title: HIV patients with latent tuberculosis living in a low-endemic country do not develop active disease during a 2 year follow-up; a Norwegian prospective multicenter study.
abstract: BACKGROUND
  Interferon-γ release assays (IGRA) serve as immunodiagnostics of tuberculosis (TB) infection to identify individuals with latent TB infection (LTBI) eligible for preventive anti-TB therapy. In this longitudinal study of HIV-infected LTBI patients we have observed for possible progression to active TB as well as evaluated repeated IGRA testing in a TB low-endemic setting.
  
  
  METHODS
  QuantiFERON TB-Gold In-tube® assay (QFT), TB-SPOT.TB® (TSPOT) and tuberculin skin test (TST) were performed on 298 HIV-patients recruited from seven out-patient clinics in Norway. Patients with active TB, LTBI and negative IGRA were followed with repeat QFTs and clinical evaluation over a period of 24 months.
  
  
  RESULTS
  Seven HIV-patients (median CD4 count 270; IQR 50-340) were diagnosed with active TB at inclusion, all IGRA positive. Sixty-four (21%) HIV-patients (median CD4 count 471; IQR 342-638) were diagnosed with LTBI and of these 39 (61%) received TB preventive treatment. Neither treated nor untreated HIV-infected LTBI patients developed active TB during the 24 months. At baseline, the median interferon-γ (INF-γ) level measured by QFT was 3.48 IU/ml (IQR 0.94-8.91 IU/ml) for treated LTBI compared to 1.13 IU/ml (IQR 0.47-4.25 IU/ml) for untreated LTBI patients (p = 0.029). The QFT reversion rates were 75% for active TB, 23% for treated LTBI and 44% for untreated LTBI, whereas the conversion rate for the non-TB group was 7% despite no new TB exposure. There was no significant difference in the trend of INF-γ levels over time between treated and untreated LTBI patients.
  
  
  CONCLUSIONS
  The prevalence of LTBI is high among HIV-patients, but the risk of developing active TB seems to be low in patients with high CD4 counts in this TB low-endemic setting. In several patients, especially with baseline IFN-γ levels close to cut-offs, the QFT tests reverted to negative independent of preventive anti-TB treatment indicating possibly false positive tests. This highlights the importance of defining reliable cut-offs for immunodiagnostic tests and deferring preventive therapy in selected patients. Randomized studies with longer follow-up time are needed to identify HIV-patients that would benefit from LTBI treatment in a TB low-endemic setting.
authors.affiliation: Department of Internal Medicine, Section for Infectious Diseases, University Hospital of Northern Norway, N-9038, Tromsø, Norway. nadine.pullar@gmail.com.|Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, N-9037, Tromsø, Norway. nadine.pullar@gmail.com.
authors.forename: Nadine Durema
authors.initials: ND
authors.lastname: Pullar
authors.affiliation: Department of Infectious Diseases, Trondheim University Hospital, N-7004, Trondheim, Norway. harald.steinum@stolav.no.
authors.forename: Harald
authors.initials: H
authors.lastname: Steinum
authors.affiliation: Department of Internal Medicine, Section for Infectious Diseases, University Hospital of Northern Norway, N-9038, Tromsø, Norway. johan.nikolai.bruun@unn.no.|Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, N-9037, Tromsø, Norway. johan.nikolai.bruun@unn.no.
authors.forename: Johan Nikolai
authors.initials: JN
authors.lastname: Bruun
authors.affiliation: Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, N-5021, Bergen, Norway. a.m.d.riise@medisin.uio.no.|Present address: Department of Infectious Diseases, Oslo University Hospital (Ullevål), pb 4956 Nydalen, 0424, Oslo, Norway. a.m.d.riise@medisin.uio.no.|Institute of Clinical Medicine, University of Oslo, 0316, Oslo, Norway. a.m.d.riise@medisin.uio.no.
authors.forename: Anne Ma
authors.initials: AM
authors.lastname: Dyrhol-Riise
mesh_terms: D000328:Adult; D018791:CD4 Lymphocyte Count; D060085:Coinfection / Q000276:immunology; D018450:Disease Progression; D019353:Endemic Diseases; D005006:Ethnicity; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000453:epidemiology / Q000276:immunology*; D006801:Humans; D059425:Interferon-gamma Release Tests; D055985:Latent Tuberculosis / Q000453:epidemiology / Q000276:immunology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009664:Norway / Q000453:epidemiology; D015995:Prevalence; D011446:Prospective Studies; D014374:Tuberculin Test; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis* / Q000453:epidemiology / Q000276:immunology