1. Incidence and risks factors of paradoxical tuberculosis-associated IRIS in HIV-infected adults enrolled in the CAMELIA clinical trial ANRS 1295/CIPRA KH001 D. Laureillard, O. Marcy, Y. Madec, S. Chan, L. Borand, N. Prak, C. Kim, K.K. Lak, C. Hak, B. Dim, E. Nerrienet, T. Sok, A.E. Goldfeld, F.X. Blanc 6 th IAS Conference, Rome, 20 July 2011

2. 2 Background IRIS is a common complication after ART initiation, particularly in patients treated for TB TB-IRIS incidence: 10-40% 2 clinical presentations: paradoxical / unmasking TB-IRIS Major recognized risk factors: –disseminated TB –low nadir CD4 cell count –short interval between starting TB therapy and ART We report incidence, time of occurrence, clinical features, outcomes and risk factors of paradoxical TB-IRIS in severely immunocompromised HIV-infected adults enrolled in the CAMELIA (CAMbodian Early vs. Late Introduction of ART) trial.

3. 3 CAMELIA trial CAMELIA was a randomized strategy trial with no placebo designed to determine the best timing for ART initiation in naïve HIV-infected adults with CD4 cell count ≤ 200/µL and newly diagnosed TB in Cambodia Two arms of ART initiation after tuberculosis treatment onset: ‘‘early’’ (at 2 weeks) vs. ‘‘late’’ (at 8 weeks) Standard TB regimen: 2RHZE/4RH ART: D4T/3TC/EFV Primary endpoint: survival at the end of the trial 661 patients enrolled and followed for a median time of 25 months Reduced risk of death in the early arm (HR: 0.62; 95% CI, 0.44 to 0.86; p=0.006)

4. 4 Definition of TB-IRIS TB-IRIS was defined as a worsening or emergence of signs or symptoms of TB at any time after ART initiation, exclusion of a newly acquired infection, the clinical evolution of drug-resistant TB, recurrent TB, the expected clinical course of a previously recognized infectious agent, or the side effects of ART Each case of suspected TB-IRIS was reported by on-site treating physicians as an Adverse Event and secondarily reviewed and validated by 2 members of the clinical coordination team

5. 5 Study profile 661 HIV-infected adults enrolled in Camelia trial 64 patients were excluded: - 16 non tuberculous mycobacteria - 37 deaths before ART initiation - 2 withdrawal before ART initiation - 9 without follow-up after start of ART 597 patients enrolled in this analysis 155 developed paradoxical TB-IRIS 442 did not develop paradoxical TB-IRIS

6. 6 Patient characteristics at ART initiation Median age (IQR): 35 years (30 – 41) Median BMI (IQR): 17.4 kg/m 2 (15.8 – 19.1) Median CD4 cell count: 26 cells/µL (12 – 62) Median viral load: 5.6 log copies/mL (5.2 – 6.0) No difference between patients with or without TB-IRIS

7. 7 Incidence & timing of TB-IRIS TB-IRIS occurred in 155 patients (26%) Incidence: 3.16 per 100 persons-months (95% CI, 2.7 to 3.7) Median time (IQR) of occurrence: Time (days) p=0.53

8. 8 Clinical manifestations N (%) Enlarged lymph nodes  Peripheral lymph nodes  Intrathoracic lymph nodes  Abdominal lymph nodes 94 27 23 Fever106 Abdominal pain44 Pulmonary opacities31 Pleural effusion / pericarditis20 Hepatomegaly17 Ascites15 Neurological symptoms8

9. 9 Treatment & outcome Treatment during IRIS  None  Non Steroidal Anti-Inflammatory Drugs  Corticosteroids 39 57 59 Median time from TB-IRIS to treatment, days IQR 5 1–14 Outcome  Cured  TB-IRIS related death  Withdrawal during TB-IRIS 148 6 1

10. 10 Risk factors of TB-IRIS Adjusted HR95% CIp Arm Early Late 2.23 1 1.51–3.27 <0.001 CD4 cell count, cells/µL ≤100 101-200 1.85 1 1.02–3.34 0.04 TB location Pulmonary Extra-pulmonary Disseminated 1 2.06 1.61 1.34–3.17 1.10–2.37 0.001 Intrathoracic lymph node Absent Present 1 1.641.19–2.26 0.003

11. 11 Conclusions High frequency (26%) of paradoxical TB-IRIS in HIV- infected patients with advanced immunodeficiency Double the risk of developing TB-IRIS (HR 2.23) when ART initiated at 2 weeks Median time of TB-IRIS occurrence: 2 weeks, irrespective of early or late ART initiation Low mortality directly related to TB-IRIS: 6/155 (3.9%) in accordance with published data During the first weeks following ART initiation, clinicians should be vigilant to recognize signs of TB-IRIS (lymph nodes, fever, abdominal pain…). However TB-IRIS should not be a barrier against early ART initiation in severely immunosuppressed patients.

12. 12 Acknowledgments Sponsors: ANRS and NIH/DAIDS Cambodian Health Committee Institut Pasteur du Cambodge Médecins Sans Frontières – Belgium Cambodian Ministry of Health Cambodian National TB Program (CENAT) Cambodian National AIDS Program (NCHADS) All investigators, nurses, technicians, monitors, social workers of study sites: Khmer-Soviet Friendship Hospital (Phnom Penh), Donkeo Provincial Hospital (Takeo), Calmette Hospital (Phnom Penh), Svay Rieng Provincial Hospital and Siem Reap Referral Hospital Members of the DSMB and the Scientific Advisory Board And especially all the patients participated to the CAMELIA trial and PLWHA representatives who joined us in this challenge.