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Tuberculosis Immune Reconstitution Inflammatory Syndrome in A5221 STRIDE: Timing, Severity, and Implications for HIV–TB Programs

Luetkemeyer, Anne F. MD*; Kendall, Michelle A. MS; Nyirenda, Mulinda MMed, FCP; Wu, Xingye MS; Ive, Prudence FCP§; Benson, Constance A. MD; Andersen, Janet W. ScD; Swindells, Susan MBBS; Sanne, Ian M. MBBS, FCP§; Havlir, Diane V. MD*; Kumwenda, Johnstone FRCPthe Adult AIDS Clinical Trials Group A5221 Study Team

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 1st, 2014 - Volume 65 - Issue 4 - p 423–428
doi: 10.1097/QAI.0000000000000030
Clinical Science

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.

Supplemental Digital Content is Available in the Text.

*HIV/AIDS Division, San Francisco General Hospital, University of California, San Francisco, CA;

Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA;

Department of Medicine, College of Medicine, Blantyre, Malawi;

§Faculty of Heath Sciences, University of the Witwatersrand, Johannesburg, South Africa;

Division of Infectious Diseases, School of Medicine, University of California, San Diego, CA; and

Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE.

Correspondence to: Anne F. Luetkemeyer, MD, HIV/AIDS Division, San Francisco General Hospital, University of California, San Francisco, 995 Potrero Avenue, Box 0874, San Francisco, CA 94110 (e-mail:

A.L., S.S., I.S., P.I., M.K., X.W., J.A., D.H., and J.K. are members of the protocol study team and were involved in study design and conduct. M.N. is a protocol team member and oversaw participant enrollment and management. C.B. participated in study monitoring and provided AIDS Clinical Trials Group leadership. M.K., X.W., and J.A. were responsible for statistical analysis. All authors contributed to manuscript preparation.

Supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases and the Statistical and Data Management Center UM1 AI068634 funded by the National Institute of Allergy and Infectious Diseases. A.L., M.K., X.W., J.A., P.I., S.S., C.B., D.H., I.S., and J.K. have received research grant support to their institutions to support this work and to support travel to study-related meetings. A.L. has received research grant support to her institution from Cepheid.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. I.S. is on the advisory board for Mylan Pharmaceuticals. All other authors have reported no potential conflict of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received July 12, 2013

Accepted October 15, 2013

© 2014 by Lippincott Williams & Wilkins