REVIEW ARTICLE
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.
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from a region where investigators do not publish readily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.
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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
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Ezzikouri et al.
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
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).
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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
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2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Ezzikouri et al.
Figure 1. Estimated HBV genotypes distribution among HBV-infected individuals in Maghreb Region.
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
815
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,
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14.
15.
16.
17.
18.
19.
20.
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