Tuberculosis immune reconstitution inflammatory syndrome in A5221 STRIDE: Timing, Severity, and Implications for HIV-TB Programs

Anne F. Luetkemeyer, Michelle A. Kendall, Mulinda Nyirenda, Xingye Wu, Prudence Ive, Constance A. Benson, Janet W. Andersen, Susan Swindells, Ian M. Sanne, Diane V. Havlir, Johnstone Kumwenda

Research output: Contribution to journalReview articlepeer-review

55 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)423-428
Number of pages6
JournalJournal of Acquired Immune Deficiency Syndromes
Issue number4
StatePublished - Apr 1 2014


  • Immune reconstitution inflammatory syndrome
  • Paradoxical reaction
  • Tuberculosis

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)


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