Transcript Introduction to chronic *hepatitis B infection

1
2017-03-21
Introduction to chronic
hepatitis B infection
2
2017-03-21
Epidemiology
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
Global distribution of CHB carriers:
350 million
Source: World Health Organization / Centers for Disease Control and Prevention
Chronic hepatitis B: Epidemiology
Epidemiology of
chronic hepatitis B infection
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
2017-03-21
Transmission of
the hepatitis B virus
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
Risk of persistence after initial
HBV infection
 At birth and infants <1 yr
90%
 Children 1–5 yrs
30%
 Older children, adults
2%
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
Components of Strategies to Prevent HBV
Transmission
 Hepatitis B immunization
 Universal infant immunization
 Prevent perinatal transmission
 Catch-up immunization
 Prevent nosocomial HBV transmission
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
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
Effect of Routine Infant Immunization on the
Prevalence of Chronic HBV Infection
Chronic HBV infection
Vaccine Before After
Coverage Program Program
Study
No.
Year Tested
Age
(yrs)
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%
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
Age of Acquisition of Chronic HBV Infections in High
Endemic Countries
Age of Acquisition
% of Chronic Infections
Perinatal
10-30
Young children
65-80
Adolescents/Adults
<5
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
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
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
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
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
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
HBV Transmission in Healthcare Settings
Patient
•Unsafe injection practices
•Reuse of contaminated
medical equipment
•Blood transfusion
Patient
•Needlestick/sharps injuries
Provider
•Invasive surgical procedures
Patient
•Use safe injection practices
•Use sterile equipment
•Screen blood supply
Provider
•Use standard precautions
•Vaccinate HCW
Patient
•Use standard precautions
Vaccination strategy for
the prevention of HBV infection
MMWR 1991; 40: 1
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
30
2017-03-21
Natural history
of hepatitis B infection
Natural history of chronic hepatitis B infection
Lee, N Engl J Med 1997; 337: 1733
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
A model of the natural history
of chronic viral hepatitis
34
2017-03-21
Factors affecting the
course of the disease
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 antiHBe patients
Hoofnagle et al, Hepatology 1987; 7: 758
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
The impact of gender
 Males higher risk1,2
 male : female ratio for HCC
 male : female crude mortality rate in
Haiman City per 100,000 person-year3
1Lai
>5:1
207:42.5
et al, Cancer 1981; 47:2746-55
2Yuen et al, Hepatology 2000; 31:330
3Evans et al, Cancer Epidemiol Biomarkers Prev 2001; 11:369
Hepatitis B virus genome
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 antigenpresenting 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
Hepatitis B virus genotypes
 8 HBV genotypes (based on complete HBV genome)
A
D
AB
CD
B C
D
A
F
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
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
HBeAg and precore mutation
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
HBeAg-negative disease demonstrates frequent
fluctuations in ALT and HBV DNA levels
Hadziyannis et al, Hepatology 2001; 34: 617
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
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
47
2017-03-21