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RANDOMIZED CONTROLLED TRIAL OF PREDNISONE FOR PREVENTION OF PARADOXICAL TB-IRIS
Graeme Meintjes1, Cari Stek2, Liz Blumenthal1, Friedrich Thienemann1, Charlotte Schutz1, Jozefien Buyze2, Gary Maartens1, Robert Wilkinson3, Lutgarde Lynen2
1Univ of Cape Town, Cape Town, South Africa,2Inst of Tropical Med, Antwerp, Belgium,3Imperial Coll, London, UK
Early initiation of antiretroviral therapy (ART) in patients with TB reduces mortality in those with low CD4 counts, but increases the risk of paradoxical TB-IRIS. Prednisone reduces symptoms when used to treat TB-IRIS. We determined whether prophylactic prednisone in patients at high risk for paradoxical TB-IRIS safely reduces the incidence of TB-IRIS.
1:1 randomized, double-blind, placebo-controlled trial of prednisone (40 mg/day for 2 weeks then 20 mg/day for 2 weeks) started with ART in ART-naïve adults at high risk of TB-IRIS (within 30 days of TB treatment initiation and CD4 count ≤100/μl) followed for 12 weeks. Exclusion criteria included rifampicin resistance, neurological TB, Kaposi's sarcoma, hepatitis BsAg+ and poor clinical response to TB treatment. Primary endpoint was development of TB-IRIS, defined using the International Network for the Study of HIV-associated IRIS (INSHI) consensus case definition, adjudicated by an independent committee. Final results are presented.
240 participants were enrolled: median age 36.8 (IQR=30-42.8), 60% men, median CD4 49/μl (IQR=24-86), and median HIV RNA 337,775 copies/ml (IQR=162,223-810,812). TB was microbiologically confirmed in 175. 18 were lost to follow-up or withdrew. TB-IRIS fulfilling INSHI criteria was diagnosed in 56 in the placebo arm (46.7%) and 39 in the prednisone arm (32.5%) (p=0.02, relative risk (RR)=0.70 (95%CI=0.51-0.96)). Open label corticosteroids to treat TB-IRIS was prescribed as necessary in 34 of the placebo arm (28.3%) and 16 (13.3%) of the prednisone arm (RR=0.47 (95%CI=0.27-0.83)). 4 deaths occurred in the placebo arm (1 attributed to TB-IRIS) and 5 in the prednisone arm (p=1.0). 27 were hospitalized (all-cause) in the placebo arm compared with 17 in the prednisone arm (p=0.10). Grade 3 adverse events occurred more frequently in the placebo arm (45.4% vs 29.4%, p=0.01), but grade 4 adverse events were similar by arm (8.4% vs 7.6%, p=0.81). Severe infections (AIDS-defining or invasive bacterial) occurred in 18 in the placebo arm and 11 in the prednisone arm (p=0.17). There was a trend towards fewer interruptions of ART or TB treatment in the prednisone arm (8.3% vs 15.8%, p=0.07).
In patients at high risk of paradoxical TB-IRIS, prednisone during the first 4 weeks of ART reduced the risk of TB-IRIS by 30% and further reduced the requirement for corticosteroids to treat TB-IRIS by 53%. The intervention was well-tolerated with no excess risk of infection or malignancy.