Tropical Medicine Department,
Faculty of Medicine, Zagazig
Zagazig, 44519, Egypt
Dr. Mohammad Hassan Emara
Occult hepatitis B: the Egyptian situation
Mohammad Hassan Emara
Occult hepatitis B infection is defined as the presence of HBV DNA in serum and/or the liver
tissue without detectable HBsAg with or without anti-HBc or anti-HBs antibodies. In Egypt
many studies on occult hepatitis B have been conducted and this infection is well established
in various patients groups. This short review sheds light on the occurrence of occult hepatitis
B infection among different disease states in Egypt. The coexistence of occult hepatitis B with
hepatitis C infection is of particular importance because of its added co-morbidity of liver
enzymes elevation, increased severity of liver disease and increased risk of hepatocellular
carcinoma. Patients on regular hemodialysis and those exposed to blood transfusion are at
high risk of acquiring this form of infection. The highest prevalence of occult hepatitis B virus
in Egypt was reported among patients with hepatocellular carcinoma and similar to the scenario
for classic hepatitis B infection, genotype D is the most prevalent genotype.
KEYWORDS: occult hepatitis B, hepatitis C, pegylated interferon, hepatocellular carcinoma
Hepatitis B virus (HBV) infection is a global health problem. Its
prevalence and patterns of transmission vary greatly
throughout the world.1 Furthermore, the consequences of
chronic HBV infection represent a major burden for health care
systems because a large proportion of these patients go on to
develop cirrhosis and hepatocellular carcinoma (HCC).2 The
prevalence of HBsAg in Egypt is of intermediate endemicity
(2–8%).3 Nearly 2-3 million Egyptians are chronic carriers of
HBV. In Egypt HBV transmission is apparently a mixture of
horizontal and perinatal transmission. However, the majority
of HBV infection is acquired by the former route.2
Occult hepatitis B virus infection (OBI) is one of the most
challenging topics in the field of viral hepatitis with its
virological and clinical relevance being debated for more than
30 years.4 Occult hepatitis B virus infection is defined as the
presence of HBV DNA in serum and/or liver tissue without
detectable HBsAg with or without anti-HBc or anti-HBs
antibodies outside the pre-seroconversion window period.5
Prevalence of OBI varies in different studies due to
differences in: (1) method of detection, including PCR primer
selection and sensitivity of the assay; (2) patient recruitment,
for example blood donors with/without anti-HBc; (3) patients
from countries highly endemic for HBV are more likely to
develop OBI; (4) prevalence may vary according to the nature
of the biological material tested, with a higher proportion for
liver compared to serum specimens and also the amount of
DNA in the tested sample may influence prevalence rates of
OBI;6 and (5) a spurious increase of OBI prevalence rates may
© Tropical Gastroenterology 2012
Tropical Gastroenterology 2012;33(4):242–250
also noticed when kits with low sensitivity for detection of
HBsAg are used. Hence to correctly test for HBsAg,
international standard samples with known quantities of HBsAg
Since the diagnosis of OBI is dependent on detection of
HBV DNA by PCR, which is an expensive tool and the Egyptian
budget for health care and scientific research is very low, many
Egyptian studies depend on anti-HBc positivity for diagnosis
of OBI leading to missing of HBV DNA positive/anti-HBc
negative cases and consequently underestimating the problem.
Although there are no accurate estimates about the prevalence
of OBI in different population groups in Egypt, this review is
an attempt to shed light on available studies examining OBI
prevalence and its impact on different population groups in
Egypt (Table 1).
OBI and genetic mutations
Replication-defective mutants of HBV have been detected in
the circulation of symptom free individuals as early as 1987.8 In
HBV sequences obtained from serum samples of HBsAg
seronegative carriers, a plethora of mutations has been
observed. Point mutations, deletions and splicing alternatives
have been associated with OBI, but it is unclear weather these
Table 1: Occult hepatitis B studies from Egypt
Author YearDiagnosis of
El-Shaarawy et al.23
2007 Anti-HBc40 patients with
HCV related liver
71 patients with
HCV positive for
29 patients with
HCV negative for
49 child with
51 child with
HCV RNA positive
HCV RNA negative
156 HCV infected
40 HCC patients:
30 HCV with liver
enzymes flare30 HCV
with no liver enzymes
Comparable severity of liver disease in Anti-HBc
positive/ HBV DNA positive and Anti-HBc positive
/HBV DNA negative cases
OBI is prevalent in HCV positive for Anti-HBcEl-Sherif et al.19
Said et al.59
2009DNA38OBI and HCV are common in multi-transfused
Ismail et al.60
6.3 OBI in chronic hemodialysis patients is low, and
does not significantly differ between patients with or
Emara et al.48
2010DNA3.9No impact on therapy
Hassan et al.24
2010DNA62.5In HCC - OBI more in tissue than serumGenotype B
and D are the prevalent genotypes
Selim et al.25
2011DNAOBI should be considered in HCV with enzymes
2012DNA4.1 OBI in chronic hemodialysis patients does not
significantly differ between patients with or without
OBI: occult hepatitis B; HCV: hepatitis C virus; HCC: hepatocellular carcinoma
Occult hepatitis B
mutations are a cause or a consequence of this occult infection.
Many of these OBI are associated with mutations in the S gene
and/or regions governing the regulation of S gene expression,
but they have also been documented in the core (C) and
polymerase (P) genes.9 Naturally occurring pre-S deletion
mutants were shown to influence not only the liver disease
progression but also chronic hepatitis B therapy. Mutations
that change the antigenicity of HBsAg or decreases its
synthesis may be the cause of lack detection of HBsAg in
patients with OBI.10
It was shown that OBI individuals are infected by viral
variants either producing an antigenically modified HBV S
protein undetectable by the available HBsAg assays,11 or
carrying mutations capable of inhibiting S gene expression
and/or viral replication.12 Pre-S variants and deletions were
also found in occult isolates. One study showed that deleted
regions were found more frequently in the 3' terminus of pre-S1
which contains several immune epitopes and functional
domains such as the site for dual topology, a nucleocapsid
binding site, and the S-promote.13 Removing sites for dual
topology and encapsidation would lead to incorrect
conformation of the large HBsAg and decrease secretion of
HBsAg and viral particles.14 Another important consequence
of the deletion is that removing the S promoter alters small
HBsAg expression and leads to HBsAg seronegativity.15
Chaudhuri et al12 found a similar pre-S variant from occult HBV
carriers and demonstrated that deletion of the S promoter alters
the ratio of large and small surface proteins and decreases the
circulating HBsAg level. Therefore, the existence of HBsAg-
negative HBV infection may result from deletion of the S
promoter in the pre-S region, thus decreasing the quantity of
HBsAg secretion below the sensitivity of a standard test but
just enough for viral assembly.10
Co-infection with hepatitis C virus (HCV)
In Egypt the rate of anti-HCV positivity is 15% (although ranges
from 6-28% are proposed) and 5% of community is positive for
both anti-HCV and HBsAg and/or anti-HBc, although the real
estimated prevalence of HBV/HCV dual infection is unclear.16
DNA positive OBI was evaluated in Egyptian chronic HCV
patients on pegylated interferon/ribavirin therapy and was
noted to occur at a rate of 3.9%,17 this rate is increased to 10%
in the subgroup of patients who developed elevated liver
enzymes while on therapy,18 and the rate increased to 20% in
the subgroup of patients who had elevated liver enzymes
without therapy.19 The prevalence of OBI in chronic HCV
patients was higher in subjects having either anti-HBs or anti-
HBc or both.20,21 Serological findings in patients with OBI and
HCV co-infection revealed that 35% of people were anti-HBs
positive, 42% were anti-HBc IgG positive and 22% were
negative for both.22
In one study from Egypt, the prevalence of OBI in chronic
HCV was projected to be 50% depending on anti-HBc positivity
only, although only 60% of these tested positive for HBV DNA
by PCR.23 This is not in agreement with the consensus of HBV
DNA positivity as a prerequisite for diagnosis of OBI.24 In
another study on Egyptian chronic HCV patients, serum HBV
DNA was detected in 22.5% of anti-HBc positive chronic HCV
patients and nothing was detected in anti-HBc-negative chronic
HCV patients.21 In another study OBI was detected in 19
patients with HCV infection (out of 40), it was higher in patients
positive for both anti-HBs and anti-HBc (50%) than those
having anti-HBc alone (20%).24 Although this was not the
observed trend in other studies.18,25 Emara et al18 examined 155
chronic HCV patients on pegylated interferon/ribavirin
combination and found six patients positive for HBV DNA.
OBI could not be predicted by serological markers of HBV
infection because only two out of the six patients with detectable
HBV DNA had anti-HBc antibodies and none had anti-HBs
antibodies.18 While one study did not notice and variation in
the prevalence of occult HBV infection with age or sex,24 another
study found OBI prevalence higher in younger chronic HCV
OBI/HCV viral interference
Preliminary data suggest that HCV core protein might inhibit
the replication of HBV.26 A similar effect was also attributed to
NS2 protein of HCV.27 Hepatitis C infection reduces the
expression of HBV proteins in the liver.28 Conversely, there is
some evidence that HBV replication might interfere with HCV
viral load29 and even lead to a higher chance of HCV RNA
clearance.30 Both events have been demonstrated in the study
of Rodriguez-Inigo et al31 where they proved that both HCV
and HBV can coexist in the same hepatocyte. Furthermore,
HBV DNA levels in co-infected hepatocytes were lower than
those in cells infected only with HBV. This finding supports
the hypothesis of inhibition of HBV replication by HCV. Also,
HCV RNA levels were lower in co-infected cells than in cells
infected with HCV only, suggesting that HBV may also inhibit
HCV replication. However, it seems that inhibition of HBV
Tropical Gastroenterology 2012;33(4):242–250
replication by HCV is more common than the opposite.
Co-infection by both occult hepatitis B and occult hepatitis
C does occur and contrary to the fact that dual chronic HBV
and HCV leads to a more severe disease than mono-infection32
dual occult infection was not associated with more severe liver
disease in comparison to single occult mono-infection. This
data suggests that in occult infections both viruses tend to
inhibit each other reciprocally. This can be explained by: (1) in
chronic dual infection, a more vigorous immune response
against the infected hepatocytes is the cause of severe liver
damage, (2) in occult infection antigen expression on infected
hepatocytes may be too low to trigger sufficient cytopathic
antiviral immune response so as to induce a greater liver damage
in occult dual infection compared to a single occult infection
and dual chronic infections.33
Impact of OBI on HCV disease states
Flares of liver enzymes
Several investigators have studied the association between
OBI and increased liver enzymes in serial serum samples.
Zignego et al34 found that ALT relapses following interferon
treatment for chronic HCV were associated with HBV viremia
in some cases. Fujiwara et al35 found that HBV viremia in chronic
HCV patients with OBI did not correlate with liver enzyme flares.
Kannangai et al36 demonstrated that episodes of viremia in
OBI/HCV dually infected non-treated intravenous drug users
can be associated with transient but significant flares in liver
transaminases. This notion supports the hypothesis that OBI
replication may be a cause of hepatocyte injury, although this
is contrary to the trend in literature about the lack of strong
correlation between ALT/AST levels and OBI in cross sectional
The ALT levels are usually mildly raised in OBI and HCV
co-infection20,39 and seem to be either equivalent40 or mildly
raised19,20,41 than in HCV mono-infection. The effect of OBI on
liver enzyme flares has not been studied extensively in the
Egyptian literature. One study found that OBI is not a cause of
liver enzyme flare during pegylated interferon/ribavirin therapy
for chronic HCV.19 Another recent Egyptian study compared
the frequency of OBI in chronic HCV with normal or slightly
raised liver enzymes with another group of patients with liver
enzyme flare (>5 folds) and found OBI in 63.3% of patients
with enzymes flare in comparison to 13.3% in the normal
Increased severity of liver disease
In a surprising contrast to the mild inflammation noticed in
OBI/HCV co-infection42 most studies have demonstrated an
increased prevalence of advanced fibrosis/cirrhosis in these
cases.41-43 Such occult HBV co-infection is associated with more
severe liver disease and higher HCV viral load.44 In one study
from Egypt the presence of OBI was found to aggravate the
severity and deterioration of liver disease in patients with
chronic HCV.45 In contrast other studies found no association
between OBI and the degree of liver necroinflammation and
fibrosis.37,46 In agreement with these latter findings is our study
where we found less hepatic fibrosis in OBI/HCV co-infected
patients in comparison to HCV mono-infections.
Necroinflmmatory activity also showed no significant
difference, although these results may be due to the small
number of patients in the co-infection group of our study.17
Altered response to antiviral treatment
Some studies suggest a negative influence of OBI on the
response to standard interferon therapy in chronic HCV
infection irrespective of HCV genotypes20,43,44,47,48 but this
observation needs to be confirmed in HCV populations treated
with the current gold standard, pegylated-interferon/ribavirin
combination therapy.4 Consequently we conducted a cross
sectional study to evaluate the prevalence and impact of OBI
in HCV patients on antiviral therapy. Out of the 155 HCV patients
under treatment, six were HBV DNA positive (OBI) and there
was no statistically significant difference in response to HCV
treatment with pegylated interferon/ribavirin combination
Increased risk of HCC
There is an elevated risk of HCC in HCV patients because this
silent infection can affect the progression of liver disease
towards HCC development.49 Studies have found high
proportion of HCV related HCC patients suffering from
Anti-HBc antibody and HCV
Advanced hepatic fibrosis has been reported in patients with
isolated anti-HBc and chronic HCV infection.47 Anti-HBc
Occult hepatitis B
antibody was linked to more severe liver disease and poor
response rates to interferon therapy for HCV in international29
and Egyptian studies alike.18,21,51
Occult hepatitis B and blood transfusion
The first recorded evidence of OBI and possible transmission
occurred via blood transfusion.52 This was further confirmed
in the chimpanzee model when cloned full-length HBV-DNA
from patients with OBI was confirmed to be infectious and
generated a typical HBV infection.53 Thus HBsAg non-reactive
blood donations containing HBV DNA have to be considered
infectious.54 In Egypt prevalence of anti-HBc antibody in
HBsAg negative blood donors was found to be 13.3% of which
10% were HBV DNA positive.55 In another large Egyptian study
among the accepted blood units for donation in blood banks,
anti-HBc antibody was found in 78/712 units (10.96%). HBV
DNA was detected in 9/78 (11.54%) of the anti-HBc-positive
units and thus OBI was detected in 9/712 (1.26%) of the
accepted blood donations. Implementing anti-HBc test to the
routine assay for the forthcoming two decades would certainly
eliminate the possibly HBV-infected units. Rejection of these
units will be beneficial to decrease the risk of HBV transmission
with its potential consequences particularly in
immunocompromised recipients.56 The prevalence of OBI is
much higher in patients exposed to multiple blood
transfusions57 especially when immunocompromised.58 OBI
was reported in 21% of Egyptian HCV infected children with
hematological disorders and malignancies.59
Occult hepatitis B and hemodialysis
HBV and HCV share common routes of transmission and hence
patients on hemodialysis are at increased risk of exposure to
infected blood and instruments and acquiring both infections.
In one study from upper Egypt 4% of hemodialysis patients
were found to have OBI. The prevalence did not significantly
vary between hemodialysis patients with or without HCV co-
infection.51 Another study from lower Egypt reported lower
prevalence of OBI in chronic hemodialysis patients and there
was no significant difference in prevalence between
hemodialysis patients with (6.3%) or without (3.8%) HCV co-
Risk of HBV reactivation
Any patient with OBI receiving systemic chemo- radio- or
immuno-therapy is potentially at risk of HBV reactivation,6
leading to the development of a typical hepatitis B infection
that often has a severe and sometimes even fulminant clinical
course.61 The risk of reactivation is well documented in HBsAg
positive hemato-oncologic patients who require pre-emptive
antiviral therapy. All patients receiving chemo- and immuno-
therapy should be tested at least once for anti-HBc antibodies
before starting therapy and monitored periodically for ALT
elevations. In case of ALT elevation, further diagnostic work-
up is required pending initiation of antiviral therapy upon
establishing the diagnosis of HBV reactivation.62 In this context
OBI patients under immunosuppression may show a
reactivation of viral replication when immunological
reconstitution is achieved with a subsequent cytotoxic T
lymphocyte mediated hepatocyte injury.63 Monitoring in such
cases should be extended for months or even years after
discontinuation of immunosuppression.64 Patients prone to OBI
reactivation are shown in Table 2.
Table 2: Categories of occult HBV carriers known to be
prone to viral reactivation
• Haematological malignances
• HIV infection
Patients who have undergone
• Bone marrow transplantation
• Liver transplantation
• Renal transplantation
• Treatment with anti-CD20 (Rituximab)
• Treatment with anti-CD52 (Alemtuzumab)
• Treatment with anti-TNF-α (Infliximab)
OBI and organ transplantation
Transmission and reactivation of OBI is important in the setting
of organ transplantation particularly with liver transplants.
There is a risk of transmission of OBI through an orthotopic
liver transplant from an OBI-seropositive (anti-HBc-positive)
donor, in particular if the recipient is negative for all HBV serum
markers, because of the presence of viral strains in the
hepatocytes which can be reactivated during
immunosuppression.65 Prophylaxis with antiviral agents such
as lamivudine prevents hepatitis B of the recipient in most (but
not all) of these cases.66 Although theoretically possible, there
is no evidence of HBV transmission from occult HBV-
seronegative organ donors.63 In immunocompetent recipients
there is no evidence that anti-HBs containing components are
infectious, even at low titers.54 The risk of occult HBV
Tropical Gastroenterology 2012;33(4):242–250
transmission is very low after kidney, heart or bone marrow
transplant.67 Although the risk of acquiring HBV infection after
bone marrow transplantation is low, nevertheless, reactivation
of the latent infection may sometimes occur and lead to
fulminant hepatic failure (FHF). A case of FHF due to HBV was
reported 22 months after bone marrow transplantation obtained
from patient found to be anti-HBs positive, HBsAg negative
and only positive for intrahepatic HBV DNA prior to
Occult hepatitis B and hepatocellular carcinoma
HCC patients living in areas endemic for HBV were frequently
found positive for HBsAg and/or anti-HBc antibodies and this
strong relationship was the first epidemiological evidence of
HBV-related oncogenic transformation.69 Persistent HBV
infection may have a critical role in development of HCC even
in HBsAg-negative patients.24 Development of HCC in OBI
patients seems to be related in most cases to the associated
co-infection with HCV and to the presence of cirrhosis, although
OBI mono-infection still bears an oncogenic potential.24,50 The
highest prevalence of OBI in Egypt was reported among
patients with HCC.24,50 A difference in OBI prevalence rates as
per the biological matter tested, is reflected in an Egyptian
study where intrahepatic occult HBV DNA was detected in
62.5% cases, whereas serum occult HBV DNA was detected in
only 22.5% of the same HCC patient group.24
OBI could accelerate the evolution to cirrhosis in HCV
patients,43 and cirrhosis is known to be the most important risk
factor for the development of HCC.37 The cryptic infection
appears to exert its pro-oncogenic role in HCV infected patients
as well as in alcoholics and in individuals with cryptogenic
liver disease.64,70 In HCV-related HCC the prevalence of serum
OBI was 47.4% (9/19). The prevalence of OBI was higher in
patients with both anti-HBs and anti-HBc 2/4 (50%) antibodies
than those with anti-HBc alone 1/5 (20%).24 One of the markers
expressed in HBsAg negative HCC cases is the expression of
the HBV-X gene. Several studies71-74 have reported the HBV-X
protein in the malignant liver tissues. The X gene deregulates
cell cycle control, interferes with cellular DNA repair and
apoptosis and plays an important role in interaction with p53
and Rb gene.71 One Egyptian study found that HBV DNA and
HBV-X gene was positive in 24/42 (57.1%) cases of HCC
patients, candidates for liver resection, HBV-X gene expression
was significantly higher in HCC patients than in the HCV
OBI and chronic liver disease
Occult HBV has been associated with more advanced fibrosis/
cirrhosis.21 About 72% of HCC patients with intrahepatic occult
HBV had cirrhosis. Cirrhosis is considered an important risk
factor for the development of HCC.20 Similarly it was found
that HBV mixed genotype infections could probably be of
clinical significance in HBV-induced liver diseases. Prevalence
of mixed genotype infections was found to be 15.7% especially
in those with chronic active hepatitis.49 One Egyptian study
observed that anti-HBc positive/HBV-DNA negative patients
showed a similar prevalence of severe liver disease to anti-
HBc positive/HBV-DNA positive patients and a significantly
higher prevalence than anti-HBc negative cases. This notion
raises the clinical significance of isolated positive anti-HBc
antibody in relation to liver disease,23 although in other studies
no association was found between OBI and the degree of liver
necroinflammation and fibrosis.37,46
HBV genotype D is the prevalent genotype among chronic
HBV infection in Egypt.2 In one Egyptian study on the role of
OBI in HCC, intrahepatic HBV infections were attributed
predominantly to viral genotypes D and B that constituted 8/
25 (32%) and 6/25 (24%) of cases, respectively. HBV genotypes
A and C infections were the least observed and constituted
4% and 8% of the cases, respectively, compared to 100% of
HBV genotype A and D mixed infections in the control group
(HBsAg positive HCC patients) with no other genotypes
observed. In addition, there was a relatively high prevalence
of mixed infections of 5/25 (20%) among the studied group.
One case had both genotypes A and D, two cases had both B
and D and two cases had genotypes B and C. No HBV
genotype E or F was found in this study and furthermore,
genotypes G and H were not determined.24
The author would like to thank Professor Amira Soliman for
revising this work.
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