HEPATITIS B ELIMINATION IN CHILDREN OF SLOVENIAN ORIGIN 
BORN IN SLOVENIA AFTER THE INTRODUCTION OF PREVENTIVE 
STRATEGIES: THE RESULTS OF A NATIONAL STUDY
Nina GRASSELLI KMET1,3*, Mario POLJAK2,3, Breda ZAKOTNIK1, Mojca MATIČIČ1,3
1University Medical Centre Ljubljana, Clinic for Infectious Diseases and Febrile Illneses, 
Japljeva 2, 1000 Ljubljana, Slovenia
2University of Ljubljana, Faculty of Medicine, Institute of Microbiology and Immunology, 
Zaloška 4, 1000 Ljubljana, Slovenia
3University of Ljubljana, Faculty of Medicine, Vrazov trg 2, 1000 Ljubljana, Slovenia
Received: Mar 22, 2021
Accepted: Feb 18, 2022
Original scientific article
*Corresponding author: Tel. + 386 40 817 921; E-mail: nina.grasselli@kclj.si
10.2478/sjph-2022-0015 Zdr Varst. 2022;61(2):109-114
109
ELIMINACIJA HEPATITISA B PRI OTROCIH SLOVENSKEGA 
IZVORA, ROJENIH V SLOVENIJI, PO UVEDBI PREVENTIVNIH 
UKREPOV: REZULTATI NACIONALNE RAZISKAVE
© National Institute of Public Health, Slovenia. 
Grasselli Kmet N, Poljak M, Zakotnik B, Matičič M. Hepatitis B elimination in children of Slovenian origin born in Slovenia after the introduction of preventive strategies: 
the results of a national study. Zdr Varst. 2022;61(2):109-114. doi: 10.2478/sjph-2022-0015.
ABSTRACT
Keywords: 
chronic hepatitis B, 
prevention strategies, 
vaccination, mandatory 
screening, HBsAg, 
pregnant women
IZVLEČEK
Ključne besede: 
kronični hepatitis B, 
preventivni ukrepi, 
cepljenje, obvezno 
testiranje, nosečnice
Introduction: In Slovenia national strategies to prevent hepatitis B virus (HBV) infection in children were 
introduced in the mid-nineties. The aim of the present study was to analyze the epidemiological characteristics 
of chronic hepatitis B infection in children in Slovenia after the introduction of mandatory HBV vaccination of 
children and mandatory screening of pregnant women for HBV surface antigen (HBsAg) with consecutive active 
and passive immunization of newborns of HBsAg-positive mothers.
Methods: Children from all regions of Slovenia whose blood samples tested positive for HBsAg at the national 
reference laboratory for viral hepatitis between January 1997 and December 2010 were included. Demographic, 
epidemiological and virological data were reviewed retrospectively. Statistical evaluation of the patients’ 
characteristics was performed and possible trends during the observation period determined.
Results: Among 52 HBsAg-positive children, there were 22 (42.3%) girls and 30 (57.7%) boys. Among 40 children 
tested for HBeAg, 17 were positive (42.5%). The most frequent risk factor for acquiring HBV infection was 
“presence of HBV infection within the family” (24/35; 68.8%). A significant association between the presence 
of HBeAg and a viral load of >20,000 IU/ml was found (p=0.001). The difference in the proportion of children 
of Slovenian origin born before 1994 and after was statistically significant (p=0.039). A statistically significant 
negative linear trend of the number of diagnosed children in the observed period was found (p=0.006).
Conclusions: Prevention strategies adopted in the mid-nineties have resulted in the elimination of chronic 
hepatitis B in children of Slovenian origin born in Slovenia.
Uvod: V Sloveniji je bila sredi devetdesetih let prejšnjega stoletja uvedena nacionalna strategija za preprečevanje 
okužbe z virusom hepatitisa B (HBV) pri otrocih. Cilj naše raziskave je bil analizirati epidemiološke značilnosti 
kronične okužbe otrok s HBV v Sloveniji po uvedbi obveznega cepljenja otrok proti HBV in obveznega presejanja 
nosečnic na površinski antigen HBV (HBsAg) s posledično aktivno in pasivno imunizacijo novorojenčkov HBsAg 
pozitivnih mater.
Metode: Vključeni so bili otroci iz vseh regij Slovenije, katerih vzorci krvi so bili pozitivni na HBsAg v 
nacionalnem referenčnem laboratoriju za virusni hepatitis med januarjem 1997 in decembrom 2010. 
Demografski, epidemiološki in virološki podatki so bili pregledani retrospektivno. Opravljena je bila statistična 
ocena značilnosti pacientov in ugotovljeni možni trendi v obdobju opazovanja.
Rezultati: Med 52 otroki, pozitivnimi na HBsAg, je bilo 22 (42,3 %) deklet in 30 (57,7 %) dečkov, njihova 
povprečna starost (± standardni odklon – SD) je bila 13,3 (± 5,5) let. Med 40 otroki, testiranimi na HBeAg, je 
bilo 17 pozitivnih (42,5 %). Najpogostejši dejavnik tveganja za pridobitev okužbe s HBV je bil “okužba s HBV 
v družini“ (24/35; 68,8 %). Ugotovljena je bila tudi pomembna povezava med prisotnostjo HBeAg in virusnim 
bremenom > 20.000 IU/ml (p = 0,001). Razlika v deležu otrok slovenskega izvora, rojenih pred letom 1994 in 
po njem, je bila statistično značilna (p = 0,039). Ugotovljen je bil statistično značilni negativni linearni trend 
števila otrok, okuženih s HBV v opazovanem obdobju (p = 0,006). 
Zaključki: Preventivne strategije, sprejete sredi devetdesetih let, so privedle do eliminacije kroničnega 
hepatitisa B pri otrocih slovenskega izvora, rojenih v Sloveniji.
1 INTRODUCTION
With an estimated 257 million chronically infected 
persons worldwide, hepatitis B virus (HBV) infection still 
represents a major global public health problem, despite 
the long-term existence of highly effective hepatitis B 
prevention strategies, including the HBV vaccine (1-3). In 
Europe the average HBV prevalence has been estimated 
at 2%, whereas in highly endemic areas of Africa and the 
Pacific it is up to 22.7% (4). In Slovenia, HBV prevalence 
has been estimated at below 1% (5).
In 2016, the World Health Organization (WHO) adopted a 
strategy to eliminate HBV infection by 2030 and stated five 
core interventions: three doses of hepatitis B vaccination 
for children, a hepatitis B birth-dose to prevent perinatal 
transmission, blood and injection safety, harm reduction 
(syringe/needle set for people who inject drugs) and 
testing services/treatment (1, 6-9). Since perinatal or early 
postnatal transmission represents the most significant 
source of chronic HBV infection (CHB) globally, in 2017 
WHO recommended that all infants should receive their 
first dose of hepatitis B vaccine as soon as possible after 
birth (10). According to the WHO report, up until 2016 
active immunization against hepatitis B had been included 
in the national programs of mandatory vaccination of 
children in 98% of member states (11). In 2015, global 
coverage with the three doses of hepatitis B vaccine in 
infancy reached 84%, while coverage with the initial birth 
dose was reported still to be low at 39% (1). In 2016 in the 
United States of America only 60.6% of newborns received 
the HBV vaccine (12). 
In Slovenia, preventive vaccination against hepatitis 
B was included in the national program of mandatory 
vaccination of children in December 1997; children born 
after 1992 were vaccinated at the age of six, before 
entering elementary school, and from 2020 children are 
vaccinated against HBV at the age of 3 months (13). 
Additionally, all the newborns of HBV surface antigen 
(HBsAg)-positive mothers receive specific human immune-
globulins immediately after birth together with the first 
dose of HBV vaccine (14). 
Mandatory screening of pregnant women for HBsAg was 
introduced in Slovenia in 1994 (15). According to the 
latest European Centre for Disease Prevention and Control 
(ECDC) data, antenatal screening for hepatitis B has been 
implemented in 23 out of 26 European countries; in the 
majority of reporting countries (8/13), screening coverage 
was ≥95% (16). 
The aim of the present study was to analyze epidemiological 
characteristics of CHB in children in Slovenia after the 
introduction of mandatory HBV vaccination and mandatory 
screening of pregnant women for HBsAg with consecutive 
active and passive immunization of newborns of HBsAg-
positive mothers.
10.2478/sjph-2022-0015 Zdr Varst. 2022;61(2):109-114
110
2 METHODS
2.1 Patients 
All HBsAg-positive children 18 years of age or younger 
extracted from the central database totaling 1,729 persons 
from all regions of Slovenia who tested positive for HBsAg 
at the national reference laboratory for viral hepatitis 
(Laboratory for Molecular Microbiology and Diagnostics 
of Hepatitis and HIV/AIDS, Institute of Microbiology and 
Immunology, Faculty of Medicine, University of Ljubljana) 
between January 1997 and December 2010 were included 
in this study.
Available epidemiological and clinical characteristics 
were reviewed from the medical documentation at five 
hospitals responsible for the management of patients with 
viral hepatitis (University Medical Centers Ljubljana and 
Maribor, and General Hospitals in Celje, Novo Mesto, and 
Murska Sobota). 
Origin was defined as “country, race, or social class of a 
person’s parents or ancestors” (17).
2.2 Serological and molecular methods
In all samples HBsAg and HBeAg were determined using the 
ARCHITECT Immunoassay analyzer (Abbott, Weisbaden, 
Germany) and HBV DNA viral load using the real-time 
polymerase chain reaction (RT-PCR) based Abbott 
RealTime HBV Test (Abbott). Viral load was categorized 
according to the clinical implications into three ranges: ≤ 
2,000 IU/mL, 2,000-20,000 IU/mL and ≥ 20,000 IU/mL (18). 
2.3 Statistical methods
Associations were tested using univariate and multiple 
logistic regression, likelihood ratio or the Mann-Whitney 
U test, as appropriate. Possible time trends during the 
observation period were determined. No correction for 
multiple comparisons was made. Significance tests were 
two-sided. P-values ≤0.05 were considered statistically 
significant. Statistical analysis was performed using R 
program 3.1.1 and SPSS 23.0. 
3 RESULTS
A total of 52 eligible children were included. Table 1 shows 
the baseline characteristics of the included children. 
A statistically significant association between the presence 
of HBeAg and a viral load above 20,000 IU/ml (p=0.001) was 
found. Table 2 presents the demographic, epidemiological, 
clinical and virological characteristics of the included 
children regarding presence/absence of HBeAg.
10.2478/sjph-2022-0015 Zdr Varst. 2022;61(2):109-114
111
Gender (N=52)
Female
Male
Mean age (SD; range) (years) (N=52)
Risk factors (N=35)
Unknown
Presence of HBV infection within the family
Blood/blood products transfusion
High-risk sexual behavior
Surgical procedure in the past
ALT (N=29) (μkat/L)
≤ 0.56
> 0.56
HBeAg (N=40)
Negative
Positive
Viral load (IU/ml) (N=24)
< 2,000
2,000–20,000
> 20,000
%
 
22 (42.3)
30 (57.7)
13.3 (5.5; 0-18)
8 (22.9)
24 (68.8)
1 (2.9)
1 (2.9)
1 (2.9)
14 (48.3)
15 (51.7)
23 (57.5)
17 (42.5)
9 (37.5)
0 (0)
15 (62.5)
Table 1. Demographic, epidemiological, clinical and virological 
characteristics of included children (N=52).
HBV – hepatitis B virus, ALT – alanine aminotransferase, SD – 
standard deviation, IU – international units
Gender (N=40)
Female
Male
Median age (range) (years) (N=40)
Risk factors (N=28)
Unknown
Presence of HBV infection within the family
Blood/blood products transfusion
High-risk sexual behavior
Surgical procedure in the past
ALT (μkat/L)(N=22)
≤ 0.56
> 0.56
Viral load (IU/ml) (N=20)
< 2,000
2,000–20,000
> 20,000
Domain HBeAg-negative 
n (%)
HBeAg-negative 
n (%)
p - value
23 (57.5)
9 (39.1)
14 (60.9)
14 (0-18)
17 (60.7)
4 (23.5)
12 (70.6)
1 (5.9)
0 (0)
0 (0)
10 (66.7)
5 (33.3)
8 (66.7)
0 (0)
4 (33.3)
17 (42.5)
8 (47.1)
9 (52.9)
17 (0-18)
11 (39.3)
3 (27.3)
6 (54.5)
0 (0)
1 (9.1)
1 (9.1)
2 (28.6)
5 (71.4)
0 (0)
0 (0)
8 (100)
 
0.616a
0.334c
0.824b
0.389b
0.312b
0.165b
0.165b
0.092b
0.001b
Table 2. Demographic, epidemiological, clinical and virological characteristics of included children regarding presence/absence of 
hepatitis B virus e antigen (N=40).
a=hi-square test; b=likelihood ratio test; c=Mann-Whitney U test
HBV – hepatitis B virus, ALT – alanine aminotransferase, HBeAg – hepatitis B virus e antigen, IU – international units
Out of the 52 children, 47 were of Slovenian origin. The 
oldest child of Slovenian origin included in the study was 
born in 1979. Altogether 41/52 (78.8%) children were born 
before or in 1994, 39 of Slovenian origin and two of foreign 
parents. There were 11/52 (21.1%) children born after 1994, 
eight Slovenians and three foreigners. The difference in 
the proportion of children of Slovenian origin born before 
1994 and after 1994 was statistically significant (p=0.039). 
Children of Slovenian origin born after 1994 with CHB 
were born in 1996, 1998, 2003, and the last chronically 
infected child in 2004 (Table 3).  Unfortunately, we found 
clinical data for three children only who are still followed. 
Two of them have active CHB and one seroconverted. 
Interestingly, the last chronically infected child was born 
to a father who acquired HBV infection while vaccinated in 
the Yugoslav National Army (YNA) (19).
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
Sum
NUMBER OF CHILDREN YEAR OF BIRTH
1
2
3
4
5
3
3
2
4
2
2
6
0
0
0
2
0
5
0
1
0
0
0
0
1
1
0
0
0
0
0
0
47
Table 3.
Figure 1.
Figure 2.
Number of children of Slovenian origin by year of 
birth (N=47). 
The annual number of newly registered hepatitis 
B virus chronically infected children in the studied 
period 1997–2010 (N=52).
The annual number of newly registered hepatitis 
B virus chronically infected persons in the studied 
period 1997–2010 (N=1.729).
112
10.2478/sjph-2022-0015 Zdr Varst. 2022;61(2):109-114
A statistically significant negative linear trend (p=0.019) 
was present in the annual number of diagnosed children 
in the period 1997–2010, as shown in Figure 1, while in 
the same period there was no linear trend present in the 
entire population (p=0.978) (Figure 2).
4 DISCUSSION
To the best of our knowledge this is the first study 
describing the epidemiological characteristics of children 
chronically infected with HBV in Slovenia. The most 
common risk factor among children included in our study 
was “presence of HBV infection within the family” (68.8%), 
as has been reported in other European countries (20). 
In countries with low HBV prevalence the most common 
routes of childhood infection are perinatal transmission 
or transmission in early childhood (10). Consequently, 
antenatal screening, antiviral prophylaxis in pregnancy 
and early HBV vaccination are vital for preventing HBV 
infection (21, 22). 
Our results have shown that mandatory vaccination of 
children and screening of  pregnant women for HBsAg with 
consecutive immunization of newborns of HBsAg positive 
mothers significantly reduced the incidence of CHB among 
children born in Slovenia. To the best of our knowledge, 
currently there are only four children with CHB in follow-
up at the main Slovenian hospital, University Medical 
Center Ljubljana (UMCL), none of them having been born 
in Slovenia (they were born in China, Ghana, Ukraine 
and Thailand, respectively) (Breda Zakotnik, MD, B.Sc, 
personal communication, unpublished data).
Similar reports on the effectiveness of the HBV child 
vaccination come from Bulgaria (23), Taiwan (24) and 
China (25). There are also reports on protection from 
HBsAg carriage after hepatitis B immunization in the 
general population (26). 
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An HBV DNA viral load greater than 20,000 IU/ml was 
found in a significant proportion of HBeAg-positive 
children. This finding is consistent with the natural course 
of HBV infection in the Mediterranean region (27, 28). 
Our children and young adults are still in phase two of 
the natural course of the disease (HBeAg-positive chronic 
hepatitis) (18), for which a high HBV DNA viral load is 
characteristic. 
The main strength of our study is its national coverage, 
while a major limitation is that some statistical analysis 
had to be performed in smaller subgroups due to lack of 
data. There is also a potential chance that some children 
and pregnant women were never diagnosed at the national 
reference laboratory for viral hepatitis, but at Blood 
Transfusion Centers of Slovenia. In further research, which 
is currently in progress, we will focus on a determination 
of the prevalence of HBsAg-positive pregnant women in 
Slovenia in the past 20 years and try to obtain data on 
chemoprophylaxis of pregnant women and the proportion 
of newborns of HBsAg-positive mothers who received 
passive and active immunization, with the aim of updating 
national guidelines for the treatment of HBsAg-positive 
pregnant women and their newborns.
5 CONCLUSIONS
Our study showed that prevention strategies adopted 
in the mid-nineties – mandatory vaccination of children 
against hepatitis B and mandatory HBsAg screening of 
pregnant women – have resulted in complete elimination 
of CHB in children of Slovenian origin born in Slovenia 
after 2004. We sincerely hope that elimination of CHB in 
children in Slovenia will soon be followed by the same 
achievement in other countries in the region, or at least 
that we can show the way forward to achieving this goal. 
CONFLICT OF INTEREST
The authors declare that no conflicts of interest exist.
FUNDING
None. 
ETHICAL APPROVAL
The study was approved by the National Medical Ethics 
Committee of the Republic of Slovenia on May 4th, 2015 
(consent number: 6/04/15). 
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