Cobicistat (COBI), a CYP3A inhibitor, is a pharmacokinetic enhancer that increases exposures of the HIV protease inhibitors (PIs) atazanavir and darunavir. The potential drug interaction between COBI-boosted PIs and hormonal contraceptives, which are substrates of intestinal efflux transporters and extensively metabolized by CYP enzymes, glucuronidation, and sulfation, was evaluated.This was a Phase 1, open-label, two cohort (n=18/cohort), fixed-sequence study in healthy females that evaluated the drug-drug interaction (DDI) between multiple-dose ATV+COBI or DRV+COBI and single-dose drospirenone/ethinyl estradiol (EE). DDIs were evaluated using 90% confidence intervals of the geometric least-squares mean ratios of the test (drospirenone/EE+boosted PI) versus reference (drospirenone/EE) using lack of DDI boundaries of 70-143%. Safety was assessed throughout the study.29/36 participants completed the study. Relative to drospirenone/EE alone, drospirenone AUCinf was 1.6-fold and 2.3-fold higher, and Cmax was unaltered, upon coadministration with DRV+COBI and ATV+COBI respectively. EE AUCinf decreased 30% with drospirenone/EE + DRV+COBI, and was unchanged with ATV+COBI + drospirenone/EE, relative to drospirenone/EE alone. Study treatments were generally well tolerated. The majority of adverse events were mild and consistent with known safety profiles of the compounds.Consistent with COBI-mediated CYP3A inhibition, drospirenone exposure increased following coadministration with COBI-containing regimens, with a greater increase with ATV+COBI. Thus, clinical monitoring for drospirenone-associated hyperkalemia is recommended with DRV+COBI and ATV+COBI should not be used with drospirenone. Lower EE exposure with DRV+COBI may be attributed to inductive effects of DRV on CYP enzymes and/or intestinal efflux transporters (ie, P-gp) involved in EE disposition.