Background:  The majority of HIV-infected women are of reproductive age and many are prescribed efavirenz (EFV) -containing antiretroviral regimens. Few data are available on the pharmacokinetics of progestin-based contraceptives with non-nucleoside reverse transcriptase inhibitors, including EFV. Women taking EFV may use LNG for emergency contraception and potential interactions between levonorgestrel (LNG) and EFV could influence efficacy or toxicity during concomitant use.

Methods:  In this open-label, single-arm study, we prospectively determined the effect of EFV on the pharmacokinetics of LNG (single-dose 0.75 mg) in HIV-seronegative women. We performed 12-hour intensive pharmacokinetic sampling for LNG following a single dose of LNG and after 14 days of EFV (600 mg by mouth, every hour of sleep) following a standardized meal. LNG plasma concentrations were measured by LC-MS and LNG pharmacokinetics was determined with non-compartmental methods (WinNonLin). Equivalence was defined as a decrease of less than 40% in LNG AUC after the addition of EFV. Geometric means and 90% confidence intervals (CI) for the pharmacokinetics of LNG were estimated. Relevant clinical parameters and liver function tests were assessed prior to and during steady-state EFV. Paired t-tests were used for analyses. Subjects were 18 to 45 years of age with normal body mass index and no recent or current use of hormonal contraceptive agents.

Results:  Of 24 women enrolled, 21 (67% white, 24 % Latina, 10% African American, median age 33 years, mean body mass index 27) completed study. LNG was well tolerated with no grade 3 or 4 treatment-related toxicities or changes in liver function tests. The estimated 56% (49% to 62%) decrease in LNG AUC was greater than the equivalence value of 40% (P <0.0001). All other LNG pharmacokinetics parameters were also significantly changed (see the table).

Conclusions:  EFV significantly reduced LNG exposure. Although the minimum effective concentration of LNG is unknown, higher LNG doses may be required to prevent pregnancy in the setting of EFV. Further research is needed of alternative LNG dosing strategies with EFV. These results reinforce the importance of dual methods of contraception, including a barrier device, in women taking EFV.