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

6th IAS Conference, Rome, 20 July 2011

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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.

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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)

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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

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Study profile661 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 developparadoxical TB-IRIS

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Patient characteristics at ART initiation

• Median age (IQR): 35 years (30–41)• Median BMI (IQR): 17.4 kg/m2 (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

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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:

Tim

e (d

ays)

p=0.53

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Clinical manifestationsN (%)

Enlarged lymph nodes Peripheral lymph nodes Intrathoracic lymph nodes Abdominal lymph nodes

942723

Fever 106Abdominal pain 44Pulmonary opacities 31Pleural effusion / pericarditis 20Hepatomegaly 17Ascites 15Neurological symptoms 8

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Treatment & outcome

Treatment during IRIS None Non Steroidal Anti-Inflammatory Drugs Corticosteroids

395759

Median time from TB-IRIS to treatment, daysIQR

5 1–14

Outcome Cured TB-IRIS related death Withdrawal during TB-IRIS

14861

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Risk factors of TB-IRISAdjusted HR 95% CI p

ArmEarlyLate

2.231

1.51–3.27<0.001

CD4 cell count, cells/µL≤100101-200

1.851

1.02–3.340.04

TB locationPulmonary Extra-pulmonary Disseminated

12.061.61

1.34–3.171.10–2.37

0.001

Intrathoracic lymph nodeAbsentPresent

11.64 1.19–2.26

0.003

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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.

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AcknowledgmentsSponsors: ANRS and NIH/DAIDSCambodian Health CommitteeInstitut Pasteur du CambodgeMédecins Sans Frontières – BelgiumCambodian Ministry of HealthCambodian 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 BoardAnd especially all the patients participated to the CAMELIA trial and PLWHA representatives who joined us in this challenge.