背景:与未接受抗逆转录病毒治疗的女性相比,同时使用以法韦仑为基础的抗逆转录病毒治疗和标准剂量的依托孕烯避孕植入物可使依托孕烯暴露量降低82%。这种减少暴露的临床影响得到了回顾性队列评估的支持,该评估表明,当避孕植入物与依非韦仑联合使用时,意外怀孕的发生率更高。我们假设在接受基于依非韦仑的抗逆转录病毒治疗的患者中放置两个依托孕酮植入物可以增加依托孕酮的暴露量并改善避孕效果。
目的:本研究比较了接受两种依托孕烯植入物(136mg,DoublET组)与一个依托孕烯植入物(68mg,对照组)。
方法:这是随机的,开放标签研究纳入了经期正常的乌干达妇女,她们正在接受基于依非韦伦的抗逆转录病毒疗法治疗HIV.参与者以1:1的比例随机分配到DoublET或对照组,和依托孕烯植入物在纳入时放置在同一臂中.所有参与者都使用铜宫内节育器来防止怀孕。通过在第3个月(第9-12周)连续4周测量每周血清孕酮浓度来评估排卵,6(第21-24周),和12(45-48周)。孕酮浓度>3ng/mL被解释为排卵。使用Fisher精确检验和48周的广义估计方程比较各组的排卵率。在植入后第3天和第1、4、12、24、36和48周收集血浆,并通过验证的LC-MS/MS方法分析依托孕酮。依托孕烯浓度被总结为中位数(四分位数间距,IQR),并通过几何平均比率(GMR)与90%置信区间(CI)进行组间比较。
结果:所有参与者(n=72)均为顺性乌干达妇女,中位年龄31岁(IQR29,36),36名参与者被纳入每个研究组.对照组中的两名参与者停药;一个在第1周由于进入时未被发现怀孕,另一个在第45周由于临床上显著的抑郁。在对照组的34名参与者中,有25名超过104人-月(45%)有47次排卵,DoublET组36名参与者中有2名超过108人月(2%)排卵[第3个月:11(31%)vs0(0%);第6个月:17(49%)vs0(0%);第12个月:19(56%)vs2(6%),分别(所有p<0.001)]。在48周内,DoublET组的排卵几率降低了97.7%(95%CI:90.1-99.5)。在每个时间点,与对照组相比,DoublET组的依托孕孕酮高出两倍以上(GMR2.30-2.83),第48周GMR为2.83(1.89,3.3590%CI)。两组之间的不良事件没有差异,没有参与者因不良事件而停药。
结论:超过48周的联合使用,在基于依非韦仑的抗逆转录病毒治疗的女性中,与一个依托孕烯植入物相比,放置两个依托孕烯植入物会抑制排卵并增加血浆依托孕烯暴露.将依托孕酮的剂量加倍与基于依非韦仑的抗逆转录病毒疗法一起使用可以提高避孕效果。
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 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.
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.