PrEP and ART adherence monitoring using dried blood spots

描述（由申请人提供）：对HIV暴露前化学预防（PrEP）和抗逆转录病毒治疗（ART）的依从性不足是常见的，也是治疗失败的主要原因。尽管这种对人类健康的破坏性影响，可靠的，方便的方法来量化遵守常规是不可用的。该申请提出了一种新的定量方法来常规监测基于富马酸替诺福韦酯（TDF）的PrEP和ART的依从性。基于TDF的方案是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，二磷酸替诺福韦（TFV-DP），TFV的活性形式，在红细胞（RBC）中具有17天的半衰期，具有低变异性。这些特征类似于糖化血红蛋白A1 C，糖化血红蛋白A1 C作为标准护理进行测量，以定量监测糖尿病的累积葡萄糖暴露。我们提出，红细胞中的TFV-DP水平可以以类似的方式用于定量监测基于TDF-PrEP和ART的累积药物暴露（依从性）。我们表明，红细胞中的TFV-DP水平可以使用干血斑（DBS）进行定量，这提供了显着的优势，如低成本和易于收集和处理的要求。拟定研究将确定DBS中依从率对TFV-DP水平的影响。将48名HIV阴性志愿者随机分配至33%、67%和100%的TDF-FTC每日剂量组。所有给药均为直接观察治疗（DOT）。将采用带有洗脱期的随机化不完全区组设计，使受试者接受3种给药方案中的2种，各持续12周。另一组32名HIV阳性志愿者将接受每日DOT和基于TDF-FTC的治疗。将定义在DOT设置中DBS中TFV-DP的预期水平，在HIV阳性与阴性人群中进行比较，并用于构建一个模型，该模型可定量预测PrEP和ART的依从性。我们将立即将我们的研究结果转化为DBS中的TFV-DP，目前正在为几个关键的PrEP示范项目收集TFV-DP，其中依从性监测是一个关键结果。我们认为，DBS中的TFV-DP作为一种新的依从性定量指标，有可能产生直接和持久的公共卫生影响。

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.