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Prevention of relapse of histoplasmosis with fluconazole in patients with the acquired immunodeficiency syndrome
Prevention of Relapse of Histoplasmosis With Fluconazole in Patients With the Acquired Immunodeficiency Syndrome Steve Norris, MD, Joseph Wheat, MD, Indianapolis, Indiana, Dave McKinsey, MD, Kansas City, Missouri, Dan Lancaster, MD, Memphis, Tennessee, Barry Katz, PhD, John Black, MD, Indianapolis, Indiana, Michael Driks, MD, Kansas City, Missouri, Robert Baker, MD, Karen Israel, MD, Don Traeger, MD, Susan Moriarity, MD, Joe Fraiz, MD, Douglas Webb, MD, Thomas Slama, MD, Indianapolis, Indiana OWECIWE:To assess the effectiveness of fluconazole for suppression of relapse of histoplasmosis in patients with acquired immunodeficiency syndrome (AIDS). DESIGN:Retrospective, nonrandomized, open trial. SETIING: Multicenter at two university referral centers and in five private practices. PATIENTS: Seventy-six patients with AlDS and disseminated histoplasmosis who completed induction treatment with amphotericin B, itraconazole, or fluconazole and maintained on treatment with fluconazole to prevent relapse. INTERVENTKINS: Fluconazole was given at dosages of 100 to 400 mg per day. Patients were followed by their primary physicians, who completed questionnaires collecting information about treatment and relapse status. Blood and urine specimens were submitted periodically for Histoplasma caps&turn var. caps&urn antigen determination. MEASUREMENTS AND MAINRESULTS:Nine of the 76 patients relapsed during fluconazole therapy and another was removed from the study because of allergic rash. Survival after initiation of therapy for histoplasmosis was 94 weeks, ranging from 74 weeks for those who received less than 1 g of amphotericin B for induction and none for maintenance therapy to 156 weeks for those who received greater than 1 g for induction and additional amphotericin B for maintenance therapy before beginning fluconazole (P ~0.02). Antigen levels fell at rates of 0.05 units/week in urine and 0.02 units/week in serum in, patients who were successfully maintained in remission and increased by r2 units/week in 4 of 6 patients who relapsed. From the Department of Medicine (SN,JW,BK,JB,RB,TS), the Department of Infectious Diseases (JF,Dw), the Department of Pathology (JW), and the Department of Biostatistics (BK1, Indiana University School of Medicine, Indianapolis, Veterans’ Affairs Hospital (JW,BK), Indianapolis, Methodist Hospital (KI), Indianapolis, St. Vincents Hospital (SM), Indianapolis, Carmel St. Vincents Hospiial CDT), Indianapolis, Indiana, the Infectious Disease Associates of Kansas City (DM), Kansas City, Baptist Medical Center (MD), Kansas City, Missouri, the Department of Medicine (DL), University of Tennessee, Memphis, Tennessee. Requests for reprints should be addressed to Joseph Wheat, MD, Wishard Memorial Hospital, Rm. OPW430, 1001 West Tenth Street, Indianapolis, Indiana 46202.2879. Manuscript submitted July 12, 1993, and accepted in revised form October 22, 1993.
504
CONCLUSIONS: Fluconazole 2200 mg daily is a reasonable choice for chronic suppressive therapy of histoplasmosis in patients who cannot take itraconazole because of drug interactions, malabsorption, or side effects.
isseminated histoplasmosis is a common and lifeD threatening infection in patients with acquired immunodeficiency syndrome (AIDS) in regions of the United States in which it is endemici Response to systemic amphotericin B is excellent, with nearly 89% of patients experiencing remission of clinical findings of infection. However, life-long maintenance therapy is necessary to prevent relapse.4 Several maintenance regimens have been used with variable success?‘4r5In a retrospective study, half of patients receiving ketoconazole for maintenance therapy relapsed.2 Amphotericin B given weekly or biweekly appeared to be more effective than ketoconazole, with relapse occurring in 3%5 to 1W of patients. In a prospective trial, relapse occurred in only 5% of 42 patients who were treated with itraconazole as maintenance therapy.6 After closure of the prospective trial, itraconazole was no longer available for maintenance treatment. In view of itraconazole’s unavailability, some physicians in Indianapolis, Memphis, and Kansas City began to use fluconazole for maintenance therapy based on the favorable experience with itraconazole. Consequently, a collaboration was established to assess fluconazole’s efficacy in patients who had completed induction treatment for histoplasmosis.
METHODS Study Population All participants had human immunodeficiency virus infection and had completed induction therapy with amphotericin B, itraconazole, or fluconazole. Successful induction treatment was documented by absence of clinical findings of histoplasmosis, but fungal blood cultures were not obtained to confirm response to induction therapy in all patients. Some patients had received maintenance therapy with amphotericin B, itraconazole, or ketoconazole before fluconazole was started. All patients were cared for by collaborators in Memphis, Kansas City, and Indianapolis. Patients were treated between June 1, 1989, and June 1, 1992.
June 1994 The AmericanJournal of Medicine Volume96
FLUCONAZOLE USE FOR AIDS/NORRIS ET AL
Study Design
1.0
Patients were treated with fluconazole at dosages determined by their physicians. No specific criteria were used to select patients for treatment with fluconazole. During the investigation, however, most patients under the care of the investigators received fluconazole for maintenance treatment because itraconazole was not available and oral therapy was preferred to intravenous amphotericin B. Patients were evaluated by their physicians for clinical evidence of relapse of histoplasmosis or side effects of fluconazole.
0.8
1
Laboratory Testing Histoplasma capsulatum variety capsulatum antigen levels in urine and serum were measured by radioimmunoassay.7 Antigen levels were measured for patients with paired samples at the beginning and the end of the study. Fluconazole plasma levels were measured by high pressure liquid chromatography.
0.2
Statistical Analysis The distribution of length of times to events were estimated according to the method of Kaplan and Meier. Mean antigen levels were compared using a paired t-test. Differences in proportions of patients with positive antigen results were compared using McNemar’s test.
RESULTS Subjects Eighty-two patients with AIDS and disseminated histoplasmosis were treated with oral fluconazole maintenance therapy. Six never returned for followup so could not be analyzed for outcome. Of the 76 cases with follow-up, 50 were treated in Indianapolis and 13 each in Memphis and Kansas City. Diagnosis of histoplasmosis was based on positive fungal cultures from extrapulmonary sites in 59 patients, bronchoalveolar lavage fluid in 1 patient, identification of organisms resembling H capsulatum var. capsulaturn by fungal stains of biopsy specimens in 6 patients, and detection of antigen in urine or serum in 10 patients.
Induction and Prior Maintenance Therapy Seventy-one patients received amphotericin B at doses ranging from 50 to 3,500 mg (median: 1,092 mg; 42 received at least 1,000 mg). Three patients were treated with fluconazole at doses from 200 to 400 mg daily for 3 months, and 2 patients received itraconazole at 400 mg daily for 3 months. Twenty-seven patients received other maintenance regimens prior to starting fluconazole: weekly amphotericin B for 3 to 21 months (median: 10 months) in 22 patients, itraconazole for 9 months in 2 patients, and ketoconazole for 6 to 11 months in 3 patients.
0.0 0
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RELAPSE AND SURVIVAL DURATION (Weeks)
Figure 1. Kaplan-Meier estimates of survival and relapse. Twentysix oatients were still living at the time of analvsis. and 22 were still receiving fluconazole maintenance therapy. * ’
TABLE I Outcomes of Maintenance Outcome Successful suppression Failure of suppression Relapse Toxicity Status at time of analysis Completed 1 year Treatment ongoing Treatment stopped Reasons stopped Death Voluntary Unable to follow Median time on study (weeks) Median survival (weeks)
Therapy Result (%) 66 (87) 10 (13)” 9 (12) 2 (3) 45 21 55
(59) (28) (72)
50 (66) 2 (3) 3 (4) 60 94t
‘One patient relapsed and also experienced toxicity, so is counted groups. Burvival after initiation of induction therapy for histoplasmosis.
in both
Relapses There were 6 culture-proven and three presumptive relapses with clinical evidence for relapse but negative cultures, for a relapse rate of 12% (95% CI, 4.6% to 19.4%) (Table I). If the 6 patients who never returned for follow-up were counted as relapses, the relapse rate would have been 15 of 82 (18%). Relapses occurred after as little as 12 weeks or as much as 80 weeks of fluconazole therapy (median: 30 weeks) (Figure 1). Four of the 9 relapses occurred in paJune
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505
FLUCONAZOLE
USE FOR AIDS/NORRIS
ET AL
All relapses occurred in patients who had received amphotericin B as induction therapy. The mean induction dose f 1 standard deviation (SD) of amphotericin B was 1,039 + 425 mg in the patients who relapsed compared to 1,099 f 703 mg in the 67 patients with sustained remissions (P = 0.80). Two of the 22 (9%) patients who had received amphotericin B maintenance therapy prior to fluconazole relapsed compared to 7 of 49 (14%) who began fluconazole at completion of amphotericin B induction therapy (P = 0.71). The relapse rate and time to relapse were not significantly different in patients who received at least 1 g of amphotericm B for induction therapy compared to those who received lower doses or in those who received amphotericin B for maintenance therapy before fluconazole compared to those who received no prior amphotericin B maintenance therapy.
1.a
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% B t 0.4
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/ i
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60
60
loo
120
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Survival
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2
SURVIVAL DURATION (weeks)
Figure 2. Kaplan-Meier estimates of survival among subgroups based on intensity of amphotericin B induction therapy and prior amphotericin B maintenance therapy. Twenty patients received rl g for induction with prioi’amphotericin B maintenance, 22 received >l g for induction without maintenance, and 27 received ~1 g of amphotericin B without maintenance.
Median survival from initiation of induction therapy for the 76 patients with follow-up was 94 weeks (Figure 1). To determine if the induction dose of amphotericin B or prior treatment with amphotericin B for maintenance therapy influenced survive, analysis was repeated for subgroups receiving different amounts of amphotericin B before beginning fluconazole (Figure 2). Survival differed significantly in these three groups (P < 0.02; Log-Rank test). Median survival was 156 weeks for those who received >l g amphotericin B induction therapy and prior amphotericin B maintenance therapy, 116 weeks for those receiving 21 g as induction therapy but none for maintenance therapy, and 74 weeks for those receiving < 1 g for induction and none for maintenance therapy. Survival was similar in subgroups receiving 400 mg (median: 82 weeks) or 200 mg (median: 104 weeks) fluconazole daily (P = 0.225; Log-Rank test) (Figure 3).
Adverse Events Two patients developed fever and skin rash that improved after stopping the fluconazole. Maintenance treatment was changed to weekly amphotericin B during the sixth week of fluconazole treatment in one patient; the other patient died without further treatment.
0.2
Antigen Clearance From Serum and Urine 0.0 0
20
4a
6a
ul
,m
120
140
16a
ioa
a
Suwlval Ountbn (Weaks)
3. Kaplan-Meier estimates of survival among subgroups based on fluconazole dosage of 200 mg or 400 mg daily.
Figure
tients treated with 100 mg of fluconazole daily. Overall, 4 of 6 patients who received fluconazole 100 mg daily relapsed. 506
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Antigen levels in patients with sustained remissions fell during treatment (Figure 4). Mean antigen levels in serum (+ 1 SD) fell by 0.4 f 2.0 units from 1.4 f. 1.1 units at enrollment to 1.0 + 2.0 unim at completion of study (P = 0.18). The rate of fall was 0.02 units/week in serum. Mean antigen levels in urine fell by 2.2 f 2.8 units from 4.4 + 3.3 units at enrollment to 2.2 + 2.7 units at final analysis (P < 0.001). The mean rate of fall was 0.05 units/week in urine. Antigen levels increased in four of six patients who relapsed (Table II).
FLUCONAZOLE USE FOR AIDS/NORRIS ET AL
Figure 4. Histoplasma antigen levels in serum and urine. Initial antigen levels and final levels after 1 year of treatment-or at withdrawal from study if before 1 year-are connected by lines for paired specimens from individual patients with sustained remissions during fluconazole therapy. Results that were negative at enrollment and followup are combined in the thick bar at the bottom of the figure; the number refers to the ., number of patients represented Dy the oar. TABLE II
Patient 1 2 3 4 : 7 8 9
Clinical and Laboratory Features of Patients Who Failed Fluconazole Therapy Maintenance Relapse Induction Flu Dose Week of Basis of Increase Antigen Fluconazole Treatment AB Dose (g) (mg/d) Relapse Relapse Urine Serum Cone’ Induct Maint 1.0 loo+ 12 Bid cult 5.6 22.2 2.2 AB Died 1.0 100 60 RM cult 2.9 ND 5.2 Flu Flu 400 mg 1.0 100 56 Antigen ND ND Flu Flu 400 mg 2.1 100 25 BM yeast ;:t ND ND AB AB 1.1 200 38 BM gran ND -0.2 48.6 Flu Flu 400 mg 0.65 2OOJ 26 Bid cult ND ND ND None, Died 74 7.7 1.0 200 Bld cult 5.6 16.2 AB Flu 400 mg 22 ND 0.8 200x Bld cult ND ND Flll§ AB 600 mg 0.45 400 30 Bld cult ND ND 33.2 AB AB
‘Fluconazole serum concentration at time of relapse. tlnterrupted therapy and concurrent corticosteroid treatment for allergic rash. *Repeatedly noncompliant with treatment. Tailed fluconazole 600 mg daily and subsequently treated with amphotericin B. Flu = fluconazole; Cone = concentration; AB = amphotericin B; Bld = blood; BM = bone marrow; induct = induction; maint = maintenance.
COMMENTS F’luconazole was moderately effective maintenance treatment for disseminated histoplasmosis in patients with AIDS. However, relapse may be more common with fluconazole (12% tolS%) than with itraconazole (5%)6 or amphotericin B (3% to19%).2~4 Survival was shorter in patients treated with fluconazole than with itraconazole (94 versus 108 weeksJ6 Several caveats should be recognized, however. Whereas all patients in the itraconazole study received at least 15 mgkg of amphotericin B as induction therapy, half of patients in the current study received lower doses or no amphotericin B. Also, 30% of patients in the fluconazole study received other forms of maintenance therapy before beginning fluconazole, while all patients in the itraconazole study began maintenance treatment within 6 weeks of completion of induction therapy.
gran = granuloma;
ND = not done;
Survival was better in patients who received amphotericin B before beginning fluconazole. Although relapse of hisloplasmosis was not documented as the cause for shorter survival, these results suggest that the dosage of prior amphotericin B may have influenced outcome. The larger dose of amphotericin B may have induced a more complete remission, prolonging survival. Relapse occurred in four of six patients who received daily fluconazole doses of 100 mg. This study did not demonstrate significant differences in relapse or survival in patients who received fluconazole 200 mg versus 400 mg daily, however. While the 100 mg daily dose appears to be too low, the choice between the 200 and 400 mg dally doses cannot be made based on this retrospective study. In conclusion, fluconazole is moderately effective maintenance therapy for histoplasmosis. A daily June 1994 The American Journal of Medicine Volume 96
507
FLUCONAZOLE USE FOR AIDS/NORRIS ET AL
dose is an with poor
of at least 200 mg should be used. Fluconazole alternative in patients who cannot be treated itraconazole because of drug interactions8 or absorption.
ACKNOWLEDGEMENTS This work was supported in part by the Division of AIDS of the National Institutes of Allergy and Infectious Diseases (JB, JW) and the Department Veterans’ Affairs (JW).
of
REFERENCES 1. Wheat LJ. Slama TG. Zeckel ML. Histoplasmosis in the acauired immune deficiency syndrome. Am J Med. 1985;78:iO3-210. 2. Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and
508
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1994
The American
Journal
of Medicine
Volume
96
treatment, and review of the literature. Medicine. 1990;69:361-374. 3. Johnson PC, Khardori N, Najjar AF, et al. Progressive disseminated histoplasmosis in patients with acquired immunodeficiency syndrome. Am J Med. 1988;85:152-158. 4. McKinsey DS, Gupta MR, Riddler SA, et al. Long term amphotericin B therapy for disseminated histoplasmosis in patients with the acquired immune deficiency syndrome. Ann Intern Med. 1989;111:655-659, 5. McKinsey DS, Gupta MR, Driks M, et al. Kansas City AIDS Research Consortium: histoplasmosis in patients with AIDS: efficacy of maintenance amphotericin B therapy. Am J Med. 1992;92:225-227. 6. Wheat J, Hafner R, Wulfsohn M, et al. Prevention of relapse histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1993;118:610-616. 7. Wheat LJ, Kohler RB, Tewari RP. Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens. NEJM. 1986;314:83-88. 8. Tucker RM, Denning DW, Hanson LH, et al. Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations. Clin Infect Dis. 1992;14:165-174.
504
CONCLUSIONS: Fluconazole 2200 mg daily is a reasonable choice for chronic suppressive therapy of histoplasmosis in patients who cannot take itraconazole because of drug interactions, malabsorption, or side effects.
isseminated histoplasmosis is a common and lifeD threatening infection in patients with acquired immunodeficiency syndrome (AIDS) in regions of the United States in which it is endemici Response to systemic amphotericin B is excellent, with nearly 89% of patients experiencing remission of clinical findings of infection. However, life-long maintenance therapy is necessary to prevent relapse.4 Several maintenance regimens have been used with variable success?‘4r5In a retrospective study, half of patients receiving ketoconazole for maintenance therapy relapsed.2 Amphotericin B given weekly or biweekly appeared to be more effective than ketoconazole, with relapse occurring in 3%5 to 1W of patients. In a prospective trial, relapse occurred in only 5% of 42 patients who were treated with itraconazole as maintenance therapy.6 After closure of the prospective trial, itraconazole was no longer available for maintenance treatment. In view of itraconazole’s unavailability, some physicians in Indianapolis, Memphis, and Kansas City began to use fluconazole for maintenance therapy based on the favorable experience with itraconazole. Consequently, a collaboration was established to assess fluconazole’s efficacy in patients who had completed induction treatment for histoplasmosis.
METHODS Study Population All participants had human immunodeficiency virus infection and had completed induction therapy with amphotericin B, itraconazole, or fluconazole. Successful induction treatment was documented by absence of clinical findings of histoplasmosis, but fungal blood cultures were not obtained to confirm response to induction therapy in all patients. Some patients had received maintenance therapy with amphotericin B, itraconazole, or ketoconazole before fluconazole was started. All patients were cared for by collaborators in Memphis, Kansas City, and Indianapolis. Patients were treated between June 1, 1989, and June 1, 1992.
June 1994 The AmericanJournal of Medicine Volume96
FLUCONAZOLE USE FOR AIDS/NORRIS ET AL
Study Design
1.0
Patients were treated with fluconazole at dosages determined by their physicians. No specific criteria were used to select patients for treatment with fluconazole. During the investigation, however, most patients under the care of the investigators received fluconazole for maintenance treatment because itraconazole was not available and oral therapy was preferred to intravenous amphotericin B. Patients were evaluated by their physicians for clinical evidence of relapse of histoplasmosis or side effects of fluconazole.
0.8
1
Laboratory Testing Histoplasma capsulatum variety capsulatum antigen levels in urine and serum were measured by radioimmunoassay.7 Antigen levels were measured for patients with paired samples at the beginning and the end of the study. Fluconazole plasma levels were measured by high pressure liquid chromatography.
0.2
Statistical Analysis The distribution of length of times to events were estimated according to the method of Kaplan and Meier. Mean antigen levels were compared using a paired t-test. Differences in proportions of patients with positive antigen results were compared using McNemar’s test.
RESULTS Subjects Eighty-two patients with AIDS and disseminated histoplasmosis were treated with oral fluconazole maintenance therapy. Six never returned for followup so could not be analyzed for outcome. Of the 76 cases with follow-up, 50 were treated in Indianapolis and 13 each in Memphis and Kansas City. Diagnosis of histoplasmosis was based on positive fungal cultures from extrapulmonary sites in 59 patients, bronchoalveolar lavage fluid in 1 patient, identification of organisms resembling H capsulatum var. capsulaturn by fungal stains of biopsy specimens in 6 patients, and detection of antigen in urine or serum in 10 patients.
Induction and Prior Maintenance Therapy Seventy-one patients received amphotericin B at doses ranging from 50 to 3,500 mg (median: 1,092 mg; 42 received at least 1,000 mg). Three patients were treated with fluconazole at doses from 200 to 400 mg daily for 3 months, and 2 patients received itraconazole at 400 mg daily for 3 months. Twenty-seven patients received other maintenance regimens prior to starting fluconazole: weekly amphotericin B for 3 to 21 months (median: 10 months) in 22 patients, itraconazole for 9 months in 2 patients, and ketoconazole for 6 to 11 months in 3 patients.
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RELAPSE AND SURVIVAL DURATION (Weeks)
Figure 1. Kaplan-Meier estimates of survival and relapse. Twentysix oatients were still living at the time of analvsis. and 22 were still receiving fluconazole maintenance therapy. * ’
TABLE I Outcomes of Maintenance Outcome Successful suppression Failure of suppression Relapse Toxicity Status at time of analysis Completed 1 year Treatment ongoing Treatment stopped Reasons stopped Death Voluntary Unable to follow Median time on study (weeks) Median survival (weeks)
Therapy Result (%) 66 (87) 10 (13)” 9 (12) 2 (3) 45 21 55
(59) (28) (72)
50 (66) 2 (3) 3 (4) 60 94t
‘One patient relapsed and also experienced toxicity, so is counted groups. Burvival after initiation of induction therapy for histoplasmosis.
in both
Relapses There were 6 culture-proven and three presumptive relapses with clinical evidence for relapse but negative cultures, for a relapse rate of 12% (95% CI, 4.6% to 19.4%) (Table I). If the 6 patients who never returned for follow-up were counted as relapses, the relapse rate would have been 15 of 82 (18%). Relapses occurred after as little as 12 weeks or as much as 80 weeks of fluconazole therapy (median: 30 weeks) (Figure 1). Four of the 9 relapses occurred in paJune
1994
The American
Journal
of Medicine
Volume
96
505
FLUCONAZOLE
USE FOR AIDS/NORRIS
ET AL
All relapses occurred in patients who had received amphotericin B as induction therapy. The mean induction dose f 1 standard deviation (SD) of amphotericin B was 1,039 + 425 mg in the patients who relapsed compared to 1,099 f 703 mg in the 67 patients with sustained remissions (P = 0.80). Two of the 22 (9%) patients who had received amphotericin B maintenance therapy prior to fluconazole relapsed compared to 7 of 49 (14%) who began fluconazole at completion of amphotericin B induction therapy (P = 0.71). The relapse rate and time to relapse were not significantly different in patients who received at least 1 g of amphotericm B for induction therapy compared to those who received lower doses or in those who received amphotericin B for maintenance therapy before fluconazole compared to those who received no prior amphotericin B maintenance therapy.
1.a
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0.6 g
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% B t 0.4
0.2
/ i
0.0
20
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loo
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Survival
I I
160
160
2
SURVIVAL DURATION (weeks)
Figure 2. Kaplan-Meier estimates of survival among subgroups based on intensity of amphotericin B induction therapy and prior amphotericin B maintenance therapy. Twenty patients received rl g for induction with prioi’amphotericin B maintenance, 22 received >l g for induction without maintenance, and 27 received ~1 g of amphotericin B without maintenance.
Median survival from initiation of induction therapy for the 76 patients with follow-up was 94 weeks (Figure 1). To determine if the induction dose of amphotericin B or prior treatment with amphotericin B for maintenance therapy influenced survive, analysis was repeated for subgroups receiving different amounts of amphotericin B before beginning fluconazole (Figure 2). Survival differed significantly in these three groups (P < 0.02; Log-Rank test). Median survival was 156 weeks for those who received >l g amphotericin B induction therapy and prior amphotericin B maintenance therapy, 116 weeks for those receiving 21 g as induction therapy but none for maintenance therapy, and 74 weeks for those receiving < 1 g for induction and none for maintenance therapy. Survival was similar in subgroups receiving 400 mg (median: 82 weeks) or 200 mg (median: 104 weeks) fluconazole daily (P = 0.225; Log-Rank test) (Figure 3).
Adverse Events Two patients developed fever and skin rash that improved after stopping the fluconazole. Maintenance treatment was changed to weekly amphotericin B during the sixth week of fluconazole treatment in one patient; the other patient died without further treatment.
0.2
Antigen Clearance From Serum and Urine 0.0 0
20
4a
6a
ul
,m
120
140
16a
ioa
a
Suwlval Ountbn (Weaks)
3. Kaplan-Meier estimates of survival among subgroups based on fluconazole dosage of 200 mg or 400 mg daily.
Figure
tients treated with 100 mg of fluconazole daily. Overall, 4 of 6 patients who received fluconazole 100 mg daily relapsed. 506
June
1994
The American
Journal
of Medicine
Volume
96
Antigen levels in patients with sustained remissions fell during treatment (Figure 4). Mean antigen levels in serum (+ 1 SD) fell by 0.4 f 2.0 units from 1.4 f. 1.1 units at enrollment to 1.0 + 2.0 unim at completion of study (P = 0.18). The rate of fall was 0.02 units/week in serum. Mean antigen levels in urine fell by 2.2 f 2.8 units from 4.4 + 3.3 units at enrollment to 2.2 + 2.7 units at final analysis (P < 0.001). The mean rate of fall was 0.05 units/week in urine. Antigen levels increased in four of six patients who relapsed (Table II).
FLUCONAZOLE USE FOR AIDS/NORRIS ET AL
Figure 4. Histoplasma antigen levels in serum and urine. Initial antigen levels and final levels after 1 year of treatment-or at withdrawal from study if before 1 year-are connected by lines for paired specimens from individual patients with sustained remissions during fluconazole therapy. Results that were negative at enrollment and followup are combined in the thick bar at the bottom of the figure; the number refers to the ., number of patients represented Dy the oar. TABLE II
Patient 1 2 3 4 : 7 8 9
Clinical and Laboratory Features of Patients Who Failed Fluconazole Therapy Maintenance Relapse Induction Flu Dose Week of Basis of Increase Antigen Fluconazole Treatment AB Dose (g) (mg/d) Relapse Relapse Urine Serum Cone’ Induct Maint 1.0 loo+ 12 Bid cult 5.6 22.2 2.2 AB Died 1.0 100 60 RM cult 2.9 ND 5.2 Flu Flu 400 mg 1.0 100 56 Antigen ND ND Flu Flu 400 mg 2.1 100 25 BM yeast ;:t ND ND AB AB 1.1 200 38 BM gran ND -0.2 48.6 Flu Flu 400 mg 0.65 2OOJ 26 Bid cult ND ND ND None, Died 74 7.7 1.0 200 Bld cult 5.6 16.2 AB Flu 400 mg 22 ND 0.8 200x Bld cult ND ND Flll§ AB 600 mg 0.45 400 30 Bld cult ND ND 33.2 AB AB
‘Fluconazole serum concentration at time of relapse. tlnterrupted therapy and concurrent corticosteroid treatment for allergic rash. *Repeatedly noncompliant with treatment. Tailed fluconazole 600 mg daily and subsequently treated with amphotericin B. Flu = fluconazole; Cone = concentration; AB = amphotericin B; Bld = blood; BM = bone marrow; induct = induction; maint = maintenance.
COMMENTS F’luconazole was moderately effective maintenance treatment for disseminated histoplasmosis in patients with AIDS. However, relapse may be more common with fluconazole (12% tolS%) than with itraconazole (5%)6 or amphotericin B (3% to19%).2~4 Survival was shorter in patients treated with fluconazole than with itraconazole (94 versus 108 weeksJ6 Several caveats should be recognized, however. Whereas all patients in the itraconazole study received at least 15 mgkg of amphotericin B as induction therapy, half of patients in the current study received lower doses or no amphotericin B. Also, 30% of patients in the fluconazole study received other forms of maintenance therapy before beginning fluconazole, while all patients in the itraconazole study began maintenance treatment within 6 weeks of completion of induction therapy.
gran = granuloma;
ND = not done;
Survival was better in patients who received amphotericin B before beginning fluconazole. Although relapse of hisloplasmosis was not documented as the cause for shorter survival, these results suggest that the dosage of prior amphotericin B may have influenced outcome. The larger dose of amphotericin B may have induced a more complete remission, prolonging survival. Relapse occurred in four of six patients who received daily fluconazole doses of 100 mg. This study did not demonstrate significant differences in relapse or survival in patients who received fluconazole 200 mg versus 400 mg daily, however. While the 100 mg daily dose appears to be too low, the choice between the 200 and 400 mg dally doses cannot be made based on this retrospective study. In conclusion, fluconazole is moderately effective maintenance therapy for histoplasmosis. A daily June 1994 The American Journal of Medicine Volume 96
507
FLUCONAZOLE USE FOR AIDS/NORRIS ET AL
dose is an with poor
of at least 200 mg should be used. Fluconazole alternative in patients who cannot be treated itraconazole because of drug interactions8 or absorption.
ACKNOWLEDGEMENTS This work was supported in part by the Division of AIDS of the National Institutes of Allergy and Infectious Diseases (JB, JW) and the Department Veterans’ Affairs (JW).
of
REFERENCES 1. Wheat LJ. Slama TG. Zeckel ML. Histoplasmosis in the acauired immune deficiency syndrome. Am J Med. 1985;78:iO3-210. 2. Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and
508
June
1994
The American
Journal
of Medicine
Volume
96
treatment, and review of the literature. Medicine. 1990;69:361-374. 3. Johnson PC, Khardori N, Najjar AF, et al. Progressive disseminated histoplasmosis in patients with acquired immunodeficiency syndrome. Am J Med. 1988;85:152-158. 4. McKinsey DS, Gupta MR, Riddler SA, et al. Long term amphotericin B therapy for disseminated histoplasmosis in patients with the acquired immune deficiency syndrome. Ann Intern Med. 1989;111:655-659, 5. McKinsey DS, Gupta MR, Driks M, et al. Kansas City AIDS Research Consortium: histoplasmosis in patients with AIDS: efficacy of maintenance amphotericin B therapy. Am J Med. 1992;92:225-227. 6. Wheat J, Hafner R, Wulfsohn M, et al. Prevention of relapse histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1993;118:610-616. 7. Wheat LJ, Kohler RB, Tewari RP. Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens. NEJM. 1986;314:83-88. 8. Tucker RM, Denning DW, Hanson LH, et al. Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations. Clin Infect Dis. 1992;14:165-174.