An open-label study of oral posaconazole has found that it safely and effectively treats oropharyngeal and oesophageal candidiasis in people resistant to fluconazole and/or itraconazole. The study was published in the February 15th issue of Clinical Infectious Diseases.
Mucosal candidiasis (‘thrush’) is an infection of the mouth and throat (oropharyngeal candidiasis) and/or oesophagus (oesophageal candidiasis) by the fungi Candida albicans and, more rarely, C. glabrata. Oral fluconazole is still the mainstay of antifungal treatment for mucosal candidiasis (MC). After repeated fluconazole treatment, 4 - 5% of people with advanced HIV (especially with CD4 cells counts below 100 cells/mm3) will develop fluconazole-resistant MC. Alternative treatments include itraconazole and voriconazole (which may be hampered by cross-resistance and drug interactions), and the more highly toxic intravenous drugs amphotericin B and caspofungin.
In this international, multicentre, phase III open-label clinical trial, American researchers studied oral posaconazole for the treatment of fluconazole- and/or itraconazole-resistant mucosal candidiasis. Adults with MC unresponsive to fluconazole or itraconazole treatment were enrolled between March 1998 and September 2000. A total of 199 such participants were enrolled from 30 sites (13 in the United States and 17 elsewhere): 149 had oropharyngeal candidiasis, 18 had esophageal candidiasis, and 32 had both. Most (80%) had CD4 cell counts below 100 cells/mm3
Analysis was done on a ‘modified intent-to-treat’ subset of 176 participants who had received at least one study dose of posaconazole, and had either: confirmed resistant MC at baseline, or shown no improvement after a minimum duration of prior azole therapy. In this group, 155 (88%) were men, 131 (74%) were white, and the mean CD4 cell count was 32 cells/mm3. Eighty-seven were resistant to fluconazole, ten were resistant to itraconazole, and seventy-two were resistant to both.
The original treatment protocol (‘regimen A’) consisted of 400mg oral posaconazole suspension twice daily for three days, followed by 400mg once daily for 25 days. A more intensive ‘regimen B’ (400mg twice daily for 28 days) was later added.
Of the 176 ‘modified intent-to-treat’ participants analysed, 93 (53%) responded (i.e. showed cure or improvement) after 14 days, and 132 (75%) responded after 28 days. Response rates were similar between regimens A (75.3%) and B (74.7%).
These results compare favourably to those shown in other studies for itraconazole (55% to 80%), voriconazole (83%), and caspofungin (64%). A high relapse rate of 74% was seen after 30 days off treatment; the twice-daily regimen B had a lower relapse rate (68%) than regimen A (80%). However, a long-term treatment extension “appeared to be well tolerated.”
Adverse events were reported in 98 (49%) of participants, principally diarrhoea (11%), neutropenia (low white blood cell count: 7%), flatulence (6%) and nausea (6%). Only nausea and vomiting were more common in regimen B than regimen A. Serious adverse events (most frequently neutropenia) were reported in 28 people (16%). Forty-seven people (24%) discontinued treatment, but only eight of these (4%) reportedly did so because of adverse events. Four people died; no deaths were considered related to posaconazole treatment.
The researchers concluded that “posaconazole therapy administered for at least 28 days was efficacious and well tolerated in subjects with advanced HIV infection and microbiologically confirmed azole-refractory [mucosal candidiasis]… [the] results of this study … support the use of posaconazole as a valuable treatment option for patients with azole-susceptible and azole-refractory MC”.
Posaconazole was licensed as Noxafil in the United States in September 2006 for the treatment of invasive candidiasis or aspergillosis in immunosuppressed people.