Rapid, Quantitative Point-of-Care Measurement of Tuberculosis Treatment Adherence

项目总结/摘要 结核病（TB）仍然是世界范围内的主要健康问题， 全球范围内的单一传染源致死原因全球估计有1000万人 2018年，全球约有120万人感染结核病，艾滋病毒感染者中估计有120万人死于结核病， 2018年，艾滋病病毒感染者中有251，000人死亡。在 美国2018年，CDC的国家监测项目确认了9,029例新的结核病， 这是有记录以来的最低水平，但据估计，美国有1300万人患有潜伏性结核病 感染，估计美洲每年有290，000例新病例，表明 沉重的区域负担。 结核病耐药菌株的出现被认为是对控制结核病的全球性威胁。 结核病尽管存在这种威胁，但如果迅速接受治疗， 适当地。因此，快速准确的诊断和有效的抗结核治疗的使用 不仅最大限度地降低发病率和死亡率，而且还能减缓结核病在 人口然而，未治愈或不坚持治疗的结核病患者 对个人和社区都构成严重风险。不依从抗结核治疗 治疗可能导致出现耐多药结核病（MDR-TB）， 传染性和结核病治疗效果差。即使在美国，坚持治疗 由于许多因素，完成工作的时间很短，具有挑战性。 治疗时间长（通常为6个月或更长），需要联合治疗， 效果可能令人不快。药物费用（即使是相对较小的自付额或免赔额） 如果不被公共卫生系统覆盖，可能是依从性的严重障碍。此外，委员会还认为， 患者通常会经历症状的快速改善，这可能会混淆 继续使用可能被认为是不必要的药物进行长期治疗。 在世界范围内，通常还有更多的障碍，包括： 直接观察治疗（DOT）的运输，缺乏对 完成治疗过程，家里的药物用完，到卫生设施的距离，艾滋病毒 血清阳性、酗酒和使用草药。不遵守也是 与药物副作用显著相关，处于 化疗，药丸负担，缺乏与卫生专业人员的充分沟通， 家庭支持。最后，抗结核药物的吸收和代谢有很大的差异 药物和血液中低药物浓度与较差的结核病治疗结果相关， 包括治疗失败和复发。药代动力学变异性已被确定为关键因素 灭菌效果和出现新的耐药突变的速度的介质 在抗结核治疗期间。 总之，仍然迫切需要对结核药物进行快速、定量的评估 给药和坚持治疗，最好是在护理点。 在这个SBIR项目中，我们将开发一个新的传感器平台，可以用来快速 测量尿液中的主要结核药物。该系统将类似于个人血糖仪， 因为有一个小的手持阅读器和一个测试条（丝网印刷电极）。 DNA适体将被固定在电极上，以提供特异性分子识别。 我们已经证明了尿液中其他分析物的灵敏识别。这 这种方法有希望教育临床医生正确的剂量和监测病人的依从性 这仍然是最终根除结核病的一个重大障碍。

Project Summary/Abstract Tuberculosis (TB) continues to be a major health concern worldwide and is the leading cause of death worldwide from a single infectious agent. Globally, an estimated 10 million people fell ill with TB in 2018, and there were an estimated 1.2 million TB deaths among HIV- negative people in 2018 and an additional 251,000 deaths among HIV positive people. In the U.S. there were 9,029 new TB confirmed by the CDC’s national surveillance program in 2018, the lowest on record, yet there are an estimated 13 million in the U.S. living with latent TB infection, and an estimated 290,000 new cases each year in the Americas indicating a significant remaining regional burden. The emergence of drug resistant strains of TB is considered a global threat to the control of TB. Despite this threat, TB is a curable disease if treatment is received quickly and appropriately. Thus, rapid and accurate diagnosis and the use of effective anti-TB treatments not only minimize morbidity and mortality, but also mitigate the spread of TB among the population. Nevertheless, TB patients who are not cured or non-adherent to their treatment pose a serious risk both for individuals and their community. Non-adherence to anti-TB treatment may result in the emergence of multidrug resistant TB (MDR-TB), prolonged infectiousness and poor TB treatment outcomes. Even in the U.S., adherence to treatment through to completion is poor and challenging due to a number of factors – the duration of treatment is long (usually six months or longer), combination therapy is required, and side effects may be unpleasant. Cost of medications (even relatively small copays or deductibles) can be a serious barrier to adherence if not covered by the public health system. Furthermore, patients often experience rapid improvement in symptoms, which may obfuscate the importance of continuing prolonged treatment with drugs that may be perceived as unnecessary. Worldwide, there are often even more obstacles to adherence including: access to transportation for directly observed therapy (DOT), lack of knowledge on the benefits of completing a treatment course, running out of drugs at home, distance to the health facility, HIV seropositivity, alcohol abuse, and use of herbal medication. Non-adherence was also significantly associated with drug side effects, being in the continuation phases of chemotherapy, pill burden, lack of adequate communication with health professionals and lack of family support. Finally, there is wide variability in absorption and metabolism of the anti-TB drugs, and low drug concentrations in blood are associated with inferior TB treatment outcomes, including treatment failure and relapse. Pharmacokinetic variability has been identified as a key mediator of the rate of sterilizing effect and the emergence of new drug resistance mutations during anti-TB therapy. In summary, there is still a desperate need for rapid, quantitative assessment of TB drug dosing and adherence to treatment, preferably at the point of care. In this SBIR project, we will develop a new sensor platform that can be used to quickly measure the primary TB drugs in urine. The system will resemble a personal glucose meter for diabetics in that there is a small handheld reader and a test strip (screen-printed electrode). DNA aptamers will be immobilized on the electrode in order to provide specific molecular recognition in a sensitive format that we have already proven for other analytes in urine. This approach has the promise to educate clinicians on proper dosing and monitor patient adherence to treatment which remains a significant hurdle to ultimately eradicating TB.