Unintended Pregnancies Observed With Combined Use of the Levonorgestrel Contraceptive Implant and Efavirenz-based Antiretroviral Therapy: A Three-Arm Pharmacokinetic Evaluation Over 48 Weeks

Abstract

Background: Levonorgestrel subdermal implants are preferred contraceptives with an expected failure rate of <1% over 5 years. We assessed the effect of efavirenz- or nevirapine-based antiretroviral therapy (ART) coadministration on levonorgestrel pharmacokinetics.

Methods: This nonrandomized, parallel group, pharmacokinetic evaluation was conducted in three groups of human immunodeficiency virus-infected Ugandan women: ART-naive (n = 17), efavirenz-based ART (n = 20), and nevirapine-based ART (n = 20). Levonorgestrel implants were inserted at baseline in all women. Blood was collected at 1, 4, 12, 24, 36, and 48 weeks. The primary endpoint was week 24 levonorgestrel concentrations, compared between the ART-naive group and each ART group by geometric mean ratio (GMR) with 90% confidence interval (CI). Secondary endpoints included week 48 levonorgestrel concentrations and unintended pregnancies.

Results: Week 24 geometric mean levonorgestrel concentrations were 528, 280, and 710 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.53; 90% CI, .50, .55 and nevirapine: ART-naive GMR, 1.35; 90% CI, 1.29, 1.43). Week 48 levonorgestrel concentrations were 580, 247, and 664 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.43; 90% CI, .42, .44 and nevirapine: ART-naive GMR, 1.14; 90% CI, 1.14, 1.16). Three pregnancies (3/20, 15%) occurred in the efavirenz group between weeks 36 and 48. No pregnancies occurred in the ART-naive or nevirapine groups.

Conclusions: Within 1 year of combined use, levonorgestrel exposure was markedly reduced in participants who received efavirenz-based ART, accompanied by contraceptive failures. In contrast, nevirapine-based ART did not adversely affect levonorgestrel exposure or efficacy.

Clinical trials registration: NCT01789879.

Keywords: contraceptive implant; efavirenz; levonorgestrel; nevirapine; unintended pregnancy.

© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Flow diagram of screened and enrolled participants who reached the primary study endpoint at 24 weeks. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus.

Figure 2.

Geometric mean levonorgestrel concentration–time profiles over 48 weeks for each study group. A standard-dose levonorgestrel implant (2-rod, 75 mg/rod) was placed at time 0 for all participants. Values represent the geometric mean levonorgestrel plasma concentrations at each study visit for participants in the antiretroviral therapy (ART)–naive group (solid line with closed circle), efavirenz group (dashed line with open triangles), and nevirapine group (dashed line with closed squares).

Figure 3.

Individual levonorgestrel area under the concentration–time curve from week 0 through week 24 (AUC0–24 weeks) for each study group. Each participant's AUC0–24 weeks is represented as a diamond; the median AUC0–24 weeks by study group is shown (line). The interindividual AUC0–24 weeks coefficient of variation (CV%) is as follows: antiretroviral therapy (ART)-naive group, 44.1%; efavirenz group, 43.7%; nevirapine group, 35.5%.