Immunopathogenesis and diagnosis of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome during early antiretroviral therapy.
BACKGROUND
In many settings, the benefits of antiretroviral therapy (ART) are reduced by the high early incidence of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS).


METHODS
We used tuberculin skin testing and the QuantiFERON-TB Gold In-Tube assay to investigate cellular immune responses to purified protein derivative (PPD) and region of difference 1 (RD1) antigens during the first 24 weeks of ART.


RESULTS
TB-IRIS and ART-associated tuberculosis occurred in 15 of 75 (20%) and 11 of 231 (4.8%) participants at risk, respectively. Greater increases in interferon gamma (IFN-gamma) and skin test responses to PPD were seen at week 24 and 12 in participants with TB-IRIS (P< or = .04), respectively. Raw IFN-gamma responses to RD1 antigens and PPD corrected for pre-ART CD4(+) T cell counts were higher at all time points in individuals with ART-associated tuberculosis (P<.001) and were associated with areas under receiver operator characteristic curves of 0.90 for RD1 (95% confidence interval [CI], 0.78-1.00) and 0.92 for PPD (95% CI, 0.83-1.00) for the diagnosis of ART-associated tuberculosis. Pre-ART IFN-gamma responses enabled stratification of participants into groups with risks of subsequent tuberculosis of 0.7%, 9.3%, and 30.0%.


CONCLUSIONS
Type 1 effector T cell responses are prominent in ART-associated tuberculosis, but additional immune defects may be more important in paradoxical TB-IRIS. IFN-gamma release assays may contribute to the prediction and diagnosis of tuberculosis during early ART.
Elliott
Julian H
JH
National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia. julian.elliott@alfred.org.au
Vohith
Khol
K
Saramony
Sarun
S
Savuth
Chin
C
Dara
Chan
C
Sarim
Chel
C
Huffam
Sarah
S
Oelrichs
Robert
R
Sophea
Pouv
P
Saphonn
Vonthanak
V
Kaldor
John
J
Cooper
David A
DA
Chhi Vun
Mean
M
French
Martyn A
MA
D000328:Adult; D044966:Anti-Retroviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000942:Antigens, Bacterial / Q000276:immunology; D000995:Antitubercular Agents / Q000627:therapeutic use; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D015497:HIV-1; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000175:diagnosis* / Q000209:etiology / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D012372:ROC Curve; D014374:Tuberculin Test; D014376:Tuberculosis / Q000175:diagnosis* / Q000188:drug therapy / Q000276:immunology*
D044966:Anti-Retroviral Agents; D000942:Antigens, Bacterial; D000995:Antitubercular Agents; D007371:Interferon-gamma