Feminizing Sex Hormones Impact on PrEP Pharmacology in Transgender Women

女性化性激素对跨性别女性 PrEP 药理学的影响

• 批准号: 9910363
• 负责人: Mackenzie Cottrell
• 金额: $ 15.66万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-09 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910363
• 关键词: AIDS prevention; AIDS/HIV problem; Adherence; Biopsy; Blood; CD4 Positive T Lymphocytes; California; Cells; Clinical; Clinical Data; Clinical Trials; Communities; Complex; DNA; Data; Dose; Drug Interactions; Drug Kinetics; Effectiveness; Enrollment; Enzymes; Equilibrium; Estradiol; Exhibits; Exposure to; FDA approved; Failure; Feminization; Fumarates; Future; Goals; Gonadal Steroid Hormones; HIV; HIV risk; Health; Hormones; Infection; Knowledge; Left; Light; Location; Lower Gastrointestinal Tract; Measures; Modeling; Mucous Membrane; Nucleotides; Outcome; Participant; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology Study; Physiological; Placebos; Plasma; Policy Maker; Population; Positioning Attribute; Premenopause; Prevention Research; Procedures; Prodrugs; Progesterone; Publishing; Randomized; Reporting; Research; Research Design; Research Personnel; Reverse Transcriptase Inhibitors; Reverse Transcription; Risk; Risk Behaviors; Risk Reduction; Sampling; Serum; Site; Subgroup; Tenofovir; Testosterone; Time; Tissues; Woman; Work; base; cisgender; cohort; data modeling; emtricitabine; group intervention; hormone therapy; improved; interest; men; men who have sex with men; models and simulation; pharmacodynamic model; pharmacokinetic model; pre-exposure prophylaxis; predictive modeling; programs; rectal; rho; simulation; tool; transfeminine; transgender; transgender women; transmission process; treatment research; uptake; virology

PROJECT SUMMARY Problem. Transgender women (TGW) have a 49-fold increased risk of becoming infected with HIV, yet they have been underrepresented in HIV prevention and treatment research. Feminizing hormone therapy (FHT) can alter the pharmacology of the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) used for HIV pre-exposure prophylaxis (PrEP) through complex physiologic mechanisms, but the clinical implication of this drug interaction is unknown. Our Overarching Goal: is to determine whether FHT diminishes PrEP's potency in TGW on FHT by decreasing concentrations of the active metabolites (TFVdp/FTCtp) relative to their competing deoxynucleotides (dATP/dCTP). We will use these data to construct a population PK model describing this ratio in HIV transmission sites and predict PrEP efficacy in a transfeminine population taking and not taking FHT given different scenarios of PrEP adherence and intermittent dosing. Study Design: In Aim 1, we will conduct a study in 10 premenopausal women taking PrEP to determine how high and low estradiol exposure impacts nucleotide concentrations in different cellular populations of the lower gastrointestinal (GI) tract. We will measure TFVdp, FTCtp, dATP, and dCTP in total rectal cells collected by cytobrush and CD4 cells isolated from tissue biopsies by LC-MS/MS. These data will be used to validate that total rectal cells can be used as a pharmacology surrogate of isolated CD4+ T cells regardless of estradiol exposure and to inform our sampling procedures for subsequent study. In Aim 2, we will leverage the San Diego sites for a currently enrolling, multi-site PrEP demonstration project (PI Morris; NCT03086200) to co-enroll TGW on PrEP taking and not taking FHT into our pharmacology study (N=10 each). We will collect blood (plasma, serum, and peripheral blood mononuclear cells; PBMCs) as well as total rectal cells via anoscopy-assisted cytobrush. We will measure sex hormones (estradiol, progesterone, and testosterone) in serum and TFVdp, FTCtp, dATP, and dCTP in PBMC and total rectal cells by LC-MS/MS. In Aim 3 we will use these PK data to build a population PK model of PrEP exposure in the lower GI tract and simulate PrEP exposure under different dosing scenarios in 1000 TGW taking or not taking FHT. We will predict effectiveness of these simulations using previously published PrEP efficacy targets. Expected Outcomes: We believe these data will confirm our preliminary observations of ~7-fold decreased concentrations in TFVdp relative to dATP in TGW taking FHT. Our population PK model to describe the impact of FHT on PrEP pharmacology in HIV transmission sites will allow us to determine the minimal adherence requirements to protect 99% of the transfeminine population taking FHT. These pharmacology data will support an R01 application to explore dose taking and risk behavior and investigate PrEP outcomes in a cohort of TGW.

项目摘要 问题.跨性别妇女（TGW）感染艾滋病毒的风险增加了49倍，但她们 在艾滋病毒预防和治疗研究中的代表性不足。女性化激素治疗（FHT）可以 改变HIV暴露前使用的核苷逆转录酶抑制剂（NRTI）的药理学 预防（PrEP）通过复杂的生理机制，但这种药物相互作用的临床意义 不明 我们的总体目标：是确定FHT是否通过减少TGW对FHT的影响来降低PrEP在TGW中的效力。 活性代谢产物（TFVdp/FTCtp）相对于其竞争性脱氧核苷酸的浓度 (dATP/dCTP）。我们将使用这些数据来构建一个群体PK模型，以描述HIV传播中的这一比例 在不同的情况下，使用和不使用FHT的跨女性人群中， PrEP依从性和间歇性给药。 研究设计：在目标1中，我们将在10名服用PrEP的绝经前妇女中进行研究，以确定 高和低雌二醇暴露影响下丘脑不同细胞群中的核苷酸浓度， 胃肠道（GI）。我们将测量通过以下方法收集的总直肠细胞中的TFVdp、FTCtp、dATP和dCTP 通过LC-MS/MS从组织活检分离细胞刷和CD 4细胞。这些数据将用于验证 总直肠细胞可用作分离的CD 4 + T细胞的药理学替代物，而不管雌二醇 并告知我们后续研究的采样程序。在目标2中，我们将利用圣地亚哥 目前正在招募的多中心PrEP示范项目（PI Morris; NCT 03086200）的研究中心，以共同招募TGW 在我们的药理学研究中，服用PrEP和不服用FHT（各N=10）。我们将收集血液（血浆， 血清和外周血单核细胞; PBMC）以及总直肠细胞 细胞刷我们将测量血清和TFVdp中的性激素（雌二醇、孕酮和睾酮）， 通过LC-MS/MS测定PBMC和总直肠细胞中的FTCtp、dATP和dCTP。 建立PrEP暴露在下消化道的群体PK模型，并模拟不同条件下的PrEP暴露 在1000 TGW服用或不服用FHT的给药方案中。我们将使用以下方法预测这些模拟的有效性 此前公布的PrEP疗效目标。 预期结果：我们相信这些数据将证实我们的初步观察结果， TGW中TFVdp相对于dATP的浓度。我们的群体PK模型来描述 FHT对HIV传播场所PrEP药理学的影响将使我们能够确定最低依从性 要求保护99%服用FHT的变性人群。这些药理学数据将支持 R 01应用程序，以探索TGW队列中的剂量服用和风险行为，并研究PrEP结局。