Tuberculosis immune reconstitution inflammatory syndrome in A5221 STRIDE: timing, severity, and implications for HIV-TB programs.
OBJECTIVE
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
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.


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.
*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.
Anne F
AF
Luetkemeyer
Michelle A
MA
Kendall
Mulinda
M
Nyirenda
Xingye
X
Wu
Prudence
P
Ive
Constance A
CA
Benson
Janet W
JW
Andersen
Susan
S
Swindells
Ian M
IM
Sanne
Diane V
DV
Havlir
Johnstone
J
Kumwenda
D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000473:pathology*; D008297:Male; D012720:Severity of Illness Index; D013997:Time Factors; D014376:Tuberculosis / Q000150:complications* / Q000473:pathology*
D044966:Anti-Retroviral Agents