Use of ARV Drug Levels in DBS to Assess and Manage ART Adherence in South Africa

 描述（由申请方提供）：作为对RFA-AI-14-071的回应，我们建议确定在南非干血斑（DBS）中测定二磷酸替诺福韦（TFV-DP）作为抗逆转录病毒治疗（ART）依从性的客观指标的效用。这种活性抗逆转录病毒药物（ARV）合成代谢物的测量量化药物摄入，可以提供病毒血症的早期预警，并可用于为患者和提供者提供激励和可操作的反馈。激励依从性的反馈具有额外的重要性，因为更多的患者在他们的疾病过程中当他们感觉健康时开始ART，并且因此可能存在维持长期依从性的问题。 常规（通常仅每年一次）病毒载量测量通常会错过预防病毒血症和/或耐药病毒发展的机会。客观的依从性措施可以为早期干预提供及时的反馈，然而，现有的措施存在有效性问题;患者/提供者负担;费用和可接受性。没有任何指示是否实际摄入了剂量。合作研究者安德森开发了一种DBS中TFV-DP的测定方法，该方法反映了过去几周/几个月的药物摄入情况;可能导致该测定方法在床旁应用的研究正在开发中。尽管该检测方法已在HIV-成人中得到表征，但我们提出的项目将在撒哈拉以南非洲的现实世界环境中检查其治疗而不是预防的效用。这项研究将提供关键信息，如果没有这些信息，这些技术的有效推广将受到严重影响-特别是在南非等资源匮乏的环境中。 根据我们最近的试点研究（Remien等人），在SA的HIV+患者中使用安德森的DBS TFV-DP检测，我们建议通过两个特定目标，研究使用该检测来评估和管理这种低资源环境中的ART依从性。目标1：在接受含TFV的ART治疗≥12个月的250名HIV+成人中，我们将通过使用每月一次的药物合成代谢物和VL检测沿着12个月内的连续Wisepill输出，确定该检测试剂盒提供客观、临床相关和可操作的依从性指标的能力。我们将比较DBS TFV-DP检测试剂盒和Wisepill预测病毒血症的能力;确定DBS TFV-DP降低的幅度-在现实世界中使用-预测病毒血症和多久;并记录保持病毒抑制的患者中DBS TFV-DP水平的范围。目标二：我们将制定信息和程序，每月向患者和供应商提供检测反馈，并在一项小型试点研究（N=60）中，检查供应商和患者在收到此信息后的行为。研究结果将为该领域提供信息，并为未来更大规模的试验提供试点数据，以确定此类反馈对患者依从性相关行为和提供者医疗管理的影响。拟议的研究代表了美国和南非行为科学家，药理学家和临床医生之间正在进行的，创新的和富有成效的多学科合作伙伴关系。

 DESCRIPTION (provided by applicant): In response to RFA-AI-14-071, we propose to determine the utility of assay of tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) as an objective measure of adherence to antiretroviral treatment (ART) in South Africa. Measurement of this active antiretroviral medication (ARV) anabolite quantifies medication ingestion, may provide early warning of viremia, and may be used to provide motivating and actionable feedback to patients and providers. Feedback that motivates adherence has additional importance as more patients begin ART earlier in their disease course when they are feeling healthy and, as a result, may have problems sustaining long-term adherence. Routine (often only annual) viral load measurement often misses the opportunity to prevent viremia and/or development of resistant virus. Objective adherence measures could provide timely feedback for earlier intervention, however, existing measures have problems with validity; patient/provider burden; and expense and acceptability. None indicates if a dose is actually ingested. Co-Investigator, Anderson, developed an assay of TFV-DP in DBS that reflects drug ingestion over past weeks/months; research likely to lead to a point- of-care application of this assay is under development. Although the assay has been characterized in HIV- adults, our proposed project would examine its utility for treatment rather than prevention in real-world settings in Sub Saharan Africa. This research will provide critical information without which the effective roll-out of such technologies would be significantly compromised - especially in low-resource settings, such as South Africa. Following our recent pilot study (Remien et al.) using Anderson's DBS TFV-DP assay among HIV+ patients in SA, we propose research on the use of this assay to assess and manage ART adherence in this low-resource setting through two Specific Aims. Aim 1: Among 250 HIV+ adults on ART containing TFV for ≥12 months, we will determine the ability of this assay to provide an objective, clinically relevant, and actionable measure of adherence by using monthly drug anabolite and VL assays along with continuous Wisepill output over 12 months. We will compare the abilities of the DBS TFV-DP assay and Wisepill to predict viremia; determine the magnitude of decrease in DBS TFV-DP - in real-world use - that predicts viremia and by how long; and document the range of DBS TFV-DP levels in patients who remain virally suppressed. Aim 2: We will develop messages and procedures for giving patients and providers monthly feedback from the assay and, in a small pilot study (N=60), examine provider and patient behaviors in response to receiving this information. Findings will inform the field and provide pilot data for a future larger trial to establish the imact of such feedback on patients' adherence-related behaviors and on medical management by providers. The proposed research represents an ongoing, innovative, and productive multidisciplinary partnership among behavioral scientists, pharmacologists, and clinicians in the US and South Africa.