The Epidemiology of Hepatitis B and A Infections. Kenrad E. Nelson, MD Johns Hopkins University

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2 The Epidemiology of Hepatitis B and A Infections Kenrad E. Nelson, MD Johns Hopkins University

3 Section A Introduction to Hepatitis Virus

4 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

5 Characteristics of Hepatitis Viruses Virus Nucleic Acid Route Trans Mortality Risk Chronic HAV HBV HCV HDV HEV HGV Unenveloped, single-stranded RNA Enveloped, double-stranded DNA Enveloped, single-stranded RNA Enveloped, single-stranded RNA Unenveloped, single-stranded RNA Enveloped, single-stranded RNA Fecal-oral Low None Parenteral, Sex High High Parenteral, Sex Med High With HBV High High Fecal-oral High None Parenteral??? 5

6 Estimates of Disease Burden for Viral Hepatitis, U.S. 6

7 Acute Viral Hepatitis by Type, United States 7

8 Section B Hepatitis B Virus: Epidemiology, Biology, and Virology

9 Hospitalization/Death Rates: Reported Acute Hepatitis B 9

10 Primary Etiology of Chronic Liver Disease 10

11 Outcome of Hepatitis B Infections 11

12 Hepatitis B: Clinical Features 12

13 Hepatitis B Virus 13

14 Hepatitis B Virus 14

15 Genome of Hepatitis B Virus 15

16 Hepatitis B Virus 16

17 The Replication Cycle of HBV Ganem, D., et al. (2004). N Engl J Med. 17

18 Course of Symptoms in Typical Acute Viral Hepatitis 18

19 Acute Hepatitis B Virus Infection with Recovery 19

20 Progression to Chronic Hepatitis B Virus Infection 20

21 Natural History of Chronic HBV Infection Source: Yim, H. J., et al., (2006). Hepatology. 21

22 Occult Hepatitis B 22

23 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 , >10 5 copies +, <10 5 copies +, <10 3 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

24 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

25 Outcome by Age at Infection 25

26 Prevalence of HBV Infection, U.S., by Race and Age 26

27 HBV Serologic Markers in Various U.S. Population Groups 27

28 Estimated Annual HBV Infections by Risk Group 28

29 Risk Factors for Patients Reported with Hepatitis B 29

30 Incidence per 100,000,

31 Number of Cases, , by Risk Factor 31

32 HBV, HCV, and HIV Transmission by Needlestick 32

33 Section C Hepatitis B: Prevention Efforts and Global Distribution

34 Global Burden (350 Million Chronic HBV Carriers) % of carriers died of liver-related disease 2 Worldwide primary cause of cancer of the liver 3 For males third leading cause of cancer mortality For females sixth leading cause of cancer mortality 1 WHO. (2000) 2 Brechot, C., et al. (2000). Semin Cancer Biol. 3 Parkin, D. M., et al. (2005). CA Cancer J Clin. 34

35 Geographic Distribution of Chronic HBV Infection 35

36 HBsAg Positive Mothers Delivering HBV Carrier Infants 36

37 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) Africa 413M 12% 49.5M Asis 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 284.3M 37

38 HBV Carriers in the World 38

39 Global Patterns of Chronic HBV Infection 39

40 Age and Transmission According to Endemicity 40

41 Immunization against HBV 41

42 Types of Hepatitis B Vaccines 42

43 Protective Efficacy of Hepatitis B Vaccine 43

44 HBV Carrier Rate: Effect of Reduction Strategies 44

45 Long-Term Protection in Cohorts Responding to Vaccine Study Group Follow-up HBV Infections No. (yr) Anti-HBs loss (%) Anti-HBc(+) HBsAg(+) Postexposure immunoprophylaxis: infants of HBeAg-positive mothers Passive-active Taiwan Taiwan United States to Active China Routine preexposure immunization of infants/children Senegal Alaska Venezuela Preexposure immunization of adults Homosexual men Homosexual men Alaskan Eskimos

46 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 (6/14) 87.5 (105/120) Loke et al (9/27) 89.6 (69/77) Collier et al (9/16) 91.2 (62/68) Carne et al (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: 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:

47 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, ,707 civil servants 12.8% of all year old male government employees 1.4% of all men in Taiwan 186,000 person-years of followup mean = 8.2 years/man Passive surveillance and active surveillance 151 cases of HCC by December

48 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 No. HCC AR/100,0 00/yr RR Pos 3, * Neg 19, *95% CI: , /1 48

49 Mortality from Primary Hepatocellular Carcinoma, Taiwan 49

50 HBsAg, HBeAg, and Hepatocellular Carcinoma 50

51 Cumulative Incidence of Hepatocellular Carcinoma 51

52 HCC Risk Factors Viral factors Host factors Environmental factors HBV HCV Age Male gender Family history Diabetes/obesity Dietary aflatoxins Alcohol consumption Cigarette smoking Oral contraceptives 52

53 Pathogenesis of HCC 53

54 Liver Cancer and Start of HBV Vaccination Program Age at Diagnosis Incidence of Liver Cancer per 100,000 Children in Birth Cohorts Determined According to the Date of Implementation of the Hepatitis B Vaccination Program Before-Program Cohort (July 1974-June 1984) After-Program Cohort (July 1984-June 1986) Population Incidence Population Incidence 6 3,940, (0.46) 648,642 0 (0.00) 7 3,938, (0.53) 647,051 1 (0.15) 8 3,931, (0.48) 644,892 2 (0.31) 9 3,928, (0.61) 340,521 0 (0.00) Total 15,739, (0.52) 2,281,106 3 (0.13) 54

55 Vaccine Coverage Rates and Seroprevalence in 6-Yr-Olds Year (July to June) Infants 6-Year-Olds Vaccine HBIG Vaccine HBsAg 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

56 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

57 Geographic Distribution of Hepatitis B Virus Genotypes 57

58 Factors Increasing Risk of Progression to Cirrhosis Factors Associated with Increased Risk of Progression to Cirrhosis Host Factors Virus Factors Environmental Factors Older age (longer duration) High levels of HBV replication Concurrent infection (HCV, HDV, HIV) Male Genotype (C>B)* Alcohol consumption Immune status HBV variant (core promoter) Obesity 58

59 Maximum AFP Level and Associated Clinical Condition 59

60 AFP Levels Before and After Resection of Primary HCC 60

61 Section D Hepatitis A

62 Hepatitis A Virus Picornavirus 62

63 Clinical Features of Hepatitis A 63

64 Clinical Features of Hepatitis A 64

65 HAV Infection: Typical Serologic Course 65

66 HAV Transmission 66

67 Age-Specific Incidence of Hepatitis A, United States 67

68 Sources of HAV Infection,

69 Maricopa County, Arizona,

70 Family Contacts and Children in Day Care 70

71 Geographic Distribution of HAV Infection 71

72 Global Patterns of Hepatitis A Virus Transmission 72

73 Hepatitis A Vaccine Efficacy Studies 73

74 HAV Vaccination Strategies: Epidemiologic Considerations 74

75 Age-Specific Mortality Due to Hepatitis A 75

76 Preexposure Vaccination Recommendations 76

77 U.S. Hepatitis A Incidence by Year,

78 Incidence Rates in Israel 78

79 HAV Antibody Prevalence among Children in Bangkok 79

80 Incidence in the U.S. and Shanghai County, PRC 80

81 Hepatitis D (Delta) Virus 81

82 Hepatitis D Clinical Features 82

83 HBV-HDV Superinfection: Typical Serologic Course 83