1. 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

2. Topics Hepatitis what is it? Hepatitis B acute Hepatitis B chronic
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

3. Liver Located upper right side abdomen
Largest gland in body; kg
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

4. 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

5. 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

6. Acute Viral Hepatitis Signs and Symptoms fatigue mild fever
(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

8. 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

9. Hepatitis B – Clinical Features
Incubation period: Average days
Range 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% 29 9

10. 2006 HBV: 4,700 Reported Cases 46,000 estimated
Chronicity 5% adults
MMWR March 21, 2008 / Vol. 57 / No. SS-2

11. Reported Cases of Acute Hepatitis B in Texas 1980-2005
Hepatitis B recombinant vaccine
licensed
Universal infant
vaccination
Universal adolescent
vaccination

12. Reported Risk Characteristics Among Adults
HBV Recent (<8 yr ago)
Injection Drug Use
Other*
MSM
Unknown
Heterosexual
HCV Recent (<15 yr ago)
Injection Drug Use
Sexual
Transfusion
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 12

13. Acute Hepatitis B Incidence By Age and Sex: United States, 2005
0.0
0.0
Female
Male
0.0
0.0
0.0
0.0
0.6
0.5
1.7
2.4
4.3
3.0
2.9
4.2
2.9
4.5
2.3
4.5
2.2
3.4
1.7
3.0
1.3
2.2
0.6
1.1
Rate per 100,000
Source: National Notifiable Diseases Surveillance System, CDC

14. Acute Hepatitis B Cases by Age Group: Texas, 2005

15. Concentration of HBV in Various Body Fluids
Low/Not
High
Moderate
Detectable
urine
feces
sweat
tears
blood
wound exudates
semen
serum
vaginal fluid
saliva
breast milk 1 1 1

16. No Evidence of HBV (or HCV) Transmission
Breastmilk
Mosquitoes
Kissing
Food
Water
Casual contact

17. 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

18. Progression of Liver Disease
Time frame: years to decades
Fibrosis
Cancer
Cirrhosis
BC Hepatitis Services, 2003

19. Zeus’s punishment of Prometheus
Prometheus was a Titan. The Centaur Chiron agreed to die because he was suffering from the poison arrow of Hercules. Hercules who helped the underdog killed the vulture or eagle with a poison arrow. The poison was from the blood of the dying hydra.
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

20. 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 M persons
70% of these persons age years
8,000-10,000 deaths per year
Elevated ALT, history IDU, and history blood transfusion identified 85% persons 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, (2):104, Armstrong et al , Ann Int Med 2006;144(10):705,

21. 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

22. 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
DNA 104 to 108 copies per ml
HBsAg Carrier State
Anti-HBe positive
normal ALT
DNA < 101 to 104 copies per ml
minimal nonspecific changes on biopsy

23. 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:
McMahon BJ, et al, Ann Intern Med, 2001;135:

24. 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.

25. Engardio. San Francisco Chronicle, 2003

26. 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
12%-14% 6%
Entecavir %
Telbivudine %-26%

27. Hepatitis B: Treatment Costs
Drug
Monthly
Annual
Interferon-alfa
$2,084
$26,267
Lamivudine
$449
$4,305
Adefovir
$900
$10,705
Entecavir
$811
$9,578
Prevent 500 chronic HBV cases - save $5M annually in Rx
Averages based on 2009 wholesale costs, Hepatitis B Foundation, HepB.org

28. HBV: A Health Disparity
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.

29. HIV HBV Co-infection Multicentre AIDS Cohort Study (MACS)
5293 men followed
Liver-related mortality:
HBV / 1000
HIV / 1000
HIV+HBV / 1000 (p0.001)
Highest mortality rates with lower CD4 nadir counts
Thio et al, NEJM 2002;360:1921

30. 2-6% of individuals infected with HBV adults progress to chronic infection. Immunizing adults and older adolescents at risk for HBV infection has been recommended since Despite these facts, infections among adults at risk for infection continue to occur, and the majority of chronic hepatitis B cases in the U.S. are the result of infections acquired in adulthood.

31. Alcohol 25% Cause of Newly Diagnosed Chronic Liver Disease HBV 4.4%
Hepatitis C 57%
Alcohol 25%
Hepatitis B
Other
NASH 10%
HBV 4.4%
National Cancer Institute – Surveillance Epidemiology and End Results
Bell et al 2001

32. HBV Prevalence and Genotype Distribution 1998F D A C
A, C, B, D D
B, C B F E
Geographic Distribution of Chronic HBV Infection
The world can be divided into areas of high, intermediate, and low endemicity based on the prevalence of HBsAg in the population. Areas of high endemicity are those in which the prevalence of HBsAg >8%. Southeast Asia, East Asia, many of the Pacific Islands, and parts of South America and Africa are areas of high endemicity. Areas of intermediate endemicity are those in which the prevalence of HBsAg is 2%-7%, and include Eastern Europe, the Middle East, and central Asia. Areas of low endemicity, in which <2% of the population is HBsAg positive, include Australia, North America, and Western Europe. D F A
A, B,C,D
8% and above = High
2% - 8% = Intermediate
G, H not determined
Below 2% = Low

33. 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 Mar;11(2):
WHO.

34. Un homme enceinte s’accouche dans son tombeau*
*A pregnant man delivers in his grave

35. Cancer rates, Gambian males 1986-96
Incidence
per 100,000
140
120
100 80
all cancer
liver cancer 60 40 20
0-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
65+
60-64
Age
GHIS Site Review Report 2004 35

36. Indonesia: 80–90% home births
Vaccinate all babies within 7 days of birth
70,000 midwives
UNIJECT

37. Hepatitis B Carrier Prevalence Before and After Immunization

38. 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:

39. SIGN Pakistan 2001

40. SIGN Pakistan 2001

41. Coalition for Safe Community Needle Disposal

42. 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

43. Estimated Births to HBsAg-Positive Mothers United States, 2002

44. 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
In utero transmission rare - accounts for <5% of perinatal infections

45. 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

46. Are Three Doses Needed? Unapparent exposures as “boosters”?
“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:
Unapparent exposures as “boosters”?

48. Biologic Processes and Bureaucratic Processes
Success

49. Hepatitis B 9 serotypes, 8 genotypes worldwide
“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

50. 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

51. 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

52. 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?

53. Hepatitis B Vaccines Twinrix
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 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
Vaccine advisory groups that have endorsed this strategy include the Immunization Practices Advisory Committee to the U.S. Public Health Service (ACIP), the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the American College of Physicians (ACP).

54. 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

55. 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

56. Perinatal HBV infections are healthcare-associated infections.
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.

57. Resources Texas Liver Coalition 800-72-LIVER Hepatitis
Affiliated St. Luke’s Episcopal Health System, Houston
Hepatitis
HIV and Hepatitis

58. HBV, HCV and HIV Viruses Commonalities Differences
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%

59. Other Viruses Associated with Acute Hepatitis
Common in U.S.*
Cytomegalovirus
Epstein-Barr
Herpes simplex
Varicella zoster
Measles
Rubella
Coxsackie
Exotic**
Yellow fever
Argentinean hemorrhagic fever
Bolivian hemorrhagic fever
Lassa fever
Rift Valley fever
Marburg
Ebola
* Each causes less than 1% of acute hepatitis ** Not usually seen in the U.S.