Vaccinatio and post imms serology teting

1. Hepatitis and travel
Dr Peter Noone,
HSE Dublin NE Area

2. Travel risk/100,000 travellers per month
to a developing country
Löscher T, Keystone JS,Steffen R, Vaccination of travellers against hepatitis A & B, J of Travel Medicine 1999; 6:107-114 . Incidence of health problems during
a month in a developing country.

3. Major and minor killers: global impact viewed on a
‘Richter’ (logarithmic) scale
7
Tobacco
HIV Infant/child ARI & diarrhoeal dis
Malaria
HBV + HCV 6 Road accidents
Measles Non-HIV tuberculosis
RSV, Rota virus
Influenza
Dengue 5
10,000-fold
Viruses Hospital infection difference in
H Papilloma v
4
Suicide impact
West Nile virus
3
SARS
Ebola
Polio
2
Hanta virus
vCJD
1
Log 10 Weiss & McMichael, 2004

4. Impact and incidence of vaccine-preventable diseases in travellers to
developing countries. CFR = case-fatality rate.

5. Type of Traveller
• The Business Traveller,
• The Backpacker,
• The Package Tourist,
• The Overseas aid worker/missionary.
• The HCW

6. Viral Hepatitis - Overview
Type of Hepatitis
A B C D E
Source of faeces blood/ blood/ blood/ faeces
virus blood-derived blood-derived blood-derived
body fluids body fluids body fluids
Route of percutaneous percutaneous percutaneous
transmission faecal-oral permucosal permucosal permucosal faecal-oral
Chronic no yes yes yes no
infection
Prevention pre/post- pre/post- blood donor pre/post- Ensure
exposure exposure screening; exposure safe
immunisation immunisation risk behaviour immunisation;
drinking
modification risk behaviour
modification water

7. These naming conventions can lead to confusion later, e.g.,
Viral hepatitis is caused by at least 6 different viruses
E n t e r ic a lly
“ In f e c t io u s ” A Et r a n s m i t t e d
V ir a l F, G ,
NANB ? O the r *
h e p a t it i
s
P a r e n t e r a lly
“ S e rum” B Ct r a n s m i t t e d
D
* 10-20% of cases of presumed viral hepatitis are still not accounted for

9. Hepatitis A
• Epidemic jaundice described by
Hippocrates
• Differentiated from hepatitis B in
1940s
• Serologic tests developed in 1970s
• Most frequently reported type of
hepatitis in the US

10. Hepatitis A Virus
• Picornavirus (RNA)
• Humans are only natural host
• Stable at low pH
• Inactivated by high temperature,
formalin, chlorine

11. G e o g r a p h ic D is t r ib u t io n o f
H A V In f e c t io n
Anti-HAV Prevalence
High
Intermediate
Low
Very Low

12. Basic Water Supply

13. Hepatitis A—United States, 1966-2002
70000
60000 Vaccine
50000 Licensed
Cases
40000
30000
20000
10000
0
1966 1970 1974 1978 1982 1986 1990 1994 1998 2002

14. Hep A reports UK
Laboratory reports of hepatitis A, England, Wales, and Northern Ireland: 1998 – 2007

15. Hep A in Ireland
Number of cases 2009: 52,
Crude notification rate: 1.2/100,000
No. of cases 2008: 42,

16. Hepatitis A Epidemiology
• Reservoir Human, Endemic
• Transmission Faeco-oral
• Temporal pattern None
• Communicability 2/52 before to 1/52
after onset

17. Declining Hepatitis A
Rates – The Bad News
100
1980
80 1990
Proportion Of
Americans 60
Susceptible
To Hepatitis A 40
(%)
20
0
20s 30s 40s 50s 60s 70s
Age (Years)
Data from NHANES II and III.

18. Consequences Of Adult
Hepatitis A And B Infections
HepA HepB
Symptoms of overt hepatitis 73%-90% 41%
Hospitalization 10%-26% 16%-19%
Acute liver failure 2-15 per 1000 7.3 per 1000
Liver transplant 1-3 per 1000 1.7 per 1000
Post-transplant survival 7-14 years 7-14 years
Case fatality rate (acute illness) 1-9 per 1000 4 per 1000
Probability of chronic infection 0% 5%-8%
Berge et al. Hepatology. 2000;31:469.
Fendrick et al. Arch Pediatr Adolesc Med. 1999;153:126.
Margolis et al. JAMA. 1995;274:120.

19. Hepatitis A Incidence* by Age Group
20
18
16
14
12
Rate
10
8
6
4
2
0
<5 5-14 15-24 25-39 40+
Age group (yrs)
*rate per 100,000 population. 1997 data.

20. Age-specific Mortality Due to Hepatitis A
A g e g r o u pC a s e - F a t a l i t y
( ye a r s ) ( p e r 10 0 0 )
<5 3.0
5-14 1.6
15-29 1.6
30-49 3.8
>49 17.5
Total 4.1
Source: Viral Hepatitis Surveillance Program CDC Atlanta, 1983-1989

21. Hepatitis A Pathogenesis
• Entry into mouth, incub 15-50 days,
• Viral replication in the liver
• Virus present in blood and faeces
10-12 days after infection
• Virus excretion may continue for up
to 3/52 after onset of symptoms

22. Hepatitis A Clinical Features
• Incubation period 28 days (range
15-50 days)
• Illness not specific for hepatitis A
• Likelihood of symptomatic illness
directly related to age
• Children generally asymptomatic,
adults symptomatic

23. Hepatitis A: Significant Public
Health Issue
• On average, infected adults lose 27 days of work1
• Between 11% and 22% of patients are hospitalized1
• Annual costs of hepatitis A estimated at $488.8
million2
• On average, in the United States, 1 person dies
every 4 days as a result of acute liver failure from
hepatitis A1
1. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 1999;48(RR-12):1.
2. Berge et al. Hepatology. 2000;31:469.

24. C o n c e n t r a t io n o f H e p a t it is
A V ir u s
in V a r io u s B o d y F lu id s
Faeces
B ody
F lu id
Serum
Saliva
Urine
100 102 104 106 108 1010
In f e c t io u s D o s e s
Source: Viral Hepatitis and Liver Disease m l
p e r 1984;9-22
J Infect Dis 1989;160:887-890

25. epatitis A—United States, 1990-200
Risk Factors
Sexual/household
14% Int'l travel
5%
MSM
Unknown 10%
45%
IDU
6%
Daycare
2%
Outbreak
Other 4%
8%
Source: NNDSS/VHSP DC contact
6%

26. Hepatitis A Vaccines
• Inactivated whole virus
• Avaxim (Sanofi Pasteur MSD)
• HAVRIX (GlaxoSmithKline)
• Paediatric and adult formulations
• Licensed for persons >2 years
• Epaxal (MASTA)

27. Hepatitis A Vaccine Immunogenicity
Adults
• 95% seropositive after one dose
• 100% seropositive after two doses
Children (>2 years) and Adolescents
• >97% seropositive after one
• 100% seropositive after 2 doses
Van Damme P, Banatvala J, Fay O et al. Hepatitis A booster vaccination: is there a need? Lancet 2003: 362:
1065-71

28. Twinrix
• Combination hepatitis B (adult
dose) and hepatitis A vaccine
(paediatric dose)
• Schedule: 0, 1, 6-12 months
• Approved for persons >16 years,
(TWINRIX PAEDIATRIC ® (Glaxo SmithKline)
this can be used from 1 year up to and including 15 years of age.
• Not recommended for post
exposure vaccination.

29. Hepatitis A Vaccines
Formulation HAVRIX VAQTA AVAXIM
Paeds
Age 1-16 yrs 2-17 yrs <16yrs
Dose 0.5ml 0.5ml Not
recommended
Adult
Age >16 yrs >18yrs >16yrs
Dose 1.0ml 1.0ml 0.5ml

30. H e p a t it is A V a c c in e
E f f ic a c y S t u d ie s
Vaccine
Site/Age Efficacy
Vaccine Group N (95% CI)
HAVRIX® Thailand 38,157 94%
(SKB) 1-16 yrs (79%-99%)
2 doses
360 EL.U.
VAQTA ™ New York 1,037 100%
(Merck) 2-16 yrs (85%-100%)
1 dose
25 units
JAMA 1994;271:1363-4
N Engl J Med 1992;327:453-7

31. Hepatitis A Vaccines
Adult
• 1 dose
• Booster dose 6-18/12 after first
dose
Children and Adolescent
• 1 dose
• Booster dose 6-18/12 after first
dose
Hepatitis A booster vaccination: is there a need?. The Lancet, Volume 362, Issue 9389, Pages 1065-1071 P. Van Damme, J.
Banatvala, O. Fay, S. Iwarson, B. McMahon, K. Van Herck, D. Shouval, P. Bonanni, B. Connor, G. Cooksley

32. Hepatitis A
Vaccine Recommendations
• International travellers
• MSM,
• IVDU’s
• Persons who have clotting-factor
disorders
• Persons with occupational risk
• Persons with chronic liver disease,
including HCV

33. Hepatitis A Serologic Testing
Prevaccination
• Not indicated for children
• May be considered for some
adults and older adolescents
Postvaccination
• Not indicated

34. Hepatitis A
Vaccine Adverse Reactions
• Pain at injection site
• Systemic reactions not common
• No serious adverse reactions
reported

35. Hepatitis A Vaccine
Contraindications and Precautions
• Severe allergic reaction to a
vaccine component or following a
prior dose
• Moderate or severe acute illness

36. Hepatitis A
Vaccine Recommendations
• Travellers to high- or
intermediate- risk countries
• Protected by 4 weeks after dose
• Give concurrent IG for travel in
<4 weeks or travellers who are
immunocomprimised.

37. HBV

38. Hepatitis B
• The first recognition of public health importance of HBV infection
by direct inoculation of blood or blood products was first
documented by Lurman in Bremen, Germany, in 1883, during a
smallpox immunisation campaign. Thousands received vaccine
that had been prepared from human lymph.
• Of 1,289 shipyard workers who received this vaccine, 191 (15%)
developed jaundice several weeks to 8 months later; jaundice did
not occur among unvaccinated workers.
• Lurman, A. 1855. Eine icterus Epidemic. Berlin Klin.
Wochenschr. 22:20–23.

39. Hepatitis B
• Epidemic jaundice described by
Hippocrates in 5th century BCE
• Jaundice reported among recipients
of human serum and yellow fever
vaccines in 1930s and 1940s
• Australian antigen described in 1965
• Serologic tests developed in 1970s

40. Hepatitis B Virus
• Hepadnaviridae family (DNA)
• Numerous antigenic components
• Humans are only known host
• May retain infectivity for at least 1
month at room temperature

41. Hepatitis B Virus Infection
•40% of world’s population had contact with
or are carriers of HBV, 2 billion infected,
•>350 million chronic carriers worldwide
•Established cause of chronic hepatitis and
cirrhosis, 600,000 death in 2002.
•Human carcinogen—cause of up to 80% of
hepatocellular carcinomas.
Banatvala J et al “Lifelong protection against Hepatitis B; role of vaccine immunogenicity in immune
memory”,Vaccine 2001;19:877-885.
Goldstein ST, Zhou F, Hadler SC, Bell BP, Mast EE, Margolis HS. A mathematical model to estimate global
hepatitis B disease burden and vaccination impact. Int J Epidemiol 2005;34(6):1329.

42. HBV infection (2)
•In Europe & US chronic infection with HBV, affects about 1-3% of
the population,
• In Africa and Asia, rate may be >10% and will remain so for many
decades,
• Immigrants from the high incidence areas will carry the same risk
of HBV carriage as the population in their country of birth,
• ~ 1/3 of HCV and a variable number of HIV patients have occult
HBV infection,
•Before widespread vacc of HCWs, >12,000 HCWs per year were
infected in U.S. in the pre-vaccine era.
Guidelines for prevention of transmission of human immunodeficiency virus and hepatitis B virus to health-care and public-safety workers. MMWR
Morb Mortal Wkly Rep 1989;38(suppl 6):1–37.

43. Hepatitis B Virion, Dane particle and
HBsAG
From Murray et. al., Medical Microbiology 5th
edition, 2005, Chapter 66, published by Mosby
Philadelphia,,

44. Hepatitis B Clinical Features
• Incubation period 6 weeks to 6
months (average 120 days)
• Non-specific prodrome of fever,
malaise, headache, myalgia
• Illness not specific for hepatitis B
• At least 50% of infections
asymptomatic

45. Hepatitis B Epidemiology
• Reservoir Human. Endemic
• Transmission Bloodborne
Subclinical cases
transmit
• Communicability 1-2 months before
and after onset of
symptoms
Chronic carriers

46. HBV 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.

47. Clinical outcomes of Hepatitis B
infections
Figure 66-11. Clinical outcomes of acute hepatitis B infection. (Redrawn from White DO, Fenner F:
Medical virology, ed 3, New York, 1986, Academic Press
From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 62, published by Mosby Philadelphia,,

48. Risk of Chronic HBV Carriage
by Age of Infection
100
90
80
Carrier risk (%)
70
60
50
40
30
20
10
0
Birth 1-6 mo 7-12 mo 1-4 yrs 5+ yrs
Age of infection

49. M Ramsay, HPA UK

50. Global Patterns of
Chronic HBV Infection
• 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

51. Geographic Distribution of
Chronic HBV Infection
HBsAg Prevalence
≥8% - High
2-7% - Intermediate
<2% - Low

52. Worldwide distribution patterns of HBV genotypes and sub-genotypes.
Regions with high, intermediate and low endemicity are shown by grey, light grey and white shades respectively.
Datta Virology Journal 2008 5:156 doi:10.1186/1743-422X-5-156

53. Hepatitis B—United States, 1978-2002
Decline among
homosexual men
30000 Decline among
IV drug users
25000
20000
Cases
15000
10000
Hepatitis B vaccine licensed
5000
0
1978 1982 1986 1990 1994 1998 2002

54. Figure 1: Notifications of Hepatitis B (acute and chronic) 2004-2009
Epidemiology of Hepatitis B in Ireland

55. Risk of Traveller Exposure HBV

56. Bloodborne Pathogen Training
Risk of Bloodborne Virus Transmission after
Occupational Percutaneous Exposure
Source Risk Risk
HBV
HBeAg + 22.0-30.0%
22.0-30.0%
HBeAg - 1.0-6.0%
1.0-6.0%
1.8%
HCV 1.8%
0.3%
HIV 0.3%

58. Risk Factors for Hepatitis B
Other
23% Multiple sex
partners
24%
Household
3%
Sex contact
13%
MSM IDU
17% 20%
CDC Sentinel Sites. 2001 data.

59. C o n c e n t r a t io n o f
H e p a t it is B V ir u s
in V a r io u s B o d y F lu id s
Low/Not
High Moderate Detectable
blood semen urine
serum vaginal fluid feces
wound exudates saliva sweat
tears
Breast milk

60. Acute Hepatitis B Virus Infection with Recovery
T y p ic a l S e r o lo g ic C o u r s e
Symptoms
HBeAg anti-HBe
Total anti-HBc
T it e r
HBsAg IgM anti-HBc anti-HBs
0 4 8 12 16 20 24 28 32 36 52 100
We e k s a fte r
E xpos ure

61. Progression to Chronic Hepatitis B Virus Infection
T y p ic a l S e r o lo g ic C o u r s e
Acute Chronic
(6 months) (Years)
HBeAg anti-HBe
HBsAg
Total anti-HBc
T it e r
IgM anti-HBc
0 4 8 12 16 20 24 28 32 36 52 Years
We e k s a fte r
E xpos ure

62. Pathogenesis of Hepatitis
HBV - Natural History
B
Modulating Factors in Hepatitis B
HOST
VIRUS
Gender
Genotype
Age
Molecular Variants
Immune Response
ENVIRONMENT
Alcohol
HCV, HDV, HIV
Carcinogens

64. Hepatitis B Vaccine
1965 Discovery of Australian antigen
1973 Successful HBV infection of chimpanzees
1981 License of plasma-derived vaccine
1986 License of recombinant vaccine
1991 Universal infant vaccination (U.S.)
1996 Universal adolescent vaccination (U.S).

65. Hepatitis B Vaccine
• Composition Recombinant HBsAg
• Efficacy 95% (Range, 80%-100%)
• Duration of
Immunity >15 years
• Schedule 3 Doses
• Booster doses not routinely recommended
Are booster immunisations needed for lifelong hepatitis B immunity? European Consensus Group on Hepatitis
B Immunity.Lancet 2000 Feb 12;355(9203):561-5.

66. Hepatitis B Vaccine
Formulations
• HB-Vax II (Sanofi)
- 5.0 mcg/0.5 mL (paediatric)
- 10 mcg/1 mL (adult)
- 40 mcg/1 mL (dialysis)
• Engerix-B (GSK)
- 10 mcg/0.5 mL (paediatric)
- 20 mcg/1 mL (adult)

67. Protection* by Age Group and Dose
Dose Infants** Teens and Adults***
1 16%-40% 20%-30%
2 80%-95% 75%-80%
3 98%-100% 90%-95%
* Anti-HBs antibody titre of 10 mIU/mL or higher
** Preterm infants less than 2 kg have been shown to
respond to vaccination less often
*** Factors that may lower vaccine response rates are age
>40 years, male gender, smoking, obesity, and immune
deficiency, HLA type.

68. Recommended Dose of
Hepatitis B Vaccine
HB-Vax II Engerix-B
Dose (mcg) Dose (mcg)
Infants and children 0.5 mL (5) 0.5 mL (10)
<11 years of age
Adolescents 11-19 0.5 mL (5) 0.5 mL (10)
years
Adults >18 years 1.0 mL (10) 1.0 mL (20)

69. Hepatitis B Vaccine
Long-term Efficacy
• Immunologic memory
established following vaccination
• Exposure to HBV results in
anamnestic anti-HBs response
• Chronic infection rarely
documented among vaccine
responders
Are booster immunisations needed for lifelong hepatitis B immunity?
European Consensus Group on Hepatitis B Immunity.Lancet 2000 Feb
12;355(9203):561-5.

70. Management of Non-response to
Hepatitis B Vaccine
• Complete a second series of
three doses or
• Give a booster dose and recheck,
• Should be given on the usual
schedule of 0, 1 and 6 months
• Retest 1-2 months after
completing the second series

71. Persistent Non-response to
Hepatitis B Vaccine
• <5% of vaccinees do not develop
anti-HBs after 6 valid doses
• May be non-responder or "hypo-
responder"
• Check HBsAg status
• If exposed, treat as non-
responder with PEP (HBIG)

72. Non-response
• Age (>40yrs),
• Gender,
• Obesity (BMI>30),
• Smokers,
• HLA_DR3+ or -DR7+ halotypes,
• Site and route of injection.
Zuckerman J et al, “Evaluation of a New Hepatitis B Triple-Antigen Vaccine in Inadequate Responders to Current Vaccine,Hepatology 2001; 34(4)798-802

73. Twinrix
• Combination hepatitis B and
hepatitis A vaccine (paediatric dose)
(720 ELISA u’s HAV, 20mcgs recomb HBsAG in 1ml)
• Schedule: 0, 1, 6-12 months
• Approved for persons >16 years
• Twinrix paediatric (360 ELISa u’s HAV, 10mcgs
recomb HBsAg protein in 0.5ml)
• Not recommended for post exposure vaccination

74. Northdruft H,Zuckerman J, “Accelerated Vaccination Schedules Provide Protection Against Hepatitis A & B in Last Minute Travellers” Vaccine 2002;
20:1157-1162. Medicine

75. Evaluation of Hepatitis B Immune-Response in Elderly, Obese or Medically
Compromised Subjects after Vaccination with HAB Combination or
Monovalent Hepatitis B Vaccines
Chlibek, R, von Sonnenburg F, Van Damme P, et al
• response to HBV vacc in elderly, overweight or with medical
conditions. Study of 4-yr persistence of anti-HBs and
immunological memory to HBV in subjects ≥41 years with these
conditions who had received either a combined HAB vaccine or
one of two monovalent HBV vaccines.
• 596 subjects ≥41-yrs randomised into 3 groups receive Twinrix™,
at 0, 1 and 6/12, or one of two different monovalent HBV vaccines
(Engerix-B™, or HBVAXPRO™) given at 0, 1 and 6/12 together
with a HAV vaccine (at 0 and 6 months).
• % with anti-HBs levels (≥10 mIU/ml) 4 yrs after vacc highest in
HAB group, lower in Engerix-B and lowest in HBVAXPRO™. 1/12
after challenge HBV dose, the % elderly who mounted anti-HBs
antibody ≥10mIU/ml highest in HAB (91.1%), lower in Engerix-B™
(89.1%) and lowest in HBVAXPRO™ group (76.4%).
• In elderly, obese or ongoing medical conditions, combined HAB
vaccine consistently greater anti-HBs than the other vaccines.
• P2-15, NECTM 20010, Hamburg,

76. Hepatitis B Vaccine
Adverse Reactions
Infants and
Twinrix Adults Children
Pain at injection site 13%-29% 3%-9%
Mild systemic complaints 11%-17% 0%-20%
(fatigue, headache)
Temperature >99.9°F (37.7°C) 1% 0.4%-6%
rare rare
Severe systemic reactions

77. Hepatitis B Vaccine
Contraindications and Precautions
• Severe allergic reaction to a vaccine component or
following a prior dose,
• Moderate or severe acute illness,
• Hernán MA, Jick DS, Olek MJ, and Jick H, Recombinant
hepatitis B vaccine and the risk of multiple sclerosis A
prospective study, NEUROLOGY 2004;63:838-842
• Numerous studies have evaluated a possible relationship between
hepatitis B vaccination and multiple sclerosis. The weight of the
available scientific evidence does not support the suggestion that
hepatitis B vaccine causes or worsens MS.
• http://www.cdc.gov/vaccinesafety/Vaccines/multiplesclerosis_and_h
ep_b.html

78. HBV variants with
mutations
•Vaccine failures with HBV mutations in small surface protein (S) gene
(S mutants) in infants who got HBV vaccine or HBIG appropriately and
who have anti-HBs in protective range.
•HBV variants resistant to neutralizing anti-HBs, reduce effectiveness
of HBV imms programs or accelerate formation of HBV variants?.
•But S mutants implicated in perinatally exposed infant vaccine
failures usually of maternal origin and not induced by vaccination.
•Mothers of infants who responded to vaccine as likely to have sAg
variants as mums of infants who did not respond, suggests
infections among vaccinated children with S mutants represent
immunoprophylaxis failures and infection with maternal viral
variants rather than breakthrough infections among successfully
vaccinated infants.
•Vaccinated chimps are protected from challenge with the most
common surface antigen variant .
• Commercial assays employing polyclonal anti-HBs detect S mutants,
making ongoing surveillance for S mutants possible.

79. Pre-core mutants
Disappearance of HBeAg and rise of anti-HBe is associated with decline in viremia titer
and replacement of wild-type HBV by the core promoter mutants and/or precore mutants.
However, the core promoter mutants become prevalent even before the rise of anti-HBe.

80. HBV in Immune-suppressed Subjects
Background*
• HBV reactivation occurs in up to 50% of HBsAg+ patients
and in ~4% anti-HBc+ patients with occult HBV receiving
chemotherapy,
• ~10% will become icteric and mortality is increased by at
least 5% and may reach 70% after a flare,
• Clinical reactivation frequently occurs following withdrawal
of chemotherapy and emergence of immune recovery
(Median onset 16w; Range:4-36w)
• There is currently no reliable way to predict severity of HBV
reactivation during and after chemotherapy,
• However, risk seems to correlate with degree of viral load,
use of corticosteroids , degree of immunosuppression, male
sex.
• *Liang R et al. J Clin Oncology 1999;17:394, Yeo W et al. British J
Cancer 2004;90:1306

81. Reactivation of HBV in
Immunosuppressed Patients
• A large number of patients undergoing immuno
or chemotherapy are still not screened for HBV
markers prior to initiation of treatment,
• As a result, patients with overt (and also occult)
HBV infection are exposed to an unnecessary
and usually preventable risk,
• Partners of such patients and their treating
HCWs maybe exposed to HBV upon reactivation

82. Patients at Risk for HBV Reactivation
• Any patients with overt or occult HBV receiving systemic
chemo- radio- or immunotherapy,
• Lymphoma, Leukaemia and hematologic malignancies,
• Bone marrow (BMT,) peripheral lymphocyte and stem cell
transplantation for any cause (incl. Autologous BMT),
• Cancer (i.e. breast cancer, gastric cancer, HCC post TACE in
HBsAg+ or anti-HBc+ patients),
• Liver, renal, heart, lung transplantation,
• Systemic diseases (i.e. HIV infection, Crohn’s disease, RA;
SLE etc.),
• Premature discontinuation of anti-viral therapy in immune
suppressed patients

83. Reactivation of HBV may occur in
two defined forms of persistent
infection:
• Reactivation of HBV in originally asymptomatic,
overt HBV, HBsAg(+) patients,
• Reactivation of HBV in HBsAg(-) patients with occult
HBV infection - OBV (HBV DNA in serum; in
hepatocytes or in immune cells (ccc HBV-DNA+,
anti-HBc+ or anti-HBc+/anti-HBs+)

84. Background
• HBV reactivation in patients at risk may be asymptomatic or
symptomatic and is associated with cytotoxic or
immunosuppressive treatment, with pregnancy or surgery,
• Reactivation may lead to hepatitis, hepatic failure, delays in
chemo or immunotherapy (M ~100 days) and decreased survival
(4-60%),
• Reactivation may occur in >50% in HBsAg+ patients receiving
chemotherapy,
• Reactivation may also occur spontaneously in up to ~22% of HBV
infected patients who do not receive immunosuppression,
• Not all forms of chemotherapy confer an equivalent risk for
reactivation,
Review: Holbrook E et al. Clin Liver Dis 2007; 11:965

85. 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.
• 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.

86. Efficacy of current drug regimens
eAg +ve eAg -ve
Drug HBeAg HBV DNA HBV DNA
seroconversion negative at negative at
at Yr 1, % Yr 1, % Yr 1, %
Interferon 18 37 60-70
Lamivudine 18 40-44 60-70
Adefovir 12 21 51
Entecavir 21 67 90
Peg-IFNa-2a 27 25 63
Telbivudine 23 60 88

87. Rates of resistance
Drug Resistance %
Interferon none
Lamivudine 23 at Yr 1
71 at Yr 4
Adefovir 0 at Yr 1
30 at Yr 5
Entecavir < 1 in naïve at Yr 4
40 in Lam-r at Yr 4
Peg IFNa-2a none
Telbivudine 22 in HBeAg +ve at Yr 2
9 in HBeAg -ve at Yr 2

88. Key Points:
Screening for HBV markers is mandatory in all
patients scheduled for chemo- or immuno-therapy,
• Immunization against HBV should be completed as soon as
possible (non-response must be investigated for occult HBV),
• Early pre-emptive anti-viral treatment is superior to treatment at
onset of reactivation,
• It is highly recommended to continue treatment for 6-12 months
after completing chemo or immuno therapy,
• Awareness regarding the risk of HBV reactivation must be
strengthened , especially among oncologists, haematologists and
transplant surgeons

89. HCV

90. HCV Epidemiology
•HCV single-stranded RNA 170 million chronically
infected with HCV. 4 million people HCV in US,
•HCV causes 17-20% of acute hepatitis cases in the US,
•CDC -150,000 new cases per year. Highest prevalence
haemophiliacs and IVDU. Before plasma screening HCV
accounted for 90% of post transfusion hepatitis cases.
•HCV is the most common cause of chronic viral hepatitis
in the US. About 80% of people infected progress to
chronic HCV infection

91. H e p a t it is C V ir u s
c a p s id e n v e lo p r o t e a s e /h e RNA- RNA
pe lic a s e d e p e n d e n tp o l y m e r a s e
p ro te i
c 2 n 33 c - 10
2 c 0
5’ 3’
c o E1 E2 NS NS NS NS
re 2 3 4 5
h y p e r v a r ia b le
r e g io n

92. Course of clinical HCV
WEDEMEYER ET AL. HEPATOLOGY, May 2004

94. HCV Transmission
• HCV can be transmitted parenterally, perinatally, and
sexually. Most reliably through transfusion of infected
blood or blood products, transplantation of organs from
infected donors, and sharing contaminated needles
among IVDU’s.
• NSI among HCW’s place them at significant risk of
infection. Incidence of HCV infection in HCW with history
of needle-stick exposure to infected blood approaches
6%.
• There is a 0.4-1% chance of developing irreversible liver
injury from a needle-stick infection in this setting.

95. Trials evaluating treatment for acute HCV
Study Type Nos SC n (%) Regimen Time of therapy SVR (%)
Jaeckel et al Non- 44 N/A A Immediately, average 89 days post 98
randomised exposure
Gerlach et al “ 60 24 (52) B 10-26 months from symptom onset 80
Kamal et al Randomised 54 5 (9) C 12 wks from symptom onset or 1St +ve 83
HCV RNA
Nomura et al “ 30 0 D 8 wks from symptom onset 87
Pimstone et al Non- 10 3 (30) E 14 wks from exposure 100
randomised
Rocca et al “ 16 1 (6) F Immediately, <70 days post exposure 92
Wiegand et al Non- 60 N/A G Immediately 95
randomised
Santantonio et “ 28 11 (38) G 12 wks from symptom onset 94
al
Broers et al “ 27 5 (19) G 100±82 days from symptom onset or 57
63±53 days from 1st +ve HCV assay
Delwaide et al “ 28 N/A H Immediate, average110 ±44days post 75
exposure
Adapted from Zekry et al. Journal of Hepatology 2005; 42: 293-296

96. HCV Infection Testing Algorithm
for Diagnosis of Asymptomatic
Persons Negative
(non-reactive)
EIA for Anti-HCV STOP
Positive (repeat reactive)
OR
Negative
RIBA for Anti-HCV RT-PCR for HCV RNA
Negative Indeterminate Positive Positive
Additional Laboratory Medical
STOP Evaluation (e.g. PCR, ALT) Evaluation
Negative PCR, Positive PCR,
Normal ALT Abnormal ALT
Source: MMWR 1998;47 (No. RR 19)

97. Acute HCV
• HCV infection is mostly asymptomatic (66-80%), incub 15-150 days,
• Spontaneous viral clearance in 1- 30% 8-12 weeks post exposure,
• Clearance can be predicted by rate of viral load decline,
• Higher clearance rates reported in children, young adults particularly young
women and persons with jaundice,
• Up to 80% risk of going on to developing chronic disease with up to >20% risk
of developing HCC,
• Therapy once disease established improving but not completely effective in
some genotypes,
• Once disease is established response to treatment is reduced.
Jaeckel E, et al “Treatment of Acute Hepatitis C with interferon Alpha-2B,N Eng J Med,2001; 345(20):1452-1456.

98. HCV Clinical course
• Incubation period is 15-150 days, with symptoms
developing anywhere from 5-12 weeks after
exposure.
• During acute infection with HCV, symptoms may
appear similar to those of HBV infection. In up to
80% of cases, however, patients are
asymptomatic and do not develop icterus.

99. Serologic Pattern of Acute HCV Infection
with Recovery
anti-HCV
Symptoms +/-
HCV RNA
Titer
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
Months Years
Time after Exposure

100. Serologic Pattern of Acute HCV Infection with
Progression to Chronic Infection
anti-HCV
Symptoms +/-
HCV RNA
Titer
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
Months Years
Time after Exposure

101. http://www.hpsc.ie/hpsc/A-Z/HepatitisHIVAIDSandSTIs/BloodborneVirus/File,4352,en.pdf

102. http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1227688128096

103. http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1227688128096

104. http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1227688128096

107. HCV in the Health care setting
European case-control study *
• France, Italy, Spain, Switzerland, UK
• 60 cases of occupationally acquired HCV in HCWs January 1993 and
December 2002)
• All cases percutaneous injuries.
Risk factors associated with transmission:
• -needle having been placed in the source patient’s vein or artery
•-deep injury
• -Hollow bore needle
•-gender of the HCW (males were more likely to have seroconverted than
females) but this factor will need further investigation into its significance.
Prevalence of infection in the specific population
Volume of inoculums and viral load in source patient
Post exposure management.
* Yazdanpanah Y, De Carli G, Migueres B, Lot F, Campins M, Colombo C, et al. Risk Factors for HCV Transmission
after Occupational Exposure in Health Care Workers: A European Case-Control Study. Interscience Conference on
Antimicrobial Agents and Chemotherapy (ICAAC); Chicago, September 2003: poster no. 1087

108. UK HCV seroconversions in HCW’s
Occupation Device Procedure 1st test positive HCW Virus
(weeks) treated cleared
Junior Doctor (1996) Hollowbore Resuscitation A&E 16 NK Yes
needle
Surgeon (2000) Solid needle Suturing 8 Yes Yes
Dentist (2001) Hollowbore Injection 4 NK Yes
needle
Nurse (2003) Hollowbore Venepuncture 8 N/A* Yes
needle
Doctor (2003) Hollowbore Venepuncture 8 Yes Yes
needle
Nurse (2004) Hollowbore Someone else’s sharp 6 Yes† Treatment
needle ongoing
Nurse (2004) Hollowbore Cannulation 7 Yes Yes
needle
Healthcare Assistant (2004) Hollowbore Someone else’s sharp 7 Yes Yes
needle
Domestic Assistant (2003) Hollowbore Collecting rubbish bag 6 Yes Yes
needle – needle protruding
HPA UK Eye of the Needle Report

109. HCV Complications
• Acute infection with HCV -fulminant hepatic failure,
associated aplastic anaemia.
• Approximately 50-85% of patients chronically infected,
29-76% later develop CAH or cirrhosis.
• In the US and Europe, chronic HCV infection is the
leading indication for liver transplant. Chronic HCV
infection causes 10,000 deaths per year in the US.
• Chronic HCV infection is also strongly linked to the
development of HCC, which usually develops after 30
years

110. Transmission in HCW
• About 65,000 HBV, 16,400 HCV and 1000 HIV infxn in
HCWs p.a worldwide from occ exposure,
• Risk infxn to HCW from patient>HCW to patient,
• Universal imms, PEP, std precautions (including barrier
precautions & proper handwashing), appropriate techniques
& devices reduce transmission,
• Down from 10,000 pa in U.S in 1993 to 400 in 2002,
• Transmission of HCV rare and seroprevalence HCV in U.S
and UK similar in HCWs to gen pop.
• High risk cardiothoracic, ortho, obs&gyn,
• Role of precore mutants in 10 published HBV reports in last
decade,
• HCW to patient HCV infection a proxy for substance misuse.