Randomized Placebo-controlled Trial of
Prednisone for the TB-Immune Reconstitution
Inflammatory Syndrome
Graeme Meintjes1,2, Robert J Wilkinson1,2,3,4,
Chelsea Morroni1, Dominique Pepper1,2, Kevin
Rebe1,2, Molebogeng Rangaka1, Tollulah Oni1,3,
Gary Maartens1
1. University of Cape Town, 2. GF Jooste Hospital, 3. Imperial
College London, 4. National Institute for Medical Research (UK)
Paradoxical TB-IRIS
• Incidence: 8-43%1
• Anecdotal reports of symptomatic improvement with corticosteroids2 but potential risks3
– Kaposi’s sarcoma
– Herpes virus reactivations
– Other infections
1. Meintjes et al, Lancet Infect Dis 2008 2. Breen et al, Thorax 2004 3. Elliott et al, J Infect Dis 2004
Study Design
• Hypothesis: 4 week course of prednisone would reduce need for medical interventions without excess adverse events
• Study drug– Prednisone or placebo, randomized, double-blind
– 1.5mg/kg for 2 weeks then 0.75mg/kg for 2 weeks
• Follow up assessments at 1, 2, 4, 8 and 12 weeks
• Open-label prednisone at physician discretion if clinical deterioration/relapse
• Predefined primary endpoint*– Cumulative number of days hospitalized and outpatient
therapeutic procedures counted as 1 additional day
*Trial registered: http://www.controlled-trials.com/ISRCTN21322548/maartens
Case Definition
• Prior to ART
– Microbiologic, histologic or very strong clinical evidence of TB
– Initial improvement during TB treatment
– Infecting strain of M. tuberculosis susceptible to rifampicin (if result available)
– Receiving TB treatment when ART initiated
• Within 3 months of initiating ART
– New or recurrent TB-related symptoms
– Presence of ≥ 1 following TB manifestations
• Lymph node enlargement
• Cold abscess
• Serous effusion
• Radiographic pulmonary infiltrate
– No other opportunistic disease to explain clinical deterioration
Exclusion criteria
• Age < 18 years
• Pregnancy
• Prior ART exposure
• Kaposi’s sarcoma
• Uncontrolled diabetes mellitus
• Adrenal failure
• Prior adjunctive corticosteroid therapy for this TB episode
• Life threatening TB-IRIS
– Neurological involvement
– Respiratory failure
– Airway compression
287 screened (June 2005 - December 2007)
110 enrolled
55 placebo arm
2 died
6 defaulted (2 LTF)
3 discontinued study drug
6 rifampicin resistance
55 prednisone arm
3 died
0 defaulted
1 discontinued study drug
4 rifampicin resistance
Alternative diagnosis = 44
Unwilling/unable to consent = 13
Did not fulfill case definition = 65
Exclusion criterion = 55
Baseline characteristics
Placebo
arm
Prednisone
arm
P-value
Age (median, years) 31.6 31.5 0.82
Gender 32F; 23M 38F; 17M 0.23
Previous TB 10 15 0.26
WHO stage 4 33 29 0.44
Duration TB treatment to ART (median, days) 43.5 66 0.02
Duration ART to IRIS (median, days) 10 14 0.21
CD4 prior to ART (median, cells/ L) 48 56 0.15
CD4 at enrollment (median, cells/ L) 109 138 0.07
Hospitalized at enrollment 19 14 0.30
Primary endpointCumulative number of days hospitalized and outpatient
therapeutic procedures (counted as 1 additional day), ITT analysis
Placebo
arm
N = 55
Prednisone
arm
N = 55
P-value
Total days hospitalized 463 282 -
Total number outpatient procedures 31 27 -
Cumulative primary endpoint (median, IQR) 3 (0-9) 1 (0-3) 0.046
Ultrasound score demonstrated no differences at week 2 or 4
Adverse events
Placebo
arm
Prednisone
arm
P-value
Death on study 2 (4%) 3 (5%) 0.65
Corticosteroid side effects* 18 (33%) 12 (22%) 0.20
Corticosteroid side effects
while on study drug
3 (5%) 8 (15%) 0.11
Infections 30 (55%) 36 (65%) 0.24
Severe infections** 4 (7%) 2 (4%) 0.40
* Included BP > 140/90, oedema, hyperglycaemia, hypomania,
acne, Cushingoid features, gastritis symptoms
** WHO stage 4 or invasive bacterial infection
Conclusions
• Prednisone reduced need for medical interventions
(days hospitalized and outpatient procedures combined)
• Consistent benefit, maximal in first 4 weeks, across a range of secondary outcome measures
– Symptom score
– Karnofsky performance score
– Radiology score
– C-reactive protein
• Benefit shown despite crossovers to open label prednisone, that may have reduced observed effect size
• No excess of steroid side effects or infections
• For some patients, 4 weeks appeared to be too short
• Exclusion of rifampicin resistance and alternative diagnoses is critical
