A Pharmacokinetic and Pharmacogenetic Evaluation Of

A pharmacokinetic and pharmacogenetic evaluation of contraceptive implants and antiretroviral therapy among women in Kenya and Uganda Rena C. Patela,b, Randy M. Stalterc, Katherine K. Thomasb, Bani Tamraze, Steven W. Bluef, David W. Eriksonf, Christina J. Kimd, Edward J. Kellyd, Kavita Nandag, Athena P. Kourtish, Jairam R. Lingappaa,b, Nelly Mugob,i, Jared M. Baetena,b,c, 05/06/2020 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3Dkys9+3wZnLBAQwV9m967KYSyNLNJCeWjq0jy3w0N9e13Ci0yNfjvg== by https://journals.lww.com/aidsonline from Downloaded Downloaded M Kimberly K. Scarsij, for the Partners PrEP Study Team from https://journals.lww.com/aidsonline Objectives: To evaluate pharmacokinetics and pharmacogenetics of contraceptive implant progestin concentrations in HIV-positive women initiating efavirenz (EFV)- containing or nevirapine (NVP)-containing antiretroviral therapy (ART). Design: We analyzed stored samples from women self-reporting implant use in the Partners PrEP Study. by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3Dkys9+3wZnLBAQwV9m967KYSyNLNJCeWjq0jy3w0N9e13Ci0yNfjvg== Methods: Plasma samples collected every 6 months were analyzed for levonorgestrel and etonogestrel concentrations. Progestin concentrations from samples collected after ART initiation were compared with pre-ART concentrations for intraindividual comparisons. We used adjusted linear mixed models to compare hormone concentrations between individuals on EFV and NVP to a no ART group. We then evaluated whether possessing certain alleles with known or possible influences on EFV, NVP, or progestin metabolism were associated with changes in progestin concentrations or modified the association between ART use and progestin concentrations. Results: Our analysis included 11 women who initiated EFV, 13 who initiated NVP, and 36 who remained ART-naive. In the EFV group, the adjusted geometric mean ratio (aGMR) of levonorgestrel was 0.39 [90% confidence intervals (0.31, 0.49); P < 0.001] and the etonogestrel aGMR was 0.51 (0.34, 0.76; P ¼ 0.006) compared with the control group. No difference was observed in the NVP group compared with controls [levonorgestrel 0.93 (0.74, 1.18); P ¼ 0.64; etonogestrel 1.07 (0.77, 1.50); P ¼ 0.73]. Pos- session of four allele variants were found to result in further reductions in progestin concentrations among those receiving EFV. Conclusion: Concomitant use of EFV significantly reduces levonorgestrel or etonogestrel concentrations by 61 and 49%, respectively, compared with no ART use. We also report allelic variants in hepatic enzymes that influenced the extent of the observed drug-interaction between progestins and EFV. Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved. AIDS 2019, 33:1995–2004 on 05/06/2020 aDepartment of Medicine, bDepartment of Global Health, cDepartment of Epidemiology, dDepartment of Pharmaceutics, University of Washington, Seattle, Washington, eDepartment of Clinical Pharmacy, University of California, San Francisco, San Francisco, California, fEndocrine Technologies Core, Oregon National Primate Research Center, Beaverton, Oregon, gGlobal Health, Population, and Nutrition, FHI 360, Durham, North Carolina, hDivision of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, iCenter for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya, and jDepartment of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, Nebraska, USA. Correspondence to Rena C. Patel, UW Box 359927, 325 Ninth Avenue, Seattle, WA 98104, USA. Tel: +1 206 520 3800; e-mail: [email protected] Ã Members of the study team listed after the Acknowledgements. Received: 27 March 2019; revised: 28 May 2019; accepted: 31 May 2019. DOI:10.1097/QAD.0000000000002308 ISSN 0269-9370 Copyright Q 2019 Wolters Kluwer Health, Inc. All rights reserved. 1995 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. 1996 AIDS 2019, Vol 33 No 13 Keywords: antiretroviral therapy, efavirenz, etonogestrel, hormonal contraception, implants, levonorgestrel, pharmacogenetic, pharmacokinetic Introduction within each woman (intrasubject comparisons) as well as comparing the changes in concentrations across The majority of people living with HIVare women, with groups by ART category (intersubject comparisons). an estimated 13 million HIV-positive women of repro- Our second objective was to characterize pharmacoge- ductive age living in sub-Saharan Africa [1]. Nearly two- netic polymorphisms associated with progestin concen- thirds of pregnancies among HIV-positive women in sub- tration changes among these women, and whether any Saharan Africa are unintended [2], and effective contra- pharmacogenetic polymorphisms modify the effect of ception can prevent unintended pregnancies, reducing ARTon hormone concentrations. maternal mortality and perinatal HIV transmission [3,4]. Contraceptive implants, containing the progestins levonorgestrel or etonogestrel, are the most effective contra- ceptives available and are increasingly being used by HIV- Methods positive women in sub-Saharan Africa [5]. Study population The WHO recommends initiation of antiretroviral therapy We used data from HIV-positive women less than 50 years (ART) for HIV-positive individuals, and dolutegravir- of age enrolled in the Partners PrEP Study in Kenya and containing ART is recommended as a first-line regimen Uganda from 2008 to 2010 who self-reported implant [6]. Enthusiasm for dolutegravir’s wide-spread rollout in use, some of whom went on to initiate ART later. resource-limited settings has been hampered by its possible Detailed enrollment and follow-up procedures for link with neural tube defects [7]. Therefore, efavirenz participants are described elsewhere [15–17]. Women (EFV)-containing ART remains the primary regimen for not eligible for ART initiation at the time of Partners women of reproductive age in resource-limited settings, PrEP Study enrollment had their clinical and immuno- including those on contraceptive implants. However, due logical status monitored at study visits. If participants to drug–drug interactions resulting from induction of became eligible to initiate ART according to national hepatic cytochrome P450 (CYP450) enzymes, the guidelines during follow-up, they were referred to HIV concomitant use of EFV reduces the effectiveness of facilities for ART initiation. Contraception was not contraceptive implants. In a prior study among Kenyan provided by the study; instead, women were referred to women, those using implants and EFV-containing ART routine clinical care if desiring contraception. Women faced three-fold higher rates of pregnancies than those self-reported implant use and the implant insertion dates using nevirapine (NVP)-containing ART [8], a result were not available. Women self-reporting the use of other supported by pharmacokinetic data showing reduced hormonal methods, intrauterine device, or surgical implant progestin concentrations with concomitant EFV methods, or those without documented ART status use [9–12]. The existing pharmacokinetic evaluations are were excluded. limited by large intersubject variability. Furthermore, though both levonorgestrel and etonogestrel are believed We analyzed 6-monthly plasma samples, which were to be metabolized primarily by CYP3A4, the mechanisms collected regardless of menstrual cycles, for each woman. that underlie metabolism of progestins are poorly For women initiating ART, we included women with at understood. Genetic polymorphisms in hepatic enzymes least one sample available for analysis pre or post-ART. and transporters, which often vary by ethnic group, may be Five women in the EFV group had one sample either pre an important factor influencing progestin metabolism, or post-ART initiation and the remainder of the women extent of drug–drug interactions, and subsequent con- had at least two samples either pre or post-ART. To be traceptive efficacy [13,14]. included in this analysis, we required that the plasma samples were within 6 months of each other and the date Pharmacokinetic studies that address intersubject vari- of ART initiation, when applicable. To help account for ability by including within-subject sampling and the expected decreases in progestin concentrations over pharmacogenetic analyses with ethnic groups tradition- time [14,18], we included samples from women who did ally less represented in such analyses are needed to fill not initiate ART but had samples available from at least six knowledge gaps regarding concomitant implant and study visits to represent levonorgestrel or etonogestrel EFV use. Our first objective was to conduct a exposure over time in the absence of ART. pharmacokinetic evaluation studying the effect of initiating EFV-containing or NVP-containing ART on One woman in the Partners PrEP Study became pregnant levonorgestrel and etonogestrel plasma concentrations, while concomitantly using an implant and EFV-contain- comparing concentrations pre and post-ART initiation ing ART. Because she initiated the implant after EFV, we Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. Contraceptive implants and antiretroviral therapy Patel et al. 1997 could not include her in the pharmacokinetic or Primary outcomes: progestin concentrations in pharmacogenetic evaluations. Nonetheless, we analyzed plasma all progestin plasma samples collected for this woman and We simultaneously quantified

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