Antiretroviral therapy adherence and exploratory proteomics in virally suppressed people with HIV and stroke

病毒抑制的艾滋病毒和中风患者的抗逆转录病毒治疗依从性和探索性蛋白质组学

• 批准号: 10748465
• 负责人: Eric Hermann Decloedt
• 金额: $ 16.59万
• 依托单位: STELLENBOSCH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748465
• 关键词: Adherence; Africa South of the Sahara; Age; Anti-Retroviral Agents; Automobile Driving; Basal Ganglia; Biological Assay; Biological Markers; Blood; Blood Vessels; Blood specimen; Cardiovascular system; Case/Control Studies; Categories; Classification; Clinical; Cohort Studies; Confidence Intervals; Country; Data; Diphosphates; Disease; Dryness; Economic Burden; Event; Female; Future; HIV; Health; Income; Inflammation; Inflammatory; Inflammatory Response; Ischemic Stroke; Knowledge; Matched Group; Measures; Morbidity - disease rate; Observational Study; Odds Ratio; Outcome; Participant; Persons; Pharmaceutical Preparations; Plasma; Population; Population Control; Premature aging syndrome; Prevalence; Proteomics; Regimen; Research; Research Personnel; Residual state; Risk; Risk Factors; Serum; South Africa; South African; Spottings; Stroke; Tenofovir; Testing; Time; Uganda; Viral; Viral Load result; Viral reservoir; Viremia; Virus Latency; Virus Replication; acute stroke; adherence rate; antiretroviral therapy; biomarker performance; candidate identification; candidate marker; cardiovascular risk factor; clinical practice; clinically relevant; cohort; comparative; detection limit; follow-up; forgiveness; health care economics; immune reconstitution; insight; men; mortality; multiplex assay; novel strategies; pill; prospective; proteomic signature; standard of care; stroke risk; success; systematic review; therapy adherence

PROJECT SUMMARY Antiretroviral therapy (ART) has dramatically changed the health outcomes of people with HIV (PWH). Newer ART regimens with more robust viral suppression may allow complacency creep for imperfect adherence, given the regimen forgiveness for achieving suppressed viral loads despite imperfect adherence. In turn, imperfect adherence may lead to ongoing viral replication below the clinically-relevant suppression threshold, driving inflammation and premature aging. Accumulating data indicate that underlying inflammation strongly contributes to PWH continuing to develop non-communicable diseases (NCD) despite viral suppression, with studies showing a 2-fold increased risk of a significant NCD, HIV-associated stroke, compared to people without HIV. HIV-associated stroke is associated with major mortality, morbidity, and healthcare economic burden. The current investigators found a stroke prevalence of 6.2% in South African PWH with suppressed viral loads compared to people without HIV. PWH were almost 10 years younger, had less traditional cardiovascular risk factors, and were predominantly female, despite being virally suppressed to <200 copies/mL. Additionally, HIV was found to be the predominant risk factor for young stroke (≤45 years) in a Malawian case-control study of 222 PWH and 503 population controls with acute stroke, with an adjusted odds ratio of 5.57 (2.43-12.8). However, none of these studies examined imperfect adherence as a risk factor for stroke. Research on the treatment success of ART focuses primarily on perfect or near-perfect adherence strategies to suppress HIV viral loads to below clinically-relevant thresholds, currently defined as <200 copies/mL. In clinical practice, however, adherence to ART is often imperfect, with a cohort study from South Africa and Uganda showing that despite most participants being classified as virally suppressed, adherence across several categories of PWH was poor. This was confirmed in a study of 64 virally suppressed participants in whom 47% had detectable viremia between 0-50 copies/mL despite adherence rates over the preceding two months of 93% (82%-98%) using unannounced pill counts. Others have shown that lower concentrations of intracellular tenofovir diphosphate (TFV-DP) on dried blood spots (DBS), an objective drug concentration biomarker indicating cumulative adherence over the preceding 8 weeks, was associated with a 2-fold higher odds of viremia between 20-200 copies/mL. Investigating imperfect ART adherence in virally suppressed PWH with stroke offers an opportunity to gain new insights into a potential modifiable factor to reduce stroke. This exploratory study will obtain important preliminary data on the association between stroke and ART adherence, as well as the novel approach of testing candidate proteomic biomarkers for the identification and prediction of stroke in virally suppressed PWH. We will test the hypothesis that imperfect ART adherence sufficient to suppress HIV viral loads to <200 copies/mL is insufficient to control viremia below this threshold, and is associated with inflammation leading to stroke.

项目摘要 抗逆转录病毒疗法（ART）极大地改变了艾滋病毒（PWH）患者的健康状况。较新 具有更健壮病毒抑制的艺术方案可能会使互补的粘合性依从性，以使其粘附不完善 实现抑制病毒负载的宽恕是目的地不完美的依从性。反过来，不完美 依从性可能导致临床上与临床相关的抑制阈值以下的病毒复制，驱动 炎症和过早衰老。累积数据表明潜在的炎症强烈贡献 通过研究 与没有艾滋病毒的人相比，显示出重大NCD，与HIV相关的中风的风险增加了2倍。 艾滋病毒相关的中风与主要死亡率，发病率和医疗保健经济负担有关。 目前的调查人员发现，南非PWH的中风患病率为6.2％，病毒载荷受到抑制 与没有艾滋病毒的人相比。 PWH年轻了将近10岁，传统的心血管风险较小 因素，主要是女性，dospite实际上被抑制至200份/ml。另外，艾滋病毒 在马拉维的病例对照研究中，发现是年轻中风（≤45岁）的主要风险因素 222 PWH和503种急性中风的人群对照，调整后的比值比为5.57（2.43-12.8）。 但是，这些研究都没有研究不完善的粘附作为中风的危险因素。 研究艺术成功的研究主要集中于完美或近乎完美的依从性策略 为了抑制HIV病毒载荷至低于临床上的阈值，目前定义为<200份/mL。在临床上 但是，通过南非和乌干达的一项研究，练习通常是不完美的，这是不完美的 表明大多数参与者被归类为几乎被抑制，遵守几个 PWH的类别很差。这是对64名几乎被压制的参与者的研究证实的，其中47％ 在前两个月的93％的情况下，已经检测到0-50份/ml目的地依从率之间的病毒血症 （82％-98％）使用未宣布的药丸计数。其他人则表明，细胞内替诺福韦浓度较低 干血点（DBS）上的双磷酸（TFV-DP），这是一种客观的药物浓度生物标志物，指示 在前8周内累积依从性与病毒血症的几率高2倍 20-200副本/毫升。 调查用中风的病毒抑制PWH中不完美的艺术依从性提供了机会 对潜在可修改因素的新见解，以减少中风。这项探索性研究将获得重要的 关于中风与艺术依从性之间关联的初步数据，以及新的测试方法 候选蛋白质组学生物标志物，用于鉴定和预测病毒抑制的PWH中的中风。我们将 检验以下假设：不完美的艺术依从性足以抑制HIV病毒载荷至<200份/ml 不足以控制该阈值以下的病毒血症，并且与导致中风的炎症有关。