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Biomarkers of CD4+ T-cell activation as risk factors for tuberculosis-associated immune reconstitution inflammatory syndrome

Chakrabarti, Lisa A.a; Boucherie, Célineb,c; Bugault, Florenced; Cumont, Marie-Christined; Roussillon, Carolineb,c; Breton, Guillaumee; Patey, Olivierf; Chêne, Genevièveb,c,g; Richert, Laurab,c; Lortholary, Olivierhthe ANRS 129 BKVIR-CYTOK STUDY GROUP

doi: 10.1097/QAD.0000000000000311
Basic Science

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.

Design: 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).

Conclusion: These findings support a role for CD4+ T-cell activation prior to massive inflammation in the development of TB-IRIS.

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.

Correspondence to Lisa A. Chakrabarti, Institut Pasteur, Unité de Pathogénie Virale, 28 rue du Dr Roux, 75724 Paris Cedex 15, France. E-mail:

Received 27 February, 2014

Revised 15 April, 2014

Accepted 16 April, 2014

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© 2014 Lippincott Williams & Wilkins, Inc.