RATIONALE: Biomarkers that can be used to evaluate new interventions against latent tuberculosis infection (LTBI) and predict reactivation TB disease are urgently required. OBJECTIVES: To evaluate ESAT-6 and CFP-10 (EC) IFN-γ ELISPOT as a biomarker for treatment efficacy in LTBI. METHODS: This was a randomized, blinded, and placebo-controlled trial of INH in EC ELISPOT and Mantoux test positive participants. MEASUREMENTS AND MAIN RESULTS: Participants received a 6-month course of 900 mg INH twice weekly or a matching placebo. INH acetylator genotypes were determined and urine tested for INH metabolites to confirm adherence. The proportion of positive responders for CFP-10 and ESAT-6 between treatment arms was compared using mixed effects logistic regression models. A Tweedie (compound Poisson) model was fitted to allow for zero inflation and overdispersion of quantitative response. The proportions of EC ELISPOT-positive subjects reduced over time (P < 0.001) but did not differ by study arm (P = 0.36). Median spot-forming units for ESAT-6 and CFP-10 also declined significantly with time (P < 0.001) but did not differ by study arm (P = 0.74 and 0.71, respectively). There was no evidence of an interaction between acetylator status and INH treatment with respect to ELISPOT results over time. CONCLUSIONS: In contacts with LTBI, INH therapy plays no role in observed decreases in Mycobacterium tuberculosis antigen-specific T-cell responses over time. IFN-γ ELISPOT is probably not a useful biomarker of treatment efficacy in LTBI. Clinical trial registered with www.clinicaltrials.gov (NCT 00130325).
RCT Entities:
RATIONALE: Biomarkers that can be used to evaluate new interventions against latent tuberculosis infection (LTBI) and predict reactivation TB disease are urgently required. OBJECTIVES: To evaluate ESAT-6 and CFP-10 (EC) IFN-γ ELISPOT as a biomarker for treatment efficacy in LTBI. METHODS: This was a randomized, blinded, and placebo-controlled trial of INH in EC ELISPOT and Mantoux test positive participants. MEASUREMENTS AND MAIN RESULTS:Participants received a 6-month course of 900 mg INH twice weekly or a matching placebo. INH acetylator genotypes were determined and urine tested for INH metabolites to confirm adherence. The proportion of positive responders for CFP-10 and ESAT-6 between treatment arms was compared using mixed effects logistic regression models. A Tweedie (compound Poisson) model was fitted to allow for zero inflation and overdispersion of quantitative response. The proportions of EC ELISPOT-positive subjects reduced over time (P < 0.001) but did not differ by study arm (P = 0.36). Median spot-forming units for ESAT-6 and CFP-10 also declined significantly with time (P < 0.001) but did not differ by study arm (P = 0.74 and 0.71, respectively). There was no evidence of an interaction between acetylator status and INH treatment with respect to ELISPOT results over time. CONCLUSIONS: In contacts with LTBI, INH therapy plays no role in observed decreases in Mycobacterium tuberculosis antigen-specific T-cell responses over time. IFN-γ ELISPOT is probably not a useful biomarker of treatment efficacy in LTBI. Clinical trial registered with www.clinicaltrials.gov (NCT 00130325).
Authors: Patricio Escalante; Tobias Peikert; Virginia P Van Keulen; Courtney L Erskine; Cathy L Bornhorst; Boleyn R Andrist; Kevin McCoy; Larry R Pease; Roshini S Abraham; Keith L Knutson; Hirohito Kita; Adam G Schrum; Andrew H Limper Journal: Am J Respir Crit Care Med Date: 2015-09-01 Impact factor: 21.405
Authors: Madhukar Pai; Claudia M Denkinger; Sandra V Kik; Molebogeng X Rangaka; Alice Zwerling; Olivia Oxlade; John Z Metcalfe; Adithya Cattamanchi; David W Dowdy; Keertan Dheda; Niaz Banaei Journal: Clin Microbiol Rev Date: 2014-01 Impact factor: 26.132
Authors: Elitza S Theel; Heather Hilgart; Margaret Breen-Lyles; Kevin McCoy; Rhiannon Flury; Laura E Breeher; John Wilson; Irene G Sia; Jennifer A Whitaker; Jeremy Clain; Timothy R Aksamit; Patricio Escalante Journal: J Clin Microbiol Date: 2018-06-25 Impact factor: 5.948
Authors: John L Johnson; Hendrik Geldenhuys; Bonnie A Thiel; Asma Toefy; Sara Suliman; Bernadette Pienaar; Phalkun Chheng; Thomas Scriba; W Henry Boom; Willem Hanekom; Mark Hatherill Journal: Chest Date: 2014-03-01 Impact factor: 9.410
Authors: Ifedayo M O Adetifa; Lindsay Kendall; Simon Donkor; Moses D Lugos; Abdulrahman S Hammond; Patrick K Owiafe; Martin O C Ota; Roger H Brookes; Philip C Hill Journal: Am J Trop Med Hyg Date: 2017-07-19 Impact factor: 2.345