Viral Hepatitis B, D

VIRAL HEPATITISB and D

Dr.T.V.Rao MD

Dr.T.V.Rao MD 1

What Is Hepatitis?• The word "hepatitis" means

inflammation of the Liver Toxins, certain drugs, some diseases, heavy alcohol use, bacterial and viral infections can all cause hepatitis. Hepatitis is also the name of a family of viral infections that affect the liver; the most common types in the United States are hepatitis A, hepatitis B, and hepatitis C.

Dr.T.V.Rao MD 2

Hepatitis

• Hepatitis (plural hepatitides) implies injury to the liver characterized by the presence of inflammatory cells in the tissue of the organ. The name is from ancient Greek hepar or hepato, meaning liver, and suffix -itis, meaning "inflammation" (c. 1727)

Dr.T.V.Rao MD 3

Viral Hepatitis• A group of viruses known as the

hepatitis viruses cause most cases of liver damage worldwide. Hepatitis can also be due to toxins (notably alcohol), other infections.

• Common viruses cause hepatitis include A,B,C,D,E. G ……….

Dr.T.V.Rao MD 4

A“Infectious”

“Serum”

Viral hepatitis

Entericallytransmitted

ParenteralytransmittedF, G, TTV

? other

E

NANB

B D C

Viral Hepatitis - Historical Perspectives

Dr.T.V.Rao MD 5

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 Hepatitis

A B C D E

Dr.T.V.Rao MD 6

Hepatitis B Infection

Dr.T.V.Rao MD 7

Hepatitis B• Hepatitis B is a liver disease caused

by the hepatitis B virus (HBV). It ranges in severity from a mild illness, lasting a few weeks (acute), to a serious long-term (chronic) illness that can lead to liver disease or liver cancer.

Dr.T.V.Rao MD 8

Hepatitis B Virus

• Blumberg in 1965 discovers, names as Australia antigen.

• 1968 identified with association in serum hepatitis.

• Surface component of HBV called as surface antigen.

Dr.T.V.Rao MD 9

Hepatitis B In the World • 2 billion people have been infected (1 out of 3

people). • 400 million people are chronically infected. • 10-30 million will become infected each year. • An estimated 1 million people die each year

from hepatitis B and its complications. • Approximately 2 people die each minute from

hepatitis B.

Dr.T.V.Rao MD 10

Hepatitis B is Serious – Global Impact

• It’s a common disease!• Over 350 million people in the world have

chronic hepatitis B1

1 Centers for Disease Control and Prevention. Hepatitis B FAQs for Health Professionals. Available at: http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm#b12. Accessed January 28, 2010.2 World Health Organization. Hepatitis B. Available at: http://www.who.int/emc-documents/hepatitis/docs/whocdscsrlyo20022/disease/world_distribution.html. Accessed June 1, 2004. Dr.T.V.Rao MD 11

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; adw, adr, ayw and ayr.

• The HBcAg is of a single serotypeDr.T.V.Rao MD 12

Typing of HBV• Hepatitis B virus (HBV) has been classified into

8 genotypes (A-H).• Genotypes A and C predominate in the US.

However, genotypes B and D are also present in the US. Genotype F predominates in South America and in Alaska, while A, D and E predominate in Africa. Genotype D predominates in Russia and in all its prior dominions, while in Asia, genotypes B and C predominate.

Dr.T.V.Rao MD 13

HBV Virology Under Electron Microscope

• Spherical particles 22 nm in diameter• Filamentous or tubular 22 nm with

varying length • Called as HBs Ag surface components

which are produced in excess.• Third type double walled spherical

structure 42 nm diameter called HBV

• Called as Dane particleDr.T.V.Rao MD 14

HBV – Surface antigens• Enveloped proteins on

surface of virions and surplus 22 nm diameter spherical and filamentous particles constitute the B surface antigens

• HBs Ag consists two major polypeptides and is glycolated

Dr.T.V.Rao MD 15

Antigenic Diversity of HBV• HBV shows antigenic diversity, two different

antigenic components and common group reactive antigen a

• Two contain specific antigens d y w rOnly one member of each pair being present at

a timeDivided into four Major antigenic subtypes adw,adr, ayw, and ayr

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Hepatitis B Virus

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HBV : Structure

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GEN

OM

E

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There are 4 open reading frames derived from the same strand (the incomplete + strand)

• S - the 3 polypeptides of the surface antigen (preS1, preS2 and S - produced from alternative translation start sites.

• C - the core protein

• P - the polymerase

• X - a trans activator of viral transcription (and cellular genes?). HBx is conserved in all mammalian (but not avian) hepadnaviruses. Though not essential in transfected cells, it is required for infection in vivo.

Open Reading Frames

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Prevalence of Divergent Strains • ayw – common in Europe,Australia,and

America.• adr - Prevalent in south, East India and Far

east,• ayr - very rare• Core antigen HB c ag• Be HBe is a soluble non particle nucelocapsid

protien • Both Hbc and Hbe are coded by same genes

Dr.T.V.Rao MD 21

Hepatitis B Perinatal Transmission

• If mother positive for HBsAg and HBeAg– 70%-90% of infants infected– 90% of infected infants become chronically

infected• If positive for HBsAg only

– 5%-20% of infants infected– 90% of infected infants become chronically

infected *in the absence of postexposure prophylaxisDr.T.V.Rao MD 22

How the HBV is transmitted

Dr.T.V.Rao MD 23

IDU16%

Other5%

Unknown16%

Hetero-sexual, multiple partners

39%

MSM24%

Risk Factors for Hepatitis B

MMWR 2006;55(RR-16):6-7Dr.T.V.Rao MD 24

Hepatitis B Virus Infection by Duration of High-Risk Behavior

Years at Risk

0 3 6 9 12 150

20

40

60

80

100

Per

cent

in

fect

ed

IV drug user

Homosexual men

HCWs

Heterosexual

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Pathogenesis of HBV infection• Disease is Immune mediated• Hepatocytes carry viral antigen• Immune response subject to antibody dependent.• N K cell and cytotoxic T cell attack• In the absence of adequate immune response HBV

infection may not cause hepatitis.• But lead to carrier state.• Infection – Immunodeficient person are likely to

because asymptomatic carrier followed infection

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Dr.T.V.Rao MD 27

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%

5 yrs, 2%-10% Premature mortality from

chronic liver disease: 15%-25%

Hepatitis B - Clinical Features

Dr.T.V.Rao MD 28

Spectrum of Chronic Hepatitis B Diseases

Chronic Persistent Hepatitis - asymptomatic

Chronic Active Hepatitis - symptomatic exacerbations of hepatitis

Cirrhosis of Liver

Hepatocellular Carcinoma

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0

10

20

30

40

50

60

70

80

90

100

Birth 1-6 mo 7-12 mo 1-4 yrs 5+ yrs

Age of infection

Ca

rrie

r ri

sk

(%

)Risk of Chronic HBV Carriage by Age of

Infection

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• 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

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Dr.T.V.Rao MD 32

High ModerateLow/Not

Detectable

blood semen urineserum vaginal fluid feces

wound exudates saliva sweat

tearsbreastmilk

Concentration of Hepatitis B Virus in Various Body Fluids

Dr.T.V.Rao MD 33

How Hepatitis B is transmitted

Contact with infectious blood, semen, and other body fluids from having sex with an infected person, sharing contaminated needles to inject drugs, or from an infected mother to her newborn.

Dr.T.V.Rao MD 34

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

Dr.T.V.Rao MD 35

Pathology• Both Hepatitis B and C

are cytopathogenic• Cellular damage is

immune mediated• Both HBV and HBC have

significant roles in in the development of Hepatocellular carcinoma

• Carcinoma may appear 15 – 60 years after the beginning of infection.

36Dr.T.V.Rao MD

、 Pathogenesis & Immunity• Virus enters hepatocytes via blood • Immune response (cytotoxic T cell) to viral antigens

expressed on hepatocyte cell surface responsible for clinical syndrome

• 5 % become chronic carriers (HBsAg> 6 months) • Higher rate of hepatocellular ca in chronic carriers,

especially those who are “e” antigen positive • Hepatitis B surface antibody likely confers lifelong

immunity (IgG anti-HBs)• Hepatitis B e Ab indicates low transmissibility

Dr.T.V.Rao MD 37

High-risk groups for HBV infection• People from endemic regions • Babies of mothers with chronic HBV• Intravenous drug abusers• People with multiple sex partners• Hemophiliacs and other patients requiting blood and

blood product treatments• Health care personnel who have contact with blood• Residents and staff members of institutions for the

mentally retarded

Dr.T.V.Rao MD 38

Hepatitis B Complications

• Fulminant hepatitis• Hospitalization• Cirrhosis• Hepatocellular carcinoma• Death

Dr.T.V.Rao MD 39

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.

Dr.T.V.Rao MD 40

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.

Dr.T.V.Rao MD 41

Treatment• 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.

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Statistics on HBV• Most healthy adults (90%) who are

infected will recover and develop protective antibodies against future hepatitis B infections

• 90% of infants and up to 50% of young children infected with hepatitis B will develop chronic infections.

Dr.T.V.Rao MD 43

Protect Yourself And Your Family!

• Hepatitis B can infect EVERYONE, regardless of age

• By getting tested and vaccinated, you can protect your family

• If you test positive, ask your doctor about your treatment/management options

• Prevention is the best approach to hepatitis B.

Dr.T.V.Rao MD 44

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.

Dr.T.V.Rao MD 45

Post vaccination Serologic Testing

Healthcare personnel who have contact with patients or blood should be tested for anti-HBs (antibody to hepatitis B surface antigen) 1 to 2 months after completion of the 3-dose seriesDr.T.V.Rao MD 46

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

Dr.T.V.Rao MD 47

Management of Nonresponse to Hepatitis B Vaccine

• Complete a second series of three doses

• Should be given on the usual schedule of 0, 1 and 6 months

• Retest 1-2 months after completing the second series

Dr.T.V.Rao MD 48

Prevention• 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.

Dr.T.V.Rao MD 49

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.Dr.T.V.Rao MD 50

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.

Dr.T.V.Rao MD 51

Hepatitis D Infection

Dr.T.V.Rao MD 52

Delta antigen• In 1977, a previously unrecognized nuclear

antigen was detected in hepatocytes of patients with chronic hepatitis B. The antigen resembled hepatitis B core antigen (HBcAg) in its subcellular localization. Its presence was always associated with hepatitis B virus (HBV) infection, but it rarely coexisted with HBcAg. It was termed "delta antigen". Patients with delta antigen develop anti-delta antibodies.

Dr.T.V.Rao MD 53

Hepatitis D virus (HDV)

• Hepatitis D virus (HDV) is found only in people who carry the hepatitis B virus. HDV may make a recent (acute) hepatitis B infection or an existing long-term (chronic) hepatitis B liver disease worse. It can even cause symptoms in people who carry hepatitis B virus but who never had symptoms.

Dr.T.V.Rao MD 54

HBsAg

RNA

antigen

Hepatitis D (Delta) Virus

Dr.T.V.Rao MD 55

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

Dr.T.V.Rao MD 56

Risk factors include:

• Abusing intravenous (IV) or injection drugs• Being infected while pregnant (the mother

can pass the virus to the baby)• Carrying the hepatitis B virus• Men having sexual intercourse with other

men, Receiving many blood transfusions

Dr.T.V.Rao MD 57

Percutaneous exposures

injecting drug use

Per mucosal exposures

sex contact

Hepatitis D Virus Modes of

Transmission

Dr.T.V.Rao MD 58

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

Dr.T.V.Rao MD 59

HDV can lead to fulminant Hepatitis

• HDV infection of chronically infected HBV-carriers may lead to fulminant acute hepatitis or severe chronic active hepatitis, often progressing to cirrhosis.

• Chronic hepatitis D may also lead to the development of hepatocellular carcinoma. Dr.T.V.Rao MD 60

Consequences of HDV Infection

• Infection with both HBV and HDV is associated with more severe liver injury than HBV infection alone. HDV infection of chronically infected HBV carries may lead to fulminant acute hepatitis or chronic active hepatitis, often progressing to cirrhosis. Chronic HDV infection may also lead to the development of hepatocellular carcinoma.

Dr.T.V.Rao MD 61

Prevention • Prompt diagnosis and treatment of hepatitis B

infection can help prevent hepatitis D.• Avoid intravenous drug abuse. If you use IV

drugs, avoid sharing needles.• A vaccine is available to prevent hepatitis B.

Adults who are at high risk for hepatitis B infection, and all children should consider getting this vaccine.

Dr.T.V.Rao MD 62

Best Way to Prevent HDV Infection

• Control of HDV infection can be achieved by targeting and limiting HBV infections. HBV vaccination is therefore recommended to avoid HBV-HDV confection.

Dr.T.V.Rao MD 63

• Programme Created by Dr.T.V.Rao MD for Medical and Nursing Students in the

Developing World • Email

• [email protected]

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