The Immune Reconstitution Inflammatory Syndrome After Antiretroviral Therapy Initiation in Patients With Tuberculosis: Findings From the SAPiT Trial

Abstract

Background Concerns about immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during anti-tuberculosis treatment in co-infected patients. Objective We assessed IRIS incidence, severity, and outcomes relative to timing of ART initiation in patients with HIV-related tuberculosis (HIV-TB). Setting An outpatient clinic in Durban, South Africa Patients 642 HIV-TB co-infected patients Design In a secondary analysis of the SAPiT trial, IRIS was assessed in patients randomized to initiate ART either within four weeks of tuberculosis treatment initiation (early integrated-treatment arm), within four weeks of completion of the intensive phase of tuberculosis treatment (late integrated-treatment arm) or within four weeks after tuberculosis therapy completion (sequential-treatment arm). IRIS was defined as new onset or worsening symptoms, signs or radiographic manifestations temporally related to treatment initiation accompanied by a treatment response. IRIS severity, hospitalization and time to resolution were monitored. Results IRIS incidence was 19.5 (n=43), 7.5 (n=18) and 8.1 (n=19) per 100 person-years in the early integrated-, late integrated-, and sequential-treatment arms, respectively; P < 0.001, and 45.5, 9.7 and 19.7 per 100 person-years in patients with baseline CD4+ counts <50 cells/mm3, P = 0.004. IRIS incidence was higher in the early integrated- compared to the late integrated- (incidence rate ratio (IRR) = 2.6, 95%confidence interval (CI): 1.5 to 4.8; P < 0.001) or sequential-treatment arm (IRR=2.4, 95%CI: 1.4 to 4.4; P < 0.001). IRIS cases in the early integrated-treatment arm were more severe (34.9% vs. 18.9%, P = 0.18); had significantly higher hospitalization rates (18/43 vs. 5/37; P = 0.01), and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) compared to IRIS cases in the other two arms. Limitation IRIS could not be assessed, due to LTFU, withdrawal or death within 6 months of scheduled ART initiation, in more patients from the sequential treatment arm (n=74) than in the late integrated treatment arm (n=50) and in the early integrated treatment arm (n=32). This study did not assess IRIS risk in non-ambulant patients and in patients with extra-pulmonary and smear negative pulmonary tuberculosis. Conclusion Initiation of ART early during tuberculosis treatment resulted in significantly higher IRIS rates, with longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings, particularly relevant to patients initiating ART with CD4+ counts < 50 cells/mm3, need to be considered together with the increased survival benefit of early ART initiation in this group. Clintrials.gov: NCT00398996

Paradoxical reactions and immune reconstitution inflammatory syndrome in tuberculosis

“…This risk has been confirmed in large RCTs seeking to optimize the timing of HAART initiation. 25,26,33 Additionally, higher bacillary/antigen loads have been measured directly in patients who go on to develop PR/IRIS compared to those who do not. In the lung, baseline sputum smear positivity was independently associated with paradoxical TB-IRIS in one study, 34 and a trend towards a similar association has been observed in patients with PR.…”

“…23,24 Similar results were reported in a large randomized controlled trial (RCT) with the aim of optimizing the timing of HAART initiation. 25,26 Understanding the pathogenesis of PR and IRIS may improve clinical outcomes for these patients through promoting avoidance of PR/IRIS and identifying potential for immunotherapies, and may also contribute to a wider understanding of inflammatory pathologies in TB and mycobacterial diseases. In this review, we discuss the definitions of PR and TB-IRIS, and explore risk factors and immunopathogenesis in these inflammatory mycobacterial syndromes.…”

Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4+T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

“…Initiating antiretroviral therapy (ART) early during tuberculosis treatment in patients with advanced human immunodeficiency virus (HIV)/tuberculosis is associated with improved survival [1,2]; however, this strategy also increases risk for worsening of tuberculosis symptoms in a condition known as paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) [3][4][5]. The incidence of TB-IRIS ranges between 8% and 54% [6,7], and associated morbidity can be significant [3][4][5].…”

“…The incidence of TB-IRIS ranges between 8% and 54% [6,7], and associated morbidity can be significant [3][4][5]. With the World Health Organization advocating early ART during tuberculosis treatment in highly immunosuppressed HIV/tuberculosis-coinfected patients [8], the incidence of TB-IRIS will likely rise [4]. Immunologically, higher pre-ART levels of immune activation and rapid increases in tuberculosis-specific interferon gamma (IFN-γ)-producing cells after ART initiation in HIV-infected adults have been associated with development of TB-IRIS [7,[9][10][11][12].…”

“…The incidence of TB-IRIS ranges between 8% and 54% [6,7], and associated morbidity can be significant [3][4][5]. With the World Health Organization advocating early ART during tuberculosis treatment in highly immunosuppressed HIV/tuberculosis-coinfected patients [8], the incidence of TB-IRIS will likely rise [4].…”