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Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome after early initiation of antiretroviral therapy in a randomized clinical trial

Laureillard, Didiera; Marcy, Olivierb,c; Madec, Yoannd; Chea, Sokeoc; Chan, Sarinc,e; Borand, Laurenceb; Fernandez, Marceloc; Prak, Naromf; Kim, Chindamonyg,h; Dim, Bunneth,i; Nerrienet, Ericb; Sok, Thimc; Delfraissy, Jean-Françoisj; Goldfeld, Anne E.c,k; Blanc, François-Xavierjfor the CAMELIA (ANRS 1295 – CIPRA KH001) Study Team

doi: 10.1097/01.aids.0000432456.14099.c7
Clinical Science

Objective: To analyze cases of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in the CAMbodian Early versus Late Introduction of Antiretrovirals (CAMELIA) randomized trial designed to compare early (2 weeks) versus late (8 weeks) antiretroviral therapy (ART) initiation after tuberculosis treatment onset in Cambodia (NCT00226434).

Methods: ART-naive adults with CD4+ cell count of 200 cells/μl or less, newly diagnosed tuberculosis, and at least one follow-up visit after ART initiation were included in this analysis. Each case of suspected TB-IRIS was systematically validated by two physicians not involved in patients’ management. Factors associated with occurrence of TB-IRIS were identified using the Cox proportional hazard model.

Results: Among 597 patients, 26% experienced TB-IRIS with an incidence rate of 37.9 cases per 100 person-years [95% confidence interval (CI) 32.4–44.4]. Main clinical manifestations included new or worsening lymphadenopathy (77.4%) and fever (68.4%). Chest radiograph revealed new or worsening abnormalities in 53.4%. Symptoms resolved in 95.5% of patients. Six deaths were directly related to TB-IRIS. Initiating ART early increased the risk of TB-IRIS by 2.61 (95% CI 1.84–3.70). Extrapulmonary or disseminated tuberculosis, CD4+ cell count of 100 cells/μl or less, and HIV RNA concentration more than 6 log10 copies/ml were also significantly associated with higher risk of TB-IRIS.

Conclusion: Shortening the delay between tuberculosis treatment onset and ART initiation to 2 weeks was associated with an increased risk of developing TB-IRIS. However, TB-IRIS was generally easily manageable. Given the marked reported survival advantage of early ART initiation after tuberculosis treatment onset, these data indicate that fear of TB-IRIS should not be an impediment to early ART in adults with advanced immunodeficiency in resource-limited, high burden settings.

aFrench National Agency for Research on AIDS and Viral Hepatitis (ANRS), Ho Chi Minh City, Vietnam

bInstitut Pasteur du Cambodge, Phnom Penh, Cambodia

cCambodian Health Committee, Phnom Penh, Cambodia

dInstitut Pasteur, Paris, France

eCalmette Hospital, Phnom Penh, Cambodia

fKhmer Soviet Friendship Hospital, Phnom Penh, Cambodia

gDonkeo Provincial Hospital, Takeo, Cambodia

hMédecins Sans Frontières, Phnom Penh, Cambodia

iSiem Reap Referral Hospital, Siem Reap, Cambodia

jAssistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Hôpitaux Universitaires Paris Sud, Le Kremlin-Bicêtre, France

kProgram in Cellular and Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Correspondence to François-Xavier Blanc, MD, PhD, Service de Pneumologie, Hôpital Bicêtre, 78 Rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France. Tel: +33 620 444 620; e-mail: xavier.blanc@bct.aphp.fr

Received 5 May, 2013

Revised 20 May, 2013

Accepted 13 June, 2013

A summary of the results was presented at the 6th International AIDS Conference, Rome, Italy, 20 July 2011.

© 2013 Lippincott Williams & Wilkins, Inc.