Fungal Diagnosis and Treatment in HIV Patients: Practical Overview
The Best Prophylaxis is Antiretroviral Therapy, Not Antifungals
The single most important intervention for preventing fungal infections in HIV patients is initiating and maintaining effective antiretroviral therapy (ART), not routine antifungal prophylaxis. 1 Primary antifungal prophylaxis is generally not recommended despite proven efficacy because acute treatment is highly effective, mucosal candidiasis has low mortality, resistance develops with prolonged use, drug interactions are problematic, and costs are substantial. 1
Diagnostic Performance: Key Practical Points
Cryptococcosis
- Routine serum cryptococcal antigen testing in asymptomatic HIV patients is not recommended because results rarely change clinical management. 1
Candidiasis
- For esophageal candidiasis with typical symptoms (dysphagia, odynophagia) plus oropharyngeal thrush, start empiric fluconazole without endoscopy. 1 Endoscopy is only indicated if symptoms persist after 7-14 days of appropriate therapy. 1
Histoplasmosis
- Routine skin testing with histoplasmin and serologic antibody/antigen testing in endemic areas are not predictive of disease and should not be performed. 1
Mechanisms of Action: The Antifungal Arsenal
Azoles (Fluconazole, Itraconazole, Voriconazole, Posaconazole)
Azoles inhibit cytochrome P-450 dependent enzyme lanosterol 14α-demethylase, blocking ergosterol synthesis in the fungal cell membrane. 2 This causes accumulation of methylated sterol precursors and ergosterol depletion, weakening fungal cell membrane structure and function. 2
Echinocandins (Caspofungin, Micafungin, Anidulafungin)
These agents target fungal cell wall synthesis (different mechanism than azoles), making them valuable alternatives for azole-refractory disease. 1
Amphotericin B
Binds to ergosterol in fungal cell membranes, creating pores that lead to cell death—reserved for refractory cases due to toxicity. 1
Treatment Guidelines by Fungal Family
Candidiasis: Azoles Are First-Line
Oropharyngeal Candidiasis (OPC)
- Fluconazole 100 mg daily for at least 7 days is the gold standard first-line treatment. 1, 3
- Alternative: Itraconazole oral solution 200 mg daily (NOT capsules due to poor absorption). 1
- Avoid topical agents (nystatin, amphotericin B lozenges)—they have suboptimal tolerability and lower efficacy. 1
- Avoid ketoconazole due to hepatotoxicity and variable absorption. 1
Esophageal Candidiasis
- Fluconazole 200-400 mg daily for 14-21 days (oral or IV if unable to swallow) is the treatment of choice. 1, 3, 4
- The 100 mg daily dose used for OPC is insufficient for esophageal disease. 3, 4
- Alternative: Itraconazole solution 200 mg daily for 14-21 days. 1
Azole-Refractory Candidiasis
This is the critical scenario where treatment escalation is needed:
- First-line for refractory disease: Itraconazole oral solution ≥200 mg daily (64-80% response rate). 1, 3
- Second-line options: Posaconazole 400 mg twice daily OR voriconazole 200 mg twice daily for 14-21 days. 1, 3
- Third-line: Any echinocandin (anidulafungin, caspofungin, micafungin) OR IV amphotericin B. 1
Recurrent Candidiasis
- Most experts do not recommend chronic suppressive therapy for the same reasons primary prophylaxis is avoided. 1
- However, if recurrences are frequent/severe despite ART: Fluconazole 100-200 mg three times weekly. 1, 3, 4
- A randomized trial showed continuous fluconazole (3×/week) reduced recurrences in patients with CD4+ <150 cells/µL without increasing clinically significant resistance when combined with ART. 1
Cryptococcosis: Azoles for Prophylaxis/Maintenance, Not Primary Treatment
- Primary prophylaxis with fluconazole or itraconazole is NOT routinely recommended despite proven efficacy, due to relative infrequency of disease, lack of survival benefit, drug interactions, resistance potential, and cost. 1
- If prophylaxis is used (e.g., CD4+ <50 cells/µL in high-risk patients): Fluconazole 100-200 mg daily. 1
- For acute cryptococcal meningitis: Initial treatment requires amphotericin B (not azoles alone), followed by lifelong fluconazole maintenance therapy. 5
Histoplasmosis: Itraconazole Is the Azole of Choice
- Prophylaxis may be considered with itraconazole in patients with CD4+ <100 cells/µL in hyperendemic areas (≥10 cases per 100 patient-years) or with high occupational exposure. 1
- A randomized trial showed itraconazole reduced histoplasmosis frequency but provided no survival benefit. 1
Aspergillosis: Voriconazole or Posaconazole, Not Fluconazole
- Aspergillosis is increasing dramatically in HIV patients due to neutropenia and corticosteroid use. 5
- Voriconazole has been the traditional first-line treatment for invasive aspergillosis. 6
- Posaconazole (300 mg twice on day 1, then 300 mg daily) is non-inferior to voriconazole with fewer treatment-related adverse events (30% vs 40%) and better tolerability. 6
- Fluconazole has no role in aspergillosis treatment. 7
Practical Rule for Azole Selection by Fungal Family
"Fluconazole First" Fungi (Candida, Cryptococcus maintenance)
- Candida species (except C. krusei, C. glabrata): Fluconazole is first-line. 1
- Cryptococcus (maintenance only): Fluconazole after amphotericin B induction. 5
"Itraconazole Preferred" Fungi (Endemic mycoses)
- Histoplasma capsulatum: Itraconazole for prophylaxis and treatment. 1
- Blastomyces, Coccidioides: Itraconazole is effective. 5, 7
- Penicillium marneffei (Southeast Asia): Responds to itraconazole. 5
"Voriconazole or Posaconazole Required" Fungi (Aspergillus, resistant Candida)
- Aspergillus species: Voriconazole or posaconazole (posaconazole preferred for better tolerability). 6
- Azole-refractory Candida: Posaconazole or voriconazole as second-line. 1
"Azoles Don't Work" Scenarios (Echinocandins or Amphotericin B needed)
- Candida krusei: Intrinsically fluconazole-resistant. 1
- Candida glabrata: Frequently azole-resistant; consider boric acid topically or echinocandins systemically. 1
- Severe/refractory disease of any type: Echinocandins or amphotericin B. 1
Critical Drug Interactions and Resistance Concerns
Cross-Resistance Among Azoles
- 30% of fluconazole-resistant Candida isolates are cross-resistant to itraconazole. 1
- Prolonged azole use, especially with CD4+ <100 cells/µL, increases resistance risk. 1
- Clinical isolates with decreased posaconazole susceptibility show reduced susceptibility to other azoles, suggesting cross-resistance. 2
Drug-Drug Interactions
- Itraconazole has higher incidence of erratic bioavailability and drug interactions compared to fluconazole. 1
- Posaconazole has fewer interactions than itraconazole or voriconazole. 1
- Healthcare providers must consider antiretroviral interactions when prescribing antifungals. 7
Special Populations: Pregnancy
Azoles should be avoided in pregnancy due to teratogenicity:
- Fluconazole ≥400 mg daily chronically causes "fluconazole embryopathy" (craniosynostosis, characteristic facies, digital synostosis, limb contractures). 1
- Single-dose fluconazole (150 mg) for vaginal candidiasis has not been associated with birth defects. 1
- Itraconazole is embryotoxic/teratogenic in animals; posaconazole causes skeletal abnormalities in rats; voriconazole is FDA category D. 1
- For pregnant women requiring systemic antifungal therapy: Substitute amphotericin B, especially in first trimester. 1
- Topical therapy is strongly preferred for oral/vaginal candidiasis in pregnancy. 1
Common Pitfalls to Avoid
Dosing Errors
- Don't use 7-10 day courses for esophageal candidiasis—requires full 14-21 days. 3
- Don't use fluconazole 100 mg daily for esophageal disease—requires 200-400 mg daily. 3, 4
- Don't use itraconazole capsules—poor absorption; use oral solution only. 1, 3
Inappropriate Prophylaxis
- Don't start primary antifungal prophylaxis routinely—ART is the best prophylaxis. 1
- Don't continue chronic suppressive therapy indefinitely—consider discontinuation when CD4+ rises to >200 cells/µL on ART. 1
Wrong Drug Selection
- Don't use fluconazole for aspergillosis—completely ineffective. 7, 6
- Don't use topical agents for esophageal candidiasis—systemic therapy always required. 4
- Don't use ketoconazole—hepatotoxicity and inferior efficacy. 1, 3