Evaluation framework of viral hepatitis prevention programmes: examples in Italy Paolo Bonanni Department of Public Health University of Florence, Italy.

Evaluation framework of Evaluation framework of viral hepatitis prevention viral hepatitis prevention

programmes: programmes: examples in Italyexamples in Italy

Paolo BonanniPaolo Bonanni

Department of Public HealthDepartment of Public HealthUniversity of Florence, ItalyUniversity of Florence, Italy

Steps for the control of hepatitis B through Steps for the control of hepatitis B through universal programmes of vaccinationuniversal programmes of vaccination

1)1) Set up a programme of routine vaccination Set up a programme of routine vaccination (single or (single or double cohort approach)double cohort approach)

2)2) Implement the programmeImplement the programme

3)3) Monitor coverageMonitor coverage

4)4) Calculate acute morbidity rates by age group Calculate acute morbidity rates by age group (verification of declining incidence in immunized (verification of declining incidence in immunized cohorts)cohorts)

5)5) Investigate whether disease cases occur in Investigate whether disease cases occur in immunized immunized subjects (wild type or mutant viruses)subjects (wild type or mutant viruses)

6)6) Register possible major adverse eventsRegister possible major adverse events

7)7) Perform sero-epidemiological studies to confirm Perform sero-epidemiological studies to confirm that that the infection is progressing towards eliminationthe infection is progressing towards elimination

8)8) Demonstrate the decline of chronic diseases Demonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohorts(cirrhosis, liver cancer) in vaccinated cohorts


• Set up a programme of routine vaccination (single or Set up a programme of routine vaccination (single or double cohort approach)double cohort approach)

• Implement the programmeImplement the programme• Monitor coverageMonitor coverage• Calculate acute morbidity rates by age group Calculate acute morbidity rates by age group

(verification of declining incidence in immunized (verification of declining incidence in immunized cohorts)cohorts)

• Investigate whether disease cases occur in immunized Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses)subjects (wild type or mutant viruses)

• Register possible major adverse eventsRegister possible major adverse events• Perform sero-epidemiological studies to confirm that the Perform sero-epidemiological studies to confirm that the

infection is progressing towards eliminationinfection is progressing towards elimination• Demonstrate the decline of chronic diseases (cirrhosis, Demonstrate the decline of chronic diseases (cirrhosis,

liver cancer) in vaccinated cohortsliver cancer) in vaccinated cohorts

Universal hepatitis B vaccination Universal hepatitis B vaccination programme in Italyprogramme in Italy

Law n° 165 of May 27, 1991 established:Law n° 165 of May 27, 1991 established: Compulsory vaccination of infants and of Compulsory vaccination of infants and of

adolescents during their 12adolescents during their 12thth year of age (end of year of age (end of adolescent programme: 2003)adolescent programme: 2003)

Mandatory HBsAg screening for all pregnant Mandatory HBsAg screening for all pregnant women during the last 3 months of pregnancywomen during the last 3 months of pregnancy

Active offer of free-of-charge vaccination to Active offer of free-of-charge vaccination to subjects belonging to categories at risksubjects belonging to categories at risk









Implementation in Italy of the universal Implementation in Italy of the universal vaccination programme against hepatitis Bvaccination programme against hepatitis B

• Programme implemented in most of the country Programme implemented in most of the country from the beginning of 1992from the beginning of 1992

• Vaccination administered to infants through public Vaccination administered to infants through public vaccination services or family paediatriciansvaccination services or family paediatricians

• Well-organized public health services for Well-organized public health services for vaccination of adolescents, who are either called to vaccination of adolescents, who are either called to apply to local health agencies or immunized in apply to local health agencies or immunized in schoolsschools

• Difficult access to some adolescents at risk who Difficult access to some adolescents at risk who escape school attendance in southern regions escape school attendance in southern regions (65% coverage in 12-year olds in 1994) (65% coverage in 12-year olds in 1994) (Stroffolini et al. (Stroffolini et al. Vaccine 1997; 15: 583-585)Vaccine 1997; 15: 583-585)









Coverage with 3 doses of hepatitis B vaccine Coverage with 3 doses of hepatitis B vaccine (95%confidence intervals) at 24 months of (95%confidence intervals) at 24 months of

age in 20 Italian Regions, 1998 age in 20 Italian Regions, 1998 (Salmaso S. et al., Bull. WHO, 1999)(Salmaso S. et al., Bull. WHO, 1999)

Abruzzo 94.8% (91.4-98.2)Abruzzo 94.8% (91.4-98.2) Basilicata 99.1% (97.8-100)Basilicata 99.1% (97.8-100) Calabria 94.8% (91.7-97.9)Calabria 94.8% (91.7-97.9)

Campania 97.6% (81.3-93.9)Campania 97.6% (81.3-93.9) Emilia R. 97.6% (95.7-99.6)Emilia R. 97.6% (95.7-99.6) Friuli V.G 97.6% (95.7-99.6)Friuli V.G 97.6% (95.7-99.6)

Liguria 97.6% (95.3-100)Liguria 97.6% (95.3-100) Lombardia 97.6%(95.7-99.6)Lombardia 97.6%(95.7-99.6) Marche 94.8% (90.4-99.1)Marche 94.8% (90.4-99.1)

Molise 89.1% (82.0-96.3)Molise 89.1% (82.0-96.3) Bolzano 85.6% (80.6-90.7)Bolzano 85.6% (80.6-90.7) Trento 98.1% (96.3-99.9)Trento 98.1% (96.3-99.9)

Piemonte 98.6% (95.8-100)Piemonte 98.6% (95.8-100) Puglia 93.0% (89.1-96.9)Puglia 93.0% (89.1-96.9) Sardegna 95.2% (92.4-98.0)Sardegna 95.2% (92.4-98.0)

Sicilia 91.1% (86.1-96.1)Sicilia 91.1% (86.1-96.1) Toscana 95.2% (92.4-98.0)Toscana 95.2% (92.4-98.0) Umbria 98.6% (97.0-100)Umbria 98.6% (97.0-100)

Val d’Aosta 100Val d’Aosta 100 Veneto 97.6% (95.7-99.6)Veneto 97.6% (95.7-99.6)

Coverage of infants and adolescents with 3 doses of Coverage of infants and adolescents with 3 doses of hepatitis B vaccine in Tuscany, central Italy hepatitis B vaccine in Tuscany, central Italy

(3.5 million inhabitants)(3.5 million inhabitants)(Bonanni P. et al, Pediatr Infect Dis J 1999; 18: 677-82)(Bonanni P. et al, Pediatr Infect Dis J 1999; 18: 677-82)

InfantsInfants AdolescentsAdolescents

YearYear EligibleEligible VaccinatedVaccinated %% EligibleEligible VaccinatedVaccinated%%

19921992 1111 1111 1061 1061 95.595.5 15601560 1540 154098.798.7

19931993 2122 2122 1922 1922 90.590.5 15941594 1512 151294.894.8

19941994 2109 2109 2053 2053 97.397.3 19321932 1812 181293.793.7

19951995 1995 1995 1935 1935 97.097.0 20552055 1968 196895.795.7

19961996 2060 2060 1943 1943 94.394.3 21662166 2065 206595.395.3

19971997 1767 1767 1692 1692 95.895.8 17931793 1702 170294.994.9

TOTALTOTAL 11164 11164 10606 10606 95.095.0 1110011100 10599 1059995.495.4









Study on the incidence of hepatitis B in Study on the incidence of hepatitis B in Tuscany, Central Italy, 1994-2001Tuscany, Central Italy, 1994-2001

Data on notifications of acute hepatitis B and Data on notifications of acute hepatitis B and information on disease cases were collected thanks information on disease cases were collected thanks to the collaboration of Regional Health Authoritiesto the collaboration of Regional Health Authorities

Vaccination status, number and time of possible Vaccination status, number and time of possible doses administered were collected for each notified doses administered were collected for each notified case of acute disease case of acute disease

Modifications of incidence were calculated by 5-Modifications of incidence were calculated by 5-year age groups between 0 and 29 years, 10-year year age groups between 0 and 29 years, 10-year age groups between 30 and 49 years, and globally age groups between 30 and 49 years, and globally over 50 years of ageover 50 years of age

(Bonanni P et al., (Bonanni P et al., VaccineVaccine 2002, in press) 2002, in press)

ResultsResults 1032 cases of acute hepatitis B were notified in Tuscany 1032 cases of acute hepatitis B were notified in Tuscany

from 1994 to 2001 (average yearly incidence: 3,7/100000)from 1994 to 2001 (average yearly incidence: 3,7/100000) From 1994 to 2001, the incidence in the 20-24 year age From 1994 to 2001, the incidence in the 20-24 year age

group turned from 14,3 to 3,7/100000; in the 15-19 year group turned from 14,3 to 3,7/100000; in the 15-19 year age group it declined from 7,3 to 1,3/100000age group it declined from 7,3 to 1,3/100000

0

2

4

6

8

10

12

14

16

18

1994 1995 1996 1997 1998 1999 2000 2001

0 - 4

5 - 9

10 - 14

15 - 19

20 - 24

25 - 29

30 - 39

40 - 49

50 - 90

Inci

den

ce

x 1

00,0

00In

cid

enc

e x

100

,000


0

2

4

6

8

10

12

14

16

18

Inci

denz

a x

1000

00

1994 1995 1996 1997 1998 1999 2000 2001

15 - 19

0

2

4

6

8

10

12

14

16

18

Incid

enza

x 10

0000

1994 1995 1996 1997 1998 1999 2000 2001

20 - 24

0

2

4

6

8

10

12

14

16

18

Incid

en

za x

100000

1994 1995 1996 1997 1998 1999 2000 2001

25 - 29

0

2

4

6

8

10

12

14

16

18

Inc

ide

nza

x 1

00

00

0

1994 1995 1996 1997 1998 1999 2000 2001

30 - 39

Incidence of acute hepatitis B in selected age Incidence of acute hepatitis B in selected age groups in Tuscany, Central Italy (1994-2001)groups in Tuscany, Central Italy (1994-2001)


5 subjects with acute hepatitis B had received 3 doses of vaccine: 5 subjects with acute hepatitis B had received 3 doses of vaccine: 2 in 1994 (11-month old infant and 36-year old woman); 1 in 2000 2 in 1994 (11-month old infant and 36-year old woman); 1 in 2000 (2-year old girl of Chinese origin born to a HBsAg + mother); 2 in (2-year old girl of Chinese origin born to a HBsAg + mother); 2 in

2001 (men of 36 and 50 years, respectively)2001 (men of 36 and 50 years, respectively)

5510321032TOTTOT

2211011020012001

1111411420002000

0013813819991999

0015815819981998

0012912919971997

0012012019961996

0012412419951995

2213913919941994

CASES IN VACCINEESCASES IN VACCINEESCASES OF HEPATITIS BCASES OF HEPATITIS BYEARYEAR

Hepatitis B cases in vaccinated subjects, Hepatitis B cases in vaccinated subjects, Tuscany (1994-2001)Tuscany (1994-2001)










Neurologic adverse events after hepatitis B Neurologic adverse events after hepatitis B vaccination in Italy, 1991-1996vaccination in Italy, 1991-1996

(source: Ministry of Health, 1999)(source: Ministry of Health, 1999)

• ParesthesiaParesthesia 7 cases7 cases

• Brachial plexus neuropathyBrachial plexus neuropathy 3 cases3 cases

• Guillain-Barré SyndromeGuillain-Barré Syndrome 2 cases 2 cases HLA DR2 and B7 HLA DR2 and B7

• ConvulsionsConvulsions 1 case1 case

• “… “… considering that, in view of a merely hypothetical and considering that, in view of a merely hypothetical and unproven damage, hepatitis B vaccination showed to be highly unproven damage, hepatitis B vaccination showed to be highly effective … the recommendation to immunize all infants and effective … the recommendation to immunize all infants and adolescents remains unchanged”adolescents remains unchanged” (Ministry of Health, (Ministry of Health, September 1999)September 1999)

• No significant impact of the Multiple Sclerosis scare in France No significant impact of the Multiple Sclerosis scare in France on coverage in Italyon coverage in Italy









Study on the prevalence of hepatitis B Study on the prevalence of hepatitis B markers in Tuscany, Central Italy, 2000markers in Tuscany, Central Italy, 2000

• In the year 2000, 643 sera from subjects aged 1-50 In the year 2000, 643 sera from subjects aged 1-50 years were collected in Florence, Italyyears were collected in Florence, Italy

• Samples from subjects of paediatric age were Samples from subjects of paediatric age were obtained from the emergency service of a paediatric obtained from the emergency service of a paediatric hospital after exclusion of subjects with immune hospital after exclusion of subjects with immune deficiency or applying for acute infectious diseasesdeficiency or applying for acute infectious diseases

• Sera from older subjects were collected in two labs Sera from older subjects were collected in two labs performing routine chemical chemistry analysis. performing routine chemical chemistry analysis. Immune deficient subjects were excludedImmune deficient subjects were excluded

• All samples were made anonymous by lab All samples were made anonymous by lab personnel; the only available data remained age personnel; the only available data remained age and sex. No information was available on and sex. No information was available on vaccination statusvaccination status

Prevalence of anti-HBs+ sera (>10 mIU/ml) in Prevalence of anti-HBs+ sera (>10 mIU/ml) in subjects aged 1-50 years in Tuscany, Central Italysubjects aged 1-50 years in Tuscany, Central Italy

Year2000 Year2000

96

71

90

36

20 2015

23

8

63

010

20304050

607080

90100

1-5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50

Age

8693

83

1725

5044

81

100

90

100

8893 93

79

50

2922

79

10010097 97

0

10

20

30

40

50

60

70

80

90

100

Age

Prevalence of anti-HBc and HBsAg positive Prevalence of anti-HBc and HBsAg positive subjects in Tuscany, year 2000subjects in Tuscany, year 2000

2,331,2

4,8

0

2

4

6

8

10

12

14

16

18

20

1-10 11-20 21-30 31-40 41-50

Age

(2 subjects age 23 yrs)

0 0,9

9,3 9,3

17,3

0

10

20

1-10 11-20 21-30 31-40 41-50

Age

(1 subject age 14 yr)

(4 subjects age 22-23 yrs)

Difference of anti-HBc Difference of anti-HBc prevalence in vaccinated vs.prevalence in vaccinated vs.non vaccinated cohorts:non vaccinated cohorts:p = 0.0001p = 0.0001









Epidemiological impact of universal hepatitis Epidemiological impact of universal hepatitis B vaccination in a hyperendemic area B vaccination in a hyperendemic area

(Afragola, southern Italy)(Afragola, southern Italy)(Da Villa G. et al., Res Virol 1998)(Da Villa G. et al., Res Virol 1998)

• Pilot project of universal hepatitis B vaccination Pilot project of universal hepatitis B vaccination introduced in 1983introduced in 1983

• Incidence of acute hepatitis B before vaccination: Incidence of acute hepatitis B before vaccination: 63/100,00063/100,000

• Anti-HBc and HBsAg prevalence rates: 66.9% and Anti-HBc and HBsAg prevalence rates: 66.9% and 13.4%13.4%

• In 1997 (after 15 years of universal infant In 1997 (after 15 years of universal infant immunization), the incidence had dropped to immunization), the incidence had dropped to 3/1000,000 population3/1000,000 population

• Anti-HBc in 1997: 34.2%; HBsAg in 1997: 3.7% Anti-HBc in 1997: 34.2%; HBsAg in 1997: 3.7% (change from 6.8% to 0.7% in young children and (change from 6.8% to 0.7% in young children and adolescents)adolescents)

• HBV was involved in 48% of chronic liver pathologies HBV was involved in 48% of chronic liver pathologies in 1982, but only in 18% in 1997in 1982, but only in 18% in 1997

Conclusions (1)Conclusions (1)• Coverage with hepatitis B in infants and adolescents is on Coverage with hepatitis B in infants and adolescents is on

average >90%, and exceeds 95% in many areas of Italyaverage >90%, and exceeds 95% in many areas of Italy

• Surveillance on acute hepatitis B cases consistently shows a Surveillance on acute hepatitis B cases consistently shows a decline of notifications, especially in the 15-24 years age decline of notifications, especially in the 15-24 years age group group

• Data from Tuscany and from the rest of Italy show the Data from Tuscany and from the rest of Italy show the virtual absence of acute HB cases in subjects belonging to virtual absence of acute HB cases in subjects belonging to compulsorily vaccinated cohorts who completed the compulsorily vaccinated cohorts who completed the immunization courseimmunization course

• Long-term surveillance on children born to HBsAg positive Long-term surveillance on children born to HBsAg positive mothers shows the occurrence of a very limited number of mothers shows the occurrence of a very limited number of asymptomatic infections in vaccinees. At present, mutant asymptomatic infections in vaccinees. At present, mutant viruses do not pose a threat to universal vaccination viruses do not pose a threat to universal vaccination programmes in the countryprogrammes in the country

Conclusions (2)Conclusions (2)• Sero-epidemiological data on anonymous sera confirm the Sero-epidemiological data on anonymous sera confirm the

high level of protection in the cohorts subject to mandatory high level of protection in the cohorts subject to mandatory vaccinationvaccination

• In Tuscany, no case of reactivity for HBsAg was detected in In Tuscany, no case of reactivity for HBsAg was detected in age groups covered by universal immunization, and only one age groups covered by universal immunization, and only one sample was anti-HBc positive. The difference between sample was anti-HBc positive. The difference between immunized and non-immunized cohorts was statistically immunized and non-immunized cohorts was statistically highly significanthighly significant

• The steady incidence in older age groups, and the The steady incidence in older age groups, and the demonstration of the role of sexual and iatrogenic exposures demonstration of the role of sexual and iatrogenic exposures (Stroffolini et al., J Hepatol 2000; 33: 980-985)(Stroffolini et al., J Hepatol 2000; 33: 980-985) stress the importance to stress the importance to complement routine immunization with non-immunological complement routine immunization with non-immunological preventive measurespreventive measures

• The results presented here consistently demonstrate the deep The results presented here consistently demonstrate the deep impact ‘on the field’ of the first universal hepatitis B impact ‘on the field’ of the first universal hepatitis B vaccination programme implemented in an industrialized vaccination programme implemented in an industrialized countrycountry

Evaluation framework of viral hepatitis prevention programmes: examples in Italy Paolo Bonanni Department of Public Health University of Florence, Italy.

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