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

Steps for the control of hepatitis B through universal programmes of vaccination 1) Set up a programme of routine vaccination (single or double cohort approach) 2)Implement the programme 3)Monitor coverage 4)Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts) 5)Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses) 6)Register possible major adverse events 7)Perform sero-epidemiological studies to confirm that the infection is progressing towards elimination 8)Demonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohorts

Steps for the control of hepatitis B through universal programmes of vaccination Set up a programme of routine vaccination (single or double cohort approach)Set up a programme of routine vaccination (single or double cohort approach) Implement the programmeImplement the programme Monitor coverageMonitor coverage Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts)Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts) Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses)Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses) Register possible major adverse eventsRegister possible major adverse events Perform sero-epidemiological studies to confirm that the infection is progressing towards eliminationPerform sero-epidemiological studies to confirm that the infection is progressing towards elimination Demonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohortsDemonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohorts

Universal hepatitis B vaccination programme in Italy Law n° 165 of May 27, 1991 established:  Compulsory vaccination of infants and of adolescents during their 12 th year of age (end of adolescent programme: 2003)  Mandatory HBsAg screening for all pregnant women during the last 3 months of pregnancy  Active offer of free-of-charge vaccination to subjects belonging to categories at risk

Steps for the control of hepatitis B through universal programmes of vaccination Set up a programme of routine vaccination (single or double cohort approach)Set up a programme of routine vaccination (single or double cohort approach) Implement the programmeImplement the programme Monitor coverageMonitor coverage Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts)Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts) Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses)Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses) Register possible major adverse eventsRegister possible major adverse events Perform sero-epidemiological studies to confirm that the infection is progressing towards eliminationPerform sero-epidemiological studies to confirm that the infection is progressing towards elimination Demonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohortsDemonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohorts

Implementation in Italy of the universal vaccination programme against hepatitis B Programme implemented in most of the country from the beginning of 1992Programme implemented in most of the country from the beginning of 1992 Vaccination administered to infants through public vaccination services or family paediatriciansVaccination administered to infants through public vaccination services or family paediatricians Well-organized public health services for vaccination of adolescents, who are either called to apply to local health agencies or immunized in schoolsWell-organized public health services for vaccination of adolescents, who are either called to apply to local health agencies or immunized in schools Difficult access to some adolescents at risk who escape school attendance in southern regions (65% coverage in 12-year olds in 1994) (Stroffolini et al. Vaccine 1997; 15: )Difficult access to some adolescents at risk who escape school attendance in southern regions (65% coverage in 12-year olds in 1994) (Stroffolini et al. Vaccine 1997; 15: )

Steps for the control of hepatitis B through universal programmes of vaccination Set up a programme of routine vaccination (single or double cohort approach)Set up a programme of routine vaccination (single or double cohort approach) Implement the programmeImplement the programme Monitor coverageMonitor coverage Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts)Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts) Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses)Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses) Register possible major adverse eventsRegister possible major adverse events Perform sero-epidemiological studies to confirm that the infection is progressing towards eliminationPerform sero-epidemiological studies to confirm that the infection is progressing towards elimination Demonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohortsDemonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohorts

Coverage with 3 doses of hepatitis B vaccine (95%confidence intervals) at 24 months of age in 20 Italian Regions, 1998 (Salmaso S. et al., Bull. WHO, 1999) Abruzzo 94.8% ( )Basilicata 99.1% ( )Calabria 94.8% ( ) Campania 97.6% ( )Emilia R. 97.6% ( )Friuli V.G 97.6% ( ) Liguria 97.6% ( )Lombardia 97.6%( )Marche 94.8% ( ) Molise 89.1% ( )Bolzano 85.6% ( )Trento 98.1% ( ) Piemonte 98.6% ( )Puglia 93.0% ( )Sardegna 95.2% ( ) Sicilia 91.1% ( )Toscana 95.2% ( )Umbria 98.6% ( ) Val d’Aosta 100Veneto 97.6% ( )

Coverage of infants and adolescents with 3 doses of hepatitis B vaccine in Tuscany, central Italy (3.5 million inhabitants) (Bonanni P. et al, Pediatr Infect Dis J 1999; 18: ) InfantsAdolescents YearEligibleVaccinated%EligibleVaccinated% TOTAL

Steps for the control of hepatitis B through universal programmes of vaccination Set up a programme of routine vaccination (single or double cohort approach)Set up a programme of routine vaccination (single or double cohort approach) Implement the programmeImplement the programme Monitor coverageMonitor coverage Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts)Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts) Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses)Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses) Register possible major adverse eventsRegister possible major adverse events Perform sero-epidemiological studies to confirm that the infection is progressing towards eliminationPerform sero-epidemiological studies to confirm that the infection is progressing towards elimination Demonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohortsDemonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohorts

Study on the incidence of hepatitis B in Tuscany, Central Italy,  Data on notifications of acute hepatitis B and information on disease cases were collected thanks to the collaboration of Regional Health Authorities  Vaccination status, number and time of possible doses administered were collected for each notified case of acute disease  Modifications of incidence were calculated by 5- year age groups between 0 and 29 years, 10-year age groups between 30 and 49 years, and globally over 50 years of age (Bonanni P et al., Vaccine 2002, in press)

Results  1032 cases of acute hepatitis B were notified in Tuscany from 1994 to 2001 (average yearly incidence: 3,7/100000)  From 1994 to 2001, the incidence in the year age group turned from 14,3 to 3,7/100000; in the year age group it declined from 7,3 to 1,3/ Incidence x 100,000 (Bonanni P et al., Vaccine 2002, in press)

Incidence of acute hepatitis B in selected age groups in Tuscany, Central Italy ( ) (Bonanni P et al., Vaccine 2002, in press)

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-year old girl of Chinese origin born to a HBsAg + mother); 2 in 2001 (men of 36 and 50 years, respectively) 51032TOT CASES IN VACCINEES CASES OF HEPATITIS B YEAR Hepatitis B cases in vaccinated subjects, Tuscany ( ) (Bonanni P et al., Vaccine 2002, in press)

Steps for the control of hepatitis B through universal programmes of vaccination Set up a programme of routine vaccination (single or double cohort approach)Set up a programme of routine vaccination (single or double cohort approach) Implement the programmeImplement the programme Monitor coverageMonitor coverage Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts)Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts) Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses)Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses) Register possible major adverse eventsRegister possible major adverse events Perform sero-epidemiological studies to confirm that the infection is progressing towards eliminationPerform sero-epidemiological studies to confirm that the infection is progressing towards elimination Demonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohortsDemonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohorts

Neurologic adverse events after hepatitis B vaccination in Italy, (source: Ministry of Health, 1999) Paresthesia7 casesParesthesia7 cases Brachial plexus neuropathy3 casesBrachial plexus neuropathy3 cases Guillain-Barré Syndrome2 cases  HLA DR2 and B7Guillain-Barré Syndrome2 cases  HLA DR2 and B7 Convulsions1 caseConvulsions1 case “… considering that, in view of a merely hypothetical and unproven damage, hepatitis B vaccination showed to be highly effective … the recommendation to immunize all infants and adolescents remains unchanged” (Ministry of Health, September 1999)“… considering that, in view of a merely hypothetical and unproven damage, hepatitis B vaccination showed to be highly effective … the recommendation to immunize all infants and adolescents remains unchanged” (Ministry of Health, September 1999) No significant impact of the Multiple Sclerosis scare in France on coverage in ItalyNo significant impact of the Multiple Sclerosis scare in France on coverage in Italy

Steps for the control of hepatitis B through universal programmes of vaccination Set up a programme of routine vaccination (single or double cohort approach)Set up a programme of routine vaccination (single or double cohort approach) Implement the programmeImplement the programme Monitor coverageMonitor coverage Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts)Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts) Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses)Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses) Register possible major adverse eventsRegister possible major adverse events Perform sero-epidemiological studies to confirm that the infection is progressing towards eliminationPerform sero-epidemiological studies to confirm that the infection is progressing towards elimination Demonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohortsDemonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohorts

Study on the prevalence of hepatitis B markers in Tuscany, Central Italy, 2000 In the year 2000, 643 sera from subjects aged 1-50 years were collected in Florence, ItalyIn the year 2000, 643 sera from subjects aged 1-50 years were collected in Florence, Italy Samples from subjects of paediatric age were obtained from the emergency service of a paediatric hospital after exclusion of subjects with immune deficiency or applying for acute infectious diseasesSamples from subjects of paediatric age were obtained from the emergency service of a paediatric hospital after exclusion of subjects with immune deficiency or applying for acute infectious diseases Sera from older subjects were collected in two labs performing routine chemical chemistry analysis. Immune deficient subjects were excludedSera from older subjects were collected in two labs performing routine chemical chemistry analysis. Immune deficient subjects were excluded All samples were made anonymous by lab personnel; the only available data remained age and sex. No information was available on vaccination statusAll samples were made anonymous by lab personnel; the only available data remained age and sex. No information was available on vaccination status

Prevalence of anti-HBs+ sera (>10 mIU/ml) in subjects aged 1-50 years in Tuscany, Central Italy Year2000

Prevalence of anti-HBc and HBsAg positive subjects in Tuscany, year 2000 (2 subjects age 23 yrs) (1 subject age 14 yr) (4 subjects age yrs) Difference of anti-HBc prevalence in vaccinated vs. non vaccinated cohorts: p =

Steps for the control of hepatitis B through universal programmes of vaccination Set up a programme of routine vaccination (single or double cohort approach)Set up a programme of routine vaccination (single or double cohort approach) Implement the programmeImplement the programme Monitor coverageMonitor coverage Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts)Calculate acute morbidity rates by age group (verification of declining incidence in immunized cohorts) Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses)Investigate whether disease cases occur in immunized subjects (wild type or mutant viruses) Register possible major adverse eventsRegister possible major adverse events Perform sero-epidemiological studies to confirm that the infection is progressing towards eliminationPerform sero-epidemiological studies to confirm that the infection is progressing towards elimination Demonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohortsDemonstrate the decline of chronic diseases (cirrhosis, liver cancer) in vaccinated cohorts

Epidemiological impact of universal hepatitis B vaccination in a hyperendemic area (Afragola, southern Italy) (Da Villa G. et al., Res Virol 1998) Pilot project of universal hepatitis B vaccination introduced in 1983Pilot project of universal hepatitis B vaccination introduced in 1983 Incidence of acute hepatitis B before vaccination: 63/100,000Incidence of acute hepatitis B before vaccination: 63/100,000 Anti-HBc and HBsAg prevalence rates: 66.9% and 13.4%Anti-HBc and HBsAg prevalence rates: 66.9% and 13.4% In 1997 (after 15 years of universal infant immunization), the incidence had dropped to 3/1000,000 populationIn 1997 (after 15 years of universal infant immunization), the incidence had dropped to 3/1000,000 population Anti-HBc in 1997: 34.2%; HBsAg in 1997: 3.7% (change from 6.8% to 0.7% in young children and adolescents)Anti-HBc in 1997: 34.2%; HBsAg in 1997: 3.7% (change from 6.8% to 0.7% in young children and adolescents) HBV was involved in 48% of chronic liver pathologies in 1982, but only in 18% in 1997HBV was involved in 48% of chronic liver pathologies in 1982, but only in 18% in 1997

Conclusions (1) Coverage with hepatitis B in infants and adolescents is on average >90%, and exceeds 95% in many areas of ItalyCoverage with hepatitis B in infants and adolescents is on average >90%, and exceeds 95% in many areas of Italy Surveillance on acute hepatitis B cases consistently shows a decline of notifications, especially in the years age groupSurveillance on acute hepatitis B cases consistently shows a decline of notifications, especially in the years age group Data from Tuscany and from the rest of Italy show the virtual absence of acute HB cases in subjects belonging to compulsorily vaccinated cohorts who completed the immunization courseData from Tuscany and from the rest of Italy show the virtual absence of acute HB cases in subjects belonging to compulsorily vaccinated cohorts who completed the immunization course Long-term surveillance on children born to HBsAg positive mothers shows the occurrence of a very limited number of asymptomatic infections in vaccinees. At present, mutant viruses do not pose a threat to universal vaccination programmes in the countryLong-term surveillance on children born to HBsAg positive mothers shows the occurrence of a very limited number of asymptomatic infections in vaccinees. At present, mutant viruses do not pose a threat to universal vaccination programmes in the country

Conclusions (2) Sero-epidemiological data on anonymous sera confirm the high level of protection in the cohorts subject to mandatory vaccinationSero-epidemiological data on anonymous sera confirm the high level of protection in the cohorts subject to mandatory vaccination In Tuscany, no case of reactivity for HBsAg was detected in age groups covered by universal immunization, and only one sample was anti-HBc positive. The difference between immunized and non-immunized cohorts was statistically highly significantIn Tuscany, no case of reactivity for HBsAg was detected in age groups covered by universal immunization, and only one sample was anti-HBc positive. The difference between immunized and non-immunized cohorts was statistically highly significant The steady incidence in older age groups, and the demonstration of the role of sexual and iatrogenic exposures (Stroffolini et al., J Hepatol 2000; 33: ) stress the importance to complement routine immunization with non-immunological preventive measuresThe steady incidence in older age groups, and the demonstration of the role of sexual and iatrogenic exposures (Stroffolini et al., J Hepatol 2000; 33: ) stress the importance to complement routine immunization with non-immunological preventive measures The results presented here consistently demonstrate the deep impact ‘on the field’ of the first universal hepatitis B vaccination programme implemented in an industrialized countryThe results presented here consistently demonstrate the deep impact ‘on the field’ of the first universal hepatitis B vaccination programme implemented in an industrialized country