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。变性妇女（TGW）患有艾滋病毒感染的风险增加了49倍，但他们 预防和治疗研究中的人为不足。女性化的激素治疗（FHT）可以 改变用于HIV前暴露于HIV的核（T）IDE逆转录酶抑制剂（NRTI）的药理学 通过复杂的生理机制进行预防（PREP），但这种药物相互作用的临床意义 是未知的。 我们的总体目标是：确定FHT是否通过减少了FHT的TGW效力是否会降低 相对于竞争性脱氧核苷酸的活性代谢产物（TFVDP/FTCTP）的浓度 （DATP/DCTP）。我们将使用这些数据来构建一个人口PK模型，该模型描述了HIV传播中的这种比率 站点并预测跨女性种群的准备疗效，而在不同情况下不服用FHT 准备依从性和间歇性给药。 研究设计：在AIM 1中，我们将对10名绝经前妇女进行研究，以确定如何 高雌二醇暴露会影响较低的不同细胞种群的核苷酸浓度 胃肠道（GI）。我们将在由总直肠细胞中测量TFVDP，FTCTP，DATP和DCTP 通过LC-MS/MS从组织活检中分离出的细胞刷和CD4细胞。这些数据将用于验证 总直肠细胞可以用作分离的CD4+ T细胞的药理学替代物，无论雌二醇如何 暴露并告知我们的抽样程序以进行后续研究。在AIM 2中，我们将利用圣地亚哥 当前注册的多站点准备演示项目（Pi Morris; NCT03086200）的网站 进行准备，而不是将FHT带入我们的药理学研究（n = 10）。我们将收集血液（等离子体， 血清和外周血单核细胞； PBMCS）以及通过隔离辅助的总直肠细胞 细胞刺激。我们将测量血清和TFVDP中的性激素（雌二醇，孕酮和睾丸激素）， PBMC中的FTCTP，DATP和DCTP和LC-MS/MS的总直肠细胞。在AIM 3中，我们将使用这些PK数据来 在下属胃肠道中建立人口PK的PR PREP曝光模型，并在不同的下模拟准备曝光 1000 TGW中的给药方案或不服用FHT。我们将使用这些模拟的有效性 先前发表的PREP功效目标。 预期的结果：我们认为这些数据将确认我们的初步观察结果约7倍 TFVDP的浓度相对于TGW服用FHT的DATP。我们的人口PK模型来描述影响 FHT在艾滋病毒传播部位的预科药理学上的FHT将使我们能够确定最小的依从性 保护99％接受FHT的跨女性人群的要求。这些药理学数据将支持 R01应用程序探索剂量服用和风险行为，并研究TGW队列中的准备成果。