A randomized trial of double vs single-dose etonogestrel implant to overcome the interaction with efavirenz-based antiretroviral therapy.

BACKGROUND: Concomitant use of efavirenz-based antiretroviral therapy and a standard-dose etonogestrel contraceptive implant led to 82% lower etonogestrel exposure when compared with women who do not receive antiretroviral therapy. The clinical impact of this reduced exposure is supported by retrospective cohort evaluations that demonstrated higher rates of unintended pregnancies when contraceptive implants were combined with efavirenz. We hypothesized that placement of 2 etonogestrel implants in those taking efavirenz-based antiretroviral therapy could increase etonogestrel exposure and improve measures of contraceptive efficacy. OBJECTIVE: This study compared the rate of ovulation and etonogestrel pharmacokinetics among women on efavirenz-based antiretroviral therapy who received 2 etonogestrel implants (136 mg; double implant group) in comparison with those who received 1 etonogestrel implant (68 mg; control group). STUDY DESIGN: This randomized, open-label study enrolled Ugandan women with regular menstrual periods who were receiving efavirenz-based antiretroviral therapy for the treatment of HIV. Participants were randomized 1:1 to the double implant or control group, and the etonogestrel implant(s) were placed in the same arm at enrollment. All participants used a copper intrauterine device to prevent pregnancy. Ovulation was evaluated by weekly serum progesterone concentrations measured over 4 consecutive weeks at months 3 (weeks 9-12), 6 (weeks 21-24), and 12 (weeks 45-48). Progesterone concentrations >3 ng/mL were interpreted as ovulation. The ovulation rate in each group was compared using Fisher's exact tests for each month and generalized estimating equations over 48 weeks. Plasma was collected at day 3 and weeks 1, 4, 12, 24, 36, and 48 after implant placement and analyzed using a validated liquid chromatography-triple quadrupole mass spectrometry method for etonogestrel. Etonogestrel concentrations were summarized as median (interquartile range) and compared between groups by geometric mean ratio with 90% confidence intervals. RESULTS: All participants (n=72) were cisgender Ugandan women with a median age of 31 years (interquartile range, 29-36), and 36 participants were enrolled in each study group. Two participants in the control group discontinued the trial; 1 at week 1 because of undetected pregnancy at entry and another at week 45 because of clinically significant depression. There were 47 ovulations over 104 person-months (45%) in 25 of 34 participants in the control group, and 2 ovulations over 108 person-months (2%) in 2 of 36 participants in the double implant group (month 3: 11 [31%] vs 0 [0%]; month 6: 17 [49%] vs 0 [0%]; month 12: 19 [56%] vs 2 [6%], respectively; all P<.001). The odds of ovulation were reduced by 97.7% (95% confidence interval, 90.1-99.5) in the double implant group over 48 weeks. At each time point, etonogestrel concentration was more than 2-fold higher in the double implant group than in the controls (geometric mean ratio, 2.30-2.83) with a geometric mean ratio of 2.83 (90% confidence interval, 1.89-3.35) at week 48. There were no differences in the adverse events between groups and no participant discontinued because of adverse events. CONCLUSION: Over 48 weeks of combined use, placing 2 etonogestrel implants suppressed ovulation and increased plasma etonogestrel exposure when compared with 1 etonogestrel implant among women on efavirenz-based antiretroviral therapy. Doubling the dose of etonogestrel during efavirenz-based antiretroviral therapy could improve contraceptive effectiveness.

Effect of double-dose levonorgestrel subdermal implant in women taking efavirenz-based antiretroviral therapy: The DoubLNG pharmacokinetic study.

OBJECTIVE: We evaluated the pharmacokinetics of double-dose levonorgestrel (LNG) implants to overcome the drug-drug interaction with efavirenz-based antiretroviral therapy (ART). STUDY DESIGN: We conducted a nonrandomized, open-label, parallel-group, longitudinal pharmacokinetic study among Ugandan women ages 18-45 years. Participants with HIV on ART containing efavirenz 600 mg received 300 mg of LNG implants (Jadelle®, Bayer, New Zealand): 300LNG+ART group. We compared our outcomes with women without HIV using standard dose, 150 mg of LNG implants: 150LNG group. The implant was placed on day zero in both groups, and we quantified plasma LNG concentrations over 48 weeks post implant insertion. LNG pharmacokinetic parameters were estimated using noncompartmental techniques. Our primary outcome was the geometric mean ratio with 90% confidence intervals of LNG area under the concentration-time curve over 24 weeks (AUC0-24w) between groups. Demographic data were described as median (interquartile range). A secondary outcome compared between-group percent of LNG concentrations ≥300 pg/mL, a minimum threshold selected a priori based on observed pregnancies in Ugandan women on standard-dose LNG implants plus efavirenz. RESULTS: We enrolled 27 women in the 300LNG+ART group (34 [28.0 to 40.5] years and 61.0 [49.8-66.0] kg) and 19 women in the 150LNG group (33 [30.0 to 34.5] years and 64.9 [59.0 to 74.5] kg). LNG AUC0-24w was 34% lower for 300LNG+ART versus 150LNG (geometric mean 9998 vs. 15,231 pg*week/mL, respectively [geometric mean ratio 0.66 (90% confidence intervals, 0.54 to 0.80)]). The percentage of participants with LNG concentrations ≥300 pg/mL was not statistically different between groups at week 24 (300LNG+ART: 74.1%; 150LNG: 89.5%; p = 0.27). CONCLUSION: Double-dose LNG implant did not completely overcome the drug-drug interaction with efavirenz. IMPLICATION: In women using ART containing efavirenz, placing two implant systems (300 mg) did not normalize LNG pharmacokinetics compared with the standard-dose implant (150 mg), and some women had evidence of ovulatory activity. Alternative ART without drug-drug interactions, such as dolutegravir, is recommended with contraceptive implants.

Pharmacokinetics of levonorgestrel and etonogestrel contraceptive implants over 48†weeks with rilpivirine- or darunavir-based antiretroviral therapy.

BACKGROUND: Pharmacokinetic data are lacking for progestin-releasing subdermal contraceptive implants when used with either rilpivirine- or darunavir/ritonavir-based ART. OBJECTIVES: To characterize the pharmacokinetics of etonogestrel or levonorgestrel implants when administered with these ART regimens over 48 weeks. PATIENTS AND METHODS: Two separate, parallel, three-group, non-randomized, pharmacokinetic studies evaluated either etonogestrel or levonorgestrel in women receiving rilpivirine- or darunavir-based ART compared with women without HIV (control group). Participants on ART were switched to rilpivirine-based ART with a run-in period of 6 weeks or darunavir-based ART with a run-in of 2 weeks prior to implant insertion. Plasma was collected on Day 0, and 1, 4, 12, 24, 36 and 48 weeks post-insertion. Plasma progestin concentrations were compared between ART and control groups by geometric mean ratio (GMR) and 90% CI. RESULTS: At the primary endpoint of Week 24, progestin concentrations were similar between the rilpivirine and control groups [etonogestrel: 1.18 (0.99-1.37); levonorgestrel: 1.16 (0.97-1.33)]. At Week 24, progestin exposure was higher in the darunavir groups compared with the control group [etonogestrel: 2.56 (1.69-3.28); levonorgestrel: 1.89 (1.38-2.29)]. Results remained consistent through to Week 48. No differences in etonogestrel-related adverse events were observed, but both ART groups experienced more menstrual abnormalities versus the control group with levonorgestrel. CONCLUSIONS: Etonogestrel and levonorgestrel concentrations were not altered by rilpivirine-based ART. Although progestin concentrations were higher in the ART groups containing ritonavir-boosted darunavir, no implant-related serious adverse events were observed. Both progestin-releasing implants are an appropriate contraceptive option with either rilpivirine- or darunavir/ritonavir-based ART.