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

• 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
• 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

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.

项目总结/摘要 尽管坚持抗逆转录病毒疗法（ART）对艾滋病毒感染者至关重要， （PLHW），一个客观和准确的方法来量化它仍然是不可用的。虽然艾滋病毒病毒载量（VL）已 作为ART依从性的替代标志物，它可能导致现代ART中的不准确结论 时代这是因为病毒血症是一种延迟的临床结果，在长期不依从后发生， 并且实现病毒抑制不需要完美的粘附。一种新兴的药理学方法， 定量ART粘附是替诺福韦二磷酸（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 从首次给药到稳定状态。PI（K23 AI 104315）的最新数据表明，DBS中的TFV-DP， 来自TDF（TFV-DPTDF），与HIV病毒抑制密切相关，并且它可以预测未来 病毒学抑制的PLWH中的病毒血症。然而，这种粘附生物标志物的药理学 TAF为基础的ART仍然未知。这是一个关键的差距，鉴于显着不同的药理学 TDF和TAF之间的差异，并且是在临床实践中实施之前不可或缺的一步。 在此修订的R 01申请中，我们将通过专注于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，并且其变异性将由PLWH中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，并可预测病毒抑制，并且它将被广泛应用于 被临床医生接受为超越HIV VL的依从性的信息性指标。为了验证这些假设，我们 提出以下目标：目标1。在PLWH中确定DBS中TFV-DPTAF的药代动力学（PK）。 该目标将使用可摄取的生物传感器来客观地建立与以下相关的TFV-DPTAF浓度： PLWH的实际依从性，并评估药物浓度变异性的来源。目标二。量化 TFV-DPTAF与病毒抑制的关系。这一目标将估计 TFV-DPTAF和HIV病毒抑制（即，药效学）。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因子的价值。目标3.前瞻性 评价TFV-DPTAF在PLWH DBS中的潜在临床效用。这一目标将评估所感知的 临床医生在目标2的参与者中使用该依从性指标，目的是了解 如何在临床上补充HIV VL。总的来说，这些研究将促进我们对 TFV-DPTAF在PLWH中的药理学和临床效用，最终目标是改善临床结果。

项目成果

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。

• DOI: 10.1111/bcp.15410
• 发表时间: 2022
• 期刊: British journal of clinical pharmacology
• 影响因子: 3.4
• 作者: Castillo-Mancilla,JoseR;Anderson,PeterL
• 通讯作者: Anderson,PeterL