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The Epidemiology of Hepatitis B and A Infections
Kenrad E. Nelson, MD
Johns Hopkins University
Section A
Introduction to Hepatitis Virus
Hepatitis Viruses of Humans
Hepatitis A virus (HAV)
Hepatitis B virus (HBV)
Hepatitis C virus (HCV), non-A, non-B hepatitis virus
Hepatitis D virus (delta agent, HDV)
Enteric non-A, non-B hepatitis virus (HEV)
Hepatitis G virus
Other hepatitis viruses?
− For example, short-incubation-period HV?
4
Characteristics of Hepatitis Viruses
Virus
Nucleic Acid
Route Trans
Mortality
Risk Chronic
HAV
Unenveloped,
single-stranded
RNA
Fecal-oral
Low
None
HBV
Enveloped,
double-stranded
DNA
Parenteral, Sex
High
High
HCV
Enveloped,
single-stranded
RNA
Parenteral, Sex
Med
High
HDV
Enveloped,
single-stranded
RNA
With HBV
High
High
HEV
Unenveloped,
single-stranded
RNA
Fecal-oral
High
None
HGV
Enveloped,
single-stranded
RNA
Parenteral?
?
?
5
Estimates of Disease Burden for Viral Hepatitis, U.S.
6
Acute Viral Hepatitis by Type, United States
7
Section B
Hepatitis B Virus: Epidemiology, Biology, and Virology
Hospitalization/Death Rates: Reported Acute Hepatitis B
9
Primary Etiology of Chronic Liver Disease
10
Outcome of Hepatitis B Infections
11
Hepatitis B: Clinical Features
12
Hepatitis B Virus
13
Hepatitis B Virus
14
Genome of Hepatitis B Virus
15
Hepatitis B Virus
16
The Replication Cycle of HBV
Ganem, D., et al. (2004). N Engl J Med.
17
Course of Symptoms in Typical Acute Viral Hepatitis
18
Acute Hepatitis B Virus Infection with Recovery
19
Progression to Chronic Hepatitis B Virus Infection
20
Natural History of Chronic HBV Infection
Source: Yim, H. J., et al., (2006). Hepatology.
21
Occult Hepatitis B
22
Typical Serological Profiles in Patients with Hepatitis B Infection
Serological
tests
Hep B
Immunization
Acute
HBV
Recovered
from HBV
Chronic Hep B
Healthy or
inactive carrier
Occult hep B
HBsAb
+
-
+
-
-
-/+
HBcAb total
-
+
+
+
+
-/+
HBeAb
-
-
+
-
+
-/+
HBsAg
-
+
-
+
+
-
HBeAg
-
+
-
+
-
-/+
HBV DNA
-
+
-
+, >105 copies
+, <105 copies
+, <103 copies
HbsAB, hep B surface antibody; HBcAb, hep B core antibody; HBeAb, hep B e antibody; HBsAg, hep B
surface antigen; HbeAg, hep B e antigen
23
Age of HBV Infection in Relation to Probability of Persistent Carriage
Age
Infections resulting in persistent HBV carriage
<1 yr
70-90%
2-3 yr
40-70%
4-6 yr
10-40%
>6 yr
6-10%
24
Outcome by Age at Infection
25
Prevalence of HBV Infection, U.S., by Race and Age
26
HBV Serologic Markers in Various U.S. Population Groups
27
Estimated Annual HBV Infections by Risk Group
28
Risk Factors for Patients Reported with Hepatitis B
29
Incidence per 100,000, 1982–1998
30
Number of Cases, 1982–1998, by Risk Factor
31
HBV, HCV, and HIV Transmission by Needlestick
32
Section C
Hepatitis B: Prevention Efforts and Global Distribution
Global Burden (350 Million Chronic HBV Carriers)1
20–25% of carriers died of liver-related disease2
Worldwide—primary cause of cancer of the liver3
− For males—third leading cause of cancer mortality
− For females—sixth leading cause of cancer mortality
1
WHO. (2000)
Brechot, C., et al. (2000). Semin Cancer Biol.
3
Parkin, D. M., et al. (2005). CA Cancer J Clin.
2
34
Geographic Distribution of Chronic HBV Infection
35
HBsAg Positive Mothers Delivering HBV Carrier Infants
36
Hepatitis B Carriers in Regions of Increased Prevalence
Hepatitis B Carriers in Regions of Intermediate and High HBV Prevalence (1985)
Region
Population
HBV carriers
No. of HBV carriers
(millions)
413M
12%
49.5M
2,757M
8%
220M
Middle East
191M
4%
7.6M
Latin America
410M
1.6%
6.6M
Oceana
6M
10%
0.6M
Totals
3,777M
Africa
Asis
284.3M
37
HBV Carriers in the World
38
Global Patterns of Chronic HBV Infection
39
Age and Transmission According to Endemicity
40
Immunization against HBV
41
Types of Hepatitis B Vaccines
42
Protective Efficacy of Hepatitis B Vaccine
43
HBV Carrier Rate: Effect of Reduction Strategies
44
Long-Term Protection in Cohorts Responding to Vaccine
Follow-up
Study Group
No.
HBV Infections
(yr)
Anti-HBs loss (%)
Anti-HBc(+)
HBsAg(+)
Postexposure immunoprophylaxis: infants of HBeAg-positive mothers
Passive-active
Taiwan
199
5
3
0
0
Taiwan
654
5
9
46
4
United States
315
4 to 11
12
30
0
55
5
17
6
4
Active
China
Routine preexposure immunization of infants/children
Senegal
100
6
22
8
4
Alaska
600
10
17
4
0
Venezuela
280
6
29
6
0
Preexposure immunization of adults
Homosexual men
634
9
54
48
4
Homosexual men
127
11
61
26
0
Alaskan Eskimos
272
10
38
6
0
45
Response Rates in HIV+ and HIV- MSM
Response rate to hepatitis B vaccine administered at 0, 1, and 6
months in HIV-positive and HIV-negative men who have sex with men
Study
Response to hepatitis B vaccine (% [n/N])
HIV+ men
HIV- men
Wong et al.
42.9 (6/14)
87.5 (105/120)
Loke et al.
33.3 (9/27)
89.6 (69/77)
Collier et al.
56.3 (9/16)
91.2 (62/68)
Carne et al.
52.9 (9/17)
94.4 (17/18)
Wong et al. Response to hepatitis B vaccination in a primary care setting: influence of HIV infection,
CD4+ lymphocyte count, and vaccination schedule. Int J STD AIDS 1996; 7:4904.
Loke et al. Diminished response to recombinant hepatitis B vaccine in homosexual men with HIV
antibody: an indicator of poor prognosis. J Med Virol 1990; 31:10911.
Collier et al. Antibody to human immunodeficiency virus (HIV) and suboptimal response to hepatitis B
vaccination. Ann Intern Med 1988; 109:1015.
Carne et al. Impaired responsiveness of homosexual men with HIV antibodies to plasma derived
hepatitis B vaccine. BMJ 1987; 294:8668.
46
Prospective Study of HCC in Taiwan Civil Servants
Prospective study of hepatocellular carcinoma (HCC) in
Taiwanese Civil Servants (Beasley et al.)
− Enrollment: March 15, 1976 to June 3, 1978
− 22,707 civil servants
X 12.8% of all 40-59 year old male government
employees
X 1.4% of all 50-59 men in Taiwan
X 186,000 person-years of followup mean = 8.2
years/man
X Passive surveillance and active surveillance
− 151 cases of HCC by December 1985
47
Prospective Study of HCC in Taiwan Civil Servants
Incidence and Relative Risk of HCC by HBsAg Carrier
Status among Taiwanese Civil Servants (Beasley et al.)
HBsAg
Pos
Neg
No.
HCC
3,456
19,253
143
8
AR/100,0
00/yr
505
5.1
22,707
151
81/1
RR
104*
*95% CI: 50.9-212.0
48
Mortality from Primary Hepatocellular Carcinoma, Taiwan
49
HBsAg, HBeAg, and Hepatocellular Carcinoma
50
Cumulative Incidence of Hepatocellular Carcinoma
51
HCC Risk Factors
Viral factors
• HBV
• HCV
Host factors
• Age
• Male gender
• Family history
• Diabetes/obesity
Environmental factors
• Dietary aflatoxins
• Alcohol consumption
• Cigarette smoking
• Oral contraceptives
52
Pathogenesis of HCC
53
Liver Cancer and Start of HBV Vaccination Program
Incidence of Liver Cancer per 100,000 Children in Birth
Cohorts Determined According to the Date of
Implementation of the Hepatitis B Vaccination Program
Age at
Diagnosis
Before-Program Cohort
(July 1974-June 1984)
After-Program Cohort
(July 1984-June 1986)
Population
Incidence
Population
Incidence
6
3,940,747
18 (0.46)
648,642
0 (0.00)
7
3,938,119
21 (0.53)
647,051
1 (0.15)
8
3,931,983
19 (0.48)
644,892
2 (0.31)
9
3,928,721
24 (0.61)
340,521
0 (0.00)
Total
15,739,570
82 (0.52)
2,281,106
3 (0.13)
54
Vaccine Coverage Rates and Seroprevalence in 6-Yr-Olds
Year
(July to
June)
Infants
6-Year-Olds
Vaccine
HBIG
Vaccine
HBsAg+
1981-1982
0
0
0
10
1982-1983
0
0
0
11
1983-1984
0
0
0
11
1984-1985
15
4.8
0
10
1985-1986
15
5.9
0
10
1986-1987
86
5.2
12
5
1987-1988
90
5.4
12
5
1988-1989
86
5.4
14
4
1989-1990
94
5.3
14
4
1990-1991
92
4.4
23
1
1991-1992
84
3.9
23
1
1992-1993
85
5
90
1
1993-1994
84
4.8
93
1
The hepatitis B vaccine
coverage rate and
HBsAg sero-prevalence
in infancy and at the
age of six were
estimated on the basis
of data from previous
field studies.
The immunization was
given only to infants
born between 1984 and
1986 to high-risk
mothers.
The coverage from
1986 to 1992 was
partially attributable to
vaccination in the
preschool period.
55
Hepatitis B Virus Genotypes
1. There are eight genotypes of HBV (A–H) which are
geographically distributed
2. Genotypes B and C predominate in Asia
− Genotype B is more likely to resolve, less risk of
cirrhosis and liver cancer than genotype C
3. In U.S.A., genotypes A–G
− Genotype B—less severe liver disease than A
4. In Africa, genotype E (Central Africa) has lower viral load
and less perinatal transmission than A or D
56
Geographic Distribution of Hepatitis B Virus Genotypes
57
Factors Increasing Risk of Progression to Cirrhosis
Factors Associated with Increased Risk of Progression to
Cirrhosis
Host Factors
Older age
(longer duration)
Male
Immune status
Virus Factors
Environmental Factors
High levels of HBV
replication
Concurrent infection
(HCV, HDV, HIV)
Genotype (C>B)*
Alcohol consumption
HBV variant
(core promoter)
Obesity
58
Maximum AFP Level and Associated Clinical Condition
59
AFP Levels Before and After Resection of Primary HCC
60
Section D
Hepatitis A
Hepatitis A Virus—Picornavirus
62
Clinical Features of Hepatitis A
63
Clinical Features of Hepatitis A
64
HAV Infection: Typical Serologic Course
65
HAV Transmission
66
Age-Specific Incidence of Hepatitis A, United States
67
Sources of HAV Infection, 1983–1993
68
Maricopa County, Arizona, 1974–1978
69
Family Contacts and Children in Day Care
70
Geographic Distribution of HAV Infection
71
Global Patterns of Hepatitis A Virus Transmission
72
Hepatitis A Vaccine Efficacy Studies
73
HAV Vaccination Strategies: Epidemiologic Considerations
74
Age-Specific Mortality Due to Hepatitis A
75
Preexposure Vaccination Recommendations
76
U.S. Hepatitis A Incidence by Year, 1966–2003
77
Incidence Rates in Israel
78
HAV Antibody Prevalence among Children in Bangkok
79
Incidence in the U.S. and Shanghai County, PRC
80
Hepatitis D (Delta) Virus
81
Hepatitis D—Clinical Features
82
HBV-HDV Superinfection: Typical Serologic Course
83
