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VHPB - Prevention of Viral Hepatitis in Italy: Lesson Learntand the Way Forward - Catania, November 7-8, 2002

EPIDEMIOLOGY OF VIRAL HEPATITIS B AND C IN ITALY

Pietro CrovariDepartment of Health SciencesUNIVERSITY OF GENOA

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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

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HEPATITIS B: CHANGING EPIDEMIOLOGICAL PATTERN

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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

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MORBIDITY RATE FOR ACUTE VIRAL HEPATITIS IN ITALY FROM 1960 TO 1975

(Data from ISTAT, Crovari 1995)

0

20

40

60

80

100

120

1960 1962 1964 1966 1968 1970 1972 1974 1976 1978 1980YEAR

MORBIDITY RATE (/100,000)

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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

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MORBIDITY RATE (/100,000) OF HEPATITIS B IN ITALY ACCORDING BY AGE GROUPS

Data from: SEIEVA

Universal vaccination of children

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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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A B NANB Non Spec. Tot.

1982 - - - - 26.5091983 - - - - 28.2511984 - - - - 33.8151985 - - - - 18.3861986 - - - - 16.0851987 2.007 2.189 662 10.062 14.9201988 1.567 4.124 1.549 2.652 9.8921989 1.295 3.915 1.510 1.510 8.2301990 2.572 3.640 1.532 1.983 9.7271991 2.764 3.260 1.560 1.363 8.9471992 6.046 3.423 1.902 1.724 13.0951993 3.308 3.344 1.788 982 9.4221994 3.531 2.733 1.569 551 8.3841995 1.434 2.600 1.455 390 5.8791996 8.651 2.248 1.149 394 12.4421997 9.952 1.996 932 303 13.1831998 2.962 1.796 845 122 5.7251999 1.693 1.575 788 101 4.157

CASES OF VIRAL HEPATITIS NOTIFIED IN ITALY (Min.San.)

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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 TO AGE-GROUPS (Min.San.)Morbosità (x 100.000 ab) per Epatite C in Italia nelle

diverse fasce d'età

0,00

1,00

2,00

3,00

4,00

5,00

6,00

1994 1995 1996 1997 1998 1999 2000 2001 *Anni

Morb

osi

tà (

x 1

00.0

00) 0-14 years

15-24 years25-64 years> 65 years

Years

Mor

bidi

ty r

ate

(x 1

00.0

00)

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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

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• 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 12-

26%, 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: 2,7%

North East: 3,2%

North West: 3,4% Coppola, J.Virol. Hepatitis, 2000Bellentani, Hepatology, 1994

Central: 8,4%

Southern: 14,4% Stroffolini, Ital. J. Gastroenterol, 1995

Guadagnino, Hepatology, 1997

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SERO-EPIDEMIOLOGY OF HCV IN LIGURIA(Bruzzone, Icardi, et Al.)

Age Samples anti-HCV % Samples anti-HCV %group positive positive

1-10 46 0 0 85 0 0

11-20 35 1 2.9 98 0 0

21-30 107 1 0.9 143 4 3.1

31-40 95 3 3.2 124 2 1.6

41-50 98 7 7.1 110 2 1.8

>50 130 11 8.5 349 12 3.4

Total 510 23 4.5 909 20 2.2

1977 1993

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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”.

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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

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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, 1990Lai, J Ped Gastr Nutr, 1993

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Intravenous drug users / life style

• Up to 60-92% of drug users are positive for anti-HCV. (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).

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Hemodialysis patients

• About 30% of these patients test positive for anti-HCV (Chiaramonte, Ital J Gastroenterol, 1991. Rivanera, Eur J Epidemiol, 1993).

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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)

CHILDBIRTHTotal

HCV positives(%)

HBsAg positives(%)

HIV positives(%)

1996 1997 1998 1996 1997 1998 1996 1997 1998 1996 1997 1998

Pregnant women regular atchildbirth

11.055 10.132 10.378 0,8 0,92 0,85 0,53 0,42 0,58 0,12 0,16 0,1

Voluntary interruptions(IVG)

4268 3755 3823 0,93 1,65 1,83 0,56 0,74 0,6 0,84 0,39 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, 1c2a, 2b, 2c3a4a5a6aNew 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, 2000Dal Molin, Ansaldi, J Med Vir, 2002

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0

10

20

30

40

50

60

0-15 16-30 31-45 46-60 >60

Subtype 1aSubtype 1bGenotype 2Subtype 3a

Pre

vale

nce

(%)

Age groups (years)

Changing of HCV genotype distribution in 318 consecutive HCV-RNA positive patients (Dal Molin, Ansaldi, J Med Vir, 2002)

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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

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MORTALITY RATE FOR LIVER CIRRHOSIS IN ITALY FROM 1965 TO 1998 (ISTAT)

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Mortality rate for primary liver cancer in Italy fom 1965 to 1998

0

2

4

6

8

10

12

14

16

1965 1970 1975 1980 1985 1990 1995

Years

Cases (

No./

100.0

00)

MORTALITY RATE FOR PRIMARY LIVER CANCER IN ITALY FROM 1965 TO 1998 (ISTAT)

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HCC AND CIRRHOSIS IN ITALY

Stroffolini 1997 Elba 2002

N° subjects 1148 100

HCV+ 71,1% 75%

HbsAg+ 11,5% 13%

Medium age >60

Hcv+ 65,6 years

HbsAg+ 59,3 years

M:F 3,3:1

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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%

Alcohol

Total 417 84 2,8%

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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

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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 the near future.

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Acknowledgments to:

Dr. Filippo AnsaldiDept. of Public Medicine Sciences, University of Trieste, Italy

Dr. Paolo DurandoDept. of Health Sciences, University of Genoa, Italy