Patterns of chronic hepatitis B in Central Italy: a cross-sectional study.

Abstract

We investigated the patterns of chronic hepatitis B virus (HBV)-related disease in a large cohort of HBsAg-positive patients, in Central Italy, by collecting a screening form with demographic, clinical and laboratory data. Overall, 737 HBsAg-positive cases were included (70% male; median age 52 years): 30% were inactive HBsAg carriers, 51% had chronic hepatitis B (CHB) and 19% had HBV-related cirrhosis. Patients from non-European Union (EU) countries (n = 65) were significantly younger, had a higher prevalence of HBeAg-positive infection and hepatitis delta virus (HDV) co-infection than patients of Italian origin. Therefore, as immigration from non-EU countries continues to grow, we can expect a change in the landscape of HBV-related disease in our area.

Full text

Page 1

Patterns of chronic hepatitis B in Central Italy: a cross-sectional study -- Piccolo et al., 10.1093/eurpub/ckp168 -- The European Journal of Public Health
http://eurpub.oxfordjournals.org/cgi/content/abstract/ckp168v1?ijkey=rdhIqn3GwMNDPgi&keytype=ref[05/11/2009 19.10.34]
This Article
Full Text
Full Text ( PDF)
E-letters: Submit a response
Alert me w hen this article is cited
Alert me w hen E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in PubMed
Alert me to new issues of the
journal
Add to My Personal Archive
Dow nload to citation manager
Request Permissions
Google Scholar
Articles by Piccolo, P.
PubMed
PubMed Citation
Articles by Piccolo, P.
Social Bookmarking

What's this?
Oxford Journals
10.1093/eurpub/ckp168
MedicineEuropean Journal of Public HealthThe European Journal of Public Health Advance Access

The European Journal of Public Health Advance Access published online on November 2, 2009
The European Journal of Public Health, doi:10.1093/eurpub/ckp168
© The Author 2009. Published by Oxford University Press on behalf of the European Public
Health Association. All rights reserved.
Short Report
Patterns of chronic hepatitis B in Central Italy:
a cross-sectional study
Paola Piccolo1, Ilaria Lenci1, Claudia Telesca1, Daniele Di Paolo1,
Franco Bandiera2, Luigi De Melia3, Orazio Sorbello3, Giuseppina
Renier4, Giovanni L. Ricci5, Lorenzo Nosotti6, Mario Romano7,
Adriano De Santis5, Massimo Levrero5, Giorgio Antonucci8, Maria
Antonella Longo8, Brigida E. Annicchiarico9, Mario Angelico1 and for
the Hep B Free Network Investigators
1 Hepatology Unit, University of Rome Tor Vergata, Rome, Italy
2 SS. Annunziata General Hospital, Sassari, Italy
3 Cagliari University Hospital, Cagliari, Italy
4 Carbonia General Hospital, Carbonia, Italy
5 La Sapienza University Hospital, Rome, Italy
6 S. Gallicano General Hospital, Rome, Italy
7 Pertini General Hospital, Rome, Italy
8 Spallanzani National Institute of Infectious Diseases, Rome, Italy
9 Catholic University Hospital, Rome, Italy
Correspondence: Paola Piccolo, MD PhD, Hepatology Unit, Department of Internal Medicine, University of Rome Tor Vergata, Via
Montpellier 1 00133 Rome, Italy, tel/fax: +39 06 72596803, e-mail: paola.piccolo@uniroma2.it
Received April 30, 2009 , accepted September 22, 2009
We investigated the patterns of chronic hepatitis B virus (HBV)-related disease in a large cohort of HBsAg-
positive patients, in Central Italy, by collecting a screening form with demographic, clinical and laboratory data.
Overall, 737 HBsAg-positive cases were included (70% male; median age 52 years): 30% were inactive HBsAg

Page 2

Patterns of chronic hepatitis B in Central Italy: a cross-sectional study -- Piccolo et al., 10.1093/eurpub/ckp168 -- The European Journal of Public Health
http://eurpub.oxfordjournals.org/cgi/content/abstract/ckp168v1?ijkey=rdhIqn3GwMNDPgi&keytype=ref[05/11/2009 19.10.34]
Online ISSN 1464-360X - Print ISSN 1101-1262
Other Oxford University Press sites:
Oxford University Press
Oxford University Press

Site Map Privacy Policy Frequently Asked Questions
carriers, 51% had chronic hepatitis B (CHB) and 19% had HBV-related cirrhosis. Patients from non-European
Union (EU) countries (n = 65) were significantly younger, had a higher prevalence of HBeAg-positive infection
and hepatitis delta virus (HDV) co-infection than patients of Italian origin. Therefore, as immigration from non-
EU countries continues to grow, we can expect a change in the landscape of HBV-related disease in our area.
Keywords: HBV DNA, HCV co-infection, HDV co-infection, hepatitis B virus, inactive HBsAg carrier.
Hep B Free Network Investigators are listed in the Acknowledgements
CiteULike
Connotea
Del.icio.us What's this?
Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may
therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the
Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our
Customer Services Department.
Copyright © 2009 European Journal of Public Health

Page 3

................................................................................................
Short Report
................................................................................................
Patterns of chronic hepatitis B in Central Italy:
a cross-sectional study
Paola Piccolo1, Ilaria Lenci1, Claudia Telesca1, Daniele Di Paolo1,
Franco Bandiera2, Luigi De Melia3, Orazio Sorbello3, Giuseppina Renier4,
Giovanni L. Ricci5, Lorenzo Nosotti6, Mario Romano7, Adriano De Santis5,
Massimo Levrero5, Giorgio Antonucci8, Maria Antonella Longo8,
Brigida E. Annicchiarico9, Mario Angelico1, for the Hep B Free Network
Investigatorsy
We investigated the patterns of chronic hepatitis B virus (HBV)-related disease in a large cohort of
HBsAg-positive patients, in Central Italy, by collecting a screening form with demographic, clinical
and laboratory data. Overall, 737 HBsAg-positive cases were included (70% male; median age
52 years): 30% were inactive HBsAg carriers, 51% had chronic hepatitis B (CHB) and 19% had HBV-
related cirrhosis. Patients from non-European Union (EU) countries (n=65) were significantly younger,
had a higher prevalence of HBeAg-positive infection and hepatitis delta virus (HDV) co-infection
than patients of Italian origin. Therefore, as immigration from non-EU countries continues to grow,
we can expect a change in the landscape of HBV-related disease in our area.
Keywords: HBV DNA, HCV co-infection, HDV co-infection, hepatitis B virus, inactive HBsAg carrier.
................................................................................................
Introduction
S
prevalence rates (2% endemicity) of hepatitis B virus
(HBV) infection.1In Italy, infection incidence has declined
since the introduction of universal vaccination for infants;2,3
however, HBV infection remains a leading cause of liver
cirrhosis and cancer. In Italy, HBV-related cirrhosis is the
second indication for liver transplantation.4The majority of
chronic HBV carriers in Italy are infected by a mutant strain
of the HBV that does not produce the hepatitis B e antigen
(HBeAg).5
HBeAg-negative hepatitis B is notably more
difficult to treat than its HBeAg-positive counterpart, and
raises numerous issues about managing both on and off
treatment.
To describe the patterns of HBV-related disease in our
region, we conducted a cross-sectional study in an area of
Central Italy, with low-to-intermediate HBV endemicity. The
aim of the study was to define the clinical manifestations of
chronic HBV infection in relation to demographics, clinical
setting, and past or present antiviral treatment.
outhern European countries are classified as having low
Methods
In January 2004, a working group called the Hep B Free
Network was created in Rome, Italy. Eighteen clinical centres
in Central Italy (Lazio, Abruzzo and Molise) and Sardinia
participated in the data collection. Of these, roughly half
were academic referral centres, whereas the remaining half
comprised primary and secondary care centres.
A double-coded screening form was used to collect the
following baseline data for each consecutive HBsAg-positive
patient referred to the participating out-patient clinics: age,
sex, country of origin; clinical data: past and present anti-
viral treatment, presence of cirrhosis (compensated or decom-
pensated), mean reported daily alcohol intake (in grams);
laboratory data: hepatitis B markers, HBV DNA (by
polymerase chain reaction, PCR; lower limit of detection
200–1000 copies/ml across laboratories) past and present
aminotransferases (AST; alanine aminotransferase, ALT),
anti-hepatitis C virus (HCV) and anti-hepatitis delta virus
(HDV) serology. Based on these data, patients were classi-
fied as inactive HBsAg carriers (persistently normal ALT
levels, undetectable serum HBV DNA), chronic hepatitis B
(CHB) (history of anti-viral treatment for hepatitis B,
persistent ALT elevation; presently elevated ALT levels and
detectable serum HBV DNA) or HBV cirrhosis (clinical
or ultrasonographical signs of portal hypertension were
present).
All assigned diagnostic categories were cross-checked by
the referring investigators for accuracy. All borderline cases
in which a clear distinction between the inactive carrier state
and CHB could not be made on the basis of the screening
tool were confirmed by the referring investigators on the
basis of additional findings, including extended clinical
records and liver biopsy, when available.
Additional baseline information (histology, co-infection
with human immunodeficiency virus, HIV; HCV or HDV;
Child–Pugh score) was also collected on individualized
follow-up queries.
Correspondence: Paola Piccolo, MD PhD, Hepatology Unit,
Department of Internal Medicine, University of Rome Tor Vergata,
Via Montpellier 1 00133 Rome, Italy, tel/fax: +39 06 72596803,
e-mail: paola.piccolo@uniroma2.it
1 Hepatology Unit, University of Rome Tor Vergata, Rome, Italy
2 SS. Annunziata General Hospital, Sassari, Italy
3 Cagliari University Hospital, Cagliari, Italy
4 Carbonia General Hospital, Carbonia, Italy
5 La Sapienza University Hospital, Rome, Italy
6 S. Gallicano General Hospital, Rome, Italy
7 Pertini General Hospital, Rome, Italy
8 Spallanzani National Institute of Infectious Diseases, Rome, Italy
9 Catholic University Hospital, Rome, Italy
y Hep B Free Network Investigators are listed in the
Acknowledgements
European Journal of Public Health, 1–3
? The Author 2009. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.
doi:10.1093/eurpub/ckp168

The European Journal of Public Health Advance Access published November 2, 2009

Page 4

Statistical analysis
Data were analysed using the NCSS 2000 statistical software
package for Windows (Number Cruncher Statistical System,
Kaysville, UT, USA). Data were mainly expressed as mean or
median values with standard deviation or ranges. For quanti-
tative variables, univariate analysis was conducted using the
Student’st-test.Statistics on
performed with the Fisher’s exact test.
qualitativevariables was
Results
Seven hundred and thirty-seven consecutive HBsAg-positive
cases (mean age 51?13 years, 69.5% male, 90% of Italian
origin)werenotified to the
Coordinating Center between January 2004 and December
2006. All were assigned to one of the following diagnostic
categories: inactive carrier, 220 (30%); CHB, 375 (51%); and
HBV-related cirrhosis, 142 (19%).
With regard to demographic characteristics, cirrhotic
patients were significantly older than inactive carriers and
CHB patients (mean age, 56?11 years vs. 49?14 years
and 49?13 years, respectively; P<0.0001); female sex
was significantly more prevalent among inactive carriers
compared with patients with CHB and cirrhosis (45% vs.
26% and 20%, respectively; P<0.0001).
HBeAg was positive in 61/479 patients (12.7%) with CHB
or cirrhosis.HBeAg-positive
younger, and had significantly higher serum HBV DNA
levels compared with HBeAg-negative patients (45?15 vs.
51?13
3.84?1.84 log copies/ml, respectively, P<0.0001).
Sixty-five patients (10%) originated from a non-European
Union (EU) country: the distribution of their geographical
origin was as follows: 45/65 (69.2%) Eastern Europe, 11/65
(16.9%) Africa, 5/65 (8%) Asia, 3/65 (4.6%) Middle East
and 1/65 (1.5%) South America. The foreign cohort differed
significantly from the Italian cohort with respect to age,
gender distribution, HBeAg-positivity and prevalence of anti-
HDV (table 1).
HepBFree Network
patients were significantly
years,respectively,P=0.001;5.74?1.9vs.
Co-infections
Overall prevalence of anti-HCV antibodies was 55/694 (8%),
while anti-HDV was positive in 30/559 (5.3%). Data for
both HCV and HDV serology were available in 547 patients.
Eight patients were positive for both anti-HCV/anti-HDV
antibodies (1.5%). HCV genotype distribution was as
follows: 52% genotype 1, 29% genotype 2, 14% genotype 3
and 5% genotype 4.
HDV RNA testing had been performed in 11 anti-HDV
positive patients, and was positive in 6 (54%). Only one
HIV-positive case was notified.
Co-infection rate with HCV was significantly higher in
cirrhotic patients than among inactive carriers and CHB
patients (16.3% vs. 3% and vs. 7.5%, respectively; P<0.0001).
Similarly co-infection rate with HDV was significantly
higher in cirrhotic patients than among inactive carriers and
CHB patients (10.6% vs. 0.7% and vs. 5.9%, respectively;
P<0.0001).
Four out of eight anti-HCV/anti-HDV-positive patients
(50%) had cirrhosis, compared with 39% of anti-HCV-
positive patients and 35% of anti-HDV-positive patients.
Discussion
This data collection from a large cohort of HBsAg-positive
subjects highlights the wide variety of patterns of HBV
infection in Central Italy. We found that cirrhotic patients
were significantly older, presumably due to longer disease
duration, and with a higher prevalence of co-infections with
HCV and HDV compared with inactive HBsAg carriers and
CHB patients. This confirms the greater disease severity
associated with multiple infections also reported in previous
studies,6although serial determinations of viral loads are
necessary to identify the dominant virus in the co-infected
patients.7
HBeAg-positive patients constitute 10% of the cohort. These
patients are younger and are more often immigrants from
non-EU countries. Consistent with the natural history of
HBV infection, HBeAg-positive patients have significantly
higher viral load compared with HBeAg-negative patients.
Although over 90% of chronic HBV infections in Italy are
caused by the HBeAg-negative virus, immigration from high-
endemic Eastern European and other developing countries
may bring about a resurgence of wild-type (HBeAg-positive)
hepatitis B; this had been the prevalent type (>40%) of HBV
infection in Italy in the 1970s and 1980s, before implementa-
tion of universal vaccination, and has now declined to <10%
of the cases among Italians.8,9
An alarming finding in this study is the extremely high
prevalence(17%) ofanti-HDV
immigrants, mostly from Eastern Europe. Co-infection with
HDV has been shown to accelerate the progression to
cirrhosis, and rates of response to anti-viral treatment are
lower than in mono-infected patients.10
HBV infection still represents a diagnostic and therapeut-
ic challenge, even though advances have been made in
prevention, laboratory testing and treatment in the past two
decades. Although universal vaccination has dramatically
reduced the incidence of HBV in Italy, prevalent cases are
still common, as well as imported cases through immigration
from highly endemic countries; as the number of immigrants
from endemic countries continues to rise, a rise in HBeAg-
positive HBV and hepatitis delta co-infections is likely to
follow. This is particularly troublesome because co-infections
with HCV and HDV are associated with greater disease
severity; therefore many of these patients will develop end-
stage liver disease requiring liver transplantation. To attempt
to reduce this burden in future years, all immigrants from non-
EU countries should be screened for HBV infection, counselled
regarding disease transmission, adequately monitored in case
of inactive infection and offered anti-viral treatment when
appropriate.
antibodiesinnon-EU
Acknowledgements
Participating investigators of the Hep B Free Network:
Angelico F, Fiorello S, University of Rome ‘La Sapienza’;
Siciliano M, Bombardieri G, Catholic University of Rome
Table 1 Comparison of baseline characteristics between
Italian patients and non-EU nationals
Italian
589 (90%)
Non-EU nationals
65 (10%)
P
Age, mean?SD (years)
Male, n (%)
HBeAg positive, n (%)
Alcohol intake,
mean?SD (g/day)
Anti-HCV positive, n/N (%)
Anti-HDV positive, n/N (%)
52?12
413 (70)
43/553 (8)
10?18
36?11
38 (58)
10/64 (16)
3.5?18
<0.0001
0.05
0.03
0.01
38/561 (6.8)
20/471 (4.2)
6/64 (9.4)
8/47 (17)
0.76
<0.0001
2 of 3
European Journal of Public Health

Page 5

‘Sacro Cuore’; Koehler B, Spallanzani Hospital, Rome; Zaru S,
Annunziata Hospital, Sassari; Barlattani A, S. Giacomo
Hospital, Rome; Farinacci I, Campobasso Hospital; Furlan C,
University of Rome ‘La Sapienza’; Grieco A, Miele L,
Pompili M, Catholic University of Rome ‘Sacro Cuore’;
Chiaramonte M, Lattanzi E, University of L’Aquila; Pierconti
S, Pietropaolo L, University of Rome ‘La Sapienza’; Mari T,
S. Giacomo Hospital, Rome; Piras MR, Brotzu Hospital,
Cagliari; Pizzigallo E, Coppolaro L, University of Chieti;
Ponti ML, Brotzu Hospital, Cagliari; Sanna G, Oristano
General Hospital; and Tarquini P, Teramo General Hospital.
Conflicts of interest: None declared.
Key points
? In recent years, patients from non-EU countries with
chronic HBV infection are increasing in Italian
hepatology/infectious disease centres.
? Compared with Italian chronic HBsAg carriers, non
EU-immigants are younger, have a higher preva-
lence of HBeAg-positive CHB and hepatitis delta
co-infection.
? Chronic HBsAg carriers from non-EU countries have
an increased risk of progression of HBV-related liver
diseaseand shouldhave
monitoring and anti-viral therapy.
access toscreening,
References
1 Pendino GM, Mariano A, Surace P, et al. Prevalence and etiology of altered
liver tests: a population-based survey in a Mediterranean town. Hepatology
2005;41:1151–9.
2Zanetti AR. Update on hepatitis B vaccination in Italy 10 years after its
implementation. Vaccine 2001;19:2380–3.
3 Bonanni P, Pesavento G, Bechini A, et al. Impact of universal vaccination
programmes on the epidemiology of hepatitis B: 10 years of experience in
Italy. Vaccine 2003;21:685–91.
4 Burra P, Smedile A, Angelico M, et al. Liver transplantation in Italy: current
status. Study Group on Liver Transplantation of the Italian Association for
the Study of the Liver (A.I.S.F.). Dig Liver Dis 2000;32:249–56.
5Santantonio T, Jung MC, Miska S, et al. High prevalence and heterogeneity
of HBV preC mutants in anti-HBe-positive carriers with chronic liver disease
in southern Italy. J Hepatol 1991;13:S78–81.
6 Gaeta GB, Stornaiuolo G, Precone DF, et al. Epidemiological and clinical
burden of chronic hepatitis B virus/hepatitis C virus infection. A multicenter
Italian study. J Hepatol 2003;39:1036–41.
7 Raimondo G, Brunetto MR, Pontisso P, et al. Longitudinal evaluation reveals
a complex spectrum of virological profiles in hepatitis B virus/hepatitis C
virus-coinfected patients. Hepatology 2006;1:100–7.
8Giusti G, Sagnelli E, Gallo C, et al. The etiology of chronic hepatitis in Italy:
a multicenter study. Hepatogastroenterology 1994;41:397–400.
9 Gaeta GB, Stornaiuolo G, Precone DF. Type B and D viral hepatitis:
epidemiological changes in Southern Europe. Forum 2001;11:126–33.
10 Farci P. Delta hepatitis: an update. J Hepatol 2003;39:212–19.
Received 30 April 2009, accepted 22 September 2009
HBV patterns in Central Italy
3 of 3