Predictive Power of PEth for HIV Prevention in the Long-Acting Era

PEth 对长效时代 HIV 预防的预测能力

• 批准号: 10542232
• 负责人: Kristina Marie Brooks
• 金额: $ 61.16万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10542232
• 关键词: AIDS clinical trial group; AIDS prevention; Address; Adherence; Alcohol consumption; Alcohols; Aliquot; Biological Assay; Biological Markers; Blood; Blood specimen; Clinic; Clinical; Colorado; Data; Diagnosis; Diphosphates; Dose; Double-Blind Method; Dropout; Epidemic; Erythrocytes; Ethanol; Failure; Fumarates; Glycosylated hemoglobin A; Gold; HIV; HIV Seronegativity; Half-Life; Individual; Injectable; Injections; Intervention; Knowledge; Laboratories; Measures; Modernization; Neoadjuvant Therapy; Oral; Outcome; Participant; Patient Self-Report; Persons; Pharmaceutical Preparations; Phospholipids; Placebos; Population; Randomized; Recording of previous events; Resources; Risk; Sampling; Seminal; Shapes; Spottings; Tenofovir; Testing; Time; Translating; Universities; Validation; Viral; Virus Replication; Whole Blood; Work; alcohol misuse; antiretroviral therapy; base; blood glucose regulation; clinical care; cohort; economic incentive; emtricitabine; experience; mass spectrometer; men; phosphatidylethanol; point of care; point of care testing; pre-exposure prophylaxis; prevent; randomized trial; recruit; transgender women who have sex with men; transmission process; trial comparing

PROJECT SUMMARY Unhealthy alcohol use, common among persons with (PWH) and at risk for HIV, is associated with multiple deleterious effects that increase the risk of HIV transmission. However, identifying individuals with unhealthy alcohol use in practice remains challenging because self-report consistently underrepresents true alcohol consumption. An objective measure of alcohol use, with clearly defined associations with clinical outcomes relevant for HIV prevention and transmission, would eliminate the time and resources dedicated to trying to subjectively quantify alcohol use, and would instead direct efforts towards swift and effective clinical interventions. Phosphatidylethanol (PEth) holds tremendous untapped potential as an objective, quantitative alcohol biomarker that could fill this unmet need. However, PEth has primarily been used in a qualitative and inconsistent manner which complicates interpretation and hinders actionable interventions. PEth's application to HIV prevention and treatment is also limited, especially with contemporary HIV pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) with injectable long-acting agents such as cabotegravir (CAB-LA) and cabotegravir/rilpivirine (CAB/RPV-LA). Delays in PEth concentration results in practice also impedes real-time interventions. This proposal will address these significant knowledge gaps and is directly responsive to RFA- AA-21-016. The long-term objective of this work is to advance PEth as an objective and actionable alcohol biomarker for HIV prevention and treatment. This will be accomplished as follows: Aim 1. Establish the relationship between PEth concentrations, PrEP adherence, and HIV acquisition among persons at risk for HIV. Using a seminal PrEP trial, HPTN-083, which compared CAB-LA vs. emtricitabine/tenofovir disoproxil fumarate (F/TDF) for HIV prevention in men and transgender women who have sex with men, the relationship between PEth and (1) time to drop-out, (2) time between cabotegravir/placebo injections, (3) intracellular tenofovir-diphosphate concentrations (an objective PrEP adherence biomarker) and (4) the risk of acquiring HIV will be established. Aim 2. Determine the ability of PEth to predict the undetectable=untransmissible (U=U) threshold among PWH with adherence barriers. To prevent HIV transmission and end the epidemic, suppression of viral replication to <200 copies/mL among PWH is essential. ACTG A5359 is a trial comparing CAB/RPV-LA vs. oral ART in PWH with a history of non-adherence to ART. A5359 includes a 12-24 week oral ART induction period with economic incentives (Step 1), followed by randomization to continued oral ART vs. monthly CAB/RPV-LA injections for 52 weeks (Step 2). The primary objective is to determine the ability of PEth in Step 1 to predict failure to achieve the U=U threshold in Steps 1 and 2. Aim 3. Develop a point-of-care test for PEth in whole blood. Using a commercially available miniature mass spectrometer, a point-of-care test will be developed for PEth. Immediate identification of unhealthy alcohol use will greatly accelerate clinical interventions and prevent deleterious clinical outcomes in persons at risk for HIV, PWH, and beyond.

项目摘要 不健康的饮酒，在患有（PWH）和有艾滋病毒风险的人中常见，与多个 有害影响增加了HIV传播的风险。但是，确定患有不健康的人 实践中的饮酒仍然具有挑战性，因为自我报告始终如一地注销不足者 消耗。饮酒的客观度量，并具有明确定义的与临床结果的关联 与预防和传播有关的艾滋病毒相关，将消除用于试图尝试的时间和资源 主观量化酒精的使用，而是将努力努力迅速有效临床 干预措施。磷脂酰乙醇（Peth）具有巨大的未开发潜力作为客观的定量 可以满足这种未满足的需求的酒精生物标志物。但是，Peth主要用于定性和 不一致的方式使解释复杂化并阻碍了可行的干预措施。 Peth的应用 预防艾滋病毒和治疗也受到限制，尤其是当代艾滋病毒预防预防 （PREP）和抗逆转录病毒疗法（ART），具有可注射的长效剂，例如Cabotegravir（Cab-LA）和 cabotegravir/rilpivirine（CAB/RPV-LA）。 peth浓度的延迟在实践中也会阻碍实时的 干预措施。该建议将解决这些重大的知识差距，并直接响应RFA- AA-21-016。这项工作的长期目标是将Peth作为一种客观且可操作的酒精 预防HIV和治疗的生物标志物。这将如下完成：AIM 1。建立 有风险的人之间的Peth浓度，依从性和艾滋病毒收购之间的关系 艾滋病毒。使用开创性预备试验，HPTN-083，该试验比较了CAB-LA与Emtrityabine/Tenofovir disoproxil 富马酸（F/TDF）用于预防艾滋病毒的男性和与男性发生性关系的跨性别女性 在Peth和（1）辍学时间之间，（2）Cabotegravir/安慰剂注射之间的时间，（3）细胞内 替诺福韦 - 二磷酸浓度（客观的准备依从性生物标志物）和（4）获取的风险 将建立艾滋病毒。 AIM 2。确定Peth预测不可发现的能力=不可转移的能力 （u = u）PWH之间具有粘附障碍的阈值。为了防止艾滋病毒传播并结束流行病， 在PWH中，抑制病毒复制至<200拷贝/mL是必不可少的。 ACTG A5359是比较的试验 CAB/RPV-LA与PWH中的口腔艺术，具有不遵守艺术的历史。 A5359包括12-24周的口服 具有经济激励措施的艺术归纳期（步骤1），然后随机分配持续口头艺术与。 每月出租车/RPV-LA注射52周（步骤2）。主要目的是确定Peth的能力 在步骤1中，要预测步骤1和2中的U = U阈值。 佩斯全血。使用市售微型质谱仪，即护即点测试 将为Peth开发。立即确定不健康的酒精使用将大大加速临床 干预措施并防止患有艾滋病毒，PWH及以后的人的有害临床结果。