title: Contribution of a heparin-binding haemagglutinin interferon-gamma release assay to the detection of Mycobacterium tuberculosis infection in HIV-infected patients: comparison with the tuberculin skin test and the QuantiFERON-TB Gold In-tube.
abstract: BACKGROUND
  The screening and treatment of latent tuberculosis (TB) infection reduces the risk of progression to active disease and is currently recommended for HIV-infected patients. The aim of this study is to evaluate, in a low TB incidence setting, the potential contribution of an interferon-gamma release assay in response to the mycobacterial latency antigen Heparin-Binding Haemagglutinin (HBHA-IGRA), to the detection of Mycobacterium tuberculosis infection in HIV-infected patients.
  
  
  METHODS
  Treatment-naïve HIV-infected adults were recruited from 4 Brussels-based hospitals. Subjects underwent screening for latent TB using the HBHA-IGRA in parallel to a classical method consisting of medical history, chest X-ray, tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube (QFT-GIT). Prospective clinical and biological follow-up ensued, with repeated testing with HBHA-IGRA. A group of HIV-infected patients with clinical suspicion of active TB was also recruited and tested with the HBHA-IGRA. Multiplex analysis was performed on the culture supernatants of this in-house assay to identify test read-outs alternative to interferon-gamma that could increase the sensitivity of the test.
  
  
  RESULTS
  Among 48 candidates enrolled for screening, 9 were identified with latent TB by TST and/or QFT-GIT results. Four of these 9 patients and an additional 3 screened positive with the HBHA-IGRA. This in-house assay identified all the patients that were positive for the TST and showed the best concordance with the presence of a M. tuberculosis exposure risk. During follow-up (median 14 months) no case of active TB was reported and HBHA-IGRA results remained globally constant. Fourteen HIV-infected patients with clinical suspicion of active TB were recruited. Active TB was confirmed for 6 of them among which 3 were HBHA-IGRA positive, each with very high interferon-gamma concentrations. All patients for whom active TB was finally excluded, including 2 non-tubercular mycobacterial infections, had negative HBHA-IGRA results. Multiplex analysis confirmed interferon-gamma as the best read-out.
  
  
  CONCLUSIONS
  The HBHA-IGRA appears complementary to the QuantiFERON-TB Gold In-Tube for the screening of latent TB in HIV-infected patients. Large-scale studies are necessary to determine whether this combination offers sufficient sensitivity to dismiss TST, as suggested by our results. Furthermore, HBHA-IGRA may help in the diagnosis work-up of clinical suspicions of active TB.
authors.affiliation: Laboratory of Vaccinology and Mucosal Immunology, Université Libre de Bruxelles, Brussels, Belgium. chloe.wyndham-thomas@erasme.ulb.ac.be.|Immunodeficiency unit, Hôpital Erasme, Brussels, Belgium. chloe.wyndham-thomas@erasme.ulb.ac.be.
authors.forename: Chloé
authors.initials: C
authors.lastname: Wyndham-Thomas
authors.affiliation: Laboratory of Vaccinology and Mucosal Immunology, Université Libre de Bruxelles, Brussels, Belgium. vdirix@ulb.ac.be.
authors.forename: Violette
authors.initials: V
authors.lastname: Dirix
authors.affiliation: Immunodeficiency unit, Hôpital Erasme, Brussels, Belgium. kindaschepers@gmail.com.
authors.forename: Kinda
authors.initials: K
authors.lastname: Schepers
authors.affiliation: Infectious Disease, CHU Saint-Pierre, Brussels, Belgium. charlotte_martin@stpierre-bru.be.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Martin
authors.affiliation: Infectious disease unit, IRIS SUD hospitals, Brussels, Belgium. MHILDEBRAND@his-izz.be.
authors.forename: Marc
authors.initials: M
authors.lastname: Hildebrand
authors.affiliation: Immunodeficiency unit, Hôpital Erasme, Brussels, Belgium. Jean-Christophe.Goffard@erasme.ulb.ac.be.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Goffard
authors.affiliation: Laboratory of Vaccinology and Mucosal Immunology, Université Libre de Bruxelles, Brussels, Belgium. fan.dom@orange.fr.
authors.forename: Fanny
authors.initials: F
authors.lastname: Domont
authors.affiliation: Laboratory of Vaccinology and Mucosal Immunology, Université Libre de Bruxelles, Brussels, Belgium. myriam.libin@ulb.ac.be.
authors.forename: Myriam
authors.initials: M
authors.lastname: Libin
authors.affiliation: INSERM U1019, Lille, France. marc.loyens@ibl.cnrs.fr.|CNRS UMR8204, Lille, France. marc.loyens@ibl.cnrs.fr.|Université Lille Nord de France, Lille, France. marc.loyens@ibl.cnrs.fr.|Center for Infection and Immunity of Lille, Institut Pasteur de Lille, Lille, France. marc.loyens@ibl.cnrs.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Loyens
authors.affiliation: INSERM U1019, Lille, France. camille.locht@pasteur-lille.fr.|CNRS UMR8204, Lille, France. camille.locht@pasteur-lille.fr.|Université Lille Nord de France, Lille, France. camille.locht@pasteur-lille.fr.|Center for Infection and Immunity of Lille, Institut Pasteur de Lille, Lille, France. camille.locht@pasteur-lille.fr.
authors.forename: Camille
authors.initials: C
authors.lastname: Locht
authors.affiliation: Immunodeficiency unit, Hôpital Erasme, Brussels, Belgium. Jean.Paul.Van.Vooren@erasme.ulb.ac.be.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Van Vooren
authors.affiliation: Laboratory of Vaccinology and Mucosal Immunology, Université Libre de Bruxelles, Brussels, Belgium. fmascart@ulb.ac.be.|Immunobiology Clinic, Hôpital Erasme, Brussels, Belgium. fmascart@ulb.ac.be.
authors.forename: Françoise
authors.initials: F
authors.lastname: Mascart
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000453:epidemiology / Q000276:immunology; D015497:HIV-1; D006801:Humans; D015994:Incidence; D007371:Interferon-gamma / Q000032:analysis / Q000378:metabolism; D059425:Interferon-gamma Release Tests / Q000379:methods*; D055985:Latent Tuberculosis / Q000150:complications* / Q000175:diagnosis* / Q000453:epidemiology / Q000276:immunology; D037102:Lectins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification*; D014374:Tuberculin Test / Q000379:methods*; D055815:Young Adult
chemical_list: D037102:Lectins; C104578:heparin-binding hemagglutinin; D007371:Interferon-gamma