Virology

Hepatitis A-E Viruses

A
“Infectious” “Serum” Viral hepatitis
Enterically transmitted
Parenterally transmitted
G, ? other
E
NANB
B
D
C
Viral Hepatitis - Historical Perspectives

Source of

virus
feces
blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
feces
Route of
transmission
fecal-oral
percutaneous
permucosal
percutaneous
permucosal
percutaneous
permucosal
fecal-oral
Chronic
infection
no
yes
yes
yes
no
Prevention
pre/post-
exposure
immunization
pre/post-
exposure
immunization
blood donor
screening;
risk behavior
modification
pre/post-
exposure
immunization;
risk behavior
modification
ensure safe
drinking
water
Type of Hepatitis
A
B
C
D
E

Hepatitis A Virus

Hepatitis A Virus
Naked RNA virus Related to enteroviruses, formerly known as enterovirus 72, now put in its own family: heptovirus One stable serotype only Difficult to grow in cell culture and also in vivo in chimpanzees. 4 genotypes exist, but in practice most of them are group 1

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
Hepatitis A - Clinical Features

Fecal HAV

Symptoms
0
1
2
3
4
5
6
12
24
Hepatitis A Infection
Total anti-HAV
Titre
ALT
IgM anti-HAV
Months after exposure
Typical Serological Course


Close personal contact(e.g., household contact, child day care centers) Contaminated food, water(e.g., infected food handlers) 
Hepatitis A Virus Transmission

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.Cell culture – difficult and take up to 4 weeks, not routinely performedDirect Detection – EM, RT-PCR of faeces. Can detect illness earlier than serology but rarely performed.

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

Hepatitis A Vaccination Strategies Epidemiologic Considerations

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 A Prevention - Immune Globulin

Hepatitis B Virus

Hepatitis B virus
HbsAg Envelope glycoprotein
HBc Capsid protein
HbeAg Viral polymerase
DNA genome
Anti-HBc IgM, IgG
Anti-HBe
Anti-HBs
Lipid membrane

Hepatitis B Virus - Virology

Double stranded DNA virus,the + strand not complete 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;  adw, adr, ayw and ayr. The HBcAg is of a single serotype. It has not yet been possible to propagate the virus in cell culture.

Incubation period: Average 60-90 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% Mortality fromchronic liver disease: 15%-25%
Hepatitis B - Clinical Features

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

Symptoms

HBeAg
anti-HBe
Total anti-HBc
IgM anti-HBc
anti-HBs
HBsAg
0
4
8
12
16
20
24
28
32
36
52
100
Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Weeks after Exposure
Titre

IgM anti-HBc

Total anti-HBc
HBsAg
Acute (6 months)
HBeAg
Chronic (Years)
anti-HBe
0
4
8
12
16
20
24
28
32
36
52
Years
Weeks after Exposure
Titre
Progression to Chronic Hepatitis B Virus Infection
Typical Serologic Course

Symptomatic Infection

Chronic Infection
Age at Infection
Chronic Infection (%)
Symptomatic Infection (%)
Birth
1-6 months
7-12 months
1-4 years
Older Children and Adults
0
20
40
60
80
100
100
80
60
40
20
0
Outcome of Hepatitis B Virus Infection by Age at Infection
Chronic Infection (%)


High
Moderate
Low/Not
Detectable
blood
semen
urine
serum
vaginal fluid
feces
wound exudates
saliva
sweat
tears
breastmilk
Concentration of Hepatitis B Virus in Various Body Fluids


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.

Hepatitis B Virus Modes of Transmission


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%.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 toxicEntecavir – most powerful antiviral known, similar to AdefovirSuccessful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and 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.

hypervariable region

capsid
envelope protein
protease/helicase
RNA-dependent
RNA polymerase
c22
5’ core
E1
E2
NS2
NS3
33c
NS4
c-100
NS5
3’ Hepatitis C Virus

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.

Incubation period: Average 6-7 wks Clinical illness (jaundice): 30-40% Chronic hepatitis: 70% Persistent infection: 85-100%
Hepatitis C - Clinical Features

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.

Symptoms

anti-HCV
ALT
Normal
0
1
2
3
4
5
6
1
2
3
4
Hepatitis C Virus Infection
Typical Serologic Course
Titre
Months
Years
Time after Exposure


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

Risk Factors Associated with Transmission of HCV

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.


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

Prevention of Hepatitis C

HBsAg

RNA
 antigen Hepatitis D (Delta) Virus

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

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 - Clinical Features

Percutanous exposures injecting drug use Permucosal exposures sex contact

Hepatitis D Virus Modes of Transmission

anti-HBs

Symptoms
ALT Elevated
Total anti-HDV
IgM anti-HDV
HDV RNA
HBsAg
HBV - HDV Coinfection
Typical Serologic Course
Time after Exposure
Titre


Jaundice
Symptoms
ALT
Total anti-HDV
IgM anti-HDV
HDV RNA
HBsAg
HBV - HDV Superinfection
Typical Serologic Course
Time after Exposure
Titre

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 D - Prevention

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


Incubation period: Average 40 days Range 15-60 days Case-fatality rate: Overall, 1%-3% Illness severity: Increased with age Chronic sequelae: None identified
Hepatitis E - Clinical Features

Symptoms

ALT
IgG anti-HEV
IgM anti-HEV
Virus in stool
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Hepatitis E Virus Infection
Typical Serologic Course
Titer
Weeks after Exposure



Most outbreaks associated with faecally contaminated drinking water. Several other large epidemics have occurred since in the Indian, China, Africa and Mexico. Minimal person-to-person transmission.

Hepatitis E - Epidemiologic Features

Avoid drinking water (and beverages with ice) of unknown purity, uncooked shellfish, and uncooked fruit/vegetables not peeled or prepared by traveler.. Vaccine?

Prevention and Control Measures for Travelers to HEV-Endemic Regions