New Pharmacologic Measures of ART Adherence and Exposure: Pathway to Clinical Implementation

项目摘要/摘要 尽管抗逆转录病毒疗法(ART)对艾滋病毒携带者的坚持至关重要 (PLHW)，一个客观而准确的方法来量化它仍然是不存在的。而艾滋病毒病毒载量(VL)一直是 它被视为艺术坚持的代理标志，可能会导致现代艺术中不准确的结论 时代。这是因为病毒血症是长期不坚持后出现的延迟临床结果， 而且，实现病毒抑制并不需要完美的坚持。一种新兴的药理学方法 将ART粘附性量化为替诺福韦二磷酸(TFV-DP，替诺福韦的磷酸化合成代谢物) 血斑(DBS)，基于其在红细胞中的长细胞内半衰期(17天)，累积25倍 从首剂到稳定状态。PI(K23AI104315)的最新数据表明，DBS中的TFV-DP， 从TDF(TFV-DPTDF)衍生出来的，与HIV病毒抑制密切相关，并可以预测未来 病毒学抑制的PLWH中的病毒血症。然而，这种黏附生物标记物的药理学 对于基于TAF的艺术来说，这仍然是未知的。考虑到显著不同的药理学，这是一个关键的差距 在TDF和TAF之间，以及在可以在临床实践中实施之前不可或缺的一步。 在此修订的R01应用程序中，我们将通过关注源自以下内容的DBS中的TFV-DP来推进该领域 TAF(TFV-DPTAF)。根据我们的初步数据，我们假设TFV-DPTAF将与 依从性，其变异性将由PLWH独特的患者特征来解释。我们也 假设它将与病毒抑制密切相关并对其进行预测，并且它将被广泛 被临床医生接受为超越HIV VL的依从性的信息指标。为了检验这些假设，我们 目的：1.建立TFV-DPTAF在PLWH的DBS中的药代动力学。 这一目标将使用可摄入的生物传感器来客观地建立与以下相关的TFV-DPTAF浓度 PLWH中的实际依从性，并评估药物浓度的变异性来源。目标2.量化 TFV-DPTAF与病毒抑制的关系。这一目标将评估两者之间的联系 TFV-DPTAF和HIV病毒抑制(即药效学)在PLWH治疗TAF的临床队列中的应用。它还将 评估该生物标志物作为该队列中未来病毒血症的预测指标的价值。目标3.前瞻性 评价TFV-DPTAF在DBS治疗PLWH中的潜在临床应用价值。这一目标将评估感知到的 临床医生对来自目标2的参与者的依从性测量的实用性，目的是为了了解 它如何在临床上补充艾滋病毒VL。总而言之，这些研究将增进我们对 TFV-DPTAF在PLWH中的药理和临床应用，最终目的是改善临床结果。

Project Summary/Abstract Despite the critical importance of antiretroviral therapy (ART) adherence in people living with HIV (PLHW), an objective and accurate method to quantify it is still unavailable. While HIV viral load (VL) has been regarded as a surrogate marker of ART adherence, it can lead to inaccurate conclusions in the modern ART era. This is because viremia is a delayed clinical outcome that develops after long-standing non-adherence, and perfect adherence is not required to achieve viral suppression. An emerging pharmacologic method to quantify ART adherence is tenofovir diphosphate (TFV-DP, the phosphorylated anabolite of tenofovir) in dried blood spots (DBS), based on its long intracellular half-life in red blood cells (17 days) with 25-fold accumulation from first dose to steady state. Recent data from the PI (K23AI104315) has demonstrated that TFV-DP in DBS, derived from TDF (TFV-DPTDF), is strongly associated with HIV viral suppression, and that it can predict future viremia in PLWH who are virologically-suppressed. However, the pharmacology of this adherence biomarker remains unknown for TAF-based ART. This is a critical gap given the significant different pharmacology between TDF and TAF, and an indispensable step before it can be implemented in clinical practice. In this revised R01 application, we will advance the field by focusing on TFV-DP in DBS derived from TAF (TFV-DPTAF). Based on our preliminary data, we hypothesize that TFV-DPTAF will be proportional to adherence, and that its variability will be explained by unique patient characteristics in PLWH. We also hypothesize that it will be strongly associated with, and predictive of, viral suppression, and that it will be widely accepted by clinicians as an informative measure of adherence beyond HIV VL. To test these hypotheses, we propose the following aims: Aim 1. Establish the pharmacokinetics (PK) of TFV-DPTAF in DBS in PLWH. This aim will use ingestible biosensors to objectively establish the TFV-DPTAF concentrations associated with actual adherence in PLWH and assess the sources of variability in the drug concentrations. Aim 2. Quantify the relationship between TFV-DPTAF and viral suppression. This aim will estimate the association between TFV-DPTAF and HIV viral suppression (i.e., pharmacodynamics) in a clinical cohort of PLWH on TAF. It will also assess the value of this biomarker as a predictor of future viremia in this cohort. Aim 3. Prospectively evaluate the potential clinical utility of TFV-DPTAF in DBS in PLWH. This aim will assess the perceived utility of this adherence measure by clinicians in the participants from Aim 2, with the goal of understanding how it complements HIV VL in the clinic. Collectively, these studies will advance our understanding on the pharmacology and clinical utility of TFV-DPTAF in PLWH, with the ultimate goal of improving clinical outcomes.