Hepatitis B: Epidemiology and Public Health Issues

Perinatal Hepatitis B Prevention Program2nd Bi-Annual State Conference

May 11, 2010Austin, Texas

Gary Heseltine MD MPHEpidemiologist - 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

• 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)

Signs and Symptoms

Aversion to alcohol and cigarettes

(Elevated ALT almost always found)

Fulminant Viral HepatitisAcute hepatic failure

• Massive hepatic necrosis within 8 weeks of onset• Signs

Neurologic - Hepatic EncephalopathyAcute Pancreatitis, jaundice, ascitesCoagulopathy - gastrointestinal bleedingAcute Renal Failure - Hepatorenal SyndromeCardiopulmonary collapse

• Incubation period: Average 60-90 daysRange 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%

Hepatitis B – Clinical Features

2006 HBV: 4,700 Reported Cases46,000 estimated

www.cdc.gov/hepatitis/statistics.htm

MMWR March 21, 2008 / Vol. 57 / No. SS-2Chronicity 5% adults

Reported Cases of Acute Hepatitis B in Texas 1980-2005

0

500

1000

1500

2000

2500Hepatitis B recombinant vaccine licensed

Universal infant vaccination

Universal adolescent vaccination

Reported Risk Characteristics Among Adults

*Other: Household contact, institutionalization, hemodialysis, occupational exposure etc.

Modified from Sentinel Counties Study of Viral Hepatitis, CDC

Sexual

Other*UnknownTransfusion

Injection Drug Use

HCV Recent (<15 yr ago)HBV Recent (<8 yr ago)Injection Drug Use

Other*

MSM

Unknown

Heterosexual

With shared risk behaviors integrated testing and prevention makes sense.

Acute Hepatitis B Incidence By Age and Sex: United States, 2005

<5

5-9

10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60+

Ag

e G

rou

p (

Yrs

)

FemalFemalee

MaleMale0.0

0.00.0

0.0

0.0

0.0

0.5

0.61.

72.4

3.0

4.34.2

2.92.9

4.54.5

2.32.

23.41.

73.0

2.2

1.3 1.

10.6

Source: National Notifiable Diseases Surveillance System, CDC

Rate per 100,000Rate per 100,000

Acute Hepatitis B Cases by Age Group: Texas, 2005

0 10 20 30 40

<19

20-29

30-39

40-49

50-59

60+

Percent of Total Cases

Low/NotHigh Moderate Detectable

semenserum vaginal fluid

blood

wound exudates saliva

urine

feces

sweat

tears

breast milk

Concentration of HBV in Various Body Fluids

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

BC Hepatitis Services, 2003

Time frame: years to decades

Cirrhosis

Fibrosis

Cancer

The Golden Fleece and the HeroesWho 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

Zeus’s punishment

of Prometheus

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

Sorrell et al, Ann Int Med, 2009 150(2):104, Armstrong et al , Ann Int Med 2006;144(10):705, www.cdc.gov/hepatitis/

What proportion of these persons know their sero-status?

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 BThree 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 • Anti-HBe positive• normal ALT DNA < 101 to 104 copies per ml • minimal nonspecific changes on biopsy

Chronic Hepatitis B con’t

• 20% will develop cirrhosis• 5% will develop hepatocellular cancerHBeAg

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 flare20% who clear HBeAg have one or more reversions

HBsAg0.5-2% / 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

HBV causes 85% of primary liver cancer worldwide

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

Drug Treated patients Controls

Interferon-alfa 33%-37% 12%-17%

Lamivudine 16%-18% 4%-6%

Adefovir 12%-14% 6%

- HBV DNA/HBeAg clearance (indicator of viral load)

Entecavir 21%Telbivudine 23%-26%

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

• 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.

HBV: A HealthDisparity

HIV HBV Co-infectionMulticentre AIDS Cohort Study (MACS)• 5293 men followed• Liver-related mortality:

HBV+ 0.8 / 1000HIV+ 1.7 / 1000HIV+HBV+ 14.2 / 1000 (p0.001)

• Highest mortality rates with lower CD4 nadir counts

Thio et al, NEJM 2002;360:1921

Hepatitis C 57%

Alcohol 25%

Hepatitis B

Oth

er

NASH 10%

National Cancer Institute – Surveillance Epidemiology and End Results 2006. http://seer.cancer.gov/resources/

HBV 4.4%

Cause of Newly Diagnosed Chronic Liver Disease

Bell et al 2001

HBV Prevalence and Genotype Distribution 1998

A, C, B, D

A

A

D

B, C

E

F

D

G, H not determined

8% and above = High

2% - 8% = Intermediate

Below 2% = Low

F

D

A, B,C,D

F

C

B

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

0

20

40

60

80

100

120

140

all cancerliver cancer

Incidenceper 100,000

Age GHIS Site Review Report 2004

40-44

0-14

15-19

20-24

25-29

30-34

35-39

45-49

50-54

55-59

60-64

65+

UNIJECT

Indonesia: 80–90% home births

•Vaccinate all babies within 7 days of birth

•70,000 midwives

Hepatitis B Carrier Prevalence Before and After Immunization

0

2

4

6

8

10

12

14

16

%

TAIWAN SHANGHAI RURALCHINA

GAMBIA

PRE

POST

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

2002 Births

HBsAg prevalence (%)

Births to HBsAg positive mothers

White 3,174,760 (0.13) 4,127

African American

593,691 (0.50) 2,968

Asian/Pacific Islander

210,907 (7.50) 15,818

Other 42,368 (0.50) 212

Total

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

Success

Hepatitis B

• 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

“serum hepatitis”

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?

• 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

Hepatitis B Vaccines

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

•Problem: Failure to screen motherFailure to give birth doseFailure to give prophylaxis

•Root Cause: Too much to doToo many people involvedToo complex a processToo few resources???

•Solutions: Put into delivery check-list (simplify)Put into publicly reported quality measuresPut development of patient safety culture first

Improving Hospital Compliance

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.*• 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.