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
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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
Dr.T.V.Rao MD 16
Hepatitis B Virus
Dr.T.V.Rao MD 17
HBV : Structure
Dr.T.V.Rao MD 18
GEN
OM
E
Dr.T.V.Rao MD 19
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
Dr.T.V.Rao MD 20
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
Dr.T.V.Rao MD 25
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
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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
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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
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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
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