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

尿液替诺福韦免疫分析可区分依从性与耐药性 HIV 治疗失败

• 批准号: 9916708
• 负责人: Suzanne McCluskey
• 金额: $ 21.15万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-16 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916708
• 关键词: Adherence; Africa; Africa South of the Sahara; Analytical Chemistry; Anti-Retroviral Agents; Antiretroviral drug resistance; Biological Assay; Biometry; Blood; California; Characteristics; Clinical; Clinical Research; Clinical Trials; Collection; Counseling; Country; Cryopreservation; Data; Derivation procedure; Development; Diagnostic; Diagnostic Procedure; Doctor of Philosophy; Drug resistance; Enrollment; Enzyme-Linked Immunosorbent Assay; Epidemic; Epidemiologist; Epidemiology; Equipment; Etiology; Failure; Funding; Genotype; Goals; Gold; Grant; Guidelines; HIV; HIV resistance; Hair; Health; Health system; Human Resources; Immunoassay; Individual; Infrastructure; Laboratories; Lateral; Liquid Chromatography; Measures; Methods; Monitor; Morbidity - disease rate; Parents; Participant; Pathway interactions; Patient Self-Report; Patients; Performance; Pharmacology; Plasma; Population; Principal Investigator; RNA; ROC Curve; Reference Standards; Regimen; Research; Research Institute; Research Personnel; Resistance; Resources; Sampling; San Francisco; Services; Site; South Africa; Specimen; Spottings; Technology; Tenofovir; Testing; Toxic effect; Translating; Treatment Failure; Uganda; United States National Institutes of Health; Universities; Urine; Validation; Viral Load result; Viremia; Virus; Visit; World Health Organization; antiretroviral therapy; base; career; clinical care; cost; experience; innovation; next generation; novel; patient population; pill; point of care; pre-exposure prophylaxis; research study; rho; side effect; tandem mass spectrometry; virology

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.

项目总结 意义：撒哈拉以南非洲多达三分之一的艾滋病毒携带者经历了病毒学失败 在开始抗逆转录病毒治疗(ART)的两年内。然而，很难辨别其病因。 在资源有限的情况下，治疗失败是由依从性驱动的，而不是由耐药性驱动的。遗传型 由于高昂的成本和有限的实验室基础设施，许多地区无法定期进行耐药性检测 设置。遵守情况评估同样具有挑战性，因为自我报告的措施效度较低，以及 目前可用的客观措施需要昂贵的设备和/或专门人员。然而，a 最近发展了一种新的检测尿中替诺福韦(TFV)浓度的免疫分析方法，该方法 被转化为用于暴露前预防的护理点依从性试验。 创新：在这里，我们提出了第一项研究，以验证这一最近开发的尿液TFV免疫分析方法在 接受治疗的艾滋病毒携带者人数。此外，我们将评估免疫分析作为一种 一种低成本、点护理方法的途径，以区分依从性驱动和耐药性驱动的治疗 失败了。调查人员：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(校长 调查员Suzanne McCluskey，职业生涯早期的调查员，适合美国国立卫生研究院的“下一代调查员” 目标)，撒哈拉以南非洲的领先临床试验(Mark Siedner)，艾滋病毒临床护理(Mwebesa Bwana)， 艾滋病毒的药理学依从性措施(莫妮卡·甘地)，病毒学(Pravikrishnen Moodley)，分析 化学(John Adamson)和生物统计学(Bethany Hedt-Gauthier)将指导这笔赠款的目标。 方法：我们将利用改造研究的基础设施，这是一项由NIH R01资助的临床试验(R01 AI124718)在乌干达和南非。REVAMP在两个国家招收不及格的一线艺术人才， 他们中的大多数都在接受基于TFV的治疗，包括病毒载量和基因耐药测试，以及 收集尿液。利用这些储存的尿样，我们将评估最近开发的尿液的有效性。 撒哈拉以南地区TFV免疫分析在区分依从性和耐药性治疗失败中的作用 非洲通过以下具体目标：1)我们将验证尿液TFV免疫分析的性能 在受试者中与液相色谱-串联质谱仪的参比标准进行比较 在改良研究中，含有TFV的ART方案。2)我们将确定 尿TFV免疫分析鉴别野毒株病毒学失败与耐药病毒学失败 未能通过含TFV一线方案的参与者感染病毒。这些AIMS产生的数据将用于 最终确定用于治疗的尿液TFV护理点依从性分析的开发，我们将建议 在NIH R01资助的试验中进行评估，以区分依从性和耐药性驱动的治疗失败 在RLS中。