Study of CD4 counts recovery in TB-HIV coinfected patients versus TB uninfected HIV positive patients after (six months) treatment

INTRODUCTION

Immune deficiency occurs in individuals infected with the human immunodeficiency virus (HIV) as a result of the depletion of cluster of differentiation 4 (CD4) + T lymphocytes.¹ Studies indicate that lower CD4 cell counts increase the risk of developing opportunistic infections, especially among HIV positive individuals.¹ Out of these, tuberculosis (TB) appears to be the most widespread; it also greatly adds to the burden of morbidity and mortality among HIV positive populations.¹

As per the 2020 Global TB Report, the risk of active TB in HIV infected individuals is 18 (15–21) times greater than in HIV-negative individuals, making TB a prevalent cause of mortality in this group.² CD4 counts give information on antiretroviral therapy (ART).¹ Further, CD4 counts are used to guide prophylaxis measures for opportunistic infections and these tests are done on HIV infected individuals every 6 months.¹

There is lack of data studying the improvement in CD4 counts in HIV-TB co-infected patients in comparison to TB uninfected HIV positive patients after initiation (6 months) of antituberculosis therapy (ATT) + ART. Hence, this study was carried out to estimate absolute CD4 counts and percentage recovery in TB-HIV coinfected patients versus TB uninfected HIV positive patients before initiation of ATT + ART/ART as well as to compare the CD4 counts and percentage recovery in TB-HIV coinfected patients versus TB uninfected HIV positive patients after (six months) initiation of ATT + ART/ART.

MATERIAL AND METHODS

This prospective observational study was carried out in the Department of Microbiology and the ART Centre at a 1532-bed tertiary care hospital in New Delhi from November 1, 2017, to March 31, 2019. Blood samples were collected at the Microbiology Department Integrated Counseling and Testing Centre (ICTC) from ART/ATT naïve (not on ART and ATT) HIV-positive patients who were coinfected with TB and TB uninfected HIV positive patients attending the hospital. We calculated a sample size of 50 in each group with a power of 90%, given the existing literature based on the study by Wanchu et al.³ (2010). Fifty HIV-positive patients and 50 HIV-positive patients coinfected with TB were taken as study groups. Drug compliance was ensured with regular follow-up of the included patients whenever they came to ART center and also telephonically. First-line drug regimen was started, that is, tenofovir, lamivudine, efavirenz in all the included patients; none of the patients developed any side effects with this regimen. ART was started after two weeks of ATT.

RESULTS

During the study period, from the total 100 patients included in the study, 2 patients died who were HIV positive and coinfected with TB, and 98 patients survived. Out of the 100 study patients, 50 had HIV-TB coinfection while 50 were suffering from HIV alone. The two patients who died had a very low CD4 count (10 cell/µL and 15 cell/µL, respectively) and severe weight loss. One died of cardiac arrest, while the other had respiratory failure.

Symptomatic distribution

It was observed that most of the patients in the study presented with symptoms of fever (48%), cough (13%), and diarrhea (11%). Other symptoms that were less commonly seen included weight loss (8%), body rash (5%), abdominal pain (4%), fatigue (4%), weakness (3%), body ache (2%), and dyspnea and loss of appetite (1%) [Figure 1].

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Figure 1:

Symptomatic distribution of patients in the study group.

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DISCUSSION

HIV-TB coinfection poses a significant health challenge, particularly in developing countries like India. Treating TB in conjunction with HIV can enhance the immune function of coinfected patients.⁴ In this research, we compared the changes in CD4 count after six months of ATT + ART/ART in TB-HIV coinfected patients and TB uninfected HIV positive patients, respectively.

Considering the total study group of 100 patients, the male to the female ratio was found to be 2.33:1. In HIV alone positive patients, 66% were males and 34% females, while in TB-HIV coinfected patients, 74% were males and 26% females (p-value of 0.383 by chi-squared test). In this study, we found male preponderance in both HIV alone and TB-HIV coinfected patients. Similar results were obtained in another study conducted in Northeast India where the preponderance of males were found.⁵ In concordance with this study, the Northeast India study also showed an insignificant p-value 0.16 for the difference in male to female ratio. Furthermore, a 2011 European study highlighted that TB-HIV coinfection was more prevalent in males, while a Brazilian study indicated a significant difference favoring males (p < 0.001).^6,7

The increased prevalence of TB-HIV coinfection in males may be linked to their higher likelihood of migrating for work, which results in greater exposure to Mycobacterium tuberculosis. Additionally, it’s important to highlight that the reactivation of TB is particularly frequent among individuals with HIV/AIDS.⁸

The mean age of TB-HIV coinfected patients was 34.36 years compared to 29.60 years in HIV patients. This age difference was statistically significant by T-test (p = 0.001). Similar findings have been reported in studies from Northeast India and Karnataka, indicating that TB-HIV coinfection tends to occur more frequently in older age groups.^5,9 A Nigerian study from 2014 found that TB-HIV coinfection was 2.7 times more prevalent in patients over 40 years old than in those under 25.¹⁰ Moreover, research from South Sudan noted a significant majority of HIV/TB coinfected patients in the 25–34 age bracket, a group that often bears familial responsibilities, thus increasing their likelihood of interacting with infected individuals.⁸

Mean weight of the patients who had HIV alone and who had TB-HIV coinfection was 55.68 years and 48.30 years, respectively. The difference was statistically significant with p = 0.001. Screening symptoms for TB, mainly in HIV-positive patients are fever, night sweat, cough, and weight loss. Weight loss is a major screening symptom of TB.¹ A study from Brazil showed a higher frequency of weight loss, that is, >10 kg in TB-HIV coinfected patients.¹¹

Out of the 100 study patients, two patients died and the rest survived during the study period. The two patients who died had TB-HIV coinfection (pulmonary TB). However, the results were not significant (p = 0.49). Our findings align with a study from Manipur that reported a predominance of pulmonary TB over extrapulmonary forms in HIV-positive patients, a trend also observed in African research.^12,13

In concordance with this study, several studies showed similar pattern of mortality, that is, high mortality in TB-HIV coinfected patients.^14–19 Both conditions that is, TB and HIV, accelerate the progression of each other and affect the cell-mediated immune system. In individuals with compromised immune systems, such as those living with HIV, the typical progression of TB is altered.²⁰ Latency period between infection and the onset of disease shortens, and those with HIV may develop active TB within just weeks to months as opposed to the usual timeline of years or even decades.²⁰

Analysis of the CD4 counts shows that the mean before starting ART in HIV alone patients was 330.42 and in TB-HIV coinfected patients, the mean before starting ATT + ART was 137.04. The findings were in correlation with the Centers for Disease Control and Prevention (CDC) classification of opportunistic infections in HIV in relation to CD4 counts, as per which TB occurs when CD4 counts are below 200 cells/µL.^1,21 The difference by both T-test and Mann-Whitney test between the mean of CD4 counts of HIV alone and TB-HIV coinfected patients was statistically significant (p = 0.001). A Nigerian study also found that TB as an opportunistic infection occurs when CD4 counts fall below this threshold.²¹ Another study from Ethiopia in 2020 reported a high incidence of TB in HIV-positive patients, especially in patients with CD4+ T cell count < 200 cells/µL.²²

The mean of CD4 counts after six months of ART in HIV alone patients was 422.54 cells/µL, while in TB-HIV coinfected patients, the mean was 376.88 cells/µL after six months of ATT + ART. But the difference was statistically insignificant (p-value of 0.242 and 0.486 by T-test and Mann-Whitney test, respectively). This may be due to the greater increase in CD4 counts after six months of ATT + ART in patients who were coinfected with TB in comparison to TB-uninfected HIV patients who were on ART alone.

The mean of changes in CD4 counts in HIV alone patients was 92.12 and the mean of changes in CD4 counts in TB-HIV coinfected patients was 234.64; so, there was less improvement in CD4 counts in HIV alone patients who were on ART in comparison to the TB-HIV coinfected patients who were on ATT + ART. When we compared the mean of changes in CD4 counts, we found that it was statistically significant with p-value < 0.001 by both T test and Mann-Whitney test. Further increase in CD4 count in patients with TB coinfection following treatment hints that the immune suppression observed at the onset of TB may result from both mycobacterial growth and the interaction between TB and HIV besides the effect of HIV alone. In correlation with this study, one more study conducted in 2010 in India also reported that there is a greater improvement in CD4 counts in HIV patients who are coinfected with TB and receive ATT + ART in comparison to HIV alone positive patients who receive only ART.³ Reduction in CD4 lymphocytes is known to occur in HIV negative TB patients and become normalized following ATT.^23–27 So, ATT also leads to improvement in CD4 counts in TB-HIV coinfected patients. In a study involving 85 patients with TB who were not infected with HIV, 37 exhibited low CD4 cell counts, while 48 had normal CD4 levels.²⁸

Research on patients with dual infections who were not receiving ART has reported varying outcomes regarding changes in CD4 counts after undergoing ATT.^28–31 In concordance to this study, a South African study showed the improvement in CD4 counts in TB-HIV coinfected patients following ATT, but the change in CD4 counts was not statistically significant.²⁹ A study conducted in Kampala, Uganda, involving HIV-positive patients with pleural TB, indicated an improvement in CD4 counts after ATT, although the change was not statistically significant.³⁰ The observed increase in CD4 counts following both ATT and ART suggests that immune reconstitution may occur after ART, especially in patients with initially low CD4 levels.³

Considering the recovery of patients out of the 50 HIV alone patients included in this study, 43 recovered, that is, they showed improvement in their CD4 counts after six months of ART, and seven did not recover. These seven patients showed a decline in their CD4 counts after six months of ART. Out of the 50 TB-HIV coinfected patients, 47 recovered, that is, they showed improvement in CD4 counts after six months of ATT + ART. So, 86% patients who had HIV alone and 94% patients who had TB-HIV coinfection showed improvement in their CD4 counts, but the difference was not statistically significant (p = 0.182 by chi-squared test). Those patients who did not show improvement in their CD4 counts were further tested for viral load. The viral load was found to be high in these patients and the patients were then put on second-line treatment. So, the reason for the treatment failure in these patients may be drug resistance.

The small sample size of our study is the major limitation of the study. Other limitations are that HIV viral load was not done for all the patients to rule out confounding factors and patients with other comorbidities were not included. Future research should consider a larger prospective study with distinct groups for TB only, HIV only, and TB-HIV coinfection to validate these findings and explore CD4 count improvements further. Hence, more studies are needed to see the pattern of CD4 counts improvement in TB-HIV coinfected patients in comparison to HIV alone patients.

CONCLUSION

This study indicates that TB-HIV coinfected patients treated with the combined ATT and ART experience showed greater improvements in CD4 counts compared to HIV-only patients receiving ART. We infer that in HIV/TB coinfected individuals, TB additionally contributes to a reduction in CD4 counts. So, the early diagnosis and treatment of TB in HIV-positive patients could enhance patient prognosis and reduce mortality rates.