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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 53  |  Issue : 4  |  Page : 745-749
CD4 cell count recovery in HIV/TB co-infected patients versus TB uninfected HIV patients


Department of Internal Medicine, PGIMER, Chandigarh, India

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Date of Web Publication27-Oct-2010
 

   Abstract 

Background: There is lack of data comparing the improvement in CD4 count following antitubercular (ATT) and antiretroviral therapy (ART) in patients presenting with Human Immunodeficiency Virus/Tuberculosis (HIV/TB) dual infection compared with CD4 matched cohort of TB uninfected HIV patients initiated on ART. We sought to test the hypothesis; TB additionally contributes to reduction in CD4 count in HIV/TB co-infected patients and this would result in greater improvement in count following treatment compared with CD4 matched TB uninfected individuals. Materials and Methods: In a retrospective cohort study design we studied the change in CD4 cell counts in two groups of patients - those with CD4 cell count >100 cells / mm 3 (Group 1) and <100/mm 3 (Group 2) at presentation. In each group the change in CD4 cell count in dually infected patients following six-month ATT and ART was compared to cohorts of CD4 matched TB uninfected patients initiated on ART. Results: In Group 1 (52 patients) dually infected subjects' CD4 count improved from 150 cells/ mm 3 to 345 cells/mm 3 (P=0.001). In the control TB uninfected patients, the change was from 159 cells/mm 3 to 317 cells/mm 3 (P=0.001). Additional improvement in dually infected patients compared to the control group was not statistically significant (P=0.24). In Group 2 (65 patients) dually infected subjects count improved from 49 cells/mm3 to 249 cells/mm 3 (P=0.001) where as in control TB uninfected patients improvement was from 50 cells/ mm 3 to 205 cells/mm 3 (P=0.001), there being statistically significant additional improvement in dually infected subjects (P=0.01). Conclusion: Greater increment in CD4 counts with ATT and ART in dually infected patients suggests that TB additionally influences the reduction of CD4 counts in HIV patients.

Keywords: Antitubercular therapy, antiretroviral therapy, CD4 cell count, HIV/TB dual infection

How to cite this article:
Wanchu A, Kuttiatt V S, Sharma A, Singh S, Varma S. CD4 cell count recovery in HIV/TB co-infected patients versus TB uninfected HIV patients. Indian J Pathol Microbiol 2010;53:745-9

How to cite this URL:
Wanchu A, Kuttiatt V S, Sharma A, Singh S, Varma S. CD4 cell count recovery in HIV/TB co-infected patients versus TB uninfected HIV patients. Indian J Pathol Microbiol [serial online] 2010 [cited 2019 Dec 11];53:745-9. Available from: http://www.ijpmonline.org/text.asp?2010/53/4/745/72070



   Introduction Top


Tuberculosis is a common opportunistic infection and a leading cause of death in HIV patients worldwide, especially in developing countries. HIV infected patients with latent TB infection are at risk of reactivation and those with recently acquired infection are at high risk of progressive primary TB. There is clinical and experimental evidence suggesting that active TB accelerate the course of HIV disease. [1],[2] TB provides a milieu of continuous cellular activation and irregularities in cytokine and chemokine circuits that are permissive of HIV replication. [3] However, TB in HIV infected subjects appears to remain as responsive to ATT as that in HIV uninfected subjects. [4] Previous study from our centre showed that CD4 counts improved significantly following ATT and ART in HIV/TB co-infected individuals. [5] There is lack of data studying the improvement in CD4 counts with ATT and ART in patients presenting with dual infection compared with a CD4 matched cohort of TB uninfected HIV patients initiated on ART.

We hypothesized that since TB infection contributes to additional reduction in CD4 cell counts in HIV patients presenting with dual infection, there would be greater improvement in CD4 count following ART and ATT when compared to TB uninfected HIV patients initiated on ART. We tested this hypothesis in a retrospective cohort study design. We studied the change in CD4 counts in dually infected subjects following ATT and ART compared with a CD4 matched cohort of HIV patients not infected with TB. Our attempt was to delineate the additional influence of TB in reduction of CD4 counts in HIV patients.


   Materials and Methods Top


This retrospective study was conducted at our tertiary care institute. Patients presenting with HIV infection are registered at this clinic and separate case files are maintained for each patient. Demographic and clinical details at presentation and also during follow-up visits were recorded in these files. Patients who presented with dual infection were identified by screening these records and clinical and demographic details of each patient collected. Patients with dual infection who had received ATT and ART were categorized into two groups based on the CD4 count at presentation - Group 1A [those with CD4 count >100 cells /mm 3 (100-250 cells/mm 3 )] and Group 2a [those with CD4 count < 100 cells/mm 3 ]. Group 1a and 2a were compared with CD4 matched cohorts of TB uninfected HIV patients who received only ART - Group 1b and 2b respectively [Figure 1]. Patients in Group 1b and 2b were also identified from the same clinic and clinical and demographic details were collected from the case files. There was a small group of TB co-infected individuals who had received ATT but not ART due to various reasons (Group 3). This group included patients who did not fulfill criteria for initiation of ART (high CD4 count), patients advised ART and ATT but turned up for ART only after completion of ATT and patients treated with ATT at peripheral centers and later referred to our center for initiation of ART.
Figure 1 :Study design- retrospective cohort study

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The baseline characteristics of patients including age, gender, weight, type of TB, symptoms at presentation, duration of therapy,CD4 count at presentation and associated chronic medical disorders were noted from the case files. Patients in Group 1a and 2a received ATT and ART. CD4 matched control groups without TB infection (1b and 2b) received ART only. Changes in weight and CD4 count before and after six months of treatment were noted in all groups. Patients in all the above groups except Group 3 had not received ART or ATT before initiation of treatment at our center. In patients with dual infection, ATT was started first and ART initiated after one month. Patients who presented with sepsis, Pneumocystis jiroveci pneumonia and severe fungal infections were not included in the study as they are known to cause lymphopenia. Patients with TB received efavirenz based three-drug ART and Category I four drug ATT and TB uninfected patients received nevirapine based ART. Antiretroviral drugs are distributed free of cost from ART centre and ATT drugs from DOTS centre.

Diagnosis of HIV positivity was made by using ELISA kits as per national guidelines. [6] CD4 cell count was done using FACS counter. Pulmonary tuberculosis was diagnosed when either sputum smears were positive for AFB or X-ray was suggestive with lack of response to antibiotic therapy and strong clinical suspicion. Extrapulmonary TB was defined as the involvement of organs other than lungs like lymph node, pleura, pericardium, meninges, abdomen or bone. Diagnosis was based on histological proof or, radiological evidence or strong clinical suspicion. Empirical ATT was given to patients who had fever, constitutional symptoms, no localization on extensive evaluation and there was response to this therapeutic trial.

Statistical Analysis

Statistical analysis was performed using SPSS 16 soft ware package. Descriptive analysis was done for demographic and clinical data and the difference between variables at baseline and end of therapy was assessed by paired t-test. For comparison between the groups, independent t-test was used. P<0.05 was taken significant for all tests.


   Results Top


In Group 1a and 1b there were a total of 52 patients each. The baseline characteristics [Table 1] were comparable between the groups. There were more male patients in the co-infection group. In Group 1a, mean CD4 count improved from 150 cells/mm 3 to 345 (P=0.001) and mean weight changed from 49 Kg to 55 Kg (P=0.001). In Group 1b, mean CD4 count improved from 159 cells/mm 3 to 317 cells/mm 3 (P=0.001) and mean weight improved from 52 Kg to 59 Kg (P=0.001). When compared between the groups, the difference in improvement in CD4 count was not significant (P=0.24) [Table 2].
Table 1 :Baseline characteristics of patients


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Table 2 :Change in parameters following treatment


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In Group 2a and 2b there were 65 patients each. The baseline characteristics [Table 1] were comparable between the groups. Here also there were more male patients in the co-infection group. In group 2a, mean CD4 count improved from 49 cells/mm 3 to 249 cells/mm 3 (P=0.001) and mean weight from 52 Kg to 60 Kg (P=0.001). Group 2b showed improvement in mean CD4 count from the baseline value of 50 cells/mm 3 to 205 cells/mm 3 (P=0.001) and mean weight changed from 51 Kg to 58 Kg (P=0.001). When compared between the groups there was more increment in mean CD4 count in Group 2b, the difference being statistically significant (P<0.01) [Table 2].

In Group 3 (20 patients, M:F-17: 3) who were dually infected but received only ATT, mean CD4 count changed from 255 cells/mm 3 to 271 cells/mm 3 . The improvement in count was seen in 12 patients only. In rest of the patients either there was no change or the count deteriorated.


   Discussion Top


In this retrospective cohort study we compared the change in CD4 count following ATT and ART in HIV/TB co-infected patients with a CD4 matched cohort of TB uninfected patients initiated on ART. There was greater improvement in CD4 count in patients with dual infection, the difference reaching statistical significance in patients with CD4 count<100 cells/ mm 3 at presentation. To our knowledge there is no published study analyzing CD4 cell recovery in HIV/TB co-infection compared with a CD4 cell count matched cohort of HIV patients uninfected with TB. Additional increment in CD4 count in patients with co-infection following treatment suggests that CD4 suppression at the onset of TB may be the direct result of mycobacterium growth and inflammation as well as interaction between TB and HIV in addition to the effect of HIV alone.

CD4 lymphocyte depletion is known to occur in TB patients not infected by HIV[7],[8] and become normalized following ATT. [9],[10] In a series of 85 patients with TB not infected by HIV, 37 showed low CD4 cell count and 48 had normal counts. [11] Disease severity was associated with greater depression in total lymphocyte as well as CD4 counts. CD4:CD8 ratio remained normal in 90% of patients with tuberculosis.

Previous studies carried out in dually infected subjects not receiving ART show variable results with regard to change in CD4 counts following ATT. [11],[12],[13],[14] In a prospective study conducted in Chennai, dually infected subjects treated with ATT and not receiving ART showed no change in CD4 counts but CD4 percentage decreased. [11] In South African patients with dual infection not receiving ART, median CD4 count improved from 186 cells/mm 3 at baseline to 239 cells/mm 3 after 6 months of ATT but the change was not statistically significant. [12] In the prospective study by Kalou M, et al. CD4 count changed from 393 cells/mm 3 at baseline to 370 cells/mm 3 at 12 months of follow-up. [13] In the study by Elliott AM, et al. in HIV patients with pleural TB, CD4 count improved following ATT but did not reach statistical significance. [14]

There are few studies comparing the change in CD4 count before and after ATT in dually infected subjects in comparison to TB patients not infected by HIV. In the study by Martin DJ et al. CD4 count increased significantly in both cohorts of HIV/TB group and TB group following routine ATT. [15] But the Thai study showed contrary results. [16] The CD4 cell count among non HIV-infected patients was 510 cells/mm 3 and increased to 867 cells/mm 3 after sixth month of therapy. Among HIV-infected patients, the CD4 cell count was 64 cells/mm 3 and decreased to 35 cells/mm 3 at sixth month of therapy. But the small sample size was a major limitation of the Thai study. The improvement in CD4 count following ATT and ART and no change following ATT alone may indicate a role for immune reconstitution following ART especially in patients with very low CD4 count. Development of TB infection is associated with increased HIV replication. In a study on patients with dual infection in the United States, TB-related increases in HIV-1 RNA in plasma decreased after 6 months of ATT. [17] But in African patients with co-infection, HIV-1 viral loads remained elevated even after successful ATT. [12],[13],[18]

Basic research also provides evidence that in dually infected subjects TB adds to the immunologic deterioration caused by HIV. HIV-1/TB co-infection has long been associated with generalized immune activation. [17] Patients with co-infection show elevated levels of proinflammatory cytokines and increased expression of cellular activation markers. [19] ATT results in decrease in levels of some of these markers of immune activation and consequently a rise in CD4 cell count is expected. [20]

Our study has the limitations of a retrospective study design. We did not have data on viral load in our patients as routine viral load testing is not available. Even with its limitations, our study provides some evidence in the clinical setting that TB additionally influences the reduction in CD4 cell count in HIV patients. A prospective study with three limbs including patients with TB infection alone, HIV infection alone and dual infection can confirm the findings in this retrospective study.

In HIV/TB co-infected individuals TB additionally contribute to reduction in CD4 counts as evidenced by greater improvement in CD4 counts in these patients following 6 months treatment with ATT and ART when compared to CD4 cell count matched cohort of TB uninfected HIV patients initiated on ART.

 
   References Top

1.Whalen C, Horsburgh CR, Hom D, Lahart C, Simberkoff M, Ellner J, et al. Accelerated course of human immunodeficiency virus infection after tuberculosis. Am J Respir Crit Care Med 1995;151:129-35.  Back to cited text no. 1
    
2.Shafer RW, Edlin BR. Tuberculosis in patients infected with human immunodeficiency virus: perspective on the past decade. Clin Infect Dis 1996;22:683-704.  Back to cited text no. 2
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4.Ackah AN, Coulibaly D, Digbeu H, Diallo K, Vetter KM, Coulibaly IM, et al. Response to treatment, mortality, and CD4 lymphocyte counts in HIV infected persons with tuberculosis in Abidjan, Cote d′Ivoire. Lancet 1995;345:607-10.  Back to cited text no. 4
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5.Sharma A, Wanchu A, Bansal V, Singh S, Varma S. Improvement in CD4 counts in HIV positive patients treated with HAART and antitubercular drugs: An observational study from North India. Indian J Pathol Microbiol 2007;50:905-7.  Back to cited text no. 5
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6.Available from: http://www.nacoonline.org [last accessed on 2009 Jul 12].  Back to cited text no. 6
    
7.Beck JS, Potts RC, Kardjito T, Grange JM. T4 lymphopenia in patients with active pulmonary tuberculosis. Clin Exp Immunol 1985;60:49-54.   Back to cited text no. 7
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8. Onwubalili JK, Edwards AJ, Palmer L. T4 lymphopenia in human tuberculosis. Tubercle 1987;68:195-200.  Back to cited text no. 8
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9.Turett GS, Telzak EE. Normalisation of CD4 T lymphocyte depletion in patients without HIV infection treated for tuberculosis. Chest 1994;105:1335-7.  Back to cited text no. 9
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10.Jones BE, Oo MM, Taikwel EK, Qian D, Kumar A, Maslow ER, et al. CD4 cell counts in human immunodeficiency virus negative patients with tuberculosis. Clin Inf Dis 1997;24:988-91.  Back to cited text no. 10
    
11.Swaminathan S, Deivanayagam CN, Rajasekaran S, Venkatesan P, Padmapriyadarsini C, Menon PA, et al. Long term follow up of HIV-infected patients with tuberculosis treated with 6 month intermittent short course chemotherapy. Natl Med J India 2008;21:3-8.  Back to cited text no. 11
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12.Morris L, Martin DJ, Bredell H, Nyoka SN, Sacks L, Pendle S, et al. Human Immunodeficiency virus-1 RNA levels and CD4 lymphocyte counts, during treatment for active tuberculosis in South African patients. J Infect Dis 2003;187:1967-71.  Back to cited text no. 12
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13.Kalou M, Sassan-Morokro M, Abouya L, Celestin B, Chantal M, Mathieu M, et al. Changes in HIV RNA viral load, CD4+ T-cell counts and levels of immune activation markers associated with anti-tuberculosis therapy and cotrimoxazole prophylaxis among HIV infected tuberculosis patients in Abidjan, Cote d′Ivoire. J Med Virol 2005;75:202-8.  Back to cited text no. 13
    
14.Elliott AM, Luzze H, Quigley MA, Nakiyingi JS, Kyaligonza S, Namujju JL, et al. A randomised double-blind placebo-controlled trial of the use of prednisolone as an adjunct to treatment in HIV-1 associated pleural tuberculosis. J Infect Dis 2004;190:869-78.  Back to cited text no. 14
    
15.Martin DJ, Sim JG, Sole GJ, Rymer L, Shalekoff S, van Niekerk AB, et al. CD4+ lymphocyte count in African patients co-infected with HIV and tuberculosis. J Acquir Immune Defic Syndr Hum Retrovirol 1995;8:386-91.  Back to cited text no. 15
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16.Saenghirunvattana S. CD4+ T counts with a course of antituberculous therapy in healthy and HIV infected patients. J Med Assoc Thai 1996;79:246-8.  Back to cited text no. 16
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17.Goletti D, Weissman D, Jackson RW, Graham MN, Vlahov D, Klein RS, et al. Effect of Mycobacterium tuberculosis on HIV replication. Role of immune activation. J Immunol 1996;157 : 1271-8.  Back to cited text no. 17
    
18.Kizza HM, Rodriguez B, Quinones-Mateu M, Aung H, Yen-Lieberman B, Starkey C, et al. Persistent replication of human immunodeficiency virus type 1 despite treatment of pulmonary tuberculosis in dually infected subjects. Clin Diagn Lab Immunol 2005;12:1298-304.   Back to cited text no. 18
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19.Wallis RS, Vjecha M, Amir-Tahmasseb M. Influence of tuberculosis on human immunodeficiency virus (HIV-1): enhanced cytokine expression and elevated beta 2 microglobulin in HIV-1 associated tuberculosis. J Infect Dis 1993;167:43-8.  Back to cited text no. 19
    
20.Lawn SD, Shattock RJ, Acheampong JW, Lal RB, Folks TM, Griffin GE, et al. Sustained plasma TNF alpha and HIV-1 load despite resolution of other parameters of immune activation during treatment of tuberculosis in Africans. AIDS 1999;13:2231-37.  Back to cited text no. 20
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Correspondence Address:
A Wanchu
Department of Internal Medicine, PGIMER, Chandigarh-160 023
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.72070

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