Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome

Abstract

Objective: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of antiretroviral therapy in resource-limited countries. We aimed to assess whether a 4-week course of prednisone would reduce morbidity in patients with paradoxical TB-IRIS without excess adverse events.

Design: A randomized, double-blind, placebo-controlled trial of prednisone (1.5 mg/kg per day for 2 weeks then 0.75 mg/kg per day for 2 weeks). Patients with immediately life-threatening TB-IRIS manifestations were excluded.

Methods: The primary combined endpoint was days of hospitalization and outpatient therapeutic procedures, which were counted as one hospital day.

Results: One hundred and ten participants were enrolled (55 to each arm). The primary combined endpoint was more frequent in the placebo than the prednisone arm {median hospital days 3 [interquartile range (IQR) 0-9] and 0 (IQR 0-3), respectively; P = 0.04}. There were significantly greater improvements in symptoms, Karnofsky score, and quality of life (MOS-HIV) in the prednisone vs. the placebo arm at 2 and 4 weeks, but not at later time points. Chest radiographs improved significantly more in the prednisone arm at weeks 2 (P = 0.002) and 4 (P = 0.02). Infections on study medication occurred in more participants in prednisone than in placebo arm (27 vs. 17, respectively; P = 0.05), but there was no difference in severe infections (2 vs. 4, respectively; P = 0.40). Isolates from 10 participants were found to be resistant to rifampicin after enrolment.

Conclusion: Prednisone reduced the need for hospitalization and therapeutic procedures and hastened improvements in symptoms, performance, and quality of life. It is important to investigate for drug-resistant tuberculosis and other causes for deterioration before administering glucocorticoids.

Figure 1. Progress of participants through the trial

^a Common alternative diagnoses were drug reaction (9), bacterial infection (8), cryptococcosis (4), diarrhoeal illness (4) and heart failure (4). ^b Among these 33 patients the most frequent immediately life threatening manifestation was neurological TB-IRIS (n=25).

Figure 2

a: Symptom score at week 2 and 4 The distribution of symptom scores in percentage at week 2 and 4 in 3 categories (deteriorated, no change, improved/resolved) is shown. Participants who switched to open label prednisone at or before week 2 were not scored at week 4 (they are shown in a separate category together with those who died within 2 weeks on the week 4 graph). There were significant differences between the 2 arms at week 2 (p=0.001) and week 4 (p=0.03). b: Chest radiograph score at week 2 and 4 Participants who had a pulmonary infiltrate on chest radiograph at baseline (week 0) had a chest radiograph score assigned at week 2 and 4 by 2 radiologists. Scores were allocated in 3 categories (deteriorated, no change, improved/resolved) in comparison with the week 0 chest radiograph. The distribution of scores in percentage is shown. There were significant differences between the 2 arms at week 2 (p=0.002) and week 4 (p=0.02).

Figure 2

a: Symptom score at week 2 and 4 The distribution of symptom scores in percentage at week 2 and 4 in 3 categories (deteriorated, no change, improved/resolved) is shown. Participants who switched to open label prednisone at or before week 2 were not scored at week 4 (they are shown in a separate category together with those who died within 2 weeks on the week 4 graph). There were significant differences between the 2 arms at week 2 (p=0.001) and week 4 (p=0.03). b: Chest radiograph score at week 2 and 4 Participants who had a pulmonary infiltrate on chest radiograph at baseline (week 0) had a chest radiograph score assigned at week 2 and 4 by 2 radiologists. Scores were allocated in 3 categories (deteriorated, no change, improved/resolved) in comparison with the week 0 chest radiograph. The distribution of scores in percentage is shown. There were significant differences between the 2 arms at week 2 (p=0.002) and week 4 (p=0.02).

Figure 3

Thirty-five participants were started on open label prednisone (20 in the placebo arm and 15 in the prednisone arm). This Kaplan-Meier graph demonstrates the differences in the time that open label prednisone was started between the two arms. In the first 4 weeks while participants were receiving study medication, 18 in the placebo arm (33%) vs 5 in the prednisone arm (9%) were switched to open label prednisone (p=0.002) because of significant symptom deterioration. After 4 weeks, 2 in the placebo arm (4%) vs 10 in the prednisone arm (18%) were started on open-label prednisone (p=0.01) mainly because of relapse of TB-IRIS symptoms.