Immunovirological and Biochemical Changes in Nigerian Patients with Hepatitis B Coinfection on Antiretroviral Therapy

doi:10.4236/wja.2011.12006

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World Journal of AIDS, 2011, 1, 31-36

doi:10.4236/wja.2011.12006 Published Online June 2011 (http://www.SciRP.org/journal/wja)

Immunovirological and Biochemical Changes in

Nigerian Patients with Hepatitis B Coinfection on

Antiretroviral Therapy

Jesse Abiodun Otegbayo1, Titilola Stella Akingbola2, Joshua Odunayo Akinyemi3,

Kayode Solomon Adedapo4, Georgina Njideka Odaibo5, Yetunde Adebisi Aken Óva2,

David Olufemi Olaleye5, Isaac Folorunsho Adewole7, Robert Murphy8, Phylis Kanki9

1Departments of Medicine, University of Ibadan, Ibadan, Nigeria; 2Department of Haematology, University of Ibadan, Ibadan, Nige-

ria; 3Department of Epidemiology and Biostatistics, University of Ibadan, Ibadan, Nigeria; 4Department of Chemical Pathology,

University of Ibadan, Ibadan, Nigeria; 5Department of Virology, University of Ibadan, Ibadan, Nigeria; 6Department of Haematology,

University of Ibadan, Ibadan, Nigeria; 7Department of Obstetrics and Gynaecology, University of Ibadan, Ibadan, Nigeria;

8Department of Infectious Diseases, North-western University Feinberg School of Medicine, Chicago, USA; 9Department of cancer

Biology, Harvard School of Public Health, Harvard University, Boston, USA.

Email: [email protected]

Received April 3rd, 2011; Revised May 3rd, 2011; Accepted May 24th, 2011.

ABSTRACT

Hepatitis B virus (HBV) co-infection with HIV is high among Nigerians. Some studies have suggested impaired CD4

recovery among coinfected patients compared to the HIV mono infected. This retrospective study of treatment-naïve

HIV infected patients was aimed at determining the trend of changes in CD4+ counts, HIV-RNA, renal and liver func-

tion tests in response to combined antiretroviral therapy (CART). A questionnaire was utilised to extract clinical and

laboratory da ta of HBV co infected HIV /AIDS patients before treatment and at six, twelve and eighteen months of ther-

apy with CART. Findings were compared to those of HIV mono infected. Relevant statistical instruments were used to

analyse for comparisons of means of Log10 HIV viral load and CD4 count using SPSS package 15.0. All levels of sig-

nificance were at 5%. Two thousand five hundred and sixty two patients were analysed. Of these, 354 (13.8%) were

HBsAg positive. Majority (63.1%) were females. Most of the recruited patients were on combivir and nevirapine. The

median CD4 count fo r the HBsAg negative was 104 cells/(mm3 IQR 34-171) and it was significantly higher than those

of the positive (91 cells/mm3) (p < 0.05). ALT and AST were higher among HBsAg positives, while urea and creatinine

levels were similar. The median change in CD4 count from baseline and during the course of therapy were similar in

the two groups. S imilarly, virological responses were not different in the two g roups at the various time points. In con-

clusion no significant difference in the rate of CD4 recovery and HIV-RNA decline in among coinfected and monoin-

fected HIV patients at different stages of therapy.

Keywords: Hepatitis B, Coinfection, CD4, Viral Load, Antiretroviral, Nigeria

1. Introduction

Hepatitis B virus (HBV) is a common major endemic

infection in Nigeria [1,2] and its association with com-

mon major liver diseases is well established in our envi-

ronment [3,4] as in other parts of the world. HIV/AIDS

continue to receive significant attention and a sizeable

proportion of the health care budget because of the yet to

be conquered pandemic. Previous studies in Nigeria have

shown a significant hepatitis B and C virus co-infection

with HIV infection [5,6]. These studies however showed

that hepatitis C, either as mono-infection or as co-

infection with HIV infection is relatively low compared

with HBV. Many of the antiretroviral drugs in current

use are associated with hepatotoxicity among other

side-effects. Hepatotoxicity of antiretroviral drugs espe-

cially co-infected patients with hepatitis viruses is a ma-

jor concern, with increasing incidence of liver lidease [7].

Some studies have addressed the immunological (CD4+)

and viral (HIV-RNA) responses in HIV/AIDS patients on

combined antiretroviral therapy (CART). Micheloud et al.

in their study among HCV-coinfected paediatric patients

32 Immunovirological and Biochemical Changes in Nigerian Patients with Hepatitis B Coinfection on Antiretroviral Therapy

found no difference in clinical, immunological and viral

response to CART over a six year period, save for in-

creased transaminases among HCV coinfected [8]. A

meta-analysis had shown that patients with HIV-HCV

coinfection have less immune reconstitution, as deter-

mined by CD4 cell count after 48 weeks of CART, than

patients with HIV monoinfection [9] suggesting some

influence of hepatitis C on immunologic recovery in HIV

infection. Clinical progression of HIV-1 disease after

starting potent antiretroviral therapy is accelerated by

concomitant infection with HCV. De Luca et al. con-

cluded in their study that compared with patients without

HCV coinfection, coinfected patients showed impaired

CD4+ cell recovery, despite similar virologic response to

HIV-1 therapy [10]. Since HBV is the most important

co-infection among Nigerians, we embarked on a retro-

spective study of CART-naive HIV infected patients.

The objective of the study was to determine the trend of

changes in CD4+ counts, HIV-RNA load as well as bio-

chemical, renal and liver function tests in response to

CART.

2. Materials and Methods

The database of the PEPFAR clinic at the University

College Hospital, Ibadan, Nigeria was searched between

January 2006 and December 2007 to retrieve the pre-

sented data. The total number of patients on CART on

the PEPFAR database at the time of data extraction was

4354 as at December 2007. A questionnaire was de-

signed to extract the clinical data, liver function tests,

CD4+ counts and HIV viral load as well as the antiretro-

viral combination of patients who were HBV-coinfected

and compare with those who were mono infected with

HIV. Hepatitis B surface antigen was detected from sera

using commercially available 3rd generation ELISA

technique (ABBOT Murex, Germany), while HIV anti-

body was initially detected by ELISA test followed by

confirmation test using the Western blot hybridization.

HIV-RNA quantification was by reverse transcriptase

polymerase chain reaction (RT-PCR), with a lower de-

tection rate of 400 copies/ml. All patients with HIV were

tested for HBsAg at first visit, but HBeAg, anti-HBeAg

and HBV-DNA were not determined. The results were

noted at entry (baseline) before commencement of CART.

HIV-RNA, CD4+ counts, ALT, AST, urea and creatinine

were then determined at six, twelve and eighteen months

respectively. Only patients with HIV-1 and HIV-2 with

detectable HIV-RNA and CD4+ count of ≤ 250 cells/ul

were included in the study. Patients who were anti-HCV

positive were excluded. Also excluded were those that

had missing CD4, ALT and AST or were non-compliant

with medication and those who were not able to do CD4

count at the time of entry due to equipment breakdown.

2.1. Statistical Methods

Quantitative variables were assessed for normality using

visual inspection of box-plots and normal probability

plots. The Chi square test was used to assess differences

in frequencies for categorical variables. Levene’s statistic

was used to assess equality of variance between groups

before independent two-sample tests for comparisons of

means of Log10 HIV viral load at baseline. Given the sig-

nificant non-normality of CD4 count and liver function

test results, a non-parametric two-sample (Mann-

Whitney) test was performed to determine differences in

their distribution between HBsAg status. Six hundred

and sixteen cases with missen values (for follow up CD4

count/Viral load, AST/ALT) were excluded list wise

automatically by the statistical software. The generalized

linear model repeated measures analysis was performed

to assess the effect of HBsAg status on treatment over

time. Sex, education, baseline AST and ALT were ad-

justed for, and all statistical tests were carried out at the

5% significance level using SPSS 15.0. Ethical approval

was obtained from the Joint University College Hospital,

Ibadan/University of Ibadan Institutional Review Board.

3. Results

3.1. Socio-Demographic and Clinical

Characteristics

Two thousand five hundred and sixty two patients who

had sufficient retrievable data were included in the

analysis. Of the 2562 patients, 354 (13.8%) were HBsAg

positive. Majority (63.1%) were females. In terms of

educational attainment, secondary (37.9%) and primary

(29.7%) were the most common. A little above half

(58.1%) were married. Table 1 shows the socio- demo-

graphic and clinical characteristics of the patients ac-

cording to the HBsAg status. The mean ages were (36 +

8.9) years and (37.1 + 9.9) years for the HBsAg positive

and negative patients respectively (p > 0.05). There is a

higher proportion of males (48.3%) in the HBsAg posi-

tive group than in the HBsAg negative (35.1%). (p <

0.05). HBsAg positivity was also found to be higher

among those with primary (32.9%) and secondary

(41.7%) level education (p < 0.05).

The median CD4 count for the HBsAg negative was

104 cells/mm3 (IQR 34-171) and it was significantly

higher than those of the positive (91 cells/mm3) (p <

0.05). Similar pattern was observed for ALT and AST

with the HBsAg negative recording significantly lower

values. Urea and creatinine levels did not show any sig-

nificant difference between the two groups of patients.

3.2. Immunological and Virological Response

The median change in CD4 count from baseline time was

Immunovirological and Biochemical Changes in Nigerian Patients with Hepatitis B Coinfection on Antiretroviral Therapy

similar in the two groups (Figure 1). At 6 months, the

median change was 143 cells/mm3 and 148 cells/mm3 for

the negative and positive respectively. Although the me-

to adjust for some baseline characteristics that differs be-

tween the groups. Results from the model shows that nei-

ther of the covariates nor HBsAg status affects CD4 count

recovery. HBV status, education, ALT and AST all did

not affect CD4 count recovery (Table 2).

dian change at 18 months was higher for the positives

(218 cells/mm3) than negatives (206 cells/mm3), the dif-

ference did not attain statistical significance (p > 0.05). A The virological response was similar in the two groups

at the various time points (Figure 2). At 6 months, the generalized linear model was fitted for CD4 count change

Table 1. Clinical and demographic characteristics of subjects.

Characteristic HBV+ (n = 354) HBV– (n = 2208) p-value

Age in Yrs Mean(SD) 36.1 (8.9) 37.1 (9.9) 0.076

Sex

Male

48.3

35.1

Female 51.7 64.9

0.001

Education

None

5.2

9.7

Primary 32.9 29.2

Secondary 41.7 37.3

Tertiary 20.1 23.8

0.011

Marital status

Divorced

4.6

4.3

Married 59.8 57.9

Separated 12.3 10.9

Single 13.7 13.5

Widowed 9.7 13.4

0.415

Baseline

CD4 count, Median (IQR)

91.5 (32 - 152)

104 (34 - 171) 0.02

Log

10 Viral Load, Mean (SD) 5.029 (0.85) 5.044 (0.91) 0.787

AST, Median (IQR) 49.0 (33.8 - 69.2) 40.0 (29.0 - 63.0) 0.005

ALT, Median (IQR) 31.0 (20 - 40) 27.0 (17 - 41) 0.004

Urea, Median (IQR) 19.0 (15.0 - 28.0) 19.0 (14.0 - 28.0) 0.731

Creatinine, Median (IQR) 0.8 (0.6 - 1.0) 0.8 (0.6 - 1.0) 0.281

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

6 month12 month18 month

Time period

Percentage with undetectable viral load

HBV+

HBV-

Figure 1. Proportion of patients by HBV infection status who achieved viral suppression.

Immunovirological and Biochemical Changes in Nigerian Patients with Hepatitis B Coinfection on Antiretroviral Therapy

percentage of patients who had achieved viral suppression

(HIV RNA level < 500 copies/mL) was 46.7% in the

negative group and 43.3% in the positive group (p > 0.05).

The percentages at 18 months were 71.0% and 68.8% for

the negatives and positives respectively. Repeated meas-

ures analysis showed that HBsAg status did not have any

effect on viral suppression over time (Table 2).

3.3. AST, ALT, Urea and Creatinine

At baseline, ALT and AST levels were higher for the

HBsAg positive patients (p < 0.05). The levels of these

parameters at 6, 12 and 18 months are shown in Table 3.

at the time points, these parameters were similar for the

two groups of patients. Majority of the monoinfected

Table 2. Summary results for GLM repeated measures model for CD4 count and Log10 RNA Viral Load over time.

CD4 count Log10 RNA Viral Load

Variable Model coefficient (β) 95% Confidence Interval

for β Model coefficient (β) 95% Confidence Interval for β

Baseline ALT 0.16 –0.60 - 0.92 0.003 –0.001 - 0.007

Baseline AST –0.06 –0.42 - 0.30 –0.001 –0.003 - 0.001

HBV 12.79 –33.08 - 58.65 0.063 –0.192 - 0.319

Gender 55.78 22.52 - 89.04* –0.002 –0.187 - 0.183

Education 10.35 –6.69 - 27.39 –0.002 –0.137 - 0.054

Marital Status –8.37 –25.52 - 4.7 –0.017 –0.09 - 0.056

Baseline CD4 0.87 0.69 - 1.00* –0.001 –0.002 - 003

Baseline Log10 RNA Viral

Load 25.85 3.94 - 47.75* –0.014 –0.135 - 0.106

HAART regimen 40.49 –17.42 - 98.39 –0.019 –0.353 - 0.314

* p < 0.05; Model R2 = 0.216

HBsAg

PosNeg

Change in CD4 Count from baseline (cells/cubic mm)

1,400

1,200

1,000

800

600

400

200

-200

-400

-600

18 mths

12 mths

6 mths

Figure 2. Change in CD4 counts from baseline.

Table 3. Laboratory parameters of subjects over time by HBV status.

Characteristic 6 month 12 month 18 month

HBV+ HBV– p-value HBV+ HBV– p-valueHBV+ HBV– p-value

ALT 30.0 (19 - 42) 27.0 (20 - 41) 0.689 26.0 (16.0 - 36.8)23.0 (15.8 - 39.3)0.692 16.0 (15.0 - 31.8) 23.5 (16.0 - 30.8)0.860

AST 41.0 (30 - 68) 35.0 (26 - 49) 0.131 NA NA NA NA

Urea 21.0 (14 - 26) 18.0 (14 - 24) 0.338 18.5 (13.5 -26.5)20 (13.0 - 24.5)0.335 20.0 (18.0 - 31.0) 21.5 (13.3 - 30.0)0.865

Creatinine 1.0 (0.8 - 1.1) 0.9 (0.7 - 1.0) 0.426 0.85 (0.7 - 1.0)0.9 (0.7 - 1.0)0.075 0.6 (0.5 - 1.0) 0.7 (0.5 - 1.1) 0.224

Median (IQR).

Immunovirological and Biochemical Changes in Nigerian Patients with Hepatitis B Coinfection on Antiretroviral Therapy 35

patients were on combivir and nevirapine, while the coin-

fected patients were mainly on truvada and nevirapine.

4. Discussion

This study has further shown a high HBV coinfection

rate among our patient cohorts as previously noted by us

and other authors in Africa [6,11,12] but higher than

values obtained in the Western world with lower inci-

dence of HBV [13,14]. The preponderance of the female

gender had been suggested to be due to the fact that

women may be more sensitive to changes in their health

and probably socioculturally conditioned to seek health

care more than men [6]. The significantly higher coinfec-

tion among men compared with women in spite of a

predominant female gender affected with HIV is likely a

reflection of HBV prevalence among the general popula-

tion which has been noted to be higher amongst men [15].

The lower prevalence of coinfection among the better

educated individuals generally could be due to the level

of awareness that may be associated with education and

therefore behaviours and practices that may reduce HBV

transmission [16]. It is however surprising that no dif-

ference in HBV prevalence was found across the differ-

ent marital status. It would have been expected, arguably

though, that divorcees and the unmarried would be more

exposed to transmission of HBV sexually. This phe-

nomenon might be confirming the well known fact that

HBV transmission is mainly horizontal in childhood

among Africans. Ola et al. however found out that HIV

monoinfection is commoner among married people

(70.4%), suggesting heterosexual transmission of HIV in

our environment as previously documented [16]. It

would appear that the immunological status of HBV

coinfection and monoinfection is similar, as evidenced

by the similar CD4 counts in HIV monoinfected and

HIV-coinfected at the start of CART. Similar observa-

tions were made Idoko et al. in the Northern part of Ni-

geria [17]. It is evident from our study that CART has no

influence on CD4 recovery regardless of HBV status

with time and duration of therapy. Idoko et al. however

found an association with Hepatitis B e antigen (HBeAg)

and CD4 T-cell recovery and HIV-RNA clearance [17].

Apart from the higher baseline values of transaminases

among HBV coinfected patients, no temporal difference

was observed in the normalization of ALT, urea and

creatinine among coinfected and monoinfected patients,

suggesting that HBV status did not significantly influ-

ence the immunovirological response to CART, renal

function and transaminase levels. The retrospective na-

ture of this study and our inability to determine the date

of acquisition of both HIV and HBV (acute or chronic),

as well as unavailability of HBV DNA are some of the

limitations of our study. The exclusion of subjects with

missen data may also affect the result as it is unclear

whether such cases were missing for reasons connected

with the study outcome.

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