Antiretroviral therapy and vaginally administered contraceptive hormones: a three-arm, pharmacokinetic study

Abstract

Drug-drug interactions between orally-administered antiretroviral therapy (ART) and hormones released from an intravaginal ring (IVR) are not known. We hypothesized that efavirenz-based ART and atazanavir/ritonavir-based ART would alter plasma concentrations of vaginally-administered etonogestrel/ethinyl estradiol, yet ART concentrations would be unchanged during IVR use. Methods: We conducted a parallel, three-group, pharmacokinetic evaluation at clinical research sites in Asia, South America, sub-Saharan Africa, and the United States between December 30, 2014 and September 12, 2016 (NCT01903031). We enrolled women with HIV who were either ART-naïve (Control group; n=25), receiving efavirenz-based ART (n=25), or receiving atazanavir/ritonavir-based ART (n=24). An IVR releasing etonogestrel/ethinyl estradiol was inserted at entry. Single plasma samples for hormone concentrations were collected 7, 14, and 21 days after IVR insertion. The primary outcome was the plasma concentration of etonogestrel and ethinyl estradiol on Day 21. Etonogestrel and ethinyl estradiol concentrations were compared between each ART group and the Control group by geometric mean ratio (GMR) with 90% confidence intervals (CI) and Wilcoxon Rank-Sum test. Secondarily, efavirenz or atazanavir/ritonavir concentrations were assessed by 8-hour intensive pharmacokinetic sampling at entry before IVR insertion and before IVR removal on Day 21. Antiretroviral areas under the concentrationtime curve (AUC0-8h) were compared before and after IVR insertion by GMR (90% CI) and Wilcoxon Signed-Rank test. Findings: On Day 21 of IVR use, participants receiving efavirenz had 79% lower etonogestrel [GMR 0•21 (0•16-0•28); p<0•0001] and 59% lower ethinyl estradiol [GMR 0•41 (0•32-0•52); p<0•0001] concentrations compared to the Control group. In contrast, participants receiving atazanavir/ritonavir had 71% higher etonogestrel [GMR 1•71 (1•37-2•14); p<0•0001], yet 38% lower ethinyl estradiol [GMR 0•62 (0•49-First Name (middle initial) Last Name

Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis

“…In ACTG study A5316, efavirenz reduced plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring [9], with CYP2B6 poor metabolizers having the greatest reductions [29]. However, study findings have not been consistent.…”

Pharmacogenetics of interaction between depot medroxyprogesterone acetate and efavirenz, rifampicin, and isoniazid during treatment of HIV and tuberculosis

“…The lack of substantial associations of CYP2B6 metabolizer status with MPA pharmacokinetic parameters is unexpected. Efavirenz is a potent inducer of CYP450 enzymes that metabolize MPA [12,13], and efavirenz has been shown to interact with some hormonal contraceptives [13,14]. When efavirenz-based ART was combined with a levonorgestrel-releasing contraceptive implant, CYP2B6 poor metabolizer genotype was associated with lower levonorgestrel C max and AUC [43].…”

“…When efavirenz-based ART was combined with a levonorgestrel-releasing contraceptive implant, CYP2B6 poor metabolizer genotype was associated with lower levonorgestrel C max and AUC [43]. Similarly, in ACTG study A5316, efavirenz reduced plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring [13], and among 24 women in the efavirenz group in that study, CYP2B6 poor metabolizer genotype was associated with greater reductions [44]. In contrast, ACTG study A5093, which compared pharmacokinetics of DMPA and selected ART regimens among women living with HIV, found no difference in MPA AUC, C max , or clearance between study groups [16,17], while a study by Nanda et al .…”

Potential risk of drug–drug interactions with hormonal contraceptives and antiretrovirals: prevalence in women living with HIV

“… 30 – 32 When the hormonal vaginal ring is used with ritonavir-boosted atazanavir, etonogestrel levels increase by 71% and ethinyl estradiol levels drop by 38%, suggesting that there is no associated drop in contraception efficacy. 33 When the vaginal ring was used with efavirenz-based ART, there were 79% lower etonogestrel levels and 59% lower ethinyl estradiol levels, threatening contraception efficacy. 33 The combination of an estrogen patch and fosamprenavir/ritonavir decreases the AUC of ethinyl estradiol by 37%, 4 which should not affect contraception efficacy.…”

“… 33 When the vaginal ring was used with efavirenz-based ART, there were 79% lower etonogestrel levels and 59% lower ethinyl estradiol levels, threatening contraception efficacy. 33 The combination of an estrogen patch and fosamprenavir/ritonavir decreases the AUC of ethinyl estradiol by 37%, 4 which should not affect contraception efficacy. In our cohort study, there were no WLH on concurrent HC and PIs boosted with cobicistat; this combination has been noted to present a potential issue, especially with drospirenone-associated hyperkalemia.…”