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

项目摘要 不健康的酒精使用，在患有（PWH）和有艾滋病毒风险的人中很常见，与多种 有害影响，增加艾滋病毒传播的风险。然而，确定个人不健康 酒精使用在实践中仍然具有挑战性，因为自我报告始终低估了真正的酒精 消费酒精使用的客观测量，与临床结果有明确的相关性 与艾滋病毒的预防和传播有关，将消除专门用于试图 主观量化酒精使用，而是将努力导向快速有效的临床 干预措施。磷脂酰乙醇（PEth）作为一种客观、定量的 酒精生物标志物可以填补这一未满足的需求。然而，PEth主要用于定性和 不一致的方式，使解释复杂化，并阻碍可采取的干预措施。PETH的应用 艾滋病毒预防和治疗也是有限的，特别是与当代艾滋病毒暴露前预防 （PrEP）和抗逆转录病毒疗法（ART），使用可注射长效剂，如卡替拉韦（CAB-LA）和 卡替拉韦/利匹韦林（CAB/RPV-LA）。在实践中，PEth浓度的延迟也会妨碍实时测量。 干预措施。本提案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推动PEth成为一种客观和可操作的酒精 用于HIV预防和治疗的生物标志物。这将通过以下方式实现：目标1。建立 高危人群中PEth浓度、PrEP依从性和HIV感染之间的关系 艾滋病病毒使用开创性的PrEP试验，HPTN-083，比较CAB-LA与恩曲他滨/替诺福韦酯 富马酸盐（F/TDF）用于男性和变性女性艾滋病预防， PEth与（1）至脱落时间，（2）卡替拉韦/安慰剂注射之间的时间，（3）细胞内 替诺福韦二磷酸盐浓度（一种客观的PrEP依从性生物标志物）和（4）获得 艾滋病毒将被发现。目标2.确定PEth预测不可检测=不可传播的能力 （U = U）具有粘附障碍的PWH之间的阈值。为了防止艾滋病毒传播和结束这一流行病， 在PWH中将病毒复制抑制至<200拷贝/mL是必要的。ACTG A5359是一项试验， 在有ART不依从史的PWH中，CAB/RPV-LA与口服ART。A5359包括12 - 24周口服 ART诱导期和经济激励（第1步），随后随机分配至继续口服ART vs. 每月注射CAB/RPV-LA，持续52周（步骤2）。主要目的是确定PEth 以预测在步骤1和2中未能达到U = U阈值。目标3：开发即时检测 全血中的PEth。使用商用微型质谱仪，即时检测 将为PEth开发。立即识别不健康的酒精使用将大大加快临床 干预措施，并防止有害的临床结果的人在艾滋病毒，PWH和超越的风险。

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.