Received on 28 March 2008; revised 14 August 2008.
Address for correspondence: Dr. Fernando Lopes Gonçales Junior. Grupo
de Estudos das Hepatites, Disciplina de Moléstias Infecciosas,
Departamento de Clínica Médica, Faculdade de Ciências Médicas,
UNICAMP. Rua Tessália Vieira de Camargo, 126. Cidade universitária,
Campinas, São Paulo, Brazil. Zip code: 13083-970. Telephone/ fax
number: 55-19- 3521-7727. Email: firstname.lastname@example.org. Research supported
by Fundo de Apoio ao Ensino, Pesquisa e Extensão (FAEPEX) -
The Brazilian Journal of Infectious Diseases 2008;12(4):300-305.
© 2008 by The Brazilian Journal of Infectious Diseases and Contexto
Publishing. All rights reserved.
Occult Hepatitis B Virus Infection in Immunocompromised Patients
Ruth Nogueira Cordeiro Moraes Jardim1, Neiva Sellan Lopes Gonçales1,2, Josiane Silveira Felix Pereira1,
Viviane Cristina Fais1 and Fernando Lopes Gonçales Junior1
1Study Group of Hepatitis, Infectious Disease, Department of Clinical Medicine, Faculty of Medical Science, State University of Campinas-
UNICAMP;2Hematology and Hemotherapy Center, State University of Campinas – UNICAMP; São Paulo, SP, Brazil
Occult hepatitis B infection is characterized by hepatitis B virus (HBV) DNA in the serum in the absence of
hepatitis B surface antigen (HBsAg). We assessed occult HBV infection prevalence in two groups of
immunocompromised patients (maintenance hemodialysis patients and HIV-positive patients) presenting HBsAg-
negative and anti-HBc positive serological patterns, co-infected or not by HCV. Thirty-four hemodialysis anti-HIV
negative patients, 159 HIV-positive patients and 150 blood donors who were anti-HBc positive (control group) were
selected. HBV-DNA was detected by nested-PCR. Occult hepatitis B infection was not observed in the hemodialysis
patients group but was found in 5% of the HIV-patients and in 4% of the blood donors. Immunosuppression in HIV
positive patients was not a determining factor for occult HBV infection. In addition, no significant relationship
between HBV-DNA and HCV co-infection in the HIV-positive patient group was found. A lack of significant
associations was also observed between positivity for HBV-DNA and CD4 count, viral load and previous lamivudine
treatment in these HIV-positive patients.
Key-Words: Occult HBV infection, HBV-DNA, anti-HBc alone, hemodialysis, HIV, immunosupressed patients.
Hepatitis B virus (HBV) infection is a major global health
problem. It is estimated that about 350,000,000 individuals are
infected by HBV; infection can induce a wide spectrum of
clinical forms, ranging from a healthy carrier state to
cirrhosis and hepatocellular carcinoma . HBV infection
is usually diagnosed when circulating HBsAg is detected.
However, the availability of highly sensitive molecular
biology techniques has also allowed the identification of
HBV infection in HBsAg-negative individuals, with or
without circulating antibodies to HBsAg (anti-HBs) and/
or hepatitis B core antigen (anti-HBc) [2-5].
The failure to detect HBsAg, despite the persistence of
the viral DNA, is due in most cases to the strong
suppression of viral replication and gene expression that
characterizes this “occult” HBV infection [6-9]; although
the mechanisms responsible for suppression of HBV are
not well understood.
Occult HBV infection has been studied in selected
groups or individuals in which its prevalence is believed to
be higher, such as intravenous drug abusers, patients on
maintenance hemodialysis, organ transplant patients,
patients with chronic HBV infection , and patients co-
infected with human immunodeficiency virus (HIV) or
hepatitis C virus (HCV) .
However the magnitude and pattern of occult HBV
infection among immunocompromised patients, such as
hemodialysis and HIV patients, is not well established yet.
In maintenance hemodialysis patients, the risk of acquiring
HBV and HCV infection is high, due to the dialysis process
[12,13]; consequently, the probability of patients becoming
chronic carriers is higher than for the general population.
In HIV-positive patients, co-infection with HBV and HCV
is common due to the common route of transmission of
these diseases. In patients coinfected with HBV and HIV, it
has been suggested that HIV interferes with the natural
history of HBV infection by enhancing HBV replication
 and that immunossupression associated with HIV
infection allows reinfection or reactivation of a past HBV
We examined occult HBV infection prevalence in two
groups of immunocompromised patients (maintenance
hemodialysis patients and HIV-positive patients), who
present HBsAg-negative and anti-HBc positive serological
patterns, co-infected or not by HCV. Possible correlations
were investigated between the prevalence of HBV DNA,
viral loads, CD4 levels and previous lamivudine
administration in the HIV group.
Material and Methods
The study was performed between 2002 and 2005 in the
Laboratory of the Hepatitis Study Group of the Infectious
Diseases Department, School of Medical Sciences, State
University of Campinas (UNICAMP), after approval by the
Institutional Ethics Committee. All adult hemodialysis patients
originated from two dialysis centers in São Jõao da Boa Vista,
São Paulo State, Brazil. HIV-positive patients were selected
during their clinical follow-up at the Clinical Hospital of the
University of Campinas; only those presenting a serological
pattern of HBsAg negative and anti-HBc positive, co-infected
or not by HCV, were included.
BJID 2008; 12 (August)
A total of 343 samples were analyzed. The samples were
distributed into three groups:
Thirty-four adult hemodialysis patients who were HBsAg
negative, anti-HBc postive and anti-HIV negative (18 [53%]
males and 16 [47%] females; mean age 53.7 ± 10.10 years;
range 29-76 years) were included. Seven (20.6%) of them were
also co-infected with HCV (Table 1).
One hundred and fifty nine HIV-positive patients co-
infected by HBV (HBsAg negative and anti-HBc positive)
were selected (129 [81%] male and 30 [19%] female; mean age
39.9 ± 8.31 years; range 22-67 years). Eighty-eight (55.3%) of
them were also co-infected by HCV (Table1).
One hundred fifty volunteer blood donors with HBsAg
negative and anti-HBc positive serological patterns (102 [68%]
males and 42 [32%] females; mean age 41.8 10.78 years; range
18-64 years) were studied. This group was being analyzed for
another study and was included in our study as a control
group. All of these individuals were negative for syphilis,
anti-HCV, anti-HIV and anti-HTLV I/II (Table 1).
Testing for HBsAg was performed with a third-
generation monoclonal enzyme immunoassay (Abbott/
Murex, Dartford, England). Anti-HBc was screened using a
competitive enzyme immunoassay (Abbott/Murex,
Dartford, England). Anti-HBs was tested using an enzyme
immunoassay (ETI-AB AUK-3, Diasorin, Itály). Antibodies
to HCV were detected with a fourth-generation enzyme
immunoassay (Abbott/Murex Dartford, England). For
detection of antibodies to HIV 1/2, two different assays
were utilized, a third-generation assay (Abbott/Murex
Dartford, England) and an antigen/antibody combo assay
(Abbott/Murex, Dartford, England), confirmed with a
Western Blot. All samples were tested according to the
manufacturer’s instructions. The samples were considered
positive when absorbance was greater than the cutoff and
presented the same result in duplicate.
The samples that tested HBV-DNA positive were retested
for HBsAg, in a fully automated quantitative chemiluminescent
microparticle immunoassay (CMIA) Architect HBsAg (Abbott
Laboratories, Sligo, Ireland) that is able to detect the most
frequent mutants of the HBV S region, in order to confirm the
status of occult HBV infection. This Architect HBsAg Qt
assay was used according to the manufacturer’s protocol.
The resulting chemiluminescent reaction was measured in
relative light units (RLUs). A direct relationship exists between
the amount of HBsAg in the sample and the number of RLUs.
Architect HBsAg Qt is capable of measuring a wide range of
from 0.05 to 250 IU/mL.
Serum samples were stored at –20o C and thawed
immediately before use. For detection of HBV DNA, nested
in house PCR was used as described by Kaneko et al. .
The 5’-3’ nucleotide (nt) sequences of the primers were as
follows: outer primers HBV1763 (GCT TTG GGG CAT GGA
CAT TGA CCC GTA TAA)’ and HBV2032R (CTG ACT ACT
AAT TCC CTG GAT GCT GGG TCT-3’); inner primers HBV
1778E (GAC GAA TTC CAT TGA CCC GTA TAA AGA ATT)’
and HBV 2017RB (ATG GGA TCC CTG GAT GCT GGG TCT
TCC AAA-3’). After both reactions, a 270 nucleotide
fragment was obtained and detected by agarose gel
electrophoresis. To prevent carryover contamination during
PCR, each step of the procedure was performed in a separate
room with dedicated equipment and directional flow from
the beginning of the procedure to the end. Negative
controls consisting of water were also included in each
extraction run, and an extra negative control consisting of
water was included as a last sample in each PCR run. Serial
dilutions were made in an HBsAg low-titer performance
Occult Hepatitis B Virus Infection
Table 1. Prevalence of occult HBV infection (HBV DNA positivity) in the groups studied.
GroupsNo HBV DNA positive (%)HBV DNA negative (%)p value
GI – Hemodialysis Patients
GII – HIV-positive patients
GIII – Blood donors
BJID 2008; 12 (August)
panel (PHA 105, Boston Biomedica Inc, Boston, Mass.),
which made it possible to establish a limit of detection by
nested PCR of 102 copies/mL.
Statistical comparison of distribution was carried out using
either the chi-square or the Fisher exact tests, as applicable.
For comparison of means and variances, other tests were used
(Student t, Kruskal-Wallis, and Mann-Whitney tests). The
level of significance was set at p<0.05.
Among 34 maintenance hemodialysis patients (Group I), 27
(79.4%) were anti-HBc positive and anti-HCV negative; among
these, eight (29.6%) were anti-HBc alone and seven (20.6%)
were anti-HBc plus anti-HCV positive. HBV-DNA was not
detected in any serum from the patients in this group (Table 1).
Among the 159 HIV-positive patients (Group II), 71 (44.6%)
were anti-HBc positive and anti-HCV negative, 15 (21%) of
them were anti-HBc alone, while the other 88 (55%) patients in
this group were co-infected with HCV; anti-HBc alone was
Occult Hepatitis B Virus Infection
Table 2. Epidemiological, clinical and laboratorial findings in HIV-positive patients and blood donors.
Clinical featuresNo HBV-DNA positive (%) HBV DNA negative (%)
Source of infection
Intravenous drug abusers
CD4+ cell count (cells/mL)
Plasma HIV-RNA load (copies/mL)
159 8 (5.0)151 (95.0)
94 (94.0) 150
Table 3. Clinical aspects, serological data, plasma HIV-RNA load, CD4+ count and lamivudine as part of HAART therapy in HIV
patients with occult HBV infection.
HIV status HIV viralCD4+
IDA=intravenous drug abusers; IDA/Homo=intravenous drug user and homosexual; Homo=homosexual; Lam=lamivudine; LD=limit of detection.
BJID 2008; 12 (August)
found in 30 (34%) of patients of this group. HBV-DNA was
detected in eight (5%) of the patients in this group. Among
the HIV-positive patients that were HCV-negative, HBV DNA
was found in 5/71 (7.0%); one (6.7%) presented anti-HBc alone
and four (7.2%) were anti-HBc and anti-HBs positive. HVB
DNA was also observed in 3/88 (3.4%) HIV-positive patients
co-infected with HCV, one (3.4%) was anti-HBC alone and
two (3.5%) had anti-HBc and anti-HBs positive markers. No
significant difference in the presence of HBV-DNA was
observed in HIV-positive patients co-infected or not with HCV;
similarly, no significant difference was observed in the
presence or absence of anti-HBs (Table1).
Among the 150 blood donors (Group III), HBV DNA was
detected in six (4%). No HBV-DNA was found in blood donors
that were anti-HBs positive only, among those that presented
anti-HBc alone. The prevalence of HBV DNA in Groups II and
III was similar (5 and 4% respectively); in Group II, HBV-DNA
was also found in HIV-positive patients that were anti-HBs
positive (Table 1).
Among the 159 patients infected with HIV-1, 51 (32%) had as
a risk factor for acquired HIV and HBV unsafe sexual practices,
46 (29%) were intravenous drug abusers, 17 (10.7%) presented
two risk factors (sexual and parenteral), and in 45 (28.3%) it was
not possible to determine the risk factor. Among 150 blood donors,
35 (23.4%) related parenteral exposure, 29 (19.3%) reported unsafe
sexual practices, 17 (11.3%) had both parenteral and sexual
exposure, and in 69 (46%) no known risk factors were reported.
The finding of HBV DNA was not significantly associated with
risk factors in the two groups (p>0.05, Table 2).
Among the other HIV-positive patients, 90 (57%) presented
a TCD4+ count of more than 350 cells/mL, 113 (71%) presented
a viral load of less than 10,000 copies/mL, 130 (82%) were under
antiretroviral treatment, and 80 (61%) of the patients received
lamivudine as part of a HAART scheme. HBV-DNA was
detected in six (6.7%) of the HIV-positive patients, with CD4+
counts above 350 cells/mL, five (4.4%) had a viral load < 10,000,
in four (5%) HIV-positive patients who were being treated with
lamivudine, and in four (8%) of the patients who had not used
lamivudine The frequency of occult HBV infection was not
significantly different, with variations in TCD4+ count, HIV
viral load or lamivudine treatment (p>0.05, Table 2).
Table 3 shows the clinical and serological features, as well
as the TCD4+ counts and HIV viral load of the eight patients
who tested positive for HBV-DNA. All patients who were HBV-
DNA positive were classified as having AIDS. Six (75%) of
them were anti-HBs positive; only one was anti-HBc alone.
These patients were in follow-up for an average of 10 years
since the initial anti-HIV serology-confirmed diagnosis.
Among these patients, six (75%) had TCD4+ counts above
350 cells/mL and three (37.5%) presented a viral load below
the detection limit.
The relationship between occult HBV infection and liver
disease is still unclear. Occult HBV infection has received
much attention recently, since it has been detected in patients
with hepatocarcinoma , in blood donors and transfused
patients [19,20], and in patients infected with hepatitis C virus
[21-23]. In chronic HCV patients on hemodialysis, the
prevalence of occult HBV infection is not yet well known
[22,24]. Some studies have demonstrated that HIV infection
modifies the natural history of HBV and HCV infections ,
increasing the progression to chronic disease. Among
immunocompromised patients, HBV-DNA can be detected in
10% of HBsAg negative/anti-HBc positive patients.
Reactivation of HBV is rare ; reactivation of HBV has
recently been described in an HIV-positive patient who was
anti-HBc alone .
The main characteristic of occult HBV infection is HBV
DNA at low levels in serum and hepatic tissue . Due to the
high sensitivity (100 copies/mL) of the in house PCR used in
our study, we were able to identify HBV DNA in the serum of
HBV infected patients even when they had few copies.
Commercial disposable tests only detect more than 1,000
The data recorded from hemodialysed patients in our study
were similar to those encountered in another study made in
Italy , in which no occult infection was found in 213 patients
from five different centers.
Clearance of HBV-DNA is expected to occur following loss
of HBsAg and seroconversion to anti-HBs; anti-HBs is
considered the classical marker of past-resolved infection. In
some cases, however, HBV DNA has been detected in anti-
HBs-positive sera  and even in individuals without HBV
serological markers . Persistence of HBV DNA after
seroconversion to anti-HBs has been documented more
frequently in patients with chronic liver disease than in
asymptomatic carriers. HBV DNA was found in 10% of patients
with anti-HBc alone and in 20% of patients with anti-HBs and
anti-HBc. These results are in agreement with previous
findings, which demonstrated that HBV DNA detection is
elevated in HBsAg-negative, HIV-infected patients .
A number of explanations for the persistence of HBV
DNA in HBS-negative samples have been proposed,
including HBV DNA in low copy numbers , genetic
variations of the S gene [30,31], and immune complexes in
which HBsAg is hidden .
A key question to understanding the role of occult HBV
infection is whether small amounts of HBV will lead to
progressive liver disease. Systemic detection of HBV DNA
levels in HIV-positive individuals, with and without HBsAg,
as well as further study of the association between HBV DNA
and markers of liver function, should help to answer this
Suppression of HBV DNA by lamivudine has been
demonstrated in studies of patients chronically infected with
HBV [33-35]. In cases of co-infected HBV-HIV patients who
received lamivudine as part of their antiretroviral treatment,
loss of HBV DNA after one year of treatment was observed in
96.3% of patients when assessed by molecular hybridization
Occult Hepatitis B Virus Infection
BJID 2008; 12 (August)
and 88.5% of patients assessed by PCR . However, trials
on lamivudine treatment have been performed with HBsAg-
positive patients alone, co-infected with HIV or not; the effects
of lamivudine were analyzed at various intervals after the
beginning of therapy [37,38].
The loss of HBV DNA due to lamivudine treatment is
usually accompanied by significant histological and
biochemical improvement . The main limitation for the use
of lamivudine is the selection of resistant mutations that affect
the YMDD motif of HBV polymerase and that may arise during
therapy. Such mutations have also been reported in studies
of patients co-infected with HIV and HBV [37,40].
In our cross-sectional study, no significant differences in
the prevalence of HBV DNA or of HBV viral load were observed
between patients under lamivudine treatment and those not
receiving lamivudine. Indeed, it is known that increased
duration of lamivudine treatment is associated with an
increasing number of resistance mutations. In a recent study
conducted with HIV-HBV co-infected patients, it was observed
that the rate of resistance mutations increased from 25% after
one year of treatment to 52% after two years . The efficacy
of lamivudine treatment and the rate of resistance mutations
in patients with occult HBV infection have not yet been
investigated. To determine the effect of lamivudine treatment
on HBsAg-negative patients, the rates and pattern of
lamivudine-resistant mutations should be investigated in this
particular group of HIV-HBV infected individuals.
In conclusion, the finding of HBV DNA in individuals
without serological markers for HBV reinforces the importance
of a revised definition of hepatitis B, which is currently based
We thank Nicola Conran for her helpful English review.
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