Improving PrEP protection of transgender women through mechanistic pharmacokinetic understanding

项目总结 这项工作的目标是通过了解跨性别妇女(TGW)的 暴露前预防药物(PrEP)对预防HIV感染和性别确认的相互作用 激素疗法(GAHT)。专业协会建议TGW推广基于雌激素的GAHTs 女性化和去男性化，以促进性别转变和减少性别焦虑症。TGW 是一个弱势群体，他们经历着重大挑战，包括性别焦虑症、抑郁症、 和歧视，所有这些都会导致生活质量的下降。对于变性人来说， 就业和医疗条件，进一步阻止社区成员在文化上获得 称职的护理。此外，与顺性相比，TGW感染艾滋病毒的风险高出49倍 育龄男性(CGM)和女性(CGW)。目前，每日固定剂量的替诺福韦制剂 富马酸异丙酚(TDF)/恩曲他滨(FTC)(PrEP)，已用于预防HIV 在艾滋病毒感染的高危人群中获得。一种不太频繁的按需服用四剂的方案也 事实证明，它在预防艾滋病毒感染方面非常有效。而TGW已纳入随机对照研究 在PREP试验中，TGW还没有招募足够的数量来有力地评估PrEP的摄取和疗效。 重要的是，PrEP和GAHT药物的相互作用还没有得到很好的表征。体外和体外 研究表明，雌激素和可能降低的睾酮对PrEP药理学的影响。 我们小组的初步工作显示，在2008年，血浆TFV和FTC AUC0-24下降了30%以上 与CGM相比，TGW对雌激素的影响。因为将每周的TDF/FTC剂量从七次减少到两次 每周的剂量导致肛交的PrEP保护从90%大幅下降到75%，我们的变化 观察到的可能大到足以影响GAHT患者TGW的PrEP结局。因此，为了更好地刻画 关于PrEP和GAHT的关系，我们提出了临床上PrEP药物之间的药物相互作用 和以雌激素为基础的GAHT，以逐步和雌激素剂量依赖的方式量化 血液、尿液和结直肠组织中的药物相互作用。我们将把这些数据与其他临床数据结合使用 试验数据，建立PrEP疗效的群体药代动力学-药效学模型。这将使 在存在和不存在GAHT的情况下对比每日和按需服用PrEP的临床试验模拟 告知TGW的PrEP剂量建议。因为我们假设GAHT会降低PrEP 浓度并导致对艾滋病毒感染的易感性增加，GAHT的TGW可能需要更高的 或者比与男性发生性关系的CGM更频繁地服用PrEP。这项工作是确保 适当的PrEP剂量，用于艾滋病毒感染风险显著较高的人群，并告知需要和 从有效性、行为学和可接受性的角度对PrEP和GAHT的未来研究进行设计。

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.