The State of Hepatitis B and C in The Mediterranean and

Journal of Viral Hepatitis, 2013, 20 (Suppl.
2), 120
doi:10.1111/jvh.12120
The State of Hepatitis B and C in the Mediterranean and

Balkan Countries: Report from a Summit Conference
A. Hatzakis,1 P. Van Damme,2 K. Alcorn,3 C. Gore,4 M. Benazzouz,5 S. Berkane,6 M. Buti,7
M. Carballo,8 H. Cortes Martins,9 S. Deuffic-Burban,10,11 A. Dominguez,12 M. Donoghoe,13
A-N. Elzouki,14,15 N. Ben-Alaya Bouafif,16 G. Esmat,17 R. Esteban,18 M. Fabri,19
K. Fenton,20 D. Goldberg,21 I. Goulis,22 T. Hadjichristodoulou,23 T. Hatzigeorgiou,24
O. Hamouda,25 S. Hasurdjiev,26 S. Hughes,24 A. Kautz,26 M. Malik,27 S. Manolakopoulos,28
M. Maticic,29 G. Papatheodoridis,30 R. Peck,31 A. Peterle,24 G. Potamitis,32 D. Prati,33
F. Roudot-Thoraval,34 T. Reic,26 A. Sharara,35 M. Shennak,36 G. Shiha,37 D. Shouval,38
M. Socan,39 H. Thomas,40 M. Thursz,40 M. Tosti,41 C. Trepo,42,43,44 A. Vince,45 E. Vounou,46
L. Wiessing47 and M. Manns48 1Athens University Medical School, Athens, Greece; 2Viral hepatitis Prevention Board, Vaccine &
Infectious Disease Institute, University of Antwerp, Antwerp, Belgium; 3NAM Publications/infohep.org, London, UK; 4Hepatitis C Trust, London, UK;
5
Ibn Sina Hospital, Rabat, Morocco; 6Department of Medicine and Gastroenterology, Bologhine Hospital, Algiers, Algeria; 7Department of Internal
Medicine, Hospital Universitari Vall dHebron, Barcelona, Spain; 8International Center for Migration Health and Development, Geneva, Switzerland;
Departamento de Doencas Infecciosas, Instituto Nacional de Sa
ude Dr Ricardo Jorge, Lisbon, Portugal; 10Inserm U995, Universite Lille Nord de
11
France, Lille, France; TIP-AVENIR Inserm Modelisation, Aide e la Decision, et Cout-Efficacite en Maladie Infectieuses, U738, Universite Denis
ublica, Universitat de Barcelona, CIBER Epidemiologa y Salud Publica (CIBERESP), Barcelona,
Diderot, Paris, France; 12Departament de Salut P
9
Spain; 13World Health Organization Regional Office for Europe, Copenhagen, Denmark;
Doha, Qatar;
15
Faculty of Medicine, Benghazi University, Benghazi, Libya;
14
Department of Medicine, Hamad General Hospital, HMC,
16
Observatory of New and Emerging Diseases, Ministry of Health, Tunis,
Tunisia; 17Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt; 18Internal Medicine and
Liver Unit of the Hospital Universitari Vall dHebron, Barcelona, Spain; 19Clinic for Infectious Diseases, Clinical Center Vojvodina, Novi Sad, Serbia;
20
Health and Wellbeing Directorate, Public Health England, London, UK;
21
Group for Blood Borne Viruses, Sexually Transmitted Infections, Vaccine
Preventable Diseases and Respiratory Infections, Health Protection Scotland, Glasgow, UK; 224th Department of Medicine, Aristotelian University of
Thessaloniki, Thessaloniki, Greece; 23Department of Hygiene and Epidemiology, University of Thessaly, Larissa, Greece; 24European Parliament,
Brussels, Belgium; 25Department for Infectious Disease Epidemiology, Robert Koch Institute, Berlin, Germany; 26European Liver Patients Association,
Sint Truiden, Belgium; 27Pandemic and Epidemic Disease, World Health Organization Regional Office for the Eastern Mediterranean, Cairo, Egypt;
28
Department of Gastroenterology, Athens Medical School, Hippokratio General Hospital, Athens, Greece; 29Clinic for Infectious Diseases and Febrile
Illnesses, University Medical Centre Ljubljana, Ljubljana, Slovenia; 302nd Department of Internal Medicine, Athens University Medical School, Athens,
Greece; 31World Hepatitis Alliance, Geneva, Switzerland; 32Pancyprian Medical Association, Nicosia, Cyprus; 33Department of Transfusion Medicine
and Hematology, Ospedale Alessandro Manzoni, Lecco, Italy; 34Departement de Sante Publique, Hopital Henri Mondor AP-HP, Universite Paris-EstCreteil, Creteil, France; 35American University Medical Center, Beirut, Lebanon; 36Jordan University Hospital, Amman, Jordan; 37Egyptian Liver
Research Institute and Hospital, Cairo, Egypt; 38Liver Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel; 39National Institute of Public
Health, Ljubljana, Slovenia; 40Imperial College, London, UK; 41Istituto Superiore di Sanita`, National Centre of Epidemiology, Surveillance and Health
Promotion, Rome, Italy; 42Service dHepatologie, Hospices Civils de Lyon, Hopital de la Croix-Rousse, Lyon, France; 43CRCL/INSERM U1052, Lyon, ;
44
Universite Lyon 1, Lyon, ; 45Croatian Referral Center for Diagnostics and Treatment of Viral Hepatitis, Zagreb, Croatia; 46Limassol General
Hospital, Limassol, Cyprus; 47European Monitoring Centre for Drugs and Drug Addiction, Lisbon, Portugal; and 48Department of Gastroenterology,
Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany
Abbreviations: AIDS, acquired immunodeficiency syndrome; ALT, alanine aminotransferase; CASCADE, Concerted Action on SeroConversion
to AIDS and Death in Europe (Collaboration); DAA, directly acting antiviral (drug); DALY, disability-adjusted life year; DG Health, Directorate General for Health and Consumers; EASL, European Association for Study of the Liver; EC DG, Research European Commission Directorate General for Research and Innovation; EMCDDA, European Monitoring Centre for Drugs and Drug Addiction; EMRO, World Health
Organization Regional Office for the Eastern Mediterranean; ETV, entecavir; EU, European Union; FYROM, the Former Yugoslav Republic of
Macedonia; GDP, gross domestic product; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC,
hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis delta virus; HIV, human immunodeficiency virus; IDU, injecting drug user;
IFN, interferon; MSM, men who have sex with men; NAT, nucleic acid testing; PAT, parenteral antischistosomal therapy; PEG-IFN, pegylated interferon; QALY, quality-adjusted life year; STI, sexually transmitted infection; SVR, sustained virological response; TDF, tenofovir; UK,
United Kingdom; USA, United States of America; VHPB, Viral Hepatitis Prevention Board; WHO, World Health Organization.
Correspondence: Angelos Hatzakis, Professor of Epidemiology and Preventive Medicine, Head, National Retrovirus Reference Center, Director, Department of Hygiene, Epidemiology and Medical Statistics, Athens University Medical School, 75, Mikras Asias str, Athens 11527,
Greece. E-mail: ahatzak@med.uoa.gr
2013 John Wiley & Sons Ltd
A Hatzakis et al.
SUMMARY. The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral
hepatitis remains largely unrecognized, including in highrisk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many
countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated
populations and migration, and a probable increase in
drug injecting. Targeted vaccination strategies for hepatitis
B virus (HBV) among risk groups and harm reduction
interventions at adequate scale and coverage for injecting
drug users are needed. Transmission of HBV and hepatitis
C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and
blood products in the Balkan and North African countries
INTRODUCTION
Globally, around 2 billion people have been infected with
the hepatitis B virus (HBV), and around 150 million with
the hepatitis C virus (HCV) [1]. In 2010, it was estimated
that 786 000 deaths worldwide were attributable to hepatitis B and 455 000 to hepatitis C, making hepatitis B the
15th ranked and hepatitis C the 22nd ranked cause of
death worldwide [2, 3].
Approximately 14 million people in the World Health
Organization (WHO) European Region are estimated to be
infected with hepatitis B and 9 million with hepatitis C.
Each year, they cause around 36 000 and 86 000 deaths,
respectively, with the number of deaths reported to be
increasing [4]. The WHO Regional Office for the Eastern
Mediterranean Region estimates that 17 million people
have chronic HCV infection, and 170 million have chronic
HBV infection; each year, around 800 000 new HCV infections and 4.3 million new HBV infections occur in the
region [5].1
Awareness of the global threat constituted by hepatitis B
and C infections led the World Health Assembly in 2010
to pass a resolution urging Member States to take comprehensive action to combat both infections by improvements
in screening, vaccination, treatment and prevention.
Together with these improvements, rapid progress in drug
discovery now affords the prospect of an eventual cure for
the majority of people infected with hepatitis C. In 2012,
WHO published a Framework for Global Action (see Panel
1) [1].
The Balkan and Mediterranean countries face particular
challenges in relation to viral hepatitis due to a legacy of
war, displacement and civil unrest in many of these
countries.2 The scale of the public health problem posed by
highlight the need to implement and monitor universal

precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has
improved outcomes of treatment for both HBV and HCV,
although access is limited by the high costs of these drugs
and resources available for health care. Egypt, with the
highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing
the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the
form of strategic plans, financial and human resources,
normative guidance and technical support from regional
agencies and research.
Keywords: Balkan region, hepatitis B, hepatitis C, hepatocellular carcinoma, Mediterranean, northern Africa, surveillance.
hepatitis B and C remains largely unrecognized due to limited surveillance, poor public awareness and a lack of
advocacy in comparison with other infectious diseases. As
countries of the Balkans progress towards European Union
(EU) accession, and closer trade links develop throughout
the Mediterranean region, it is essential for policy makers
and stakeholders in the EU to pay greater attention to public health issues in neighbouring states and to support
responses to viral hepatitis. Promoting the health of
migrants and other marginalized populations, particularly
people who inject drugs, will also have a substantial
impact on the future burden of chronic liver disease in the
EU.
PANEL 1: WHO FRAMEWORK FOR GLOBAL

ACTION ON VIRAL HEPATITIS [1]
The Framework for Global Action has four domains:
Axis one: Increase engagement through awareness,
partnerships and mobilizing resources.
Axis two: Evidence-based policy and data for action.
Axis three: Prevention of virus transmission by the
promotion of vaccination and behavioural and structural interventions.
Axis four: Screening, care and treatment; develop
guidelines and advocate and negotiate for price
reductions for treatment, assist countries in developing national strategies.
Following a European Summit Conference on Hepatitis B

and C in Europe in 2010, the Hepatitis B and C Public Policy Association organized a meeting in December 2012 for
stakeholders in the EU, Balkan and Mediterranean regions,
Hepatitis B and C in the Mediterranean and Balkan Countries

bringing together expert clinicians, specialists in public
health, national policy makers, EU institutions and patient
groups from 26 countries to review the current situation
and identify opportunities for action.3 This article summarizes the main findings presented to the conference, the
conclusions of its discussions and a Call to Action.
EPIDEMIOLOGY
Prevalence
The prevalence of hepatitis B surface antigen (HBsAg) in
the WHO European Region varies from 0.1% in Ireland
and the Netherlands to >7% in Eastern Turkey and is
higher in south and central Europe (Turkey, Romania, Bulgaria and Greece). Data on prevalence among the general
population are lacking in most of the countries, and burden of disease and mortality data are not available for
countries with the highest prevalence [6].
The prevalence of HCV antibody ranges from 0.4% in
Sweden, Germany and the Netherlands to >2.2% in Italy
(although the studies on HCV prevalence in Italy are old
and not representative of the general population). The
prevalence of HCV in Italy is much higher than that of
HBV, probably because of a period of increased iatrogenic
transmission in the 1950s [6].
There are large numbers of chronically HBV- and HCVinfected migrants in countries such as Germany, Spain,
France, Italy, Greece and the United Kingdom (UK). They
remain unidentified, as they and other risk groups are
often not included in general population screening studies.
A study among immigrants to six EU countries found high
rates of HBsAg positivity among migrant populations [7].
In France, the prevalence of anti-HCV is much higher
among natives of the Middle East (10.2%) than in the
indigenous French population (0.73%) [8]. In Portugal and
Greece, both countries with large migrant populations,
studies conducted between 2006 and 2008 found high
rates of HBsAg among pregnant immigrants and children
of migrants [9], and pregnant Albanian and Asian refugees
[10,11].
Information on the prevalence of chronic hepatitis B and
C infections is lacking in most of the Mediterranean and
Balkan states due to limited screening and surveillance (see
Tables 1 & 2). With the exception of Croatia [1214],
there is very little information on recent prevalence in
high-risk groups such as injecting drug users (IDUs),
healthcare workers, men who have sex with men (MSM)
and sex workers.
General population prevalence of HBsAg tends to be
higher in the Balkan, North African and eastern Mediterranean countries than in northern and central Europe, and
similar to prevalence in European Mediterranean countries.
Surveys for anti-HCV prevalence carried out in North
Africa and the Middle East since 2008 suggest a general
population prevalence of 1.69% in Lebanon (presentation

by AI Sharara at Hepatitis B and C in the Mediterranean
and Balkan countries, December 2012), 1.3% in Libya and
14.7% in Egypt [15,16].
The high prevalence of HCV in Egypt is most likely due
to a history of parenteral antischistosomal therapy (PAT)
and is perhaps one of the most illustrative examples of iatrogenic transmission. Prevalence is higher in those
>30 years, reflecting the exposure index to PAT [17], and
is highest in those aged 5559 years (39.4%) [16].
Prevalence of hepatitis delta virus

The hepatitis delta virus (HDV) is a defective RNA virus
that can infect only individuals who have hepatitis B. Coinfection with HBV/HDV causes severe liver disease with
rapid progression to cirrhosis and liver decompensation;
diagnosis is difficult as there are no specific clinical or histological features.
The prevalence of HDV is declining in some endemic
areas but increasing in northern and central Europe
because of migration [18]. A study from Hannover in
2006 found a prevalence of anti-HDV/HBsAg positivity of
11.3% among 2354 subjects, of which 26% were from
Turkey and 28% from East Europe [19]. Another study
from London found a high prevalence among immigrants
from southern and eastern Europe (28.1%), Africa (26.8%)
and the Middle East (7.3%) [20]. A study from Egypt found
that HDV coinfection in HBV carriers is related to severity
of liver disease [21]. Improved detection of such cases is
needed, as HDV does not respond well to treatment
(response rate 2025%), and relapse rates are high as long
as HBsAg is positive.
Burden of chronic liver disease

In many southern European countries, the burden of
chronic liver disease due to hepatitis B is increasing due to
ageing of unvaccinated populations, and hepatitis C
acquired due to injecting drug use. In Italy, although the
incidence of both HBV and HCV is decreasing, the burden
of associated chronic liver disease due to past epidemics is
substantial (330 000) and is highest in the population
aged 60 years and above, reflecting vaccination coverage
of the population below 31 years (M. Zuin Personal communication; Italian Ministry of Health, 2012) [22].
Chronic hepatitis and cirrhosis are among the top ten
causes of death in Portugal, but there is no public health
programme on liver disease. In Spain, cirrhosis accounted
for 17 68420 897 disability-adjusted life years (DALYs)
lost due to HCV-related chronic hepatitis and 5021 DALYs
lost due to chronic hepatitis B in 2006. Hepatocellular carcinoma (HCC) due to chronic hepatitis C and B was
responsible for 12 00514 004 DALYs and 2005 DALYs
lost, respectively [23].
(2011)
(2007)
(2007)
(20032007)
2.9% (1997)
1.69%
0.7%
2.62%
0.02%
0.2%
0.23%
13%
52%
0.4%
0%
(2011)
(2007)
(2005)
(2010)
(1999)
(1997)
2.2% (2013)
HBsAg
HBsAg
HCV Ab
6 million
4.2 million
1.3% (2013)
1.96%
0.05%
18%
35.7%
27% (2003)
2.7% (2003)
0.751.5%
1.3% (2005)
HBsAg
32.3 million
4% (2010)
45.7% (1996)
1.87% (2011)
19.5% (2006)
HBsAg
1.5% (2008)
30.5% (2008)
0.21.7% (1996)
0.40.7% (2011)
39%
30% (2011)
HCV Ab
0.7% to
24.5% to
HCV Ab
10 million
Tunisia
4.3% (2001)
1.5%
5.9% (2008)
9.9%
HBsAg
6.5 million
Jordan
3% (2009)
HCV Ab
(20012010)
(2011)
(2000)
(20032005)
HCV Ab
Morocco
3.5% (2008)
17.6% (HBc+)
(1992)
1.7% (2005)
(0.66% in
Jewish and
2.84%
in Arab
populations)
0.1% (2011)
HBsAg
7.7 million
HCV Ab
6.4% (2010)
16.4% (2011)
1.5% (2011)
4% (2010)
14.7% (2008)
16.8% (2011)
46% (1994)
1.6% (2003)
Libya
0.3% (1997)
n/a
0.21% (2010)
23.8% (2008)
HCV Ab
Lebanon
1.8% (1998)
2.15% (1998)
0.88% (2010)
10.5% (2008)
HBsAg
HBsAg
HCVAb
84 million
36.3 million
Israel
EU, European Union; HBsAg, hepatitis B surface antigen; HCV Ab, antibody against hepatitis C virus.
Source: Speakers presentations at the Conference on Hepatitis B and C in Mediterranean and Balkan countries.
General population
Blood donors
Haemodialysis
Injecting drug users
Healthcare workers
Pregnant women
Population
Pregnant women
General population
Blood donors
Haemodialysis
Healthcare workers
Population (2011)
Egypt
Algeria
Table 1 Prevalence estimates of hepatitis B surface antigen and antibody against HCV in the non-EU Mediterranean states
4
A Hatzakis et al.
4569%
1.5% (no date)

2% (no date)
EU, European Union; HBsAg, hepatitis B surface antigen; HCV Ab, antibody against hepatitis C virus.
0.5% (2011)
0.22% (2011)
(2005)
(2010)
(2009)
(2008)
1.3%
0.07%
8.4%
41%
0.290.89%
0.29%
58.9%
35%
0.4%
Incidence reports only
General population
Blood donors
Haemodialysis
Healthcare workers
Pregnant women
HCV Ab
(2011)
(2011)
(2006)
(2006)
(2006)
1.5%
0.09%
<1%
0.63%
(2005)
(2010)
(2009)
(2008)
HCV Ab
MAJOR ROUTES OF EXPOSURE AND PRIORITIES

FOR PREVENTION
4.2% (2009)
12% (2009)
HBsAg
HBsAg
Population
Croatias national cancer registry reports a slowly

increasing burden of HCC, although the incidence of HCV
is declining [24].
In Egypt, mortality due to HCC is increasing. Whereas
chronic HCV infection accounted for 65% of HCC in 1995
and chronic HBV infection for 9% [25], in 2010, chronic
HCV infection accounted for 94% of HCC and chronic HBV
infection for 4% (Gomaa et al. National Liver Institute
unpublished data, 2010). The reason for the declining proportion with chronic hepatitis B could be the increasing
effect of vaccination of the population against HBV in
childhood.
0.29% (2009)
43% (2009)
37% (2011)
HBsAg
1.7 million
4.4 million
3.8 million
HBsAg
Kosovo
Croatia
Bosnia-Herzegovina
Table 2 Prevalence estimates hepatitis B surface antigen and antibody against HCV for the non-EU Balkan states
HCV Ab
7.2 million
Serbia
HCV Ab
Both hepatitis B and C are bloodborne viruses; hepatitis B

can also be transmitted through contact with contaminated body fluids. Transmission may be both perinatal, as
from mother to child, and horizontal, as in other cases.
The predominant modes of transmission vary across the
EU, Balkans, Mediterranean and North African countries,
depending on cultural practices, screening for blood and
organ donors, prevalence of specific risk behaviours such
as injecting drug use, and the extent to which universal
precautions against bloodborne virus transmission are consistently implemented.
INJECTING DRUG USE

Sharing of injecting equipment among IDUs accounts for a
substantial proportion of transmission of HCV infection
(and to a lesser extent of HBV) in European countries. Preliminary data from the European Monitoring Centre for
Drugs and Drug Addiction (EMCDDA) in 2010 suggest a
possible increase in the seroprevalence of both HBV and
HCV among IDUs in some EU and Balkan countries, suggesting inadequate harm reduction interventions for IDUs
and/or increasing levels of drug injecting. Data are not
available on the magnitude of injecting drug use in the
North African countries, probably because of a lack of
research into this hidden population.
Levels of HCV antibody prevalence among IDUs in the
EU vary widely, ranging from <25% in some studies
among IDUs in the Czech Republic, Hungary and Slovenia
to >75% in some studies from Belgium, Italy, Portugal and
Romania in 20092010 [26]. Among young IDUs
<25 years, HCV prevalence is increasing in Bulgaria,
Cyprus, Greece, Romania and Austria, and among new
IDUs in Greece [27, 28].
In the Balkan countries, preliminary unconfirmed data
suggest that, among IDUs, the prevalence of HCV is increasing in Bosnia and Herzegovina, Kosovo, the Former Yugoslav Republic of Macedonia (FYROM) and Serbia varying
from 24% in Kosovo to >80% in FYROM. In Albania, HCV
A Hatzakis et al.
prevalence is low (59%) but HBV prevalence is very high

and increasing (1218%). Prevalence data are largely lacking for IDUs in North Africa and the Eastern Mediterranean.
Harm reduction
Harm reduction interventions to reduce transmission
among IDUs are vaccination, needle and syringe programmes (NSPs), opioid substitution therapy (OST) and
testing and treatment. Combining or integrating these services could lead to better results, for examples, OST and
treatment for viral hepatitis. The EMCDDA recommends
targeted service delivery designed to meet the needs of
drug users [29]. NSPs have been introduced in EU Member
States but the scale and coverage are probably not enough
to interrupt transmission. An IDU may inject hundreds of
times in a year; ideally, this should be with clean injecting
equipment each time to stop sharing of injecting equipment. The average number of syringes and needles distributed through specialized programmes per IDU from 2009
to 2010 was the highest in Norway (>300) followed by
Luxembourg (>200), but in many countries, it falls far
short of what is needed [30].
In the Balkan countries, NSPs and OST are available in
Albania, Bosnia and Herzegovina, Macedonia (FYROM),
Montenegro and Serbia, although the scale and coverage
are low. Kosovo has only one NSP, and OST was introduced in 2012. In many Mediterranean and North African
countries, NSPs and OST are not available [31], although
OST has been recently introduced in Morocco.
HEALTHCARE SETTINGS
Transmission of HBV and HCV in healthcare settings due
to poor infection control practices has been observed in
many Balkan and Mediterranean countries. High HCV
prevalence has been reported in a number of countries,
including Bosnia and Egypt, leading to the implementation
of dedicated dialysis facilities for chronic HCV patients in
the latter country [32,33]. In Italy, according to the estimate of the population attributable risks, dental therapy
accounted for 12.9% of HBV infections, and nosocomial
exposure for 11.4% of HBV and 48.7% of HCV infections
between 2007 and 2011 (Italys Integrated Epidemiological
System for the Surveillance of Acute Viral Hepatitis [SEIEVA], 20072011, unpublished data). In Spain, outbreaks
of HCV infection were reported among 395 persons in
diverse healthcare settings from 1996 to 2009 [34]. In
another study from Spain, hospital admission accounted
for 73% of HCV infections compared with 9% for injecting
drug use [35]. There is thus a need to implement and
monitor universal precautions across a wide range of
healthcare settings in the Balkan and Mediterranean countries.
Inadequate screening of blood

Many epidemics of hepatitis C in the Balkan and Mediterranean areas were seen in the aftermath of wars in the past
two decades, largely due to inadequate screening of blood
donors and rapid demand for blood [36]. In Bosnia, screening for HCV among blood donors was introduced only in
1995 at the end of the war [32]. Although 100% of the
blood supply is now screened for HBsAg and anti-HCV, in
the North African countries, recipients of blood and blood
products have a much higher prevalence of HBV and HCV,
as in Egypt and Tunisia [37,38], probably because of the
large number of paid, replacement and infected first-time
donors. More emphasis is needed on procuring voluntary,
nonremunerated, repeat donors.
Blood, organ and injection safety

Screening for HBsAg and anti-HCV is highly effective in
preventing transmission of bloodborne HBV and HCV,
although infection may still be transmitted during the window period. Many countries have implemented HCV RNA
and HBV DNA testing and nucleic acid testing (NAT) for
blood and organ donors to identify infections in the window period. However, the cost of NAT is very high, and
there is insufficient evidence to recommend routine NAT in
developing and middle-income countries.
In Europe and the southern Mediterranean countries,
blood supply and transplant procedures are very safe. In
the Balkans, blood transfusion is generally safe due to
mandatory donor screening for HBsAg, HCV and human
immunodeficiency virus (HIV). Kosovo, for example, has
an HBV prevalence among blood donors of 4.2%, and HCV
prevalence of 0.3%, which is similar to that for other
South-East European countries [39]. However, a cause for
concern is the high percentage of paid donors, as in Albania (23%), and hepatitis B-infected first-time donors, such
as in Romania, Bulgaria, Moldova, Serbia and Montenegro,
Bosnia and Herzegovina, with the highest percentage in
Albania (76.2%). The use of replacement donors ranges
from 71.5% in Albania to 96% in Moldova [40]. In addition, national transfusion services are fragmented, resulting in incomplete reporting of data on transfusion safety,
haemovigilance and appropriate use of blood.
Globally, about 4070% of all injections are believed to
be unsafe and account for 33% of cases of hepatitis B and
42% of hepatitis C [41]. In Tunisia, intramuscular injections appear to play an important role in the horizontal
transmission of HBV via inadequately sterilized syringes
used for iatrogenic intramuscular injections in a community with high HBV prevalence [42].
Activities to prevent transmission in healthcare settings
must address high rates of reuse of needles and syringes,
improper sterilization procedures, financial pressure to
reuse needles and syringes, lack of implementation of

universal precautions, low HBV vaccination rates of
healthcare workers and the lack of accountability at facility and health system level for failures in infection control.
A mathematical model estimated that, in 2004, in the
WHO Eastern Mediterranean Region, approximately
2.5 million HBV infections and 645 000 HCV infections
could be attributed to unsafe injections annually [43].
Cosmetic and cultural practices

Household transmission of hepatitis B (intrafamilial) is a
common route of infection in countries such as Tunisia
and Jordan due to practices such as scarification, tattooing,
circumcision, body piercing and hijama or wet cupping, a
form of traditional Arab medicine [44]. In Italy, between
2007 and 2011, 20% of the notified acute hepatitis B and
12.5% of acute hepatitis C infections were attributable to
percutaneous exposures during cosmetic procedures (SEIEVA 20072011, unpublished data). Better education of
those who practise these procedures, screening and observance of universal precautions are needed in these settings.
Transmission in closed settings

Prison populations seem to have a much higher prevalence
of both HBV and HCV. Prison inmates in Slovenia had a
high prevalence of anti-HCV (26%) [45,46], while in Croatia, Italy and Egypt, they had a high prevalence of both
HBV and HCV [4749]. Injecting drug use and tattooing
in prisons are likely to contribute to the high prevalence
among current and former prisoners.
SEXUAL EXPOSURE
In Italy, of the notified acute HBV and HCV infections,
10.3% and 22%, respectively, were attributable to sexual
intercourse (SEIEVA 20072011, unpublished data).
Evidence is emerging of increasing transmission of HCV
among HIV-positive MSM in Europe. Data from 12 cohorts
within the Concerted Action on SeroConversion to AIDS
and Death in Europe (CASCADE) Collaboration showed
that HCV incidence had been increasing among HIVinfected MSM from the mid-1990s, but increased much
faster after 2002 [50]. Data on coinfection in the Balkans
and southern Mediterranean are lacking.
PREVENTION
MSM, sexually transmitted infection (STI) clinic attendees,

healthcare workers and those with multiple sex partners.
In 2009, 22 EU countries had universal vaccination programmes, and seven had targeted vaccination programmes. Most countries had selective vaccination
programmes for risk groups [51].
Many countries in the Mediterranean region have noted
a sharp decline in the number of notified cases of hepatitis
B after the introduction of universal vaccination. For
example, in Greece, following vaccination programmes, the
prevalence of HBsAg has fallen, particularly among
migrants and the Muslim minority [52]. In Italy, notifications of acute cases of hepatitis B fell sharply after the start
of HBV vaccination in 1992 (SEIEVA 19852011, unpublished data). However, cases of hepatitis B were observed
among risk groups who should have been vaccinated and
were not, such as healthcare workers, household members
of HBsAg-positive individuals and IDUs in treatment centres, highlighting the need to specifically target these
groups (SEIEVA 20012011, unpublished data). Notification of cases of acute hepatitis B among immigrants has
also been declining, which could be accounted for by
vaccination for hepatitis B in the countries of origin or
in Italy, and by herd immunity [SEIEVA 20042011,
unpublished data].
In Catalonia (Spain), despite the introduction and high
coverage of universal vaccination among pre-adolescents
since 1991 and infants since 2002, no reduction in the incidence of HBV infection has been observed since 2001. Statistical models suggest that the incidence has increased due to
immigration. Vaccination strategies for risk groups should
thus be applicable to susceptible immigrants (children and
adolescents) from countries with high or intermediate prevalence where hepatitis B vaccination programmes have still
not been launched or where coverages are low [53].
Among the Mediterranean and North African countries,
Tunisia, Jordan and Egypt reported sharp declines in the
incidence of hepatitis B after the introduction of universal
vaccination programmes. While most countries have a policy for universal vaccination of newborns, most do not
have standardized policies for vaccination of risk groups,
and few have catch-up immunization programmes for adolescents. Algeria, Morocco, Tunisia and Israel provide vaccination to healthcare workers (data from presentations at
Hepatitis B and C in the Mediterranean and Balkan Countries, December 2012). Libya provides voluntary vaccination to persons from high-risk groups free of charge since
1999 [54,55].
Vaccination
SCREENING
WHO recommends universal vaccination of newborns and

catch-up vaccination for those born before the start of universal infant immunization in a country, and for those
with risk factors for acquiring hepatitis B, such as IDUs,
Both HBV and HCV are silent diseases with high morbidity
and mortality. Screening programmes for early diagnosis,
followed by referral to care and treatment, could result in
considerable public health gains [6].
A Hatzakis et al.
Table 3 Comparative HBV and HCV screening policies in the non-EU Mediterranean countries
Antenatal screening
Blood and organ donors
Blood transfusion or products prior to
1992 in EU, or any transfusion
outside EU
Clinical signs or laboratory signs
(including cirrhosis and HCC)
Candidates for chemotherapy or
immunosuppressive treatment
Haemophiliacs who received concentration
factors prior to 1987
Haemodialysis
History of shared injecting equipment
History of long-term imprisonment
Hospital surgery patients
Household contacts
HIV
IVF candidates
Men who have sex with men
Migrants from high prevalence countries
Military recruits
Organ or tissue transplants prior to
1992 in EU or outside EU
Pre-employment
Algeria
Egypt
Israel
Jordan Lebanon
Both
Both
Both
Both
Both
Both
Both
Both
HCV
Both
Both
Both
Both
Both
Both
Both
Both
Morocco Tunisia
HBV
Both
HBV
Both
Both
Both
Both
Both
HBV
HBV
HBV
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
HBV
HBV
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Pregnant women and newborns

Prenuptial
STI clinic patients
Traditional medicine exposure
Unvaccinated healthcare workers
Occupational exposure and/or carrying
out exposure-prone procedures
Libya
Both
Both
HCV,
health care
Selective risk
groups: HBV
Both
HBV
HBV
HBV
Both
HBV
HBV
Both
HCV
HBV
Both
Both
Both
Both
HBV
Both
HBV
Both
Both
Both
Both
HBV
HBV
HBV
HBV
EU, European Union; HBV, hepatitis B virus; HCV Ab, hepatitis C virus.
The World Health Organization is developing guidelines

on screening, treatment and care for viral hepatitis for
publication in 2013. At present, high-risk populations
such as migrants, IDUs, prisoners, STI clinic attendees
and MSM are not screened routinely within the EU or
neighbouring countries. A study by WHO EURO among
41 EU countries found that a national policy for screening followed by referral to care was in place in 51% of
countries for hepatitis B, and 49% for hepatitis C (WHO/
World Hepatitis Alliance/University of Copenhagen. Viral
hepatitis: global prevention and control report; preliminary results).
Screening practices are limited in most countries of
North Africa and the Middle East, and few countries in the
Balkans have yet developed systematic screening practices

(see Tables 3 & 4).
There is a lack of evidence on the cost effectiveness of
screening, with the exception of screening for HCV among
IDUs and migrants in one country and for HBV among
pregnant women [6]. A study from the Netherlands demonstrated the cost effectiveness of screening for chronic
hepatitis B among migrants [9000 per quality-adjusted
life year (QALY) gained, 56]. The US Preventive Task Force
in 2012 recommended screening for HCV infection in
adults at high risk, including those with a history of injecting drug use or blood transfusions prior to 1972, and onetime screening for HCV among all those born between
1945 and 1965 [57]. Screening in this population has
Table 4 Comparative HBV and HCV screening policies in the non-EU Balkan countries
Antenatal screening
Blood and organ donors
Blood transfusion or products prior to 1992 in EU, or any
transfusion outside EU
Clinical signs or laboratory signs (including cirrhosis and HCC)
Candidates for chemotherapy or immunosuppressive treatment
Haemophiliacs who received concentration factors prior
to 1987
Haemodialysis
History of shared injecting equipment
History of long-term imprisonment
Household contacts
HIV
IVF candidates
Military recruits
Organ or tissue transplants prior to 1992 in EU or outside EU
Pregnant women and newborns
Traditional medicine exposure
Unvaccinated healthcare workers
Occupational exposure and/or carrying out exposure-prone
procedures
Bosnia-Herzegovina Croatia
Kosovo Serbia
HBV
Both
HCV
HBV
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
Both
HBV
Both
Both
Both
Both
HBV
Both
HCV
HBV
HBV
HBV
Both
Both
Both
HBV
Both recommended
as a part of
postexposure
procedures
Both
Both
EU, European Union; HBV, hepatitis B virus; HCV Ab, hepatitis C virus.
been found to be as cost effective as other routine screening programmes [58].
SCREENING FOR MIGRANTS

Bloodborne hepatitis viruses (B, C and D) occur at varying
prevalence in all regions of the world. Global population
movements caused by economic migration, war and civil
unrest are changing the global distribution of viral hepatitis. Migrant populations often represent the overlap
between viral hepatitis epidemics in the EU and those in
their countries of origin in the Balkan and Mediterranean
regions.
A recent systematic review and meta-analysis found a
high prevalence of chronic hepatitis B infection (7%)
among migrants in 110 pooled studies, particularly those
from East Asia and sub-Saharan Africa, and among
refugees [59]. Similarly, a comparison of hepatitis B
prevalence in the three largest migrant populations in six
northern European countries showed a five- to forty-fold
higher prevalence among these populations when compared with the overall population prevalence [7].
The importance of targeting migrants in surveillance
studies cannot be overemphasized. New and undocumented migrants may prefer to stay hidden, and have
pressing priorities such as food, shelter, sanitation, and
may not opt for detection and treatment of chronic, silent

conditions. Language barriers may further limit their
access to health care.
A comparison of screening programmes for HBV among
migrants in six European countries shows that Germany
(20% migrant population) offers screening to the largest
number of high-risk groups [7]. The country is examining
a number of indicators of migrant health for inclusion in
Health Interview and Examination Surveys for children,
adolescents and adults.
TREATMENT
Natural history of HBV
HBV causes a chronic disease that can be controlled but not
cured. Progression of hepatitis B depends mainly on the age
at which the patient becomes infected. The majority of children infected at birth or up to the age of 2 years progress to
chronicity, while <5% of adults do. Of those who are chronically infected, 210% per year progress to liver cirrhosis
and, finally, to decompensation and death. Patients treated
before the age of 50 years to effect HBsAg loss have a significantly reduced risk of developing HCC [60]. The risk of progression to HCC is 60 times higher in persons who are
HBsAg and hepatitis B e antigen (HBeAg) positive [61].
10
A Hatzakis et al.
Treatment
The goal of treatment is prevention of long-term negative
clinical outcomes (e.g. cirrhosis, HCC, death) by durable
suppression of HBV DNA. Treatment is two-pronged; provision of immunomodulators such as interferon (IFN) or
pegylated interferon (PEG-IFN) and antiviral agents (nucleos(t)ide analogues) such as lamivudine, adefovir, entecavir
(ETV), telbivudine and tenofovir (TDF) [62].
The European Association for Study of the Liver (EASL)
Guidelines of 2012 recommend treatment of all those with
evidence of active disease based on HBV DNA levels
>2000 IU/mL, alanine aminotransferase (ALT) levels above
the normal limit and perhaps active histological lesions for
both HBeAg-positive and HBeAg-negative patients. The
current guidelines for first-line therapy include PEG-IFNalpha or one of the two nucleos(t)ide analogues with a
high genetic barrier, ETV and TDF [63]. ETV and TDF
have shown higher rates of maintained viral suppression
compared with other antivirals, even in those with e antigen positive disease with very high levels of HBV DNA
[64]. With ETV and TDF, at 3 years of treatment, 95%
and 99% of both e-positive and e-negative patients, respectively, achieve undetectable HBV DNA, which is maintained at 6 years without major adverse events and with
negligible rates of resistance (1.2% for ETV and 0% for
TDF) [65,66].
Treatment with ETV or TDF improves liver histology
over a long follow-up period, even in those who enter
treatment with cirrhosis [67,68]. As these drugs became
available, liver transplantation for hepatitis has decreased
in Europe. Advantages over PEG-IFN include the oral route
of administration, potent inhibition of replication, negligible side effects, safety at all stages of the disease and low
risk of developing viral resistance.
Many of the Balkan, Mediterranean and North African
countries have added ETV and/or TDF to their standard
regimens, such as Serbia, Lebanon, Egypt, Jordan, Algeria,
Morocco and Libya. Routine use is limited by the high
costs of these drugs, although a large part of the costs are
borne by governments or through insurance.
Hepatitis delta virus: natural history and treatment

Hepatitis delta virus (HDV) makes use of HBsAg to
assemble and infect cells and causes progressive, early cirrhosis, mainly in persons who are anti-HBe positive. Low
serum HBV DNA and normal ALT levels and absence of
specific clinical/histological features make the diagnosis
difficult.
There is no definitive therapy for HDV infection at present. The current recommendation is PEG-IFN alpha weekly
for 1218 months, but only about 2025% of patients
respond. HDV may relapse as long as HBsAg is positive;
therefore, the only reliable end-point of therapy is clearance of HBsAg.
Hepatitis C
Natural history
Acute infection with HCV progresses to chronic infection
in 6580% of patients. Of these, about 20% will develop
cirrhosis after about 20 years. Factors that increase progression to cirrhosis are infection at a later age, male sex,
history of alcohol intake, coinfection with HIV or HBV and
obesity [69]. Chronic HCV infection increases mortality by
50% among acquired immunodeficiency syndrome (AIDS)
patients [70].
Treatment
HCV infection is curable. The end-point of therapy is sustained virological response (SVR), defined earlier as undetectable serum HCV RNA 24 weeks after the end of
therapy, but now at 12 weeks after the end of therapy
[71].
Those with cirrhosis at the time of diagnosis are at a
much higher risk of developing HCC, variceal bleeding,
hepatic encephalopathy and ascites, resulting in death
even within one year [72]. Therapy is effective even in
those with cirrhosis, although the outcomes of treatment
are not as good as in noncirrhotic patients. Elimination of
virus substantially reduces the rate of progression to cirrhosis, and to decompensation among those with compensated cirrhosis [73], but not from cirrhosis to cancer in the
long term, although it does reduce mortality [74].
Treatment options
Treatment for HCV has been improving over the years.
The 1990s regimen of IFN for 2448 weeks achieved SVR
in 10% and 25% of patients with genotypes 1 and 2/3
infection, respectively. The addition of ribavirin and later
PEG-IFN further improved outcomes. The standard duration of treatment for infection with genotypes 1 and 4 is
48 weeks and 24 weeks, respectively (no cirrhosis and low
baseline viraemia), in rapid virological responders, but
extended to 72 weeks for slow responders. For genotypes 2
and 3, treatment duration is 24 weeks (12 weeks in rapid
responders and 48 weeks in slow responders). Therapy
should be stopped in patients who do not show early virological response (>2 log drop in HCV RNA) at 12 weeks or
remain viraemic at 24 weeks of therapy [71]. Response to
therapy is much lower in HIV-coinfected persons [75].
The directly acting antivirals (DAAs) boceprevir and telaprevir, discovered in 2010, provide the best opportunity for
eradication of HCV. They are active against infection with
genotype 1 but not with genotypes 2, 3 and 4. Challenges
to the use of the DAAs include complex treatment algorithms, need for immediate results of HCV RNA testing with
sensitive assays, new adverse events, new drugdrug interactions, difficulties in compliance due to a large pill burden,
lack of benefit in infections with genotypes 3/4 and high
costs (reimbursement for these agents has still to be

approved in some countries). SVR rates among IDUs are
similar to those in patients with other routes of exposure
[76,77]. These drugs have not yet been licensed for use in
those with HIV coinfection due to the potential for drug
drug interactions. In the United States of America (USA)
and most European countries, current first-line therapy for
infection with genotype 1 is a combination of PEG-IFNalpha plus ribavirin plus either boceprevir or telaprevir.
This combination is effective in both treatment-nave and
treatment-experienced patients, but SVR is higher in treatment-nave patients. High SVR rates can be achieved even
in those with evidence of fibrosis and cirrhosis, but response
is poor in prior null responders, especially those with cirrhosis [78]. New drugs under development include other
protease inhibitors, the NS5B polymerase and NS5A inhibitors [79]. Preliminary data from investigational studies suggest the potential for cure rates of 8090% in genotype 1
infection using combinations of DAAs and ribavirin without
PEG-IFN, but larger studies will be needed to confirm these
results across a wider range of populations [8082].
CASE STUDY OF TREATMENT SCALE-UP IN THE

MEDITERRANEAN REGION: EGYPT
Egypt has the highest HCV prevalence in the world (10%)
[83]. Prevalence of chronic HCV infection was strongly
age-related in a survey conducted in 2008, reaching 23%
in the 5054 years age group and 25% in the 5559 years
age group [16]. HCV incidence is around 20 times higher
than rates observed in European countries and is estimated
to lie between 100 000 and 500 000 cases per year
[84,85]. Around 67% of seroconverters are under 20 years
of age, with HCV-positive family or household members
being the strongest predictors of HCV acquisition [84].
Other high-risk groups include healthcare workers [86],
prisoners, child recipients of multiple blood transfusions
[87] and adult haemodialysis patients [88]. Genotype 4
HCV infection is highly predominant in Egypt [89].
While death rates due to other major cancers have stabilized or fallen since the 1980s, deaths due to HCC have
increased from 2.4 per 100 000 in 1987 to 8 per
100 000 in 2010, accounting for 60007000 deaths per
year (National Cancer Institute, Egypt).
The Egyptian government responded by instituting a
National Control Strategy in 2008 to reduce the prevalence of chronic HBV and HCV in the 1530 years age
group by 20% by 2012, treat 20% of all those in need of
treatment and ensure that treatment would be available
within 100 km of all Egyptians by 2012 [90].
Egypt is the worlds largest provider of treatment for
HCV. Treatment is provided through 23 specialist treatment centres, seven of which are each treating more than
2000 patients. The national standard of care is PEG-IFN
and ribavirin in patients with F1F3 fibrosis, costing
approximately 2000 for a 48-week course. Around 90%
11
of HCV treatments are funded by the government and, in

other cases, discounts of up to 75% are available on treatment costs. The Egyptian government devoted 7% of the
health budget to HCV treatment and treated 190 000
patients between 2008 and 2011 (45 000 in 2009, the
largest single enrolment to date). Approximately 54% of
patients receiving treatment are cured, leaving a substantial pool of patients who require further treatment options.
At present, newer HCV treatments remain largely untested
in genotype 4 populations (presentation by I. Waked, at
Hepatitis B and C in the Mediterranean and Balkan Countries, December 2012).
Modelling suggests that within current financial constraints, ensuring treatment of patients with F4 fibrosis,
instead of those with F1 fibrosis, would have the greatest
impact on mortality due to HCV in Egypt [91].
ACCESS TO TREATMENT IN THE MEDITERRANEAN

AND BALKAN REGIONS
Treatment access is highly variable across the southern
European and Mediterranean regions due to the cost of
treatment and variations in the resources available for
health care. Recent reductions in public spending in many
countries, particularly in southern Europe, have resulted in
constraints in health services. The cost and availability of
treatment in each country is determined by a number of
interlocking factors, which throw up discrepancies in treatment access even between countries with similar levels of
development. For example, hepatitis C treatment with PEGIFN is around five to eight times more expensive in Algeria
and Morocco than in Egypt, while some antivirals for hepatitis B are more costly in Algeria, Morocco and Israel than
in France or Spain (see Table 5). (Data presented by invited
speakers from Algeria, Egypt, Israel, Italy, Morocco and
Spain, at Hepatitis B and C in the Mediterranean and Balkan Countries, December 2012).
Urgent action is required at EU Commission and Council
levels to address the inequalities in access to treatment and
arrive at equitable pricing arrangements in the EU and
Mediterranean region. A pricing structure that supports
national government investments in a comprehensive
approach to diagnosis and treatment, for example, by
adjusting costs according to the volume of patients treated,
requires further discussion. Opportunities to reduce costs
through production of generic and biosimilar agents should
be examined. The potential benefits of pooled procurement
arrangements for drugs and diagnostics also need to be
investigated.
RAISING AWARENESS AND POLICY INITIATIVES

Policy developments at the global and regional level have
the potential to support countries in developing national
plans. Addressing the burden of viral hepatitis in the
A Hatzakis et al.
12
Table 5 Costs of treatment for hepatitis B and C in some Mediterranean and Balkan countries
Country
GDP per capita, 2011, USD*
HBV drug costs (euro)
HCV drug costs (euro)
Algeria
$5244
Entecavir: 5788
PEG-IFN alpha-2a: 15 893
PEG-IFN alpha-2a/rib: 16 412
Egypt
France
$2781
$42 377
Greece
$25,622
Israel
$31,282
Italy
$36,103
Morocco
$3054
Serbia
$6310
Spain
$31943
Entecavir:5812
Tenofovir: 4676
PEG-IFN alpha-2a: 9000
Adefovir: 4225
Entecavir: 3895
Lamivudine: 400
Telbivudine: 3928
Tenofovir: 2858
Adefovir: 1925
Entecavir: 6646
Lamivudine: 1657
PEG-IFN alpha-2a: 5544-9010
Telbivudine: 3795
Tenofovir: 4266
Entecavir: 5000
Tenofovir: 3000
Adefovir: 2940
Entecavir: 5760
IFN: 3264
Lamivudine: 1524
PEG-IFN: 12 000
Telbivudine: 1920
Lamivudine: 600
Tenofovir: 3600
Adefovir: 4894
Entecavir: 4745
Telbivudine: 4745
Tenofovir: 3474
Peg-IFN/rib: 2000
PEG-IFN/rib: 16 000
Triple therapy:
16 000 + 27 180 (telaprevir)
16 000 + 36 452 (boceprevir)
PEG-IFN/rib: 10 680-13 812
PEG-IFN: 9010
Ribavirin: 5308
Telaprevir: 18 552
Boceprevir: 20 165
PEG-IFN/rib: 12 00018 000

DAA: 12 00050 000
PEG-IFN/rib: 12 000
Protease inhibitor: 27 300
PEG-IFN/rib: 12 000
protease inhibitor: 27 300
PEG-IFN/rib: 3500-7000
*Source: World Bank GDP per capita. http://data.worldbank.org/indicator/NY.GDP.PCAP.CD, accessed 29 March 2013.
Source: Country representative presentations, Conference on Hepatitis B and C in the Mediterranean and Balkan Countries.
Ibid.
Balkan and Mediterranean regions will require national
commitments in the form of strategic plans, financial and
human resources, as well as normative guidance and technical support from regional agencies. Some of the key lessons from successful national programme development are
outlined in Panel 3.
PANEL 2: FACTORS INFLUENCING TREATMENT

ACCESS AT NATIONAL LEVEL
Gross domestic product (GDP) and overall resources

for health.
Membership of the EU. Countries in the EU are bound to

a reference pricing system for medicines, which imposes
high drug prices on recent EU entrants relative to GDP.
Speed of reimbursement approval for new medicines.
National treatment guidelines.
Expanded access arrangements organized by pharmaceutical companies.
Prices negotiated with pharmaceutical companies relative to volumes.
Differential pricing policies of pharmaceutical companies.

There is also a need for expanded investment in research
into viral hepatitis. Up-to-date information on the epidemiology and burden of disease attributable to hepatitis B and
C is critical for the development of appropriate policy at
national and EU levels. New opportunities for EU funding
may emerge in Horizon 2020, the EU Framework Programme for Research and Innovation, 20142020, subject
to agreement on the proposed budget of 80 billion. Prioritization of disease-specific research calls within the Horizon
2020 framework will depend on the identification of gaps
in knowledge. WHO is working to develop a public health
research agenda for viral hepatitis.
World Hepatitis Day (28 July) is an official WHO disease
awareness day and provides an important opportunity to
raise awareness through educational and screening activities at the national level. It also provides a platform for
civil society and professional lobbying of government. Government support for World Hepatitis Day would be an
important step in raising awareness and challenging the
stigma of viral hepatitis.
PANEL 3: LESSONS FOR SUCCESS FROM THE

DEVELOPMENT OF NATIONAL AND REGIONAL
HEPATITIS STRATEGIES AND RESPONSES
At both international and national levels, viral hepatitis is cross-cutting it will involve people working
across a variety of disciplines and services to come
together as problem-solving teams to address complex
systemic problems.
Collaboration and involvement of all stakeholder
groups has proved successful in influencing government to give greater priority to viral hepatitis in a
wide range of European and Mediterranean countries
at all levels of economic development.
Patient associations have proved highly influential
political actors in several countries and at EU level;
support for the development of patient advocacy is a
key element in the promotion of wider access to hepatitis diagnosis and treatment.
The generation of evidence through research has been
critical in making the case for scaling up hepatitis treatment in countries that have taken the boldest steps
towards expanding screening and treatment; a greater
emphasis on advocacy for enhanced research support
at the national and international levels is needed.
Development of independent national guidelines on
treatment which adopt international standards also
acts as a form of pressure on governments.
Comparative benchmarking of national performance
through independent audits, such as the Hepatitis
Care Index developed by the European Liver Patients
Association, can also act to raise standards and generate debate.
13
A consistent framework is needed for disaggregating

and tracking resource allocations at country level to
monitor performance.
Opportunities to leverage health system resources to
support viral hepatitis services should be examined.
For example, given the high rate of HIV and HCV coinfection, how can HIV-related infrastructure be used
to improve hepatitis care?
CONCLUSIONS
There has been welcome progress towards developing
European-level and international strategic approaches to
viral hepatitis. These include general surveillance and risk
group-specific monitoring (ECDC and EMCDDA), research
(EC DG Research and DG Health) and the development of
guidance (WHO, ECDC, Viral Hepatitis Prevention Board
[VHPB] and EMCDDA). Nevertheless, the growing burden
of liver disease caused by viral hepatitis requires further
urgent action at European and international levels. Viral
hepatitis is now estimated to cause more deaths than
HIV in the WHO European region. Concerted action is
required to achieve universal access to prevention, care
and treatment for viral hepatitis. Recent improvements in
the treatment for viral hepatitis, and the future promise
of new therapies that could cure the majority of people
with HCV infection, could remain out of reach for the
majority of people with viral hepatitis in southern Europe
and the Mediterranean region without actions on the
part of governments, normative authorities, pharmaceutical companies and advocates to promote and expand
access.
An extension of screening for hepatitis B and C, according to the respective local epidemiology, will be required to
reduce the future burden of liver disease in the Balkan and
Mediterranean countries as most people with viral hepatitis
do not know they have been infected. Undiagnosed people
cannot benefit from treatment.
Migrant populations and people who inject drugs in Balkan and the Mediterranean countries are at high risk of
viral hepatitis and liver disease and require diagnosis, prevention measures (including vaccination and harm reduction) and treatment.
ACKNOWLEDGEMENTS
The authors would like to thank Marilyn Clark for valuable
contributions towards the success of the conference and
towards the drafting of this manuscript. The financial support of Bristol-Myers Squibb, Gilead Sciences, MSD and
Janssen is gratefully acknowledged.
14
A Hatzakis et al.
DISCLOSURES
Keith Alcorn is Senior Editor at NAM Publications, which
has received educational grants from Boehringer Ingelheim, Janssen, Merck and Roche for work relating to hepatitis C or hepatitis C/HIV coinfection.
M Benazzouz has no conflict of interests.
Saadi Berkane has received fees for serving as speaker,
consultant and advisory board member from Bristol-Myers
Squibb, Roche, Merck and Janssen.
Maria Buti has received fees as a speaker for BristolMyers Squibb (BMS), Merck, Gilead and Janssen.
Manuel Carballo has no conflict of interests.
Helena Cortes Martins has no conflict of interests.
Angela Dominguez Garcia has no conflict of interests.
Martin Donoghoe has no conflict of interests.
Sylvie Deuffic-Burban has received fees for serving as a
speaker, consultant and an advisory board member for Abbott, Cellestis, GlaxoSmithKline (GSK), Janssen, Merck
Sharp & Dohme (MSD) and Roche.
Abdul Naser Elzouki has no conflict of interests.
Nissaf Ben-Alaya-Bouafif has no conflict of interests.
Gamal Esmat has no conflict of interests.
Rafael Esteban has received fees as a speaker or adviser
for MSD, Janssen, BMS, Gilead, Abbott, Novartis and
GlaxoSmithKline.
Milotka Fabri has no conflict of interests.
Kevin Fenton has no conflict of interests.
David Goldberg has received consultancy fees from
Merck and Janssen for epidemiological/public health work
associated with hepatitis C virus (HCV) over the past
4 years. He has also served on the advisory boards for
these 2 companies but at no time has he advised on anything related to specific products.
Charles Gore is CEO of The Hepatitis C Trust, which has
received grants from Roche, MSD, Boehringer Ingelheim,
Janssen, Gilead and BMS (never amounting in total to
more than 25% of the Trusts income), and is the unremunerated President of the World Hepatitis Alliance, which
has received educational grants from Roche, BMS, Merck,
Janssen, Novartis, Boehringer Ingelheim, Gilead, Achillion,
Abbvie/Abbott and GSK. He has received no personal payments at all.
Iannis Goulis has served as a speaker and consultant for
Bristol Myers Squibb, Gilead, Janssen, Merck, Novartis and
Roche. He has received research support from Bristol
Myers Squibb and Roche.
Osamah Hamouda has no conflict of interests.
T Hadjichristoloudou has no conflict of interests.
Angelos Hatzakis has served on advisory boards for
Gilead and has received travel grants and research
grants from Gilead. He is Co-Chair of the Hepatitis B
and C Public Policy Association, which is supported by
grants from Gilead, Bristol-Myers Squibb, Janssen and
MSD.
Stanimir Hasurdjiev is a patient representative and advocate and in these capacities has participated and held presentations on behalf of the following organizations:
European Liver Patients Association (ELPA) (Executive
Director) and Bulgarian National Patients Organization
(NPO) (Chairperson). As nongovernmental not-for-profit
organizations ELPA and NPO receive unconditional financial support from their benefactors. While representing
either organization before third parties, Mr. Hasardzhiev
has not received any specific fees apart from coverage of
travel and accommodation. Mr. Hasardzhiev has also
served on advisory boards for HCAB, ECAB and the Bulgarian National Health Insurance Fund as a patient representative. Neither of those mentioned bodies has paid any
speaker fees.
Raquel J.J. Peck is the International Relations Director of
the World Hepatitis Alliance and a secondee to the Global
Hepatitis Programme (GHP) at the World Health Organization. As a nongovernmental, not-for-profit organization,
the World Hepatitis Alliance has received educational,
unrestricted grants from Roche, BMS, Merck, Janssen, Novartis, Boehringer Ingelheim, Gilead, Achillion, Abbvie/Abbott and GSK. She has not received personal payments.
Regarding her position at the GHP, there are no conflict of
interests to report.
Achim Kautz has no conflict of interests.
Mamunur Malik has no conflict of interests.
Michael Manns received financial compensation for consultancy and/or lecture activities from Roche, BMS, Gilead,
Boehringer Ingelheim, Novartis, Merck, Achillion, Janssen
and GSK and research grants from Roche, Gilead, Novartis,
Boehringer Ingelheim, BMS, Merck and Janssen, within the
past three years.
Spilios Manolakopoulos has served as an advisory board
member and speaker for Gilead, BMS, Novartis, Roche and
Merck and has received research grants from BMS but not
for this study.
Mojca Maticic has received travel grants and speaker
fees from Bayer, Berlin Chemie, Gilead, GSK, Janssen, MSD,
Roche and Schering Plough.
George Papatheodoridis has received fees for serving as a
speaker, consultant and an advisory board member for Abbott, Boehringer, BMS, Gilead, Janssen, Merck, Novartis
and Roche and has received research support from BMS,
Gilead and Roche.
George Potamitis has no conflict of interests.
Daniele Prati has received research grants and fees for
serving as a speaker, consultant and an advisory board
member for Abbott, Roche, Gilead, BMS and Novartis.
Tatjana Reic has no conflict of interests.
Ala I. Sharara has no conflict of interests.
Mustafa Shennak has no conflict of interests.
Gamal Shiha has no conflict of interests.
Daniel Shouval is a member of the advisory board of Scigen, Israel, expert advisory board of Jansen European and

recipient of speaker fees. He also served as speaker for Biotest, Germany, DiaSorin Israel, and GSK, Belgium.
Maja Socan has no conflict of interests.
Mark Thursz has received fees for serving as a speaker,
consultant and an advisory board member for BMS, Gilead,
Janssen and Abbott within the past three years.
Elena Tosti has no conflict of interests.
Christian Trepo has served on advisory boards for Roche,
Schering Plough, MSD, Gilead and Flamel and received
research grants from Janssen, Roche, MSD and Flamel.
Pierre Van Damme is full professor at the University of
Antwerp and full-time personnel member of the University.
Pierre Van Damme is head of the Vaccine and Infectious
Disease Institute at the University of Antwerp, which is a
WHO collaborating centre for the prevention and control
of infectious diseases. He acts as chief and principal investigator for vaccine trials conducted on behalf of the University of Antwerp, for which the University obtains research
grants from vaccine manufacturers. He is the executive
secretary of the Viral Hepatitis Prevention Board (VHPB);
the executive VHPB secretariat benefits from being seated
at the Centre for the Evaluation of Vaccination (CEV) of
the University of Antwerp, where it has the infrastructure
and administrative services of the University at its disposal.
VHPB is supported by unrestricted grants from the vaccine
industry (GSK Biologicals, Sanofi Pasteur MSD, Sanofi Pasteur and Merck), several universities in Europe and other
15
institutions (www.vhpb.org). He receives no personal

remuneration for this work.
Adriana Vince has received fees for serving as a speaker
for MSD, Janssen, Novartis and Roche and as an advisory
board member for MSD.
Emmelia Vounou has no conflict of interests.
Lucas Wiessing has no conflict of interests.
Notes:
1
WHO Eastern Mediterranean region comprises Afghanistan,
Bahrain, Djibouti, Egypt, Islamic Republic of Iran, Iraq, Jordan,
Kuwait, Lebanon, Libya, Morocco, Occupied Palestinian territory, Oman, Pakistan, Qatar, Saudi Arabia, Somalia, South
Sudan, Sudan, Syrian Arab Republic, Tunisia, United Arab
Emirates, Yemen.
2
In this report, Mediterranean refers to countries bordering
the Mediterranean, and Balkans refers to non-European
Union countries in south-eastern Europe.
3
Participating countries in the Conference were: Albania,
Algeria, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus,
Egypt, France, Former Yugoslav Republic of Macedonia (FYROM), Greece, Israel, Italy, Jordan, Lebanon, Libya, Malta,
Montenegro, Portugal, Romania, Serbia, Slovenia, Spain,
Syria, Tunisia, United Kingdom and United States, with representatives from European Centre for Disease Control and Prevention (ECDC), European Monitoring Centre for Drugs and
Drug Addiction (EMCDDA), European Commission, European
Parliament, WHO, WHO EMRO, WHO Regional Office for
Europe and the Viral Hepatitis Prevention Board (VHPB).
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APPENDIX CALL TO ACTION

This Call to Action is endorsed by:
Takis Hatzigeorgiou MEP
Stephen Hughes MEP
Alojz Peterle MEP
Viral Hepatitis Prevention Board
European Association for the Study
of the Liver
European Liver Patients Association
World Hepatitis Alliance
International Centre for Health,
Migration and Development
Hepatitis B and C Public Policy
Association.
The conference on Hepatitis B and
C in Mediterranean and Balkan countries has united a range of stakeholders to urge the formulation and
implementation of effective policies
and targeted actions by national governments, healthcare providers and
civil society in the fight against hepatitis B and C.
The conference commends previous
work in the domain of hepatitis B
and C, in particular the 63rd World
Health Assemblys resolution on Viral
Hepatitis of May 2010, MEP Thomas
Ulmers Call to Action on Hepatitis B
launched at the European Parliament
in 2006, the European Parliaments
Written Declaration on Hepatitis C in
2007, the Call to Action launched at
the Brussels Conference on Hepatitis
B and C in Europe in 2010 and the
WHO Prevention and Control of Viral
Hepatitis Infection: Framework for
Global Action, launched in July
2012.1
The Steering Group of the Conference on Hepatitis B and Hepatitis C
in Mediterranean and Balkan Countries, together with its partner associations, calls on the countries of these
regions to create national viral hepatitis strategies and action plans and,
in particular, to
1. Involve all sectors of society in the
fight against hepatitis B and C.
2. Place the fight against hepatitis B
and C within a Right to Health
framework.
3. Actively participate in World Hepatitis Day.

4. Improve awareness of the health
and economic impact of hepatitis
B and C.
5. Strengthen surveillance of hepatitis B and C.
6. Build intercountry research capacities dedicated to hepatitis B and
C.
7. Make prevention and control of
hepatitis B and C a key part of
public health action.
8. Invest in better case detection and
treatment programmes in primary
health care.
9. Develop outreach programmes to
ensure more voluntary counselling
and testing.
10. Explore innovative ways of
reaching all vulnerable groups,
including migrants.
11. Ensure universal access to treatment.
12. Create community-based programmes to support people living
with viral hepatitis.
WHOs Global Hepatitis Programme launched on World Hepatitis
Day 2012 the Prevention and Control
of Viral Hepatitis Infection: Framework
for Global Action. This sets out four
axes for action:
1. Partnership,
mobilization
and
communication.
2. Data for policy and action.
3. Prevention.
4. Screening, care and treatment.
Axis 1
1. Involve all sectors of society in the
fight against hepatitis B and C
organize technically backed
briefings for senior policy
makers in all government sectors
work with all stakeholders to
mobilize the necessary funding
to implement the action plan
nongovernmental
involve
organizations representing key
risk groups in decision making.
19
2. Place the fight against hepatitis B

and C in a Right to Health framework
adopt and use human rights
approaches that have been
developed in HIV/AIDS
link human rights approach
to public health principles and
health benefits
ensure that those living with
hepatitis B and C are aware of
their rights.
3. Actively participate in World Hepatitis Day
work with experts, civil society and healthcare providers
to raise hepatitis awareness
create public health campaigns around the impact of
hepatitis B and C on health
take all necessary measures,
including legislation, to tackle
stigma and discrimination.
Axis 2
4. Improve awareness of the health
and economic impact of hepatitis
B and C
develop robust national databases on hepatitis B and C
and liver cancer
emphasize hepatitis B and C
in all medical and nursing
education curricula
make policy makers more
aware of the economic impact
of untreated hepatitis B and C.
5. Strengthen the surveillance of
hepatitis B and C in all countries
in these regions
promote routine centralized
hepatitis reporting with standardized case definitions
promote national and intercountry use of standard routine surveillance protocols
monitor and evaluate the
effectiveness of prevention and
control interventions.
6. Build
intercountry
research
capacities dedicated to hepatitis B
and C
A Hatzakis et al.
20
promote and fund research on

epidemiology
and
factors
affecting hepatitis B and C
promote and fund research on
ways of preventing and managing hepatitis B and C
promote and fund collaborative intercountry research
using common protocols.
Axes 3 and 4
7. Make prevention of hepatitis B
and C a central part of public
health action
ensure high coverage of universal neonatal HBV vaccination, especially birth dose
ensure HBV vaccination of
healthcare workers and other
risk groups
develop tailored initiatives for
injecting drug users and other
special risk groups.
8. Invest in better case detection and
treatment programmes in primary
health care
develop protocols on case
detection and contact prevention for PHC
develop special training
programmes for PHC staff
based on standardized new
protocols
ensure referral for people who
need to be seen at a secondary
or tertiary level.
9. Develop outreach programmes to
ensure more voluntary counselling
and testing
develop/adapt voluntary counselling and testing (VCT) protocols and train national staff
identify ways of encouraging/
incentivizing high-risk people
to be tested, including screening

ensure that policies on hepatitis B and C VCT include access
to and retention in treatment.
10. Explore innovative ways of
reaching all vulnerable and
underserved groups
identify the most vulnerable groups and their barriers
to health care, including
migrants
give special attention to
groups with highest rates of
transmission and burden of
disease
ensure equity of access to hepatitis prevention and control
measures.
11. Ensure universal access to treatment
strengthen treatment policies
and health systems capacities
in treatment
adopt international guidelines
and recommendations on
treatment
train healthcare providers in
hepatitis B and C management.
12. Create community-based programmes for people living with
viral hepatitis
assess the needs of people
living with hepatitis B and C,
especially vulnerable groups
train and support communitybased groups to improve living with hepatitis B and C
ensure the integration of community-based groups into the
national action plan.
1
Of particular note are:
The 63rd World Health Assembly
Resolution on Viral Hepatitis,
adopted on 21 May 2010;
MEP Thomas Ulmers Call to

Action on Hepatitis B launched at
the European Parliament in 2006,
and the European Parliaments
Written Declaration on Hepatitis C
requesting i.a. a Council Recommendation to promote screening
for Hepatitis;
The European Parliament Report
of April 2010 on the European
Commissions Communication on
Action Against Cancer, which
Urges that the prevention and
control of diseases which can
develop into cancer, for instance
primary and secondary prevention
of viral hepatitis and treatment
where appropriate, should be
addressed by the Cancer Partnership and in future EU initiatives,
such as a revised Council recommendation on cancer screening;
The inclusion of Hepatitis B and C
in the surveillance and monitoring
programmes of the European Centre for Disease Prevention and
Control (ECDC) and the European
Monitoring Centre for Drugs and
Drug Addiction (EMCDDA);
The state of hepatitis B and C in
Europe: Report from the Hepatitis B
and C Summit Conference. J Viral
Hepatitis 2011, 18 (Suppl. 1);
116
The joint ECDC and EMCDDA
guidance. Prevention and control
of infectious diseases among people who inject drugs, EMCDDA/
ECDC, Stockholm, October 2011;
Work currently undertaken by the
European Association for Disease
of the Liver (EASL), the European
Liver Patient Association (ELPA)
and the Viral Hepatitis Prevention
Board (VHPB).

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Journal of Viral Hepatitis, 2013, 20 (Suppl.

The State of Hepatitis B and C in the Mediterranean and

Faculty of Medicine, Benghazi University, Benghazi, Libya;

Department of Medicine, Hamad General Hospital, HMC,

Observatory of New and Emerging Diseases, Ministry of Health, Tunis,

Health and Wellbeing Directorate, Public Health England, London, UK;

Group for Blood Borne Viruses, Sexually Transmitted Infections, Vaccine

2013 John Wiley & Sons Ltd

highlight the need to implement and monitor universal

PANEL 1: WHO FRAMEWORK FOR GLOBAL

Following a European Summit Conference on Hepatitis B

Hepatitis B and C in the Mediterranean and Balkan Countries

population prevalence of 1.69% in Lebanon (presentation

Prevalence of hepatitis delta virus

Burden of chronic liver disease

2013 John Wiley & Sons Ltd

1.5% (no date)

MAJOR ROUTES OF EXPOSURE AND PRIORITIES

2013 John Wiley & Sons Ltd

Croatias national cancer registry reports a slowly

Hepatitis B and C in the Mediterranean and Balkan Countries

Both hepatitis B and C are bloodborne viruses; hepatitis B

INJECTING DRUG USE

prevalence is low (59%) but HBV prevalence is very high

Inadequate screening of blood

Blood, organ and injection safety

Hepatitis B and C in the Mediterranean and Balkan Countries

Cosmetic and cultural practices

Transmission in closed settings

MSM, sexually transmitted infection (STI) clinic attendees,

WHO recommends universal vaccination of newborns and

2013 John Wiley & Sons Ltd

Pregnant women and newborns

The World Health Organization is developing guidelines

Balkans have yet developed systematic screening practices

2013 John Wiley & Sons Ltd

Hepatitis B and C in the Mediterranean and Balkan Countries

SCREENING FOR MIGRANTS

may not opt for detection and treatment of chronic, silent

Hepatitis delta virus: natural history and treatment

Hepatitis B and C in the Mediterranean and Balkan Countries

CASE STUDY OF TREATMENT SCALE-UP IN THE

of HCV treatments are funded by the government and, in

ACCESS TO TREATMENT IN THE MEDITERRANEAN

RAISING AWARENESS AND POLICY INITIATIVES

GDP per capita, 2011, USD*

HBV drug costs (euro)

HCV drug costs (euro)

PEG-IFN alpha-2a/rib: 16 412

PEG-IFN/rib: 12 00018 000

PANEL 2: FACTORS INFLUENCING TREATMENT

Gross domestic product (GDP) and overall resources

Membership of the EU. Countries in the EU are bound to

2013 John Wiley & Sons Ltd

Hepatitis B and C in the Mediterranean and Balkan Countries

PANEL 3: LESSONS FOR SUCCESS FROM THE

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A consistent framework is needed for disaggregating

Hepatitis B and C in the Mediterranean and Balkan Countries

institutions (www.vhpb.org). He receives no personal

2013 John Wiley & Sons Ltd

2009 [EM/RC 56/3]. Available

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