Table 5.

Summary of observed/predicted drug-drug interactions between antiretrovirals and azole antifungals.

Anti retroviral	Antifungal	Interactions	Dosing recommendation/ clinical comments	Ref.
Entry and fusion inhibitors
Enfuvirtide	Fluconazole	↔	↔	[72]
	Itraconazole	↔	↔	[72]
	Ketoconazole	↔	↔	[72]
	Posaconazole	↔	↔	[72]
	Voriconazole	↔	↔	[72]
Maraviroc	Fluconazole	Fluconazole may ↑ maraviroc concentration via CYP3A4 inhibition	Although dosage adjustment is not necessary maraviroc-related toxicity should be closely monitored	[78]
	Itraconazole	Itraconazole can ↑ maraviroc concentration via CYP3A4 inhibition	Maraviroc dose is recommended to be reduced to 150 mg b.i.d.	[77]
	Ketoconazole	Maraviroc AUC and Cmax ↑ by 5- and 3.4-fold	Maraviroc dose is recommended to be reduced to 150 mg b.i.d.	[77]
	Posaconazole	Posaconazole may ↑ maraviroc concentration via CYP3A4 inhibition	lthough dosage adjustment is not necessary maraviroc-related toxicity should be closely monitored	[78]
	Voriconazole	Voriconazole may ↑ maraviroc concentration via CYP3A4 inhibition	Although dosage adjustment is not necessary maraviroc-related toxicity should be closely monitored	[78]
Nucleoside/nucleotide reverse transcriptase inhibitors
	Fluconazole	↔	↔	[80,81,99–103]
	Itraconazole	↔	↔
	Ketoconazole	↔	↔
	Posaconazole	↔	↔
	Voriconazole	↔	↔
Non-nucleoside reverse transcriptase inhibitors
Delavirdine	Fluconazole	↔	↔	[82]
	Itraconazole	↔	↔	[82]
	Ketoconazole	Delavirdine Cmin ↑ by 50%	↔	[82]
	Posaconazole	↔	↔	[82]
	Voriconazole	↔	↔	[82]
Efavirenz	Fluconazole	Efavirenz AUC ↑ by 16%; no change in fluconazole AUC	Dosage adjustment is not necessary	[83]
	Itraconazole	No change in efavirenz AUC; itraconazole AUC and Cmax ↓. by 39 and 37%	Coadministration should be avoided. If used concomitantly, therapeutic monitoring of itraconazole is needed	[84]
	Ketoconazole	No change in efavirenz AUC; ketoconazole AUC and Cmax ↓ by 72 and 44%	Coadministration should be avoided	[86]
	Posaconazole	No change in efavirenz AUC; posaconazole AUC and Cmax ↓ by 50 and 45%	Coadministration should be avoided unless benefits outweigh the risks. If used concomitantly therapeutic monitoring of posaconazole is needed	[85]
	Voriconazole	Efavirenz AUC and Cmax ↑ by 44 and 38%; voriconazole AUC and Cmax ↓. by 77 and 61 %	Dosage adjustment is necessary. Reduce efavirenz dose to 300 mg/day and increase voriconazole dose to 400 mg b.i.d. Dosage adjustment is not	[87]
Etravirine	Fluconazole	Etravirine AUC ↑ by 86%; no		[104]
	Itraconazole	change in fluconazole AUC	necessary; use with caution	[104]
		Concomitant use may result in ↑ plasma concentration of etravirine and ↓. plasma concentration of itraconazole	Dose adjustments for itraconazole may be necessary; consider therapeutic monitoring
	Ketoconazole	Concomitant use may result in ↑ plasma concentration of etravirine and ↓. plasma concentration of ketoconazole	Dose adjustments for ketoconazole may be necessary; consider therapeutic monitoring	[104]
	Posaconazole	Posaconazole may ↑ plasma concentration of etravirine	Dose adjustments for posaconazole may be necessary; consider therapeutic monitoring	[104]
	Voriconazole	Etravirine AUC ↑ by 36%; voriconazole AUC ↑ by 14%	Dosage adjustment is not necessary; use with caution	[104]
Nevirapine	Fluconazole	Nevirapine exposure ↑ by 100%; no change in fluconazole AUC	Use with caution. Increased risk of nevirapine-associated toxicities	[105]
	Itraconazole	No change in nevirapine AUC; itraconazole AUC and Cmax ↓. by 61 and 38%	Consider itraconazole monitoring	[106]
	Ketoconazole	Nevirapine AUC ↑ by 15 –20%; ketoconazole AUC and Cmax ↓ by 72 and 44%	Avoid concomitant use; consider other antiretrovirals or antifungals	[105]
	Posaconazole	↔	↔	[105]
	Voriconazole	↔	↔	[105]
Rilpivirine	Fluconazole	Fluconazole may ↑ rilpivirine concentration via CYP3A4 inhibition	Dosage adjustment is not necessary; monitor for breakthrough fungal infections	[107]
	Itraconazole	Itraconazole may ↑ rilpivirine concentration via CYP3A4 inhibition	Dosage adjustment is not necessary; monitor for breakthrough fungal infections	[107]
	Ketoconazole	Rilpivirine AUC and Cmax ↑ by 49 and 30%; ketoconazole AUC and Cmax ↓. by 24 and 15%	Dosage adjustment is not necessary; monitor for breakthrough fungal infections	[107]
	Posaconazole	Posaconazole may ↑ rilpivirine concentration via CYP3A4 inhibition	Dosage adjustment is not necessary; monitor for breakthrough fungal infections	[107]
	Voriconazole	Voriconazole may ↑ rilpivirine concentration via CYP3A4 inhibition	Dosage adjustment is not necessary; monitor for breakthrough fungal infections	[107]
Integrase strand transfer inhibitors
Dolutegravir	Fluconazole	↔	↔	[88]
	Itraconazole	↔	↔	[88]
	Ketoconazole	↔	↔	[88]
	Posaconazole	↔	↔	[88]
	Voriconazole	↔	↔	[88]
Elvitegravir/	Fluconazole	↔	↔	[108]
cobicistat	Itraconazole	Concomitant use may result in ↑ itraconazole and/or elvitegravir and cobicistat concentrations	The maximum daily dose of itraconazole should not exceed 200 mg	[108]
	Ketoconazole	Concomitant use may result in ↑ ketoconazole and/or elvitegravir and cobicistat concentrations	The maximum daily dose of ketoconazole should not exceed 200 mg	[108]
	Posaconazole	↔	↔	[108]
	Voriconazole	Concomitant use may result in ↑ voriconazole and/or elvitegravir and cobicistat concentrations	An assessment of benefit:risk ratio is recommended to justify use of voriconazole with elvitegravir/cobicistat	[108]
Raltegravir	Fluconazole	↔	↔	[89]
	Itraconazole	↔	↔	[89]
	Ketoconazole	↔	↔	[89]
	Posaconazole	↔	↔	[89]
	Voriconazole	↔	↔	[89]
Protease inhibitors (Pls)(/r represents ritonavir-boosted)
Atazanavir	Fluconazole	↔	↔	[109]
	Itraconazole	Concomitant use may result in negligible increase in atazanavir; ↑ concentration of itraconazole. Concomitant use of atazanavir/r may result in ↑ concentration of both PI and itraconazole	Dosage adjustment is not necessary; monitor for itraconazole-related toxicities	[109]
	Ketoconazole	Concomitant use may result in negligible increase in atazanavir; ↑ concentration of ketoconazole. Concomitant use of atazanavir/r may result in ↑ concentration of both PI and ketoconazole	Dosage adjustment is not necessary; monitor for ketoconazole-related toxicities	[109]
	Posaconazole	Concomitant use ↑ AUC of atazanavir by 268%. Concomitant use of atazanavir/r ↑ AUC of atazanavir by 146%	Dosage adjustment is not necessary; monitor for atazanavir-related toxicities	[85]
	Voriconazole	Concomitant use may affect atazanavir concentration. Concomitant use of atazanavir/r in patients with a functional CYP2C19 results in ↓. concentration of atazanavir and voriconazole; patients without a functional CYP2C19 results in ↓ concentration of atazanavir and ↑ voriconazole	Coadministration of atazanavir/r and voriconazole should be avoided unless benefits outweigh the risks. If used concomitantly, therapeutic monitoring is needed	[109]
Darunavir	Fluconazole	↔	↔	[110]
	Itraconazole	Concomitant use of darunavir/r and itraconazole may ↑ plasma concentration of darunavir and itraconazole	While administering with darunavir/r, the daily dose of itraconazole should not exceed 200 mg	[110]
	Ketoconazole	Concomitant use ↑ AUC and Cmax of darunavir by 155 and 78%; no change in ketoconazole concentration. Concomitant use of darunavir/r ↑ AUC and Cmax of darunavir by 42 and 21 %; ↑ AUC and Cmax of ketoconazole by 212 and 111 %	While administering with darunavir/r, the daily dose of ketoconazole should not exceed 200 mg	[111]
	Posaconazole	↔	↔	[110]
	Voriconazole	Concomitant use of darunavir/r results in ↓. concentration of voriconazole	Coadministration of darunavir/r and voriconazole should be avoided unless benefits outweigh the risks	[94]
Fosamprenavir	Fluconazole	↔	↔	[91]
	Itraconazole	Concomitant use may result in ↑ concentration of amprenavir and itraconazole.	Dosage adjustment is not necessary; monitor for dose- related toxicities.	[91]
		Concomitant use of fosamprenavir/r may result in ↑ concentration of both PI and itraconazole	While administering with fosamprenavir/r, the daily dose of itraconazole should not exceed 200 mg
	Ketoconazole	Concomitant use ↑ AUC and Cmax of amprenavir by 31 and 16%; ↑ AUC and Cmax of ketoconazole by 44 and 19%.	Dosage adjustment is not necessary; monitor for dose- related toxicities. While administering with fosamprenavir/r, the daily dose of ketoconazole should not exceed 200 mg	[92]
	Posaconazole	Concomitant use ↓. AUC and Cmax of posaconazole by 23 and 21%	Do not coadminister	[93]
	Voriconazole	Concomitant use may ↑ fosamprenavir and voriconazole concentration via CYP3A4 inhibition Concomitant use of fosamprenavir/r results in ↓ concentration of voriconazole	Coadministration of fosamprenavir/r and voriconazole should be avoided unless benefits outweigh the risks	[94]
Indinavir	Fluconazole	↔	↔	[112]
	Itraconazole	Concomitant use may result in ↑ concentration of indinavir	Dosage adjustment is necessary. Reduce indinavir dose to 600 mg every 8 h	[112]
	Ketoconazole	Concomitant use may result in ↑ concentration of indinavir	Dosage adjustment is necessary. Reduce indinavir dose to 600 mg every 8 h	[112]
	Posaconazole Voriconazole	↔ Concomitant use of indinavir/r results in ↓. concentration of voriconazole	↔ Coadministration of indinavir/r and voriconazole should be avoided unless benefits outweigh the risks	[112] [94]
Lopinavir/r	Fluconazole	↔	↔	[95]
	Itraconazole	Concomitant use of lopinavir/r may result in ↑ concentration of itraconazole	While administering with lopinavir/r, the daily dose of itraconazole should not exceed 200 mg	[95]
	Ketoconazole	Concomitant use of lopinavir/r may result in ↑ concentration of ketoconazole	While administering with lopinavir/r, the daily dose of ketoconazole should not exceed 200 mg	[95]
	Posaconazole Voriconazole	↔ Concomitant use of lopinavir/r results in ↓. concentration of voriconazole	Coadministration of lopinavir/r and voriconazole should be avoided unless benefits outweigh the risks	[95] [94]
Nelfinavir	Fluconazole	Concomitant use may result in ↑ concentration of nelfinavir and fluconazole	Dosage adjustment is not necessary; monitor for dose- related toxicities	[113]
	Itraconazole	Concomitant use may result in ↑ concentration of nelfinavir and itraconazole	Dosage adjustment is not necessary; monitor for dose- related toxicities	[113]
	Ketoconazole Posaconazole	Concomitant use ↑ AUC and Cmax of nelfinavir by 35 and 25%	Dosage adjustment is not necessary; monitor for dose- related toxicities	[113] [113]
		Concomitant use may result in ↑ concentration of nelfinavir and posaconazole	Dosage adjustment is not necessary; monitor for dose- related toxicities
	Voriconazole	Concomitant use of nelfinavir/r results in ↓. concentration of voriconazole	Coadministration of nelfinavir/r and voriconazole should be avoided unless benefits outweigh the risks	[94]
Saquinavir	Fluconazole	Concomitant use may result in ↑ concentration of saquinavir and fluconazole	Dosage adjustment is not necessary; monitor for dose- related toxicities	[114]
	Itraconazole	Concomitant use ↑ exposure of saquinavir and itraconazole	Dosage adjustment is not necessary; monitor for dose- related toxicities	[115,116]
	Ketoconazole	Concomitant use of saquinavir/r ↑ AUC and Cmax of ketoconazole by 45 and 168%	While administering with saquinavir/r, the daily dose of ketoconazole should not exceed 200 mg	[117]
	Posaconazole	↔	↔	[114]
	Voriconazole	Concomitant use of saquinavir/r results in ↓. concentration of voriconazole	Coadministration of saquinavir/r and voriconazole should be avoided, unless benefits outweigh the risks	[94]
Tipranavir	Fluconazole	Concomitant use ↑ AUC and Cmax of tipranavir by 56 and 46%; no change in fluconazole AUC	Dosage adjustment is not necessary; however doses > 200 mg/day are not recommended.	[118]
	Itraconazole	Possible ↑ itraconazole concentration	The daily dose of itraconazole should not exceed 200 mg	[119]
	Ketoconazole	Possible ↑ ketoconazole concentration	The daily dose of ketoconazole should not exceed 200 mg	[119]
	Posaconazole	↔	↔	[119]
	Voriconazole	Difficult to predict due to involvement of multiple CYP enzymes	Difficult to predict due to involvement of multiple CYP enzymes	[119]