2. Viral Hepatitis AlphabetViral Hepatitis Alphabet
Hepatitis A
Hepatitis B
Hepatitis C
Hepatitis D
Hepatitis E
Hepatitis F
Hepatitis GHepatitis G
Hepatitis TTVHepatitis TTV
3. Viral hepatitisViral hepatitis
Hepatitis AHepatitis A
Hepatitis BHepatitis B
Hepatitis CHepatitis C
Hepatitis DHepatitis D
Enteral rout of transmission
Parenteral rout of
transmission
By ways of transmission
Hepatitis EHepatitis E
8. WHO data
About 2 billion people are infected with HBV infection worldwideAbout 2 billion people are infected with HBV infection worldwide
Around 400 million persons are living with chronic HBV infectionAround 400 million persons are living with chronic HBV infection
There are 4 million people with HBV infection in the USAThere are 4 million people with HBV infection in the USA
58% of HIV infected patients have coinfection with HBV
(AntiHBc(total)
58% of HIV infected patients have coinfection with HBV
(AntiHBc(total)
From 5 to 20% of Asian population is infected with HBVFrom 5 to 20% of Asian population is infected with HBV
HBV Prevalence and IncidenceHBV Prevalence and Incidence
9. WHO data
HBV associated morbidity and mortalityHBV associated morbidity and mortality
Around 1 000 000 patients die due to end stage liver disease caused
by HBV annually
Around 1 000 000 patients die due to end stage liver disease caused
by HBV annually
About 550 000 persons die due to liver cancer caused by chronic
HBV infection annually
About 550 000 persons die due to liver cancer caused by chronic
HBV infection annually
This accounts 2 800 deaths everydayThis accounts 2 800 deaths everyday
This is 1-2 deaths every minuteThis is 1-2 deaths every minute
Annually tens of thousand persons with chronic HBV infection
undergo liver transplantation
Annually tens of thousand persons with chronic HBV infection
undergo liver transplantation
10. HBV 400 million
HCV 180 million
HIV >40 million
HIV/HBV 2-4 million
HIV/HCV 4-5 million
WHO
HBV; HCV; HIV prevalence worldwide
12. Epidemiology of
hepatitis B in Georgia
Infectious Diseases, AIDS & Clinical Immunology Research Center, Tbilisi. Georgia
(General Population)
13. #
High Risk
Behavior Groups
Percent (%)
1 IDUs 11.9%
2 STD 5.53%
3 CSW 5.1%
4 Blood donors 1.7%
5 TB Patients 5.39%
Prevalence of HBV among high risk behavior group
By HBsAg
Infectious Diseases, AIDS & Clinical Immunology Research Center, Tbilisi. Georgia
14. #
High Risk
Behavior Groups
Percent (%)
1 IDUs 63.2%
2 STD 18.1%
3 CSW 16.1%
4 Blood donors 5.9%
5 TB Patients 9.7%
Prevalence of HBV among high risk behavior group
By Anti-HBc(total)
Infectious Diseases, AIDS & Clinical Immunology Research Center, Tbilisi. Georgia
15. Prevalence of HCV and HBV amongPrevalence of HCV and HBV among
HIV patients in GeorgiaHIV patients in Georgia
Badridze et al. Georgian Med News, 2008
HBsAg
19. Genotype Geographical distribution
A Africa, India, North Europe, USA.
B Asia, USA
C Asia, USA
D
India, Near East, South Europe, USA.
E West and South Africa.
F Central and South Africa.
G Europe, USA.
H Central and South America. Califrnia, USA.
HBVHBV GenotypesGenotypes
20. Clinical Importance of HBV genotypesClinical Importance of HBV genotypes
A Interferon therapy is effective
B
Slow progression of disease.
Low incidence of hepatocelular carcinoma.
Interferon therapy is effective
C
Rapid progression of disease.
High incidence of hepatocelular carcinoma.
Low response to Interferon therapy
D Low response to Interferon therapy
23. Transmission routes of HBV
Transfussion of infected blood or its products, using nonsterile syringes, needles
and medical instruments, transplantation of infected donor organs or tissues,
occupasional exposure with infected blood
Parenteral
Risk of sexual tramission of HBV is high (40-45%). The risk is much higher
among persons having multiple sexual partners (commercial sex workers, men
who have sex with men etc.)
Sexual
Mother to child
Chance of Vertical transmission of HBV is about 10%. The risk is increased if
HBV viral load in mother’s blood is high.
HBV is not transmitted
HBV is not transmitted by air, dropltes, vectors or from animals.
24. • Have unprotected sex with multiple sex partners or
with someone who's infected with HBV
• Share needles during intravenous (IV) drug use
• Are a man who has sex with other men
• Live with someone who has a chronic HBV infection
• Are an infant born to an infected mother
• Have a job that exposes you to human blood
• Travel to regions with high infection rates of HBV,
such as Africa, Central and Southeast Asia, and Eastern
Europe
Risk Factors
26. hepatitis B virus is not directly cytopathic to hepatocytes.
The fact that patients with defects in cellular immune
competence are more likely to remain chronically
infected rather
than to clear HBV supports the role of cellular immune
responses
in the pathogenesis of hepatitis B–related liver injury.
hepatitis B virus is not directly cytopathic to hepatocytes.
The fact that patients with defects in cellular immune
competence are more likely to remain chronically
infected rather
than to clear HBV supports the role of cellular immune
responses
in the pathogenesis of hepatitis B–related liver injury.
27. HBV pathogenesis. HBV life cycle
Stable reservoir of genetic materialStable reservoir of genetic material
28. • The virus gains entry into the cell on the
surface and being endocytosed.
• The partially double stranded viral DNA is
then made fully double stranded by viral
polymerase and transformed into covalently
closed circular DNA (cccDNA). This cccDNA
serves as a template for transcription of four
viral RNAs by host RNA polymerase.
29. • The largest RNA, (which is longer than the
viral genome), is used to make the new copies
of the genome and to make the capsid core
protein and the viral DNA polymerase.
• The long RNA is then transported back to the
cytoplasm where the virion P protein (the
DNA polymerase) synthesizes DNA via its
reverse transcriptase activity.
36. Acute Hepatitis B
Definition
Acute Hepatitis B is an infectious disease caused by
hepatitis B virus, which developes within 6 months
after entering virus to the organizm. Disease has
symptomatic (with jaundice and without jaundice)
and asymptomatic course. In >90% of cases acute
hepatitis B is self-limited disease.
37. Acute hepatitisAcute hepatitis BBAcute hepatitisAcute hepatitis BB
With symptomsWith symptoms
infeqciuri paTologiis, Sidsisa da klinikuri imunologiis
samecniero-praqtikuli centri
Without symptomsWithout symptoms
38. • Discomfort in Abdominal cavity
• Jaundes
• Dark urine
• clay-colored stools
• Fever
• Joint pain
• Loss of appetite
• Nausea and vomiting
• Weakness and fatigue
• And others
Main symptoms
39. Natural history of Hepatitis B
Acute HBV Infection
< 10% Persistent infection>90%
Recovery
20-35%
cirrhoses
5-7%
HCC
Chronic
replicate form
Healthy carriers
41. The prodromal symptoms of acute
viral hepatitis B
are systemic and quite variable.
Constitutional symptoms:
• anorexia,
• nausea and vomiting,
• fatigue, malaise,
• arthralgias, myalgias,
• headache, photophobia, pharyngitis,
May precede the onset of jaundice by 1–2
weeks.
42. Dark urine and clay-colored stools may be
noticed by the patient from 1–5 days
before the onset of clinical jaundice.
43. With the onset of clinical jaundice , the constitutional prodromal
symptoms usually diminish, but in some patients mild weight loss
(2.5–5 kg) is common and may continue during the entire icteric
phase.
The liver becomes enlarged and may be associated with right upper
quadrant pain and discomfort.
Infrequently, patients present with a cholestatic picture, suggesting
extrahepatic biliary obstruction.
Splenomegaly are present in 10–20% of patients with acute hepatitis B.
Rarely, a few spider angiomas appear during the icteric phase and
disappear during convalescence.
Period of jounces
44. During the recovery phase, constitutional symptoms
disappear, but usually some liver enlargement and
abnormalities in liver biochemical tests are still evident.
The duration of the posticteric phase is variable, ranging
2–12 weeks, and is usually more prolonged in acute hepatitis
B.
Complete clinical and biochemical recovery is to be expected
3–4 months after the onset of jaundice in self-limited cases of
hepatitis B.
Recovery Phase
46. Chronic Hepatitis B
Definition
Chronic hepatitis B is a chronic infection caused
by HBV which developes after 6 months from
acute phase of infection. Chronic hepatitis B
usually progresses slowly and is characterised
with non-specific clinical symptoms.
47. • Chronic hepatitis B
– HBe Ag positive chronic hepatitis B
– HBe Ag negative chronic hepatitis B
– Nonactive healthy carriers (HBsAg)
– Occult HBV infection
• Chronic hepatitis B
– HBe Ag positive chronic hepatitis B
– HBe Ag negative chronic hepatitis B
– Nonactive healthy carriers (HBsAg)
– Occult HBV infection
Clinical spectrum of Chronic HBV infection (variants)
49. 1. HBsAg
5. HBeAg
2. Anti HBs
3. Anti HBc IgG
4. Anti HBc IgM
6. Anti HBe
qualitative and
quantitative
• Blood
• liver
HBV DNA
Serologic and virologic markers of HBV
infection
50. HBs AgHBs Ag
Anti-HBsAnti-HBs
HBe AgHBe Ag
Anti- HBeAnti- HBe
Anti-HBc(total)Anti-HBc(total)
Anti-HBcIgMAnti-HBcIgM
HBs AgHBs Ag
Anti-HBsAnti-HBs
HBe AgHBe Ag
Anti- HBeAnti- HBe
Anti-HBc(total)Anti-HBc(total)
Anti-HBcIgMAnti-HBcIgM
Infectious Diseases, AIDS & Clinical Immunology Research Center
Serologic markers of HBV infection
Each serologic marker has its clinical significant
51. After a person is infected with HBV, the first virology marker
detectable in serum within 1–12 weeks, usually between 8–12
weeks, is HBsAg
Circulating HBsAg precedes elevations of serum aminotransferase
activity and clinical symptoms by 2–6 weeks and remains detectable
during the entire icteric or symptomatic phase of acute hepatitis B
and beyond.
In typical cases, HBsAg becomes undetectable 1–2 months after
the onset of jaundice and rarely persists beyond 6 months.
After HBsAg disappears, antibody to HBsAg (anti-HBs) becomes
detectable in serum and remains detectable indefinitely thereafter.
(self-limited case of HBV)
HBsAg
52. The temporal association between the appearance of anti-HBs and
resolution of HBV infection as well as the
observation that persons with anti-HBs in serum are protected
against reinfection with HBV suggests that anti-HBs is the
protective antibody.
Patients with HBsAg and without anti-HBs should be categorized
as having chronic HBV infection.
Anti-HBs
53. Anti-HBc of the IgM class (IgM anti-HBc) predominates during the
first six months after acute infection, whereas IgG anti-HBc is
the predominant class of anti-HBc beyond six months.
Therefore, patients with current or recent acute hepatitis B, have IgM
anti-HBc in their serum.
In patients who have recovered from hepatitis B, as well as those with
chronic HBV infection, anti-HBc is predominantly of the IgG class.
Infrequently, in 1–5% of patients with acute HBV infection,
levels of HBsAg are too low to be detected; in such cases, the presence
of IgM anti-HBc establishes the diagnosis of acute hepatitis B.
Anti-HBc IgM Anti-HBc IgG
54. Generally, in persons who have
recovered from hepatitis B, anti-HBs
and anti-HBc persist indefinitely.
55. The other readily detectable serologic marker of HBV infection,
is HBeAg.
HBeAg appears concomitantly with or shortly after HBsAg.
Its appearance coincides temporally with high levels of virus
replication and reflects the presence of circulating intact virions and
detectable HBV DNA (with the notable exception of patients with
precore mutations who cannot synthesize HBeAg)
In self-limited HBV infections, HBeAg becomes undetectable shortly
after peak elevations in aminotransferase activity, before the
disappearance of HBsAg, and anti-HBe then becomes detectable,
coinciding with a period of relatively lower infectivity
HBeAg.
56. During acute and early chronic HBV infection, HBV
DNA can be detected both in serum and in hepatocytes.
This replicative stage of HBV infection is the time of maximal
infectivity and liver injury;
HBeAg is a qualitative marker and HBV DNA a quantitative
marker of this replicative phase.
In the nonreplicative phase of chronic infection, when HBV DNA
is demonstrable in hepatocyte nuclei, it tends to be integrated into
the host genome.
In this phase, liver injury tends to fall down.
Most such patients would be characterized as inactive HBV
carriers.
HBV DNA
57. Occasionally, nonreplicative HBV infection converts
back to replicative infection.
Such spontaneous reactivations are accompanied by re-
expression of HBeAg and HBV DNA, and sometimes
of IgM anti-HBc, as well as by exacerbations of liver
injury.
58. HBs Ag (+) -- positive
Anti-HBs (-) - negative
HBe Ag (+) - positive
Anti- HBe (-) - negative
Anti-HBc(total) (+) - positive
Anti-HBcIgM (+) - positive
HBV DNA (+) - positive
HBs Ag (+) -- positive
Anti-HBs (-) - negative
HBe Ag (+) - positive
Anti- HBe (-) - negative
Anti-HBc(total) (+) - positive
Anti-HBcIgM (+) - positive
HBV DNA (+) - positive
Infectious Diseases, AIDS & Clinical Immunology Research Center
acute HBV Infection
59. Chronic HBV infection
HBs Ag (+) positive
Anti-HBs (-) negative
HBe Ag (+) positive
Anti- HBe (-) negative
Anti-HBc(total) (+) positive
Anti-HBcIgM (±) positive/negative
HBV DNA (+) positive
HBs Ag (+) positive
Anti-HBs (-) negative
HBe Ag (+) positive
Anti- HBe (-) negative
Anti-HBc(total) (+) positive
Anti-HBcIgM (±) positive/negative
HBV DNA (+) positive
HBe Ag (+) positiveHBe Ag (+) positive
60. HBs Ag (+) positive
Anti-HBs (-) negative
HBe Ag (-) negative
Anti- HBe (-) negative
Anti-HBc(total) (+) positive
Anti-HBcIgM (-) negative
HBV DNA (-) negative
HBs Ag (+) positive
Anti-HBs (-) negative
HBe Ag (-) negative
Anti- HBe (-) negative
Anti-HBc(total) (+) positive
Anti-HBcIgM (-) negative
HBV DNA (-) negative
Chronic HBV infection
Nonactive healthy carriers
61. After vaccinationAfter vaccination
HBs Ag (-) negative
Anti-HBs (+) positivepositive
HBe Ag (-) negative
Anti-HBe (-) negative
Anti-HBc(total) (-) negative
Anti-HBcIgM (-) negative
HBV DNA (-) negative
HBs Ag (-) negative
Anti-HBs (+) positivepositive
HBe Ag (-) negative
Anti-HBe (-) negative
Anti-HBc(total) (-) negative
Anti-HBcIgM (-) negative
HBV DNA (-) negative
67. • In hepatitis B, among previously healthy adults
who present with clinically apparent (visible)
acute hepatitis, recovery occurs in > 90%;
• Therefore, antiviral therapy is not likely to
improve the rate of recovery and is not required.
• In rare cases of severe acute hepatitis B,
treatment with a nucleoside analogues at oral
doses is used.
74. The goal of treatment of
chronic hepatitis B
1. Suppression of HBV DNA to undetectable level
2. Normalization ALT/AST
3. Improvement liver histology
4. Loss of HBeAg/ HBeAg
5. Reduction of clinical progression,
hepatic decompensation and death
Virus eradication is impossible from the organism
75. Drugs for HBV (FDA approved)
•INF
•Peg.INF
•Lamivudine
•Adefovir
•Telbivudine
•EntecavirInfectious Diseases, AIDS & Clinical Immunology Research Center, Tbilisi. Georgia
76. Indications for treatment of chronic
hepatitis B
This is based mainly
on the combination of three criteria:
• Serum HBV DNA levels.
• Serum ALT levels.
• Severity of liver disease.
77. Indications for treatment
Patients should be considered for treatment when they have
• HBV DNA levels above 2000 IU/ml,
• serum ALT levels above the upper limit of normal (ULN)
• severity of liver disease assessed by liver biopsy (or non-
invasive markers once validated in HBVinfected
patients) showing moderate to severe active
necroinflammation and/or at least moderate fibrosis using a
standardised scoring system: >A2;>F2.
78. Treatment of patients with cirrhosis
Clinical studies indicate that prolonged and adequate suppression
of HBV DNA can stabilize patients and prevent the progression to
decompensated liver disease.
Regression of fibrosis and even reversal of cirrhosis have been
reported in patients with prolonged suppression of viral
replication.
Treatment should be started as soon as possible
Antiviral treatment is indicated irrespective of HBV DNA level
80. Currently, there are two different treatment
strategies:
• Treatment of finite duration with PEG-IFN
• Long-term treatment with NAs.
81. Drugs Administrati
on
dosage duration
Peg.
Interferon
S/c 180 mkg
Once in a week
48 კვირა
Lamivudine Per os 100mg daily Lon term
Tenofovir Per os 300mg daily Lon term
ADefovir Per os 10mg daily Lon term
Entecavir Per os 0.5-1.0mg daily Lon term
telbivudine Per os 600mg daily Lon term
HBV drugs and treatment regimens
82. • Passive Immunization by Human
Hepatitis B immunoglobulin
• Active Immunization by Hepatitis B
Vaccine
Prophylaxis
83. Hepatitis B Vaccine
The first vaccine for active immunization, introduced in 1982.
The first vaccine was purified HBsAg derived from the plasma
of healthy HBsAg carriers.
In 1987, the plasma-derived vaccine was replaced by a
genetically engineered vaccine.
The latter vaccine consists of HBsAg particles that are
nonglycosylated but are otherwise indistinguishable from natural
HBsAg;
The first vaccine for active immunization, introduced in 1982.
The first vaccine was purified HBsAg derived from the plasma
of healthy HBsAg carriers.
In 1987, the plasma-derived vaccine was replaced by a
genetically engineered vaccine.
The latter vaccine consists of HBsAg particles that are
nonglycosylated but are otherwise indistinguishable from natural
HBsAg;
84. Hepatitis B Vaccine
Hepatitis B vaccine is Genetically Engineered
recombinant vaccine
Hepatitis B vaccine is Genetically Engineered
recombinant vaccine
The two available recombinant hepatitis B vaccines are
comparable, one containing 10 μg of HBsAg (Recombivax-HB)
and the other containing 20 μg of HBsAg (Engerix-B), and
recommended doses for each injection vary for the two
preparations.
Combinations of hepatitis B vaccine with other childhood
vaccines are available as well
The two available recombinant hepatitis B vaccines are
comparable, one containing 10 μg of HBsAg (Recombivax-HB)
and the other containing 20 μg of HBsAg (Engerix-B), and
recommended doses for each injection vary for the two
preparations.
Combinations of hepatitis B vaccine with other childhood
vaccines are available as well
85. For pre-exposure prophylaxis against hepatitis B
Hepatitis B Vaccine can be used for pre-exposure
and postexposure prophylaxis.
Three IM (deltoid, not gluteal) injections of hepatitis B
vaccine are recommended
at 0, 1, and 6 months
(other, optional schedules also exists)
Three IM (deltoid, not gluteal) injections of hepatitis B
vaccine are recommended
at 0, 1, and 6 months
(other, optional schedules also exists)
Vaccination SchedulesVaccination Schedules
86. • Newborns
• Children and adolescents not vaccinated at birth
• Anyone who has a sexually transmitted infection, including
HIV
• Health care workers, emergency workers and other people
who come into contact with blood
• Men who have sex with men
• People who have multiple sexual partners
• People with chronic liver disease
• People who inject illicit drugs
• Sexual partners of someone who has hepatitis B
• Travelers planning to go to an area of the world with a high
hepatitis B infection rate
The hepatitis B vaccine is recommended for:
87. Hepatitis B immunoglobulin (HBIG)
For persons experiencing a direct percutaneous inoculation or
transmucosal exposure to HBsAg-positive blood (e.g., accidental
needle stick, other mucosal penetration, or ingestion), a single IM
dose of HBIG, 0.06 mL/kg, administered as soon after
exposure as possible, is followed by a complete course of hepatitis
B vaccine to begin within the first week.
For persons experiencing a direct percutaneous inoculation or
transmucosal exposure to HBsAg-positive blood (e.g., accidental
needle stick, other mucosal penetration, or ingestion), a single IM
dose of HBIG, 0.06 mL/kg, administered as soon after
exposure as possible, is followed by a complete course of hepatitis
B vaccine to begin within the first week.
For post exposure prophylaxis with vaccine
For those exposed by sexual contact to a patient with acute hepatitis
B, a single IM dose of HBIG, 0.06 mL/kg, should be given within 14
days of exposure, to be followed by a complete course of hepatitis B
vaccine. When both HBIG and hepatitis B vaccine are recommended,
they may be given at the same time but at separate sites.
For those exposed by sexual contact to a patient with acute hepatitis
B, a single IM dose of HBIG, 0.06 mL/kg, should be given within 14
days of exposure, to be followed by a complete course of hepatitis B
vaccine. When both HBIG and hepatitis B vaccine are recommended,
they may be given at the same time but at separate sites.
90. All pregnant women should be screened for HBsAg
The prevention of HBV perinatal transmission, is based on
The combination of passive and active
immunisation with hepatitis B
immunoglobulin (HBIg) and HBV
vaccination
The prevention of HBV perinatal transmission, is based on
The combination of passive and active
immunisation with hepatitis B
immunoglobulin (HBIg) and HBV
vaccination
Prevention of Perinatal Hepatitis B Virus Transmission
If Pregnant women is HBsAg(+) positive
91. If NBV DNA concentration is high antiviral treatment
should be started with NA from the third trimester
and
Passive and active Immunization of newborn
If NBV DNA concentration is high antiviral treatment
should be started with NA from the third trimester
and
Passive and active Immunization of newborn
If NBV DNA concentration is low
only
Passive and active Immunization of newborn
If NBV DNA concentration is low
only
Passive and active Immunization of newborn
Official recommendations for PMTCT
HBsAg (+) positive cases
92. Official recommendations for PMTCT
HBsAg (+) positive
cases
Passive and active Immunization of newborn
A single dose of HBIG, 0.5 mL, should be administered IM
in the thigh immediately after birth in the delivery room
A single dose of HBIG, 0.5 mL, should be administered IM
in the thigh immediately after birth in the delivery room
followed by a complete course of three injections of
recombinant hepatitis B vaccine to be started within the first
12 hours of life.
followed by a complete course of three injections of
recombinant hepatitis B vaccine to be started within the first
12 hours of life.
93. Sexual contact. You may become infected if you have unprotected
sex with an infected partner whose blood, saliva, semen or vaginal
secretions enter your body.
Sharing of needles. HBV is easily transmitted through needles and
syringes contaminated with infected blood. Sharing intravenous (IV)
drug paraphernalia puts you at high risk of hepatitis B.
Accidental needle sticks. Hepatitis B is a concern for health care
workers and anyone else who comes in contact with human blood.
Mother to child.
Pregnant women infected with HBV can pass the virus to their babies
during childbirth. However, the newborn can be vaccinated to avoid
getting infected in almost all cases. Talk to your doctor about being
tested for hepatitis B if you are pregnant or want to become pregnant.
Common ways of HBV transmission
95. Hepatitis D
Is a Viral infection of the liver
caused by the hepatitis D virus.
Definition
96. RNA virus
Family- Unassigned
Genus - Deltavirus
HDV is considered to be a subviral
satellite because it can propagate
only in the presence of hepatitis B
virus.
97. Transmission of HDV can occur
either via simultaneous infection with
HBV (coinfection) or superimposed
on chronic hepatitis B or Hepatitis B
carrier state (superinfection)
Transmission of HDV can occur
either via simultaneous infection with
HBV (coinfection) or superimposed
on chronic hepatitis B or Hepatitis B
carrier state (superinfection)
98. Hepatitis Delta
In case of coinfection recovery rate
from
infection is about > 90 %
In case of coinfection recovery rate
from
infection is about > 90 %
In case of superinfection recovery rate
from
infection is about <10 %
In case of superinfection recovery rate
from
infection is about <10 %