1. Introduction to chronic hepatitis B infection1
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Introduction to chronic hepatitis B infection

2. 2
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Epidemiology

3. Hepatitis B virus infection
Virus discovered in 1966
Infects 350–400 million people worldwide
Affects 1.25 million people in the US1
>1 million people die annually of HBV-related chronic liver disease
Approximately 15-40% who develop CHB progress to cirrhosis, end-stage liver disease or HCC
1Maddrey, J Med Virol 2000; 61: 362

4. Global distribution of CHB carriers: 350 million
Source: World Health Organization / Centers for Disease Control and Prevention

5. Chronic hepatitis B: Epidemiology

6. Epidemiology of chronic hepatitis B infection

7. Epidemiology of HBV: United States
1.25 million in US have chronic HBV infection; highest incidence is in Alaska (6.4%)
Local factors influence incidence and prevalence
ethnicity
immigration patterns
IVDA
high-risk sexual activity
Increased incidence of infection in first generation children of families from high risk area

8. Transmission of the hepatitis B virus8
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Transmission of the hepatitis B virus

9. Transmission of hepatitis B virus
Perinatal – with risk of transmission affected by HBeAg status of the mother
Sexual transmission
Non-sexual person-to-person contact, e.g., household contact
Present in blood, saliva, vaginal secretions, menstrual blood
less so in perspiration, tears, breast milk
Percutaneous
blood / blood products, needlestick, injection drug use, tattoo, acupuncture
Lavanchy, J Viral Hepat 2004; 11: 97

10. Risk of persistence after initial HBV infection
At birth and infants <1 yr 90%
Children 1–5 yrs 30%
Older children, adults 2%

11. Hepatitis B infection: Transmission prevention
Universal vaccination
Education regarding alterations in sexual behavior
Screening of high risk populations
Screening of blood products
Needle exchange programs
Cultural outreach and education

12. Components of Strategies to Prevent HBV Transmission
Hepatitis B immunization
Universal infant immunization
Prevent perinatal transmission
Catch-up immunization
Prevent nosocomial HBV transmission
The priority for incorporation of strategies to prevent perinatal HBV transmission in a particular country should take into account several factors, including:
relative contribution of perinatal transmission to the overall disease burden B vaccine
feasibilty of delivering hepatitis B vaccine at birth.

13. Hepatitis B Vaccination Targets 45th World Health Assembly, 1992
Integrate hepatitis B vaccine into national
childhood vaccination programs
By 1995 in countries with HBsAg prevalence 8%
By 1997 in all countries
Routine infant hepatitis B vaccination is the primary essential element of hepatitis B prevention strategies in all countries.
In 1992, the 45th World Health Assembly established global hepatitis B vaccination targets

14. Impact of Hepatitis B Immunization
Reduces prevalence of chronic HBV infection in
immunized cohorts
<1% in areas with low rate of perinatal transmission
<2% in areas with high rate of perinatal transmission
Reduces infection "pressure"
Unvaccinated persons with chronic infection lose
HBeAg
and become less infectious
Results in greater than expected impact on transmission
Reduces liver cancer

15. Chronic HBV infection Age Vaccine Before After (yrs) Coverage Program
Effect of Routine Infant Immunization on the
Prevalence of Chronic HBV Infection
Chronic HBV infection
No.
Age
Vaccine
Before
After
Study
Year
Tested
(yrs)
Coverage
Program
Program
Alaska
1995
268
1-10
96%
16% 0%
Taiwan
1994
424
7-10
73%
10%
1.1%
Samoa
1996
435
7-8
87% 7%
0.5%
Lombok
1994
2519 4
> 90%
6.2%
1.9%
Saipan
1994
200
3-4
94% 9%
0.5%
Ponape
1994
364
3-4
82% NA
1.0%
Micronesia
1992
544 2
40%
12%
3.0%

16. Impact of vaccination schedules in the US
1991 CDC published guidelines recommending universal vaccination of infants and children
In period from 1990–2002, incidence of acute HBV decreased
67% in all age groups
89% in children < 20 years of age
MMWR 2004: 52; 1252

17. Age of Acquisition of Chronic HBV Infections in High Endemic Countries
% of Chronic Infections
Perinatal
10-30
Young children
65-80
The most important factor in determining the critical ages for vaccination to interrupt HBV transmission is the proportion of chronic infections that are acquired in each age group.
In countries with a high endemicty of infection, virtually all chronic infections are acquired either perinatally or from transmission among young childre -- so vaccination programs in these countries should pimarily target these age groups for vaccination.
Preventing perinatal and early childhood transmission is also important in low-endemic countriesbecause about 1/3 of chronic infections are acquired in these age groups.
In addition , vaccination programs targeted to adolescents and adults at high risk of infection are needed in these countries, because the majority of chronic infections are acquired among adolescents and adults.
Adolescents/Adults
<5

18. Strategies to Prevent Perinatal HBV Transmission (1)
Selective Immunoprophylaxis
Screen pregnant women for HBsAg
Give prophylaxis to infants of HBsAg+ mothers
prophylaxis targeted to infants that need it
can administer both HBIG/HepB vaccine
Issues
Requires extensive resources to screen pregnant women/track infants of HBsAg+ mothers
Few successful programmes
Two different strategies can be used to prevent perinatal HBV transmission.
First, perinatal hepatitis B prevention can be integrated as a component of routine infant vaccination by beginning vaccination of all infants at birth and assuring infants complete the 3-dose vaccine series by 6 months of age. This strategy is desirable for countries where it is feasible to deliver the first dose of vaccine to all infants soon after birth.
Second, all pregnant women can be screened for HBsAg and immunoprophylaxis provided to infants of HBsAg-positive mothers. This strategy is desirable in countries where all infants are not vaccinated at birth; however, extensive resources are required to screen all pregnant women and to track infants of HBsAg positive mothers to assure delivery of post-exposure prophylaxis.

19. Strategies to Prevent Perinatal HBV Transmission (2)
Integrate as Component of Routine Infant Vaccination
Vaccinate all infants beginning at birth
No need to screen pregnant women
Very feasible to implement if a high proportion of infants are born in health care facilities
Issues
Need to assure effective HepB vaccine delivery for all infants
Two different strategies can be used to prevent perinatal HBV transmission.
First, perinatal hepatitis B prevention can be integrated as a component of routine infant vaccination by beginning vaccination of all infants at birth and assuring infants complete the 3-dose vaccine series by 6 months of age. This strategy is desirable for countries where it is feasible to deliver the first dose of vaccine to all infants soon after birth.
Second, all pregnant women can be screened for HBsAg and immunoprophylaxis provided to infants of HBsAg-positive mothers. This strategy is desirable in countries where all infants are not vaccinated at birth; however, extensive resources are required to screen all pregnant women and to track infants of HBsAg positive mothers to assure delivery of post-exposure prophylaxis.

20. Priority of Perinatal Hepatitis B Prevention
High proportion of chronic infections acquired perinatally (e.g., SE Asia)
A birth dose should be given when feasible (e.g., in birthing hospitals)
Efforts should be made to administer HepB vaccine to infants who deliver at home
Low proportion of chronic infections acquired perinatally (e.g., Africa)
A birth dose may be considered after evaluating disease burden, cost-effectiveness, and feasibility

21. Priority of Catch-up Immunization
High endemicity of HBV infection
Catch-up immunization not generally needed
Most chronic infections acquired before age 5 years
Immunizing infants will rapidly reduce transmission

22. Priority of Catch-up Immunization II
Lower endemicity of HBV infection
May be large disease burden from infections acquired in older age groups
Immunizing infants alone may not substantially lower disease incidence for decades
Catch-up immunization may be desirable:
single-age cohorts (e.g., routine adolescent immunization)
high risk groups (e.g., MSM, IDUs, persons w/STDs)
STD clinics, correctional facilities, drug treatment

23. Potential factors affecting the natural history of chronic hepatitis B
Age of patient at infection
Host factors
gender
age
immune status
Viral factors
HBV genotype
viral mutation
level of HBV replication
External factors
concurrent infection with HCV, HDV, HIV
immune suppression – transplantation, chemotherapy
alcohol
Adapted from Fattovich, Semin Liver Dis 2003; 23: 47

24. HBV Transmission in Healthcare Settings
Patient
Patient
Unsafe injection practices
Reuse of contaminated
medical equipment
Blood transfusion
Use safe injection practices
Use sterile equipment
Screen blood supply
Patient
Provider
Use standard precautions
Vaccinate HCW
Needlestick/sharps injuries
Provider
Patient
Invasive surgical procedures
Use standard precautions

25. Vaccination strategy for the prevention of HBV infection
MMWR 1991; 40: 1

26. Chronic Hepatitis B: Counseling
Vaccinate against hepatitis A
Non-pharmacologic
supportive
diet, rest, fluid balance
Reduce risk for spreading HBV
no needle sharing, notify partner etc.
condoms, vaccinate sexual partner(s)
vaccinate household members against hepatitis B
Avoid alcohol and other hepatotoxins

27. Natural history of hepatitis B infection30
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Natural history of hepatitis B infection

28. Natural history of chronic hepatitis B infection
Lee, N Engl J Med 1997; 337: 1733

29. Natural history of hepatitis B virus infection and mechanism of disease progression
Slowly progressive disease
Complications of cirrhosis develop after 5–50+ years
Progression of disease influenced by the phase of viral replication and the incidence of hepatitis (ALT) flares
A recent liver biopsy is usually required for assessment of disease stage

30. A model of the natural history of chronic viral hepatitis

31. Factors affecting the course of the disease34
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Factors affecting the course of the disease

32. Effect of timing of infection: Birth or early childhood
Asian, Africans, some Mediterraneans, South Pacific Islanders
Prolonged immune tolerance and immune clearance phases
Respond less well to immunomodulatory therapy
Disease continues to progress in a proportion of anti- HBe patients
Hoofnagle et al, Hepatology 1987; 7: 758

33. Effect of timing of infection: Adolescence and adulthood
Majority of Caucasian patients
No immune tolerance phase
Active hepatitis of shorter duration
Responds better to immunomodulatory therapy
Disease in many non-progressive after HBeAg seroconversion, with low HBV-DNA levels undetectable by hybridization assays – “HBsAg carriers”1
Some may develop anti-HBe chronic hepatitis
1Hoofnagle et al, Hepatology 1987; 7: 758

34. The impact of gender Males higher risk1,2
male : female ratio for HCC >5:1
male : female crude mortality rate in Haiman City per 100,000 person-year :42.5
1Lai et al, Cancer 1981; 47: Yuen et al, Hepatology 2000; 31:330 3Evans et al, Cancer Epidemiol Biomarkers Prev 2001; 11:369

35. Hepatitis B virus genome

36. The impact of viral load on the progression of hepatocellular damage
Viral load probably significant factor in natural history both for disease and HCC
prolonged immune destruction of antigen-presenting liver cells results in cirrhosis
prolonged low-level viremia may influence progression in CHB
HCC develops through:
cirrhotic necroinflammation and regeneration
direct viral effect through replication and/or random integration

37. Hepatitis B virus genotypes
8 HBV genotypes (based on complete HBV genome) A D B C A B C D D F A E G H F
A,B,C,D US
Lindh et al, J Infect Dis 1997; 175: 1285 Norder et al, J Gen Virol 1993; 74: 1341

38. Association of HBV genotype with long-term sequelae
A: Potentially less cirrhosis, but hepatocellular carcinoma does occur
B: When compared to genotype C
younger age at HBeAg seroconversion
lower risk of chronic hepatitis
increased risk of icteric and fulminant acute hepatitis
increased risk of HCC, but higher proportion of patients with HCC in the absence of cirrhosis
C: Increased risk of hepatitis and HCC
D: Increased risk of anti-HBe hepatitis and HCC; associated with vasculitis in Alaska natives
E, G, H: Limited information available
F: HCC reported in young Alaska natives
Kao, Intervirology 2003; 46: 400 Nakayoshi et al, J Med Virol 2003; 70: 350

39. HBeAg and precore mutation

40. Viral factors: HBeAg-negative disease
Late phase in the natural history of chronic HBV infection
More common in subjects infected during childhood and in those with B or D genotype
HBeAg-negative variants have mutations in the core promotor and / or the pre-core region of the HBV genome
abolishes HBeAg production but high level of viral replication occurs
May develop severe disease with cirrhosis or HCC
Responds to antiviral medications but relapses after withdrawal
Hadziyannis et al, Semin Liv Dis 2003; 23: 81

41. HBeAg-negative disease demonstrates frequent fluctuations in ALT and HBV DNA levels
Hadziyannis et al, Hepatology 2001; 34: 617

42. The impact of age on the development of HCC
Peak incidence for cirrhosis complication / HCC 50–60 years of age
Prospective study of 684 Taiwan patients (509 HBeAg+; 175 anti-HBe+)
median follow-up 35.3 months
cirrhosis incidence increased with age at entry (p<0.001)
Liaw et al, Hepatology 1988; 8:493

43. Summary CHB significant public health concern worldwide
Natural history and outcome dependent on number of factors
Persons infected with CHB at increased risk of developing cirrhosis and/or HCC
These risks can likely be reduced by effective treatment interventions
Prevention is a central strategy to reduce the future impact of the disease

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