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Hepatitis B: Epidemiology and Public Health Issues

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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,

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 1998
F 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

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, 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.

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