Transcript Hepatitis B: Epidemiology and Public Health Issues Perinatal Hepatitis B Prevention Program 2nd Bi-Annual State Conference May 11, 2010 Austin, Texas Gary Heseltine MD MPH Epidemiologist -

Hepatitis B: Epidemiology and
Public Health Issues
Perinatal Hepatitis B Prevention Program
2nd Bi-Annual State Conference
May 11, 2010
Austin, Texas
Gary Heseltine MD MPH
Epidemiologist - Infectious Disease Control Unit
Chronic Illnesses Demand Chronic Attention
Topics
• Hepatitis what is it?
• Hepatitis B acute
– Basic epidemiology, risks, transmission
• Hepatitis B chronic
– Disease burden and sequelae
– A health disparity
• Global burden of hepatitis B
– Modes of transmission, including injection safety
• Perinatal hepatitis B
– Efficacy of prevention strategies
• Patient safety culture and process improvement
Liver
• Located upper right side abdomen
• Largest gland in body; 1.3 - 1.6kg
• Receives most nutrients absorbed by
GI tract
• Essential role in metabolism of fats,
sugars, and proteins
• Produces bile, clotting substances,
proteins, stores sugar
• Detoxifies compounds
• Processes old erythrocytes
Hepatitis: Inflammation of the Liver
• Disease process characterized by
– diffuse inflammatory infiltrate
– with or without necrosis and local fibrosis.
• Clinical forms
– Acute
– Chronic - persistent infection/inflamation > 6 months
• Etiology
– Usually a virus sometimes a toxic or chemical substance,
immunologic process
• Origin: [hepat- + -itis]
– G. hēpar- (liver) + G. -itis (f. form -ites)
– -itis: usage now denotes inflammation
Agents of Viral Hepatitis
• Enteric transmission
– Hepatitis A and E
– Acute diseases with no chronic phase
• Bloodborne transmission
– Hepatitis B, C and D
– All may produce chronic infections
• Agents not associated with disease?
– GBV-C (HGV), TTV, SenV
Acute Viral Hepatitis
(Elevated ALT almost always found)
Signs and Symptoms
•
•
•
•
•
•
•
•
•
fatigue
mild fever
loss of appetite
flu-like illness (prodromal)
muscle/joint aches
abdominal pain
nausea and vomiting
dark urine - light-colored stool
yellow eyes and skin (jaundice)
Aversion to alcohol and cigarettes
Fulminant Viral Hepatitis
Acute hepatic failure
• Massive hepatic necrosis within 8 weeks of onset
• Signs
Neurologic - Hepatic Encephalopathy
Acute Pancreatitis, jaundice, ascites
Coagulopathy - gastrointestinal bleeding
Acute Renal Failure - Hepatorenal Syndrome
Cardiopulmonary collapse
Hepatitis B – Clinical Features
• Incubation period:
Average 60-90 days
Range 45-180 days
• Clinical illness (jaundice):
<5 yrs, <10%
>5 yrs, 30%-50%
• Acute case-fatality rate:
0.5%-1%
• Chronic infection:
<5 yrs, 30%-90%
>5 yrs, 2%-10%
2006 HBV: 4,700 Reported Cases
46,000 estimated
www.cdc.gov/hepatitis/statistics.htm
Chronicity 5% adults
MMWR March 21, 2008 / Vol. 57 / No. SS-2
Reported Cases of Acute Hepatitis B in Texas
1980-2005
2500
2000
Hepatitis B recombinant vaccine
licensed
1500
1000
500
Universal infant
vaccination
Universal adolescent
vaccination
19
80
19
82
19
84
19
86
19
88
19
90
19
92
19
94
19
96
19
98
20
00
20
02
20
04
0
Reported Risk Characteristics Among Adults
HBV Recent (<8 yr ago)
Unknown
HCV Recent (<15 yr ago)
Injection Drug Use
Injection Drug Use
Sexual
Other*
MSM
Transfusion
Heterosexual
Unknown
Other*
With shared risk behaviors integrated testing and prevention makes sense.
*Other: Household contact, institutionalization, hemodialysis, occupational exposure etc.
Modified from Sentinel Counties Study of Viral Hepatitis, CDC
Acute Hepatitis B Incidence
By Age and Sex: United States, 2005
0.0
0.0
5-9
0.0
0.0
10-14
0.0
0.0
<5
Female
Age Group (Yrs)
15-19
0.6
2.9
35-39
2.9
45-49
50-54
55-59
60+
2.4
4.3
3.0
30-34
40-44
0.5
1.7
20-24
25-29
Male
4.2
4.5
2.3
4.5
2.2
3.4
1.7
3.0
1.3
0.6
2.2
1.1
Rate per 100,000
Source: National Notifiable Diseases Surveillance System, CDC
Acute Hepatitis B Cases
by Age Group: Texas, 2005
60+
50-59
40-49
30-39
20-29
<19
0
10
20
30
Percent of Total Cases
40
Concentration of HBV
in Various Body Fluids
High
Moderate
Low/Not
Detectable
blood
semen
urine
serum
vaginal fluid
feces
wound exudates
saliva
sweat
tears
breast milk
No Evidence of HBV (or HCV)
Transmission
•
•
•
•
•
•
Breastmilk
Mosquitoes
Kissing
Food
Water
Casual contact
Chronic Hepatitis: A Syndrome
Chronicity – continuing disease, no improvement
– greater than 6 months duration
Hepatitis - inflammation of the liver
– Causes
• Viral, drug, toxin, autoimmune, idiopathic
– Characterized by necrosis and inflammation
• Cirrhosis – end stage liver disease, fibrosis, diffuse
parenchymal damage, nodular regeneration
Sequelae - 10 to 20 years
– Cirrhosis and hepatocellular carcinoma
Progression of Liver Disease
Time frame: years to decades
Fibrosis
Cirrhosis
BC Hepatitis Services, 2003
Cancer
Zeus’s
punishment
of
Prometheus
The Golden Fleece and the Heroes
Who Lived before Achilles
Prometheus Bound
For Prometheus to be set free:
•An Immortal would have to give up his life for Prometheus – Chiron (centaur)
•A mortal would have to slay the liver-eating eagle - Hercules
Chronic Hepatitis Burden U.S.
• HBV estimated 1.2M persons
– 50-70% of these persons born outside U.S.
– 2,000-4,000 deaths per year
• HCV estimated 3.2-3.7M persons
– 70% of these persons age 35-54 years
– 8,000-10,000 deaths per year
– Elevated ALT, history IDU, and history blood transfusion
identified 85% persons 20-59 years
• Chronic liver disease and cirrhosis 12th leading cause
of death nationally, 6th for Hispanics
What proportion of these persons know their sero-status?
Sorrell et al, Ann Int Med, 2009 150(2):104, Armstrong et al , Ann Int Med 2006;144(10):705, www.cdc.gov/hepatitis/
Chronic Viral Hepatitis Disease Burden =
409,400 cases
Hepatitis B
Hepatitis C
Prevalence in General Population
5% or 1,115,000
1.6% or 368,000
% Chronic Hepatitis
10% or 115,000
80% or 294,400
Texas 2006 population est. 23 million
Chronic Hepatitis B
Three Clinical Forms
•
•
•
HBeAg Positive Chronic Hepatitis B
•
•
•
raised ALT
DNA 107 to 1011 copies per ml
chronic hepatitis on biopsy
HBeAg Negative Chronic Hepatitis B
•
•
•
raised ALT
DNA 104 to 108 copies per ml
chronic hepatitis on biopsy
HBsAg Carrier State
•
•
l
•
Anti-HBe positive
normal ALT
DNA < 101 to 104 copies per ml
minimal nonspecific changes on biopsy
Chronic Hepatitis B con’t
HBV causes 85% of primary liver cancer worldwide
• 20% will develop cirrhosis
• 5% will develop hepatocellular cancer
HBeAg
10% / yr lose HBeAg - become less (non)infectious
– 40% - 50% in 5 years
– 70% - 80% in 10 years
More frequent in older carriers, associated ALT flare
20% who clear HBeAg have one or more reversions
HBsAg
0.5-2% / yr lose HBsAg - become non-carriers
Lok ASF, McMahon BJ, Hepatology, 2001;34:1225-1241
McMahon BJ, et al, Ann Intern Med, 2001;135:759-768
Monitoring HBsAg+ Patients
• Discuss monitoring with a liver specialist having much
experience in managing viral liver diseases.
–
–
–
–
–
Annual physical exam.
Blood work every 6-12 mos.
Liver biopsy?
Liver ultrasound or CT scan every 6-12 mos.
fetoprotein (AFP) every 6-12 mos.
• Education of patient about disease.
Engardio. San Francisco Chronicle, 2003
Hepatitis B: Treatment
• Acute hepatitis B
– Supportive care
• Chronic hepatitis B
- HBV DNA/HBeAg clearance (indicator of viral load)
Drug
Treated patients
Controls
Interferon-alfa
33%-37%
12%-17%
Lamivudine
16%-18%
4%-6%
Adefovir
Entecavir
Telbivudine
12%-14%
21%
23%-26%
6%
Hepatitis B: Treatment Costs
Drug
Interferon-alfa
Lamivudine
Adefovir
Entecavir
Monthly
$2,084
$449
$900
$811
Annual
$26,267
$4,305
$10,705
$9,578
Prevent 500 chronic HBV cases - save $5M annually in Rx
Averages based on 2009 wholesale costs,
Hepatitis B Foundation, HepB.org
• 10% of Asian Americans have chronic HBV versus less than
0.3% of the general population.
• Liver cancer second leading cancer for Asian men.
• Liver cancer among Asian Americans is 6 to 13 times higher
than the general population.
HIV HBV Co-infection
Multicentre AIDS Cohort Study (MACS)
• 5293 men followed
• Liver-related mortality:
HBV+ 0.8 / 1000
HIV+ 1.7 / 1000
HIV+HBV+ 14.2 / 1000 (p0.001)
• Highest mortality rates with lower CD4 nadir
counts
Thio et al, NEJM 2002;360:1921
Cause of Newly Diagnosed
Chronic Liver Disease
HBV 4.4%
NASH
10%
Alcohol
25%
Hepatitis C
57%
National Cancer Institute – Surveillance
Epidemiology and End Results 2006.
http://seer.cancer.gov/resources/
Bell et al 2001
HBV Prevalence and Genotype Distribution
1998
F
D
A
A, C, B, D
C
D
B, C
B
E
F
F
D
A
A, B,C,D
8% and above = High
G, H not determined
2% - 8% = Intermediate
Below 2% = Low
Global Burden of Hepatitis B Disease
• 2 billion with markers of current or past infection
• 350 million chronic carriers
– 130 million Chinese (1 in 10) have chronic HBV
– 15%-25% will die from cirrhosis or liver cancer
• 10th leading cause of death
– 600,000 to 1 million preventable deaths / year
– Second only to tobacco in cause of cancer deaths
• Risk of dying from liver cancer 100 greater for
carriers than non-carriers
Lavanchy D., J Viral Hepat. 2004 Mar;11(2):97-107.
WHO. www.who.int/csr/disease/hepatitis/en/
Un homme enceinte
s’accouche dans son tombeau*
*A pregnant man delivers in his grave
Cancer rates, Gambian males 1986-96
Incidence
per 100,000
140
120
100
80
all cancer
liver cancer
60
40
20
0
014
1519
2024
2529
3034
3539
4044
Age
4549
5054
5559
6064
65+
GHIS Site Review Report 2004
Indonesia: 80–90% home births
•Vaccinate all babies within 7
days of birth
•70,000 midwives
UNIJECT
Hepatitis B Carrier Prevalence Before and After
Immunization
16
14
12
10
% 8
PRE
POST
6
4
2
0
TAIWAN
SHANGHAI
RURAL
CHINA
GAMBIA
Safe Injection Global Network
• ~16 billion injections/year / 12 billion syringes sold
~33% unsafe in developing countries
~12 million HBV infections
~3 million HCV infections
~ 120,000 HIV infections
• Estimated 1 billion injections for childhood immunizations
• Little change until Global Alliance for Vaccine and
Immunizations (GAVI) and SIGN were formed
– Eligible countries get auto-disable syringes for 3 years. 200 million already
distributed
• Countries responsible for national plan, training, waste
management
Kane A, et al, Bulletin of WHO, 1999, 77:801-807
SIGN Pakistan 2001
SIGN Pakistan 2001
Coalition for Safe Community Needle Disposal
800-643-1648
HBV Childhood Exposure Routes
• In Asia, HBV infection is vertical, mother-to-child
– 30-40% mothers HBeAg+
• In Africa, horizontal transmission is predominant
– About 10% mothers HBeAg+, mothers may be HBsAg-
• Studies in two Gambian villages have shown
– infection uncommon first year of life
– 50% of the children infected by age of 5
– By the age of 10, almost everybody infected, 15 to 20% chronic
carriers.
• Significant associations, but no predominant route of
exposure
– Number of siblings
– Tropical ulcer scars
– E antigen positive household member
GHIS Site Review Report 2004
Estimated Births to HBsAg-Positive Mothers
United States, 2002
Race/Ethnicity
White
African
American
Asian/Pacific
Islander
Other
Total
2002
Births
HBsAg
Births to HBsAg
prevalence (%) positive mothers
3,174,760
(0.13)
4,127
593,691
(0.50)
2,968
210,907
(7.50)
15,818
42,368
(0.50)
212
4,021,726
23,125
Perinatal HBV Transmission Efficacy
• If mother positive for HBsAg and HBeAg
– 70%-90% of infants infected
– 90% of infected infants become chronic carriers
• If positive for HBsAg only
– 20-30% of infants infected
– 90% of infected infants become chronic carriers
• In utero transmission rare - accounts for
<5% of perinatal infections
HBV Vaccine and HBIG
• HBIG only ~ 75% effective in preventing carriage
– Protection wanes
• HBIG & Vaccine ~ 85 – 95% effective
• HBV Vaccine only ~ 80 – 90% effective
– Birth dose (3-7 days)
• HBIG not cost effective developing countries
– Little value added
Are Three Doses Needed?
“Thus, protection against chronic carriage does not depend on the number of doses
received as originally assumed…results from GHIS follow-up of vaccinated
subjects, more than 95% of children that received at least one dose are protected
against the acquisition of chronic carriage early in life.”
Fortuin, M. et al Lancet 1993; 341:1129-31
Unapparent exposures as “boosters”?
Biologic Processes and Bureaucratic Processes
1
0.9
0.8
0.7
0.6
0.5
Success
Failure
0.4
0.3
0.2
0.1
0
1
7
13
19
25
31
37
43
49
55
61
67
73
79
85
91
97
103
109
115
121
127
133
139
145
151
157
163
169
175
181
187
193
199
E
f
f
i
c
a
c
y
Time
Hepatitis B
“serum hepatitis”
• Hepatitis B virus (1970 Dane particle) - Hepadnaviridae
• Enveloped, spherical 42 nm
• Partial ds circular DNA genome, about 3.2 kb
• Partial + strand, full length - strand, 5’ RT
• Four overlapping open reading frames
• 9 serotypes, 8 genotypes worldwide
– Genotype B milder disease than C
• Resistant to environmental stress
• 44º C for 7 days, room temperature 6 months, years at -20 º C
HBV: Gene Products and Mutants
Genome encodes 4 groups of proteins:
• C gene - HBcAg (nucleocapsid protein), HBeAg (soluble protein
circulates in serum)
– ?Associated fulminant hepatitis and severe liver disease
– Pre-core mutants lack HBeAg production, 20%-30% US patients
• P gene - Polymerase (DNA synthesis)
– Associated with resistance to treatment with nucleoside analogs
(e.g., lamivudine)
• S gene - HBsAg (surface protein)
– Concern that these variants may allow replication in the presence
of vaccine-induced anti-HBsAg
– No evidence to date that variants spread in immunized populations
• X gene - X protein (regulates gene transcription)
– Associated with hepatocellular carcinoma
HBV S-gene mutants
•Emergence of HBV variant able to escape the vaccine-induced
response suggested in Italy 20 years ago
(Zanetti et al, Lancet 1988)
•Evidence indicates that amino acid substitution
lead to
conformational changes which allows mutated HBV to escape
vaccine-induced antibodies (G145R)
•44 of 1590 (2.8%) vaccinated people, including babies born to
HBsAg mothers, became HBV infected despite immunization. All
cases showed co-existence of HBsAg and anti-HBs.
•At present there is no evidence that S-gene mutants pose a
threat to the established PH program of vaccination
Hepatitis D Virus
• Tiny single stranded RNA virus
• A “defective” virus that requires HBVsAg for
replication.
• Coinfection produces severe disease
• Sperinfection often produces chronic disease
• Exposure risks same as HBV
• Preventing HBV infection prevents HDV
infection, why?
Hepatitis B Vaccines
• Licensed in 1981; currently recombinant (in US)
• 3 dose series, 0, 1-2, 4-6 months - no maximum time between
doses (no need to repeat missed doses or restart)
• 2 dose series (using adult dose) for 11-15 year olds (Merk)
• Protection ~50% dose 1; 85% - 2; 96% - 3
Twinrix
• Combination adult A and B vaccine
• Schedule: 0, 1, 6-12 months
• Approved for persons >18 years
Recommended for Hepatitis B Vaccination
(Adults)
•
•
•
•
•
•
•
•
•
•
•
•
High-risk heterosexual men and women
MSM
Injection drug users
Inmates of correctional facilities
Health care workers
Household and sex partners of persons with chronic infection
Hemodialysis patients
Recipients of blood products
Clients and employees of institution for developmentally disabled
Families of adoptees from endemic countries
Persons with chronic liver disease
Persons who are immunocompromised - HIV
Routine vaccine for all children
Missed Opportunities for
Adult Hepatitis B Vaccination
Of all persons with reported acute hepatitis B:
• 37% reported prior treatment for an STD
• 29% reported prior incarceration
• 56% had been treated for an STD and/or
incarcerated in a prison or jail prior to their
illness
Source:Goldstein ST et.al., JID 2002;185:713-9
Improving Hospital Compliance
•Problem:
Failure to screen mother
Failure to give birth dose
Failure to give prophylaxis
•Root Cause:
Too much to do
Too many people involved
Too complex a process
Too few resources???
•Solutions:
Put into delivery check-list (simplify)
Put into publicly reported quality measures
Put development of patient safety culture first
Perinatal HBV infections are
healthcare-associated infections.
Resources
• Texas Liver Coalition
800-72-LIVER
– www.TexasLiver.org
– Affiliated St. Luke’s Episcopal Health System, Houston
• Hepatitis
– www.LiverFoundation.org
– www.TexasDisease.org
• HIV and Hepatitis
– www.HIVandHepatitis.com
– www.numedx.com
HBV, HCV and HIV Viruses
• Commonalities
– Infection through blood and body fluids containing virus
– Transmission from mother to child at birth
– Produce chronic infections
• Differences
– Infectivity after sharps injury
• HBV 30%, HCV 3%, HIV 0.3%
– Level of chronicity
• HBV 10% (variable), HCV 75-85%, HIV 100%
Other Viruses Associated
with Acute Hepatitis
Common in U.S.*
Exotic**
•
•
•
•
•
•
•
• Yellow fever
• Argentinean
hemorrhagic fever
• Bolivian hemorrhagic
fever
• Lassa fever
• Rift Valley fever
• Marburg
• Ebola
Cytomegalovirus
Epstein-Barr
Herpes simplex
Varicella zoster
Measles
Rubella
Coxsackie
* Each causes less than 1% of acute hepatitis.
** Not usually seen in the U.S.