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.

项目概要 不健康的饮酒在艾滋病毒感染者（PWH）和有感染艾滋病毒风险的人群中很常见，与多种疾病有关。 增加艾滋病毒传播风险的有害影响。然而，识别患有不健康的人 实践中饮酒仍然具有挑战性，因为自我报告始终低于真实饮酒情况 消耗。酒精使用的客观测量，与临床结果有明确的关联 与艾滋病毒预防和传播相关的，将消除专门用于尝试的时间和资源 主观地量化酒精使用量，而是将努力转向快速有效的临床 干预措施。磷脂酰乙醇 (PEth) 作为一种客观、定量的方法具有巨大的未开发潜力。 酒精生物标记物可以满足这一未满足的需求。然而，PEth 主要用于定性和 不一致的方式使解释变得复杂并阻碍了可行的干预措施。 PEth的应用 HIV 预防和治疗的效果也很有限，尤其是当代 HIV 暴露前预防 (PrEP) 和使用可注射长效药物的抗逆转录病毒治疗 (ART)，例如卡博特韦 (CAB-LA) 和 卡博特韦/利匹韦林 (CAB/RPV-LA)。实践中 PEth 集中结果的延迟也阻碍了实时性 干预措施。该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 成为一种客观且可操作的酒精 HIV预防和治疗的生物标志物。这将按如下方式实现： 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 对于艾滋病毒。使用开创性的 PrEP 试验 HPTN-083，该试验比较了 CAB-LA 与恩曲他滨/替诺福韦二吡呋酯 富马酸盐（F/TDF）对于男男性行为者和跨性别女性预防艾滋病毒的关系 PEth 与 (1) 退出时间、(2) 卡博特韦/安慰剂注射之间的时间、(3) 细胞内 替诺福韦二磷酸盐浓度（客观的 PrEP 依从性生物标志物）和 (4) 获得的风险 艾滋病毒将成立。目标 2. 确定 PEth 预测不可检测=不可传播的能力 (U=U) 存在依从性障碍的感染者的阈值。为了防止艾滋病毒传播并结束这一流行病， 将感染者中的病毒复制抑制至 <200 拷贝/mL 至关重要。 ACTG A5359 是一个试用比较 CAB/RPV-LA 与有不遵守 ART 病史的 PWH 中的口服 ART 对比。 A5359 包括 12-24 周的口服 带有经济激励的 ART 诱导期（步骤 1），然后随机分为继续口服 ART 与非口服 ART。 每月注射 CAB/RPV-LA，持续 52 周（第 2 步）。主要目标是确定 PEth 的能力 在步骤 1 中预测无法达到步骤 1 和 2 中的 U=U 阈值。目标 3. 开发即时测试 全血中的 PEth。使用市售微型质谱仪进行即时测试 将为 PEth 开发。立即识别不健康的饮酒行为将大大加速临床 对有艾滋病毒、艾滋病毒感染者等风险的人群进行干预并预防有害的临床结果。