How should fluconazole be used in patients receiving antiretroviral therapy (ART), particularly regarding interactions with protease inhibitors (PIs), non‑nucleoside reverse‑transcriptase inhibitors (NNRTIs), and integrase‑strand‑transfer inhibitors (INSTIs)?

Fluconazole Interactions with Antiretroviral Therapy

Fluconazole is the preferred antifungal agent for patients on ART due to its relatively weak interaction potential with the CYP450 system, making it safe to use with most antiretroviral regimens without dose adjustments. 1

Key Interaction Profile by ART Class

Integrase Strand Transfer Inhibitors (INSTIs) - Preferred Class

• INSTIs (raltegravir, dolutegravir, bictegravir) have minimal drug-drug interaction potential with fluconazole and represent the safest ART option when antifungal therapy is needed. 2, 3
• These agents avoid the CYP3A4 inhibition concerns seen with protease inhibitors and have superior tolerability during concurrent antifungal therapy 2
• No dose adjustments are required for either the INSTI or fluconazole when used together 3

Protease Inhibitors (PIs)

• Fluconazole increases saquinavir exposure by 50% (AUC increase from 1800 to 2700 μg·L⁻¹·h) and peak concentrations by 56%, but dose adjustments are not necessary due to saquinavir's favorable safety profile. 4
• Ritonavir pharmacokinetics remain unchanged when combined with fluconazole, requiring no dose modifications 4
• High-dose fluconazole (>200 mg/day) should be used cautiously with boosted PI regimens, though it remains safer than other azoles like itraconazole or voriconazole. 1
• Ritonavir-boosted regimens carry the greatest risk for drug interactions due to potent CYP3A4 inhibition, but fluconazole's weak CYP450 interaction profile minimizes this concern 2, 5

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Nevirapine-based ART can be safely initiated in patients receiving fluconazole (either 200 mg daily or 400 mg weekly) without increased risk of clinical hepatitis, elevated transaminases, or skin rashes. 6
• In a cohort of 686 patients, clinical hepatitis rates were similar across groups: 0.9% (no fluconazole), 1.0% (fluconazole 400 mg/week), and 0% (fluconazole 200 mg/day) 6
• At 6 months, 77-84% of patients remained on nevirapine regardless of fluconazole use, demonstrating good tolerability 6
• Efavirenz can be used with fluconazole without dose adjustments, though both agents carry hepatotoxicity risk requiring monitoring. 2, 1

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

• Tenofovir requires close monitoring for renal function when combined with amphotericin B, but has no significant interactions with fluconazole. 1
• Other NRTIs (emtricitabine, lamivudine, abacavir) have no metabolic interactions with fluconazole 2

Clinical Algorithm for Fluconazole Use with ART

Step 1: Assess Current ART Regimen

• If on INSTI-based regimen: Proceed with standard fluconazole dosing without modifications 2, 3
• If on PI-based regimen: Use fluconazole as preferred azole; monitor for increased saquinavir effects if applicable 1, 4
• If on NNRTI-based regimen: Safe to use fluconazole; monitor liver function tests monthly 6

Step 2: Determine Fluconazole Indication and Dosing

• For cryptococcal prophylaxis: 400 mg weekly or 200 mg daily are both safe with NVP-based ART 6
• For active cryptococcal meningitis: Initiate ART 2-4 weeks after starting antifungal therapy (earlier at 2 weeks if clinically improved with negative CSF cultures) 2
• For asymptomatic cryptococcal antigenemia: Start immediate ART with preemptive fluconazole 2

Step 3: Consider Alternative ART if Needed

• If patient requires voriconazole or posaconazole (not fluconazole), switch to INSTI-based regimen to avoid contraindications with efavirenz or boosted PIs. 2
• Raltegravir, maraviroc, rilpivirine, tenofovir, emtricitabine, lamivudine, and abacavir have no interactions with azoles 2

Critical Monitoring Parameters

Hepatotoxicity Surveillance

• Monthly liver function tests are essential when combining fluconazole with NNRTIs, particularly nevirapine (12.5% hepatotoxicity incidence) or efavirenz. 7, 6
• Baseline and follow-up AST/ALT monitoring should occur regardless of fluconazole dose 6

Drug Interaction Risk Stratification

• Patients on >5 non-antiretroviral medications have 1.86-fold increased risk of clinically significant drug-drug interactions. 3
• PI-based regimens carry 4.96-fold higher interaction risk compared to raltegravir-based regimens (2.48-fold for NNRTIs). 3

Common Pitfalls to Avoid

• Do not confuse fluconazole's safety profile with other azoles: Itraconazole >200 mg/day is not advised with boosted PIs; posaconazole is contraindicated with efavirenz or fosamprenavir; voriconazole is contraindicated with high-dose ritonavir 1
• Do not delay ART initiation for most opportunistic infections: Start within 2 weeks except for tuberculous meningitis and cryptococcal meningitis 2
• Do not use simeprevir (HCV treatment) with fluconazole: Systemically administered azoles including fluconazole are contraindicated with simeprevir 2
• Do not assume all antifungals are interchangeable: Echinocandins may be preferred alternatives when azole interactions are prohibitive 1