Clinical Pearls & Morning Reports
Tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) is associated with considerable morbidity, and 25% of patients with this syndrome are hospitalized. Meintjes et al. conducted a phase 3, randomized, double-blind, placebo-controlled trial to test the hypothesis that a low dose of glucocorticoids to attenuate the aberrant inflammatory response that underlies tuberculosis-associated IRIS during early antiretroviral therapy (ART) would reduce the risk of this syndrome. Read the latest NEJM Original Article here.
Q: What are features of paradoxical tuberculosis-associated IRIS?
A: Paradoxical tuberculosis-associated IRIS — an immunopathologic reaction characterized by recurrent or new inflammatory features of tuberculosis that manifest shortly after the initiation of ART in patients receiving antituberculosis treatment — occurs in 18% of patients (range, 4 to 54), according to a pooled estimate derived from 40 observational cohort studies. Features include recurrent symptoms, fever, lymphadenitis, and worsening pulmonary infiltrates on radiography.
Q: What are risk factors for the development of tuberculosis-associated IRIS?
A: Low CD4 counts and a short interval between the start of antituberculosis treatment and the start of ART increase the risk of tuberculosis-associated IRIS. Clinical trials that evaluated the timing of ART in patients with tuberculosis showed that early initiation of ART (initiation approximately 2 weeks after the start of antituberculosis treatment) resulted in a higher survival rate than ART initiated approximately 8 weeks after the start of antituberculosis treatment in patients with CD4 counts of 50 cells or fewer per microliter. These findings informed World Health Organization guidelines, which emphasize accelerating ART initiation in patients with tuberculosis and low CD4 counts. However, despite the survival benefit, early initiation of ART more than doubles the risk of tuberculosis-associated IRIS. No evidence-based strategy to prevent tuberculosis-associated IRIS exists.
A: The trial by Meintjes et al. was conducted at an HIV–TB clinic in Khayelitsha, Cape Town, South Africa. Enrolled patients had a CD4 count of 100 cells or fewer per microliter, and had been receiving antituberculosis treatment for less than 30 days before initiating ART. The prednisone or placebo was started within 48 hours after the initiation of ART. Patients in the prednisone group received 40 mg of prednisone (in 5-mg tablets) per day for 14 days, followed by 20 mg per day for 14 days. The primary end point was the development of paradoxical tuberculosis-associated IRIS within 12 weeks after initiating ART. Prophylactic prednisone during the first 4 weeks after the initiation of ART in adult patients at high risk for tuberculosis-associated IRIS resulted in a 30% lower incidence of tuberculosis-associated IRIS than placebo. A total of 39 of 120 patients (32.5%) in the prednisone group and 56 of 120 patients (46.7%) in the placebo group received a diagnosis of paradoxical tuberculosis-associated IRIS (relative risk, 0.70; 95% confidence interval [CI], 0.51 to 0.96; P=0.03).
A: Prednisone use was not associated with an excess risk of severe infections, cancers, or adverse events. A total of 33 severe infections (defined as new acquired immunodeficiency syndrome [AIDS]–defining illnesses or invasive bacterial infections) were diagnosed in 29 patients: 11 (9.2%) in the prednisone group and 18 (15.1%) in the placebo group (P=0.23).