PrEP and ART adherence monitoring using dried blood spots

描述(由申请人提供)：对艾滋病毒暴露前化学预防(PrEP)和抗逆转录病毒治疗(ART)的坚持不足是常见的，也是治疗失败的主要原因。尽管这对人类健康造成了破坏性的影响，但还没有可靠、方便的方法来定期量化依从性。本申请提出了一种新的定量方法来常规监测富马酸替诺福韦(TDF)为基础的PrEP和ART的依从性。基于TDF的治疗方案是PrEP和ART的基石，大约80%的ART患者和100%的PrEP患者接受基于TDF的治疗。我们发现，替诺福韦-二磷酸(TFV-DP)是TFV的活性形式，在红细胞内的半衰期为17天，变异性很低。这些特征类似于糖化血红蛋白A1C，它被测量为标准护理，以定量监测糖尿病的累积葡萄糖暴露。我们建议，RBC中的TFV-DP水平可以以类似的方式用于定量监测基于TDF的PrEP和ART的累积药物暴露(依从性)。我们发现，用干血斑(DBS)可以定量检测RBC中的TFV-DP水平，该方法具有费用低、采集和加工要求容易等显著优点。拟议的研究将确定依从率对DBS中TFV-DP水平的影响。48名HIV阴性志愿者将被随机分配到每日剂量分别为33%、67%和100%的TDF-FTC。所有剂量都将直接观察治疗(DOT)。将采用带有冲洗期的随机不完全区组设计，使参与者接受3种给药方案中的2种，每种方案为期12周。另一组32名HIV阳性志愿者将接受基于TDF-FTC的每日DOT治疗。将定义DOT环境下DBS中TFV-DP的预期水平，比较HIV阳性和阴性患者的TFV-DP水平，并用于构建一个模型，用于定量预测PrEP和ART的依从性。我们将立即将我们的发现转化为DBS中的TFV-DP，目前正在为几个关键的PrEP示范项目收集TFV-DP，其中遵守情况监测是关键结果。我们认为，DBS的TFV-DP作为一种新的依从性量化指标，有可能对公共卫生产生直接和持久的影响。

DESCRIPTION (provided by applicant): Inadequate adherence to HIV pre-exposure chemoprophylaxis (PrEP) and antiretroviral therapy (ART) is common, and the leading cause of therapeutic failure. Despite this damaging impact on human health, reliable, convenient methods with which to quantify adherence routinely are not available. This application proposes a new quantitative approach to routinely monitor adherence to tenofovir disoproxil fumarate (TDF)-based PrEP and ART. TDF-based regimens are the cornerstone of PrEP and ART with approximately 80% of ART patients and 100% of PrEP patients receiving TDF-based therapy. We discovered that tenofovir-diphosphate (TFV-DP), the active form of TFV, has a 17 day half-life in red blood cells (RBC) with low variability. These characteristics are analogous to glycosylated hemoglobin A1C, which is measured as standard- of-care to quantitatively monitor cumulative glucose exposure for diabetes. We propose that the level of TFV-DP in RBC can be used in a similar way to quantitatively monitor cumulative drug exposure (adherence) for TDF-based PrEP and ART. We showed that the level of TFV-DP in RBC can be quantified using dried blood spots (DBS), which offers significant advantages such as low expense and easy collection and processing requirements. The proposed study will determine the effect of adherence rate on the level of TFV-DP in DBS. Forty eight HIV-negative volunteers will be randomized to 33%, 67% and 100% of daily dosing with TDF-FTC. All dosing will be directly observed therapy (DOT). A randomized incomplete block design with a washout period will be employed such that participants receive 2 of 3 dosing regimens for 12 weeks each. A separate cohort of 32 HIV-positive volunteers will receive daily DOT with TDF-FTC-based therapy. Expected levels of TFV-DP in DBS in the setting of DOT will be defined, compared in HIV-positive versus negative persons, and used to construct a model that predicts adherence quantitatively for PrEP and ART. We will immediately translate our findings to interpret TFV-DP in DBS that are currently being collected for several pivotal PrEP demonstration projects where adherence monitoring is a key outcome. We believe that TFV-DP in DBS, as a new quantitative measure of adherence, has the potential to make an immediate and lasting public health impact.