A urine tenofovir immunoassay to distinguish adherence versus resistance-based HIV treatment failure

项目摘要 重要性：撒哈拉以南非洲多达三分之一的艾滋病毒感染者经历病毒学失败 在开始抗逆转录病毒治疗（ART）的两年内。然而，很难辨别的病因， 在资源有限的环境中，治疗失败是依从性驱动还是耐药驱动（RLS）。基因型 在许多国家，由于成本高和实验室基础设施有限， 设置.依从性评估同样具有挑战性，因为自我报告的测量有效性低， 目前可用的客观措施需要昂贵的设备和/或专门人员。但 最近开发了一种测量尿中替诺福韦（TFV）浓度的新型免疫测定法， 被转化为用于暴露前预防的护理点依从性测定。 创新：在此，我们提出了第一项研究，以验证这种最近开发的尿液TFV免疫测定法， 接受治疗的艾滋病毒感染者人数。此外，我们将评估免疫测定作为 一种低成本、即时方法的途径，以区分依从性驱动和耐药性驱动治疗 失败研究人员：我们的跨学科团队，具有艾滋病毒耐药性和流行病学方面的专业知识（主要 调查员苏珊娜·麦克拉伦基，一位适合NIH“下一代调查员”的早期职业调查员。 目标），撒哈拉以南非洲领先的临床试验（Mark Siedner），艾滋病毒临床护理（Mwebesa Bwana）， 艾滋病毒药物依从性测量（Monica Gandhi），病毒学（Pravikrishnen Moodley），分析 化学（约翰亚当森）和生物统计学（贝瑟尼Hedt-Gauthier），将进行这项赠款的目标。 方法：我们将利用REVAMP研究的基础设施，这是一项由NIH R 01资助的临床试验（R 01 AI 124718）在乌干达和南非。REVAMP在这两个国家招募一线抗逆转录病毒治疗失败的个人， 其中大多数接受基于TFV的治疗，包括病毒载量和基因型耐药检测，沿着 尿液收集。使用这些储存的尿液样本，我们将评估最近开发的尿液的有效性 TFV免疫测定法用于区分撒哈拉以南非洲患者的依从性和耐药治疗失败 非洲通过以下具体目标：1）我们将验证尿液TFV免疫测定的性能 与参与者中的液相色谱-串联质谱参考标准进行比较， REVAMP研究中含TFV的ART方案。2)我们将确定诊断性能的 尿TFV免疫测定用于区分野生型病毒的病毒学失败与耐药病毒的病毒学失败 含TFV的一线治疗方案失败的受试者中的病毒。这些目标产生的数据将用于 完成尿液TFV即时治疗依从性检测的开发，我们将建议 在NIH R 01资助的试验中进行评估，以区分依从性和耐药驱动的治疗失败 在RLS。

PROJECT SUMMARY Significance: As many as one third of people living with HIV in sub-Saharan Africa experience virologic failure within two years of initiating antiretroviral therapy (ART). However, it is difficult to discern the etiology of treatment failure as adherence-driven versus resistance-driven in resource-limited settings (RLS). Genotypic resistance testing is not routinely available due to high costs and limited laboratory infrastructure in many settings. Adherence assessment is similarly challenging because self-reported measures have low validity, and currently available objective measures require costly equipment and/or specialized personnel. However, a novel immunoassay to measure tenofovir (TFV) concentrations in urine has been recently developed and is being translated into a point-of-care adherence assay for use in the context of pre-exposure prophylaxis. Innovation: Herein, we propose the first study to validate this recently developed urine TFV immunoassay in a population of people living with HIV on treatment. Furthermore, we will evaluate the immunoassay as a pathway to a low-cost, point-of-care method to distinguish adherence-driven from resistance-driven treatment failure. Investigators: Our interdisciplinary team, with expertise in HIV resistance and epidemiology (Principal Investigator Suzanne McCluskey, an early career investigator fitting the NIH's “Next Generation Investigator” goals), leading clinical trials in sub-Saharan Africa (Mark Siedner), HIV clinical care (Mwebesa Bwana), pharmacologic adherence measures in HIV (Monica Gandhi), virology (Pravikrishnen Moodley), analytical chemistry (John Adamson) and biostatistics (Bethany Hedt-Gauthier), will conduct the aims of this grant. Approach: We will leverage the infrastructure of the REVAMP study, an NIH R01-funded clinical trial (R01 AI124718) in Uganda and South Africa. REVAMP enrolls individuals failing first-line ART in the two countries, most of whom are on TFV-based therapy, and includes viral load and genotypic resistance testing, along with urine collection. Using these stored urine specimens, we will assess the validity of a recently developed urine TFV immunoassay to differentiate between adherence and resistance-based treatment failure in sub-Saharan Africa through the following specific aims: 1) We will validate the performance of the urine TFV immunoassay compared to a reference standard of liquid chromatography-tandem mass spectrometry among participants on TFV-containing ART regimens in the REVAMP study. 2) We will determine the diagnostic performance of the urine TFV immunoassay to distinguish virologic failure with wild-type virus from virologic failure with resistant virus in participants failing TFV-containing first-line regimens. Data generated from these aims will be used to finalize development of a urine TFV point-of-care adherence assay for treatment, which we will propose to evaluate in an NIH R01-funded trial to differentiate between adherence and resistance-driven treatment failure in RLS.