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Immunological profiling of tuberculosis-associated immune reconstitution inflammatory syndrome and non-immune reconstitution inflammatory syndrome death in HIV-infected adults with pulmonary tuberculosis starting antiretroviral therapy: a prospective observational cohort study

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Summary

Background

Patients co-infected with advanced HIV and tuberculosis are at risk of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) and death soon after initiation of antiretroviral therapy (ART). Tuberculosis-associated IRIS has been associated with quicker recovery of cellular immune responses after ART initiation and early mortality with slower recovery of these responses. We aimed to assess whether patients who have these outcomes have distinct immunological profiles before and after ART initiation.

Methods

We undertook this prospective cohort study at 22 public clinics and the main public hospital in Gaborone, Botswana, in ART-naive adults (aged ≥21 years) with advanced HIV (CD4 cell counts ≤125 cells per μL) and pulmonary tuberculosis. We obtained data for clinical variables and for levels of 29 plasma biomarkers, quantified by Luminex assay. We classified patients as having tuberculosis-associated IRIS, early mortality, or survival without a diagnosis of tuberculosis-associated IRIS (controls), on the basis of outcomes recorded in the 6 months after ART initiation. We used rank-sum or χ2 tests, and logistic regression with odds ratios (OR) and 95% CIs, to assess the association between variables measured before and 4 weeks after ART initiation with death and tuberculosis-associated IRIS, compared with controls.

Findings

Between Nov 12, 2009, and July 3, 2013, we enrolled 201 participants. 31 (15%) patients left the study before ART initiation, leaving 170 (85%) patients for analysis. Patients with tuberculosis-associated IRIS had reduced pre-ART concentrations of several pro-inflammatory biomarkers, including interleukin (IL)-6 (adjusted OR per 1 log10 increase 0·40 [95% CI 0·18–0·89]). However, patients with early death had increased pre-ART concentrations of inflammatory biomarkers, including monocyte chemoattractant protein-1 (adjusted OR 9·0 [95% CI 1·0–80·0]) and tumour necrosis factor (TNF)α (7·8 [1·1–55·2]). At week 4 after ART initation, tuberculosis-associated IRIS was independently associated with greater increases in several inflammatory biomarkers, including IL-6 (adjusted OR 1·7 [95% CI 1·2–2·5]) and TNFα (1·5 [1·0–2·2]), versus controls. Death was likewise associated with greater increases in systemic inflammatory markers, including granulocyte colony-stimulating factor (adjusted OR 2·8 [95% CI 1·3–6·1]), IL-12p40 (1·8 [1·0–3·4]), and IL-15 (2·0 [1·1–3·7]), versus controls. However, changes in CD4 cell count during ART, which were similar between controls and patients with tuberculosis-associated IRIS (p=0·45), were substantially lower in patients who died (p=0·006).

Interpretation

Distinct immunological profiles before and after ART initiation characterise patients with advanced HIV and tuberculosis who have tuberculosis-associated IRIS and death. Interventions that decrease inflammation while promoting cellular immune recovery during ART should be considered in patients co-infected with HIV and tuberculosis.

Funding

National Institutes of Health and the Penn Center for AIDS Research.

Introduction

In 2013, HIV-infected patients accounted for 13% of 9·0 million tuberculosis cases and 24% of 1·5 million tuberculosis-associated deaths worldwide.1 Initiation of antiretroviral therapy (ART) during tuberculosis treatment can decrease mortality in HIV-infected individuals.2 The need for ART is particularly urgent in patients with advanced HIV, because patients with the lowest CD4 T-cell counts have improved survival when ART is started within the first few weeks of anti-tubercular therapy.3, 4, 5 Nonetheless, patients with advanced HIV and tuberculosis have a persistently high risk of death despite starting therapy for both diseases. For example, 120 (18%) of 661 patients and 55 (7%) of 783 patients in two trials of ART timing in patients with HIV and tuberculosis died within 48 weeks despite starting both ART and anti-tubercular therapy (M Kendall, Harvard School of Public Health, personal communications).3, 5

Early ART initiation after tuberculosis treatment is also associated with an increased risk of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS),3, 4, 5, 6, 7 characterised by pathological inflammation after ART initiation in patients concurrently treated for tuberculosis.8, 9, 10, 11, 12, 13 Although mortality from tuberculosis-associated IRIS is low,14 morbidity can be substantial.7, 14, 15 Studies of outcomes in patients with HIV and tuberculosis have frequently focused on tuberculosis-associated IRIS while excluding early deaths; as such, mechanisms of early mortality after ART in patients with HIV and tuberculosis are largely unknown. However, failure to recover CD4 cell counts despite virological suppression has been associated with early death after ART initiation in adults with advanced HIV and tuberculosis.16 This finding is notable because the diminished cellular immune recovery reported in early mortality16 contrasts with the more rapid cellular immune responses often noted in patients with tuberculosis-associated IRIS,8, 12, 13, 17 suggesting that the underlying immunopathogenesis for tuberculosis-associated IRIS and early mortality differ. Understanding of the risk factors for these outcomes is important, because interventions designed to prevent tuberculosis-associated IRIS could increase early mortality if the immunological processes, such as rapid immune recovery, driving that disorder are associated with survival. In view of these differences, we postulated that patients who go on to develop tuberculosis-associated IRIS would differ from those who die early after ART initiation in terms of immune activation and recovery before and early after ART initiation.

We investigated the relation of clinical variables and immunological characteristics before and 4 weeks after ART initiation to risk of non-traumatic death (early mortality) and paradoxical tuberculosis-associated IRIS in adults with advanced HIV and tuberculosis.

Section snippets

Study design

We did a prospective cohort study at 22 public clinics and Princess Marina Hospital (the main public hospital) in Gaborone, Botswana, with previously described methods.16 Eligible patients (aged ≥21 years) were HIV-infected, ART-naive citizens of Botswana with pre-ART CD4 cell counts of 125 cells per μL or less, a new diagnosis of pulmonary tuberculosis, and plans to initiate ART within 2 months of starting standard anti-tuberculosis therapy.18 Diagnosis of pulmonary tuberculosis required a

Results

Between Nov 12, 2009, and July 3, 2013, we enrolled 201 participants. Before ART initiation, 31 (15%) patients left the study: three withdrew, ten transferred out, five died, and 13 were discontinued from the study because of failure to follow study procedures, leaving 170 (85%) patients for analysis. The median CD4 cell count of included participants was 60 cells per μL (IQR 31–90), nearly three-quarters of patients had smears positive for acid-fast bacilli or GeneXpert assays positive for

Discussion

Our findings show that individuals who had early mortality or paradoxical tuberculosis-associated IRIS had substantially different pre-ART biomarker concentrations compared with those with uncomplicated immune recovery. Furthermore, patients with IRIS and early mortality had rapid increases in immune activation and inflammation early during ART, but differed substantially in terms of the magnitude of early cellular immune recovery after ART initiation.

Although several studies8, 9, 10, 11, 12, 22

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