Hepatitis A-E Viruses

Enock Anassi MD, PharmD

AA“ Infectious”

“ Serum”

Viral hepatitis

Entericallytransmitted

ParenterallytransmittedF, G, TTV

? other

EE

NANBNANB

BB DD CC

Viral Hepatitis - Historical Perspectives

Source ofvirus

feces blood/blood-derived

body fluids

blood/blood-derived

body fluids

blood/blood-derived

body fluids

feces

Route oftransmission

fecal-oral percutaneouspermucosal

percutaneouspermucosal

percutaneouspermucosal

fecal-oral

Chronicinfection

no yes yes yes no

Prevention pre/post-exposure

immunization

pre/post-exposure

immunization

blood donorscreening;

risk behaviormodification

pre/post-exposure

immunization;risk behaviormodification

ensure safedrinking

water

Type of HepatitisA B C D E

Hepatitis A Virus

HEPATITIS A: signs and symptoms

Nausea and vomiting, anorexia, jaundice

Self limited No chronic disease Stool excretion 2 weeks before and

1 week after appearance

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 hepatitisCholestatic

hepatitisRelapsing

hepatitis Chronic sequelae: None

Hepatitis A - Clinical Features

FecalHAV

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, 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

EndemicityDisease

RatePeak Age

of Infection Transmission Patterns

High Low to High

Early childhood

Person to person;outbreaks uncommon

Moderate High Late childhood/

young adults

Person to person;food and waterborne outbreaks

Low Low Young adults Person to person;food and waterborne outbreaks

Very low Very low Adults Travelers; outbreaks uncommon

Global Patterns of 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.

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 Vaccination

StrategiesEpidemiologic Considerations

Pre-exposure travelers to intermediate and high

HAV-endemic regions Post-exposure (within 14 days)

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

infected food handler)

Hepatitis A Prevention - Immune Globulin

VIRAL HEPATITIS

HEPATITIS B

Hepatitis B Virus

Incubation period: Average 60-90 daysRange 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%

immunocompetent 5 yrs, 1%-5%

Premature 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

Hepatitis B

ACUTE CHRONIC- 5-10% <6 months (infection >6months)

Every year 1 to 2 million people die due to an infection by this virus

complications of chronic hepatitis

Endemicity

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

Global Patterns of Chronic HBV Infection

Symptoms

HBeAg anti-HBe

Total anti-HBc

IgM anti-HBc anti-HBsHBsAg

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

Acute Hepatitis B Virus Infection with RecoveryTypical Serologic

Course

Weeks after Exposure

Titre

IgM anti-HBc

Total anti-HBc

HBsAg

Acute(< 6 months)

HBeAg

Chronic(>6 months)

anti-HBe

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

Weeks after Exposure

Titre

Progression to Chronic Hepatitis B Virus InfectionTypical Serologic

Course

Symptomatic Infection

Chronic Infection

Age at Infection

Chronic Infection (%)

Sym

pto

matic In

fection

(%)

Birth 1-6 months 7-12 months 1-4 years Older Childrenand Adults

0

20

40

60

80

100100

80

60

40

20

0

Outcome of Hepatitis B Virus Infection

by Age at Infection

Ch

ron

ic In

fect

ion

(%

)

Interpretation of Serologic Tests in Hepatitis B

+

Viral Hepatitis and Serology

Type of Viral Hepatitis Positive Virology

Acute HBV HBsAg, HBeAg, HBcAb IgM

Acute HBV, windows period

HBcAb IgM

Chronic active HBV HBsAg, HBeAg, HBcAb IgG

Recovery HBV HBsAb IgG, HBcAb IgG, Normal ALT

Immunized HBV HBsAb IgG

Serological Marker Hep B

1) HBsAg (Hepatitis B surface antigen):• if positive, person is infectious• Sensitivity = 0.15 ng/ml• Specificity = 99.5%

2) Anti-HBs (Antibody to HBV surface antigen):

• indicates immunity to HBV and protection from disease

• Protective level is >10 IU/ml

Serological Markers Hep B 3) Anti - HBc (Antibody to HBV core

antigen):• Total - indicates past or active

infection; present whether person is immune or chronic carrier

• Specificity = 99.8% to 99.9%• IgM - early indicator of acute

infection• No antigen test

Serological Marker Hep B 4) HBeAg (Hepatitis Be antigen):

• indicates person is highly infectious

• Selecting patients for therapy 5) Anti-HBe (Antibody to HBVe

antigen):• prognostic for resolution of infection; less infectious; spontaneous seroconversion in 10 to 20% of healthy adults per year

Serologic markers – caveats: Precore or HBeAg negative mutants:

Due to mutation in precore (abolishes HBeAg production) or core promoter region (down-regulates HBeAg production)

No effect on viral replication (may be enhanced)

More difficult to treat; greater risk of cirrhosis

Co-infection with HCV may suppress both HBeAg and HBsAg

Serologic markers – caveats: Persistent HBsAg for >6 mos = chronic

infection HBsAg and anti-HBs may co-exist in up

to 24% of chronically infected individuals; likely due to mutations in the “a” determinant of the S gene Surface antigen escape mutants described

in infants infected with HBV after HBIG + vaccination and in Liver transplants after prolonged HBIG

Anti-HBc IgM may persist for up to 2 years in 20%; chronically infected individuals may have low titres which rise during acute flares

Hepatitis B – Laboratory Tests

Serologic markers – caveats: Isolated HBcAb may be due to:

Remote infection (immune or chronic carrier)

“Window” period between HBsAg and HBsAb Co-infection with HCV False positive test result – HBcAb is marker

most prone to false positives HBV DNA may help sort this out

High ModerateLow/Not

Detectable

blood semen urineserum vaginal fluid feces

wound exudates saliva sweat

tearsbreastmilk

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. Perinatal transmission is the main means of transmission in high prevalence populations.

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 (PEGinterferon-2α) , - 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.

Entecavir and Adefovir Successful 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.

Complications Arthritis Glomerulonephritis Polyarteritis nodosa Hepatocellular carcinoma

Hepatitis D

Subviral satellite because it can propagate only in the presence of hepatitis B

coinfection superinfection

Transmission: parenteral (intravenous drug use mostly)

> 60% develop cirrhosis

HBsAg

RNA

antigen

Hepatitis D (Delta) Virus

Hepatitis D Anti-HDV Total (IgG & IgM) available Incubation time – similar to Hepatitis B High titires of HDV antibodies indicate

ongoing chronic infection Treatment same as HBV If acquired as superainfection in

chronic HBV there is in severity of infection i.e fulminant hepatitis, chronic hepatitis with rapid progression to cirhosis

Jaundice

Symptoms

ALTTotal anti-HDV

IgM anti-HDV

HDV RNA

HBsAg

HBV - HDV SuperinfectionTypical 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 C Affects each person differently No vaccine available Many people have the virus and do

not even know it By blood transfusion and IV drug

abuse Intranasal cocaine use, piercing Type 1 (most resistant) type II and

III

Incubation period: Average 6-7

wksRange 2-26 wks

Clinical illness (jaundice): 30-40% (20-30%)

Chronic hepatitis: 70%

Persistent infection: 85-100%

Immunity: No protective antibody

response identified

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.

Waxing and waning aminotransferases (ALT/AST)

Symptoms

anti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4

Hepatitis C Virus InfectionWaxing and Waning ALT/AST

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

Hepatitis C Dispelling Myths

Hepatitis C is not spread by: Casual contact

Hugging/kissing Sharing eating utensils and drinking

glasses Sneezing/coughing Shaking hands Sitting on a toilet seat

Prevention

Never share drug equipment Straws, bills, needles, syringes,

water, filter, cooker, pipes etc… Never share tooth brushes/razors

or any personal hygiene articles that have blood on them (even tiny amounts).

Practice safer sex

Prevention Always make sure new & sterilized

equipment is being used for tattooing & piercing Make sure ink for tattooing is not

being shared Do not touch dirty needles without

proper equipment or following proper procedures

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 Types 1 II and III

Type I is resistant than II and III

Acute HCV –alfa- interferon for 6 months also type II and III

Chronic HCV –alfa interferon+ ribavirin or peginterferon +ribavirin

Type I use alfa interferon +Ribavirin for 1 year, Telaprevir, Betapravir

HAV and HBV vaccination.

Screening of blood, organ, tissue donors

High-risk behavior modification

Blood and body fluid precautions

Prevention of Hepatitis C

Complications Cryoglobulinemia Membranoproliferative

glomerulonephritis Hepatocellular Carcinoma Cirrhosis Alfa interferon is contraindicated with

major depression and organ transplant Ribavirin contraindicated in pregnancy,

avoid for 6 months after therapy

Treatment Alcoholics should stop for 1 month

before starting treatment Screen for hepatocellular carcinoma

every 6 months Inteferon S/E: flu like syndrome

(malasia, HA, fever, myalgia) depression, myelosuppression (neutropenia, anemia)

Ribavirin S/E HA, fatigue, hemolysis

Hepatitis E Virus

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 - 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 InfectionTypical Serologic

Course

Titer

Weeks after Exposure

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.

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.

IG prepared from donors in Western countries does not prevent infection.

Unknown efficacy of IG prepared from donors in endemic areas.

Vaccine?

Prevention and Control Measures for Travelers to HEV-Endemic Regions

Hepatitis Virus – Molecular Tests Molecular assays available as follows:

Commercial assays for HBV DNA and HCV RNA In-house assays for HAV RNA & HDV RNA No molecular assay for HEV RNA

HCV RNA & HBV DNA, plasma or serum must be separated from cells within 6 hrs and plasma can be stored at 4oC for several days or -70oC for long-term

No licensed tests for diagnostic purposes; all tests are for monitoring or donor screening HCV RNA will be done in HIV or other

immunocompromised patients if requested

Nucleic Acid Amplification Tests (NAAT) for Detection of RNA/DNA Quantitation of RNA or DNA may be

reported as copies/ml or IU/ml Conversion factor for copies/ml to IU/ml is

not the same for different assays measuring the same target or different targets HBV DNA: 5.82 copies/IU HCV RNA: PCR - 2.4 copies/IU; bDNA: 5.2

copies/IU Coefficient of variation (COV) may range

from 15 to 50%

HBV DNA in Clinical Practice Routine monitoring on therapy to

assess response to treatment Every 3 months X years on oral agents Every 1 month X 6-12 on PEG/IFN

Routine monitoring off therapy to estimate prognosis and to evaluate need for treatment Every 6 –12 months normally Diagnosis of occult HBV infection