Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia.
Aouri M, Decosterd LA, Buclin T, et al.
AIDS, 2012, 26(6): 776-778.

This case describes a 52-year-old HIV-infected patient who commenced a new treatment regimen which included darunavir/ritonavir (800/100 mg daily), etravirine (400 mg daily), elvitegravir (150 mg daily), tenofovir (300 mg daily), emtricitabine (200 mg daily) and foscarnet( 5 g daily five times a week). The patient was cotreated with voriconazole (200 mg twice daily) for Candida albicans infection, which was then increased to 400 mg in the morning and 200 mg in the evening. Darunavir was increased to 1200 mg daily at the end of voriconazole therapy, to compensate for the anticipated lifting of voriconazole-mediated cytochrome P450 3A4 metabolism inhibition. Mid-interval plasma concentrations (average sampling time 12 ± 1 h after drug intake) of darunavir, ritonavir, etravirine, elvitegravir, voriconazole and its metabolite (voriconazole N-oxide) were determined at several occasions while on and off voriconazole therapy and trough concentrations extrapolated using percentiles curves.

Darunavir plasma concentrations measured at three occasions while on voriconazole therapy were within the 50-75th percentile range established for DRV 800 mg daily and remained within the same range after voriconazole cessation and darunavir dosage increase to 1200 mg daily. Ritonavir plasma concentrations remained above 0.025 mg/L during voriconazole treatment, and were regarded as sufficiently high to guarantee the efficient boosting of darunavir as well as elvitegravir. Concentrations of elvitegravir reached the previously reported range for RTV-boosted elvitegravir combination. Etravirine concentrations were not significantly affected by voriconazole. At a total daily dose of 600 mg, voriconazole trough plasma concentrations were within therapeutic range except on week 25, with unremarkable voriconazole N-oxide concentrations indicating no evidence of impaired hepatic metabolism. Voriconazole treatment was stopped at week 25 as the esophageal candidiasis resolved upon immune reconstitution. Forty eight weeks after antiretroviral treatment initiation, the patient’s CD4 cell count had increased from 6 cells/ml to 123 cells/ml and viral load had decreased from 35000 copies/ml to 80 copies/ml.

These results are in contrast to an earlier case report by Toy et al (AIDS, 2011, 25: 541-542) where an HIV-infected patient treated with darunavir/ritonavir (900/100 mg daily) and etravirine (200 mg twice daily) was found to have an unexpectedly low trough darunavir plasma concentration, an undetectable ritonavir concentration and an increased etravirine concentration while on voriconazole (400 mg twice daily) for Aspergillus pneumonia. After stopping voriconazole, trough darunavir and ritonavir concentrations returned to expected values. The authors of this earlier case postulated that the increased etravirine concentration led to a greater induction effect on darunavir, or that low ritonavir concentration resulted in reduced darunavir boosting.  However given that darunavir concentrations were in the expected range on multiple occasions in the second case, Aouri et al are of the opinion that drug interactions per se unlikely to explain the single extremely low darunavir concentration in the first case and other reasons should be considered, such as missed dose of ritonavir and/or darunavir or diluted sample (e.g. multilumen catheter).