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

项目总结 不健康的饮酒，在慢性前列腺炎(PWH)患者中很常见，并有感染艾滋病毒的风险，与多个 增加艾滋病毒传播风险的有害影响。然而，识别出不健康的个人 酒精在实践中的使用仍然具有挑战性，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，与临床结果有明确定义的关联 与艾滋病毒预防和传播相关的，将减少专门用于尝试 主观地量化酒精的使用，转而将努力引导到快速有效的临床 干预措施。磷脂酰乙醇(PEH)作为一种客观的、定量的、具有巨大潜力的 酒精生物标记物可以满足这一未得到满足的需求。然而，peth主要用于定性和 方式不一致，使解释复杂化，妨碍可采取行动的干预措施。佩斯的申请 对艾滋病毒的预防和治疗也是有限的，特别是在当代艾滋病毒暴露前预防的情况下 (PREP)和抗逆转录病毒治疗(ART)，使用可注射长效药物，如卡波替格韦(CAB-LA)和 卡波替格韦/利培韦林(CAB/RPV-LA)。在实践中，PEST集中结果的延迟也阻碍了实时 干预措施。这项建议将解决这些重大的知识差距，并直接回应RFA- AA-21-016。这项工作长期目标是推动多酚作为一种客观和可操作的酒精 艾滋病毒预防和治疗的生物标志物。这将按如下方式完成：目标1.建立 高危人群中Peth浓度、PrEP依从性与HIV感染的关系 治疗艾滋病病毒。使用一项开创性的PrEP试验HPTN-083，该试验比较了CAB-LA与恩曲他滨/替诺福韦异丙酚 富马酸(F/TDF)在男性和变性女性中预防艾滋病毒与男性发生性行为的关系 在心跳时间和(1)退出时间之间，(2)卡替格雷/安慰剂注射之间的时间，(3)细胞内 替诺福韦-二磷酸浓度(一个客观的PrEP依从性生物标志物)和(4)获得 艾滋病病毒将被确立。目标2.确定PEH预测不可检测=不可传播的能力 (U=U)有黏附障碍的PWH的阈值。为了防止艾滋病毒的传播，结束疫情， 在PWH中抑制病毒复制到200拷贝/毫升是至关重要的。ACTG A5359是一款比较 在威尔斯亲王医院中CAB/RPV-LA与口腔艺术的对比，并有不坚持艺术的历史。A5359包括12-24周的口试 有经济诱因的ART诱导期(步骤1)，随后随机选择继续口腔艺术与。 每月注射CAB/RPV-LA，共52周(步骤2)。主要目的是确定佩斯的能力。 在步骤1中预测未能达到步骤1和步骤2中的U=U阈值。目标3.开发护理点测试 全血中的佩斯。使用商业上可获得的微型质谱计，医疗点测试 将为佩斯开发。立即识别不健康的酒精使用将极大地促进临床 干预措施，防止艾滋病毒、先天疱疹和其他疾病高危人群出现有害的临床后果。

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.