What is the best treatment approach for an HIV positive patient with suspected invasive fungal infection and impaired renal function?

Treatment of Invasive Fungal Infection in HIV-Positive Patients with Renal Impairment

For HIV-positive patients with suspected invasive fungal infection and impaired renal function, lipid formulations of amphotericin B (liposomal amphotericin B at 3-5 mg/kg/day IV) should be used as first-line therapy, avoiding conventional amphotericin B deoxycholate due to its nephrotoxicity. 1

Initial Assessment and Risk Stratification

Determine the CD4+ count immediately, as this guides both diagnostic approach and treatment intensity:

• CD4+ <250 cells/μL: Treat all clinical evidence of fungal infection aggressively 1
• CD4+ <50 cells/μL: Highest risk for disseminated disease and mortality 2, 3
• Evaluate for specific endemic mycoses based on geographic exposure (cryptococcosis, histoplasmosis, coccidioidomycosis, talaromycosis) 1, 2

Assess renal function severity to guide antifungal selection:

• Calculate eGFR and evaluate for proteinuria 1
• Review current antiretroviral therapy for nephrotoxic agents (tenofovir disoproxil fumarate, atazanavir, ritonavir-boosted protease inhibitors) 1
• Check electrolytes, particularly potassium and magnesium 4, 5

Antifungal Selection Algorithm

For Patients with Significant Renal Impairment

First-line: Lipid formulations of amphotericin B 1

• Liposomal amphotericin B (L-AmB): 3-5 mg/kg/day IV for 10-14 days 1
• This is superior to amphotericin B deoxycholate (AmB-d) for renal safety while maintaining efficacy 1
• Conventional AmB-d causes nephrotoxicity in the majority of patients, with 3% requiring discontinuation within 2 weeks 1

Alternative: Echinocandins (if azole-resistant or azole-intolerant) 6

• Caspofungin, micafungin, or anidulafungin have favorable renal safety profiles 6
• Particularly useful for invasive candidiasis 1, 6
• No dose adjustment needed for renal impairment 6

Azole Considerations in Renal Dysfunction

Fluconazole remains an option for consolidation therapy after initial amphotericin B induction 1, 7:

• Standard dose: 400 mg daily for 8-10 weeks consolidation 1
• Requires dose adjustment in severe renal impairment (CrCl <50 mL/min) 7
• Monitor closely for breakthrough infections due to variable exposure in renal dysfunction 5

Posaconazole requires caution 5:

• Patients with severe renal impairment should be monitored closely for breakthrough fungal infections due to variability in exposure 5
• Delayed-release tablets preferred over oral suspension in renal impairment 5

Avoid itraconazole as primary therapy in renal impairment due to unpredictable absorption and lack of safety data 1

Treatment Protocol by Clinical Scenario

Cryptococcal Meningitis (Most Common in HIV)

Induction phase (2 weeks): 1

• Liposomal amphotericin B 3-5 mg/kg/day IV (preferred in renal impairment) 1
• Add flucytosine 100 mg/kg/day if renal function permits (requires dose adjustment for CrCl <40 mL/min) 1

Consolidation phase (8-10 weeks): 1

• Fluconazole 400-800 mg daily (adjust for renal function) 1

Maintenance phase: 1

• Fluconazole 200 mg daily until CD4+ >200 cells/μL for ≥6 months on ART 1

Disseminated Endemic Mycoses (Histoplasmosis, Coccidioidomycosis, Talaromycosis)

Induction therapy: 1

• Liposomal amphotericin B 3-5 mg/kg/day IV for 10-14 days 1
• This approach is extrapolated from cryptococcal treatment guidelines for immunosuppressed patients 1

Consolidation: 1

• Transition to oral azole (fluconazole or itraconazole) after clinical improvement 1
• Continue until CD4+ >250 cells/μL sustained 1

Invasive Candidiasis

First-line in renal impairment: 1, 6

• Echinocandin (anidulafungin, caspofungin, or micafungin) 1, 6
• Alternative: Fluconazole 400 mg loading dose, then 200-400 mg daily (dose-adjusted for renal function) 1, 7

Critical Monitoring Parameters

During amphotericin B therapy: 4

• Monitor serum creatinine, BUN, potassium, magnesium daily initially 4
• Correct electrolyte disturbances before and during therapy 4, 5
• Infuse over 2-6 hours to minimize infusion-related toxicity 4
• Maximum daily dose: Never exceed 1.5 mg/kg (fatal cardiac arrest risk) 4

During azole therapy: 5

• Monitor liver function tests at baseline and periodically 5
• Check for QTc prolongation, especially with posaconazole 5
• Assess for drug-drug interactions with antiretrovirals 1, 5

Renal function monitoring: 1

• Serial creatinine and eGFR measurements 1
• Urinalysis for proteinuria 1
• Consider switching nephrotoxic antiretrovirals (TDF to TAF, atazanavir to darunavir) 1

Common Pitfalls to Avoid

Do not use conventional amphotericin B deoxycholate as first-line in renal impairment 1:

• Causes predictable nephrotoxicity with hypokalemia, hypomagnesemia, and renal tubular acidosis 1
• Only 3% tolerate it without dose-limiting toxicity in the first 2 weeks 1

Do not rely on fluconazole monotherapy for initial treatment of severe invasive fungal infections 1:

• Pilot studies show unsatisfactory outcomes with fluconazole as initial therapy for cryptococcal meningitis 1
• Amphotericin B induction is superior for mortality reduction 1

Do not ignore breakthrough infections in patients with severe diarrhea or vomiting 5:

• Azole absorption is compromised, leading to subtherapeutic levels 5
• Consider IV formulations or echinocandins 6, 5

Do not continue nephrotoxic antiretrovirals unnecessarily 1:

• Switch from TDF to TAF where available 1
• Avoid ritonavir-boosted protease inhibitors (atazanavir, lopinavir) in favor of darunavir or integrase inhibitors 1

Duration of Therapy

Induction phase: 10-14 days of IV amphotericin B 1

Consolidation phase: 8-10 weeks of oral azole 1

Maintenance/suppressive therapy: 1

• Continue until immune reconstitution (CD4+ >200-250 cells/μL for ≥6 months on effective ART) 1
• For cryptococcal meningitis: Lifelong suppression if CD4+ remains <200 cells/μL 1
• For coccidioidomycosis: Continue while CD4+ <250 cells/μL 1