A Randomized, Double-Blind, Placebo-Controlled Trial of the Use of Prednisolone as an Adjunct to Treatment in HIV-1-Associated Pleural Tuberculosis
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
MAJOR ARTICLE
A Randomized, Double-Blind, Placebo-Controlled
Trial of the Use of Prednisolone as an Adjunct
to Treatment in HIV-1–Associated Pleural Tuberculosis
Alison M. Elliott,1,3 Henry Luzze,2 Maria A. Quigley,3 Jessica S. Nakiyingi,1 Steven Kyaligonza,2
Proscovia B. Namujju,1 Constance Ducar,2 Jerrold J. Ellner,4 James A. G. Whitworth,1,3 Roy Mugerwa,2
John L. Johnson,2 and Alphonse Okwera2
1
Uganda Virus Research Institute, Entebbe, and 2Uganda–Case Western Reserve University Research Collaboration, Mulago Hospital,
Kampala, Uganda; 3London School of Hygiene and Tropical Medicine, London, United Kingdom; 4University of Medicine and Dentistry
of New Jersey, Newark
Downloaded from http://jid.oxfordjournals.org/ by guest on August 14, 2015
Background. Active tuberculosis may accelerate progression of human immunodeficiency virus (HIV) infection
by promoting viral replication in activated lymphocytes. Glucocorticoids are used in pleural tuberculosis to reduce
inflammation-induced pathology, and their use also might reduce progression of HIV by suppressing immune
activation. We examined the effect that prednisolone has on survival in HIV-1–associated pleural tuberculosis.
Methods. We conducted a randomized, double-blind, placebo-controlled trial of prednisolone as an adjunct
to tuberculosis treatment, in adults with HIV-1–associated pleural tuberculosis. The primary outcome was death.
Analysis was by intention to treat.
Results. Of 197 participants, 99 were assigned to the prednisolone group and 98 to the placebo group. The
mortality rate was 21 deaths/100 person-years (pyr) in the prednisolone group and 25 deaths/100 pyr in the
placebo group (age-, sex-, and initial CD4+ T cell count–adjusted mortality rate ratio, 0.99 [95% confidence
interval, 0.62–1.56] [P p .95 ]). Resolution of tuberculosis was faster in the prednisolone group, but recurrence
rates were slightly (though not significantly) higher, and use of prednisolone was associated with a significantly
higher incidence of Kaposi sarcoma (4.2 cases/100 pyr, compared with 0 cases/100 pyr [P p .02]).
Conclusions. In view of the lack of survival benefit and the increased risk of Kaposi sarcoma, the use of
prednisolone in HIV-associated tuberculous pleurisy is not recommended.
Glucocorticoids, such as prednisolone, have potent sup- infection status [2, 3]. In pleural tuberculosis, the ben-
pressive effects on the immune response to tuberculosis. efits are less dramatic, but, in HIV-negative patients,
In the absence of specific treatment, this leads to in- the rate of clinical resolution is also more rapid [4–6].
creased susceptibility to tuberculosis [1] but, given with Glucocorticoids have also been recommended in forms
antituberculosis drugs, glucocorticoids have some ben- of tuberculosis in which inflammatory damage is of
efits. In patients with tuberculous pericarditis, the use particular concern (such as meningeal, ocular, and ure-
of prednisolone is associated with better survival and teric tuberculosis) and in patients who are seriously ill
more-rapid resolution of the effusion, regardless of HIV with any form of tuberculosis [7].
Several lines of evidence suggest that prednisolone
may have particular benefits in HIV-associated tuber-
Received 10 October 2003; accepted 26 January 2004; electronically published culosis. Observational studies in Zambia, where pred-
29 July 2004.
Presented in part: 33rd International Union against Tuberculosis and Lung nisolone has been used as an adjunct to tuberculosis
Disease World Conference on Lung Health, Montreal, Canada, October 2002; Third treatment for conventional indications [8], have, after
National AIDS Conference, Kampala, Uganda, October 2002.
Financial support: Wellcome Trust Career Development Fellowship (grant 049523 2 years of follow-up, suggested a survival benefit in
to A.M.E.); National Institutes of Health (contract NO1-AI45244/AI95383); British patients with HIV-associated pleural tuberculosis (mor-
Medical Research Council Programme on AIDS in Uganda (to J.A.G.W. and J.S.N.).
Reprints or correspondence: Dr. Alison Elliott, Uganda Virus Research Institute, tality rate ratio, 0.3 [P p .03]; A.M.E., unpublished
PO Box 49, Entebbe, Uganda (alison.tom@infocom.co.ug). data). Laboratory studies have emphasized the high de-
The Journal of Infectious Diseases 2004; 190:869–78
2004 by the Infectious Diseases Society of America. All rights reserved.
gree of immune activation associated with active tu-
0022-1899/2004/19005-0001$15.00 berculosis [9] and the role that immune activation plays
Prednisolone in Pleural Tuberculosis • JID 2004:190 (1 September) • 869in promoting replication of HIV. Cytokines such as tumor ne- diagnostic purposes; if they were found to have empyema; if they
crosis factor (TNF)–a, induced in response to tuberculosis, had a second, major HIV-related disease (Kaposi sarcoma, oral-
promote transcription of proviral DNA through activation of esophageal thrush, or a positive serum cryptococcal antigen test);
host transcription factors, such as NF-kB, which have binding if they had risk factors for serious steroid-related adverse events
sites on the long-terminal repeat sequence of the viral genome (a history of diabetes or positive urine glucose, a history or
[10]. Furthermore, glucocorticoids induce transcription and clinical finding of hypertension, or a history of peptic ulcer dis-
synthesis of the inhibitor of NF-kB (IkB), suggesting that this ease or mental illness); if standard doses of antituberculosis drugs
might be an important mechanism for their immunosuppres- could not be used (as in participants with concurrent liver dis-
sive effects [11, 12] and that glucocorticoids might block cy- ease); or if they were seronegative for HIV.
tokine-induced increases in HIV transcription through this Ethics approval for the study was given by the Uganda National
pathway. Such effects might be of considerable significance, AIDS Research subcommittee, the science and ethics committee
because active tuberculosis is associated with increased viral of the Uganda Virus Research Institute, the Uganda National
load in vivo [13] and with a subsequent increase in the mortality Council for Science and Technology, and the ethics committee
rate in HIV-infected subjects [14]. The use of prednisolone in of the London School of Hygiene and Tropical Medicine.
asymptomatic HIV-infected subjects is associated with reduced Randomization and blinding. The randomization se-
immune activation and a sustained increase in CD4+ T cell quence was generated by a statistician who was not involved
counts [15]. in the care of the patients, by use of STATA (version 5; Stata
Downloaded from http://jid.oxfordjournals.org/ by guest on August 14, 2015
We therefore proposed the hypothesis that the use of pred- Corporation). Randomization was done in blocks of 20. Pred-
nisolone as an adjunct to tuberculosis therapy in HIV-infected nisolone and matching placebo tablets (Berk Pharmaceuticals)
patients with pleural tuberculosis would be associated with a were packaged in identical plastic bags, which were labeled with
decrease in viral replication and with a long-term improvement randomization code numbers by 2 people who were not in-
in survival. Prednisolone is widely available and is cheap; if we volved in the study. Medical staff gave participants the next
could demonstrate a substantial survival benefit, we hoped that number in the sequence in the order in which they were en-
the use of prednisolone for this indication could be widely rolled. All participants and medical, laboratory, and statistical
recommended in sub-Saharan Africa. Set against this, we were
concerned that prednisolone-induced immunosuppression might
increase the risk of opportunistic diseases, including Kaposi
sarcoma, cryptococcal meningitis, and herpes zoster. We de-
signed the present study to address this hypothesis and to assess
the benefits and risks of the intervention.
PARTICIPANTS, MATERIALS, AND METHODS
Participants. Participants were recruited at the National Tu-
berculosis Treatment Centre, Mulago Hospital (Kampala, Ugan-
da), between November 1998 and January 2002. Follow-up for
all participants continued until July 2002. Participants were
screened for inclusion in the study if they (1) were ⭓18 years
old and they presented with clinical features suggesting pleu-
ral tuberculosis, with a pleural effusion occupying at least one-
third of 1 hemithorax (as determined by a radiograph); (2) had
not previously received treatment or prophylaxis for tuberculosis;
(3) had not recently received treatment with glucocorticoids; (4)
were not pregnant or breast-feeding; and (5) were residents of
Kampala. After providing written, informed consent for partic-
ipation in the study and for HIV testing, potential participants
received a full medical examination, provided urine and blood
samples, and underwent pleural aspiration and, if possible, bi-
opsy. All participants received pre– and post–HIV test counseling.
Participants were excluded if they failed to complete the
screening procedures; if pleural fluid could not be obtained for Figure 1. Trial profile. +, Positive.
870 • JID 2004:190 (1 September) • Elliott et al.Table 1. Comparison of placebo and prednisolone groups at enrollment.
Placebo Prednisolone
a
Category, variable (n p 98) (n p 99) P
Age, mean (SD), years 34 (8) 34 (9) .70
Sex
Male 60 (61) 54 (55) .34
Female 38 (39) 45 (45) …
Weight, mean (SD), kgb 53 (8) 54 (9) .21
Blood pressure, mean (SD), mm Hg
Systolic 101 (10) 102 (13) .29
Diastolic 72 (11) 73 (11) .81
Symptoms
Fever 60 (61) 66 (67) .43
Cough 84 (86) 91 (92) .17
Dyspnea 86 (88) 83 (84) .43
Chest painb 82 (85) 84 (85) .95
Anorexia 77 (79) 72 (73) .34
Weight loss 83 (85) 86 (87) .66
Signs
Downloaded from http://jid.oxfordjournals.org/ by guest on August 14, 2015
Fever ⭓37.5C 53 (54) 55 (56) .84
Karnofsky score ⭓80%c 49 (51) 59 (60) .17
d
Oral thrush 5 (5) 9 (9) .28
Herpes zoster scars 12 (12) 13 (13) .85
Lymphadenopathyd 11 (11) 12 (12) .86
Laboratory findings
CD4+ T cell count, median (interquartile range), cells/mL 93 (58–219) 118 (57–211) .57
Confirmed TB 91 (93) 89 (90) .46
Isoniazid resistancee 5 (6) 5 (6) 1.00
Pyrazinamide resistancee 0 1 (1) .32
Radiography findingsf
1 zone affected 18 (19) 14 (15) .75
2 zones affected 46 (47) 49 (51) …
⭓3 zones affected 33 (34) 33 (34) …
NOTE. Data are no. (%) of participants, unless otherwise noted. TB, tuberculosis.
a
For proportions, the x2 test was used; for means, the t test was used; for medians, the Wilcoxon rank sum
test was used.
b
One missing value.
c
Two missing values.
d
Three missing values.
e
Eighty-two participants in each group had complete drug sensitivity data.
f
One zone equals one-third of 1 hemithorax; enrollment radiographs were not analyzed for 4 participants.
staff remained blinded to the treatment allocation until all data used for participants with predominantly pleural tuberculosis,
collection had been completed. to make allowance for the effect that rifampicin has on steroid
Treatment regimens. Tuberculosis treatment comprised metabolism [8, 17].
ethambutol, isoniazid, rifampicin, and pyrazinamide taken on a Patient care and follow-up. Participants either were
daily basis for 2 months, followed by isoniazid and rifampicin admitted to the tuberculosis ward or (in exceptional circum-
taken on a daily basis for 4 months. Doses were adjusted ac- stances) attended the ward daily, for directly observed treatment
cording to each participant’s weight, using standard criteria [16]. for 1 week; during this period, blood pressure was also mon-
Prednisolone was supplied as 5-mg tablets and was given itored daily. After 1 week, participants were taken home by the
concomitantly with tuberculous therapy at a dosage of 50 mg home health visitor, to fully identify their addresses. During
daily for 2 weeks, followed by 40 mg daily for 2 weeks, followed the 8-week period of treatment with the study drug, participants
by 25 mg daily for 2 weeks, followed by 15 mg daily for 2 collected their medicine from the clinic every 2 weeks; in ad-
weeks; prednisolone treatment was then stopped. This dosage dition, they were visited regularly by the home health visitor,
regimen was ∼2.5 times that used in the previous study in who counted the number of tablets remaining, for comparison
Zambia, during which rifampicin-containing regimens were not with the expected number. Thereafter, participants attended the
Prednisolone in Pleural Tuberculosis • JID 2004:190 (1 September) • 871Table 2. Comparison of follow-up and adherence to treatment.
Placebo Prednisolone
a
Category, variable (n p 98) (n p 99) P
Follow-up and attendance
Losses to follow-up/withdrawals 6 (6) 3 (3) .30
Follow-up time, median (interquartile range), years 1.48 (0.78–2.45) 1.65 (0.90–2.63) .23
Follow-up time, total person-years 153 172 …
Scheduled visits, total 923 983 …
Unscheduled visits, total 563 561 …
b b
(n p 97) (n p 97)
Treatment deviations from the study protocol
Unscheduled removal of pleural fluid 3 (3) 4 (4) .70
Temporary discontinuation of TB treatment due to TB drug reaction 6 (6) 2 (2) .15
Change in TB treatment for TB drug resistance 3 (3) 1 (1) .31
Discontinuation of study drug 9 (9) 13 (13) .36
Participants’ adherence to treatment with study drug
No. of home visits/patient, mean 5 5 .87
Proportion of visits at which tablet counts were correct, meanc 0.96 0.98 .07
Downloaded from http://jid.oxfordjournals.org/ by guest on August 14, 2015
Participants known to have missed 1 week to 1 monthd 8 (8) 4 (4) .23
Participants known to have missed ⭓1 monthd 4 (4) 5 (5) .73
Participants’ adherence to tuberculosis treatment
Urine isoniazid tests, no. positive/performed (%)
1 month 82/88 (93) 85/88 (97) .30
2 months 73/85 (86) 78/85 (92) .22
6 months 60/76 (79) 60/80 (75) .56
Participants known to have missed 1 week to 1 monthd 6 (6) 4 (4) .52
Participants known to have missed ⭓1 monthd 8 (8) 8 (8) 1.00
Completion of tuberculosis treatment
Completede 81 (83) 85 (86) .76
Defaulted before completion 6 (6) 4 (4) …
Died before completion 11 (11) 10 (10) …
NOTE. Data are no. (%) of participants, unless otherwise noted. TB, tuberculosis.
a
For proportions, the x2 test was used; for means, the t test was used; for medians, the Wilcoxon rank sum test was used.
b
Excluding 1 participant in the placebo group and 2 participants in the prednisolone group who had no follow-up.
c
Excluding 5 participants who were not visited at all.
d
Including participants whose drugs were omitted for legitimate reasons as well as defaulters.
e
Including 3 participants who received all drugs but were not seen at or after completion of treatment.
clinic monthly until the end of tuberculosis therapy (at 6 therapy was monitored by use of urine tests for isoniazid me-
months) and then every 3 months afterward. In addition, par- tabolites (BBL Taxo INH strips; Becton Dickinson) at 1, 2, and
ticipants were encouraged to attend the clinic at unscheduled 6 months. Blood and pleural fluid samples from the first 40
times for clinical care if they became sick, and investigations participants were analyzed for HIV load by use of the Amplicor
and treatment were provided free of charge. HIV-1 Monitor test (version 1.5; Roche Diagnostic Systems);
Clinical laboratory investigations. A diagnosis of HIV in- samples of pleural fluid were analyzed at enrollment and at 1
fection was made at enrollment on the basis of a positive rapid week; samples of plasma were analyzed at enrollment, at 1 week,
test for HIV (Determine HIV-1–2; Abbott Laboratories) and was and at 1, 2, and 6 months.
confirmed either by ELISA (Vironostika HIV-1 Microelisa; Or- Diagnosis of tuberculosis. The diagnosis of tuberculosis
ganon Teknika) or by a 3-level, rapid-test algorithm. Serum cryp- was made as described elsewhere [18]. Pleural tuberculosis was
tococcal antigen tests (Crypto LA; Wampole Laboratories) were considered to be confirmed if a patient had a positive culture
performed at enrollment and as clinically warranted. CD4+ T cell for Mycobacterium tuberculosis from pleural biopsy tissue, pleu-
counts (FACScount; Becton Dickinson) were measured at en- ral fluid, or sputum or if histopathologic analysis of pleural
rollment and at 1, 2, 6, and 18 months after treatment was begun. tissue was consistent with tuberculous pleurisy. Susceptibility
Serum glucose levels were measured at enrollment and at 1 week. testing against isoniazid, rifampicin, ethambutol, and pyrazin-
Urine was examined for glucose by dipstick testing at enrollment amide was performed by use of the BACTEC radiometric cul-
and at 1 week, 1 month, and 2 months. Adherence to tuberculosis ture system (Becton Dickinson).
872 • JID 2004:190 (1 September) • Elliott et al.signed rank test for matched pairs. We calculated rates for death
and for progression to the first episode of each HIV-related
disease. Crude and adjusted rate ratios were estimated by use
of Cox proportional hazards regression, and P values were es-
timated by use of the likelihood ratio test. For HIV-related
diseases that could occur more than once, we also calculated
overall rates and estimated rate ratios (using a random-effects
Poisson model) and P values (using the Wald test).
Two interim analyses were conducted by a data monitoring
committee not otherwise involved in the trial. The first interim
analysis was for safety and included the first 40 participants,
with follow-up to at least 1 week. The main outcome was viral
load; the objective was to ensure that prednisolone was not
associated with an unexpected increase in viral load. The second
interim analysis was conducted after 150 participants had been
Figure 2. Kaplan-Meier survival estimates and data showing the num- enrolled; the objective was to seek the committee’s advice on
ber of participants at risk at the beginning of each time interval. whether additional funding should be sought for an extension
Downloaded from http://jid.oxfordjournals.org/ by guest on August 14, 2015
of the trial.
Diagnosis of major HIV-associated diseases. Kaposi sar- RESULTS
coma was diagnosed on the basis of clinical findings and was
supported, if the patient consented, by histological examination Three hundred seventy-seven participants were screened (figure
of a biopsy of a typical lesion. Cryptococcal meningitis was 1). Of these, 22 failed to complete the screening procedures.
diagnosed on the basis of clinical findings and a positive se- Seventy-six participants were excluded, the majority (48) be-
rum or cerebrospinal fluid cryptococcal antigen test. Esopha- cause pleural fluid could not be obtained; in many of these
geal candidiasis was a presumptive diagnosis, made on the basis cases, fluid had already been removed at the referring ward or
of the presence of oral thrush with dysphagia. Diagnoses of clinic. Eighty-two were HIV seronegative. One hundred ninety-
herpes zoster, herpes simplex, oral thrush, and gastroenteritis seven HIV-1–seropositive participants entered the trial; 98 re-
were made on the basis of clinical grounds alone. ceived placebo and 99 received prednisolone.
Definition of hypertension and hyperglycemia. Hyper- Clinical, radiological, and laboratory findings at enrollment
tension was defined as systolic blood pressure of 1160 mm Hg in the placebo and prednisolone groups were similar (table 1).
or diastolic blood pressure of 190 mm Hg. Hyperglycemia was The duration of follow-up, attendance at the clinic, and ad-
defined as a random blood glucose level of 1160 mg/dL. herence to protocol in the 2 groups also were similar (table 2).
Statistical analysis. The primary outcome was mortality. Three participants were not seen at any follow-up visit, 1 from
On the basis of the preliminary data from Zambia, we designed the placebo group and 2 from the prednisolone group (1 of
the study to have 80% power to detect a 2-fold difference in whom had died within 1 week, with clinical findings suggestive
mortality between the placebo and prednisolone groups, with of deep vein thrombosis and pulmonary embolism). Therefore,
P ! .05. We calculated that, for mortality rates of 35 deaths/100 clinical findings during follow-up are reported for 97 partici-
person-years (pyr) and 17.5 deaths/100 pyr and allowing for pants in each group. Participants’ adherence to treatment, as
15% loss to follow-up, this would require enrollment of 200 assessed by tablet counts and urine testing for isoniazid, in the
participants, to give a total follow-up of 134 pyr in each group. 2 groups was similar and appeared to be excellent, except at
The analysis was conducted by intention to treat. Secondary the 6-month visit when the percentages of participants with
outcomes were adverse events attributable to the use of glu- positive urine results for isoniazid were 75%–79%; however, at
cocorticoids, resolution of tuberculosis, clinical episodes of HIV- the 6-month visit a proportion of participants had already com-
associated disease, and changes in CD4+ T cell count and viral pleted the full treatment regimen before attending the clinic.
load (in a subset of cases). Adverse events that were attributed to prednisolone and that
Data were entered and analyzed by use of FoxPro for Win- required discontinuation of the use of the study drug were more
dows (version 2.6; Microsoft) and STATA (version 7; Stata Cor- frequent in the prednisolone group (9/97 [9%]) than in the
poration). Simple comparisons were made by use of x2 tests placebo group (2/97 [2%]) (P p .03). In the prednisolone group,
and t tests. Comparisons of CD4+ T cell counts, which show the study drug was discontinued for 2 participants with hyper-
a markedly skewed distribution, were made by use of the Wil- glycemia, 3 with hypertension, 3 with episodes of active herpes
coxon rank sum test for unmatched groups and the Wilcoxon zoster, and 1 with esophageal candidiasis; in the placebo group,
Prednisolone in Pleural Tuberculosis • JID 2004:190 (1 September) • 873Downloaded from http://jid.oxfordjournals.org/ by guest on August 14, 2015 Figure 3. Symptoms and signs of pleural tuberculosis in the study population. A, anorexia; B, weight gain; C, cough; D, pleural effusion obscuring ⭓1 hemidiaphragm on chest radiograph. *P ! .05 ; **P ! .01 ; ***P ! .001 . Superscript a denotes one missing value for weight at enrollment (participant could not stand on scale). the study drug was discontinued for 1 participant with hyper- but the median blood glucose level was 98 mg/dL in both groups glycemia and for 1 with hypertension. After 1 week of treatment, (P p .86). The mean systolic blood pressure was significantly the proportion of participants with a random blood glucose level higher in the prednisolone group than in the placebo group after of 1160 g/dL was higher in the prednisolone group than in the 1 week of treatment (111 mm Hg, compared with 104 mm Hg placebo group (6/96 [6%], compared with 1/95 [1%] [P p .06]), [P p .002]) and after 1 month of treatment (again 111 mm Hg, 874 • JID 2004:190 (1 September) • Elliott et al.
Table 3. Proportion of participants who developed HIV-related diseases and rates of progression to disease events.
Placebo Prednisolone
a
HIV-related disease, rate (n p 97) (n p 97) Rate ratio (95% CI) P
b c
Kaposi sarcoma 0 6 (6) … .03
Rate to first event, per 100 pyr 0 4.2d … .02e
b
Cryptococcal meningitis 5 (5) 3 (3) … .47
d
Rate to first event, per 100 pyr 3.8 2.0 0.55 (0.13–2.29) .40
Esophageal candidiasis 23 (24) 35 (36)b … .06
d
Rate to first event, per 100 pyr 20.6 28.6 1.39 (0.82–2.36) .22
Rate allowing for multiple events in the same participant, per 100 pyr 34.4 34.2f 1.07 (0.60–1.93) .82
Herpes zoster 19 (19) 22 (23)b … .60
Rate to first event, per 100 pyr 16.7 17.7d 1.07 (0.58–1.98) .83
Oral or genital herpes simplex 20 (21) 22 (23)b … .73
Rate to first event, per 100 pyr 17.1 16.9d 0.98 (0.53–1.79) .94
f
Rate allowing for multiple events in the same participant, per 100 pyr 18.3 20.8 1.19 (0.63–2.25) .59
Oral thrush 31 (32) 31 (32)b … 1.00
d
Rate to first event, per 100 pyr 28.3 25.0 0.90 (0.54–1.48) .67
Rate allowing for multiple events in the same participant, per 100 pyr 32.1 38.3f 1.35 (0.75–2.43) .31
b
Gastroenteritis 28 (29) 34 (35) … .36
Downloaded from http://jid.oxfordjournals.org/ by guest on August 14, 2015
d
Rate to first event, per 100 pyr 24.2 27.5 1.15 (0.70–1.90) .58
Rate allowing for multiple events in the same participant, per 100 pyr 29.8 36.2f 1.21 (0.70–2.07) .50
NOTE. CI, confidence interval; pyr, person-years.
a
P values given are for x2 tests for proportions. Rate ratios and P values for single events were estimated by use of Cox proportional hazards
methods. Rate ratios and P values for multiple events (in italics) were estimated by use of a random effects model, to allow for clustering of events
within individual participants.
b
Data are the number (%) of participants who had at least 1 episode (for a total of 194 subjects).
c
Fisher’s exact test.
d
Data are the rate per 100 pyr and rate ratio for progression to the first event (for a total of 194 subjects).
e 2
x test for unequal rates.
f
Data are the rate per 100 pyr and rate ratio allowing for multiple episodes in the same patient (for a total of 3030 clinic visits). Multiple episodes
were defined as episodes separated by at least 2 weeks.
compared with 104 mm Hg [P p .001]), but not at later visits. was compared in participants with CD4+ T cell counts of ⭓200
Symptoms suggestive of gastritis or peptic ulcer disease occurred cells/mL (n p 54) and !200 cells/mL (n p 143). The mortality
in 18 (19%) of the 97 participants in the prednisolone group rate ratio for participants who received prednisolone, compared
and in 12 (12%) of the 97 participants in the placebo group with those who received placebo, was 0.47 (95% CI, 0.14–1.61
(P p .23); in both groups, edema occurred in 15 (15%) of the [P p .22]) in participants with CD4+ T cell counts of ⭓200/
97 participants (P p 1.00). mL, whereas it was 1.04 (95% CI, 0.64–1.71 [P p .87]) in par-
The use of prednisolone had no effect on survival (figure 2). ticipants with CD4+ T cell counts of !200/mL. These 2 rates
There were 36 deaths in the prednisolone group and 39 in the were not statistically significantly different (P p .13 , for inter-
placebo group. The mortality rate was 21 deaths/100 pyr in the action). The second analysis was to determine whether the pred-
prednisolone group and 25 deaths/100 pyr in the placebo group, nisolone’s effect changed with time. The mortality rate ratio was
giving a crude mortality rate ratio of 0.84 (95% confidence in- 0.94 (95% CI, 0.57–1.56 [P p .81]) during the first 1.5 years of
terval [CI], 0.53–1.32 [P p .44]). The mortality rate was higher follow-up and was 0.52 (95% CI, 0.18–1.47 [P p .21]) during
in participants with low initial CD4+ T cell counts, and this the follow-up period after 1.5 years. These 2 rates were not
was the main confounder. Mortality rates were also higher in statistically significantly different (P p .32, for interaction).
participants who were older and in men (compared with The use of prednisolone was associated with more-rapid im-
women), but these 2 effects were not statistically significant. provement in all of the principal symptoms and signs of pleural
After adjusting for age, sex, and the natural logarithm of the tuberculosis. This effect was statistically significant, particularly
initial CD4+ T cell counts, the mortality rate ratio for the pred- during the first few weeks of treatment, for anorexia, weight
nisolone group, compared with the placebo group, was 0.99 loss, and cough (figure 3A–C). Radiological resolution of the
(95% CI, 0.62–1.56 [P p .95]). pleural effusion was also more rapid and more complete in the
Two additional, exploratory analyses of mortality were per- prednisolone group (figure 3D) than in the placebo group. Ten
formed. The first analysis was to determine whether predni- participants required retreatment for recurrent tuberculosis.
solone’s effect was different in participants with relatively pre- The recurrence rate was higher in the prednisolone group (4.5
served immunity. The effect that prednisolone has on survival cases/100 pyr) than in the placebo group (1.8 cases/100 pyr),
Prednisolone in Pleural Tuberculosis • JID 2004:190 (1 September) • 875Table 4. Effect that prednisolone has on CD4+ T cell count and viral load.
Placebo Prednisolone
No. of No. of
a
samples samples P (placebo vs.
Category, variable analyzed Result analyzed Result prednisolone)
Peripheral blood CD4+ T cell count, median (interquartile
range), cells/mL
Enrollment 98 93 (58–219) 99 118 (57–211) .57
4 weeks 88 150 (74–236)b 92 132 (65–266)b .90
8 weeks 87 153 (75–276)b 90 180 (98–272)b .58
24 weeks 77 176 (114–292)b 83 200 (104–349)b .33
72 weeks 46 174 (85–280)c 49 200 (112–294)
c
.36
Peripheral blood viral load, mean (SD), log10 RNA copies/mL
Enrollment 20 5.39 (0.52) 20 5.16 (0.78) .29
1 week 20 5.57 (0.55)c 19 5.47 (0.80)
b
.62
4 weeks 19 5.75 (0.48)b 19 5.53 (0.69)
c
.26
c c
24 weeks 15 5.79 (0.49) 17 5.44 (0.65) .09
Pleural fluid viral load, mean (SD), log10 RNA copies/mL
Enrollment 20 6.25 (0.74) 20 5.74 (1.52) .19
Downloaded from http://jid.oxfordjournals.org/ by guest on August 14, 2015
1 week 16 6.28 (0.60) 11 5.93 (1.14) .30
a
For means, the t test was used; for medians, the rank sum test was used.
b
P ⭐ .001, for comparison of value at enrollment with value at given time point for individuals with data at both time points (Wilcoxon signed rank test).
c
P ⭐ .05, for comparison of value at enrollment with value at given time point for individuals with data at both time points (Wilcoxon signed rank test).
but this difference was not statistically significant (rate ratio, for the first week, and subsequent tablet counts suggested good
2.3 [95% CI, 0.6–9.0] [P p .20]). compliance with the prescribed regimen. The dose prescribed
The use of prednisolone had little effect on HIV-associated was sufficient to achieve demonstrable pharmacological effects
opportunistic infections; the exception was Kaposi sarcoma, in the prednisolone group (i.e., increases in blood sugar and
which occurred only in the prednisolone group (table 3). The blood pressure). In addition, the dramatic effect that predni-
diagnosis was confirmed by biopsy in 5 of the 6 cases; the sixth solone had on radiological resolution of effusions in the pred-
patient had florid disease with typical lesions but refused to nisolone group indicated that the dose was adequate to achieve
undergo a biopsy. All but 1 of the cases occurred during or a significant anti-inflammatory effect. On the other hand, we
soon after treatment with prednisolone: the diagnoses were found no evidence that prednisolone has any effect on viral
made at 2, 4, 7, 9, 16, and 138 weeks from the start of treatment. replication—a quite remarkable result, given the potent effects
In contrast, other conditions, such as cryptococcal meningitis, that glucocorticoids have on gene transcription, and on im-
occurred in both groups and throughout the follow-up period. mune responses (such as TNF-a and Th1 and Th2 cytokine
In both the placebo and prednisolone groups, CD4+ T cell production) that are believed to influence viral replication and
counts and viral loads (the latter analyzed in the first 40 partic- immunity to HIV infection [19].
ipants) increased following treatment (table 4). There were no Active pulmonary tuberculosis has been found to have a
statistically significant differences in CD4+ T cell counts or viral greater effect on mortality in people with CD4+ T cell counts of
loads at any time point, nor were there any statistically significant 1200 cells/mL and after follow-up of 11 year [14]. This finding
differences in the changes between the values at enrollment and suggests that the expected benefit of prednisolone might be
those at subsequent time points (data not shown). greater in participants with higher CD4+ T cell counts and after
prolonged follow-up. However, the present study was not de-
DISCUSSION
signed for these subgroup analyses and no statistically significant
Our results showed that the use of prednisolone as an adjunct differences in effect were observed between participants with high
to treatment for tuberculosis did not improve survival in the and low CD4+ T cell counts, or by duration of follow-up.
HIV-1–infected adults with pleural tuberculosis who partici- There was a marked and sustained increase in CD4+ T cell
pated in our study. This result could have occurred because counts following treatment for tuberculosis, but, paradoxically,
the treatment was not taken or because the dose prescribed this was accompanied by an increase in viral load, suggest-
was insufficient to achieve the expected effects. These expla- ing that the increase in CD4+ T cell counts may not have
nations are unlikely, however. Treatment was directly observed been associated with an improvement in the immune response
876 • JID 2004:190 (1 September) • Elliott et al.against HIV infection. A similar increase in CD4+ T cell counts specifically enhances the risk of developing Kaposi sarcoma.
occurred in both the prednisolone and placebo groups, which Current theories suggest that the production of Th1 cytokines
is in keeping with prednisolone’s lack of effect on mortality. and extravasation of lymphocytes and monocytes are involved
We did, however, observe a considerable benefit from the in the development of Kaposi lesions [26]; surprisingly, these
use of prednisolone with respect to the rate of improvement in processes are the opposite of the principal systemic effects of
symptoms and in radiological resolution of tuberculosis. This glucocorticoids [27]. Thus, the mechanisms by which pred-
finding was in keeping with those of previous studies of HIV- nisolone promotes the development of Kaposi sarcoma remain
seronegative patients [4–6]. The adverse pharmacological ef- to be determined.
fects of prednisolone observed were relatively minor and could Kaposi sarcoma is a disease that causes prolonged suffering,
be monitored quite easily. Given the neutral effect that pred- is difficult and expensive to treat, and is usually fatal. We there-
nisolone has on mortality and viral load, these results might fore conclude that, in view of the lack of survival benefit and
suggest that the use of prednisolone should be implemented. the significant increase in incidence of Kaposi sarcoma, pred-
Despite limited diagnostic facilities, the identification of suitable nisolone should not be used in the treatment of pleural tu-
patients would be relatively straightforward in sub-Saharan Af- berculosis. This recommendation can be applied regardless of
rica, where, after the exclusion of such clinically obvious diag- HIV status, because no long-term benefits have been reported
noses as empyema and cardiac, renal, or hepatic failure, the vast with regards to the use of glucocorticoids in patients with pleu-
majority of patients presenting with lymphocytic pleural effusions ral tuberculosis who are not infected with HIV [28]. This rec-
Downloaded from http://jid.oxfordjournals.org/ by guest on August 14, 2015
are found to have tuberculosis [18, 20]. Of concern would be ommendation cannot necessarily be generalized to apply to the
the inadvertent treatment of patients with a second opportunistic use of prednisolone for other forms of tuberculosis or for other
infection, such as the 3 participants with cryptococcal disease in indications in HIV-infected patients. In the case of pericardial
the present study, who were identified by serum cryptococcal tuberculosis, the use of prednisolone has been shown to im-
antigen testing and would not have been excluded without the prove survival regardless of HIV status, and its use should be
use of this expensive, and rarely available, test. continued [2, 3]. Similarly, the use of prednisolone is lifesaving,
Of much greater concern was the striking association observed and should continue, in severe Pneumocystis carinii pneumonia;
however, in HIV-infected patients, prednisolone should be used
between the use of prednisolone and the incidence of Kaposi
with caution for indications where no beneficial effect on im-
sarcoma. Given the relatively small number of cases and the fact
mediate survival can be expected.
that similar associations were not seen for other opportunistic
infections, this finding might be dismissed as a chance associa-
tion. We believe that this would be inappropriate, for several
Acknowledgments
reasons. First, the result supports the findings of the previous
study in Zambia in which cases of Kaposi sarcoma occurred We thank the staff of the Uganda–Case Western Reserve University Re-
search Collaboration, Mulago Hospital (Kampala, Uganda); the Depart-
only in the prednisolone-treated group [8]. Second, in the pres- ment of Medicine, New Mulago Hospital (Kampala, Uganda); and the
ent study, there was a marked temporal association between AIDS Support Organization (Entebbe, Uganda), for referral and care of
the use of prednisolone and the date of diagnosis of Kaposi the study participants. We are indebted to all of the patients who partic-
ipated in this study and to the staff of the tuberculosis ward, for nursing
sarcoma in all but 1 of the cases. Third, there have been a care. We thank the staff of the statistics unit and of the microbiology
considerable number of reports of Kaposi sarcoma occurring laboratory of the Medical Research Programme on AIDS in Uganda; Moses
in patients not infected with HIV following the use of immu- Joloba and the staff of the Joint Clinical Research Centre Mycobacteriology
Laboratory; the Uganda Tuberculosis Investigations Bacteriological Unit
nosuppressive drugs—particularly of glucocorticoids—after (Wandegeya, Kampala); and Michael Odida, who performed the histolog-
transplantation, in treatment of autoimmune diseases, and in ical investigations. We thank the Data Monitoring and Ethical Committee.
tuberculous pericarditis [21–23]. In some of these cases, Kaposi
sarcoma resolved spontaneously after immunosuppressive ther-
apy had been stopped [21, 23]. Exacerbation of Kaposi sarcoma References
during the use of glucocorticoids has also been observed in 1. Fred L, Levin MH, Rivo JB, Barrett TF. Development of active pul-
HIV-infected patients and, in one of these patients, the lesions monary tuberculosis during ACTH and cortisone therapy. JAMA 1951;
resolved spontaneously when immunosuppressive therapy was 147:242–6.
2. Strang JIG, Kakaza HHS, Gibson DG, et al. Controlled clinical trial of
discontinued [24]. Kaposi sarcoma has also been noted to im- complete open surgical drainage and of prednisolone in treatment of
prove after treatment of HIV with antiretroviral therapy [25]. tuberculous pericardial effusion in Transkei. Lancet 1988; 2:759–64.
Kaposi sarcoma is an angioproliferative disease and is associated 3. Hakim JG, Ternmouth I, Mushangi E, Siziya S, Robertson V, Malin A.
Double blind randomised placebo controlled trial of adjunctive pred-
with infection with human herpesvirus–8. Taken together with nisolone in the treatment of effusive tuberculous pericarditis in HIV
earlier reports, our findings suggest that the use of prednisolone seropositive patients. Heart 2000; 84:183–8.
Prednisolone in Pleural Tuberculosis • JID 2004:190 (1 September) • 8774. Lee C-H, Wang W-J, Lan R-S, Tsai Y-I, Chiang Y-C. Corticosteroids 18. Luzze H, Elliott AM, Joloba ML, et al. Evaluation of suspected tuber-
in the treatment of tuberculous pleurisy. Chest 1988; 94:1256–9. culous pleurisy: clinical and diagnostic findings in HIV-1–positive and
5. Galarza I, Canete C, Granados A, Estopa R, Manresa F. Randomised HIV-negative adults in Uganda. Int J Tuberc Lung Dis 2001; 5:746–53.
trial of corticosteroids in the treatment of tubercouls pleurisy. Thorax 19. Sereti I, Lane HC. Immunopathogenesis of human immunodeficiency
1995; 50:1305–7. virus: implications for immune-based therapies. Clin Infect Dis 2001;
6. Wyser C, Walzl G, Smedema JP, Swart F, van Schalkwyk EM, van de 32:1738–55.
Wal BW. Corticosteroids in the treatment of tuberculous pleurisy. Chest 20. Batungwanayo J, Taelman H, Allen S, Bogaerts J, Kagame A, van de
1996; 110:333–8. Perre P. Pleural effusion, tuberculosis and HIV-1 infection in Kigali,
7. Ross JD, Horne NW, Crofton J. Modern drug treatment in tuberculosis. Rwanda. AIDS 1993; 7:73–9.
5th ed. London: The Chest Heart and Stroke Association, 1976.
21. Nagy S, Gyulai R, Kemeny L, Szenohradsky P, Dobozy A. Iatrogenic
8. Elliott AM, Halwiindi B, Bagshawe A, et al. Use of prednisolone in the
Kaposi’s sarcoma: HHV8 positivity persists but the tumors regress
treatment of HIV-positive tuberculosis patients. Q J Med 1992; 85:855–60.
almost completely without immunosuppressive therapy. Transplanta-
9. Vanham G, Edmonds K, Qing L, et al. Generalized immune activation
tion 2000; 69:2230–1.
in pulmonary tuberculosis: coactivation with HIV infection. Clin Exp
Immunol 1996; 103:30–4. 22. Sato-Matsumura KC, Matsumura T, Nabeshima M, Katano H, Sata T,
10. Zhang Y, Nakata K, Weiden M, Rom WN. Mycobacterium tuberculosis Koizumi H. Serological and immunohistochemical detection of human
enhances human immunodeficiency virus–1 replication by transcriptional herpesvirus 8 in Kaposi’s sarcoma after immunosuppressive therapy
activation at the long terminal repeat. J Clin Invest 1995; 95:2324–31. for bullous pemphigoid. Br J Dermatol 2001; 145:633–7.
11. Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS. Role of tran- 23. Sangiorgi G, Orlandi A, De Nardo D, Sangiorgi M, Spagnoli LG. Com-
scriptional activation of IkBa in mediation of immunosuppression by plete regression of iatrogenic Kaposi’s sarcoma due to corticosteroid
glucocorticoids. Science 1995; 270:283–6. treatment in a patient with tubercular pericarditis: a case report. Ann
12. Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immuno- Ital Med Int 1993; 8:21–4.
Downloaded from http://jid.oxfordjournals.org/ by guest on August 14, 2015
suppression by glucocorticoids: inhibition of NF-kB activity through 24. Gill PS, Loureiro C, Bernstein-Singer M, Rarick MU, Sattler F, Levine
induction of IkB synthesis. Science 1995; 270:286–90. AM. Clinical effects of glucocorticoids on Kaposi’s sarcoma related to
13. Goletti D, Weissman D, Jackson RW, et al. Effect of Mycobacterium the acquired immunodeficiency syndrome (AIDS). Ann Intern Med
tuberculosis on HIV replication: role of immune activation. J Immunol 1989; 110:937–40.
1996; 157:1271–8. 25. Gill J, Bourboulia D, Wilkinson J, et al. Prospective study of the effects
14. Whalen CC, Nsubuga P, Okwera A, et al. Impact of pulmonary tu- of antiretroviral therapy on Kaposi sarcoma–associated herpesvirus in-
berculosis on survival of HIV-infected adults: a prospective epidemi- fection in patients with and without Kaposi sarcoma. J Acquir Immune
ologic study in Uganda. AIDS 2000; 14:1219–28. Defic Syndr 2002; 31:384–90.
15. Andrieu J-M, Lu W, Levy R. Sustained increases in CD4 cell counts in
26. Ensoli B, Sturzl M, Monini P. Reactivation and role of HHV-8 in
asymptomatic human immunodeficiency virus type 1–seropositive pa-
Kaposi’s sarcoma initiation. Adv Cancer Res 2001; 81:161–200.
tients treated with prednisolone for 1 year. J Infect Dis 1995; 171:523–30.
27. Elenkov IJ, Chrousos GP. Stress hormones, proinflammatory and anti-
16. American Thoracic Society. Treatment of tuberculosis and tuberculosis
infection in adults and children. Am J Respir Crit Care Med 1994; inflammatory cytokines, and autoimmunity. Ann N Y Acad Sci 2002;
149:1359–74. 966:290–303.
17. McAllister WA, Thompson PJ, Al-Habet SM, Rogers HJ. Rifampicin 28. Dooley DP, Carpenter JL, Rademacher S. Adjunctive corticosteroid ther-
reduces effectiveness and bioavailability of prednisolone. Br Med J (Clin apy for tuberculosis: a critical reappraisal of the literature. Clin Infect
Res Ed) 1983; 286:923–5. Dis 1997; 25:872–87.
878 • JID 2004:190 (1 September) • Elliott et al.You can also read
