Improving PrEP protection of transgender women through mechanistic pharmacokinetic understanding

项目摘要 这项工作的目标是通过了解跨性别妇女（TGW）的医疗保健， 暴露前预防药物（PrEP）预防HIV感染和性别确认的相互作用 激素治疗（GAHT）。专业协会建议TGW推广基于雌激素的GAHT 消除女性化和非男性化现象，以促进性别过渡和减少性别焦虑。TGW 是弱势群体，他们面临重大挑战，包括性别焦虑，抑郁症， 和歧视，所有这些都导致生活质量下降。跨性别者在以下方面存在障碍： 就业和医疗条件，进一步阻止社区成员接受文化 称职的照顾。此外，与顺性别者相比，TGW感染艾滋病毒的风险高49倍 男性（CGM）和育龄女性（CGW）。目前，替诺福韦的每日固定剂量制剂 (TFV)富马酸二异山梨酯（TDF）/恩曲他滨（FTC）（PrEP）已用于预防HIV 艾滋病毒感染高危人群中的艾滋病感染。一种频率较低的按需四剂方案也 在预防艾滋病毒感染方面非常有效。虽然TGW已入组随机对照研究， PrEP试验，TGW尚未招募足够数量的患者来稳健地评估PrEP吸收和疗效。 重要的是，PrEP和GAHT药物的相互作用尚未得到很好的表征。体外和离体 研究表明雌激素和潜在减少的睾酮对PrEP药理学的影响。 我们小组的初步工作表明，在2009年， 与CGM相比，TGW对雌激素的影响。因为将每周TDF/FTC剂量从7次减少到2次， 每周剂量导致PrEP对肛交的保护从90%大幅下降至75%， 观察到的可能足够大，以影响GAHT上TGW的PrEP结果。因此，为了更好地表征 PrEP和GAHT之间的关系，我们提出了PrEP药物之间的临床药物相互作用 和基于雌激素的GAHT以逐步和雌激素剂量依赖的方式定量 血液、尿液和结肠直肠组织中的药物相互作用。我们将使用这些数据，结合其他临床 试验数据，以建立PrEP疗效的群体药代动力学-药效学模型。这将使 临床试验模拟，以对比在存在和不存在GAHT的情况下每日和按需PrEP给药， 告知TGW的PrEP剂量建议。因为我们假设GAHT会减少PrEP 浓度，并导致艾滋病毒感染的易感性增加，GAHT上的TGW可能需要更高的 或更频繁的PrEP剂量比CGM谁与男性发生性关系。这项工作是确保 适当的PrEP剂量组在艾滋病毒感染的高风险，并告知需要和 从有效性、行为和可接受性的角度设计未来的PrEP和GAHT研究。

PROJECT SUMMARY The goal of this work is to improve the medical care of transgender women (TGW) through understanding the interaction of drugs for pre-exposure prophylaxis (PrEP) for prevention of HIV acquisition and gender affirming hormonal therapy (GAHT). Professional Societies recommend estrogen-based GAHTs for TGW to promote feminization and demasculinization in order to facilitate gender transition and diminish gender dysphoria. TGW are a vulnerable population, who experience significant challenges, including gender dysphoria, depression, and discrimination, all resulting in a compromised quality of life. There are barriers for transgender persons in terms of employment and healthcare, further preventing members of the community from receiving culturally competent care. In addition, TGW are 49-times at greater risk for HIV acquisition when compared to cisgender men (CGM) and women (CGW) of reproductive age. Currently, a daily, fixed dose formulation of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) (PrEP), has been used for the prevention of HIV acquisition in persons at high risk of HIV infection. A less-frequent, on demand, four-dose regimen has also proven highly effective in preventing HIV infection. While TGW have been enrolled in randomized controlled PrEP trials, TGW have not been enrolled in sufficient numbers to robustly evaluate PrEP uptake and efficacy. Importantly, the interaction of PrEP and GAHT drugs has not been well characterized. In vitro and ex vivo studies suggest an influence of estrogen and, potentially reduced testosterone, on PrEP pharmacology. Preliminary work by our group demonstrated greater than 30% reduction in plasma TFV and FTC AUC0-24 in TGW on estrogen when compared to CGM. Because reducing the weekly TDF/FTC dose from seven to two doses per week results in a sizeable drop in PrEP protection of anal sex from 90 to 75%, the change we observed may be sufficiently large to impact PrEP outcomes in TGW on GAHT. Thus, to better characterize the relationship between PrEP and GAHT, we propose a clinical drug-drug interaction between PrEP drugs and estrogen-based GAHT in a stepwise and estrogen dose-dependent manner to quantify the magnitude of drug interaction in blood, urine, and colorectal tissue. We will use these data, in conjunction with other clinical trials data, to build a population pharmacokinetic-pharmacodynamic model of PrEP efficacy. This will enable clinical trial simulations to contrast daily and on demand PrEP dosing in the presence and absence of GAHT to inform PrEP dose recommendations for TGW. Because we hypothesize that GAHT will decrease PrEP concentrations and result in increased susceptibility for HIV infection, TGW on GAHT will likely require higher or more frequent PrEP dosing than CGM who have sex with men. This work is a critical next step in ensuring appropriate PrEP dosing to group at substantially higher risk of HIV acquisition, and informs the need and design for future study of PrEP and GAHT from an efficacy, behavioral, and acceptability perspective.