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Posaconazole for Azole-Refractory Candidiasis in Patients with HIV Infection
By Dean L. Winslow, MD, FACP, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor of Medicine, Stanford University School of Medicine
Dr. Winslow serves as a consultant to Siemens Diagnostics and is on the speakers bureaus of Boehringer-Ingelheim and GSK.
This article originally appeared in the April 2007 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, and peer reviewed by Connie Price, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Dr. Price is Assistant Professor, University of Colorado School of Medicine. Dr. Deresinski serves on the speaker's bureau for Merck, Pharmacia, GlaxoSmithKline, Pfizer, Bayer, and Wyeth, and does research for Merck. Dr. Price reports no financial relationship relevant to this field of study.
Synopsis: 176 HIV-infected patients with either oropharyngeal candidiasis (OPC) or esophageal candidiasis (EC) who had not responded to standard courses of either fluconazole or itraconazole were treated with posaconazole. 132 (75%) of patients achieved a clinical response. The 2 regimens tested were generally well-tolerated with only 8 patients (4%) discontinuing treatment due to a treatment-related adverse event.
Source: Skiest DJ, et al. Posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with HIV infection. Clin Infect Dis 2007;44:607-614.
This paper reports the results of an important multinational trial which evaluated the use of 2 different regimens of posaconazole in the treatment of OPC or EC, which had been refractory to either fluconazole or itraconazole. The 2 regimens studied were oral posaconazole 400 mg BID for 3 days followed by 400 mg once daily for 25 days or posaconazole 400 mg BID for the entire initial 28 days. After 28 days on the induction regimen patients who had clinically responded could receive posaconazole 400 mg BID 3 times/week as suppressive therapy for up to 3 months.
Both dosing regimens were equally effective. Posaconazole was active against both Candida albicans and other Candida species. The posaconazole regimens were also effective in patients from whom Candida isolates demonstrated in vitro resistance to either or both fluconazole and itraconazole.
Despite the significant reduction in the prevalence of severe and refractory mucosal candidiasis in HIV patients due to the use of HAART, management of OPC and EC refractory to older azoles remains a relatively common clinical problem. While parenteral echinocandins and amphotericin B preparations are extremely useful in acute treatment of esophageal candidiasis, they are a very heavy hammer with which to treat recurrent OPC. As a result we are often left with a number of unsatisfactory measures to try to manage OPC, which is refractory to fluconazole or itraconazole. Oral voriconazole is often ineffective due to cross-resistance with the older azoles. Anecdotally some clinicians have found success with pushing the doses of older azoles, but I have never been impressed that this works for long and is often complicated by hepatotoxicity and significant drug interactions in the case of itraconazole. Nystatin oral suspension has seldom been effective in my hands nor has the use of "homebrew" oral suspensions of amphotericin B, which I have occasionally tried out of desperation in the past.
Posaconazole is a broad spectrum antifungal triazole with in vitro activity against many molds as well as most fluconazole and itraconazole resistant yeasts. Posaconazole received FDA market clearance in the fall of 2006.
These results are encouraging and show that posaconazole is a useful addition to our therapeutic armamentarium for the treatment of azole-refractory and azole-resistant OPC and EC. However, the trial only followed patients out for a few months. As we know from our experience in the past with treating recurrent mucosal candidiasis with the older azoles in the setting of HIV infection, development of resistance to posaconazole in vivo is likely to occur. Reversal of the underlying HIV-related immunosuppression is ultimately the best way to suppress all opportunistic infections.