.
• In addition to their own morbidity and
mortality, HBV carriers represent the
largest reservoir for transmission of HBV
 EXTRAHEPATIC
MANIFESTAIONS
10-20% of patients
 Arthritis-dermatitis
 CNS: Seizures, Guillain-Barre' syndrome,
peripheral neuropathy
 CVS: Pericarditis, myocarditis Polyarteritis
nodosa
 GI: Pancreatitis
 RENAL:. Membranous glomerulonephritis
 HEME: aplastic anemia Cryoglobulinemia
 Hepatitis B - Clinical Features

 Incubation period: Average 60-90 days

Range 45-180 days
 Clinical illness (jaundice): <5 yrs, <10%
5 yrs, 30%-50%
 Acute case-fatality rate: 0.5%-1%
 Chronic infection: <5 yrs, 30%-90%
5 yrs, 2%-10%
 Spectrum of Chronic Hepatitis B Diseases

1Chronic Persistent Hepatitis – (asymptomatic)

2. Chronic Active Hepatitis - (symptomatic
exacerbations of hepatitis)
3. Cirrhosis of Liver
4. Hepatocellular Carcinoma
 Hepatitis B-pregnancy
HBV can infect pregnant women but does not
cause more severe disease than seen in the general
population
•Chronic carriers should have uncomplicated
pregnancies unless liver failure is present.
Significance of HBV infection during pregnancy lies in

risk of transmission to the infant-90% of infants

develop chronic HBV
 Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Symptoms
HBeAg anti-HBe

Total anti-HBc
Titre

HBsAg IgM anti-HBc anti-HBs

0 4 8 12 16 20 24 28 32 36 52 100

Weeks after
Progression to Chronic Hepatitis B Virus Infection
Typical Serologic Course
Acute Chronic
(6 months) (Years)
HBeAg anti-HBe
HBsAg
Total anti-HBc
Titr
e

IgM anti-HBc

0 4 8 12 16 20 24 28 32 36 52 Years
Weeks after Exposure
 Outcome of Hepatitis B Virus
100 Infection 100
by Age at Infection
80
80
(%)
Chronic Infection

Symptomatic Infection (%)

60 60
Chronic Infection

40 Chronic Infection (%) 40

20 20

Symptomatic Infection
0 0
Birth 1-6 months 7-12 months 1-4 years Older Children
and Adults
Age at Infection
Chronic Hepatitis B Virus
Infection
 Chronic viremia
 Responsible for most mortality
 Overall risk 5%
 Higher risk with early infection
 Global Patterns of Chronic
HBV Infection
 High (>8%):
 lifetime risk of infection >60%
 early childhood infections common
 Intermediate (2%-7%):
 lifetime risk of infection 20%-60%
 infections occur in all age groups
 Low (<2%):
 lifetime risk of infection <20%
 most infections occur in adult risk groups
CHRONIC HEPATITIS
 A history of acute hepatitis is elicited in only a small
percentage of patients with chronic HBV infection.
 Many patients with chronic hepatitis B are
asymptomatic, while others have nonspecific
symptoms such as fatigue. Some patients
experience exacerbations of the infection which may
be asymptomatic, mimic acute hepatitis, or manifest
as hepatic failure.
 Physical examination may be normal or there may be
stigmata of chronic liver disease. Jaundice,
splenomegaly, ascites, peripheral edema, and
encephalopathy may be present in patients with
decompensated cirrhosis. Laboratory tests may be
normal, but most patients have mild to moderate
elevation in serum AST and ALT.
 During exacerbations, the serum ALT concentration
may be as high as 50 times the upper limit of normal
and alfa-fetoprotein (AFP) concentrations as high as
1000 ng/mL may be seen .
 Concentration of Hepatitis B
Virus in Various Body Fluids

Low/Not
High Moderate Detectable

blood semen urine

serum vaginal fluid feces
wound exudates saliva sweat
tears
breastmilk
Hepatitis B Complications

 Fulminant hepatitis
 Hospitalization
 Cirrhosis
 Hepatocellular carcinoma
 Death
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.
 Laboratory Diagnosis
• Detection of HBV infection involves
detecting the presence of:
– Viral genetic material.
– Viral proteins (antigens).
– Antibody response to viral antigens.
 Hepatitis B-treatment

 No need to treat acute HBV infection

 Chronic HBV can be treated because of high

risk of progression to:

– Cirrhosis
– Hepatocellular carcinoma
 Hepatitis B-treatment

• Options are 4:
– Interferon-α-response rate of around 30% after 4-6
months of therapy, most durable of available therapies
because lower relapse rate.
– Lamivudine(3TC)-arrests viral replication
temporarily, however mutation renders virus
resistant, viral load rises again but lower
 Hepatitis B-treatment

 Adefovir- former HIV agent that is active against

HBV at lower concentrations. Active against
lamivudine resistant virus as well with no new
resistance mutations detected after 1 year.
Tenofovir- HIV agent that has activity against HBV,

good for treating dual infected patients, less

experience overall.
Treatment
 Interferon - for HBeAg +ve carriers with chronic active hepatitis.
Response rate is 30 to 40%.
 alpha-interferon 2b (original)
 alpha-interferon 2a (newer, claims to be more efficacious and efficient)
 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.
 Adefovir – less likely to develop resistance than Lamivudine and may be
used to treat Lamivudine resistance HBV. However more expensive and
toxic
 Entecavir – most powerful antiviral known, similar to Adefovir
 Successful response to treatment will result in the disappearance of
HBsAg, HBV-DNA, and seroconversion to HBeAg.
 Hepatitis B-prevention

• Pillars of prevention are:

– Recombinant vaccine
– Hepatitis B Immune Globulin
 Hepatitis B-prevention

• Vaccine:
– Recombinant protein (HBsAg) purified and
combined with adjuvant
– 3 doses given routinely to infants OR to
adolescents and high risk adults as catch
up program
– Prevents 90-95% protection that is durable
VACCINATION

 > 90% efficacy

 Indications:
 All neonates
 Household contacts
 High risk behavior
 Health care workers
 Chronic dialysis
 Repeated transfusion
 Hepatitis B Vaccine
 Composition Recombinant HBsAg
 Efficacy 95% (Range, 80%-100%)
 Duration of
Immunity 20 years or more
 Schedule 3 Doses
 Booster doses not routinely recommended
 Recommended Dose of Hepatitis B
Vaccine

Infants and children Recombivax HB Engerix-B

<11 years of age Dose (mcg) Dose (mcg)
0.5 mL (5) 0.5 mL (10)
Adolescents 11-19
years
0.5 mL (5) 0.5 mL (10)
Adults >20 years

1.0 mL (10) 1.0 mL (20)

 Hepatitis B-prevention
• HBIG:
– Concentrated IVIG with high anti-HBV titer
– Used primarily for high risk post-exposure
prophylaxis
• Needle stick exposure
• Infant born to mother with known chronic infection or
unknown status-dose in first 12 hours if known HBsAg+
mom, up to 7th day if mom is determined later to be
HBsAg+ >>90-95% efficacy in preventing transmission
• Household contact with blood exposure
• Sexual contact with person with chronic HBV
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 envelo protease/ RNA- RNA

pe helicase dependent polymerase
protei
c2 n 33 c-
2 c 100
5’ 3’

cor E1 E2 NS NS NS NS
e 2 3 4 5

hypervariable
region
Hepatitis C Virus

 Genome resembled that of a flavivirus

positive stranded RNA genome of around 10,000 bases
 1 single reading frame, structural genes at the 5' end, the non-
structural genes at the 3' end.
enveloped virus, virion thought to 30-60nm in diameter
 morphological structure remains unknown
 HCV has been classified into a total of six genotypes (type
1 to 6) on the basis of phylogenetic analysis
 Genotype 1 and 4 has a poorer prognosis and response to
interferon therapy,
Hepatitis C Virus

• First discovered in 1989 to be the major

cause of transfusion related “non-A, non-B”
hepatitis
• Currently, there is no established cell culture
system for HCV
• chimpanzees are the only available
laboratory animal model, so little is still known
about the mechanisms of infection
Hepatitis C- The Burden

• Epidemiology-
– Approximately 2% of US is HCV antibody
positive- 4 million people
– 350 million people worldwide
– 0.2 to 0.4% of children are HCV antibody
positive
– Leading indication for adult liver transplant
in US
Hepatitis C-Transmission

• HCV is transmitted by contact with

contaminated blood or blood containing body
fluids:
– intravenous drug use
– blood transfusion or transplantation prior to
1992
– Vertical transmission
Hepatitis C-Transmission
• HCV is possibly transmitted by other routes, but
substantial proof is lacking:
– Breastfeeding-not likely and not contraindicated by
CDC
– Sexual transmission-not likely, but if so, VERY
inefficient means of transmission
– Sharing razors and toothbrushes-more likely than
others, actually contraindicated by CDC in guidelines
– Tattooing-unlikely and not an indication for testing
according to CDC
 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-HCV-positive
contact
 Multiple sex partners
 Birth to HCV-infected mother
 Hepatitis C - Clinical
Features
Incubation period: Average 6-7
wks
Range 2-26 wks
Clinical illness (jaundice): 30-40% (20-30%)
Chronic hepatitis: 70%
Persistent infection: 85-100%
Immunity: No protective
antibody
response
Clinical features
• Clinical manifestations:
– Acute subclinical hepatitis is most common after
blood borne exposure
– chronic hepatitis is also relatively asymptomatic.
– Symptoms are indolent when they do occur,
sometimes months to years later and include:
• Fever
• Fatigue
• jaundice.
– Patients may only present with signs of end stage
liver disease.
Clinical features

Clinical manifestations:
– 60-70% of adults progress to chronic
infection, men>women
– Only about 50% of children, increases with
age
– Acute Fulminant hepatic failure with HCV is
exceedingly rare
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
Symptom
s

Titr
e

ALT

Norma
l
0 1 2 3 4 5 6 1 2 3 4
Mont Years
hsTime after
Exposure
Hepatitis C-Pregnancy

• Acute HCV infection can and does occur

during pregnancy
• more common to see a pregnant patient who
either has known chronic HCV infection or has
chronic infection diagnosed during her prenatal
evaluation
• HCV infection has not been shown to be more
severe during pregnancy
• HCV has not been shown to more rapidly progress
during pregnancy
Hepatitis C-Pregnancy

• HCV is vertically transmitted

– 5-10% overall transmission, but only 3-
5% go on to chronic infection
– Jumps to 20-25% in setting of HIV- HCV
co-infection (pre-HAART era)
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.
Prognostic Tests
 Genotyping – genotype 1 and 4 have a worse prognosis overall and
respond poorly to interferon therapy. A number of commercial and in-
house assays are available.
 Genotypic methods – DNA sequencing, PCR-hybridization e.g. INNO-LIPA.
 Serotyping – particularly useful when the patient does not have detectable
RNA.
 Viral Load – patients with high viral load are thought to have a poorer
prognosis. Viral load is also used for monitoring response to IFN therapy.
A number of commercial and in-house tests are available.
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)
 antigenVirus HBsAg

RNA
Hepatitis D Virus
 The delta agent is a defective virus which
shows similarities with the viroids in plants.
 The agent consists of a particle 35 nm in diameter
consisting of the delta antigen surrounded by an outer
coat of HBsAg.
 The genome of the virus is very small and consists of
a single-stranded 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
 HBV - HDV Coinfection
Typical Serologic Course
Symptoms

ALT
Elevated

Titre
anti-HBs
IgM anti-
HDV

HDV RNA

HBsAg
Total anti-HDV

Time after
 HBV - HDV
Superinfection
Typical Serologic
Course
Jaundice

Symptoms

Total anti-HDV
ALT
Titre

HDV RNA
HBsAg

IgM anti-HDV

Time after
 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 Virus
 Calicivirus-like viruses
 unenveloped RNA virus, 32-34nm in
diameter
 +ve stranded RNA genome, 7.6 kb in size.
 very labile and sensitive
 Can only be cultured recently
 Hepatitis E - Clinical Features

 Incubation period: Average 40 days

Range 15-60 days
 Case-fatality rate: Overall, 1%-3%
Pregnant women,
15%-25%
 Illness severity: Increased with
age
 Chronic sequelae: None identified
 Hepatitis E Virus Infection
Typical Serologic
Course Symptom
s

ALT IgG anti-HEV

Titer IgM anti-HEV

Virus in stool

0 1 2 3 4 5 6 7 8 9 1 1 1 1
0 1 2 3
Weeks after
 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?