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Rationale for the infant and adolescent vaccination programmes in Italy
Vaccine 18 (2000) S31±S34
www.elsevier.com/locate/vaccine
Rationale for the infant and adolescent vaccination programmes in Italy Giuliano Da Villa* Italian Institute for the Prevention of Liver Diseases, Institute ``Fernando de Ritis'', Via Generale Orsini, 42-80132 Naples, Italy
Abstract In Italy in the 1980s, the incidence of acute hepatitis B was about 13 per 100,000, corresponding on average to 7500 new symptomatic cases per year was about 3%, making Italy an area of intermediate endemicity. HBV infection was also associated with 12 per 100,000 deaths from cirrhosis and with 5.1 per 100,000 deaths from hepatocellular carcinoma. In view of the large numbers of pregnant women who were hepatitis B surface antigen (HBsAg)-positive, selective hepatitis B vaccination of all newborns to these mothers and of other high-risk groups was introduced in 1983. Compliance was high among the newborns but low in other high-risk groups. Hepatitis vaccination was adopted in Italy in 1991, including each year all newborns, all adolescents aged 12 years and other high-risk groups. Compliance has been nearly 95% for newborns and 80% for adolescents. Since the introduction of vaccination, both the incidence of acute hepatitis B and the prevalence of HBV carriage have fallen, the latter from 3.4% in 1985 to 0.9% in 1996. There is good evidence that these decreases are mainly the result of the vaccination programmes. Although the full economic impact cannot yet be assessed, about 18,000 cases of acute HBV infection have been prevented over the 6 years since starting the mass vaccination programme, with cost savings of about US$ 244,308,000. # 2000 Published by Elsevier Science Ltd. All rights reserved. Keywords: Hepatitis B; Epidemiology; Italy; Vaccination programme; Health impact; Economic impact
This paper describes the epidemiological situation in Italy with reference to hepatitis B virus (HBV), the vaccination strategy in Italy, which occurred in two phases (selective vaccination adopted in 1983 and mass vaccination adopted in 1991), and the health and economic impact of these vaccination programmes on the Italian population. 1. Epidemiology of HBV in Italy In the 1980s, the incidence of acute viral hepatitis B in Italy was about 13 per 100,000, corresponding on average to 7500 new symptomatic cases per year noti®ed to the National Recording System. The epidemiological situation in Italy was moderate, as in other * Tel.: +39-081-8511002; fax: +39-081-851029.
Mediterranean countries. However, it was notable that in the north of Italy the acute viral hepatitis B incidence in groups of subjects aged 0±14 years was 1 while in the south of the country it was 15; on the other hand the acute viral hepatitis B incidence in the groups of subjects aged 15±24 years was 45 and 32 respectively [1]. The prevalence of HBV surface antigen (HBsAg) was 3% in blood donors in 1980 [2], 3.4% in navy recruits in 1985 [3] and 2.4% in pregnant women in 1988 [4]. Thus, during this time, Italy was an area of intermediate endemicity. In the same period of time, liver cirrhosis was prevalent in over 600,000 cases, of which 10.6% (64,000 cases) were HBV related. The mortality rate for cirrhosis was on average 25.8% per year while the mortality rate for hepatocellular carcinoma was on average 8.8 per 100,000 HBV related [5].
0264-410X/00/$ - see front matter # 2000 Published by Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 9 9 ) 0 0 4 5 9 - 4
S32
G. Da Villa / Vaccine 18 (2000) S31±S34
2. Vaccination programmes in Italy The large numbers of pregnant women in the population who were HBV carriers (2.4%) indicated that nearly 14,000 newborn babies were at risk of infection at birth. This meant that the reservoir of carriers in the country would increase, because about 90% of those infected at birth by hepatitis B e antigen carrier mothers can become carriers. For this reason, selective vaccination against hepatitis B was adopted in Italy in 1983, extending to all newborns of hepatitis B surface antigen (HBsAg)-positive mothers and certain high-risk groups: health workers, poly-transfused people, family members of HBsAgpositive carriers, prisoners, drug addicts, etc. The vaccine used was plasma-derived, and was given free of charge. Compliance was high among newborns of HBsAg-positive mothers, but low in the high-risk groups, particularly among family members of carriers in the community. When DNA recombinant vaccines became available, the vaccination against viral hepatitis B was extended to all newborn babies and adolescents aged 12 years. According to this universal vaccination programme about 500,000 newborn babies and 600,000 adolescents are compulsory immunized every year in Italy. 2.1. Vaccination schedules Dierent vaccination schedules are used. Babies born to HBsAg-positive mothers are given four pae-
diatric doses of DNA hepatitis vaccine, starting at birth and then at months 2, 3 and 11. At months 3, 5 and 11, they also received a dose of oral polio vaccine and the combined diphtheria/pertussis/tetanus vaccine. Babies born to HBV-negative mothers received three paediatric doses of DNA hepatitis B vaccine at months 3, 5 and 11, together with oral polio vaccine and the combined diphtheria/pertussis/tetanus vaccine. Three adult doses of DNA hepatitis B vaccine were also given to adolescents and adults belonging to the high risk groups. An initial dose at time 0, with boosters after 1 and 6 months. 2.2. Vaccine administration network Administration of the vaccination programme in Italy was undertaken by 2800 vaccine dispensaries, coordinated by the regional health services and ultimately by the Ministry of Health. Compliance with the mass vaccination programme reached nearly 95% for newborns and 80% for adolescents.
3. Health impact of the vaccination programmes The incidences of acute viral hepatitis infection from 1970 to 1996 and of acute HBV infection from 1983 to 1996 are shown in Fig. 1. It is evident that since 1986 there has been a reduction in the incidence of all kinds of acute viral hepatitis in Italy, including viral hepatitis B. In fact, the incidence rates were: 24 per 100,000 in
100
Cases of acute viral hepatitis/100 000
90 80
Hepatitis B high risk groups vaccination
Hepatitis B universal vaccination
70 60 50 Acute viral hepatitis Acute viral hepatitis B
40 30 20 10 0
1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1995 1996
Year Fig. 1. Incidence of acute viral hepatitis ocially noti®ed in Italy, 1970±1996.
G. Da Villa / Vaccine 18 (2000) S31±S34
S33
44
Cases of acute viral hepatitis/100 000
42 40 38 36 34 32 30 28 26 24
Hepatitis B
22
vaccination introduced
20 18 16 14 12 10 8 6 4 2 0 1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
15Ð24 years old
v
Years 25 years old
0Ð14 years old
Fig. 2. Age-speci®c incidence of HBV infection in Italy, 1985±1996.
1980, 13 per 100,000 in 1985, 6.4 per 100,000 in 1990 and 4.2 per 100,000 in 1996. With this fall there was a corresponding reduction of HBsAg carrier prevalence rate as follows: 3% in 1980, 3.4% in 1985, 1.6% in 1990 and 0.9% in 1996. The age-speci®c incidence of HBV infection was greatest in the 15±24-year age group, and it was in this group that the greatest reduction was seen (Fig. 2). The improvement in the epidemiological status of HBV infection in Italy might have been related to the vaccination programme, or to improvements in hygiene conditions, particularly safer blood transfusions, safer sex and use of disposable syringes. In this regard, we have to emphasize that the mass vaccination strategy not only directly protects those who are vaccinated but also protects non-vaccinated people through a reduction in the number of carriers in the population. This means there is less infection because of the weakening of the carrier status in the environment. Based on this observation, we believe that mass vaccination against hepatitis B in Italy played a large part in reducing the incidence and prevalence rates. This hypothesis is supported by ®ndings from a previous study carried out by the author in two neighbouring towns near Naples, Afragola and Frattamaggiore, where dierent vaccination strategies were performed from 1983 to 1993. The two districts had comparable HBV endemicity levels and social indicators, but universal vaccination was employed in Afragola, while in Frattamaggiore only selective vaccination of high-risk groups was carried out. After several years, the reduction in incidence was more marked in Afragola than in Frattamaggiore [6].
4. Economic impact of the vaccination programmes in Italy Assessment of the economic impact of mass vaccination must take into account on the one hand the vaccination cost, including the total expenditure (vaccine purchase, the vaccine administration, its storage, etc), and on the other hand the assistant and social costs concerning the treatment of the patients and their working days lost due to HBV infection. The direct and indirect costs of vaccination in Italy are about US$ 61 million per year, compared with annual costs of about US$ 888 million associated with HBVrelated disease, excluding the interferon therapy and liver transplantation costs. As it is necessary to wait for 15±20 years to evaluate the impact of mass vaccination on chronic infection and sequelae (HBV related cirrhosis and hepatitis C virus), at the moment it is possible to evaluate only the economic saving of acute viral hepatitis cases avoided thanks to vaccination. In this regard, we compared the cases that occurred in 6 years, from 1991 to 1996, to those that occurred from 1985 to 1990. This comparison showed a global reduction of 18,006 new cases, corresponding to a saving of US$ 244,308,000.
5. Conclusion It is demonstrated, therefore, that decreases in the incidence of acute hepatitis B and the prevalence of HBV carriage have mainly occurred as a consequence of vaccination programmes which, while full economic
S34
G. Da Villa / Vaccine 18 (2000) S31±S34
impact is yet to be measured, do have tangible economic bene®ts.
References [1] Mele A, Conti S, Gill ON, et al. Sistema epidemiologico integrato dell'epatite virale acuta. Rapporto ISTISAN 1987;1:1±30. [2] Giusti G, Galanti B, Gaeta GB, Piccinino F, Ruggiero G. HBsAg carriers among blood donors in Italy: A retrospective survey of data from 189 blood banks. Hepatogastroenterol 1981;28:96±8. [3] Pasquini P, Kahn HA, Pileggi D, Pana A, Terzi J, Guzzanti E.
Prevalence of hepatitis B markers in Italy. Am J Epidemiol 1983;118:699±709. [4] Stroolini T, Pasquini P, Mele A. HBsAg carriers among pregnant women in Italy: results from the screening during a vaccination campaign against hepatitis B. Public Health 1988;102:329±33. [5] Giusti G, Sagnelli E, Gallo C, et al. Etiology of chronic hepatitis in the 1979±1989 period. A multicenter study of the Italian Association for the study of the liver. In: Gentilini P, Dianzani MU, editors. Experimental and clinical hepatology. UK: Elsevier, 1991. p. 155. [6] Da Villa G, Picciotto L, Elia S, Peluso F, Montanaro F, Maisto T. Hepatitis B vaccination: Universal vaccination of new-born babies and at 12 years of age versus high-risk groups. A comparison in the ®eld. Vaccine 1995;13:1240±3.
www.elsevier.com/locate/vaccine
Rationale for the infant and adolescent vaccination programmes in Italy Giuliano Da Villa* Italian Institute for the Prevention of Liver Diseases, Institute ``Fernando de Ritis'', Via Generale Orsini, 42-80132 Naples, Italy
Abstract In Italy in the 1980s, the incidence of acute hepatitis B was about 13 per 100,000, corresponding on average to 7500 new symptomatic cases per year was about 3%, making Italy an area of intermediate endemicity. HBV infection was also associated with 12 per 100,000 deaths from cirrhosis and with 5.1 per 100,000 deaths from hepatocellular carcinoma. In view of the large numbers of pregnant women who were hepatitis B surface antigen (HBsAg)-positive, selective hepatitis B vaccination of all newborns to these mothers and of other high-risk groups was introduced in 1983. Compliance was high among the newborns but low in other high-risk groups. Hepatitis vaccination was adopted in Italy in 1991, including each year all newborns, all adolescents aged 12 years and other high-risk groups. Compliance has been nearly 95% for newborns and 80% for adolescents. Since the introduction of vaccination, both the incidence of acute hepatitis B and the prevalence of HBV carriage have fallen, the latter from 3.4% in 1985 to 0.9% in 1996. There is good evidence that these decreases are mainly the result of the vaccination programmes. Although the full economic impact cannot yet be assessed, about 18,000 cases of acute HBV infection have been prevented over the 6 years since starting the mass vaccination programme, with cost savings of about US$ 244,308,000. # 2000 Published by Elsevier Science Ltd. All rights reserved. Keywords: Hepatitis B; Epidemiology; Italy; Vaccination programme; Health impact; Economic impact
This paper describes the epidemiological situation in Italy with reference to hepatitis B virus (HBV), the vaccination strategy in Italy, which occurred in two phases (selective vaccination adopted in 1983 and mass vaccination adopted in 1991), and the health and economic impact of these vaccination programmes on the Italian population. 1. Epidemiology of HBV in Italy In the 1980s, the incidence of acute viral hepatitis B in Italy was about 13 per 100,000, corresponding on average to 7500 new symptomatic cases per year noti®ed to the National Recording System. The epidemiological situation in Italy was moderate, as in other * Tel.: +39-081-8511002; fax: +39-081-851029.
Mediterranean countries. However, it was notable that in the north of Italy the acute viral hepatitis B incidence in groups of subjects aged 0±14 years was 1 while in the south of the country it was 15; on the other hand the acute viral hepatitis B incidence in the groups of subjects aged 15±24 years was 45 and 32 respectively [1]. The prevalence of HBV surface antigen (HBsAg) was 3% in blood donors in 1980 [2], 3.4% in navy recruits in 1985 [3] and 2.4% in pregnant women in 1988 [4]. Thus, during this time, Italy was an area of intermediate endemicity. In the same period of time, liver cirrhosis was prevalent in over 600,000 cases, of which 10.6% (64,000 cases) were HBV related. The mortality rate for cirrhosis was on average 25.8% per year while the mortality rate for hepatocellular carcinoma was on average 8.8 per 100,000 HBV related [5].
0264-410X/00/$ - see front matter # 2000 Published by Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 9 9 ) 0 0 4 5 9 - 4
S32
G. Da Villa / Vaccine 18 (2000) S31±S34
2. Vaccination programmes in Italy The large numbers of pregnant women in the population who were HBV carriers (2.4%) indicated that nearly 14,000 newborn babies were at risk of infection at birth. This meant that the reservoir of carriers in the country would increase, because about 90% of those infected at birth by hepatitis B e antigen carrier mothers can become carriers. For this reason, selective vaccination against hepatitis B was adopted in Italy in 1983, extending to all newborns of hepatitis B surface antigen (HBsAg)-positive mothers and certain high-risk groups: health workers, poly-transfused people, family members of HBsAgpositive carriers, prisoners, drug addicts, etc. The vaccine used was plasma-derived, and was given free of charge. Compliance was high among newborns of HBsAg-positive mothers, but low in the high-risk groups, particularly among family members of carriers in the community. When DNA recombinant vaccines became available, the vaccination against viral hepatitis B was extended to all newborn babies and adolescents aged 12 years. According to this universal vaccination programme about 500,000 newborn babies and 600,000 adolescents are compulsory immunized every year in Italy. 2.1. Vaccination schedules Dierent vaccination schedules are used. Babies born to HBsAg-positive mothers are given four pae-
diatric doses of DNA hepatitis vaccine, starting at birth and then at months 2, 3 and 11. At months 3, 5 and 11, they also received a dose of oral polio vaccine and the combined diphtheria/pertussis/tetanus vaccine. Babies born to HBV-negative mothers received three paediatric doses of DNA hepatitis B vaccine at months 3, 5 and 11, together with oral polio vaccine and the combined diphtheria/pertussis/tetanus vaccine. Three adult doses of DNA hepatitis B vaccine were also given to adolescents and adults belonging to the high risk groups. An initial dose at time 0, with boosters after 1 and 6 months. 2.2. Vaccine administration network Administration of the vaccination programme in Italy was undertaken by 2800 vaccine dispensaries, coordinated by the regional health services and ultimately by the Ministry of Health. Compliance with the mass vaccination programme reached nearly 95% for newborns and 80% for adolescents.
3. Health impact of the vaccination programmes The incidences of acute viral hepatitis infection from 1970 to 1996 and of acute HBV infection from 1983 to 1996 are shown in Fig. 1. It is evident that since 1986 there has been a reduction in the incidence of all kinds of acute viral hepatitis in Italy, including viral hepatitis B. In fact, the incidence rates were: 24 per 100,000 in
100
Cases of acute viral hepatitis/100 000
90 80
Hepatitis B high risk groups vaccination
Hepatitis B universal vaccination
70 60 50 Acute viral hepatitis Acute viral hepatitis B
40 30 20 10 0
1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1995 1996
Year Fig. 1. Incidence of acute viral hepatitis ocially noti®ed in Italy, 1970±1996.
G. Da Villa / Vaccine 18 (2000) S31±S34
S33
44
Cases of acute viral hepatitis/100 000
42 40 38 36 34 32 30 28 26 24
Hepatitis B
22
vaccination introduced
20 18 16 14 12 10 8 6 4 2 0 1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
15Ð24 years old
v
Years 25 years old
0Ð14 years old
Fig. 2. Age-speci®c incidence of HBV infection in Italy, 1985±1996.
1980, 13 per 100,000 in 1985, 6.4 per 100,000 in 1990 and 4.2 per 100,000 in 1996. With this fall there was a corresponding reduction of HBsAg carrier prevalence rate as follows: 3% in 1980, 3.4% in 1985, 1.6% in 1990 and 0.9% in 1996. The age-speci®c incidence of HBV infection was greatest in the 15±24-year age group, and it was in this group that the greatest reduction was seen (Fig. 2). The improvement in the epidemiological status of HBV infection in Italy might have been related to the vaccination programme, or to improvements in hygiene conditions, particularly safer blood transfusions, safer sex and use of disposable syringes. In this regard, we have to emphasize that the mass vaccination strategy not only directly protects those who are vaccinated but also protects non-vaccinated people through a reduction in the number of carriers in the population. This means there is less infection because of the weakening of the carrier status in the environment. Based on this observation, we believe that mass vaccination against hepatitis B in Italy played a large part in reducing the incidence and prevalence rates. This hypothesis is supported by ®ndings from a previous study carried out by the author in two neighbouring towns near Naples, Afragola and Frattamaggiore, where dierent vaccination strategies were performed from 1983 to 1993. The two districts had comparable HBV endemicity levels and social indicators, but universal vaccination was employed in Afragola, while in Frattamaggiore only selective vaccination of high-risk groups was carried out. After several years, the reduction in incidence was more marked in Afragola than in Frattamaggiore [6].
4. Economic impact of the vaccination programmes in Italy Assessment of the economic impact of mass vaccination must take into account on the one hand the vaccination cost, including the total expenditure (vaccine purchase, the vaccine administration, its storage, etc), and on the other hand the assistant and social costs concerning the treatment of the patients and their working days lost due to HBV infection. The direct and indirect costs of vaccination in Italy are about US$ 61 million per year, compared with annual costs of about US$ 888 million associated with HBVrelated disease, excluding the interferon therapy and liver transplantation costs. As it is necessary to wait for 15±20 years to evaluate the impact of mass vaccination on chronic infection and sequelae (HBV related cirrhosis and hepatitis C virus), at the moment it is possible to evaluate only the economic saving of acute viral hepatitis cases avoided thanks to vaccination. In this regard, we compared the cases that occurred in 6 years, from 1991 to 1996, to those that occurred from 1985 to 1990. This comparison showed a global reduction of 18,006 new cases, corresponding to a saving of US$ 244,308,000.
5. Conclusion It is demonstrated, therefore, that decreases in the incidence of acute hepatitis B and the prevalence of HBV carriage have mainly occurred as a consequence of vaccination programmes which, while full economic
S34
G. Da Villa / Vaccine 18 (2000) S31±S34
impact is yet to be measured, do have tangible economic bene®ts.
References [1] Mele A, Conti S, Gill ON, et al. Sistema epidemiologico integrato dell'epatite virale acuta. Rapporto ISTISAN 1987;1:1±30. [2] Giusti G, Galanti B, Gaeta GB, Piccinino F, Ruggiero G. HBsAg carriers among blood donors in Italy: A retrospective survey of data from 189 blood banks. Hepatogastroenterol 1981;28:96±8. [3] Pasquini P, Kahn HA, Pileggi D, Pana A, Terzi J, Guzzanti E.
Prevalence of hepatitis B markers in Italy. Am J Epidemiol 1983;118:699±709. [4] Stroolini T, Pasquini P, Mele A. HBsAg carriers among pregnant women in Italy: results from the screening during a vaccination campaign against hepatitis B. Public Health 1988;102:329±33. [5] Giusti G, Sagnelli E, Gallo C, et al. Etiology of chronic hepatitis in the 1979±1989 period. A multicenter study of the Italian Association for the study of the liver. In: Gentilini P, Dianzani MU, editors. Experimental and clinical hepatology. UK: Elsevier, 1991. p. 155. [6] Da Villa G, Picciotto L, Elia S, Peluso F, Montanaro F, Maisto T. Hepatitis B vaccination: Universal vaccination of new-born babies and at 12 years of age versus high-risk groups. A comparison in the ®eld. Vaccine 1995;13:1240±3.