Académique Documents
Professionnel Documents
Culture Documents
2), 120
doi:10.1111/jvh.12120
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
14
16
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
21
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
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
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.
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
2013 John Wiley & Sons Ltd
(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
Injecting drug users
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%
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.
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
Injecting drug users
Healthcare workers
Pregnant women
HCV Ab
(2011)
(2011)
(2006)
(2006)
(2006)
1.5%
0.09%
<1%
0.63%
(2005)
(2010)
(2009)
(2008)
HCV Ab
4.2% (2009)
12% (2009)
HBsAg
HBsAg
Population
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
A Hatzakis et al.
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.
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
Vaccination
SCREENING
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
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.
Source: Speakers presentations at the Conference on Hepatitis B and C in Mediterranean and Balkan countries.
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.
Source: Speakers presentations at the Conference on Hepatitis B and C in Mediterranean and Balkan countries.
been found to be as cost effective as other routine screening programmes [58].
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 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
2013 John Wiley & Sons Ltd
11
A Hatzakis et al.
12
Table 5 Costs of treatment for hepatitis B and C in some Mediterranean and Balkan countries
Country
Algeria
$5244
Entecavir: 5788
PEG-IFN alpha-2a: 15 893
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
PEG-IFN alpha-2a: 6840
Telbivudine: 3928
Tenofovir: 2858
Adefovir: 1925
Entecavir: 6646
Lamivudine: 1657
PEG-IFN alpha-2a: 5544-9010
Telbivudine: 3795
Tenofovir: 4266
Entecavir: 5000
PEG-IFN alpha-2a: 9000
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: 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.
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
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
2013 John Wiley & Sons Ltd
15
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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
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
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