Vazquez, José A MD*; Schranz, Jennifer A MD†; Clark, Kay RN†; Goldstein, Beth P PhD†; Reboli, Annette MD‡; Fichtenbaum, Carl MD§
Azole-refractory mucosal candidiasis (ARMC) is a serious, debilitating disease frequently seen in patients who are immunosuppressed as a result of HIV infection, malignancy, posttransplant immunosuppressive therapy, persistent neutropenia, steroid use, or diabetes.1,2
Refractory oropharyngeal (OPC) and esophageal (EC) candidiasis impair quality of life due to a cycle of poor oral intake, malnutrition, wasting syndrome, the inability to take oral drugs and can lead to eventual death.2,3 Recurrent infections are not uncommon in patients with HIV, particularly in those failing immune reconstitution with highly active antiretroviral therapy.4,5 The need for repetitive or prolonged antifungal therapy in these immunocompromised patients has contributed to the increase in fluconazole-resistant Candida albicans isolates.2,6,7 Furthermore, some non-C. albicans species, which arise in the setting of frequent fluconazole use, may be less susceptible to fluconazole than C. albicans.8,9
Current treatment options for ARMC are limited. Oral suspensions of amphotericin B, although well tolerated, have limited efficacy in the treatment of fluconazole-resistant mucosal candidiasis.10 In the past decade, other azole antifungals (eg, itraconazole and voriconazole) have been studied for the treatment of refractory mucosal candidiasis.1,3 Response rates in ARMC generally do not exceed two thirds of subjects studied. Parenteral amphotericin B, although somewhat effective, is associated with high rates of adverse events, and caspofungin, which is partially metabolized by cytochrome P-450 isozymes, requires dose adjustments for moderate hepatic dysfunction and when given concurrently with P450 inducers.11,12 Although escalating antifungal dosages or switching to another azole antifungal may be effective short-term management strategies, recurrent disease remains an important dilemma.
Cross-resistance among azoles may account for some of the low success rates and high relapse rates observed with azole therapy.13-15 Moreover, these agents are subject to drug interactions, which are of particular concern in patients with HIV who are on multiple medications simultaneously. This combination of factors identifies an unmet medical need for alternative antifungal agents that are safe and efficacious, with a low potential for drug-drug interactions.15
Anidulafungin, an echinocandin, has a mechanism of action that offers promise in the management of mucosal and systemic fungal infections.16,17 Anidulafungin has been shown to be fungicidal against most Candida and has potent activity against a broad spectrum of Candida species, including strains resistant to azoles and polyenes.18,19 In addition, anidulafungin is safe, well tolerated, and highly effective in patients with EC, candidemia, and invasive candidiasis.20,21 In a double-blind, comparative clinical trial involving 601 patients with documented EC, anidulafungin was as efficacious as fluconazole at end of treatment.21 Because the dose of anidulafungin at 50 mg daily was effective in this prior study population, the same dose was utilized for this study. Moreover, there are no clinically significant drug interactions when anidulafungin is administered together with other drugs, and no dose modifications or adjustments are required for any degree of renal or hepatic impairment.22,23
These data suggest that anidulafungin may be an appropriate therapeutic alternative to azole and polyene antifungals in patients with ARMC. The current phase 2, open-label, noncomparative study was designed to further examine safety and clinical, microbiological, and endoscopic response to anidulafungin in this patient population.
Conduct of the Study
The study protocol, amendments, and informed consent documents were approved by the appropriate independent ethics committees and institutional review boards before study initiation. Informed consent was obtained from all patients or their legally authorized representatives before enrollment.
The study was conducted in the United States at 11 sites, 4 of which enrolled at least one patient. The trial was designed and monitored in accordance with the Declaration of Helsinki and the International Conference on Harmonization.
Eligible patients were 12 years and older and had ARMC, defined as active oropharyngeal and/or esophageal disease within 1 month of receiving a 14-day course of either fluconazole (≥200 mg/d) or voriconazole. Patients with EC were enrolled if they had endoscopic findings of grade I or higher (evidence of plaques and/or increased friability of the esophageal mucosa) and confirmation of disease by culture or microscopy. If microscopy was positive, culture confirmation was not required before enrollment. Patients with OPC were enrolled if they had a clinical diagnosis of OPC with detection of Candida by microscopy and/or culture of a mucosal lesion scraping. Once clinically diagnosed, the severity of OPC was graded on a 4-point scale (0: absence of lesions; I: <5 localized lesions; II: ≥5 localized lesions; III: extensive or confluent lesions).
Patients were ineligible for the study if they had bilirubin >2 times the upper limit of normal or aspartate or alanine aminotransferase >4 times the upper limit of normal. Patients were also excluded if they required continued treatment with another systemic, topical, or oral antifungal agent.
This was a phase 2, open-label, noncomparative trial. Patients who met diagnostic criteria for ARMC received a 100-mg intravenous loading dose of anidulafungin on day 1, followed by 50 mg daily on day 2 through the completion of therapy, or for a maximum of 21 days. Therapy was discontinued on day 14 for patients who achieved a complete resolution of symptoms as determined by the investigator. Partial responders at day 14 were allowed to continue therapy through day 21. End of therapy was the point at which anidulafungin was discontinued. Patients who had a positive response to initial treatment with anidulafungin, who tolerated anidulafungin well, and who relapsed within 90 days of the end-of-therapy visit were potentially eligible for retreatment with anidulafungin under an extension of this protocol.
Clinical evaluations were performed daily during anidulafungin therapy and at a final follow-up visit 10-14 days after end of therapy (or earlier in the event of relapse or upon introduction of another systemic antifungal therapy due to failure). Evaluations included loss of taste (OPC), severity of oral lesions (OPC), and difficulty and/or pain when swallowing (OPC/EC). Overall severity of candidiasis symptoms was judged as mild, moderate, or severe. Endoscopy was conducted at baseline and end of therapy among patients with EC. Samples for microbiological evaluations were obtained at baseline, end of therapy, and follow-up. Fungal isolates were collected and sent to a central microbiology reference laboratory at the University of Iowa (Iowa City, IA) for definitive identification and determination of minimum inhibitory concentrations (MICs) using Clinical and Laboratory Standards Institute (National Committee for Clinical Laboratory Standards [CLSI-(NCCLS)]) methods.24
The primary efficacy end point for patients with OPC was clinical response. In patients with EC, the coprimary efficacy end points were endoscopic response and clinical response. All primary end points were assessed at end of therapy in the modified intent-to-treat (MITT) population (defined below). Secondary efficacy end points included clinical response at follow-up and microbiological responses at end of therapy and follow-up.
Safety assessments included reporting of adverse events, clinical laboratory tests (including hematology and serum chemistry), physical examination findings, and vital signs.
The safety population included all patients who received any study drug (intent-to-treat population). The MITT population included all patients in the intent-to-treat population who had a baseline culture that was positive for Candida species. Analyses were also performed on subgroups of patients with OPC (with or without EC) or EC (with or without OPC).
Clinical response at end of therapy was defined by the investigator as follows: success (cure)-absence of symptoms and no requirement for additional systemic antifungal therapy to treat the study condition; success (improvement)-decrease in severity of symptoms as compared with baseline evaluations and no further need for systemic antifungal therapy for the study condition; or failure-no significant improvement or worsening of signs and/or symptoms of ARMC after receiving ≥72 hours of anidulafungin therapy, with additional systemic antifungal therapy required. Patients for whom circumstances prevented an evaluation from being made (eg, lost to follow-up or death for reasons other than mucosal candidiasis) and those who received <72 hours of therapy were classified as failure (indeterminate).
At end of therapy, the endoscopic response for each patient with EC was defined as follows: success (cure)-endoscopic grade 0 (normal esophageal mucosa) at end of therapy; success (improvement)-a decrease of ≥1 grade from baseline; or failure-no change or a worsening of endoscopic grade from baseline. Patients for whom circumstances prevented an evaluation from being made were also classified as failure (indeterminate).
For each Candida species identified at baseline, the per-pathogen microbiological outcomes at end of therapy and at follow-up were determined by committee review of the culture data and categorized as follows: success (eradication)-culture negative for the Candida species present at baseline (proven) or culture data not available for a patient with a successful clinical outcome (presumed); or failure (persistence)-baseline Candida species present in a subsequent culture (proven) or culture data not available for a patient with a clinical outcome of failure (presumed). Similar criteria were used to assess recurrence (proven or presumed) at follow-up.
Baseline and Disease Characteristics
Nineteen patients received study medication, and 18 patients remained in the study through the follow-up visit. One patient did not complete the study due to a serious adverse event. All 19 patients enrolled had a baseline pathogen recovered and were included in the MITT analysis. Four patients were retreated with anidulafungin.
Baseline demographic and disease characteristics are shown in Table 1. More than half (58%) of patients had both OPC and EC. Among patients with OPC, 10 (56%) had grade III disease; 7 and 1 patients had grade II and I disease, respectively. Of the 12 patients with EC, 10 (83%) had grade III disease and 2 (17%) had grade II disease.
All 18 patients with OPC and all 12 patients with EC had clinical signs and symptoms of moderate or severe disease: Signs of severe disease were seen in 11 (61%) patients with OPC and 8 (67%) patients with EC. Seventeen patients (89%) had advanced HIV infection as the underlying disease. The remaining 2 patients had documented or suspected connective tissue diseases (1 patient with rheumatoid arthritis and Sjögren syndrome and 1 with chronic mucocutaneous candidiasis). Thirteen of the 17 HIV-positive patients (76%) were profoundly immunocompromised, with CD4+ counts ≤50 cells/mm3. The median CD4+ count was 9 cells/mm3.
All patients had a prior history of recurrent episodes of OPC and/or EC and were clinically refractory to azole therapy. Eleven patients had suffered from ≥3 episodes of mucosal candidiasis before enrollment into this study. The median number of previous episodes of OPC and/or EC for the 16 patients who had a known history of preceding mucosal candidiasis episodes was 5.5 (range, 2-24).
Of the prior antifungal medications taken by the MITT population, fluconazole and itraconazole were the most commonly prescribed antifungals. All 19 patients had been exposed to fluconazole, and 8 patients (42%) had been exposed to itraconazole. Four patients had been previously treated with voriconazole, 3 (16%) with amphotericin B, 2 (10%) with liposomal amphotericin B, 2 (10%) with caspofungin, and 1 with ketoconazole. Furthermore, of the patients who had previously received systemic antifungal therapy, 50% had a history of mucosal candidiasis that was clinically refractory to either voriconazole (38%) or caspofungin (12%).
Candida albicans was the most common baseline pathogen recovered, isolated from 18 (95%) patients. Fifteen patients had only Candida species recovered at baseline, and 3 patients had 2 Candida species. One patient had Candida glabrata alone; however, 4 patients were coinfected with C. glabrata and C. albicans, whereas 1 patient was coinfected with C. glabrata and Candida tropicalis. Of the 4 patients who had more than one Candida species isolated, 3 had EC and were infected with both C. albicans and C. glabrata. Additionally, 1 patient with OPC had 3 pathogens recovered at baseline (C. albicans, C. glabrata, and C. tropicalis). Seventeen baseline isolates underwent susceptibility testing and, as would be expected in this population of azole-refractory patients, the fluconazole MIC90 was high, 128 μg/mL (range, 0.25-128 μg/mL). At baseline, most patients (88%) had isolates that were either susceptible dose dependent (MIC 16-32 μg/mL, 53%) or resistant (MIC ≥64 μg/mL, 35%) to fluconazole.24 In vitro susceptibility assays of anidulafungin against the baseline Candida species revealed anidulafungin MICs (MIC-0, 48 hours) that ranged from 0.03 to 0.5 μg/mL, the results were well within the range previously seen in other clinical trials.
Course of Therapy
The median and mean durations of anidulafungin therapy were 21 and 19 days, respectively (range 13-21 days). Four patients were retreated with anidulafungin for a median of 25 days.
Primary End Point
Clinical success was observed in 18 of 19 patients (95%) with ARMC at end of therapy (Table 2). Clinical success was observed in 17 of 18 patients (94%) with OPC and 11 of 12 patients (92%) with EC. The majority of successes were cures. Endoscopic success was observed in 11 of 12 patients (92%) at end of therapy. Only one patient was a treatment failure at end of antifungal therapy. This 39-year-old male had a 10-year history of HIV with multiple prior episodes of OPC and 2 prior episodes of EC; he was enrolled with severe OPC and EC at baseline. After 21 days of treatment, the patient was considered both a clinical and endoscopic failure. Although he had no clinical signs or symptoms of OPC at end of therapy, symptoms of EC remained severe. The patient had previously failed to respond to itraconazole and oral amphotericin B and subsequently required treatment with granulocyte/macrophage-colony-stimulating factor and parenteral amphotericin B to control his disease. Interestingly, this patient had a CD4+ lymphocyte count >500 cells/mm3, suggesting a possible localized mucosal immune deficiency.
Secondary End Points
At follow-up, clinical success was observed in 14 patients (47%) overall, 8 of 18 patients with OPC (44%) and 6 of 12 patients with EC (50%). A similar proportion of follow-up successes was seen in patients with fluconazole-susceptible or fluconazole-nonsusceptible pathogens: 14 patients (47%) with fluconazole-nonsusceptible baseline pathogens had successful clinical and endoscopic (if applicable) responses at the end of therapy, and 6 (20%) had clinical success at follow-up. Four patients (13%) were retreated with anidulafungin, and all were considered clinical successes at end of therapy.
Microbiological success was observed in 37% of patients at end of therapy and 32% of patients at follow-up. Pathogen eradication was observed for 7 of 18 C. albicans isolates (39%) at end of therapy and 6 of 18 (33%) at follow-up. Of the 5 baseline C. glabrata isolates, 2 were eradicated at end of therapy and 1 during follow-up. No shifts or changes in anidulafungin MICs relative to baseline isolates were observed for Candida isolates recovered after therapy.
Anidulafungin was well tolerated in this population of patients with ARMC. Notably, because of increased nutritional intake, study patients experienced a median weight gain of approximately 2 kg (a 3% increase in weight) by the end of therapy.
The most common adverse event was nausea and/or vomiting, which occurred in 4 of 19 patients (21%). Four patients (21%) experienced adverse events that were possibly or probably related to the study drug. No other adverse event occurred in more than 4 patients. The most common treatment-related adverse event was hypokalemia reported in 2 patients (11%). One patient had a possible drug-related serious adverse event consisting of a diffuse maculopapular rash on the upper extremities and trunk on day 15. This resulted in the discontinuation of anidulafungin, the rash eventually resolved without sequelae. Infusion-associated adverse events were rare with only one patient experiencing mild flushing. Hypersensitivity was not documented among the 4 patients who were retreated with anidulafungin. Clinical laboratory results did not detect any clinically meaningful trends and did not suggest any toxicity.
The incidence of severe mucosal candidiasis has decreased in the past decade after the advent of highly active antiretroviral therapy. However, in patients with advanced HIV infection who have multidrug-resistant viruses, severe and refractory mucosal candidiasis continues to be a major problem. These patients will frequently experience odynophagia, sore throat, dysphagia, and dysgeusias leading to severe anorexia, decreased oral intake, and significant weight loss. In addition, studies indicate a higher rate of mortality in patients with documented ARMC. In the absence of immune reconstitution, nearly all patients with successfully treated mucosal candidiasis will eventually experience a recurrence and, consequently, maintenance therapy is frequently required in these patients.25,26
Currently available agents provide limited treatment options for ARMC. Dose escalation of fluconazole or a switch to a different azole may temporarily ameliorate disease. Treatment with itraconazole or amphotericin B oral solutions results in response rates ranging from 44% to 65%.27,28 In a retrospective analysis of 37 patients with fluconazole-refractory candidiasis, Kartsonis et al4 reported a response to caspofungin of 82% of patients with EC and in 100% of patients with OPC. A retrospective analysis of 4 phase 2 and 3 studies indicated that caspofungin was successful in approximately 64% of patients who had been clinically refractory to fluconazole.11
Although the study is limited by its small sample size (19 patients), anidulafungin seems to offer patients with ARMC a new, effective, and well-tolerated treatment option. In the present study, the majority of patients enrolled in the study demonstrated both clinical and endoscopic responses at end of therapy. All patients infected with fluconazole-nonsusceptible baseline isolates were clinical successes at the end of therapy. There was a single failure (both clinical and endoscopic) at end of therapy in a patient who had a high CD4+ cell count, suggestive of a deficiency in mucosal immunity. At follow-up, clinical success was sustained in approximately half of the patients. Moreover, all patients who were retreated with anidulafungin were clinical successes. Notably, even the 2 patients who had been pretreated with caspofungin responded well to anidulafungin. This may be due to the fact that, recently, Candida isolates with in vitro reductions in susceptibility to caspofungin and micafungin have been reported. Interestingly, all these isolates have retained their susceptibility to anidulafungin.29,30
The observed high relapse rate described in this study is consistent with the natural history of this severe disease and with the use of echinocandins in EC in HIV-positive subjects.4,21 This underlines the requirement for chronic suppressive antifungal therapy if the immune system cannot be reconstituted.
The safety and efficacy data obtained from this study are consistent with a large, double-blind phase 3 clinical trial that evaluated anidulafungin versus fluconazole in patients with EC.21 In this study, anidulafungin was well tolerated with few adverse events. Overall, the most common adverse events associated with the administration of anidulafungin seem to be pyrexia, vomiting, headache, nausea, and diarrhea.
This phase 2 noncomparative study demonstrated the efficacy and safety of anidulafungin in patients with azole-refractory esophageal and/or OPC. Clinical recurrence was expected and not uncommon in this population of patients who remained severely immunosuppressed. Further comparative clinical studies are needed to determine the optimal initial treatment approach in this difficult-to-treat population. In addition, studies evaluating secondary prophylaxis in this same population using either echinocandins, such as anidulafungin, or other azoles, such as voriconazole, are needed to determine the best approach to prevent both recurrences and the selection of multidrug-resistant Candida species. However, we also need to realize that the development of secondary antifungal resistance has already been demonstrated with caspofungin and is not common in this severely immunosuppressed population of patients.26,31
The authors would like to acknowledge Jose Hernandez, DO, for his contributions to the design and conduct of the study and the following individuals for their participation in study: Suzanne Woodrich, RN; Mary Pileggi, BSN; Michele Wible; and Bill Birmingham.
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