title: Interferon-γ ELISPOT as a biomarker of treatment efficacy in latent tuberculosis infection: a clinical trial.
abstract: BACKGROUND
  Biomarkers that can be used to evaluate new interventions against latent tuberculosis infection (LTBI) and predict reactivation TB disease are urgently required.
  
  
  OBJECTIVE
  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.
  
  
  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.affiliation: Medical Research Council Unit, The Gambia, Fajara, P.O. Box 273, Banjul, The Gambia.  iadetifa@mrc.gm.
authors.forename: Ifedayo M
authors.initials: IM
authors.lastname: Adetifa
authors.forename: Martin O C
authors.initials: MO
authors.lastname: Ota
authors.forename: David J
authors.initials: DJ
authors.lastname: Jeffries
authors.forename: Moses D
authors.initials: MD
authors.lastname: Lugos
authors.forename: Abdulrahman S
authors.initials: AS
authors.lastname: Hammond
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Battersby
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Owiafe
authors.forename: Simon D
authors.initials: SD
authors.lastname: Donkor
authors.forename: Martin
authors.initials: M
authors.lastname: Antonio
authors.forename: Hannah B
authors.initials: HB
authors.lastname: Ibanga
authors.forename: Roger H
authors.initials: RH
authors.lastname: Brookes
authors.forename: Peter
authors.initials: P
authors.lastname: Aka
authors.forename: Robert
authors.initials: R
authors.lastname: Walton
authors.forename: Richard A
authors.initials: RA
authors.lastname: Adegbola
authors.forename: Philip C
authors.initials: PC
authors.lastname: Hill
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D004311:Double-Blind Method; D058501:Enzyme-Linked Immunospot Assay / Q000379:methods* / Q000592:standards; D005260:Female; D005714:Gambia; D006801:Humans; D007371:Interferon-gamma / Q000097:blood* / Q000187:drug effects; D007538:Isoniazid / Q000627:therapeutic use*; D055985:Latent Tuberculosis / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D015415:Biomarkers; D007371:Interferon-gamma; D007538:Isoniazid