Posaconazole versus Fluconazole for the Treatment of Oropharyngeal Candidiasis in HIV Patients

By Ronald Baker, PhD

Oropharyngeal candidiasis (OC) holds the dubious distinction of being the most common opportunistic infection (OI) in individuals with HIV infection worldwide. In individuals experiencing OC for the first time, the infection indicates a decreasing CD4+ cell count and strongly suggests the onset of significant immunodeficiency in HIV positive individuals. For patients on HAART, a relapse of OC indicates non-adherence and therefore, immune function decline.

Current guidelines from the Infectious Disease Society of America (IDSA) recommend the use topical agents, including nystatin and clotrimazole troches for treatment of initial episodes of OC, although HIV patients likely will experience relapse [1]. In addition, these medications are inconvenient to administer, require frequent applications, and are less effective than systemic therapies, according to the results of several studies [2-4].

Systemic therapy with oral fluconazole (Diflucan) or itraconazole (Sporanox) usually is effective for treatment of OC [5,1], but the emergence of fluconazole-resistant Candida, estimated at <5%, is not uncommon. Several new antifungal agents, including voriconazole (Vfend), caspofungin (Cancidas for Injection), and micafungin (Mycamine), have shown promise in the treatment of  mucocutaneous candidiasis, but the necessity for intravenous administration of caspofungin and micafungin is a significant limitation to their use.

Posaconazole versus Fluconazole

Posaconazole is an wide-spectrum triazole that has demonstrated potent in vitro activity against Candida species, including fluconazole-resistant strains, Cryptococcus, Aspergillus, and many pathogenic molds. [6,7]. Posaconazole also has shown in vitro activity against Candida species other than Candida albicans [7]. In addition, anecdotal reports suggest success of posaconazole in patients with systemic candidiasis caused by C. glabrata and Candida tropicalis who could not tolerate or had disease resistant to treatment with other antifungal agents [8,9].

In the current issue of Clinical Infectious Diseases (April 15, 2006), [10] Jose Vazquez and others report the results of their multi-center randomized trial that evaluated the clinical effectiveness of posaconazole versus fluconazole in the treatment of oropharyngeal candidiasis in subjects with HIV infection. Secondary objectives included evaluating mycological efficacy, safety and clinical relapse.


Three hundred fifty study participants received either 200 mg of posaconazole (n = 178) or fluconazole      (n = 172) oral suspension on day 1, followed by 100 mg/day for 13 days. The primary study end point—clinical success (cure or improvement) on day 14—was evaluated for 329 subjects. Durability of clinical success was evaluated on day 42.

Results    

Clinical success occurred in 155 (91.7%) of 169 posaconazole recipients and in 148 (92.5%) of 160 fluconazole recipients, indicating that posaconazole was not inferior to fluconazole.

On day 14, mycological success was 68% in both arms, but by day 42, significantly more posaconazole recipients than fluconazole recipients continued to have mycological success (40.6% vs. 26.4%; P = .038).

Fewer posaconazole recipients than fluconazole recipients experienced clinical relapse (31.5% vs. 38.2%).

Adverse events were similar between treatment arms.

Based on these finding, the study authors conclude, “Results demonstrate that posaconazole was as effective as fluconazole in producing a successful clinical outcome. However, posaconazole was more effective than fluconazole in sustaining clinical success after treatment was stopped [fewer clinical relapses].”

Discussion

Both posaconazole and fluconazole were generally well tolerated, and no laboratory results showed significant changes in either treatment group. In patients with invasive fungal infections, the most common adverse events associated with posaconazole were headache and gastrointestinal abnormalities (nausea and abdominal pain) [11].

Results of this trial indicate that posaconazole is equivalent in efficacy to fluconazole for treatment of OC, has an adverse event profile similar to that of fluconazole, but is more effective in prolonging clinical efficacy following cessation of therapy (fewer clinical relapses were seen).

Following FDA approval of the posaconazole, do these results indicate that clinicians should prescribe the drug as first-line treatment rather than fluconazole for HIV patients with evidence of OC? Or are there other perspectives for evaluating the results of this study?

In a editorial that accompanies the article by Vazquez et al, Stephen Klotz, MD, at the University of Arizona, Tucson, Arizona suggests that posaconazole offers “a beneficial alternative to other antifungal agents currently in clinical use for treating oropharyngeal candidiasis” [12]. However, Dr. Klotz emphasizes that fluconazole, Metronidazole and ceftriaxone (Rocephin) are the ‘workhorse’ antimicrobial drugs that are “highly cost-effective” and “without equal” in their low incidence of adverse effects.

Dr. Klotz also believes that that posaconazole likely will be prescribed for the treatment of Candida species other than C. albicans, Aspergillus species, Scedosporium species, and some Zygomycetes. He concludes, “Posaconazole's niche in the antifungal armamentarium will be determined over time and with clinical use.”

03/20/06

Additional Candidiasis Articles on HIVandHepatitis.com

Continuous versus Episodic Use of Fluconazole for Candidiasis in HIV Patients on HAART - 10/19/05

Decline in Esophageal Candidiasis and Use of Antimycotics in European HIV Patients - 7/06/05

Oral Candidiasis During HAART Treatment Suggests Immune Failure 3/23/05

Oral Opportunistic Infections in HIV Positive Individuals 12/06/04

Oral Opportunistic Infections in HIV Positive Individuals: Role of Mucosal Immunity 09/27/04

Anidulafungin May Be Useful Treatment Alternative for Esophageal Candidiasis, Especially for Patients Intolerant to Other Drugs 09/03/04

Study Results Suggest Micafungin Is a Valuable New Treatment Option for Esophageal Candidiasis in HIV Patients 09/03/04

Oral Candidiasis and Seborrheic Dermatitis in HIV-infected Patients on HAART 03/15/04

Guidelines for Treatment of Candidiasis, a Common and Often Dangerous Fungal OI in People with AIDS 01/07/04

Trial of High-dose Fluconazole (Diflucan) Versus Fluconazole plus Amphotericin B as Therapy for Candidemia - 06/09/03

Vulvovaginal Candidiasis Occurs among HIV-infected Women More Frequently and with Greater Persistence, but Not Greater Severity - 04/02/03

High Incidence of Vulvovaginal Candidiasis in HIV-infected Women - 03/31/03

CD8+ T Cells May Combat Oral Candidiasis, but Activity Lessened in HIV Patients - 03/12/03

Sources

JA Vazquez and others. A Multicenter Randomized Trial Evaluating Posaconazole versus Fluconazole for the Treatment of Oropharyngeal Candidiasis in Subjects with HIV/AIDS. Clincial Infectious Diseases 42(8): 1179-1186. April 15, 2006.

SA Klotz. Oropharyngeal Candidiasis: A New Treatment Option. Clinical Infectious Diseases 42(8): 1187-1188. April 15, 2006.

References

1. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis 2004; 38:161–89.

2. Pons V, Greenspan D, Debruin M. Therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, prospective multicenter study of oral fluconazole versus clotrimazole troches. Multicenter Study Group. J Acquir Immune Defic Syndr 1993; 6:1311–6.

3. Koletar SL, Russell JA, Fass RJ, Plouffe JF. Comparison of oral fluconazole and clotrimazole troches as treatment for oral candidiasis in patients infected with human immunodeficiency virus. Antimicrob Agents Chemother 1990; 34:2267–8.

4. Goldman M, Cloud GA, Wade KD, et al. A randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal candidiasis: AIDS clinical trials group study 323/mycoses study group study 40. Clin Infect Dis 2005; 41:1473–80.

5. Vazquez JA. Options for the management of mucosal candidiasis in patients with AIDS and HIV infection. Pharmacotherapy 1999; 19:76–87.

6. Pfaller MA, Messer SA, Hollis RJ, Jones RN. In vitro activities of posaconazole (SCH 56592) compared with those of itraconazole and fluconazole against 3685 clinical isolates of Candida spp. and Cryptococcus neoformans. Antimicrob Agents Chemother 2001; 45:2862–4.

7. Pfaller MA, Messera SA, Boyken L, et al. In vitro activities of voriconazole, posaconazole, and fluconazole against 4169 clinical isolates of Candida spp. and Cryptococcus neoformans collected during 2001 and 2002 in the ARTEMIS Global Antifungal Surveillance Program. Diagn Microbiol Infect Dis 2004; 48:201–5.

8. Anstead GM, Martinez M, Graybill JR. Control of a Candida glabrata prosthetic endovascular infection with posaconazole. Med Mycol (in press).

9. Tobón A, Correa AL, Arango M, de Bedout C, Restrepo A. Posaconazole therapy for severe abdominal candidiasis: a case report. Rev Iberoam Micol 2004; 21:79–81.

10. Vazquez JA and others. A Multicenter Randomized Trial Evaluating Posaconazole versus Fluconazole for the Treatment of Oropharyngeal Candidiasis in Subjects with HIV/AIDS. 2006; Clin Infect Dis 42:1179-86.

11. Graybill JR, Raad I, Negroni R, Corcoran G, Pedicone L. Posaconazole (POS) long-term safety in patients with invasive fungal infections (IFIs) [abstract M-1025]. In: Program and abstracts of the 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (Washington, DC). Washington, DC: American Society for Microbiology, 2004.

12. Klotz SA. Oropharyngeal Candidiasis: A New Treatment Option. Clin Infect Dis; 2006 42:1187-88.