World Journal of AIDS, 2013, 3, 313-319
Published Online December 2013 (
Open Access WJA
Hepatitis B Virus Co-Infection: Yet Another Reason for
Early Initiation of Treatment in HIV Infected Individuals*
Yared Hailaye1, Muluken Dessalegn2, Solomon Gebre-Selassie3
1Department of Medicine, School of Medicine, Debre Berhan University, Debre Berhan, Ethiopia; 2Addis Ababa Science and Tech-
nology University, Medicine and Health Science College, Addis Ababa, Ethiopia; 3Department of Medical Microbiology, Medical
Parasitology and Immunology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
Received August 24th, 2013; revised September 23rd, 2013; accepted September 27th, 2013
Copyright © 2013 Yared Hailaye et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Hepatitis B virus (HBV) co-infection with HIV is becoming a major challenge due to shared routes of
transmission. The burden is apparent in regions with widespread use of antiretroviral treatment, which led to the en-
hanced emergence of liver-related diseases and mortality. Though there are conflicting results about the effect of
chronic HBV infection on response to highly active antiretroviral therapy (HAART) (CD4+ cell count and HIV viral
load, HIV RNA copies/ml), HAART is known to cause immune mediated HBV specific liver damage after it reconsti-
tutes cell-mediated immunity. The relationship of different HAART regimes with immune recovery is an area of re-
search interest. Objective: It is in order to determine the changes in immune recovery during HBV infection in the set-
ting of HAART among HIV positive individuals attending care and treatment services. Methods: Two cohorts of
co-infected patients were analyzed from data of one to seven months retrospectively. The first group (n = 380) was
antiretroviral drug naive and the second cohort (n = 380) was on HAART for the entire period. The study was con-
ducted in one referral hospital and six health centers. Data were gathered from 760 patients using their intake form, their
follow-up form and their medical records supplemented by data from a structured questionnaire. HBV infection was
determined by using HBsAg rapid and confirmatory tests and CD4 cells were enumerated by using laboratory registers
and patient cards. Bivariate and multivariate logistic regressions were done by using SPSS Version 18 and Epi info Ver-
sion 3.5. Results: Poor immune recovery due to HBV infection was improved after initiation of HAART. Before the
initiation of HAART, the mean CD4 cell count of HBV infected individuals was lower than that of non-HBV infected
ones, 234/mm3 and 384/mm3, respectively (p < 0.05). Individuals co-infected with HBV had experienced delayed re-
covery of immune cells (CD4 cell count). However, after, on average, more than two years of therapy, the association is
reversed. In addition to HBV infection, CD4 cell count of patients on chronic HIV care/pre-ART was decreased by
older age, living in rural areas and previous opportunistic infections. Conclusion: HBV infection has different out-
comes between pre-ART and ART-initiated individuals. In the former cohort, HBV infection causes significant delays
in immune recovery which is reversed after initiation of anti-HIV treatment. HBV co-infection has a significant and
immediate negative effect on CD4 cell counts and immune recovery before HAART but such effects slowly subside
after initiation of the treatment. As a result, HBV infection is another issue to consider for swift initiating of HAART
for HIV infected individuals in long-term care.
Keywords: HAART; CD4 Cell Count; HBsAg; HBV/HIV Co-Infection; Immune Recovery
1. Introduction
Since the introduction of highly active antiretroviral
treatment (HAART) for treatment of HIV, morbidity and
mortality have decreased greatly in HIV-infected indi-
viduals. However, the management of other non-HIV
associated chronic diseases in HIV patients has become
increasingly important. In this regard, Hepatitis B virus
(HBV) co-infection with HIV is still a major challenge
*Conflict of interest: no conflict of interest detected.
Authors’ contribution: authors, Yared Hailaye and Muluken Dessalegn,
contributed equally from the inception to the manuscript preparation o
this article, whereas Dr. Solomon Geberesillasie, commented and ed-
ited the manuscript.
Hepatitis B Virus Co-Infection: Yet Another Reason for Early Initiation of Treatment in HIV Infected Individuals
HBV is the leading cause of chronic liver disease and
liver-related death worldwide, with the majority of these
cases occurring in areas of Africa and Asia where HBV
prevalence is high with population prevalence sometimes
over 8%. Around the world, 90% of HIV-infected per-
sons have biological signs of prior HBV infection and
5% - 15% suffer from chronic infection [3]. As a conse-
quence, 2 - 4 million of the 34 million people living with
HIV globally also have chronic HBV infection [4]. Con-
ditions associated with hepatitis B and C infections are
currently among the leading causes of hospital admission
of HIV infected individuals, and recent studies have
shown increasing rates of liver disease and related death
among those with HIV [5].
Infections with HIV and HBV are often shared be-
cause of similar routes of transmission (sexual inter-
course, blood transfusion) [3]. Many countries with a
high HBV disease burden are also affected by a high
HIV burden, leading to frequent HIV/HBV co-infection
[6]. The impact of HIV and HBV co-infection is espe-
cially apparent in regions with widespread use of
HAART. Studies have showed that in HIV-HBV co-in-
fected patients, HBV increases HIV replication, ART re-
lated hepatotoxicity and delays immune recovery (CD4+
cell count) [7].
A study on extra-chromosomal HBV-DNA in periph-
eral mononuclear cells has found that this type of HBV-
DNA is more prevalent among AIDS patients than that
among asymptomatic HIV carriers. Another in vitro
study has demonstrated that HBV-X protein (HBx) su-
per-induces ongoing HIV replication and HIV-1 long-
terminal repeat (LTR) transcription. These findings sug-
gest that HBV could alter the course of HIV infection,
inducing faster progression to AIDS [8]. HIV in turn in-
creases HBV carriage rates, increased replication, hepati-
tis flares, progression to chronic HBV infection and end
stage liver disease (cirrhosis and hepatocellular carci-
noma). It also increases the number and frequency of
reactivation episodes. [9]. Cirrhosis due to HBV is more
common in co-infected patients than those mono infected
by HBV despite low ALT levels [10,11]. The annual risk
of developing cirrhosis during HBV infection appears to
be much higher in those co-infected with HIV. This may
be especially true in those with low CD4 counts [12].
Data of such HBV-HIV interaction in different settings
and geographical areas are limited.
There are conflicting results about the effect of chronic
hepatitis B on the response to HAART (CD4+ cell count
and HIV viral load, HIV RNA copies/ml). A cohort study
in Italy has showed increasing divergence of mean CD4
lymphocyte counts up to 36 weeks after HAART initia-
tion between patients with and without chronic hepatitis
B as compared to those with chronic hepatitis B having a
lesser CD4 increase (P = 0.03) [13]. In a cohort study in
Denmark HBV infection sero-status is observed to have
no effect on the response to HAART in terms of HIV
viral load suppression and CD4+ cell count [3]. Similar
findings were documented in Nigeria where HIV RNA
suppression and absolute CD4 rise were found to be
similar between HBsAg positive and negative patients
started on HAART [14].
HAART in turn was associated with immune mediated
HBV specific liver damage after HAART-reconstituted
cell-mediated immunity [9,15]. As the potential of chro-
nic hepatitis B to blunt immune recovery after initiation
of HAART is an area of special relevance to low-income
settings in Africa and Asia, which comprises the coun-
tries with high HBV endemicity, more studies are needed
to characterise the effect of chronic hepatitis B co-infec-
tion on CD4 lymphocyte recovery during antiretroviral
therapy. If reduced immune recovery is found to occur
more frequently in co-infected populations, current WHO
guidelines for antiretroviral monitoring may be sub-opti-
mal [6].
Despite these mounting challenges, HIV/HBV co-in-
fection in the setting of HAART and immune recovery is
not explored at large in Ethiopia. So the intention of the
current study is to determine whether there is a need for
early screening and treatment for HBV among HIV pa-
tients as well as its ultimate effect on immune recovery
before and after initiation of HAART.
2. Materials and Methods
2.1. Patient Selection
Two cohorts of patients were chosen retrospectively from
a database of patients followed in the ART units of De-
bre Berhan Hospital and six health centers (Shewarobit,
Debresina, Mendida, Deneba, Enewary and DebreBer-
hansix Health Centers, North Shoa Zone, Amhara, Ethio-
pia). These patients are previously identified as HIV in-
fected individuals. A total of 760 patients, all of them
above the age of 15 years, were included in the study.
Blood specimens were collected during the course of
routine clinical follow up, other clinical and socio-demo-
graphic data were obtained from patient interviews and
follow up chart, and Debre Berhan University Institu-
tional Ethical Review Committee approved the research.
Oral consent was obtained from each participant after the
purpose, confidentiality, protection and anonymity of the
research was explained.
The cohorts are defined as;
HAART naive—380 HIV infected individuals that did
not initiate HAART throughout the study period (three
HAART initiated—380 HIV infected individuals that
were on HAART at the baseline and for the entire dura-
tion of the study which lasts for three months.
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Hepatitis B Virus Co-Infection: Yet Another Reason for Early Initiation of Treatment in HIV Infected Individuals 315
Exclusion criteria: HIV patients under the age of 15
years and with less than three months of follow up were
excluded from analysis.
2.2. HBV Infection Determination
Serological testes for determining HBV infection were
done by detecting the presence of HBsAg presence in
patients serum with SD HBsAg rapid test kit (SD Com-
pany, Korea), and positive results were confirmed with
HBV confirmatory reagent AxSYM HBsAg (Abbott
AXSYM System, ABBOTT Diagnostic division, Ger-
many ) according to the manufacturer’s manual.
2.3. CD4 Cell Count
CD4 cell count of patients was done with FACS counter
as cells/mm3 (BD FACSCount™ System, (BD Biosci-
ences, 2350 Qume Drive, San Jose, CA, United states of
America) The mean CD4 cell count of patients was cal-
culated as the average numbers of CD4 cell count of an
individual for the period in follow up calculated by add-
ing all CD4 counts in patients follow up chart and di-
vided by the number of counts.
2.4. Statistical Analysis
Data was entered, cleaned using EPI INFO software and
analyzed using SPSS 18. Both descriptive and analytical
statistical procedures were employed. Univariate, Bivari-
ate and multivariate logistic regressions with relative risk
(RR) along with the 95% confidence interval were used
to ascertain the association between covariates and de-
pendent variables. Fisher exact tests, analysis of variance,
correlation and relative risk (RR) were used to assess the
relationship between HIV/AIDS patient’s characteristics
and immune recovery (CD4 cell count).
Logistic regression was carried out to determine ad-
justed effect of each factor on immune recovery. Vari-
ables with more than two categories were entered in to
the model in the form of two “indicator” contrasts com-
paring each category to the first group as reference. A
backward stepwise procedure based on the likelihood
ratio was used to select the variables included in the final
model. The significance for variable removal and entry
was set to 0.10 and 0.05 respectively. The Hosmer and
Lemeshow test was used to check the goodness-of-fit of
the model. Only covariates that were statistically signifi-
cant at the bivariate level were included in the multivari-
ate binary logistic regression to control for confounding.
Though many variables were included in the analysis,
only covariates significantly associated with dependent
variable were considered. Risk Ratio (RR) and 95% con-
fidence intervals were derived from each variable coeffi-
cient in the final model. The significance of each coeffi-
cient was tested by the Wald test.
3. Results
3.1. Socio-Demographic and Clinical
Characteristics of Study Population
A total of 760 HIV-positive adults, 50:50 Pre-ART and
ART initiated, were included in the analysis of this study;
the study participants composed of 61.6% females and
80% live in urban areas, half of these without a secure
source of income. Half of them were without a secure
source of income.
According to the current study, 182 (23.9%) had been
treated for TB and one out of five HIV-infected indi-
viduals developed pulmonary tuberculosis. According to
the medical history, 372 (48.9%) individuals developed
opportunistic infections, 308 of whom are currently tak-
ing cotrimoxazole.
3.2. Clinical Characteristics of HIV Infected
Individuals on Pre-ART and ART Follow-Up
The average enrolment of pre-ART cohort in chronic
HIV care was 6 months (54.2%), 7 - 12 month (15.7%),
13 - 24 months (18.9%), and 24 months (11%) from
whom 172 (46.6%), had CD4 cell count 350 cells/mm3.
In the ART initiated cohort same number of patients
was followed for, on average, 28 ± 17.4 months. Half of
them had been on ART for 24 months (2 years), 17.6%
of individuals started ART at a very low baseline CD4
cell count, <50 cells/mm3 and only 40% started at the
right time (baseline CD4 count of 101 - 200 cells/mm3).
In addition, adherence was based on self-report, func-
tional status (working status), as well as type of regimen
a patient is taking and whether there was a substitution
was assessed.
3.3. Immune Recovery in the Pre-ART Cohort
According to the results of the current study, an infection
with HBV did greatly decrease the CD4 cells of HIV co-
infected individuals and further increase the progression
of HIV infection. CD4 cell count records were found
from 94% of the patients. Each CD4 cell count was the
average value of all CD4 cell counts registered on the
patient’s follow up card for the whole duration the pa-
tient was enrolled in chronic HIV care. A CD4 cell count
of 200 cells/mm3 was positively associated with HBsAg
seropositivity (P = 0.02) in which individuals co-infected
with HBV had experienced delayed recovery of immune
cells. In those individuals, the likelihood of a low CD4
cell count (200 cells/mm3) was 2.55 times higher in
those with a positive HBsAg test result (RR = 2.55, 95%
CI: 1.49 - 4.38).
The mean CD4 cell count of HBsAg positive and
negative Pre-ART individuals also showed that the mean
CD4 cell count of HBsAg negative study subjects was
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Hepatitis B Virus Co-Infection: Yet Another Reason for Early Initiation of Treatment in HIV Infected Individuals
Open Access WJA
higher than that of HBsAg positive individuals, 384/mm3
and 234/mm3 respectively(P = 0.02, 95% CI: 229, 531)
(Figure 1).
The results indicated that individuals with a positive
HBsAg test had relatively a higher mean CD4 cell count
than those with negative HBsAg test result, 262 cells/
mm3 and 248 cells/mm3 respectively. But the difference
was not statistical significant (P > 0.05) (Figure 1). Be-
sides HBV infection, CD4 recovery induced by HAART
was boosted by high baseline CD4 count, 50 cells/ mm3
(P = 0.00) and long duration of HAART, >2 years (P =
0.00). In the contrary any substitutions in the first line
regimen (P = 0.02) and current usage of cotrimoxazole (P
= 0.00, RR: 6.51, 95% CI 2.73, 15.55) halted CD4 cell
recovery after initiation of HAART (Table 2).
In addition to Hepatitis B virus infection, CD4 cell
count of patients on chronic HIV care/pre-ART was de-
creased by older age, living in rural area and previous
opportunistic infections (Table 1).
3.4. Immune Recovery in the ART Cohort
In contrast to the Pre-ART cohort, the relationship be-
tween HBV infection and immune recovery was reversed.
In our research, it was found that after initiation of
HAART, the effect of HBV infection on CD4 cells was
halted. The CD4 count of individuals for the whole dura-
tion of initiated ART indicated that 151 (39.7%) had
CD4 cell count ranging from 201 - 350 cells/mm3. The
true population mean was estimated to be 249 ± 8, (95%
CI: 170, 326).
The authors compared the prevalence of HBV-HIV co-
infection among ART cohorts on different treatment
regimens. The result indicated that though only 25 (6%)
of the total 380 ART initiated study groups were taking
TDF-3TC combined regimen, they accounted for 10% of
HBsAg positive individuals, high proportion than any
other regimen.
In those cohorts, the median CD4 cell count of patients
was 249 cells/mm3 ranging from 19 to 1068 cells/mm3. 4. Discussion
HBsAg sero status
(P = 0.19)
(P = 0.02)
ART Status
248 234
By categorize HIV patients in two cohorts based on ini-
tiation of HAART, the current study identified important
clinical difference with respect to Immune recovery
when HIV patients are co infected with HBV. In the first
cohort, Pre-HAART individuals, significant decrement of
CD4 cell recovery was sought in HBV co infected sub-
jects, Adjusted P = 0.02 [ARR: 5.97; 95% CI: (1.32,
27.04)] consistent with previous studies. A study re-
ported in the international AIDS society conference that
HBV infection independently reduce CD4 cell recovery
[7-16]. In contrast two longitudinal studies from Britain
did not show any impact of HBV co-infection on CD4
depletion, progression to full-blown AIDS, or AIDS in-
duced mortality. However, these studies suffer from
Figure 1. Mean CD4 cell count by HBsAg sero status of
HIV infected individuals, North Shoa Zone, 2012.
Table 1. Multivariate logistic regression analysis of variables associated with immune recovery (CD4 cell count) in patients at
Pre-ART cohort, North Shoa Zone, 2012.
CD4 count among patients
Characteristics Response
200 cells/mm3 >200 cells/mm3
Crude RR (95% CI) Adjusted RR (95% CI)
Positive 6 82 2.55 (1.49, 4.38) 5.97 (1.32, 27.04)*
HBsAg sero-status
Negative 4 267
15 - 25 11 84
>25 77 188 2.52 (1.40, 4.52) 2.47 (1.14, 5.36)*
Urban 61 226
Rural 27 45 1.76 (1.22, 2.56) 2.58 (1.41, 4.73)*
Yes 43 63 2.28 (1.60, 3.24) 2.81 (1.64, 4.81)*
History of previous
opportunistic infection No 45 208
*Significant at P value < 0.05.
Hepatitis B Virus Co-Infection: Yet Another Reason for Early Initiation of Treatment in HIV Infected Individuals 317
Table 2. Multivariate logistic regression analysis of variables associated with immune recovery (CD4 cell count) in patients at
ART cohort, North Shoa Zone, 2012.
CD4 count among patients
Characteristics Response
200 cells/mm3>200 cells/mm3Crude RR (95% CI) Adjusted RR (95% CI)
Positive 6 82 0.71 (0.36, 1.41) 0.48 (0.16, 1.43)
HBsAg sero-status
Negative 4 267
2 years 103 77
Duration on ART
>2 years 54 146 0.48 (0.39, 0.60) 0.32 (0.19, 0.54)
<50 45 18
Baseline CD4
50 112 205 0.47 (0.38, 0.58) 0.14 (0.07, 0.29)
Yes 150 158 4.38 (2.25, 8.51) 6.51 (2.73, 15.55)
Are you currently
taking Cotrimoxazole? No 8 64
Yes 13 39 0.57 (0.35, 0.92) 0.41 (0.19, 0.88)
Substitution in the
first line regimen No 145 183
small sample size and lack of baseline CD4 cell count
[15]. HBV could affect CD4 recovery either directly or
by increasing HIV replication [7]. Such changes point
out the importance of screening for HBV co-infection
regardless of the individual’s CD4 cell level and consider
management options for co-infected cases. Additional
parameters to consider include old age (Adjusted P =
0.02 [ARR: 2.47; 95% CI: (1.14, 5.3)]) and rural resi-
dence (Adjusted P = 0.00 [ARR: 2.58; 95% CI: (1.41,
4.73)]) both of which were found to independently halt
immune recovery. The consequence of older age could
be explained by a possible decrease in memory T-cells
and lower naïve CD4 cell production in the course of
time [17].
In HAART-initiated cohort, the effect is halted or in-
significantly reversed. Individuals with a positive HBsAg
test had relatively a higher mean CD4 cell count than
those with negative HBsAg test result, 262 cells/mm3 and
248 cells/mm3 respectively. Though a slight increase in
mean CD4 cell count was observed in HBsAg sero-posi-
tive individuals, the difference was not statistically sig-
nificant (P > 0.05). The repression of the HBV effect on
CD4 recovery after initiation of ART could be the result
of boosting immunity and a consequent diminution of the
HBV suppressive action. In the study of Chang and col-
leagues, HBV was found to have no effect on CD4 cell
loss [18]. In Thailand, a cohort study showed that CD4
lymphocyte increases were similar regardless of hepatitis
B status. A similar absolute CD4 cell rise between
HBsAg positive and negative individuals who are started
HAART was also found in Nigeria [6,15,16,19]. In this
group high baseline CD4 cell level (>50 cells/mm3) and
long duration of therapy (more than 2 years) were found
to boost patients CD4 cells, (P < 0.001). A unit increase
in baseline CD4 cell count will result in a 0.56 increase
in each CD4 cell count after initiation of HAART (cor-
relation coefficient, r = 0.56, P < 0.00). The type of pri-
mary regimen a patient start with did not have an effect
on the expected immune recovery, a critical finding for
clearing the confusion for putting regimen preferences
based on their difference on effective increment of CD4
cells. Other studies reported similar findings [17,20] so
physicians and patients should select the type of regimen
based on the adverse effect and contraindication profile
of treatment regimens but their difference in increasing
CD4 cell counts.
In the current study, prevalence of HBV was also as-
sessed in the two cohorts. Accordingly the prevalence of
HBV co infection was two times higher in HAART initi-
ated cohort, 5.3% versus 2.6%), a rate comparable with
the prevalence in the general population and other studies
done elsewhere. In a study done in Thailand, a chronic
HBV prevalence of 8.7% was reported among patients
receiving ART, consistent with the population prevalence
of Thailand (5% - 10%) [6]. Though it is difficult to ex-
plain the higher rate of HBsAg positivity among ART
initiated individuals, it may be explained by the fact that
a nucleoside anti HBV drug like lamivudine requires a
long term treatment to achieve HBsAg clearance or sero-
conversion to anti-HBsAg. After short-term treatment,
clearance could be achieved only in <5% of patients [21].
So if complete suppression was not achieved during
treatment, then rather quickly resistance commences. It is
reported that within the first year of treatment, 20% pa-
tients on lamivudine may develop mutation resulting in
loss of activity on HBV [18]. In addition HIV could also
reduce efficacy of anti-HBV therapy, including the risk
of lamivudine resistance and decreased response to In-
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Hepatitis B Virus Co-Infection: Yet Another Reason for Early Initiation of Treatment in HIV Infected Individuals
[7]. In addition, we reported that type of first
line regimen lacks association in contrary to the expected
effect of Lamivudine on HBV clearance. In addition we
have found that though only 25 (6%) of the total 380
ART initiated study groups were taking TDF-3TC com-
bined regimen, they accounted for 10% of HBsAg posi-
tive individuals, high proportion than any other regimen.
As we recalled otherwise this finding challenged impor-
tance of combination therapy containing tenofovir and
lamivudine as part of combination antiretroviral treat-
ment as it is superior in terms of HBV DNA suppression
than was tenofovir or lamivudine administered alone.
Since the mean duration of ART follow up was 28
months (more than 2 years), it was possible to explain
such findings with emergence of mutant strains [7,15,18,
21,22]. But emergence of resistant mutation should be
decided after a detectable HBV viral load measured as
HBV DNA copies in serum or plasma.
5. Conclusion
This study analyzes the effect of HBV co-infection in
HIV patients on immune recovery before and after initia-
tion of HAART. We have shown that HBV co-infection
has a significant and immediate negative effect on CD4
cell count and affiliated immune recovery before HAA-
RT but such effects subside after initiation of the anti-
HIV treatment. As a result, HBV infection is another
important issue to consider for rapidly initiating HAART
among HIV-infected individuals in chronic care. Whe-
ther such drug resistance strains of HBV do exist, as also
reported by other studies, as well as its effect on immune
recovery, CD4 cell count requires further studies.
6. Acknowledgements
The authors thank Debre Berhan University for financial
support, Debre Berhan Hospital and health centers and
staff, and the study participants for their participation.
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