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Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, NE, USADepartment of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, NE, USADepartment of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
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.
Availability of integrated family planning services in HIV care and support sites in sub-Saharan Africa: a secondary analysis of national health facility surveys.
Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks.
Effect of efavirenz on levonorgestrel concentrations among Malawian levonorgestrel implant users for up to 30 months of concomitant use: a subanalysis of a randomized clinical trial.
]. We previously reported a 57% decrease in levonorgestrel (LNG) concentrations and three unintended pregnancies among Ugandan women using the 150 mg LNG implant (two-rod subdermal implant, LNG 75 mg/rod) plus efavirenz 600 mg-based antiretroviral therapy (ART) over 48 weeks [
Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks.
]. Efavirenz is a known inducer of the cytochrome P450 (CYP) 3A4 enzyme, the enzyme primarily responsible for LNG metabolism. Thus, managing drug–drug interactions between contraceptive implants and efavirenz is a pressing public health need.
We investigated dose adjustment of the LNG implant to overcome the established drug–drug interaction with efavirenz-based ART. Our primary objective was to determine the LNG plasma concentrations over 24 weeks of double-dose LNG implant in women with HIV taking efavirenz-based ART. We hypothesized that double-dose LNG would result in similar LNG exposure compared with a control group using a standard-dose implant.
2. Materials and methods
We conducted a nonrandomized, open-label, longitudinal pharmacokinetic study to assess the safety and pharmacokinetics of 300 mg LNG subdermal implants (2×2-rod 75 mg LNG/rod; Jadelle®; Bayer, New Zealand) among Ugandan women taking efavirenz-based ART (300LNG+ART group, n = 27) [
]. We compared outcomes with a contemporaneous cohort of 19 adult Ugandan women without HIV and not on efavirenz-based ART receiving standard-dose LNG implant (1×2-rod 75 mg LNG/rod, 150LNG group) [
]. Investigators performed study-related procedures at the Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda, in accordance with the Declaration of Helsinki. Ethics boards at the Joint Clinical Research Centre Kampala, Uganda National Council for Science and Technology, and the University of Nebraska Medical Center approved all study procedures. All volunteers provided written informed consent. This study is registered in ClinicalTrials.gov (Identifier: NCT02722421).
2.1 Study population
We included women ages 18 and 45 years who desired the LNG implant based on clinical need [
]. Participants in the 300LNG+ART group were all living with HIV, taking once-daily efavirenz 600 mg-based ART for at least 3 months before enrollment who had an undetectable viral load at screening (HIV-1 RNA<50 copies/mL) [
]. All 150LNG group volunteers had a negative HIV test at entry and received HIV prevention counseling at each visit. We excluded volunteers within 30 days postpartum, those breastfeeding within 6 months of delivery, those with contraindications to the LNG subdermal implant, and those taking products known to interact with LNG or efavirenz [
All 300LNG+ART participants agreed to have a copper intrauterine device placed at entry to avoid the risk of undesired pregnancy. On day 0, after confirming a negative pregnancy test and reviewing participants’ self-reported sexual activity before entry, a trained clinician inserted the LNG subdermal implants according to product labeling [
]. In the 300LNG+ART group, the clinician inserted one system into each arm to avoid impacting LNG absorption from two systems at a single-implant site. In the 150LNG group, clinicians inserted one implant system.
2.3 Sampling strategy and clinical assessments
All participants had whole blood collected on day 0 and weeks 1, 4, 12, 24, 36, and 48 to determine plasma LNG concentrations, a urine pregnancy test, and laboratory safety assessments. For participants taking efavirenz, we quantified mid-dose efavirenz concentrations (12–14 hours post dose) from the same plasma sample to assess ART adherence. The 150LNG group completed follow-up at week 48. The 300LNG+ART group had extended follow-up every 24 weeks through week 144 (Fig. 1). The 300LNG+ART group had optional visits on days 1 to 4 to characterize LNG maximum concentrations and the time to maximum concentrations.
Fig. 1Study schema. ART, antiretroviral therapy; EFV, efavirenz; LNG, levonorgestrel; SHBG, sex hormone-binding globulin; WLH, women living with HIV.
To characterize possible ovulatory activity, we sampled endogenous serum progesterone concentrations and summarized the number of samples with progesterone concentrations ≥3 ng/mL (9.5 nmol/L) and ≥5 ng/mL (16 nmol/L) [
]. In the 300LNG+ART group, we sampled progesterone at individual study visits in all participants, and for 4 weeks around week 48 and 96 study visits for those who consented to return weekly (Fig. 1). Because the 150LNG group had serum progesterone concentrations sampled for 4 weeks around the week-48 visit only, we statistically compared the percent of participants with at least one progesterone sample ≥3 ng/mL and ≥5 ng/mL between both groups at week 48. We measured sex hormone binding globulin (SHBG) levels at regular intervals over 48 weeks.
Site investigators assessed study-related clinical and laboratory adverse effects at all visits using the Division of AIDS Adverse Event Grading Tables [
Division of AIDS. National Institute of Allergy and Infectious Diseases. Division of AIDS (DAIDS) table for grading the severity of adult and pediatric adverse events, corrected version 2.1. National Institutes of Health, U.S. Department of Health and Human Services; 2017. Available from: 〈https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf〉 (cited July 4, 2022).
]. Investigators assessed HIV treatment response and immune function by determining plasma HIV-1 RNA and CD4 T lymphocyte cell counts every 6 months during the first year and then yearly thereafter.
2.4 Assay characteristics
Plasma was separated by centrifugation and stored at −80 °C until sample shipment. LNG concentrations were determined by a validated liquid chromatography–tandem mass spectrometry assay at the University of Nebraska Medical Center Antiviral Pharmacology Laboratory, Omaha, Nebraska (limit of quantification: 25.0 pg/mL; linear calibration range: 25.0–30,000 pg/mL); the interday coefficient of variation was between 4.4% and 5.0%; accuracy was between −6.3% and −0.7% [
Development, validation and utilization of a highly sensitive LC-MS/MS method for quantification of levonorgestrel released from a subdermal implant in human plasma.
]. We determined plasma efavirenz concentrations using a high-performance liquid chromatography assay with ultraviolet detection at the Makerere University College of Health Sciences Translational Research Laboratory, Infectious Diseases Institute, Kampala, Uganda (linear calibration range: 0.20–10 mg/L); the interday coefficient of variation was between 2.8% and 5.3%; accuracy was between −6.4% and 7.0% [
Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks.
Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks.
], 25 participants in the 300LNG+ART group and 17 participants in the 150LNG group provided 83% power to test bioequivalence of the natural log-transformed LNG area under the plasma concentration–time curve from weeks 0 to 24 (AUC0–24w) relative to our 150LNG group using a no-effect boundary of 0.8 to 1.25 [
]. We calculated the plasma LNG AUC0–24w using the linear trapezoidal rule and compared between groups using geometric mean ratios (90% confidence intervals [CI]) and an unpaired t-test, based on normality of the result distribution. A two-sided alpha level of 0.05 was considered significant. We summarized and compared LNG concentrations at each visit using geometric means (95% CI) and medians (interquartile ranges) and Wilcoxon rank-sum test. A two-sided alpha level of 0.008 (Bonferroni correction) was considered significant.
As a proposed pharmacokinetic threshold for contraceptive effectiveness, we compared between-group LNG concentrations ≥300 pg/mL at weeks 24 and 48 using Fisher’s exact test with two-sided alpha level of 0.025 (Bonferroni correction). The threshold of 300 pg/mL was based on the last measured plasma LNG concentration before unintended pregnancies in a similar Ugandan cohort receiving standard-dose LNG implants and efavirenz-based ART (303 pg/mL) [
Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks.
]. We summarized the percent of participants with efavirenz concentrations ≥1 mg/L at all study visits; this threshold was defined a priori based on antiviral effectiveness [
]. We compared SHBG concentrations between groups using unpaired t-tests with two-sided alpha level of 0.017 (Bonferroni correction). We compared data between groups using Wilcoxon rank-sum tests or unpaired t-tests, and Χ2 or Fisher exact tests as appropriate based on data distribution (SAS software, v9.2, SAS Institute Inc, Cary, NC).
3. Results
3.1 Baseline characteristics
We enrolled 28 women with HIV and 23 women without HIV between March 2017 and October 2019; 27 300LNG+ART participants and 19 150LNG participants reached the primary endpoint (Fig. 2). Twenty (74.0%) participants in the 300LNG+ART group completed study procedures through week 144. Except for weight and body mass index, which were slightly lower in the 300LNG+ART group, and SHBG, which was significantly higher in the 300LNG+ART group, participants had similar baseline characteristics (Table 1). SHBG levels were higher in 300LNG+ART versus 150LNG at all time points (Supplementary Table 1).
Fig. 2Participant disposition. ART, antiretroviral therapy; EFV, efavirenz; LNG, levonorgestrel; LTFU, lost to follow-up; WLH, women living with HIV.
Table 1Baseline demographics and clinical characteristics of cis-gender Ugandan female participants with HIV on efavirenz 600 mg-based ART who received double-dose LNG implant (300LNG+ART) and participants without HIV who received standard-dose LNG implant (150LNG)
n = 22; 5 (of 27) participants in the 300LNG+ART group had baseline SHBG concentrations>250 nmol/L, the assay upper limit of quantification, and were excluded from the SHBG summary statistics.
All data were collected at screening, unless indicated. Body weight, BMI, SHBG, CD4 count, and ART duration were measured or assessed at enrollment.
44 (28–51)
NA
-
ART, antiretroviral therapy; BMI, body mass index; LNG, levonorgestrel; NA, not applicable; SHBG, sex hormone-binding globulin.
Continuous data presented as median (interquartile range); categorical data presented as n (%).
a All data were collected at screening, unless indicated. Body weight, BMI, SHBG, CD4 count, and ART duration were measured or assessed at enrollment.
b n = 22; 5 (of 27) participants in the 300LNG+ART group had baseline SHBG concentrations>250 nmol/L, the assay upper limit of quantification, and were excluded from the SHBG summary statistics.
The geometric mean LNG AUC0–24w was 9998 pg*week/mL (95% CI, 8492 to 11,771 pg*week/mL) in the 300LNG+ART group compared with 15,231 pg*week/mL (95% CI, 12,969 to 17,887 pg*week/mL) in the 150LNG group (geometric mean ratio: 0.66 [90% CI, 0.54 to 0.80], p < 0.001). During day1 to 4 blood sampling visits in the 300LNG+ART group (n = 14), the median LNG maximum concentration was 806 pg/mL (interquartile range: 595 to 866) pg/mL and median time to maximum concentration was 3 days. Over 48 weeks, LNG concentrations were up to 40% lower in the 300LNG+ART group relative to the 150LNG group (Fig. 3; Table 2). At week 144, 300LNG+ART median LNG concentrations were 471 pg/mL (interquartile range: 353 to 617 pg/mL) (Table 2). When considering our proposed LNG threshold for effectiveness, the percent of participants with LNG concentrations ≥300 pg/mL in 300LNG+ART versus 150LNG was 74.1% versus 89.5%, respectively, at week 24 (p = 0.27) and 80.8% versus 100%, respectively, at week 48 (p = 0.14).
Fig. 3Plasma levonorgestrel concentration versus time profile over 48 weeks post implant insertion for women with HIV receiving double-dose levonorgestrel implants (300 mg) plus efavirenz-based antiretroviral therapy (n = 27, solid line) compared with women without HIV taking standard-dose levonorgestrel implant (150 mg) alone (n = 19, dashed line)
Table 2Plasma LNG concentrations over 144 weeks post implant placement among study participants with HIV on efavirenz 600 mg-based ART who received double-dose LNG implant (300LNG+ART) and women without HIV who received standard-dose LNG implant (150LNG)
Fig. 4 describes all serum progesterone samples collected through week 51 and Table 3 describes characteristics of participants with possible ovulatory activity. Among participants who consented to the optional 4-weekly progesterone measurements around week 48, 5 of 24 (20.8%) 300LNG+ART participants had possible ovulatory activity (progesterone ≥3 ng/mL); four of these participants (16.7% of 24) had progesterone concentrations ≥5 ng/mL. No 150LNG group participants had ovulatory activity (zero of nine participants; 0.0%, p = 0.29; Fig. 4) [
]. Over weeks 96 through 99, 4 of 12 (33.3%) 300LNG+ART group participants had progesterone samples ≥5 ng/mL. The LNG concentrations measured around the time of possible ovulatory activity ranged from 130 to 751 pg/mL (Table 3).
Fig. 4Endogenous serum progesterone concentrations through 51 weeks post implant insertion. Dashed lines indicate two serum progesterone concentration thresholds associated with recent possible ovulatory activity (3 ng/mL and 5 ng/mL) [
]. The 300LNG+ART group (300 mg levonorgestrel plus efavirenz-based antiretroviral therapy, closed circles) progesterone concentrations were sampled at weeks 48, 49, 50, and 51 post insertion. 150LNG group (150 mg of levonorgestrel alone, open circle) progesterone concentrations were sampled at weeks 45, 46, 47, and 48 post insertion
Table 3Selected characteristics of study participants with HIV on efavirenz 600 mg-based ART who received double-dose LNG implant (300LNG+ART) and had possible ovulatory activity over 99 weeks post implant placement
All 300LNG+ART group participants had undetectable viral loads and stable CD4 counts through week 144 (726 [546 to 895] cells/microliter vs. baseline [Table 1], p = 0.36). Eighteen (66.6%) participants had efavirenz concentrations ≥1 mg/L at all study visits.
3.4 Safety and tolerability related to study procedures
Over 24 weeks post implant placement, 300LNG+ART participants had higher frequencies of menorrhagia (two moderate, remainder mild intensity; p = 0.02), dysmenorrhea (one moderate, remainder mild intensity; p < 0.001), and weight gain (all mild intensity [≤5% body weight increase from enrollment], p = 0.001) compared with the 150LNG group. All other adverse effect frequencies were similar between groups over 48 weeks and most were mild intensity (Supplementary Table 2). No participants discontinued the study before week 48 due to adverse events. Among 300LNG+ART participants remaining in the study, seven did not complete study procedures through week 144. Two (7.4%) of these participants discontinued due to an LNG-related adverse effect (persistent moderate-intensity menorrhagia, weeks 51 and 72; Supplementary Table 3).
4. Discussion
We observed 34% lower plasma LNG exposure (AUC) over 24 weeks among women with HIV taking efavirenz-based ART and using double-dose LNG implant compared with a control group of women without HIV on standard-dose LNG implant. We also observed higher, but not statistically different, ovulatory activity at 1 year in the 300LNG+ART group compared with the 150LNG group. Double-dose LNG was well-tolerated among study participants.
Although double-dose LNG concentrations were higher than historical concentrations of standard-dose LNG in combination with efavirenz [
Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks.
], the higher concentrations were not proportional to the increased dose. LNG concentrations were 29% to 40% lower in the 300LNG+ART group compared with the 150LNG group (Table 2). Although we did not enroll a concurrent group of women receiving efavirenz-based ART with standard-dose LNG, we previously observed 45% to 57% lower LNG exposure with a standard-dose LNG implant in Ugandan women with HIV receiving efavirenz compared with women with HIV not on ART [
Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks.
]. Progestin dose adjustment overcame physiological and pharmacological decreases in systemic progestins in other studies. For example, among women with body mass index ≥30 kg/m2, maximum plasma LNG concentrations were ∼90% higher among obese participants who received double-dose (3.0 mg) versus standard-dose (1.5 mg) oral LNG emergency contraception [
]. In a recent study of women with HIV, giving 3 mg of LNG emergency contraception plus efavirenz-based ART resulted in similar LNG maximum concentration and AUC over 8 hours compared with a control group of participants receiving 1.5 mg of LNG in the absence of a drug–drug interaction [
Pharmacokinetics of dose-adjusted levonorgestrel emergency contraception combined with efavirenz-based antiretroviral therapy or rifampicin-containing tuberculosis regimens.
]. However, women receiving efavirenz had 30–40% lower AUCs by 24 and 48 hours after the emergency contraception dose and reflected an elimination half-life of 12 hours in participants receiving efavirenz compared with 24 hours in the control group. Similar to our findings with LNG implants, these oral LNG results illustrate the effect of efavirenz-related CYP 3A4 enzyme induction on LNG exposure.
Other factors may influence LNG concentrations. Body weight ≥70 kg is associated with lower LNG plasma concentrations compared with body weight ≤50 kg [
]. However, fewer 300LNG+ART participants had body weights ≥70 kg through week 48 relative to the 150LNG group (15.4% vs. 50.0%, respectively). LNG binds with high affinity to SHBG, and differences in SHBG concentrations by LNG [
Gonadotropin and sex steroid levels in HIV-infected premenopausal women and their association with subclinical atherosclerosis in HIV-infected and -uninfected women in the women's interagency HIV study (WIHS).
] may have influenced the free concentrations of LNG. However, our SHBG results do not support this hypothesis, as SHBG levels were higher in the 300LNG+ART group throughout the study. Further, 300LNG+ART participants had a smaller percent change in SHBG levels from baseline after LNG initiation (Supplementary Table 1). Finally, pharmacogenetic characteristics of participants in the 300LNG+ART group may influence our findings. Slow metabolizers of efavirenz have higher systemic efavirenz concentrations relative to people with normal or intermediate metabolizer status, resulting in greater CYP 3A4 enzyme induction, leading to lower exogenous progestin concentrations [
At 1 year post implant insertion, 20.8% of the 300LNG+ART group had ovulatory activity compared with no participants in the 150LNG group (p = 0.29). Although this finding was not statistically significant, the number of participants with evaluable serial progesterone data was small. In two cohorts of women without HIV using contraceptive implants (200 mg of LNG), investigators reported that 11.1–18.0% of cycles were ovulatory over the first year of implant use (progesterone threshold: 4.7 ng/mL and 3.0 ng/mL, respectively) [
]. Despite possible ovulatory activity observed in our study, progestins have additional mechanisms of contraceptive effectiveness, specifically cervical mucus changes that maintain effectiveness despite ongoing ovulation.
We used an LNG efficacy threshold (300 pg/mL) established by observed pregnancies in a similar cohort of Ugandan women and a similar liquid chromatography-tandem mass spectrometry assay to quantify plasma LNG between cohorts. However, the pharmacodynamic threshold for contraceptive efficacy is not well defined. If using an often-proposed 200 pg/mL plasma LNG efficacy threshold [
], more than 93% of 300LNG+ART participants had concentrations ≥200 pg/mL at weeks 24 and 48. However, we observed elevated progesterone levels in some participants, despite LNG concentrations measured at the nearest visit well above either proposed threshold (Table 3). These results highlight uncertainty around the pharmacokinetic–pharmacodynamic relationship for LNG, and the desired threshold may have high interindividual variation [
This study has certain limitations. We cannot rule out potential physiological differences between the 300LNG+ART and 150LNG groups. Reassuringly, our HIV-negative control group had similar LNG exposure over 24 weeks to Ugandan women with HIV not yet receiving ART in a separate study: 15,231 pg*week/mL in 150LNG versus 15,168 pg*wk/mL in women with HIV not on ART [
Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks.
]. We did not design this study to assess contraceptive effectiveness, and questions remain regarding the clinical interpretation of hormone pharmacokinetic studies without a clear pharmacodynamic measure of contraceptive effectiveness. We cannot evaluate the effects of lower-dose efavirenz on double-dose LNG pharmacokinetics [
Physiologically based pharmacokinetic modelling prediction of the effects of dose adjustment in drug-drug interactions between levonorgestrel contraceptive implants and efavirenz-based ART.
Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks.
], but it did not overcome the drug–drug interaction with efavirenz-based ART. For women desiring the LNG contraceptive implant and taking efavirenz-based ART, double-dose LNG implants may offer an alternative to other less effective forms of contraception. Because updated international HIV treatment guidelines recommended dolutegravir-based ART as the preferred first-line treatment of HIV [
], these antiretroviral regimens should be prioritized for women with HIV desiring hormonal contraception for family planning to avoid detrimental efavirenz-related drug–drug interactions.
Acknowledgments
The authors thank the members of the clinical study team at Infectious Diseases Institute, the staff of the Infectious Diseases Institute Core Laboratory, and the staff of the Antiviral Pharmacology Laboratory at the University of Nebraska Medical Center, including Leah Mbabazi, Ian Musinguzi, Johnson Magoola, Emmanuel Sempijja, and Jeff Jeppson. We thank members of the Safety Monitoring Committee for oversight of this study, including Concepta Merry, Robert Murphy, and Heather Watts. Finally, we are grateful to David Back for his guidance and collaboration.
Availability of integrated family planning services in HIV care and support sites in sub-Saharan Africa: a secondary analysis of national health facility surveys.
Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks.
Effect of efavirenz on levonorgestrel concentrations among Malawian levonorgestrel implant users for up to 30 months of concomitant use: a subanalysis of a randomized clinical trial.
Division of AIDS. National Institute of Allergy and Infectious Diseases. Division of AIDS (DAIDS) table for grading the severity of adult and pediatric adverse events, corrected version 2.1. National Institutes of Health, U.S. Department of Health and Human Services; 2017. Available from: 〈https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf〉 (cited July 4, 2022).
Development, validation and utilization of a highly sensitive LC-MS/MS method for quantification of levonorgestrel released from a subdermal implant in human plasma.
Pharmacokinetics of dose-adjusted levonorgestrel emergency contraception combined with efavirenz-based antiretroviral therapy or rifampicin-containing tuberculosis regimens.
Gonadotropin and sex steroid levels in HIV-infected premenopausal women and their association with subclinical atherosclerosis in HIV-infected and -uninfected women in the women's interagency HIV study (WIHS).
Physiologically based pharmacokinetic modelling prediction of the effects of dose adjustment in drug-drug interactions between levonorgestrel contraceptive implants and efavirenz-based ART.
☆Declaration of Competing Interest: KKS has received investigator-initiated research support from Organon, LLC, paid to her institution. CAC has received investigator-initiated research support from Organon, LLC and Gilead Sciences, paid to her institution. ML has received investigator-initiated research support from Janssen, paid to his institution. All other authors declare no conflicts of interest.
☆☆Funding: This work was supported by the Eunice Kennedy Shrive National Institute of Child Health and Human Development (grant number R01 HD085887 to KS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funder had no role in the conduct, analyses, and conclusions of the study. The corresponding author had full access to all study data and had final responsibility for the decision to submit for publication.
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