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 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% in later ART, 11.5% with CD4+ <50 vs. 5.4% with CD4+ ≥50 cells per cubic millimeter. 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%); central nervous system 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 per cubic millimeter. As ART is implemented earlier in HIV–TB coinfection, programs will require the diagnostic capabilities, clinical resources, and training necessary to manage TB IRIS.