title: Biomarkers of CD4+ T-cell activation as risk factors for tuberculosis-associated immune reconstitution inflammatory syndrome.
abstract: OBJECTIVE
  Patients coinfected with HIV and Mycobacterium tuberculosis frequently experience a paradoxical worsening of tuberculosis (TB) symptoms early after the initiation of combination antiretroviral therapy (cART). This immune reconstitution inflammatory syndrome (TB-IRIS) can lead to significant morbidity and needs to be distinguished from TB recurrence due to ineffective treatment. We investigated whether plasma biomarkers could predict the occurrence of TB-IRIS.
  
  
  METHODS
  ANRS 129 BKVIR is a single-arm multicentre trial that enrolled 69 cART-naïve HIV-1-infected patients treated for TB. The patients received once-daily tenofovir/emtricitabine/efavirenz first-line regimen. TB-IRIS cases (IRIS+) were validated by an Event Review Committee.
  
  
  METHODS
  A panel of 26 plasma biomarkers was monitored longitudinally for 24 weeks from cART initiation onward, using multiplexed assays and high-sensitivity ELISA. Statistical analyses of biomarkers were adjusted for test multiplicity.
  
  
  RESULTS
  One-third of patients (n=23) experienced TB-IRIS. The inflammatory cytokines and chemokines interleukin (IL)-6, IL-8, interferon-gamma-induced protein 10 (IP-10), and tumour necrosis factor-alpha (TNF-α) showed increased plasma levels at week 4 in IRIS-positive (IRIS+) patients (P<0.05 for each biomarker). The soluble IL-2 receptor sCD25, which is released upon CD4 T-cell activation, was significantly increased at week 0 in IRIS+ patients (P<0.05), and remained elevated throughout follow-up. IL-7, a key homeostatic cytokine for CD4 T-cells, showed a trend for higher values in the TB-IRIS group. Both sCD25 and IL-7 baseline levels were independently associated with a shorter time to TB-IRIS occurrence (P=0.005 and P=0.02, respectively).
  
  
  CONCLUSIONS
  These findings support a role for CD4 T-cell activation prior to massive inflammation in the development of TB-IRIS.
authors.affiliation: aUnité de Pathogénie Virale, INSERM U1108, Institut Pasteur, Paris bUniversity Bordeaux, ISPED cINSERM ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux dUnité d'Immunologie Cellulaire, Institut Pasteur eService de Médecine Interne, Hôpital de La Pitié-Salpêtrière, Paris fHôpital Villeneuve St-Georges, Villeneuve St-Georges gCHU de Bordeaux, Pole de santé publique, Service d'information médicale, Bordeaux hUniversité Paris Descartes, Hôpital Necker Enfants malades, APHP, Paris, France.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Chakrabarti
authors.forename: Céline
authors.initials: C
authors.lastname: Boucherie
authors.forename: Florence
authors.initials: F
authors.lastname: Bugault
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Cumont
authors.forename: Caroline
authors.initials: C
authors.lastname: Roussillon
authors.forename: Guillaume
authors.initials: G
authors.lastname: Breton
authors.forename: Olivier
authors.initials: O
authors.lastname: Patey
authors.forename: Geneviève
authors.initials: G
authors.lastname: Chêne
authors.forename: Laura
authors.initials: L
authors.lastname: Richert
authors.forename: Olivier
authors.initials: O
authors.lastname: Lortholary
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003521:Cyclopropanes; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000068679:Emtricitabine; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000175:diagnosis*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects; D012307:Risk Factors; D000068698:Tenofovir; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D015415:Biomarkers; D003521:Cyclopropanes; D063065:Organophosphonates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; C098320:efavirenz