TREATMENT OF HIV-RELATED FLUCONAZOLE-RESISTANT ORAL CANDIDOSIS WITH D0870, A NEW TRIAZOLE ANTIFUNGAL

Objectives: To evaluate the efficacy and tolerance of D0870 in the tre atment of HIV-related fluconazole-resistant oro-oesophageal candidosis . Design: Multicentre open study. Patients: HIV-seropositive patients with oro-oesophageal candidosis despite at least 7 days of treatment w ith fluconazole at doses of 100 mg per day or more. Methods: Patients received an initial dose of D0870 (150 mg), then 25 mg per day for 6 d ays. Symptoms and signs of candidosis were compared at entry and on da ys 3 and 7 of treatment. At each visit, samples were taken for safety monitoring and for in vitro susceptibility testing of Candida isolates . Limited pharmacokinetic samples were taken on days 1 and 7. Results: Of 26 evaluable patients, 16 showed partial improvement, nine showed no improvement, and only one had full clearance of thrush by day 7. In vitro testing of the cleared patient's isolate suggested that it was susceptible to fluconazole. Symptoms of dysphagia cleared in 14 and im proved in five of the 22 patients with presumptive oesophageal involve ment at entry. Pharmacokinetic measurement showed wide variability in maximum D0870 levels recorded on day 1 (range, 0.07-0.34 mg/l) and sus ceptibility testing of isolates also showed a range of minimal inhibit ory concentration values to D0870 (range, < 0.06-8 mg/l; median, 0.25 mg/l). When these data were combined with clinical response there was a strong suggestion that lack of symptomatic improvement was related t o low plasma D0870 levels or to the presence of less D0870-susceptible isolates. Six patients were noted to have a fall in haemoglobin, thre e of whom were receiving concomitant therapy known to suppress bone ma rrow. Three patients reported headaches as adverse events that were at tributed to study medication, but D0870 was well tolerated overall. Co nclusions: D0870 shows promise in the treatment of fluconazole-resista nt oro-oesophageal candidosis and was well tolerated, although efficac y in this difficult-to-treat patient group was probably limited due to the inadequate plasma levels achieved in this pilot study with the lo w doses of D0870 administered. (C) 1998 Rapid Science Ltd.