Viral Hepatitis B, D

1. VIRAL HEPATITIS
B and D
Dr.T.V.Rao MD
Dr.T.V.Rao MD 1

2. 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

3. 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

4. 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

5. A“Infectious”
“Serum”
Viral hepatitis
Enterically
transmitted
Parenteraly
transmitted
F, G, TTV
? other
E
NANB
B D C
Viral Hepatitis - Historical
Perspectives
Dr.T.V.Rao MD 5

6. 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
Dr.T.V.Rao MD 6

7. Hepatitis B Infection
Dr.T.V.Rao MD 7

8. 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

9. 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

10. 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

11. 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

12. 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 serotype
Dr.T.V.Rao MD 12

13. 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

14. 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 particle
Dr.T.V.Rao MD 14

15. 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

16. 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 r
Only one member of each pair being present at
a time
Divided into four Major antigenic subtypes
adw,adr, ayw, and ayr
Dr.T.V.Rao MD 16

17. Hepatitis B Virus
Dr.T.V.Rao MD 17

18. HBV : Structure
Dr.T.V.Rao MD 18

19. GENOME
Dr.T.V.Rao MD 19

20. 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

21. 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

22. 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

23. How the HBV is transmitted
Dr.T.V.Rao MD 23

24. IDU
16%
Other
5%
Unknown
16%
Hetero-
sexual,
multiple
partners
39%
MSM
24%
Risk Factors for Hepatitis B
MMWR 2006;55(RR-16):6-7Dr.T.V.Rao MD 24

25. Hepatitis B Virus Infection by
Duration of High-Risk Behavior
Years at Risk
0 3 6 9 12 15
0
20
40
60
80
100
Percentinfected
IV drug user
Homosexual men
HCWs
Heterosexual
Dr.T.V.Rao MD 25

26. 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
Dr.T.V.Rao MD 26

27. Dr.T.V.Rao MD 27

28.  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%
 Premature mortality from
chronic liver disease: 15%-25%
Hepatitis B - Clinical Features
Dr.T.V.Rao MD 28

29. Spectrum of Chronic Hepatitis B
Diseases
Chronic Persistent Hepatitis -
asymptomatic
Chronic Active Hepatitis -
symptomatic exacerbations of hepatitis
Cirrhosis of Liver
Hepatocellular Carcinoma
Dr.T.V.Rao MD 29

30. 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
Carrierrisk(%)
Risk of Chronic HBV Carriage by Age of
Infection
Dr.T.V.Rao MD 30

31. • 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
Dr.T.V.Rao MD 31

32. Dr.T.V.Rao MD 32

33. 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
Dr.T.V.Rao MD 33

34. 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

35.  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

36. 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

37. 、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

38. 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

39. Hepatitis B Complications
• Fulminant hepatitis
• Hospitalization
• Cirrhosis
• Hepatocellular carcinoma
• Death
Dr.T.V.Rao MD 39

40. 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

41. 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

42. 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.
Dr.T.V.Rao MD 42

43. 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

44. 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

45. 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

46. 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

47. Hepatitis B Vaccine
• CompositionRecombinant 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

48. 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

49. 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

50. 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

51. 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

52. Hepatitis D Infection
Dr.T.V.Rao MD 52

53. 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

54. 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

55. HBsAg
RNA
 antigen
Hepatitis D (Delta) Virus
Dr.T.V.Rao MD 55

56. 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

57. 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

58.  Percutaneous exposures
injecting drug use
 Per mucosal exposures
sex contact
Hepatitis D Virus Modes of
Transmission
Dr.T.V.Rao MD 58

59.  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

60. 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

61. 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

62. 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

63. 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

64. • Programme Created by Dr.T.V.Rao MD
for Medical and Nursing Students in the
Developing World
• Email
• doctortvrao@gmail.com
Dr.T.V.Rao MD 64