Two hundred and eighty-seven patients were screened and 110 were enrolled (55 to prednisone, 55 to placebo). Progress of participants through the trial is shown in .
Progress of participants through the trial
Seventy (64%) were female and the median age was 31.6 years (range 19-56). Median CD4 count prior to ART was 53 cells/μL, and at enrolment 116 cells/μL. shows baseline characteristics comparing the two arms. Median duration from antitubercular therapy to ART initiation was significantly longer in the prednisone arm. Random cortisol was significantly lower in the prednisone arm, but no participant had a value below reference range. Otherwise the arms were evenly matched. Forty-four participants received antibiotics prior to enrollment.
Participant characteristics at enrollment
Initial tuberculosis diagnosis was made by culture of Mycobacterium tuberculosis in 46 (42%), a positive smear for acid fast bacilli in 26 (24%), and was empiric based on clinical and radiographic findings in 38 (35%). Fourteen of the 38 participants with an initial empiric tuberculosis diagnosis had microbiologic confirmation at some stage during the study (7 culture positive and 7 smear positive).
Outcomes are shown in and . The median cumulative number of hospital days (with outpatient therapeutic procedures counted as one additional day) was 0 (interquartile range, IQR 0-3) in the prednisone arm and 3 (IQR 0-9) in the placebo arm (p=0.04). In a multivariate regression model controlling for baseline differences between the two arms, this difference remained significant (p=0.009).
Primary and secondary outcomesa
a: Symptom score at week 2 and 4
The symptom score showed more rapid improvement in the prednisone arm at 2 weeks (p=0.001) and 4 weeks (p=0.03) (). The chest radiograph score demonstrated greater improvement in the prednisone arm at 2 and 4 weeks (). The ultrasound score (n=29) demonstrated no significant difference at either time point (data not shown). There were significantly greater improvements in MOS-HIV physical and mental health summary scores, Karnofsky performance score and CRP at weeks 2 and 4 in the prednisone arm, but not at later time points.
Five participants switched to open label prednisone during the period of study medication (first 4 weeks) in the prednisone arm and 18 in the placebo arm (p=0.002) (). Three such participants had study allocation unblinded. There was concern of hepatitis B flare in one, oesophagitis due to herpes virus (not confirmed) in another and pancreatitis in a third. All 3 had been allocated placebo. 10 participants in the prednisone arm and 2 in the placebo arm were started on open-label prednisone after completing the 4 weeks of study medication (p=0.01) due to ongoing deterioration or, more frequently, relapse after having improved on study medication. Participants who initiated open label prednisone were weaned according to response. Median duration of open label prednisone was 84 days (IQR 60-126).
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 (more ...)
Eight participants in the prednisone arm and 3 in the placebo arm had events that could potentially be attributed to a glucocorticoid adverse drug reaction while on study medication (p=0.11). Infections while on study medication occurred in 27 participants in the prednisone arm and 17 in the placebo arm (p=0.05). The majority of these infections were mild, mainly oral and vaginal candidiasis, and uncomplicated herpes simplex. Severe infections, defined as invasive bacterial infections or new World Health Organisation stage 4 conditions, occurred in 2 participants in the prednisone arm and 4 in the placebo arm during the 12 week study period (p=0.40). These severe infections were a Klebsiella wound infection complicated by fatal sepsis syndrome, oesophageal candidiasis, pneumocystis pneumonia and cryptococcal meningitis in the placebo arm. The participant who developed oesophageal candidiasis was on open label prednisone when this occurred. In the prednisone arm the severe infections were fatal pneumonia and cytomegalovirus retinitis.
There were 3 deaths in the prednisone arm and 2 in the placebo arm (p=0.70). Six participants defaulted follow up for more than 7 days (all in the placebo arm; p=0.01). Five subsequently returned to care.
Ten cases of rifampicin-resistant tuberculosis were diagnosed after study enrollment. In 8, it was diagnosed after completion of study medication. Three received open label prednisone. In the placebo arm there were 6 cases (5 multidrug-resistant (MDR) and 1 rifampicin-monoresistant) and in the prednisone arm 4 (2 MDR, 1 rifampicin monoresistant and 1 rifampicin resistant on FASTplaque™ assay but other drug susceptibility testing could not be done due to contamination) (p= 0.50). INH-monoresistant tuberculosis was present in 1 participant in the placebo arm (diagnosed at tuberculosis diagnosis) and 1 in the prednisone arm (diagnosed at TB-IRIS presentation).