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. 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). 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. 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 <.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. 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.

中文翻译：

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双剂量与单剂量依托孕烯植入物的随机试验，以克服与基于依非韦伦的抗逆转录病毒治疗的相互作用

与未接受抗逆转录病毒治疗的女性相比，同时使用基于依非韦伦的抗逆转录病毒治疗和标准剂量依托孕烯避孕埋植剂可使依托孕烯暴露量降低 82%。回顾性队列评估支持了这种减少暴露的临床影响，该评估表明，当避孕埋植剂与依非韦伦联合使用时，意外怀孕的发生率更高。我们假设，在接受依非韦伦抗逆转录病毒治疗的患者中放置 2 个依托孕烯植入物可以增加依托孕烯暴露并改善避孕效果。本研究比较了接受基于依非韦伦的抗逆转录病毒治疗、接受 2 颗依托孕烯植入物（136 毫克；双植入物组）的女性与接受 1 颗依托孕烯植入物（68 毫克；对照组）的女性的排卵率和依托孕烯药代动力学。这项随机、开放标签的研究纳入了月经规律的乌干达妇女，她们正在接受基于依非韦伦的抗逆转录病毒疗法来治疗艾滋病毒。参与者按 1:1 的比例随机分配到双植入物组或对照组，并且在入组时将依托孕烯植入物放置在同一组中。所有参与者都使用铜宫内节育器来避孕。通过在第 3 个月（第 9-12 周）、第 6 个月（第 21-24 周）和第 12 个月（第 45-48 周）连续 4 周测量每周血清孕酮浓度来评估排卵。黄体酮浓度 >3 ng/mL 被解释为排卵。使用每月的 Fisher 精确检验和 48 周内的广义估计方程来比较每组的排卵率。在种植体植入后第 3 天和第 1、4、12、24、36 和 48 周收集血浆，并使用经过验证的液相色谱-三重四极杆质谱法对依托孕烯进行分析。依托孕烯浓度总结为中位数（四分位数范围），并通过几何平均比和 90% 置信区间进行组间比较。所有参与者 (n=72) 均为顺性别乌干达女性，中位年龄为 31 岁（四分位数范围为 29-36），每个研究组有 36 名参与者。对照组的两名参与者终止了试验；第 1 周有 1 次，因为入组时未检测到妊娠；第 45 周有 1 次，因为有临床意义的抑郁症。对照组 34 名参与者中，有 25 名参与者在 104 个人月内有 47 次排卵 (45%)，双种植体组 36 名参与者中的 2 名在 108 人月内有 2 次排卵 (2%)（第 3 个月：11 [31%] vs 0 [0%]；第 6 个月：17 [49%] vs 0 [0%]；第 12 个月：19 [56%] vs 2 [6%]；全部 <.001)。 48 周内，双假体植入组的排卵几率降低了 97.7%（95% 置信区间，90.1-99.5）。在每个时间点，双植入组中的依托孕烯浓度比对照组高 2 倍以上（几何平均比，2.30-2.30）。83），第 48 周时几何平均比率为 2.83（90% 置信区间，1.89-3.35）。各组之间的不良事件没有差异，并且没有参与者因不良事件而停药。在联合使用超过 48 周的时间里，在接受依非韦伦抗逆转录病毒治疗的女性中，与 1 个依托孕烯植入物相比，放置 2 个依托孕烯植入物抑制了排卵，并增加了血浆依托孕烯暴露。在基于依非韦伦的抗逆转录病毒治疗期间加倍依托孕烯剂量可以提高避孕效果。