1. Epidemiology of Hepatitis A and E Epidemiology of Hepatitis A and E R. C. Coppola 21th VHPB meeting Prevention of viral hepatitis in Italy: Prevention of viral hepatitis in Italy: lessons learnt and the way forward 21th VHPB meeting Prevention of viral hepatitis in Italy: Prevention of viral hepatitis in Italy: lessons learnt and the way forward Catania, 7-8 November 2002

2. CDC, 1999

3. Epidemiology of HAV infection Reported cases of HAV underestimate the true incidence of the infection because of: subclinical infections, very common subclinical infections, very common in young people in young people underreporting underreporting

4. YearYear Reported Acute Cases Reported Acute Cases Estimated Acute Cases Estimated Acute Cases Estimated TotalNew InfectionsEstimated TotalNew Infections 19801980 29,08729,087 124,000124,000 234,000234,000 19811981 25,80225,802 110,000110,000 223,000223,000 19821982 23,40423,404 100,000100,000 228,000228,000 19831983 21,53421,534 92,00092,000 221,000221,000 19841984 22,03822,038 94,00094,000 232,000232,000 19851985 23,21123,211 99,00099,000 228,000228,000 19861986 23,42923,429 100,000100,000 239,000239,000 19871987 25,28025,280 108,000108,000 255,000255,000 19881988 28,50628,506 122,000122,000 305,000305,000 19891989 35,82235,822 153,000153,000 380,000380,000 19901990 31,52231,522 135,000135,000 373,000373,000 19911991 24,21924,219 104,000104,000 288,000288,000 19921992 23,11223,112 99,00099,000 274,000274,000 19931993 24,23824,238 104,000104,000 284,000284,000 19941994 26,79626,796 115,000115,000 333,000333,000 19951995 31,58231,582 135,000135,000 356,000356,000 19961996 31,03231,032 133,000133,000 335,000335,000 19971997 30,02130,021 128,000128,000 341,000341,000 19981998 23,29923,299 99,00099,000 243,000243,000 19991999 17,04717,047 73,00073,000 181,000181,000 20002000 13,39713,397 57,00057,000 143,000143,000 20012001 10,61610,616 45,00045,000 93,00093,000 YearYear Reported Acute Cases Reported Acute Cases Estimated Acute Cases Estimated Acute Cases Estimated TotalNew InfectionsEstimated TotalNew Infections 19801980 29,08729,087 124,000124,000 234,000234,000 19811981 25,80225,802 110,000110,000 223,000223,000 19821982 23,40423,404 100,000100,000 228,000228,000 19831983 21,53421,534 92,00092,000 221,000221,000 19841984 22,03822,038 94,00094,000 232,000232,000 19851985 23,21123,211 99,00099,000 228,000228,000 19861986 23,42923,429 100,000100,000 239,000239,000 19871987 25,28025,280 108,000108,000 255,000255,000 19881988 28,50628,506 122,000122,000 305,000305,000 19891989 35,82235,822 153,000153,000 380,000380,000 19901990 31,52231,522 135,000135,000 373,000373,000 19911991 24,21924,219 104,000104,000 288,000288,000 19921992 23,11223,112 99,00099,000 274,000274,000 19931993 24,23824,238 104,000104,000 284,000284,000 19941994 26,79626,796 115,000115,000 333,000333,000 19951995 31,58231,582 135,000135,000 356,000356,000 19961996 31,03231,032 133,000133,000 335,000335,000 19971997 30,02130,021 128,000128,000 341,000341,000 19981998 23,29923,299 99,00099,000 243,000243,000 19991999 17,04717,047 73,00073,000 181,000181,000 20002000 13,39713,397 57,00057,000 143,000143,000 20012001 10,61610,616 45,00045,000 93,00093,000 YearYear Reported Acute Cases Reported Acute Cases Estimated Acute Cases Estimated Acute Cases Estimated TotalNew InfectionsEstimated TotalNew Infections 19801980 29,08729,087 124,000124,000 234,000234,000 19811981 25,80225,802 110,000110,000 223,000223,000 19821982 23,40423,404 100,000100,000 228,000228,000 19831983 21,53421,534 92,00092,000 221,000221,000 19841984 22,03822,038 94,00094,000 232,000232,000 19851985 23,21123,211 99,00099,000 228,000228,000 19861986 23,42923,429 100,000100,000 239,000239,000 19871987 25,28025,280 108,000108,000 255,000255,000 19881988 28,50628,506 122,000122,000 305,000305,000 19891989 35,82235,822 153,000153,000 380,000380,000 19901990 31,52231,522 135,000135,000 373,000373,000 19911991 24,21924,219 104,000104,000 288,000288,000 19921992 23,11223,112 99,00099,000 274,000274,000 19931993 24,23824,238 104,000104,000 284,000284,000 19941994 26,79626,796 115,000115,000 333,000333,000 19951995 31,58231,582 135,000135,000 356,000356,000 19961996 31,03231,032 133,000133,000 335,000335,000 19971997 30,02130,021 128,000128,000 341,000341,000 19981998 23,29923,299 99,00099,000 243,000243,000 19991999 17,04717,047 73,00073,000 181,000181,000 20002000 13,39713,397 57,00057,000 143,000143,000 20012001 10,61610,616 45,00045,000 93,00093,000 YearYear Reported Acute Cases Reported Acute Cases Estimated Acute Cases Estimated Acute Cases Estimated TotalNew InfectionsEstimated TotalNew Infections 19801980 29,08729,087 124,000124,000 234,000234,000 19811981 25,80225,802 110,000110,000 223,000223,000 19821982 23,40423,404 100,000100,000 228,000228,000 19831983 21,53421,534 92,00092,000 221,000221,000 19841984 22,03822,038 94,00094,000 232,000232,000 19851985 23,21123,211 99,00099,000 228,000228,000 19861986 23,42923,429 100,000100,000 239,000239,000 19871987 25,28025,280 108,000108,000 255,000255,000 19881988 28,50628,506 122,000122,000 305,000305,000 19891989 35,82235,822 153,000153,000 380,000380,000 19901990 31,52231,522 135,000135,000 373,000373,000 19911991 24,21924,219 104,000104,000 288,000288,000 19921992 23,11223,112 99,00099,000 274,000274,000 19931993 24,23824,238 104,000104,000 284,000284,000 19941994 26,79626,796 115,000115,000 333,000333,000 19951995 31,58231,582 135,000135,000 356,000356,000 19961996 31,03231,032 133,000133,000 335,000335,000 19971997 30,02130,021 128,000128,000 341,000341,000 19981998 23,29923,299 99,00099,000 243,000243,000 19991999 17,04717,047 73,00073,000 181,000181,000 20002000 13,39713,397 57,00057,000 143,000143,000 20012001 10,61610,616 45,00045,000 93,00093,000 YearYear Reported Acute Cases Reported Acute Cases Estimated Acute Cases Estimated Acute Cases Estimated TotalNew InfectionsEstimated TotalNew Infections 19801980 29,08729,087 124,000124,000 234,000234,000 19811981 25,80225,802 110,000110,000 223,000223,000 19821982 23,40423,404 100,000100,000 228,000228,000 19831983 21,53421,534 92,00092,000 221,000221,000 19841984 22,03822,038 94,00094,000 232,000232,000 19851985 23,21123,211 99,00099,000 228,000228,000 19861986 23,42923,429 100,000100,000 239,000239,000 19871987 25,28025,280 108,000108,000 255,000255,000 19881988 28,50628,506 122,000122,000 305,000305,000 19891989 35,82235,822 153,000153,000 380,000380,000 19901990 31,52231,522 135,000135,000 373,000373,000 19911991 24,21924,219 104,000104,000 288,000288,000 19921992 23,11223,112 99,00099,000 274,000274,000 19931993 24,23824,238 104,000104,000 284,000284,000 19941994 26,79626,796 115,000115,000 333,000333,000 19951995 31,58231,582 135,000135,000 356,000356,000 19961996 31,03231,032 133,000133,000 335,000335,000 19971997 30,02130,021 128,000128,000 341,000341,000 19981998 23,29923,299 99,00099,000 243,000243,000 19991999 17,04717,047 73,00073,000 181,000181,000 20002000 13,39713,397 57,00057,000 143,000143,000 20012001 10,61610,616 45,00045,000 93,00093,000 YearYear Reported Acute Cases Reported Acute Cases Estimated Acute Cases Estimated Acute Cases Estimated TotalNew InfectionsEstimated TotalNew Infections 19801980 29,08729,087 124,000124,000 234,000234,000 19811981 25,80225,802 110,000110,000 223,000223,000 19821982 23,40423,404 100,000100,000 228,000228,000 19831983 21,53421,534 92,00092,000 221,000221,000 19841984 22,03822,038 94,00094,000 232,000232,000 19851985 23,21123,211 99,00099,000 228,000228,000 19861986 23,42923,429 100,000100,000 239,000239,000 19871987 25,28025,280 108,000108,000 255,000255,000 19881988 28,50628,506 122,000122,000 305,000305,000 19891989 35,82235,822 153,000153,000 380,000380,000 19901990 31,52231,522 135,000135,000 373,000373,000 19911991 24,21924,219 104,000104,000 288,000288,000 19921992 23,11223,112 99,00099,000 274,000274,000 19931993 24,23824,238 104,000104,000 284,000284,000 19941994 26,79626,796 115,000115,000 333,000333,000 19951995 31,58231,582 135,000135,000 356,000356,000 19961996 31,03231,032 133,000133,000 335,000335,000 19971997 30,02130,021 128,000128,000 341,000341,000 19981998 23,29923,299 99,00099,000 243,000243,000 19991999 17,04717,047 73,00073,000 181,000181,000 20002000 13,39713,397 57,00057,000 143,000143,000 20012001 10,61610,616 45,00045,000 93,00093,000 CDC,Viral Hepatitis Surveillance

5. Incubation period:Average 30 days Range 15-50 days Jaundice by 14 yrs, 70%-80% Complications:Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis Chronic sequelae:None Hepatitis A: Clinical Features

6. Distribution of acute hepatitis in 1998 ISS, SEIEVA 2000

7. Non-ABCDE Source: CDC Sentinel Counties Study 55% 32% 12% 1% Hepatitis A Hepatitis B Hepatitis C Acute Viral Hepatitis by type United States, 1991-1997

8. Distribution of notified cases of viral hepatitis 1997-20011987-1990 ISS, SEIEVA 2002

9. ISS, SEIEVA 2001 Incidence of hepatitis A in Italy Rates x 100.000

10. Hepatitis A :incidence rates 6 1.5 n° cases/100.000 ITALY 3/100.000 ISS, SEIEVA 2001

11. Area and sex specific incidence of hepatitis A (2001) ISS, SEIEVA 2001 Rates x 100.000

12. Endemicity Disease Rate Peak Age of Infection Transmission Patterns HighLow to High Early childhood Person to person; outbreaks uncommon Moderate High Late childhood/ young adults Person to person; food and waterborne outbreaks Low Young adults Person to person; food and waterborne outbreaks Very low AdultsTravelers; outbreaks uncommon

13. Epidemiology of Hepatitis A from high to intermediate endemicity As a consequence of better sanitation and hygienic conditions decline of HAV infection in children of Western countries increasing proportion of adults is becoming susceptible to the virus

14. Hepatitis A Shifting epidemiological pattern HIGHHIGH INTERMEDIATELOWINTERMEDIATELOW

15. Age specific incidence of hepatitis A in Italy Rates x 100.000 ISS, SEIEVA 2002

16. Age-specific incidence of hepatitis A in South and islands Rates x 100.000 ISS SEIEVA, 2002

17. Age-specific incidence of hepatitis A in North Center Italy Rates x 100.000 ISS SEIEVA, 2002

18. Age and sex specific incidence 0-14 years ISS, SEIEVA 2001 Rates x 100.000

19. >25 years (2001) 15-24 years (2001) Age and sex specific incidence of Hepatitis A ISS, SEIEVA 2001

20. Epidemiology of Hepatitis A in Italy Shifting epidemiological pattern: high intermediate-low

21. Prevalence of anti-HAV in the general population of Cagliari (Sardinia) in 1988 (no.299) and in 1995 (no. 714) Coppola,1998 =p<0.01 % 96

22. Anti-HAV prevalence in general population in 1988 and 1995 (Cagliari) Coppola,1998 Classi di età =p<0.01 %

23. Prevalence of anti-HAV among Italian recruits (range 18-26 years) Prevalence of anti-HAV among Italian recruits (range 18-26 years)

24. Anti-HAV prevalence in recruits in Cagliari (2000) No. 218No.279 No.22 (Coppola,submitted)

25. Anti-HAV prevalence in Health Care Workers (1998) and general population (1995) in Cagliari

26. Anti-HAV prevalence in students of Cagliari Masia.1996 Age (years) =p<0.01

27. Risk factors for hepatitis A SEIEVA 2001

28. Geographic Distribution of Hepatitis E Outbreaks or Confirmed Infection in >25% of Sporadic Non- ABC Hepatitis CDC

29. Distribution of notified cases of viral hepatitis ISS, SEIEVA 2002

30. Prevalence of antibody to hepatitis E virus among normal human populations Prevalence of antibody to hepatitis E virus among normal human populations Country% Anti-HEV positivesreference Endemic country India4 Khuroo MS, 1994 Bangladesh7,3 Sheikh A, 2002 Brasile2,4 Santos DC, 2002 Non-endemic country Italy 0,6 Coppola R.C., 2000 1,7-0,8 Pavia M, 1998 2,6 Stroffolini T, 1996 2,6 Gessoni G, 1996 0,74-1,94 Zanetti A, 1994 Germany2,1 Ritter A,1994 France0,9 Ritter A,1994 Spain2,8 Mateos M.L. 1999 Grecia2,2 Psichogiou M.,1996

31. Anti-HEV in the general population of Cagliari in 1988 (691 subjects) and 1995 (751 subjects) Syn=Synthetic antigens (ORF 2,3) (Immunodiagnostics, Ca,USA) (Coppola,1997) % Age classes (years)

32. Anti-HEV in the general population of Cagliari in 1988 (691) and 1995 (751) Synthetic and recombinants Antigens from ORF 1 (Alfa Scientific, San Diego, Ca) Age classes (years) (Coppola, personal data) %

33. Anti-HEV in the general population of Cagliari (2 different assays) Syn+Rec= Synthetic and recombinants Antigens from ORF 1 (Alfa Scientific, San Diego, Ca) Syn= Synthetic antigens (ORF 2,3) (Immunodiagnostics, Ca,USA) Age classes (years)

34. Anti-HEV in the general population of Cagliari Synthetic antigens from ORF2 and ORF3 (BioChem, ImmunoSystem; Bologna, Italy) 1988 (no. Subjects) (214) (229)(237) 1995 (230) (200)(321) 2000 (193) (148)(120) Age classes (years) (Coppola, personal data) %

35. HEV epidemiology in non endemic areas  The diagnostic tool is crucial for the real interpretation of HEV epidemiology in non- endemic areas