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

ART 依从性和暴露的新药理学措施：临床实施途径

基本信息

批准号：
10611354
负责人：
PETER L. ANDERSON
金额：
$ 66.56万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-24 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611354
关键词：
Address Adherence Anti-Retroviral Agents Benchmarking Biologic Characteristic Biological Biological Markers Biosensor Blood Body mass index Characteristics Chronic Clinic Clinical Complement Data Development Diphosphates Dose Drug Exposure Drug Kinetics Drug resistance Dryness Enrollment Erythrocytes Failure Fumarates Future Gender Goals HIV Hair Half-Life Knowledge Longitudinal cohort Measures Methods Modeling Modernization Outcome Participant Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacodynamics Pharmacology Phosphorylation Plasma Population Positioning Attribute Prevention Race Source Spottings Surrogate Markers Tenofovir Testing United States National Institutes of Health Viral Viral Load result Viremia antiretroviral therapy behavioral adherence clinical care clinical implementation clinical practice cohort data submission emtricitabine esterase forgiveness improved medication compliance novel pharmacologic pre-exposure prophylaxis prospective public health relevance response therapy adherence tool transmission process

项目摘要

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.

项目摘要/摘要尽管抗逆转录病毒疗法（ART）遵守艾滋病毒的人至关重要（PLHW），一种量化它的客观和准确方法仍然不可用。而艾滋病毒载荷（VL）已经被视为艺术依从性的替代标志，它可能导致现代艺术的不准确结论时代。这是因为病毒血症是一种延迟的临床结局，在长期不遵守之后发展，并且不需要完美的依从性即可实现病毒抑制。一种新兴的药理学方法量化ART依从性是干燥的Diphosphate（TFV-DP，Tenofovir的磷酸化的变性物）基于其在红细胞（17天）中的细胞内半衰期（17天），积累25倍的血液斑点（DBS）从初次剂量到稳态。 PI（K23AI104315）的最新数据证明了DBS中的TFV-DP，源自TDF（TFV-DPTDF），与HIV病毒抑制密切相关，并且可以预测未来在病毒学上抑制的PLWH中的病毒血症。但是，这种依从性生物标志物的药理学基于TAF的艺术仍然未知。考虑到显着不同的药理学，这是一个关键的差距在TDF和TAF之间，以及在临床实践中实施之前必不可少的一步。在此修订后的R01应用程序中，我们将通过重点关注来自 TAF（TFV-DPTAF）。根据我们的初步数据，我们假设TFV-DPTAF与依从性，其可变性将由PLWH中的独特患者特征来解释。我们也是假设它将与病毒抑制密切相关并预测，并将广泛地相关联被临床医生接受，作为对HIV VL以外的依从性的一份信息。为了检验这些假设，我们提出以下目的：目标1。建立PLWH中DBS中TFV-DPTAF的药代动力学（PK）。该目标将使用可耐用的生物传感器来客观地建立与之相关的TFV-DPTAF浓度 PLWH中的实际依从性并评估药物浓度的可变性来源。目标2。量化 TFV-DPTAF与病毒抑制之间的关系。这个目标将估计 TFV-DPTAF和HIV病毒抑制（即药物动力学）在TAF上的PLWH临床队列中。它也会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。前瞻性评估TFV-DPTAF在PLWH中的TFV-DPTAF的潜在临床实用性。这个目标将评估所感知的临床医生在AIM 2的参与者中的这种遵守措施的效用，目的是理解它如何补充诊所中的HIV VL。总的来说，这些研究将提高我们对 TFV-DPTAF在PLWH中的药理学和临床实用性，其最终目标是改善临床结果。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Association of Incomplete Adherence to Antiretroviral Therapy With Cardiovascular Events and Mortality in Virologically Suppressed Persons With HIV: The Swiss HIV Cohort Study.

DOI：
10.1093/ofid/ofab032
发表时间：
2021-03
期刊：
Open forum infectious diseases
影响因子：
4.2
作者：
Castillo-Mancilla JR;Cavassini M;Schneider MP;Furrer H;Calmy A;Battegay M;Scanferla G;Bernasconi E;Günthard HF;Glass TR;Swiss HIV Cohort Study
通讯作者：
Swiss HIV Cohort Study

Long-acting injectable Cabotegravir: How drug concentrations could help guide patient management.

长效注射卡博特韦：药物浓度如何帮助指导患者管理。