Original Article
A Placebo-Controlled Trial of Maintenance Therapy with Fluconazole after Treatment of Cryptococcal Meningitis in the Acquired Immunodeficiency Syndrome
N Engl J Med 1991; 324:580-584February 28, 1991
- Abstract
- Abstract
Background and Methods.
In patients with the acquired immunodeficiency syndrome (AIDS), the rate of relapse after primary treatment for cryptococcal meningitis remains high. We conducted a controlled, doubleblind trial to evaluate the efficacy of maintenance therapy with fluconazole. At entry into the study, all participants had sterile cultures of cerebrospinal fluid, blood, and urine after following a standardized course of therapy for culture-proved cryptococcal meningitis. The patients were randomly assigned to take either fluconazole or placebo as maintenance therapy. The dose of fluconazole was 100 mg daily in the first phase of the study and 200 mg daily in the second phase.
Results.
Of 84 patients initially enrolled, 16 (19 percent) were found to have silent, persistent infection on the basis of cultures that became positive after entry into the study; 7 other patients were lost to follow-up shortly after entry. Of the remaining 61 patients, 10 of 27 assigned to placebo (37 percent) and 1 of 34 assigned to fluconazole (3 percent) had a recurrence of cryptococcal infection at any site (difference in risk, 34 percent; 95 percent confidence interval, 15 to 53). Of the 11 recurrent infections, 7 were detected in urine obtained after prostatic massage. There were four recurrent meningeal infections in the patients taking placebo, but none in those taking fluconazole (mean duration of follow-up, 164 days) (P = 0.03). In multivariate analyses, the best predictors of recurrence-free survival were fluconazole treatment (P = 0.02; relative hazard, 13.2), a lower serum cryptococcal-antigen titer (P = 0.05; relative hazard, 1.2), and more prolonged primary therapy with flucytosine (P = 0.09; relative hazard, 1.1). Survival and toxicity were similar in the two maintenance-treatment groups.
Conclusions.
In patients with AIDS, silent persistent infection is common after clinically successful treatment for cryptococcal meningitis. Maintenance therapy with fluconazole is highly effective in preventing recurrent cryptococcal infection. (N Engl J Med 1991; 324:580–4.)
Media in This Article
Figure 1
Proportion of Patients Remaining Free of Recurrence after Treatment for Acute Cryptococcal Meningitis.Table 1
Base-Line Characteristics of 61 Male Patients Who Could Be Evaluated.*Article Activity
- Article
CRYPTOCOCCAL disease accounts for 8 to 13 percent of hospital admissions for the acquired immunodeficiency syndrome (AIDS) in the United States, and it is likely to increase in importance as survival of patients with advanced human immunodeficiency virus (HIV) disease improves.1 2 3 Retrospective series have indicated a high risk of recurrence after primary therapy for cryptococcal meningitis in AIDS, but this risk has not been defined prospectively.4 5 6
Retrospective studies have also suggested a benefit from long-term maintenance therapy after the completion of primary treatment.5 6 7 8 Amphotericin B, ketoconazole, and itraconazole may be poor agents for maintenance therapy, because of their limited penetration into cerebrospinal fluid.9 10 11 Fluconazole may be superior for this indication because of its activity against Cryptococcus neoformans, its excellent penetration into cerebrospinal fluid, and its long serum halflife.10 11 12 13 We conducted a placebo-controlled, doubleblind, randomized trial of maintenance therapy with fluconazole in persons with AIDS who had completed successful primary therapy for cryptococcal meningitis.
Methods
Study Population
The study design was reviewed and approved by the institutional review board at each participating institution, and all participants gave written informed consent before enrollment. The participants were adults with documented HIV infection who had successfully completed a standardized course of therapy for an episode of culture-proved cryptococcal meningitis that had been diagnosed within the four months preceding enrollment. Minimal standard therapy was defined as 6 to 24 weeks of treatment with amphotericin B, up to a minimal total cumulative dose of at least 2 g, or combination therapy for at least 6 weeks with flueytosine at a dose of 150 mg per kilogram of body weight per day (adjusted to maintain therapeutic levels) plus a total dose of at least 1 g of amphotericin B at an average daily dose of at least 0.3 mg per kilogram. To be enrolled in the study, patients who received combination therapy for shorter periods had to have received additional therapy with amphotericin B alone, in an amount determined by a formula that assumed 2 g of monotherapy with amphotericin B and six weeks of combination therapy to be equivalent. Thus, the minimal amount of additional amphotericin B monotherapy, in grams, that was required after an early discontinuation of combination therapy was calculated as follows: 2 — (weeks of combination therapy ÷ 3).
Successful primary treatment was confirmed by at least two consecutive negative cultures of cerebrospinal fluid obtained at least one week apart, plus negative cultures of blood and urine. After the first 10 patients had been enrolled, the frequency of clinically silent prostatic infection was appreciated, and a negative culture of urine obtained after prostatic massage was required thereafter.14 Randomization was required to occur within three weeks of the completion of primary therapy and after the patients' base-line cultures were at least one week old. Patients whose base-line cultures turned positive after randomization were considered ineligible and were removed from the study and the analysis.
Patients were excluded if they had a history of intolerance to imidazoles, moderate liver-function abnormalities, or a serum creatinine level greater than 190 μmol per liter; if they were pregnant or lactating; or if they were receiving systemic or intrathecal antifungal therapy or certain other medications.
Study Design
A double-blind, placebo-controlled trial was conducted in two phases. In phase I, the investigators were restricted by the investigational-new-drug license to administering 100 mg of fluconazole or a placebo identical in appearance daily by mouth for three months. Because this dosage produced neither excessive toxicity nor risk of recurrence, the investigators were allowed to proceed to phase II before the planned recruitment of patients for phase I was complete. In phase II, the patients were followed indefinitely while they received 200 mg of fluconazole or placebo daily. In both phases, randomization was blocked centrally according to site, in a 1:1 proportion. The medication was packaged in sequentially numbered containers, identical in appearance, that were dispensed in ascending order to successive patients by the pharmacy at each site.
The study medications were continued until the end of the study (which was limited to three months in phase I) or a recurrence of cryptococcal infection at any site, another infection requiring systemic antifungal medication, serious drug-related side effects, death, or the patient's withdrawal of consent. Topical therapy for cutaneous or mucosal fungal infection was permitted.
Evaluations
The patients' conditions were evaluated weekly for the first four weeks and every four weeks thereafter. Each evaluation included an assessment of signs and symptoms and a determination of complete blood counts and serum values obtained on laboratory testing. Cultures of blood and urine for C. neoformans were performed every four weeks. After 10 patients had been enrolled, the protocol was altered to include cultures of urine obtained after prostatic massage.14 Cultures of cerebrospinal fluid for C. neoformans were performed every 12 weeks and as clinically indicated. Titers of cryptococcal antigen in serum and cerebrospinal fluid were determined whenever samples of blood or cerebrospinal fluid were obtained for culture.
Statistical Analysis
The target for enrollment in phase I of the study was 60 patients, but enrollment was discontinued on receipt of permission to begin phase II. The target for enrollment in phase II was 100 patients, with planned interim analyses by a blinded independent data and safety monitoring board to examine the phase II results alone after 30 and 60 patients had been enrolled.
All analyses were performed on an intention-to-treat basis, according to the initial treatment assignments. The outcomes were compared by the MantelHaenszel method in order to control for the two phases of the study. Risk differences and 95 percent confidence intervals were calculated for meningeal and urinary recurrences and recurrences at any site. Survival analyses were performed with the Kaplan–Meier method, and the treatment groups were compared by the log-rank test. Multivariate proportional-hazards modeling was used to assess the effect of potentially confounding variables on the time to a recurrence. Relative hazards and unadjusted 95 percent confidence intervals were determined for significant predictors of relapse. The variables tested included the previous cumulative dose of amphotericin B, duration of flucytosine treatment, and values obtained at entry for titers of cryptococcal antigen in serum and cerebrospinal fluid and for white-cell count and protein and glucose concentrations in cerebrospinal fluid.
Clinical symptoms were recorded after each evaluation by the study personnel, who were unaware of the treatment-group assignments. Abnormal laboratory values were defined as follows: hemoglobin, a decrease of more than 19 percent from the value at entry into the study; leukocyte count, a decrease of more than 24 percent from the entry value to less than 2500 cells per cubic millimeter; platelet count, a decrease of more than 24 percent from the entry value to less than 100,000 cells per cubic millimeter; alanine aminotransferase and aspartate aminotransferase, an increase to three times the upper limit of normal if the entry value was within normal limits, or to at least three times the entry value if that value was abnormal; alkaline phosphatase, an increase to two times the upper limit of normal if the entry value was normal, or to two times the entry value if that value was abnormal; and bilirubin, blood urea nitrogen, and serum creatinine, an increase to 50 percent more than the upper limit of normal if the entry value was normal, or to at least 50 percent more than the entry value if that value was abnormal. Serious clinical and laboratory adverse events were tabulated, and their rates expressed per 100 patient-months of observation. For each category, a Z score was calculated and a P value assigned for the comparison of the fluconazole and placebo groups.15
Results
Subjects
A total of 84 patients were enrolled in the study at the University of Southern California (38 patients), the University of California, San Diego (32), the University of California, Irvine (10), and the Sherman Oaks Medical Group (4). Thirty-two of these patients were enrolled in phase I, and 52 in phase II. On November 17, 1989, the study was discontinued at the recommendation of the data and safety monitoring board considering the first interim analysis of phase II. Data from both phases were combined in this report, because the entry criteria, follow-up evaluations, and end points were identical and the outcomes similar.
Forty-two of the 84 patients enrolled were randomly assigned to fluconazole therapy, and 42 to placebo. Sixteen patients were determined not to have met the entry criteria, because their base-line cultures, which had showed no growth at the time of randomization, later turned positive. Three of these patients had positive cultures of cerebrospinal fluid, and 13 had positive cultures of urine. The mean periods of incubation of these base-line cultures before randomization were 9.2 days for these 16 patients and 7.8 days for the remaining patients. Seven of the remaining patients were lost to follow-up immediately after enrollment, and because they had not been known to take any study medication, they were excluded from the analysis.
The remaining 61 patients were able to be evaluated for meningeal recurrence. At entry into the study and at follow-up, 47 of them had adequate cultures of urine obtained after prostatic massage; these patients could therefore be evaluated for urinary recurrence as well. The characteristics of the patients enrolled in phases I and II were similar, as were those of the patients receiving fluconazole and the patients receiving placebo, with the exception of higher median cryptococcal-antigen titers in serum (8 and 192, respectively) and cerebrospinal fluid (4 and 16) (Table 1Table 1
Base-Line Characteristics of 61 Male Patients Who Could Be Evaluated.*).Follow-up and Concomitant Medications
The mean duration of follow-up was 164 days (range, 14 to 529) for the fluconazole recipients and 117 days (range, 13 to 350) for the placebo recipients (Table 2Table 2
Outcomes of Maintenance Treatment with Fluconazole or Placebo.). Zidovudine was taken by 18 patients in the fluconazole group (53 percent) for 40 percent of the time they were studied, and by 10 patients in the placebo group (37 percent) for 30 percent of the time they were studied (P = 0.22 and 0.24, respectively). One subject in the placebo group received four days of treatment with ketoconazole; no other patients received any concomitant systemic antifungal therapy.Risk of Recurrence
Five of 28 patients in phase I (18 percent) and 6 of 33 patients in phase II (18 percent) had recurrence at any site, for a total of 11 of 61 patients (18 percent) at a median of 12 weeks. Ten of 27 patients receiving placebo (37 percent) and 1 of 34 patients receiving fluconazole (3 percent) had recurrence at any site (P<0.001; difference in risk, 34 percent; 95 percent confidence interval, 15 to 53) (Table 2). Four of 27 patients receiving placebo (15 percent) and none of 34 patients receiving fluconazole had meningeal recurrence (P = 0.03; difference in risk, 15 percent; 95 percent confidence interval, 1 to 28) (Table 2). Of the 47 patients who could be evaluated for urinary recurrence, 6 of 20 patients receiving placebo (30 percent) and 1 of 27 receiving fluconazole (4 percent) had a recurrence (P = 0.03; difference in risk, 26 percent; 95 percent confidence interval, 5 to 48) (Table 2). All seven of these positive cultures were cultures of urine obtained after prostatic massage. Six of the patients with urinary recurrence were treated with amphotericin B (one patient), fluconazole (two), or itraconazole (three) and did well, whereas the single patient who declined further therapy had recurrent meningitis and cryptococcemia within six weeks.
The cumulative risk of recurrence at any site after one year was 100 percent in the placebo group and 5 percent in the fluconazole group (P<0.001) (Fig. 1Figure 1
Proportion of Patients Remaining Free of Recurrence after Treatment for Acute Cryptococcal Meningitis.A). The best independent predictors of recurrence in the multivariate proportional-hazards models were treatment with placebo (P = 0.02; relative hazard, 13.2; 95 percent confidence interval, 1.6 to 107), higher log-transformed serum cryptococcal-antigen titer (P = 0.05; relative hazard, 1.2; 95 percent confidence interval, 1.0 to 1.4), and fewer days of flucytosine therapy (P = 0.09; relative hazard, 1.1; 95 percent confidence interval, 1.0 to 1.3). The cumulative risk of meningeal recurrence was 25 percent in the placebo group and 0 in the fluconazole group (P = 0.019) (Fig. 1B). No proportional-hazards model could be fitted for this end point, because of the small number of occurrences.Mortality
Four patients in the placebo group died during the study (or within 4 weeks of discontinuing participation), after a mean of 84 days, for a rate of 3.8 deaths per 100 patient-months of observation. These deaths were attributed to cryptococcal disease (in two patients), pneumocystis pneumonia (in one), and lymphoma (in one). Seven patients in the fluconazole group died during the study (or within 4 weeks of discontinuing participation), after a mean of 216 days — a rate of 3.8 deaths per 100 patient-months of observation. These deaths were attributed to HIV wasting syndrome (in one patient), toxoplasmosis (in one), disseminated cytomegalovirus infection (in one), bacterial pneumonia (in one), bacterial sepsis (in two), and a motor vehicle accident (in one). During long-term follow-up, 17 of 27 patients originally assigned to placebo (63 percent) and 22 of 34 patients originally assigned to fluconazole (65 percent) died after a mean of 286 and 275 days of follow-up, respectively.
Adverse Events
The recipients of fluconazole and placebo had 5.9 and 6.7 adverse clinical events, respectively, per 100 patient-months of observation (P = 0.80) (Table 3Table 3
Adverse Events during Treatment with Fluconazole or Placebo.*). Gastrointestinal symptoms were reported the most frequently, with rates in the two groups of 4.3 and 2.9, respectively, per 100 patient-months of follow-up (P = 0.55) (Table 3). Cytopenias occurred at higher rates in the fluconazole group than in the placebo group (P not significant) (Table 3). Other laboratory abnormalities, including elevations, of aminotransferase levels, developed at similar rates in the two groups (Table 3).Discussion
Cryptococcal disease in AIDS usually presents as meningitis with disseminated infection.1 2 3 4 5 6 Initial reports emphasized a poor response to primary therapy and a high risk of subsequent meningeal recurrence that was usually fatal.1 2 3 4 5 6 More recently, an improved prognosis has been reported, but the risk of meningeal recurrence was still thought to be substantially higher in patients with AIDS than in non—HIV-infected patients with cryptococcosis.5 , 6 , 16 17 18 Since previous studies did not use a standard definition of adequate primary therapy or systematic follow-up evaluation of clinically silent infection as determined on the basis of persistently positive culture, recurrences could not be accurately distinguished from cases of unsuccessful primary therapy, and the rate of true recurrence remained unclear.
In this study, clinically silent infections with persistently positive cultures were found at the end of a full course of primary therapy in 16 of 84 persons randomized (19 percent). Three patients had persistently positive cultures of cerebrospinal fluid, and 13 had persistently positive cultures of urine. These values represent a conservative estimate of the true risk of clinically silent infection with persistently positive cultures, because such infection was found in some candidates before randomization, and others did not receive optimal evaluation of the urinary tract at entry into the study. We have previously reported a 28 percent risk of asymptomatic prostatic infection after clinically successful primary therapy in patients with AIDS evaluated on the basis of cultures of urine obtained after prostatic massage.14
Clinically silent recurrent infection in the urinary tract was found in 6 of 27 recipients of placebo (22 percent) who provided sterile urine samples after prostatic massage at base line. This indicates that the urinary tract is a common site of recurrent infection even when no such infection can be documented at the completion of primary therapy. Patients with persistent or recurrent urinary tract infection were removed from the study and given active therapy, because preliminary data and clinical reasoning indicated a high risk of meningeal relapse in persons with persistent urinary cryptococcosis.19 , 20
Four of 27 placebo recipients (15 percent) had meningeal recurrence, and two of these recurrences were fatal. This risk was similar to that reported in the pre-AIDS era and much lower than the rates of meningeal recurrence (50 to 60 percent) reported in retrospective series of patients with AIDS not receiving maintenance therapy.2 , 4 , 18 The higher rate reported in these early series of patients with AIDS is similar, however, to the overall rate of 56 percent seen in this study for persistent (19 percent) and recurrent (22 percent) extrameningeal infection and for meningeal infection (15 percent).2 , 4 This suggests that the reduced risk of meningeal recurrence observed in our study may be due to the detection and treatment of clinically silent persistent or recurrent infection of the urinary tract or to the suppression of other accompanying sites of silent infection.5 , 6 , 12
All the patients with meningeal recurrence presented between their scheduled monthly visits with clinical disease and conditions attributable to the central nervous system. None had had symptoms or a substantial rise in the cryptococcal-antigen titer at the most recent previous monthly visit or quarterly lumbar puncture. Because this study used an aggressive course of standardized primary therapy and monthly monitoring, it is unlikely that any currently available and practical program could reduce the risk of meningeal recurrence further than the 25 percent risk observed in the placebo group (Fig. 1B).
Fluconazole was completely protective against meningeal recurrence at both doses tested in this study, and it was almost completely protective against recurrence of urinary tract infection. The only such recurrence in the fluconazole group was in a patient who did not follow the study protocol (Fig. 1). Although cryptococcal-antigen titers were higher in the placebo group, it is unlikely that confounding by a difference in prognosis accounted for the much lower rate of recurrence in the recipients of fluconazole. Multivariate proportional-hazards analysis confirmed the large treatment effect after we controlled for the smaller effects of the other statistically significant factors (serum antigen titer and duration of previous flucytosine therapy).
Since the study end point was recurrence at any site, and since meningeal recurrences were few, no survival benefit could be demonstrated for maintenance therapy with fluconazole. The demonstrated mycologie superiority of fluconazole is clinically relevant nonetheless, because even after we screened for culturepositive persistent infection, all the surviving recipients of placebo eventually had recurrent infection, and those with meningeal recurrence were indistinguishable from those with urinary tract recurrence. Furthermore, fluconazole was tolerated very well. Rates of clinical and laboratory toxicity in the two treatment groups were similar. The higher, but not significantly increased, rate of hematologic toxicity in the fluconazole group probably reflects the greater proportionate and absolute amount of zidovudine use in that group.
Patients who complete clinically successful standard therapy for cryptococcal meningitis should receive a full evaluation for clinically silent persistent infection, including cultures of cerebrospinal fluid and prostatic secretions (or the first urine voided after prostatic massage). In patients without evidence of persistent infection, treatment with fluconazole at a dosage of 100 to 200 mg per day is well tolerated and effective in preventing recurrence.
Supported by the California University—Wide AIDS Research Program and by Pfizer Central Research, Groton, Conn.
*The following persons also participated in this study: University of California, San Diego — T.C. Meng, M.D., Kris Large, R.N., Mary McCarthy, R.N., and Chris Fegan, R.N.; University of California, Irvine — Sheila Fitzgibbons, R.N., P.H.N., M.P.A.; and Pfizer Central Research — Donald N. Buell, M.D.
We are indebted to Dr. Joshua Fierer for his assistance in the design of this study.
Source Information
California Collaborative Treatment Group*
From the Division of Infectious Diseases (S.A.B., JAM., D.D.R.) and the Departments of Medicine and Pathology (D.D.R), University of California, San Diego; the Divisions of Infectious Diseases and Departments of Medicine, University of Southern California and Los Angeles County Hospital, Los Angeles (R.A.L., M.A.E.L., J.M.L.); the Department of Medicine, University of California, Irvine (J.C., J.T.); Pfizer Central Research, Groton, Conn. (J.J., P. Robinson, G.G.); and the Sherman Oaks Medical Group, Sherman Oaks, Calif. (P. Rothman). Address reprint requests to Dr. Bozzette at the University of California—San Diego Medical Center, Box H208, 225 Dickinson St., San Diego, CA 92103.
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