A Point of Care Test to Monitor Long-Term Adherence to Tenofovir-based Regimens For The Prevention and Treatment of HIV

项目摘要 艾滋病毒仍然是一种危险和流行的疾病，在全球造成数百万人感染， 每年的死亡人数和数百亿美元的医疗费用。暴露前预防（PrEP）为99% 如果每天服用，可以有效预防艾滋病毒感染，但其对减少艾滋病毒负担的影响有限， 坚持。疾病控制中心（CDC）建议在高风险人群中使用PrEP。 艾滋病毒感染者，包括男男性行为者、静脉吸毒者和艾滋病毒感染者 积极的伙伴。同样，用于治疗艾滋病毒的抗逆转录病毒疗法也可以有效抑制病毒载量 当遵循给药方案时。由于依从性差，不仅患者治疗不当， 增加了产生耐药菌株的机会。药物依从性监测是众所周知的，以改善药物治疗。 遵守，但没有商业产品用于快速长期遵守PrEP和ART的监测。 因此，对于允许医生监测PrEP依从性的工具存在关键的未满足需求 患者的ART。为了让患者接受并在医生工作流程中可行， 测试需要是微创、无痛、廉价、易于管理并提供快速， 准确的结果。值得注意的是，现有的SBIR赠款正在资助UrSure开发用于 代谢物替诺福韦（TFV）。TFV测试测量最近的依从性（最近一次服药时间 在过去7天内），而本申请提出开发一种测试来测量替诺福韦二磷酸盐 这是长期依从性的量度（在过去6周内服用的平均剂量数）。 该项目的总体目标是开发一种即时（POC）检测， POC测试将基于现有的文献，测量细胞内 使用基于实验室的质谱法测定TFV-DP。POC检测将更快（几分钟即可获得结果） 并且可以在诊所访问期间使用，以测量PrEP和ART依从性，并且如果合适，可以为患者提供咨询 如何提高他们的依从性。也有证据表明TFV-DP水平是病毒感染的可靠指标。 抑制和预测未来的病毒血症或血清转化，为提供者提供有价值的信息， 提高临床疗效。本课题的主要目的是：1）优化筛选前3位单克隆抗体 抗体，3）建立LFIA测试条的基本性能和结构，4）优化性能 并生产验证批次，以及5）扩大试验程序，并生产中试批次， 确保批次间的重现性。 该直接进入第二阶段项目的最终可交付成果将是具有高灵敏度/特异性的mAb，即 经验证的侧流免疫测定TFV-DP血液POC检测用于长期替诺福韦依从性， 确保批间重现性。这个项目的成功完成将使我们能够 开始FDA验证研究，并将我们的上市前501 k汇总以获得FDA批准。

PROJECT ABSTRACT HIV remains a dangerous and prevalent disease globally contributing to millions of infections and deaths per year and tens of billions of dollars in healthcare costs. Pre-Exposure Prophylaxis (PrEP) is 99% effective at preventing HIV infection if taken daily, but its impact on reducing HIV burden is limited by poor adherence. PrEP is recommended by the Centers for Disease Control (CDC) in populations at a high risk of HIV infection, which include men who have sex with men, intravenous drug users, and people with a HIV positive partner. Similarly, antiretroviral therapy, used to treat HIV, can be effective and suppress viral load when following the dosing schedule. Due to poor adherence, not only are patients inappropriately treated, the chance of developing resistant strains is increased. Drug adherence monitoring is well known to improve drug compliance, but there are no commercial products for rapid long-term adherence monitoring of PrEP and ART. Hence, there is a critical unmet need for a tool that will allow physicians to monitor adherence to PrEP and ART in patients. To be acceptable to patients and feasible in the physician workflow, this adherence test needs to be minimally-invasive, painless, inexpensive, easy to administer and provide rapid, accurate results. Of note, an existing SBIR grant is funding the development at UrSure of a POC test for the metabolite Tenofovir (TFV). The TFV test measures recent adherence (when was the most recent dose taken over the last 7 days) while this application proposes developing a test to measure Tenofovir Diphosphate which is a measure of long-term adherence (average number of doses taken over the last 6 weeks). The overall goal of this project is to develop a point-of-care (POC) test that will measure long-term adherence with PrEP and ART. The POC test will be based on existing literature that measures intracellular TFV-DP using a laboratory-based mass spectrometry. The POC assay will be faster (minutes to get a result) and can be used during a clinic visit to measure PrEP and ART adherence and, if appropriate, counsel patients on how to improve their compliance. There is also evidence that TFV-DP level is a reliable indicator of viral suppression, and prediction of future viremia or seroconversion, offering provider valuable information and improving clinical efficacy. The aims of this project are to: 1) optimize and screen for the top 3 monoclonal antibodies, 3) establish basic performance and architecture of an LFIA test strip, 4) optimize the performance of the POC device and produce a verification lot, and 5) Scale-up assay procedures, and produce pilot lots to ensure lot-to-lot reproducibility. The final deliverables of this Direct to Phase II project will be mAbs with high sensitivity/specificity, a validated Lateral Flow Immunoassay TFV-DP blood POC test for long-term tenofovir adherence, and 3 pilot lots to ensure lot-to-lot reproducibility. Successful completion of this project will leave us in a position to start FDA validation studies and put together our pre-market 501k for FDA approval.