Tuberculosis Immune Reconstitution Inflammatory Syndrome in A5221 STRIDE

Abstract

Rationale and Objectives Earlier initiation of antiretroviral therapy (ART) in HIV-tuberculosis(TB) is associated with increased immune reconstitution inflammatory syndrome (IRIS). The severity, frequency and complications of TB IRIS were evaluated in A5221, a randomized trial of earlier ART (within 2 weeks after TB treatment initiation) vs. later ART (8-12 weeks after TB treatment) in HIV-infected patients starting TB treatment. Methods and Measurements In 806 participants, TB IRIS was defined using published clinical criteria. Cases were classified as severe(hospitalization/death), moderate(corticosteroid use/invasive procedure), or mild(no hospitalization/procedures/steroids). Fisher's Exact, Wilcoxon, and log rank tests were used for comparisons. Main Results TB IRIS occurred in 61 (7.6%) patients: 10.4% in earlier vs. 4.7% later ART, 11.5% with CD4+ < 50 vs. 5.4% CD4+ ≥ 50 cells/mm3. The CD4+/ART arm interaction was significant, p=0.014, with 44.3% of TB IRIS occurring with CD4+ < 50 and earlier ART. TB IRIS occurred sooner with earlier vs. later ART initiation, at a median of 29 vs. 82 days after TB treatment initiation (p<0.001). IRIS manifestations included lymphadenopathy(59.0%), constitutional symptoms(54.1%), and radiographic changes(41.0%); CNS TB IRIS was uncommon (6.6%). TB IRIS was mild in 27.9%, moderate in 41.0%, and severe in 31.1%. No TB IRIS-associated deaths occurred. IRIS management required ≥ 1 invasive procedures in 34.4%, hospitalization in 31.1% and corticosteroids in 54.1%. Conclusions TB IRIS was more frequent with earlier ART initiation and CD4+ <50 cells/mm3. As ART is implemented earlier in HIV-TB co-infection, programs will require the diagnostic capabilities, clinical resources and training necessary to manage TB IRIS.

Paradoxical reactions and immune reconstitution inflammatory syndrome in tuberculosis

“…3 The mortality of paradoxical TB-IRIS has been estimated as 3.2% within a recent meta-analysis, 13 and considerable rates of hospitalization and intervention in TB-IRIS patients have been observed. 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 HIV-seronegative individuals, low baseline lymphocyte counts at the time of TB diagnosis are associated with an increased risk of developing PR, 2,8 whilst in HIV-seropositive individuals, low CD4+ T cell counts have been related to subsequent IRIS in a range of studies. 13,18,23,24,34 Advanced HIV disease has also been identified as a risk factor for IRIS, consequent on high pre-HAART HIV-1 viral loads. 34 Given that a relationship between active TB and lymphopenia has been reported, 42 and it is suggested that active TB is associated with a degree of immunodeficiency, 43 one could hypothesize that a baseline immunodeficient phenotype in both HIV seronegative and seropositive individuals is implicated in the development of both PR and IRIS.…”

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].…”

The ERS-endorsed official ATS/CDC/IDSA clinical practice guidelines on treatment of drug-susceptible tuberculosis

“…We suggest that a 4-month treatment regimen is adequate for treatment of HIV-negative adult patients with AFB smear-and culture-negative pulmonary TB [38]. IRIS may include high fever, worsening respiratory symptoms, inflammation and increased size of involved lymph nodes, new lymphadenopathy, expanding central nervous system lesions, worsening of pulmonary parenchymal infiltrations, new or increasing pleural effusions, and development of intra-abdominal or retroperitoneal abscesses [39].…”