The effect of tuberculosis on immune reconstitution among HIV patients on highly active antiretroviral therapy in Adigrat general hospital, eastern Tigrai, Ethiopia; 2019: a retrospective follow up study

Human Immunodeficiency Virus (HIV) infection is still a major public health problem in the globe. In countries of Sub-Sahara, there were about 23 million HIV infected people. Most of the infected Sub-Saharan patients had reported late to health facilities for treatment [1, 2]. HIV infection depletes immune cells especially CD4+ T lymphocytes [3]. Immune destruction due to HIV proceeds increased morbidity and mortality which may also be associated with different opportunistic infections and tuberculosis (TB) [4].

Globally, by the year 2017, there were about 20.9 million HIV patients estimated to receive highly active antiretroviral therapy (HAART) [5]. Antiretroviral drugs are targeted at inhibiting viral attachment and replication. Hence, leading to the recovery of immune function [3, 6]. HAART reduces HIV associated morbidity and mortality which in turn enables patients to have a productive life and stay longer. CD4+ T cell count is one of the important markers for assessing treatment response and immune recovery among HIV patients on HAART. World health organization (WHO) recommends that CD4+ T cell count should be performed before HAART, at 3, 6, 9 and 12 months after initiation of HAART. Determine the CD4+ cell counts at every follow-up time helps clinicians to confirm suspected treatment failure detected clinically and immunologically to provide necessary interventions (adherence support and HAART regimen switching) [6].

Among HIV infected patients in developing countries, TB remains a major public health problem [7]. Moreover, HIV is the most potent risk factor for TB. Additionally, TB is the leading cause of morbidity and mortality in HIV infected patients [8]. Among peoples of African countries, the prevalence of immunological failure to HAART medication is increased [9]. HIV/TB co-infected patients are less likely to have good recovery of CD4+ cells. However, studies assessing CD4+ T cells reconstitution of individuals on HAART have found to be poor CD4+ T cells recovery occured among patients who developed TB after initiating therapy [10, 11]. TB infection can also cause T lymphocytopenia in which the consequence is worsened due to HIV co-infection [12].

In Ethiopia, access to HAART started massively in 2005 [13]. The treatment has been successful as demonstrated by the improvement of survival and immune recovery [14, 15]. This makes HIV a manageable disease. Some studies indicated the level of adherence is suboptimal for patients on HAART ranging from 7 to 28% [16‐21]. Generally, the longer a person is failing HAART, the higher the mortality [22]. Monitoring immunological treatment response of HAART is challenging in resource-limited settings. Regular follow up of HAART among HIV patients detection and management of treatment failure is recommended [23, 24]. Although TB/HIV coinfection is a major public health problem in Ethiopia, there are few studies that have reported the effect of TB on immunological responses of HIV patients during HAART. Hence, assessing the effect of TB and other determinant factors on immune reconstitution of HIV patients will provide information for clinicians for appropriate management of TB/HIV co-infected patients.

In this study, the overall rate of immune reconstitution failure among HIV patients on HAART is 24.7% (97/393). This is similar to studies reported from Tanzania, 25% [26] and China, 18.4% [27]. However, studies from Northern Ethiopia, 6.5% [28], Liberia, 5.1% [29], Southern Ethiopia, 11.5% [30], Southwestern Ethiopia, 9.8% [31], Addis Ababa, 15.7 and 15% [32, 33], Northwestern Ethiopia 15.1% [34] and Colombia, 14% [35] reported lower immunological failure. To the contrary, other studies from Kenya, 64.4% [36], Thailand, 33.5% [37] and Nepal, 35% [38] reported higher immunological failure than this study. This variation in immunological response might be attributed to the differences in adherence to HAART. It might also be related to the WHO guideline which varies over time. In our study, we defined immunological failure, as the fall of CD4 + T cell count to baseline or below, or persistently low CD4+ T cell count (below 100 cells/μL) [6]. However, reports from the above studies [30‐32, 35, 36] defined immunological failure as fall of CD4+ T cell count to baseline or below severe immune suppression (CD4+ T cell count < 200 cells/μL) [38], 50% fall from on-treatment peak value [33, 36] or 30% or above fall from on treatment peak value [26, 36]. Failure to achieve CD4+ T cell count above 350 cells/μL [27, 37].

In this study, the rate of immunological failure was 2.966 per 100 PY. This is in line with previous reports from Latin America, 2.57 per 100 PY [39]. However, the present study reported lower immune reconstitution failure than the studies from Northwestern Ethiopia, 8.7 per 100 PY [40] and Debremarkos, Ethiopia, 8 per 100 PY [41]. This variation might be due to the differences in adherence towards ART drugs, the WHO guidelines to define immunological failure/ success and the presence of opportunistic infections.

Two hundred eighty-five (72.5%) of our study participants had good adherence to treatment. Similar study reported from Southern Ethiopia, 81.8% [30], Northwestern Ethiopia, 82.7% [34], New Guinea, 82.4% [42] and Addis Ababa, Ethiopia, 78.5% [32]. However, our study reported lower treatment adherence than the studies conducted in Colombia, 92% [35]. Southern Ethiopia, 85.8% [30], Addis Ababa, Ethiopia, 97.7% [33] and Southwestern Ethiopia, 100% [31]. These variations in patient adherences might be due to differences in psychosocial support of relatives or the society, stigma and lack of commitment to take medications so that HIV patients might drop themselves from on course ART treatment, not feeling well (perceived it from the medication), scaring of treatment side effects and being busy (forgetting the HAART medication) [6, 43, 44].

The median baseline CD4+ T cell count of our study participants was 196 cells/μL. This is comparable with the studies reported in Southwestern Ethiopia, 191 cells/μL [31]. However, this is observed to be higher than the reports from Northern Ethiopia, 162 cells/μL [28], Southern Ethiopia, 156 cell/μL [30], Kenya, 152 cells/μL [36], Addis Ababa, 115 cells/μL [32] and 177 cells/μL [33]. A study from Liberia [29] reported a higher median baseline CD4+ T cell count of 238 cell/μL. This variation might be explained with the differences in time of HAART initiation among HIV patients for a long period. This is because a long duration of HIV infection without the ART leads to progressive viral replication, which in turn leads to lower CD4+ T cell count.

Lower baseline CD4+ T cell count (baseline CD4+ T cell count less than 250 cells/μL) was statistically associated with immune reconstitution failure of HAART (p <  0.001). This report is supported by previous studies from Debremarkos, Ethiopia [41] and Thailand [37]. Moreover, immune recovery depends on the baseline CD4+ T cell count. The timing of HAART initiation is important to optimize the CD4+ T cell immune response to medication [45]. These reports may highlight that patients with low CD4+ T cell count have poor long term CD4+ T cell immune response. Study participants with poor adherence towards HAART were 9.4 times more likely to experience CD4+ T cell recovery failure than those who had good adherence (p <  0.001). This is supported by a study conducted in Northwestern Ethiopia [34], Southern Ethiopia [36], Colombia [35] and France [46]. Poor treatment adherence might allow viral replication which in turn increases infection of more CD4+ T cells and ultimately depletion of their number [44].

This study revealed that, immune reconstitution failure was 11.5 times more likely to occur among TB co-infected individuals compared to TB non-infected individuals (p <  0.001). This was similar to reports from Southern Ethiopia [30], Gondar [40], and Nigeria [47]. TB infection impairs cellular immune responses through Mycobacterium tuberculosis-induced apoptosis of CD4+ T cells which subsequently lead to depletion of CD4+ T cells and results in immunological failure [48]. The prevalence of low immune reconstitution among HIV/TB co-infected participants was 48.8% (60/123) comparing to the failure of HIV mono-infected participants, 13.7% (37/270). The higher immune reconstitution failure among TB co-infected HIV participants is supported by previous studies from Uganda [49], South Africa [50] and Senegal [51]. This might be due to the fact that TB infection will contribute to the low CD+ T cells recovery by attaching and neutralizing CD4+ T cells. Incidence of TB during the course of HAART might have decreased the adherence f the treatment due to its high pill burden and side-effects [1].

The other associated factor for experiencing low immune reconstitution was residence. Participants from an urban residence were 2.1 times more likely to have low CD4+ T cells recovery than rural residents (p = 0.020). A previous study conducted in Ethiopia [52] has reported increased immunological failure among HIV patients living in urban areas. This might be due to the reason that HAART users of urban residence are more likely to be enrolled in harmful activities like chewing chat, smoking and drinking alcohol. Hence, experiencing immunological failure will be attributed to these possible factors.

The overall rate of immune reconstitution failure among HIV patients on HAART was high. TB co-infection has shown to contribute to the higher rate of low CD4+ T cells to HIV therapy. Other factors like low CD4+ T cell baseline count, poor adherence and urban residence were also associated with low immune recovery. HIV patients who are coinfected with TB should be monitored for evaluation of CD4+ T cell count determination strictly. Hence, there would be a good immune recovery of HAART. Moreover, a virological response shall be assessed to HIV patients on HAART to determine the recovery from viral antigen replications.