You are on page 1of 10

Liver International ISSN 1478-3223

REVIEW ARTICLE

Hepatitis B virus in the Maghreb Region: from epidemiology to


prospective research
Sayeh Ezzikouri1*, Pascal Pineau2 and Soumaya Benjelloun1*
1 Viral Hepatitis Laboratory, Pasteur Institute of Morocco, Casablanca, Morocco
2 Unit
e Organisation Nucl
eaire et Oncogen
ese, INSERM U993, Institut Pasteur, Paris, France

Keywords
HBV North Africa public health
seroprevalence variants

Correspondence
Sayeh Ezzikouri, Virology Unit, Viral Hepatitis
Laboratory, Institut Pasteur du Maroc 1, Place
Louis Pasteur, 20360 Casablanca-Maroc
Tel: +212 5 22434470
Fax: +212 5 22260957
e-mail: sayeh.ezzikouri@pasteur.ma
Received 8 October 2012
Accepted 28 January 2013
DOI:10.1111/liv.12135
Liver Int. 2013: 33: 811819

Abstract
Hepatitis B virus (HBV) represents an important health problem in the Maghreb
countries, Algeria, Libya, Mauritania, Morocco and Tunisia, but no detailed synthesis of its epidemiology is available. In this review, we systematically searched
for data about HBV in the Maghreb in peer-reviewed databases and included in
our analysis works written in English and French, as well as institutional reports
and regional conference meeting abstracts. We estimated national and regional
prevalence of chronic HBV infection. In addition, we discuss molecular features
of the viral strains circulating in the region. Data analysis suggests that in the
Maghreb region HBs antigen carriage concerns 1.84.9% of the population
for an estimated number of 2.7 million persons. Genotype D, subtype D7, is
predominant and mutations in the precore region of HBV genome are highly
prevalent. This epidemiological situation requires obviously widespread
active interventions for prevention and control. In addition, anti-hepatitis B
vaccination programme should be applied with the utmost discipline in the
five countries considered in this present review. This systematic review will,
hopefully, increase knowledge at disposal of Public Health authorities,
enabling better resource allocation and healthcare delivery. The present synthesis intends to stimulate policies aiming at preventing the spread of HBV,
keeping in mind that eradication of the virus from Maghrebi populations
should be the ultimate objective of Public Health authorities.

Hepatitis B is an affection of global distribution that still


represents worldwide major causes of severe liver disease, including cirrhosis and hepatocellular carcinoma
(HCC). The people with chronic hepatitis B are estimated to 360 million resulting in 0.51 million deaths
annually (1). According the World Health Organization,
chronic hepatitis B prevalence is intermediate (HBsAg
prevalence range from 2 to 7%) in the Maghreb region.
The recurrent observation in various European countries that immigrants from the Maghreb region are more
frequently infected with HBV than the general population illustrates this preoccupying situation (24). The
epidemiology of hepatitis B virus is not well defined in
the Maghreb. Epidemiological data are, however, a
mandatory starting point for the development of appropriate diagnostic and preventive measures. We aimed to
systematically review publications related to HBV epidemiology, including their major modes of transmission
as well as the molecular features of viral strains circulating in the Maghreb populations. Such systematic review
will, hopefully, increase knowledge at disposal of Public
*Both authors contributed equally to this manuscript.

Liver International (2013)


2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Health authorities, enable better resource allocation or


healthcare delivery and stimulate policies to prevent the
spread of HBV.
Study design and search strategy

We undertook our review in line with PRISMA guidelines relevant to a descriptive review of this nature (5).
Our procedures consisted of multiple stages of searches
of the peer-reviewed published work until 20 June 2012.
Beside documents available from PubMed, we included
in our analysis works written in French, as well as data
from institutional reports, regional meeting abstracts
updated in April 2012. Our purpose was to produce a
synthesis from the available corpus of data emanating
from a region where investigators do not publish readily
in English and to provide, therefore, genuinely new
information to the reader. In addition, we e-mailed hepatitis experts in the Maghreb region. All reports selected
were grouped according to the target population general
population, blood donors (1st blood donation screening), pregnant women and the haemodialyzed patients
(HD) for each country.

811

Ezzikouri et al.

HBV infection in North Africa

For data extraction and selection, we catalogued documents with Endnote. Two authors systematically
screened search results. Other references were reviewed
if the title or abstract suggested that the document had
relevant information about the prevalence of HBV in
Maghreb region. Data were regarded as eligible when
the number, prevalence, viral strains in the Maghreb
region, in a given country or a region were mentioned.
For HBV, prevalence is based predominantly on serological testing for HBsAg.
We extracted information about study design (eligibility criteria, recruitment and enrolment dates, and
recruitment methods and locations), participant characteristics (age range and sex), and hepatitis reports (number of participants tested, number and proportion of
patients who tested positive for HBsAg). The same
methodology was followed to extract molecular characteristics of HBV. The prevalence of HBV in the general
population, blood donors, pregnant women and HD
were estimated on the average prevalence, calculated
and weighted by study size in the case of multiple estimates from comparable studies. Microsoft Excel software was used to calculate prevalence.
Chronic hepatitis B epidemiology in the Maghreb

The endemicity of chronic hepatitis B, influenced primarily by the age at which infection occurs, is known to
vary greatly throughout the world. In Africa, the level of
endemicity is generally high and increases from North
to South with the Sahara representing a real epidemiological frontier with regard to HBV carriage. The data
reported from the Maghreb are heterogeneous, and even
occasionally inconsistent within the same country, plausibly reflecting diversity of environmental, socio-economic or cultural factors. However, it may be as well a
mere consequence of inappropriately designed studies.
Overall, in the Maghreb region, the estimated HBsAg
prevalence range is 1.84.9% with a number 2.7 million
persons persistently infected (Table 1).
In Algeria, to date, there is a conspicuous absence of
figures estimating the overall prevalence of HBsAg in
populations. Level of HBV endemicity is, however, suspected to be intermediate according to the WHO standards (27%). The first epidemiological survey,
published in 1984, showed a prevalence of HBsAg carriers within a range of 1.82.8% (6). Regional variations
Table 1. Estimates for the prevalence of hepatitis B (HBsAg) (%)

General
population
Blood Donors
Pregnant
Women
Haemodialysis

Algeria

Libya

Mauritania

Morocco

Tunisia

2.6

2.2

18.5

1.8

4.9

1
1.6

3
1.5

15.6
13.2

1
1.3

5
3.5

NA

NA

NA, non-available data.

812

were observed with higher levels of infection in Eastern


and Saharian regions of Algeria. The authors observed
that HBsAg positivity increases with age and low socioeconomic status (6). A decade later, a survey conducted
to assess hepatitis B seroprevalence in 1112 apparently
healthy blood donors and 715 pregnant women in different regions in Algeria, detected HBsAg seropositivity
in 3.6% and 1.6% of cases respectively (7). In 1998, the
estimated national prevalence of HBsAg carrier state
was 2.2% (8). The authors observed that for the majority of the cases, diagnosis was fortuitous resulting from
a blood donation, a pre-operative evaluation, a premarital or a prenatal check-up. The number of intra-familial
cases was very high suggesting an important horizontal
transmission in Algerian populations (8).
In Libya, hepatitis B remains an important communicable disease because of an intermediate prevalence of
the carriage, a strong incidence of new cases, accompanied by a high rate of hospitalization for liver diseases. A
national population-based sero-epidemiological survey
between October 2004 and March 2005 was conducted
on more than 67 000 participants chosen to obtain a
representative sampling of the general population from
all parts of Libya. This survey reported an overall prevalence of 2.2% with 120 000150 000 chronic HBsAg
carriers (9). Interestingly, the prevalence of HBs carriage
remains lower in Libyan blood donors (1.3%) underlining the efforts produced by the health system to recruit
safe donors (10). In the country, HBV chronic infection
is primarily related to male gender, skin scarification
practices, unsafe injections, history of blood transfusion
and familial history of hepatitis B. It is generally
acknowledged that a majority of HBV infections are
acquired horizontally (9, 11). However, it was observed
that infected pregnant women represent a significant
source of viral spread in the community. A recent study
conducted on 1500 pregnant women and 1500 cord
blood samples of their neonates delivered at Tripoli
Medical Centre showed a prevalence of 1.5% in pregnant women and 0.9% in neonates. All HBsAg-positive
neonates were born from HBs Ag-positive mothers with
a rate of maternal transmission of 61% (12). Universal
new-born hepatitis B vaccination was introduced in
1993. The vaccine was also recommended for household
contacts of HBV-infected individuals and healthcare
workers. Finally, the prevalence of chronic hepatitis B in
high-risk population, as prison inmates of western
Libya, rises to 7% (13).
In Morocco, systematic nationwide screening of
blood donors for HBsAg was introduced in 1985 and
vaccination of neonates started in 1999. In absence of a
national survey, it is, however, difficult to estimate precisely the overall prevalence rate of chronic hepatitis B.
Overall, according to available data, the prevalence is
considered as low to intermediate; ranging from 1 to
3% (1418). In our previous study, we reported that the
rate of HBs antigen carriage in the general population
was 1.5%, a prevalence consistent with that reported in
Liver International (2013)
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Ezzikouri et al.

healthcare workers (1%) (1416, 19). It appears that the


modes of contamination in the Moroccan Kingdom are
diverse either vertical, intra-familial, sexual or parenteral (14). In a recent study conducted to assess HBsAg
prevalence on more than 16 000 sexually active subjects,
the marker was detected in 1.7% of the subjects and an
at-risk sexual behaviour was identified as the main cause
of contamination (44% of cases) (14, 16). Another study
conducted in barbers and their clients showed a congruent HBsAg prevalence of 1.71.9%. In this study, the
dominant risk factors for HBV carriage is older age, low
education level, urban dwelling, married life and history
of transfusion (20). In blood banks, an early XXIst century survey found that HBsAg prevalence reaches 2.5
2.8% (19). More recently, surveys were conducted to
assess the prevalence of serological markers of hepatitis
B at the Blood Transfusion Centre of Military Teaching
Hospital Mohammed V in Rabat (n = 19 800 donors),
in the blood bank of Casablanca (n = 169 600) or in the
blood bank of a southern Moroccan hospital (Guelmim). The observed HBsAg prevalences were ranging
from 0.8 to 1.3% (17, 21). Authors concluded that from
1991 to 2010, HBV seropositivity underwent a significant decline in Morocco (17). Besides, studies conducted on high-risk populations showed a prevalence of
HBsAg ranging from 36% in new-borns of HBV-chronically infected mothers to 6% in prison inmates (19),
whereas in pregnant women, the prevalence of HBsAg
was 1.3%, close from the levels reported in general population (22). An early study conducted at the sexually
transmitted diseases (STD) clinic of the Pasteur Institute
of Morocco showed a seroprevalence of 3.0% for HBsAg
confirming the tight link between chronic infection and
at-risk sexual practices (18). Recently, a retrospective
study carried out at Department of Gastroenterology at
the University Hospital of Rabat on 12 000 hospitalized
individuals for any admission excluding liver cases
between 1990 and 2004, produced a 15.8% prevalence
of HBsAg (23). Finally, Boulaajaj et al. conducted a
study on a group of haemodialyzed patients previously
vaccinated against hepatitis B. A proportion of 96% of
the subjects presents a titre of anti-HBs greater than
10 UI/ml, but the prevalence of HBsAg was 2% (24).
Multivariate statistical analysis showed that a history of
surgical treatment, blood transfusion or injection drug
use were the main risk factors of chronic hepatitis B in
Morocco (23).
Mauritania, in close contact with sub-Saharan Africa,
has, without surprise, the highest prevalence of HBV
carriage in the Maghreb region. Early studies assessing
HBsAg seroprevalence were performed in 1992 on blood
donors by the National Hospital laboratory. At that
time, a very high prevalence of HBsAg was observed
(20.3%) (25). At the same period, a serological survey
was conducted in different ethnic groups of Mauritania.
Authors concluded that poor hygienic conditions
related to nomadic lifestyle, favour contamination with
hepatitis B virus (26). Recently, other factors such as
Liver International (2013)
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

HBV infection in North Africa

polygamy, low educational level and history of transfusion were correlated with a risk of HBV infection (27).
A survey searching for different markers of HBV infection in 267 primary and secondary schoolchildren from
two Mauritanian localities in the south and south-east
of the country, produced figures as high as 17% HBsAg
carriers (28). The rates of HBsAg in pregnant women
was ranging from 11 to 16% (29) (27). More recently,
another study conducted from October 2008 to December 2009 in 11 000 blood donors reported a 15% prevalence of HBsAg (30). These data, remarkably stable over
three decades, confirmed the serious problem posed to
Public Health by hepatitis B and should prompt a programme to combat it. An expanded programme of
immunization including hepatitis B has been, fortunately, introduced in Mauritania in 2000. Finally, it is
worth mentioning that most Mauritanian references are
ancient and novel surveys should be launched to monitor the trends of hepatitis B epidemiology in the population.
For Tunisia, hepatitis B represents historically a
major public health problem with its inherent high morbidity and mortality. Seroprevalence studies were, thus,
conducted quite early and, as a consequence, it is in
Tunisia that we get the most detailed knowledge about
the trends affecting HBV endemicity. According to early
works, prevalence of HBsAg varies throughout the
country, ranging from 3 to 13% with higher prevalence
in the south and central-western regions. A prevalence
of the chronic carriage exceeding 15% in some villages
was even observed (3133). A large study conducted in
more than 33 000 healthy people found HBsAg in 6.5%
of individuals (33). These prevalences positioned the
country close to the upper threshold of intermediate
endemicity. At the same period, the carriage rate of HBs
antigen in blood donors was about 5% (34). At that
time, the predominant modes of contamination in
Tunisia were identified as vertical, intra-familial or sexual. Tunisian men, having plausibly more sex partners
than the women, were shown to sustain higher HBV
infection rates (current and/or past) than women (31
33). Not surprisingly, the youngest population subset
(under 20 years old) was consistently shown to be at
higher risk of HBsAg carriage than the adult population
(3133). The magnitude of vertical and perinatal transmission of HBV was addressed in a study conducted on
a cohort of 2300 pregnant Tunisian women among
whom 4% were HBsAg positive and 1.4% were previously vaccinated against hepatitis B (35). Vertical/perinatal transmission of HBV in the first 3 months of life
occurred in only 0.4% of the 177 mothers and child
pairs. In contrast, in the general population, HBsAg
positivity which was 11% in infants under 5 years old,
increased rapidly with age till 25 years of age and then
more slowly in mature adulthood (33). Thus, it was
concluded that vertical and perinatal transmission of
HBV does not play a major role in Tunisia; contrasting
with horizontal transmission, mainly in childhood and

813

HBV infection in North Africa

adolescence, that appears to be the major mode of infection. To address this preoccupying situation, the systematic nationwide screening of blood donors for
HBsAg was introduced in 1985 and vaccination of neonates started in 1995. Lately, a population-based seroepidemiological study enrolled around 10 000 volunteers in the governorates of Beja in the north and Tataouine in the south of Tunisia. It showed that the overall
prevalence of HBsAg was 5.3% albeit with significant
differences observed between the two governorates
(4.2% in Beja and 5.6% in Tataouine; P = 0.001) (36).
At the individual level, the presence of a family member
infected with HBV, scarification practices, injectable
medication and male sex significantly increased the risk
of HBsAg positivity (36). In Tunisia, the prevalence of
HBsAg in high risk groups is not drastically different
from that observed in the general population underlining the high standards of the medical practice in the
country. Actually, the prevalence of chronic hepatitis B
was only 8.4% and 7.1% in polytransfused and haemophiliacs respectively (37, 38).
HBV Genotypes/subtypes in the Maghreb

HBV has evolved in multiple genetic strains that are differentially distributed among human populations.
HBsAg subtype is determined by amino acids residues
at positions 122, 127, 134, 159 and 160 enabling virus
allocation to one of the nine immunological subtypes:
adw (adw2 and adw4), ayw (ayw1, ayw2, ayw3 and
ayw4), adr (adrq+, adrq ) and ayr (39).
In 134 Moroccan patients with HBV, the majority of
strains belonged to HBsAg subtype ayw2 (82.1%,
n = 110) followed by adw2 (10.4%, n = 14), ayw3 (3%,
n = 4) and ayw4 (3%, n = 4) (40). A similar distribution was found in Algerian HBV strains with the predominant ayw2 subtype (73%).
In Tunisia, there was little information regarding the
distribution of immunological subtype. A study conducted by BorchaniChabchoub and colleagues on five
hepatitis B virus strains isolated from plasma samples of
patients showed, however, that all sequences belonged
to subtype ayw2 (41).
In Libya, no data about the distribution of HBV subtypes is available and a seminal study is still eagerly
expected.
In Mauritania, a survey conducted in sera from 515
black and 499 white individuals living in 8 villages
showed two main subtypes, ayw2 (34.7%) and ayw4
(63%). The subtypes ayw2 was more prevalent in North
of the country and ayw4 in the South. Analysis of the
subtype distribution in each village indicates that there
is no relationship between HBsAg subtype and ethnic
groups, but there is a correlation between HBsAg subtype and the geographical location of the villages (42).
This result is in agreement with the reported predominance of subtype ayw2 in Mediterranean countries and
ayw 4 in West Africa (43).

814

Ezzikouri et al.

Based on a minimum divergence of 8% of the complete genome sequences, HBV has been classified in different genotypes consecutively identified as genotypes
A-H (4447). Within some HBV genotypes, subgenotype diversity was also described, with a minimum
genetic distance of 4%. Recently, a ninth genotype isolated in Laos (48) and in Vietnam (49) and tentatively
termed I, though it is still subject to debate (50).
Finally, a tenth genotype provisionally assigned to genotype J was isolated from a Japanese patient (51).
In Algeria, little remains known about molecular
diversity of HBV. The only study conducted on 75
chronic hepatitis B patients from north-east Algeria,
showed that the genotype D was predominant (93%,
n = 70) followed by genotype A (5%, n = 4) and E
(1.3%, n = 1). Moreover, according to the authors,
Algerian strains clustered independently from other
genotype D sequences, suggesting the possible emergence of a new subtype (8). This result seems in keeping
with the data obtained on Moroccan patients (14, 40)
(Figure 1). In Libya, data about molecular features of
HBV are scarce. The only result available showed a predominance of genotype D like other countries in North
Africa (52). In Mauritania, few information about the
molecular characteristics of HBV, but genotypes prevailing were genotype D (53%, n = 43), genotype E (35%,
n = 28) and genotype A (12%, n = 10) (27) determined
in 81 samples (Figure 1).
In Morocco, four surveys were published about the
distribution of HBV genotypes reporting the predominance of genotype D (14, 40, 53, 54). In addition, phylogenetic analysis based on pre-S/S sequences suggested
that Moroccan HBV strains drifted on the Western margins of the genotype D distribution area to produce isolates differing subtly from other D strains (14). Later on,
in 134 patients, we showed that among the genotype D
strains (90%, n = 120), the majority (70.8%, n = 85)
belonged to subgenotype D7, 25.8% to subgenotype D1
(n = 31) and 0.9% to subgenotype D2 (n = 1), whereas
all genotype A (10%, n = 14) strains belonged to subgenotype A2 (40).
In Tunisia, the diversity of HBV was assessed by four
studies. The first study published in 2006 in 79 Tunisian
patients with chronic HBV infection reported predominance of genotype D (80%, n = 66) followed by genotype A (9%, n = 7) and genotype E (8%, n = 6). No
significant difference was observed between genotypes
with regard to the clinical status of infected patients
(55). At the same period, Ayed and co-workers conduct
another study on 164 patients confirming the predominance of genotype D (84.75%, n = 139), as well as a
marginal presence of genotypes A, B and C (56) (Figure 1). These various molecular studies were performed
essentially in the northern part of the country. Another
survey conducted on 130 HBV-infected patients originating from the central part of Tunisia reported an even
higher prevalence of genotype D (96%, n = 125) followed by genotype A (4%, n = 5) (57). Two reports
Liver International (2013)
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Ezzikouri et al.

HBV infection in North Africa

Figure 1. Estimated HBV genotypes distribution among HBV-infected individuals in Maghreb Region.

described HBV subtypes with a novel variant named D7


(57, 58). Hannachi et al. concluded that subgenotype
D7 is endemic to northern Africa and is progressively
replaced by subgenotype D1 towards the East of the
continent (57).
Precore and core promoter mutants of hepatitis B

During the course of chronic HBV infection, HBe antigen (HBeAg) is considered a marker of active viral replication. Seroconversion to anti-HBe is usually
accompanied by a decreased HBV replication and often
coincides with clinical remission of liver disease. In
some patients, however, detectable serum levels of HBV
DNA, persistently elevated alanine aminotransferase
(ALT), as well as continued hepatic necrosis and inflammation, are still noticed after anti-HBe seroconversion.
Most of these patients are infected with HBV variants
that decrease or abolish the production of HBeAg. The
search for a molecular basis to such anomaly led to the
discovery of precore (PC, nt18141900) and the basal
core promoter (BCP, nt 16131849) mutations that
abolish or decrease HBeAg production (5961). A classical mutation, G1896A, within PC gene would introduce a stop codon at residue 28 (W?Stop),
terminating the translation of the precore protein (62).
In Algeria, a single study, published in 2008, showed
that HBV PC mutants were present in 87% of patients.
BCP mutants were observed in 60% of cases (n = 39).
They were frequently characterized by the concomitance
(80% of cases, n = 51) of BCP double mutation and
stop-codon mutation at nucleotide 1896 (8). No correlation was found between the presence of PC and BCP
and viral load (8).
In Libya, the natural history of hepatitis B has not
been completely studied in details and, therefore, the
steps and rates leading from an HBe proficient to an
Liver International (2013)
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

HBe deficient strain are poorly described. El zouki and


colleagues reported a high prevalence rate of HBeAgnegative/anti-HBe-positive in 150 chronic hepatitis B
patients, which accounted for 80% (n = 120). This
study indicated that patients suffering from a HBeAgnegative chronic hepatitis B were older, display a higher
frequency of family history of hepatitis and a higher
prevalence of fibrosis and cirrhosis than HBeAg-positive
patients (63).
In Mauritania, the only survey searching for different
markers of HBV infection in 267 primary and secondary
school children in two Mauritanian sites located at the
southern part of the country. Data indicated a high
prevalence rate of HBeAg-negative/anti-HBe-positive
(71%, n = 190) among chronically infected patients
(28).
In Morocco, several reports published from 1993 to
2011 showed a constant predominance of PC stop
codon G1896A mutation detected in 8486% of chronic
hepatitis B (14, 64). More recently, other mutations
were described in the BCP: an A to T substitution at
nucleotide 1762 and a G to A substitution at nucleotide
1764 and G1613A (65, 66). The BCP A1762T/G1764A
double mutation that diminishes HBe Ag production
was found in 22.924.4% of Moroccan patients (54, 67).
The higher prevalence of G1896A compared with A1762T/
G1764A mutations may be attributed to the predominance of HBV genotype D in Moroccan patients (14,
67). G1896A is restricted to genotypes that have T at nt
1858 (non-A genotypes), since its stabilizes the encapsidation signal, essential for viral replication, whereas CP
A1762T/G1764A mutation occurred preferentially in genotypes with C1858 (genotype A). The presence of G1896A
was associated with a decreased risk of advanced liver
disease (AdLD) compared with the wild-type virus. In
contrast, the prevalence of double mutation A1762T/
G1764A increased significantly with the progression of

815

HBV infection in North Africa

disease from inactive carrier to AdLD state with high


viral load and elevated ALT levels compared to wildtype virus, suggesting that BCP mutations determine, at
least partially, disease severity (67).
In Tunisia, the frequency of HBV precore mutants is
high. The team of the Institut Pasteur of Tunis observed
that the rate of HBV mutants at precore region (position 1896) and/or in the basal core promoter were
detected in 33 of HBeAg-negative patients was 57.5%
(n = 19), (55). Ayed and co-workers confirmed this
result in 73 HBeAg-negative patients (57.7%, n = 42)
(56). In another report, the premature precore stop
codon at G1896A was twice as common in HBV/D (87/
102, 85%) than in HBV/A (3/7, 43%) (58). In patients
with HBV mutants, viral loads were either moderate
(49%) or high (>2000UI/ml) (51%) (55). In addition, a
study of HBV in Tunisian HBsAg-positive blood donors
indicated that the basal core promoter mutations
A1762T and G1764A are found in 86% of HBsAg-positive individuals (58).
Hepatitis D in Maghreb region

In the Maghreb region, data about the prevalence of


hepatitis delta virus (HDV) infection in HBV carriers
are scarce. In Morocco, for example, a single study performed two decades ago on 142 HBsAg carriers, 1.4%
had anti-Delta antibody (19). It was concluded at that
time that delta infection is not a problem in Morocco
(19). In contrast, Algeria, Mauritania and Tunisia were
countries where hepatitis Delta was an important issue
for Public Health authorities. Actually, 2030 years ago,
HDV was found in 1733% of Tunisian HBsAg carriers,
in 620% of HBsAg-positive patients with chronic liver
diseases in Algiers, whereas it was found in 20% of
blood donors and 15% of pregnant women from Mauritania (27, 33, 6870). Its prevalence was more important
in the Southern part of Tunisia in connection with high
HBV endemicity and cultural practices (scarification,
traditional circumcision). Current studies indicate that,
at least for Tunisia, the prevalence of HDV decreased in
the last decades to reach levels ranging from 3 to 10% of
HBsAg carriers (71). The molecular characterization of
HDV strains showed that genotype 1 was present in
Tunisia (71) and genotypes 1 (90%) and 5 (10%) circulating strains in Mauritania (27, 68).
Overall, a significant effort should be made to clarify
the current epidemiological status of hepatitis D in
Algeria, Libya and Morocco.
Co-infection hepatitis B in HIV group in Maghreb
region

As a result of the sharing of transmission routes, infection with HBV is common among patients with human
immunodeficiency virus (HIV) infection. In these
patients, chronic co-infection with HBV is associated
with a significant excess of morbidity and mortality (72,

816

Ezzikouri et al.

73). As a consequence, liver disease, resulting from


chronic hepatitis or other aetiologies, is nowadays one
of the most frequent causes of death among HIVinfected people (74). The prevalence of co-infection
with HBV is variable and depends on the route of HIV
acquisition (75). In Algeria, the prevalence of HBsAg is
6% in HIV patients (76). In Libya and in Mauritania,
there is no data regarding the prevalence of co-infection
HBV/HIV. In Morocco, a study conducted among HIVpositive patients in Military hospital in Rabat detected a
prevalence of 6.7% for HBsAg (77). In Tunisia, the first
study to assess the co-infection rate of viral hepatitis B
in HIV-positive patients reported a prevalence of 5.6%
for HBsAg (78).
Co-infection with hepatitis C in the Maghreb
region

Hepatitis C is affection of global distribution that still


represents worldwide major causes of severe liver disease, including cirrhosis and hepatocellular carcinoma
(HCC). The prevalence of anti-HCV antibodies in the
Maghreb region varies between 0.4% and 1.9% (79).
The prevalence HBsAg in hepatitis C group was estimated at 1.9% in Libya (80) and 5% in Morocco (81)
and Tunisia (82). In Algeria and in Mauritania, there is
no data regarding the prevalence of co-infection HBV/
HCV.
HBV in hepatocellular carcinoma in the Maghreb

Chronic infection with HBV is still the most important


causes of HCC in the world (83). The relative importance of HBV infection in HCC aetiology is known to
vary greatly from one part of the world to another (84),
and can change over time (85). However, despite intermediate levels of chronic hepatitis B in the general population (15%, except in Mauritania where HBV is
high), HCC incidence in the Maghreb region is particularly low (1.3/105 ASR, according to Globocan 2008)
ranging far below incidences observed in most European
countries, where hepatitis viruses are far less prevalent.
To explain this situation, we conducted in collaboration
with the Institutes Pasteur of Algiers and Tunis, a multicentre case-control study in 164 patients with HCC. We
observed that 60% of HCC patients were positive for
anti-HCV and 18% for HBsAg. By opposition, the
HBsAg prevalence in HCC was lower than in Middle Eastern countries, like Saudi Arabia and Lebanon
(8587). Thus, our data suggest that the low incidence
of HCC in the region is may be linked to a weaker
tumorigenic potential of circulating hepatitis viruses
strains (genotype D7 vs. other D for HBV), to an
absence of usual tumorigenic cofactors as aflatoxin B1
and also the life expectancy in each country. It would be
of great interest to perform a similar study on Mauritanian (genotype A of HBV) to figure out whether
changes in viral and environmental conditions are
Liver International (2013)
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Ezzikouri et al.

capable to induce relevant alterations in the molecular


epidemiology of HCC and stimulate an increased HCC
incidence.

HBV infection in North Africa

13.

Conclusions and needs for future research

Chronic Hepatitis B infection remains an important


Public Health problem in the Maghreb, as in so many
countries of the world. Based on published evidence
presented above, striking epidemiological similarities
exist between most Maghreb countries even if Mauritania stays apart because of its stronger links with SubSaharan Africa and its high endemicity of HBV. Nevertheless, in all countries, targeted interventions should be
considered and notably the intensification of the immunization programme. In addition, the quality of epidemiological data about hepatitis B virus in the Maghreb
remains rather disparate, whereas knowledge about
HDV is almost nil except in Tunisia and Mauritania.
Novel large-scale epidemiological studies aiming at
prevalence and risk factors identification should be
launched on cooperative bases. Accurate molecular
methods to identify subtypes, variants and recombinant
genomes, are required to estimate current and future
burdens of HBV infection to implement effective preventive measures.

14.
15.
16.
17.

18.

19.

20.

References
1. Lee WM. Hepatitis B virus infections. N Engl J Med 1997;
337: 1733.
2. Chiaramonte M, Pupo A, Menegon T, et al. HBV and
HCV infection among non-European Union immigrants
in North-East Italy. Epidemiol Infect 1998; 121: 17983.
3. Hemminki K, Mousavi SM, Brandt A, Ji J, Sundquist J.
Liver and gallbladder cancer in immigrants to Sweden. Eur
J Cancer 2010; 46: 92631.
4. Chiaramonte M, Pupo A, Menegon T, et al. HBV and
HCV infection among non-European Union immigrants
in North-East Italy. Epidemiol Infect 1998; 121: 17983.
5. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred
reporting items for systematic reviews and meta-analyses:
the PRISMA statement. PLoS Med 2009; 6: e1000097.
6. Khalfa S, Ardjoun H. Epidemiology of viral hepatitis in
Algeria (French). Med Trop (Mars) 1984; 44: 24752.
7. Ayed Z, Houinato D, Hocine M, Ranger-Rogez S, Denis F.
Prevalence of serum markers of hepatitis B and C in blood
donors and pregnant women in Algeria (French). Bull Soc
Pathol Exot 1995; 88: 2258.
8. Khelifa F, Thibault V. Characteristics of hepatitis B viral
strains in chronic carrier patients from North-East Algeria
(French). Pathol Biol (Paris) 2009; 57: 10713.
9. Elzouki AN. Hepatitis B, C and HIV infection in Libya.
Libyan J Infect Dis 2007; 1: 1323.
10. Khmmaj A, Habas E, Azabi M, Rayani A. Frequency of
hepatitis B, C, and HIV viruses among blood donors in
Libya. Libyan J Med 2010; 5: 5333.
11. Elzouki AN. Hepatitis B infection in Libya: The magnitude
of the problem. Libyan J Infect Dis 2008; 2: 205.
12. El-Magrahe H, Furarah AR, El-Figih K, El-Urshfany S,
Ghenghesh KS. Maternal and neonatal seroprevalence of

Liver International (2013)


2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

21.
22.

23.
24.

25.

26.

27.

28.

Hepatitis B surface antigen (HBsAg) in Tripoli, Libya.


J Infect Dev Ctries 2010; 4: 16870.
ELahmer O, Zorgani A, Abudher A, Ziglam H. Prevalence
of human immunodeciency virus, hepatitis B virus, hepatitis C virus among prison inmates, western Libya. The
22nd Annual European Congress of Clinical Microbiology
and Infectious Diseases 2012, (Abstract).
Ezzikouri S, Chemin I, Chafik A, et al. Genotype determination in Moroccan hepatitis B chronic carriers. Infect
Genet Evol 2008; 8: 30612.
Djeriri K, Laurichesse H, Merle JL, et al. Hepatitis B in
Moroccan health care workers. Occup Med (Lond) 2008;
58: 41924.
Sbai A, Baha W, Ougabrai H, et al. Hepatitis B prevalence
and risk factors in Morocco. Pathol Biol(Paris) 2012; 60:
e659.
Zohoun A, Hadef R, Zahid H, Benkirane M. Seroprevalence of HBV and HCV in blood donors at the Blood
Transfusion Center of Mohammed V Military Teaching
Hospital in Rabat Morocco (French). Med Trop (Mars)
2011; 71: 5134.
Heikel J, Sekkat S, Bouqdir F, et al. The prevalence of
sexually transmitted pathogens in patients presenting to
a Casablanca STD clinic. Eur J Epidemiol 1999; 15: 711
5.
Benjelloun S, Bennani A, Sekkat S, Benslimane A. Les
hepatites virales au Maroc. Aspects epidemiologique et
moleculaire. Journees scientifiques de medecine 2002; 604
(Abstract).
Belbacha I, Cherkaoui I, Akrim M, Dooley KE, El Aouad
R. Seroprevalence of hepatitis B and C among barbers and
their clients in the Rabat region of Morocco. East Mediterr
Health J 2011; 17: 9119.
Aqodad N, Lahbabi M, Elyousfi M, et al. Prevalence of
VHC-Ab and HBsAg among blood donors in Guelmim in
the south of Morocco. Hep Intl 2011; 5/11936-0533.
Sekkat M. Prevalene de lAg HBs chez les femmes enceintes
resulats preliminaires dune etude prospective menee au
CHU Hassan II fes Maroc a propos de 156 cas fes: Sidi
Mohammed Ben Abdellah, 2010, (Thesis).
Rouibaa F, Acharki M, Amrani L, et al. Prevalence of Hepatitis B and C markers in high risk hospitalized patients in
Morocco. Arab J Gastroenterol 2008; 9: 704.
Boulaajaj K, Elomari Y, Elmaliki B, et al. Prevalence of
hepatitis C, hepatitis B and HIV infection among haemodialysis patients in Ibn-Rochd university hospital, Casablanca (French). Nephrol Ther 2005; 1: 27484.
Lo BB, Meymouna M, Boulahi MA, et al. Prevalence of
serum markers of hepatitis B and C virus in blood donors
of Nouakchott, Mauritania (French). Bull Soc Pathol Exot
1999; 92: 834.
Lepers JP, Billon C, Pesce JL, Rollin PE, De Saint-Martin J.
Sero-epidemiological study in Mauritania (19851986):
incidence of treponematosis, hepatitis B virus, HIV virus
and viral hemorrhagic fevers (French). Bull Soc Pathol Exot
Filiales 1988; 81: 2431.
Mansour W, Malick FZ, Sidiya A, et al. Prevalence, risk
factors, and molecular epidemiology of hepatitis B and
hepatitis delta virus in pregnant women and in patients in
Mauritania. J Med Virol 2012; 84: 118698.
Rui WZ, Lo Baidy B, NDiaye M. Hepatitis B virus infection in the school milieu of Kiffa and Selibaby, Mauritania
(French). Bull Soc Pathol Exot 1998; 91: 2478.

817

HBV infection in North Africa

29. Mansour W, Aye M, Le Gal F, et al. Impact of Hepatitis B


and Delta Viruses Coinfection on Liver Disease in Mauritania. EASL Monothematic Conference: Delta Hepatitis
Turkey, Istanbul, 2010;. (Abstract).
30. Mansour W, Bollahi MA, Hamed CT, et al. Virological
and epidemiological features of hepatitis delta infection
among blood donors in Nouakchott. Mauritania. J Clin
Virol 2012; 55: 126.
31. Gorgi Y, Ayed K, Jenhani F, Pichoud C, Trepo C. Prevalence of viral hepatitis B markers in the region of Tataouine (southern Tunisia) (French). Arch Inst Pasteur Tunis
1989; 66: 25161.
32. Triki H, Ben Slimane S, Ben Mami N, et al. High circulation of hepatitis B virus (HBV) precore mutants in Tunisia, North Africa. Epidemiol Infect 2000; 125: 16974.
33. Triki H, Said N, Ben Salah A, et al. Seroepidemiology of
hepatitis B, C and delta viruses in Tunisia. Trans R Soc
Trop Med Hyg 1997; 91: 114.
34. Jemni L, Chatti N. Epidemiology of hepatitis B virus infection. Tunisie Maghreb Medical 1994; 278: 1518.
35. Hannachi N, Bahri O, Mhalla S, et al. Hepatitis B virus
infection in Tunisian pregnant women: risk factors and
viral DNA levels in HBe antigen negative women (French).
Pathol Biol (Paris) 2009; 57: e437.
36. Ben-Alaya-Bouafif N, Bahri O, Chlif S, et al. Heterogeneity of hepatitis B transmission in Tunisia: risk factors for
infection and chronic carriage before the introduction of a
universal vaccine program. Vaccine 2010; 28: 33017.
37. Hannachi N, Boughammoura L, Marzouk M, et al. Viral
infection risk in polytransfused adults: seroprevalence of
seven viruses in central Tunisia (French). Bull Soc Pathol
Exot 2011; 104: 2205.
38. Langar H, Triki H, Gouider E, et al. Blood-transmitted
viral infections among haemophiliacs in Tunisia (French).
Transfus Clin Biol 2005; 12: 3015.
39. Magnius LO, Norder H. Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by
sequence variability of the S-gene. Intervirology 1995; 38:
2434.
40. Kitab B, El Feydi AE, Afifi R, et al. Hepatitis B genotypes/
subgenotypes and MHR variants among Moroccan
chronic carriers. J Infect 2011; 63: 6675.
41. Borchani-Chabchoub I, Gargouri A, Mokdad-Gargouri R.
Genotyping of Tunisian hepatitis B virus isolates based on
the sequencing of preS2 and S regions. Microbes Infect
2000; 2: 60712.
42. Malkin JE, Druilhe P, Courouce AM, Monjour L, Gentilini
M. Geographical and ethnical distribution of HBs antigen
subtypes in Mauritania. Rev Fr Transfus Immunohematol
1983; 26: 5917.
43. Courouce-Pauty A, Plancon A, Soulier JP. Distribution of
HBsAg subtypes in the World. Vox Sang 1983; 44: 197211.
44. Okamoto H, Tsuda F, Sakugawa H, et al. Typing hepatitis
B virus by homology in nucleotide sequence: comparison
of surface antigen subtypes. J Gen Virol 1988; 69: 257583.
45. Norder H, Courouce AM, Magnius LO. Complete genomes, phylogenetic relatedness, and structural proteins
of six strains of the hepatitis B virus, four of which represent two new genotypes. Virology 1994; 198: 489503.
46. Kramvis A, Arakawa K, Yu MC, et al. Relationship of serological subtype, basic core promoter and precore mutations to genotypes/subgenotypes of hepatitis B virus.
J Med Virol 2008; 80: 2746.

818

Ezzikouri et al.

47. Stuyver L, De Gendt S, Van Geyt C, et al. A new genotype


of hepatitis B virus: complete genome and phylogenetic
relatedness. J Gen Virol 2000; 81: 6774.
48. Olinger CM, Jutavijittum P, Hubschen JM, et al. Possible
new hepatitis B virus genotype, Southeast Asia. Emerg
Infect Dis 2008; 14: 177780.
49. Tran TT, Trinh TN, Abe K. New complex recombinant
genotype of hepatitis B virus identified in Vietnam. J Virol
2008; 82: 565763.
50. Kurbanov F, Tanaka Y, Kramvis A, Simmonds P, Mizokami M. When should I consider a new hepatitis B virus
genotype? J Virol 2008; 82: 82412.
51. Tatematsu K, Tanaka Y, Kurbanov F, et al. A genetic variant of hepatitis B virus divergent from known human and
ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J. J Virol 2009; 83:
1053847.
52. Alnagih NM, Bashein AM, Rayes A. HBV genotype D is
the most prevalent in Libyan patients. Infectious & Endemic Diseases Scientific Conference 2007; 3536 (Abstract).
53. Sbai A, Bennani A, Benjouad A, Hassar M. HBV genotypes
in Morocco. J Clin Virol 2007; 38: 1845.
54. Baha W, Ennaji MM, Lazar F, et al. HBV genotypes prevalence, precore and basal core mutants in Morocco. Infect
Genet Evol 2012; 12: 115762.
55. Bahri O, Cheikh I, Hajji N, et al. Hepatitis B genotypes,
precore and core promoter mutants circulating in Tunisia.
J Med Virol 2006; 78: 3537.
56. Ayed K, Gorgi Y, Ayed-Jendoubi S, et al. Hepatitis B virus
genotypes and precore/core-promoter mutations in Tunisian patients with chronic hepatitis B virus infection.
J Infect 2007; 54: 2917.
57. Hannachi N, Fredj NB, Bahri O, et al. Molecular analysis
of HBV genotypes and subgenotypes in the Central-East
region of Tunisia. Virol J 2010; 7: 302.
58. Meldal BH, Moula NM, Barnes IH, Boukef K, Allain JP. A
novel hepatitis B virus subgenotype, D7, in Tunisian blood
donors. J Gen Virol 2009; 90: 16228.
59. Laras A, Koskinas J, Hadziyannis SJ. In vivo suppression
of precore mRNA synthesis is associated with mutations
in the hepatitis B virus core promoter. Virology 2002; 295:
8696.
60. Jammeh S, Tavner F, Watson R, Thomas HC, Karayiannis
P. Effect of basal core promoter and pre-core mutations on
hepatitis B virus replication. J Gen Virol 2008; 89: 9019.
61. Du H, Li T, Zhang HY, et al. Correlation of hepatitis B
virus (HBV) genotypes and mutations in basal core promoter/precore with clinical features of chronic HBV infection. Liver Int 2007; 27: 2406.
62. Carman WF, Jacyna MR, Hadziyannis S, et al. Mutation
preventing formation of hepatitis B e antigen in patients
with chronic hepatitis B infection. Lancet 1989; 2: 58891.
63. Elzouki AN, Belkhair S, Tumi A, Abdulmoti S, Arabi M.
Comparison between HBe antigen-negative patients and
HBe antigen-positive patients with chronic hepatitis B
infection in Benghazi, Libya. Libyan J Infect Dis 2007; 1: 26
31.
64. Benjelloun S, Tong S, Li J, et al. Pre-core mutation associated with lack of hepatitis B e antigenaemia in Moroccan
asymptomatic carriers of the virus. Res Virol 1993; 144:
15967.
65. Elkady A, Tanaka Y, Kurbanov F, Oynsuren T, Mizokami
M. Virological and clinical implication of core promoter

Liver International (2013)


2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Ezzikouri et al.

66.

67.

68.
69.

70.
71.

72.

73.

74.

75.
76.

C1752/V1753 and T1764/G1766 mutations in hepatitis B


virus genotype D infection in Mongolia. J Gastroenterol
Hepatol 2008; 23: 47481.
Li MS, Lau TC, Chan SK, et al. The G1613A mutation in
the HBV genome affects HBeAg expression and viral replication through altered core promoter activity. PLoS ONE
2011; 6: e21856.
Kitab B, Afifi R, El Feydi AE, et al. Genetic variability of
Hepatitis B virus in Morocco. Hong Kong: Institut Pasteur
International Network Annual Scientific Meeting, 2010;.
(Abstract).
Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta
virus. Lancet 2011; 378: 7385.
Jenhani F, Ayed K, Gorgi Y, et al. Delta infection in
chronic HBs Ag carriers in Tunisia: high prevalence in
chronic asymptomatic HBs Ag carriers and in HBs Ag
positive cirrhosis. Ann Trop Med Parasitol 1990; 84: 349
53.
Belabbes EH. The hepatitis delta virus in Algiers (Algeria).
Prog Clin Biol Res 1987; 234: 4434.
Djebbi A, Rebai WK, Bahri O, et al. Serological markers,
viral RNA and genotype of hepatitis delta virus in HBs
antigen positive Tunisian patients (French). Pathol Biol
(Paris) 2009; 57: 51823.
Tedaldi E, Peters L, Neuhaus J, et al. Opportunistic disease and mortality in patients coinfected with hepatitis B
or C virus in the strategic management of antiretroviral
therapy (SMART) study. Clin Infect Dis 2008; 47: 1468
75.
Ribes J, Cleries R, Rubio A, et al. Cofactors associated with
liver disease mortality in an HBsAg-positive Mediterranean cohort: 20 years of follow-up. Int J Cancer 2006; 119:
68794.
Hooshyar D, Napravnik S, Miller WC, Eron JJ. Effect of
hepatitis C coinfection on discontinuation and modification of initial HAART in primary HIV care. AIDS 2006;
20: 57583.
Alter H. Viral hepatitis. Hepatology 2006; 43: S2304.
Berkane S. French Luncheon comment prendre en charge
les patients atteints dhepatite C avec les medicaments dis-

Liver International (2013)


2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

HBV infection in North Africa

77.

78.

79.
80.

81.
82.

83.
84.
85.

86.
87.

ponibles en Algerie. 3rd Paris Hepatitis Conference, Paris,


2009, (Abstract).
El Annnaz H, Arrouchi H, Haoudi F, et al. Les Co-infections VIH-VHC et VIH-VHB a lHMIMV de Rabat. Troisiemes journees de la Societe Marocaine dImmunologie, 2011
(Abstract).
Maaref F, Kilani B, Ammari L, et al. Prevalence of hepatitis G, B and C virus infections among positive HIV population in a Tunisian Hospital, La Rabta, Tunis (French).
Pathol Biol (Paris) 2011; 59: 2136.
Kamal SM, Mahmoud S, Hafez T, EL-Fouly R. Viral hepatitis A to E in South Mediterranean Countries. Medit J Hemat Infect Dis 2010; 2: e2010001.
Kutrani H, El-Gatit A, Shekhteryea A, et al. DemoFigureic
factors influencing hepatitis B and C infection in Benghazi.
Libyan Arab Jamahiriya. East Mediterr Health J 2007; 13:
8597.
Cacoub P, Ohayon V, Sekkat S, et al. Epidemiologic and
virologic study of hepatitis C virus infections in Morocco
(French). Gastroenterol Clin Biol 2000; 24: 16973.
Ben Halima S, Bahri O, Maamouri N, et al. Serological
and molecular expression of Hepatitis B infection in
patients with chronic Hepatitis C from Tunisia, North
Africa. Virol J 2010; 7: 229.
IARC Monographs. Overall Evaluations of Carcinogenicity:
An Updating of IARC Monographs. Lyon: IARC Press,
1987; 142.
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74108.
Lu SN, Su WW, Yang SS, et al. Secular trends and geographic variations of hepatitis B virus and hepatitis C
virus-associated hepatocellular carcinoma in Taiwan. Int
J Cancer 2006; 119: 194652.
Ayoola EA, Gadour MO. Hepatocellular carcinoma in
Saudi Arabia: role of hepatitis B and C infection. J Gastroenterol Hepatol 2004; 19: 6659.
Yaghi C, Sharara AI, Rassam P, et al. Hepatocellular carcinoma in Lebanon: etiology and prognostic factors associated with short-term survival. World J Gastroenterol 2006;
12: 357580.

819

Copyright of Liver International is the property of Wiley-Blackwell and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.