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VHPB - Prevention of Viral Hepatitis in Italy: Lesson Learnt
and the Way Forward - Catania, November 7-8, 2002
EPIDEMIOLOGY OF VIRAL HEPATITIS B AND C IN ITALY
Pietro Crovari
Department of Health Sciences
UNIVERSITY OF GENOA
1
EPIDEMIOLOGICAL PARAMETERS
 Annual incidence of acute hepatitis cases (morbidity rate)
 Annual incidence of death for acute hepatitis (mortality rate)
 Sero-epidemiological data
 Mortality rate for liver cirrhosis and primitive liver cancer
2
HEPATITIS B: CHANGING EPIDEMIOLOGICAL PATTERN
3
THE FOUR AGES OF HBV SPREAD IN ITALY
• Up to the Mid Seventies: the age of high spread infection
 use of unscreened blood and blood-products
 Re-used of inadeguately sterilized medical equipment
 high birthrate and large size of families

increase of I.V. drug use
• The Eighties
• The Nineties
• The Present
4
MORBIDITY RATE FOR ACUTE VIRAL HEPATITIS IN ITALY
FROM 1960 TO 1975
120
(Data from ISTAT, Crovari 1995)
100
MORBIDITY RATE (/100,000)
80
60
40
20
0
1960 1962 1964 1966 1968 1970 1972 1974 1976 1978 1980
YEAR
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THE FOUR AGES OF HBV SPREAD IN ITALY
• Up to the Mid Seventies
• The Eighties: the age of progressive reduction
 improved health care, (use of disposables, RIA and EIA test for
screening of blood, education of health care workers)
 better standards of living and reduction of the average size of
families
 the ‘AIDS effect’
 availability of the post vaccines for selective strategies of
immunization (newborns to HBsAg positive women, household
contacts of HBV carriers, health care workers immunization)
• The Nineties
• The Present
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THE FOUR AGES OF HBV SPREAD IN ITALY
• Up to the Mid Seventies
• The Eighties
• The Nineties: the age of the universal mandatory
immunization of children (newborns + adolescent at 12
years of age); mandatory HBsAg test for women and
vaccination free-of-charge for high risk groups.
• The Present
7
MORBIDITY RATE (/100,000) OF HEPATITIS B IN
ITALY ACCORDING BY AGE GROUPS
Universal vaccination of children
Data from: SEIEVA
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THE FOUR AGES OF HBV SPREAD IN ITALY
• Up to the Mid Seventies
• The Eighties
• The Nineties
• The Present :
 attainment of the historical low in acute disease
 meaningful persistence of new infections
 Shift in the prevalence of HBsAg positive subjects towards
more advanced age groups
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THE FUTURE
Objective: to consolidate and improve the achieved results
 Maintain mandatory vaccination of infants
 Maintain HBsAg testing for pregnant women
 Increase coverage in adults at risk
 Maintain a high safety level of invasive treatments for both
medical and non medical purposes
 Increase health education of the general public on sexually
transmitted infections
 Buster doses ???
 Surveillance
 Research
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HEPATITIS C: EPIDEMIOLOGY PATTERN
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CASES OF VIRAL HEPATITIS NOTIFIED IN ITALY (Min.San.)
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
A
B
2.007
1.567
1.295
2.572
2.764
6.046
3.308
3.531
1.434
8.651
9.952
2.962
1.693
2.189
4.124
3.915
3.640
3.260
3.423
3.344
2.733
2.600
2.248
1.996
1.796
1.575
NANB
Non Spec.
Tot.
662
1.549
1.510
1.532
1.560
1.902
1.788
1.569
1.455
1.149
932
845
788
10.062
2.652
1.510
1.983
1.363
1.724
982
551
390
394
303
122
101
26.509
28.251
33.815
18.386
16.085
14.920
9.892
8.230
9.727
8.947
13.095
9.422
8.384
5.879
12.442
13.183
5.725
4.157
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Impact of HCV Viral Hepatitis
(Min. San., 1999)
HCV Acute Viral Hepatitis vs Total Viral Hepatitis:
18,9 %
HCV Acute Viral Hepatitis vs Total Parenteral Hepatitis:
33,3 %
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MORBIDITY RATE (/100,000) FOR HEPATITIS C IN
ITALY
ACCORDING
Morbosità
(x 100.000 TO
ab) AGE-GROUPS
per Epatite C in (Min.San.)
Italia nelle
diverse fasce d'età
100.000)
rate(x(x100.000)
Morbidity
Morbosità
6,00
0-14 years
15-24 years
25-64 years
> 65 years
5,00
4,00
3,00
2,00
1,00
0,00
1994
1995
1996
1997
1998
Anni
Years
1999
2000
2001 *
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…… acute symptomatic anti-HCV-positive cases do not
reflect the true overall incidence of hepatitis C…...
….. the current perception of the HCV problem is that
of a widespread infection with apparently limited
clinical expression.
R. Coppola, et Al. JPMH , 1999
15
• Past studies indicated that in Italy no more than 1% of
the general population was infected.
• Recent field studies involving open populations suggest
the global prevalence of HCV infection is much higher
than currently perceived…..
At present, in Italy, the prevalence of HCV infection in
the general population is estimated at about 3%,
although areas with much higher prevalence, up to 1226%, have been described.
Bellentani, Hepatol, 1994
Guadagnino, Hepatol, 1997
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Regional pattern of HCV seroprevalence in Italy
Anti HCV positive rates:
Sardinia:
North East:
North West:
2,7%
3,2%
3,4%
Central:
Southern:
8,4%
14,4%
Coppola, J.Virol. Hepatitis, 2000
Bellentani, Hepatology, 1994
Stroffolini, Ital. J. Gastroenterol, 1995
Guadagnino, Hepatology, 1997
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SERO-EPIDEMIOLOGY OF HCV IN LIGURIA
(Bruzzone, Icardi, et Al.)
1993
1977
Age
group
Samples
anti-HCV
positive
%
Samples
anti-HCV
positive
%
1-10
46
0
0
85
0
0
11-20
21-30
31-40
41-50
>50
Total
35
107
95
98
130
510
1
1
3
7
11
23
2.9
0.9
3.2
7.1
8.5
4.5
98
143
124
110
349
909
0
4
2
2
12
20
0
3.1
1.6
1.8
3.4
2.2
18
In all these studies, infection sharply concerns subjects over
50 years of age, with prevalence peaks of up to 18% - 30%
in the 7th and 8th decades.
The increasing prevalence of anti-HCV rates with
increasing age suggests a “cohort effect”.
19
Target groups of seroepidemiological investigation
•
•
•
•
•
•
•
Blood donors
Subjects receiving blood products
Intravenous drug users / life style
Hemodialysis patients
Health care workers
Vertical / perinatal transmission
Pregnant women
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Blood donors
• The prevalence of HCV positives in blood donors in Italy was
initially estimated at about 1%.
• The incidence of post-transfusion hepatitis C cases has
dropped from 7/1.000.000 in 1986 to 1,1/1.000.000 in 1991
with the introduction of screening tests.
• It was further reduced to 0,4/1.000.000 cases in 1993 by using
the second generation EIA anti-HCV.
Sirchia, Lancet,1989.
Chiaramonte, Ital Journ Gastroenterol, 1991
21
Subjets receving haemoderivates
(blood products, i.e., F VIII, FIX)
• Up to 85% of hemophiliac and 61% of thalassemic patients
test positive for anti-HCV.
Donors screening and the virucidal treatment of blood
products have, minimised, at present, the risk of infection
trough trasfusion of blood or its derivatives.
Rumi, Ann Intern Med, 1990
Lai, J Ped Gastr Nutr, 1993
22
Intravenous drug users / life style
• Up to 60-92% of drug users are positive for antiHCV. (Coppola, Eur J Epidemiol, 1994).
• Tattoing, piercing, etc. with shared needles is also
a route of transmission (Abildgaard, Lancet, 1991.
Caraffa De Stefano, Epatiti Virali Min. San.).
• Intravenus drug use remains the main mode of
transmission (Zanetti, J Prev Med Hyg, 1999).
23
Hemodialysis patients
• About 30% of these patients test positive for antiHCV (Chiaramonte, Ital J Gastroenterol, 1991.
Rivanera, Eur J Epidemiol, 1993).
24
Health care workers
• Accidental needle-stick injuries with contamined needles
or sharp instruments causes infection in 3-10% of health
care workers. Nurses, housekeepers, training personnel,
surgeons and laboratory workers seem to be the groups
at highest risk (SIROH Epinet).
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Pregnant Women
Seroprevalence in pregnant women regular at childbirth and in
voluntary pregnancy interruptions in Liguria during 1996-1997-1998
(Bruzzone B., Gabutti G., Icardi G. 1998)
CHILD BIR TH
HC Vp ositives
HBsA gpositiv es
HI Vpo sitiv e s
T otal
(% )
(% )
(% )
1 9 9 61997 1 9 9 81996 1997 1998 1996 1997 1998 1996 1 9 9 7 1998
Pr e nant
g w o men r ula
e g ra t 11.055 10.132 10.378
childbirth
V olunt a r inter
y ru ptions
4 2 6 83755 3823
(I VG)
0,8
0,92
0,93 1,65
0 , 8 5 0 , 5 3 0 , 4 2 0 , 5 8 0 , 1 2 0 , 1 6 0,1
1 , 8 3 0 , 5 6 0 , 7 4 0 , 6 0 , 8 4 0 , 3 9 0,52
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Vertical/perinatal transmission
• The mode of delivery (caesarean section/vaginal) does
not appear to influence the rate of HCV transmission
from mother to child.
• There is an increased risk of neonatal infection from
HCV infected mothers in the presence of maternal HIV
infection (Tanzi, Bellelli and Tagger Eur J Epidemiol,1997.
Novati, J Inf Dis, 1992)
This risk is usually greater in mothers with >106 genome
copies of HCV/ml (Lin, J Inf Dis, 1994).
• There is no association between breast-feeding and
trasmission of HCV from mother to child.
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Nevertheless…...
• In about 30-40% of patients with acute and
chronic epatitis C the source of infection
remains unidentified.
Alter, Vir Hep Liv Dis, 1994
Alter, N Engl J Med, 1999
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Molecular epidemiology of HCV
(6 main genotypes and about 100 subtypes)
Most common HCV genotypes:
1a, 1b, 1c
2a, 2b, 2c
3a
4a
5a
6a
New ones appear to be confined to defined geographic areas:
7, 8, 9, 10, 11
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Molecular epidemiology of HCV
Objectives of HCV genotyping:
– epidemiological surveillance
– identification of outbreaks - source
– to establish associations between viral genotype
and liver damage, the response to antiviral
treatment and clinical management
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Molecular epidemiology of HCV in Italy
• Genotype 1b is the most prevalent, followed by 2a/2c,
1a and 3a.
Mangia, J Hepatol, 1997
• Recently some Authors have observed changes in the
incidence of the different genotypes.
Grima, Cataldini, J Prev Med Hyg, 2000
Dal Molin, Ansaldi, J Med Vir, 2002
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Changing of HCV genotype distribution in 318 consecutive
HCV-RNA positive patients (Dal Molin, Ansaldi, J Med Vir, 2002)
60
Prevalence (%)
50
40
Subtype 1a
Subtype 1b
Genotype 2
Subtype 3a
30
20
10
0
0-15
16-30
31-45
46-60
Age groups (years)
>60
32
CHANGING MOLECULAR EPIDEMIOLOGY OF HCV
INFECTION IN NORTHEAST ITALY
.”…the epidemiological picture of HCV is changing, with the
introduction of subtypes 1a and 3a and a marked reduction of
genotype 2”
“ … subtype 1a and 3a infection were predominant in injection
drug users…”
“Logistic regression showed that age and injection drug use are
independent determinants of genotype distribution”
Dal Molin, Ansaldi, J Med Vir, 2002
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Cirrhosis and HCC associated with HBV and
HCV infections
34
MORTALITY RATE FOR LIVER CIRRHOSIS IN ITALY
FROM 1965 TO 1998 (ISTAT)
Mortality rate for liver cirrhosis in Italy fom 1965 to 1998
40
Cases (No./100.000)
35
30
25
20
15
10
5
0
1965
1970
1975
1980
1985
1990
1995
Years
35
MORTALITY RATE FOR PRIMARY LIVER CANCER IN
ITALY FROM 1965 TO 1998 (ISTAT)
Mortality rate for primary liver cancer in I taly fom 1965 to 1998
16
14
Cases (No./100.000)
12
10
8
6
4
2
0
1965
1970
1975
1980
1985
1990
1995
Years
36
HCC AND CIRRHOSIS IN ITALY
Stroffolini 1997
Elba 2002
N° subjects
1148
100
HCV+
HbsAg+
Medium age
Hcv+
HbsAg+
M:F
71,1%
11,5%
>60
65,6 years
59,3 years
3,3:1
75%
13%
37
Natural history of 417 patients with cirrhosis in relation to etiology
(10 years follow-up)
Etiology
N° cirrhosis
N° HCC Annual incidence HCC
Anti-HCV+
280
60
3,2%
HbsAg pos.+
137
24
1,8%
417
84
2,8%
Alcohol
Total
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ATTRIBUTABLE RISK (AR) AND POPULATION
ATTRIBUTABLE RISK (PAR) FOR CIRRHOSIS AND HCC
Dionysos Study: 6917 subjects
Bellentani and Tiribelli, J Hepatol, 2001
Risk factors for cirrhosis and HCC
AR%
PAR%
>30g/day alcohol consuption
83.9
65
HCV infection alone
88.5
38
HBV infection alone
60.4
7
>30g/day alcohol consuption +
viral infection
91.6
92.4
39
Conclusions
• General and immunological prevention measures adopted for HBV
infections have caused a significative reduction in new infections and
associated patologies.
• The hepatitis B prevention measures together with those directed to HIV
have also caused a reduction of new HCV infections.
• The health-care and social burden of chronic disease associated both with
HBV and especially with HCV still remains relevant. This burden has not so
far been positively influenced until now by the decrease in new cases of
infection.
• The annual rate of new infections both for HBV and HCV shows that control
of these infections has not been achieved up to now. Considering the heavy
long term complications, it appears necessary to further reduce the rate of
these infection rates; this is possible by strict application of the
recommended preventive measures, waiting for an effective HCV vaccine in
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the near future.
Acknowledgments to:
Dr. Filippo Ansaldi
Dept. of Public Medicine Sciences, University of Trieste, Italy
Dr. Paolo Durando
Dept. of Health Sciences, University of Genoa, Italy
41