3. 3
The Global Impact of HBV Disease
WHO and CDC fact sheets, available at www.who.int and www.cdc.gov
• Almost half of the world’s population lives in an area with high HBV
prevalence
World population
6 billion
2 billion with evidence of
HBV infection
300–400 million with
chronic HBV
25–40% die of
cirrhosis or
liver cancer
4. 4
Dr Samy Zaky
High Moderate
Low/Not
Detectable
blood semen urine
serum vaginal fluid feces
wound exudates saliva sweat
tears
breast milk
Concentration of Hepatitis B
Virus in Various Body Fluids
Hepatitis B is not spread through food or water or by casual contact.
5. 5
Dr Samy Zaky
5
· unsafe injection and blood transfusions;
· sexual contact.
· from child to child;
· from mother to baby (perinatal);
The primary routes of transmission
are through :
6. 6
Dr Samy Zaky
6
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
7. 7
Historical View of HBV Distribution
Chronic infection
prevalence
8% – High
2–7% – Intermediate
< 2% – Low
Predominant age at infection
All age: Early childhood
Perinatal and early childhood
Adult risk groups
Past infection
prevalence
40– 90%
16– 55%
4– 15%
CDC, 1991
• Many of the data relating to
the global distribution of HBV
are over 10 years old
• More recent data suggest that
this is an over-simplification
• There is an increasing trend
towards HBeAg-negative HBV
in many areas
• Global distribution of HBV is
being affected by population
movements from high
prevalence areas
lifetime risk
of infection
>60%
20%-60%
<20%
8. 8
• 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
9. 9
Immunization strategy to eliminate
transmission of hepatitis B virus (HBV)
• Prevention of perinatal HBV infection through
-routine screening of all pregnant women for HBsAg, and
immunoprophylaxis of infants born to HBsAg +ve women
or to women with unknown HBsAg status
• Universal vaccination of infants beginning at
birth
• Routine vaccination of previously
unvaccinated children and adolescents
• Vaccination of previously unvaccinated adults at
risk for HBV infection.
10. 10
Dr Samy Zaky
10
Prevention
I. General measures:
-Screening of blood for HBsAg , anti-HBc and ALT.
-Body fluid precautions.
-Not sharing utensils, such as tooth brushes and shaving razors.
-Health care workers education regarding care in contacting and
performing procedures on patients.
- An educational strategy targeted at the sexually promiscuous and
parenteral drug abusers.
II. Immunoprophylaxis:
(1) Passive immunization: Hepatitis B Immunoglobulin
HBIG: standardized to 100.000 IU of anti-HBs/ml.
(2) Active immunization :- recombinant HBsAg vaccine.
11. 11
Dr Samy Zaky
11
(1) Passive immunization
Hepatitis B Immunoglobulin -HBIG is effective, if given in
combination with hepatitis B vaccine, as
post exposure prophylaxis (within 48 hours of the incident):
An infant born to HBsAg-positive mother (perinatal exposure).
Exposure to HBsAg-positive blood (percutaneous or mucus membrane).
sexual exposure to an HBsAg-positive person.
Following liver transplantation: to protect patients from
severe recurrent HBV infection
Prevention
12. 12
(2) Active immunization
• 3 intramuscular (deltoid, not gluteal)
injections of hepatitis B vaccine
• are recommended at 0, 1, and 6
months.
• Pregnancy is not a contraindication to
vaccination.
NB: HBV Rapid immunization (days 0, 10, 21) 70%. A booster dose was given 1 year later 99-
100%
13. 13
Safety of Hepatitis B Vaccine:
• Hepatitis B vaccines have been shown to
be safe when given to infants, children,
adolescents, and adults..
• Pain at the injection site and temperature are the most frequently
reported side effects.
• A number of case-reports and case series have claimed a possible
association between hepatitis B vaccination and Guillain-Barre
Syndrome (GBS), multiple sclerosis, optic neuritis, rheumatoid arthritis,
type I diabetes, and autoimmune disease.
The majority of these reported adverse events have been in adults
receipt of the first dose of plasma-derived hepatitis B vaccine and no
published report has compared the frequency of these events with an
appropriate background rate for these diseases.
14. 14
Anti-HBs concentration is >10 mlU/ml.
• Maximum antibody response occurs
approximately 6 weeks after the last 1ry dose of
vaccine.
• Testing should be performed 1-2 months after
completion of the 1ry vaccination series, except for
infants born to HBs-Ag +ve mothers, in whom
testing should be performed at age 9-15 months.
• It is considered that non-responders remain
susceptible to infection with hepatitis B
virus.
15. 15
Dr Samy Zaky
Hepatitis B immunization
strategies include:
prevention of perinatal HBV
transmission;
routine infant vaccination;
catch-up vaccination of older age groups.
15
16. 16
HBsAg +ve pregnant Mother
Increased risk of transmission with high levels of viremia (> 8
log10 copies/mL or ~ 7.3 log10 IU/mL)[Burk 1994; Xu 2009; van Zonneveld 2003]
Treatment with lamivudine, telbivudine, or tenofovir may be
considered in the 3rd trimester in mothers with high viremia, with
careful discussion of the risks and benefits [EASL HBV]
Data on the role of elective Cesarean section in preventing mother-to-child
transmission of HBV are conflicting,[Zou 2010; Pan 2013; Hu 2013] and this
strategy is not currently recommended (B)[CDC 2006]
If therapy is administered only for prevention of mother-to-child
transmission, it may be discontinued within the first 3 months after
delivery[EASL HBV]
17. 17
Postpartum Follow-up
• Neonates of HBsAg+ive mothers should receive the HBV vaccine and
HB immunoglobuline within 12 hours of birth (Management
Guidelines)[Mast 2005]
• 2 additional doses of the hepatitis B pediatric vaccine series should be
given at 4-8 weeks of age, and 6 months of age.
• Follow-up HBsAg and HBsAb titers should be tested at 9-15 months of
age[Mast 2005]
• The mother should be followed postpartum for HBV flares due to
discontinuation of medicines or other causes[Tan 2008; Kim 2013a; Giles 2013]
• Current recommendations from the CDC support breast-feeding
immediately after birth in this population.[Mast 2005] Breast-feeding
should be paused in mothers with cracked or bleeding nipples
19. 19
Dr Samy Zaky
Hepatitis B immunization
strategies include:
prevention of perinatal HBV transmission;
routine infant vaccination;
catch-up vaccination of older age groups.
19
20. 20
Universal HB immunization for infants
Should translate into a markedly
reduced incidence of hepatitis B in
the next decade.
Centers for Disease Control and Prevention. Hepatitis B vaccination among high-risk adolescents and
adults -- San Diego, California, 1998-2001. MMWR. 2002;51:618-621.
The success of HB immunization in
reducing HBV infection and its related
consequences was documented
worldwide (Bonanni et al.,1999)
21. 21
• Vaccination and
• changes in risk-reduction behaviors among
populations at-risk
have led to declines in the number of persons
infected.
Centers for Disease Control and Prevention. Hepatitis B vaccination
among high-risk adolescents and adults -- San Diego, California,
1998-2001. MMWR. 2002;51:618-621.
22. 22
Prevention of HBV Infection: Impact of Vaccination
Lin HH, et al. J. Med. Virol. 2003; 69:471–4. Chang MH, et al. N. Engl. J. Med. 1997; 336:1855–9
Average annual incidence of HCC
in children aged 6–14 years
(per 100,000)
1986–1990
0.57
1981–1986
0.7
1990–1994
0.36
1980 1990 2000 2010 2020 2030 2040
HBsAg
carriage
Chronic
hepatitis
Cirrhosis
and HCC
HBV vaccination programme
launched in 1984
23. 23
Effectiveness of routine immunization of infants
against hepatitis in reducing the prevalence of
chronic HBV infection in children
Introduction of HepB vaccine - Management guidelines
25. 25
Impact of universal infant immunization for
HBV on frequency of acute HBV infection
in Egypt
In 1992, Egypt adopted a hepatitis B vaccine
schedule at two, four and sex months of age as a
part of the EPl (El Sawy and Mohamed., 2000).
26. 26
In a major referral center, Abbassia
Fever Hospital (AFH), Cairo, Egypt,
• Hammad et al. 2003, reported acute HBV
and HAV infections in 14.4% and 40.5%
respectively out of 284 patients admitted
with AVH. Hammad OM, Fakher OA, Shehata FA. Prevalence of
acute hepatitis A and B after HBV mass vaccination and spread of outdoor
eating in Cairo. Al-Azhar Med. J.April 2003; 32 (2):237-244.
• The overall infection by HBV was much lower
than that reported by Bassily et al (38.9%),
Zakaria et al (54.5%), and Gomatos et al
(36.3%) (before HBV vaccination program).
27. 27
The frequency of acute HBV infection in EFH
in year 2000 compared to year 1983
P
In 2000 (T=200)
In year 1983 (T=235)
%
N
%
N
S
31.5
63
43.4
102
Acute HBV
S
5.5
11
14.5
34
-Children
N.S
26
52
28.9
68
-Adult
Zakaria et al.,
28. 28
The frequency of acute HBV in different age
group in year 2000 compared to year 1983
P
2000
1983
N %
All (200)
N %
All (235)
AGE
0 -
23
7 (19.4)
36
< 5 y
0 -
35
9 (40.9)
22
6-8 y
NS
6 (27.3)
22
5 (41.7)
12
9-11 y
NS
10 (38.5)
26
28 (58.3)
48
12-20 y
NS
41 (56.2)
73
38 (52.1)
73
21-40 y
NS
6 (31.6)
19
11 (39.3)
28
41-60 y
NS
0 -
2
4 (25)
16
> 60 y
Zakaria et al.,
29. 29
Vaccine coverage rate in different age groups
Age N tested
200
Anti HBs + ve& Anti HBc -ve
N (%)
< 9 ys 58 22 37.9%
9-11 ys 22 3 13.6%
12-14 ys 13 1 7.7%
15-19 ys 13 0 0%
20-39 ys 73 1 1.4%
40-59 ys 19 3 15.8%
>60 ys 2 0 0%
Total 200 30 15 %
Zakaria et al.,
30. 30
In those under 9 years
•Anti HBs + ve & Anti HBc –ve= 37.9%.
Is it Vaccination coverage or decline in
protective level with time?
•If it represents “Persistence of
protective level=37.9%”
Why Acute HBV infection is 0%?
Dr Samy Zaky
31. 31
Persistence of protective level of HBs Ab (> 10
mIU/ml) 10 years after immunizations
P
<10
mIU/ml
>10
mIU/ml
Titer
y
<0.001
HS
40
(65.6%)
21
(34.4%)
GI>10 y
61
9 (21.4%)
33
(78.6%)
G II<10y
42
49
47.5%
54
52.5%
Total 103 0
20
40
60
80
100
120
total <10 years >10 years
+ve -ve
103 Egyptian individuals :
G I: 61 individuals who had received 3 doses of HBV vaccine more than 10 years ago.
GII: 42 individuals who had received 3 doses of HBV vaccine less than 10 years ago.
Tropical Med. Al-Azhar U. sdudy In Nahia, Giza Dr Samy Zaky
32. 32
Persistence of protective level of HBs Ab (> 10
mIU/ml) 10 years after immunizations in series of 65
persons from privet clinic
0%
20%
40%
60%
80%
100%
>1 year 5 > 10
years
- ve
+ ve
Dr Samy Zaky
35. Table(14): The mean level of HBs-Ab
titer in relation to sex
Groups
Mean ± SD. IU/L
t p
Total Male (72) Female (72)
204.3± 341.6 148.2±288.3 6.75 0.000**
GI
245.2± 332 280.1± 360.4 207.3±302.3 2.91 0.001**
GII 98.6±234 189.1±332.3 28.2±38.5 3.80 0.003**
GIII 198.5±36 152.4±338.8 242.9±379.8 2.25 0.034*
Zaky et al., Response to a booster dose, Cairo , 2010
36. 36
Does decline
in Hbs-Ab
levels mean
decline in
immunity
(protection)?
Do we
recommend
booster
dose/s to
ensure long
term
protection?
37. Table (15): Response to a booster
dose
HBV Abs No
Mean+SD of HBs Abs
level t p
Before booster
dose
2 wk After
booster dose
+ve 15 46.8+29.6 819.8+402.9 4.18 0.014
-ve 45 4.9+3.5 676.2+401.9 6.49 0.000
Zaky et al., Response to a booster dose, Cairo , 2010
38. 38
Boosters are not necessary 10 years after childhood
vaccination for hepatitis B (HBV), according to the results of an
Italian multicenter study reported in the Oct. 15 issue of The Lancet 2005.
• They evaluated 1,212 children previously
vaccinated as infants and 446 Italian Air Force
recruits vaccinated as adolescents
• Protective anti-HBs concentrations were
maintained in 779 children (64%) and in 398
recruits (89%).
• Antibody concentrations were less than 10 IU per L
in 433 children (36%) and in 48 recruits (11%).
• 2 weeks after the booster dose: An amnestic
response was present in 332 (97%) of 342 children
and 46 (96%) of 48.
Barclay et al., Lancet. 2005;366:1337-1338, 1379-1384
Dr Samy Zaky
39. 39
•“Strong immunological memory
persists more than 10 years after
immunisation of infants and
adolescents with a primary course of
vaccination,”
• the authors write. “Booster doses of
vaccine do not seem necessary to
ensure long term protection.” Lancet.
2005;366:1337-1338, 1379-1384
40. 40
Post-vaccination Testing :
Determine antibody response
• is not necessary after routine vaccination,
• but is recommended for persons at risk:
- to guide post exposure management
- to ensure protection for infants born to HBsAg+ve mothers;
- to ensure protection in immuno-compromised persons
- to provide sexual partners of HBsAg-positive persons who do
not respond to vaccination the opportunity to use other
means to protect themselves from HBV infection (e.g.,
condoms).
41. 41
Failure of antibody response
to hepatitis B vaccine: Causes
• Age > 50 years
• Underlying disease
• HIV positive
• Genetics (HLA-B8)
• Buttock injection
• Frozen vaccine
• Unknown
42. 42
Persons who did not respond
to a primary 3-dose vaccine series with anti-HBs
concentrations of >10 mIU/mL,
• 25%–50% responded to an additional
vaccine dose,
• 44%–100% responded to a 3-dose
revaccination series
43. 43
Non-responders, or hypo-responders
(that they respond poorly)
• Persons who do not respond to the 1ry vaccine
series should complete a 2nd three-dose vaccine
series or be evaluated to determine if they are
actually HBs-Ag+ve.
• Revaccinated persons should be retested at the
completion of the 2nd vaccine series.
New vaccines will contain pre-S1 and pre-S2
domains and may be effective in those failing to
respond to conventional vaccination.
45. 45
Dr Samy Zaky
Hepatitis B immunization
strategies include:
prevention of perinatal HBV transmission;
routine infant vaccination;
catch-up vaccination of older age
groups.
45
46. 46
Persons at High Risk for Hepatitis B Virus Infection
Who Should Receive Hepatitis B Vaccine
- Hemodialysis patients
- Patients who receive clotting-factor concentrates
Medical
indications
- Healthcare workers - Public safety workers
- Persons in training in schools of medicine, dentistry,
nursing, laboratory technology, and other allied health professionals
Occupation
al
indications
- more than 1 sex partner - Homosexual men
- acquired sexually transmitted disease
- All clients in sexually- transmitted disease clinics
- Injection-drug users
Behavioral
indications
- Household contacts and sex partners
- staff of institutions for the developmentally disabled
- Inmates of correctional facilities
- International travelers to high or intermediate prevalence
Other
indications
47. 47
In areas of low HBV endemicity
A strategy of vaccinating persons in high-risk
groups has not been effective.
• The incidence of new hepatitis B cases continued
to increase.
• Fewer than 10% of all targeted persons in high-
risk groups have actually been vaccinated.
• ? 30% of persons with sporadic acute hepatitis B
do not fall into any high-risk-group category.
So universal hepatitis B vaccination in childhood
has been recommended
49. 49
Groups Requiring
Different Vaccination Doses or Schedules
• immunocompromised persons e.g.,
- HIV-infected persons,
- hematopoietic stem-cell transplant recipients,
and
- patients undergoing chemotherapy
Modified dosing regimens, including
-doubling the standard antigen dose or
-administering additional doses,
might increase response rates
50. 50
Hemodialysis and immunocomromized
patients
• 2 ml on a 4 dose schedule at 0, 1, 2,6 months.
MMWR December 8, 2006
the seroprotection rate among adult predialysis patients with s.creatinine <4.0
mg/dL was 86%, compared with 37% among patients with s.creatinine >4.0
mg/dL, 88% of whom were dialysis patients
51. 51
Chronic HCV Infection
• HBV vaccine is recommended as the primary
means to prevent HBV super-infection and its
associated increase in morbidity and
mortality in HCV-infected subjects.
• A poor response rate to HBV vaccination was
observed in HCV infected subjects (53%),
while a high response rate was observed in
healthy or spontaneously HCV-resolved individuals
(94%).
Moorman et al. 2011
52. 52
Response to HBV vaccine in HCV
patients Vs control G
The studied
groups
Positive HBsAb
titer >10 mIU/ml
(responders)
Negative HBsAb
titer < 10
mIU/ml (non
responders)
P-value
G I HCV +ve
(No. = 100)
58 (58%) 42(42%)
P < 0.05
Significant
Group II
(No.=100) 89 (89%) 11 (11%)
At El Rekabia, Damietta, number of patients with positive HBsAb titer, one month after the 3 doses of
20 µg HBV recombinant vaccine at 0, 1, 6 months interval.
At El Rekabia, Damietta
53. 53
Additional vaccine dose,
Non
responders*
Positive HBsAb
titer >10 mIU/ml
(responders)
Negative HBsAb titer
< 10 mIU/ml
(non responders)
P-value
G Ia (booster dose
40 µg/ml)
(No. =21)
17 (81%) 4 (19%)
P < 0.05
Significant
G Ib (booster dose
20 µg/ml)
(No. = 21) 9 (43%) 12(57%)
G II non
responders
(booster dose 20
µg/ml)
(No. = 11)
10(90.9%) 1(9.1%)
P < 0.01
Significant
*Persons who do not have protective levels of anti-
HBs 1–2 months after primary series of HB vaccine
At El Rekabia, Damietta
54. 54
An accelerated vaccination protocol (0-
7-21 days)
• According to the anti-HBs seroprotection rate,
HCV-infected patients developed protective anti-
HBs titres (>10 IU/l)
in 77 % and 82 % of cases one month after
the accelerated and the standard vaccination
scheme-at month 2 and 7, respectively.
• increased to 84 % when initial HCV-infected
nonresponders where given a booster dose
55. 55
Patients at Risk for
Hepatitis B Virus Reactivation
• Reactivation of HBV occurs in 20-50% of infected
patients who undergo immunosuppressive or
cancer chemotherapy and can result in liver
failure or death [Lok 2009].
• screening for hepatitis B prior to initiating
immunosuppressive therapies
• HBsAg or anti-HBc +ve with detectable HBV DNA should
receive prophylactic antiviral therapy from the onset of
immunosuppressive therapy until 12 months after its
completion
• ? isolated anti-HBc ? monitored /1-3 months and antiviral
therapy should be initiated in the event of HBV reactivation,
before ALT is elevated
56. 56
Liver Transplantation Recipients
• Before transplant: HBV viremic patients have a
higher rate of recurrence posttransplantation.
• Antiviral therapy reduce serum HBV DNA to low or
undetectable levels may delay or even prevent the need
for transplantation
• Posttransplantation prophylaxis of HB recurrence is
– Lifelong HB Ig + an oral antiviral agent (A)[EASL HBV]
- Tenofovir and entecavir should be considered, due to
their potency and lower rates of resistance (Management
Guidelines)[EASL HBV].
• The same to prevent HB reactivation after anti-HBc+ive liver
donation
58. 58
Infection with hepatitis B virus still represents an encountered public
health burden in Egypt.
HBV super-infection is associated with increase in morbidity and
mortality in HCV-infected subjects.
The protective efficacy of HB vaccine was clearly demonstrated.
The underutilization of vaccines is attributable to :
- limited appreciation of the importance of vaccine-preventable
diseases.
-Poor infrastructure for delivery of the vaccines.
-Issues regarding payment.
-age-based recommendations
Dr Samy Zaky
At A Glance
59. 59
A comprehensive strategy to eliminate acute
HBV transmission in Egypt can be attained by :
programs to increase awareness about:
- the hazards of HBV infection
- important of reduction in risk- behaviors
- the importance of HBV vaccination.
expanding the vaccination program to include routine HBV
vaccination in the age group between 12 & 40 years.
Dr Samy Zaky
At A Glance
60. 60
• Hemodialysis and immunocomromized patients
2 ml on a 4 dose schedule at 0, 1, 2,6 months.
• HBV viremic patients have a higher rate of
recurrence posttransplantation (HB Ig + an oral
antiviral agent)
• screening for hepatitis B
- Pregnant women
- prior to initiating immunosuppressive therapies.
At A Glance
62. 62
The underutilization of vaccines is
attributable to several factors:
• A limited appreciation of the importance of
vaccine-preventable diseases.
• Uncertainties about the safety and efficacy
of the vaccines.
• Risk-based rather than age-based
recommendations (ie, different target
groups for different vaccines).
• Poor infrastructure for delivery of the
vaccines.
• Issues regarding payment.
According to the National Vaccine Advisory Committee
64. 64
Active immunization of HBV Infection
• Hepatitis B vaccine
– Available since 1981
– Vaccination programmes adopted in >150 countries
worldwide
– Inactivated or recombinant HBsAg
– Routine vaccination of infants and previously
unvaccinated children (by age 11)
– Catch-up vaccination of high-risk groups of all ages
– Screening pregnant women and rapid vaccination of
infants born to infected women (HBIg and vaccine)
WHO-CSR, HBV Report 2002, available at www.who.int/emc-documents (12/10/2003)
Prevention
65. 65
HCV
• HBV vaccine is recommended as the primary
means to prevent HBV super-infection and its
associated increase in morbidity and mortality in
HCV-infected subjects.
66. 66
• However, vaccine response (seroconversion with a
hepatitis B surface antibody titer >10 IU/L) in this
setting is often blunted, with poor response rates
to a standard course of HBV vaccinations in
chronically HCV-infected individuals when
compared to the healthy populations (40∼60%
versus 90∼95%); this is especially noted in the
setting of advanced fibrosis and liver cirrhosis.
67. 67
Postexposure Prophylaxis
• The major determinant of the effectiveness of PEP
is early administration of the initial dose of
vaccine.
