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

项目摘要/摘要 结核病(TB)仍然是世界范围内的一个主要健康问题，是世界上最主要的 全球范围内死于单一感染源的死因。在全球，估计有1000万人 2018年，人们感染了结核病，估计有120万人死于结核病-- 2018年艾滋病毒阴性者人数增加，艾滋病毒阳性者死亡人数增加251,000人。在 2018年美国疾病控制与预防中心的国家监测项目确认了9029例新的结核病病例， 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，估计美洲每年新增病例29万例，表明 遗留下来的重大区域负担。 结核病耐药菌株的出现被认为是对控制的全球威胁 结核病的风险。尽管存在这种威胁，但如果迅速接受治疗，结核病是一种可以治愈的疾病。 恰如其分。因此，快速准确的诊断和有效的抗结核治疗的使用 不仅将发病率和死亡率降至最低，而且还可以减少结核病在 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了严重的风险。不坚持抗结核 治疗可能导致多药耐药结核病(MDR-TB)的出现，并延长 传染性和结核病治疗结果不佳。即使在美国，坚持治疗 由于许多因素，从完成到完成是很差和具有挑战性的--持续时间 治疗时间较长(通常为六个月或更长时间)，需要联合治疗， 影响可能会令人不快。药费(即使是相对较小的自付费用或免赔额) 如果不被公共卫生系统覆盖，可能会成为遵守的严重障碍。此外， 患者通常症状迅速改善，这可能混淆了重要性。 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，遵守公约往往面临更多障碍，包括：获得 直接观察治疗(DOT)的运输，缺乏对其益处的了解 完成一个疗程，家里的药物用完了，距离医疗机构很远，艾滋病毒 血清阳性，酗酒，以及使用草药。不遵守也是 与药物副作用显著相关，处于持续阶段 化疗、避孕药负担、缺乏与卫生专业人员的充分沟通以及缺乏 对家庭的支持。最后，抗结核药物的吸收和代谢有很大的变异性。 药物和血液中的低药物浓度与较差的结核病治疗结果有关， 包括治疗失败和复发。药代动力学变异性已被认为是关键 绝育效果与新耐药突变发生的介体 在抗结核治疗期间。 总之，仍然迫切需要对结核病药物进行快速、定量的评估。 给药和坚持治疗，最好是在护理时。 在这个SBIR项目中，我们将开发一种新的传感器平台，可以用于快速 检测尿液中的主要抗结核药物。该系统将类似于个人血糖仪 糖尿病患者中有一个小型手持阅读器和一个试纸(丝网印刷电极)。 DNA适配子将固定在电极上，以提供特定的分子 以一种我们已经证明用于尿液中其他分析物的敏感形式进行识别。这 方法承诺教育临床医生正确的剂量和监测患者的依从性 治疗仍然是最终根除结核病的重大障碍。

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.