Article Sections
A Randomized, Double‐Blind, Parallel‐Group, Dose‐Response Study of Micafungin Compared with Fluconazole for the Treatment of Esophageal Candidiasis in HIV‐Positive Patients
1Prime Cure Clinic, Durban, 2Embassy Drive Medical Center, Pretoria, and 3Quinta‐Med, Bloemfontein, South Africa; 4Universidad Peruana Cayetano Heredia, Lima, Peru; 5Instituto de Infectologia Emílio Ribas, São Paulo, Brazil; and 6Fujisawa GmbH, Munich, Germany
Background.
Severely immunocompromised individuals are highly susceptible to Candida infection of the esophagus. This randomized, double‐blind study assessed the dose‐response relationship of the new echinocandin antifungal, micafungin, compared with that of standard fluconazole treatment.
Methods.A total of 245 patients (age, 
18 years) with a prior diagnosis of acquired immunodeficiency syndrome/human immunodeficiency virus (HIV) infection and esophageal candidiasis, confirmed by endoscopy and culture, were randomized to receive micafungin (50, 100, or 150 mg per day) or fluconazole (200 mg per day). Both agents were administered once per day by a 1‐h intravenous infusion for 14–21 days. The primary efficacy end point was endoscopic cure rate, defined as endoscopy grade of 0 at the end of therapy.
Results.The endoscopic cure rate (grade 0) was dose‐dependent with 50, 100, and 150 mg of micafungin per day at 68.8%, 77.4%, and 89.8%, respectively. Symptoms improved or resolved rapidly (3–7 days of treatment in the majority of patients). The endoscopic cure rate for 100 and 150 mg of micafungin per day (83.5%) was comparable to that for 200 mg of fluconazole per day (86.7%; 95% confidence interval for the difference in endoscopic cure rate, −14.0% to 7.7%). The overall safety and tolerability was acceptable, with no important differences between micafungin (all doses) and fluconazole.
Conclusions.The dose‐response findings demonstrate a greater efficacy with micafungin at 100 and 150 mg per day than at 50 mg per day. This study also indicates that the efficacy of micafungin (at dosages of 100 and 150 mg per day) was comparable to that of fluconazole, suggesting that micafungin represents a valuable new treatment option for esophageal candidiasis in HIV‐positive patients.
Received 8 December 2003; accepted 8 April 2004; electronically published 27 August 2004.
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(See the editorial commentary by Darouiche on pages 850–2 and the article by Krause et al. on pages 770–5)
Esophageal candidiasis (EC), occurring with or without oropharyngeal involvement, has a reported mean incidence of 10%–15% in patients with AIDS [1]. Candida albicans is the predominant infecting fungal pathogen in HIV‐positive patients, representing approximately 70%–80% of oral isolates, followed by Candida glabrata and Candida tropicalis, each of which accounts for 5%–8% of infections [2]. The frequency of colonization with non‐albicans species of Candida is increasing [3].
Fluconazole is considered the preferred treatment for EC, with a reported endoscopic cure rate of approximately 70%–90% and a good tolerability profile [1, 4–7]. However, colonization with azole‐resistant strains, including C. albicans, C. glabrata, and Candida krusei, represents an increasing problem [8, 9].
Micafungin, a member of the new echinocandin class, is a parenteral antifungal that inhibits the synthesis of (1,3)‐β‐d‐glucan, an essential component of fungal cell walls. Micafungin is currently licensed in Japan for the treatment of invasive fungal infections and is expected to become more widely available shortly. Advantages of this novel agent include low toxicity, fungicidal activity against most Candida isolates, and a pharmacokinetic profile that allows reliable once‐daily dosing [10–12].
Recently, a study was conducted to assess the minimal effective dose of micafungin for the treatment of EC in HIV‐positive patients [13]. The response to micafungin was dose‐dependent, with clearance or improvement of symptoms observed in 67% of patients who received a dosage of 12.5 mg per day, in 92% and 93% of patients receiving dosages of 25 and 50 mg per day, respectively, and 100% of patients who received dosages of 75 or 100 mg per day. Furthermore, 76% of patients who received micafungin dosages of 75 mg per day achieved an endoscopic grade of 0. These findings suggest that further investigation is required to define the optimal dose of micafungin in EC.
Consequently, the aim of this randomized, double‐blind, parallel‐group study was to determine the optimal daily dose of micafungin (50, 100, or 150 mg q.d.) for the treatment of EC in HIV‐positive patients, compared with standard therapy with fluconazole (i.e., 200 mg q.d.).
Methods
Patients
A total of 251 patients (age, 18 years) with a prior diagnosis of AIDS/HIV infection and clinical symptoms of EC, with or without oropharyngeal candidiasis, were enrolled in the study. Patients were included if EC was confirmed by esophageal endoscopy with microscopy and culture of a brushing or tissue biopsy specimen.
Exclusion criteria included pregnancy or breast‐feeding, liver disease (aspartate aminotransferase or alanine aminotransferase level of >5 times the upper limit of normal [ULN], a total bilirubin level of >2.5 times the ULN, or an alkaline phosphatase level of >2.5 times the ULN), renal impairment (serum creatinine level of >2.0 mg/dL), contraindications to study drugs, esophageal abnormalities preventing endoscopy, life expectancy of <2 months, and infection with a known fluconazole‐resistant strain of Candida species. Patients who had received topical or systemic antifungal therapy (within 48 or 72 h, respectively) before the first dose of study drug were not eligible for inclusion.
Written informed consent was obtained from each participant before enrollment. The study protocol was reviewed and approved by the institutional review board or ethics committee of participating institutions. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practices.
Study Design
This was a multicenter, randomized, double‐blind, parallel‐group study conducted at 24 sites in Brazil, Peru, and South Africa. Eligible patients were randomized 1:1:1:1 to receive micafungin at 50, 100, or 150 mg per day or fluconazole at 200 mg per day, all of which were administered once per day via a 1‐h intravenous infusion. The treatment period was a minimum of 14 days, extended to a maximum of 21 days for patients who did not achieve endoscopic clearance by day 14. Assessments were made at baseline (
48 h before administration of the first dose) and on days 3, 7, and 14 and at the end of treatment. Patients were assessed 2 weeks after treatment.
Efficacy
Primary efficacy assessment.The primary efficacy end point was endoscopic cure rate, defined as an endoscopy grade of 0 at the end of treatment. The endoscopist assigned grades for no evidence of EC‐associated plaques (grade 0), individual raised plaques of 2 mm in diameter (grade 1), multiple raised plaques of >2 mm in diameter (grade 2), and confluent plaques combined with ulceration (grade 3) [14].
Mycology.Samples obtained from brush or lesion biopsies were assessed at the end of treatment, and eradication was defined as a fungal culture and histological/cytological tests negative for all Candida species.
Secondary efficacy assessment.Secondary efficacy assessments included changes in endoscopic cure rate compared with baseline, endoscopic cure rate at day 14, clinical response at the end of treatment, EC severity score, overall therapeutic success at the end of treatment, and incidence of relapse.
Dysphagia, odynophagia, and retrosternal pain were each assigned a clinical grade of 0 (no symptoms), 1, 2, or 3. Dysphagia was given a grade of 3 if the patient could swallow small amounts of liquid or could not swallow; odynophagia was given a grade of 3 if the patient could only accept small sips of liquids or if the patient spitted; retrosternal pain was given a grade of 3 if the patient characterized it as very painful and if it required analgesia. Clinical response at the end of treatment was assessed relative to baseline and was categorized as cleared (i.e., clinical grade of 0), improved (reduction of symptoms by 2 clinical grades or achievement of a clinical grade of 0 for 1 symptom), or unchanged/worse (no change or a progression of symptoms). EC severity scores, defined as the sum of individual clinical grades, were assessed over time. Overall therapeutic success was defined as clearance or improvement between baseline and the end of treatment (improvement defined as a reduction of 2 for at least 1 clinical grade and an improvement by 1 endoscopic grade). Relapse was considered to have occurred if the EC severity score worsened between the end of treatment and the end of the study or if nonprophylactic antifungal therapy was started during the 2‐week follow‐up period.
Safety Assessments
All adverse events and laboratory abnormalities were considered in the safety assessment. Adverse events were monitored on an ongoing basis, and investigators determined their severity (mild, moderate, or severe) and possible relation to study drugs (highly probably, probable, possible, unlikely, definitely not, or not assessable). A serious adverse event was defined as any event that resulted in death, was life‐threatening, caused persistent disability or incapacity, or required hospitalization or intervention to prevent worsening of the condition. Laboratory tests (i.e., hematological tests and clinical chemistry) were performed at baseline, on days 7 and 14, at the end of treatment, and at the end of study.
Susceptibility Tests
Testing of positive fungal culture results for study drug susceptibility was performed at baseline and at the end of treatment. Candida species isolated and identified on‐site were further characterized by in vitro susceptibility testing at a central laboratory. MICs were determined using the protocol from the NCCLS document M27‐A [15]. To date, no interpretive breakpoints have been determined for any echinocandin [16].
Statistical Analysis
Statistical analyses were performed on data for the intent‐to‐treat (ITT) population, including all randomized patients who received 1 dose of the study drug. Analyses were repeated on the per‐protocol (PP) population, which consisted of patients who had confirmed EC at baseline, who received 10 doses of study drug, who had endoscopic assessment at baseline and the end of treatment, and who did not receive antifungal therapy in addition to micafungin or fluconazole.
The analysis of the primary end point was done using the closed‐test principle. As a first step, a 2‐sided Cochran‐Mantel‐Haenszel test adjusted for the variable pooled center was used for the micafungin dose groups on a significance level of 
to assess the difference between the dose groups. If the results allowed rejection of the null hypothesis of equality of the proportion px of patients with response (for H0, 
), then the groups were tested further with pairwise comparisons (
, 
, 
), each at a significance level of 
, using a 2‐sided Cochran‐Mantel‐Haenszel test adjusted for the variable pooled center.
The analysis of secondary end points was done using the Cochran‐Armitage trend test [17, 18] for dichotomous variables, such as mycological response, clinical response, incidence of disease progression, and overall therapeutic success. The trend test by Jonckheere [19] and Terpstra [20] was used for variables such as changes in quantitative endoscopic and clinical assessments of EC, compared with baseline.
Results
Patients
A total of 245 patients received 50, 100, or 150 mg of micafungin per day or fluconazole at 200 mg per day and constituted the ITT population. Demographic and baseline characteristics were similar between treatment groups (table 1). Although there was a numerical difference between fluconazole‐ and micafungin‐treated patients with respect to endoscopy grade 3 at baseline, Fisher’s exact test comparing the 4 treatment groups revealed a P value of .320.
1.Demographic and baseline characteristics of the intent‐to‐treat population. A total of 199 patients were included in the PP population; exclusions were due to negative assessment for EC at baseline (
), missing endoscopic assessment at the end of treatment (
), or receipt of <10 doses of study drug (
) (some patients had >1 reason for exclusion). The rates of discontinuation in the micafungin groups and the fluconazole group were similar. Thirty‐six patients discontinued treatment (8 patients in the micafungin 50 mg q.d. group, 13 patients in the micafungin 100 mg q.d. group, 7 patients in the micafungin 150 mg q.d. group, and 8 patients in the fluconazole group). The mean duration of therapy (±SD) in each of the 3 micafungin arms (50, 100, and 150 mg q.d.) was 
, 
, and 
days, respectively; it was 
days in the fluconazole group.
Efficacy
Primary assessments.Micafungin at 50, 100, and 150 mg per day showed a clear dose response for endoscopic cure rate (for the ITT population, 68.8%, 77.4%, and 89.9%, respectively). Differences in the endoscopic cure rate were statistically significant for the overall comparison of the 3 micafungin groups (for the ITT population, 
) and for comparison of the 50 versus 150 mg per day groups (for the ITT population, 
) (table 2). The findings for the ITT population were confirmed in the PP population (table 2). Results from logistic regression, which included important prognostic factors (country of residence, baseline CD4+ cell count, baseline endoscopic grade, and baseline EC severity score), confirmed the primary analysis.
2.Cure rate at the end of treatment for the intent‐to‐treat (ITT) and per‐protocol (PP) populations. P values (using the Cochran‐Mantel‐Haenszel test) for comparison of the endoscopic cure rates for micafungin (100 mg q.d.) versus fluconazole and for micafungin (150 mg q.d.) versus fluconazole were >.05 (
and 
, respectively) (table 3). A stratified analysis showed that fluconazole had a lower endoscopic cure rate than micafungin at 150 mg per day (14 [77.8%] of 18 vs. 11 [100%] of 11) for patients with endoscopic grade 3 at baseline.
3.Differences in cure rate at the end of treatment between the micafungin groups and the fluconazole group in the intent‐to‐treat population. Mycology.In patients with microscopy and culture data at baseline and the end of treatment, the rates of mycological eradication were 35.1% (20 of 57 persons), 78.3% (36 of 46 persons), and 57.1% (28 of 49 persons) for micafungin at 50, 100, and 150 mg per day, respectively, and 67.3% (35 of 52 persons) for fluconazole. The eradication rate for micafungin at 100 mg per day was higher than at 150 mg per day (
); comparisons of 100 mg of micafungin per day versus fluconazole and of 150 mg of micafungin per day versus fluconazole resulted in P values of .263 and .312, respectively (by 2‐sided Fisher’s exact test).
Secondary assessments.All treatment groups showed an improvement in endoscopic findings from baseline to the end of treatment, and this was dose‐dependent among the micafungin groups (table 4). Endoscopic cure rate at day 14 and the clinical response (assessed as cleared) at the end of treatment were dose‐dependent in the micafungin dose groups and were comparable between the combined dose groups for micafungin (100 and 150 mg per day) versus fluconazole (table 5). Therapeutic success displayed a dose‐response trend in the micafungin dose groups and was comparable between the combined dose groups for micafungin (100 and 150 mg per day) versus fluconazole (table 5).
4.Improvement in endoscopic grade between baseline and the end of treatment (EOT) in the intent‐to‐treat (ITT) population. 
5.Clinical responses in the intent‐to‐treat population. EC improved rapidly, as measured by severity scores. Approximately 50% of the patients had improved severity scores after 3 days of treatment, and 
75% had improved severity scores by day 7. Between baseline and day 7, the mean (±SD) improvement in EC severity score was 
, 
, and 
for micafungin at 50, 100, and 150 mg per day, respectively, and it was 
for fluconazole (ITT population). The rate of improvement of severity scores for micafungin at 100 and 150 mg per day and for fluconazole was comparable.
During the posttreatment period, 9 patients in the micafungin groups had a worsening of EC severity score or received nonprophylactic antifungal therapy (1, 5, and 3 patients in the 50, 100, and 150 mg q.d. groups, respectively). None of the patients in the fluconazole group experienced a relapse.
Tolerability and Safety
The incidence of adverse events was 93.3% in the micafungin groups and 89.2% in the fluconazole group, with no apparent differences between micafungin dose groups. The most common treatment‐related adverse events were fever, abdominal pain, nausea, diarrhea, leukopenia, injection‐site inflammation, and headache (table 6). The vast majority of treatment‐related adverse events were mild or moderate in severity.
6.Incidence of most common treatment‐related adverse events in the intent‐to‐treat population. There were no clinically relevant changes in laboratory parameters. Mild elevations in the alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin levels occurred in a total of 12.7% of patients, with no difference between the micafungin groups (24 of 185 patients) and the fluconazole group (7 of 60 patients). Renal adverse events were observed in 7 (3.8%) of 185 micafungin‐treated patients and in 0 of 60 fluconazole‐treated patients. There were no apparent dose‐dependent differences for changes in renal or hepatic parameters in the micafungin groups. No patient discontinued treatment because of a hepatic or renal adverse event.
Ten patients died during the posttreatment period. None of the deaths were considered to be related to use of the study drugs. Overall, there were no clinically relevant differences between the safety and tolerability profile of micafungin and that of fluconazole.
Susceptibility
All Candida species (isolates collected at baseline) were highly susceptible to micafungin, with MICs of 0.004–0.03 μg/mL. Fluconazole resistance (MIC, >64 μg/mL) was demonstrated for 2 C. albicans isolates (one in the micafungin 50 mg q.d. group and the other in the fluconazole group).
Discussion
This study indicates that the endoscopic cure rate (endoscopic grade 0) in patients with AIDS/HIV infection who have EC is dose‐dependent after daily 50‐, 100‐, or 150‐mg infusions of micafungin. The results show that micafungin doses of 100 and 150 mg per day were more effective than doses of 50 mg per day, with endoscopic cure rates of 77.4%, 89.8%, and 68.8%, respectively (
). Between baseline and the end of therapy, the mean improvements in endoscopic grade were 1.5, 1.8, and 2.0 in the 50‐mg, 100‐mg, and 150‐mg micafungin groups, respectively.
At the end of therapy, clinical symptoms were cleared in 93% of patients who received micafungin at 100 or 150 mg per day, compared with 76% in the 50 mg group. Symptoms improved or resolved within 3–7 days of treatment in the majority of patients.
Before this trial, a dose‐ranging (12.5–100 mg q.d.) study assessed the minimal effective dose of micafungin for the treatment of EC in patients with AIDS [13]. From baseline to the end of therapy (median duration, 14 days), the improvement in endoscopic grades was similar with dosages of 12.5, 25, and 50 mg per day, but improvements with the 75‐ and 100‐mg daily doses were 3‐ to 4‐fold greater than in the lower dose groups. Analysis of changes in endoscopic grade from baseline to end of therapy demonstrated a significant linear trend across the dose groups. Furthermore, 76% of patients who received micafungin at 75 mg per day achieved endoscopic grade 0 [13]. Thus, the current study was conducted to further define the optimal dose for treatment of EC. The endoscopic cure rate was used as the primary outcome measure, because this was considered to be the most stringent end point for this indication. The efficacy of micafungin was compared with that of fluconazole, which is the established treatment for EC. No other echinocandin was on the market at the date of the first enrolment (12 April 2002).
The endoscopic cure rate for fluconazole (86.7%) was consistent with previous reports, which demonstrated endoscopic cure rates of approximately 70%–90% for fluconazole (100–200 mg q.d.) for treatment of EC [1, 4–7]. In this study, the endoscopic cure rates for micafungin (100 and 150 mg q.d.) and fluconazole (200 mg q.d.) were comparable (
and 
, respectively). In addition, adverse events were consistent with those normally observed in patients with advanced AIDS, there were no clinically relevant differences in the tolerability profile of micafungin (all doses) and fluconazole, and there was no dose‐related toxicity in the micafungin groups.
In the micafungin groups, 9 (7%) of 123 patients who achieved endoscopic grade 0 at the end of treatment received nonprophylactic therapy and/or had a worsening of symptoms during the 2‐week follow‐up period, although only 1 patient had reversion to baseline clinical symptoms. However, it is not clear whether these cases represented true relapses or reinfections. Villanueva et al. [21] reported similar relapse rates with caspofungin (7 [11%] of 66 patients) at 2 weeks after treatment, but in contrast to the current study, these investigators also reported similar relapse rates (6 [8%] of 76 patients) in the fluconazole group.
The echinocandins display fungicidal activity against clinically relevant Candida species in vitro [11, 22], which is generally thought to be associated with better long‐term efficacy, compared with that for fungistatic agents. Nevertheless, as suggested by Dinubile et al. [23], who examined relapse rates in patients with AIDS and EC following caspofungin therapy, it is likely that the extent of ongoing immunodeficiency influences long‐term relapse or reinfection rates. Indeed, recurrence of EC is expected in patients with AIDS, and antiretroviral therapy should be considered key for prevention of recurrent fungal infections in this patient population [24].
Mycological eradication rates did not display the clear dose response that was found with the other end points. However, cytological and histological investigation of brushing and biopsy samples may have been confounded by contamination with dead fungal material.
Clinical data now support the use of micafungin for the treatment of EC and suggest that it is a viable alternative to the established therapy (fluconazole). Nevertheless, parenteral administration may be considered a limitation in some patient groups. However, the current study shows that once‐daily infusions are convenient and ease the treatment in patients who have difficulty swallowing or are totally unable to ingest oral therapies.
Another important consideration is drug interactions, which have been reported between the echinocandin caspofungin and various agents, including efavirenz and nevirapine [25]. However, in the current study, 31 and 10 patients received concomitant efavirenz and nevirapine, respectively, and no drug interaction–related adverse events were reported. A recent study [26] investigated potential interactions between micafungin and rifampicin (potent inducer of CYP3A4) and ritonavir (potent inhibitor of CYP3A4). Coadministration of rifampicin or ritonavir did not affect the pharmacokinetics of micafungin.
In conclusion, the dose‐response findings demonstrate a greater efficacy for micafungin at dosages of 100 and 150 mg per day, compared with a dosage of 50 mg per day. This study also indicates that micafungin (at dosages of 100 and 150 mg q.d.) provides efficacy comparable to that of fluconazole, with no clinically relevant differences in the tolerability profile of these agents. This suggests that micafungin represents a valuable additional treatment option for EC, particularly in view of emerging azole‐resistant strains reported in HIV‐positive patients.
Acknowledgments
We gratefully acknowledge the following investigators who enrolled patients in the study: E. Ticona Chavez (Lima, Peru), M. E. Botes (Pretoria, South Africa), A.E. Simjee (Durban, South Africa), K. Pettengell (Durban), R. Dietze (Vitória, Brazil), F. De Queirós Telles Filho (Curitiba, Brazil), B. G. G. Grinsztejn (Rio de Janeiro, Brazil), A. Timerman (São Paulo, Brazil), B. Riagel Santos (Porto Alegre, Brazil), T. McD Kluyts (Pretoria), R. Siebert (Pretoria), T. I. Branken (Durban), T. Smit (Cape Town, South Africa), D. Salomao Lewi (São Paulo), J. V. Ramalho Madruga (São Paulo), D. Petit (Cape Town), A. C. Gales (Bragança Paulista, Brazil), and F. J. Maritz (Bellville, South Africa).
Financial support.Fujisawa GmbH.
Conflict of interest.E.B. has received research grants and educational grants (both as speaker and participant for Continuing Medical Training events) from and has been involved in contract research for Roche Diagnostics, Pfizer, Bristol‐Myers Squibb, Fujisawa, Boeringer Ingelheim, Lilly, Hollis Eden, Triangle Pharmaceuticals, SKB, and Chiron Corporation. E.F.K. has been involved in 4 Fujisawa studies and will help in 2 studies from Bristol‐Myers Squibb. H.D.B is an employee of Fujisawa GmbH. All other authors: No conflict.
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Presented in part: 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, 14–17 September 2003 (abstract M‐1754); and the 1st meeting of Trends in Medical Mycology, Amsterdam, The Netherlands, 28 September–1 October 2003 (abstract O2.02).