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.

项目概要 抗逆转录病毒治疗 (ART) 极大地改变了艾滋病毒感染者 (PWH) 的健康状况。 具有更强大病毒抑制作用的 ART 治疗方案可能会导致人们因不完美的依从性而自满，因为 尽管依从性不理想，但仍能实现抑制病毒载量的治疗方案宽恕。 坚持可能导致病毒持续复制低于临床相关抑制阈值，从而驱动 越来越多的数据表明，潜在的炎症对炎症和过早衰老有很大影响。 研究显示尽管病毒受到抑制，感染者仍继续患上非传染性疾病 (NCD) 与未感染艾滋病毒的人相比，患非传染性疾病、艾滋病毒相关中风的风险增加了两倍。 HIV 相关中风与重大死亡率、发病率和医疗保健经济负担相关。 目前的研究人员发现，在病毒载量受到抑制的南非感染者中，中风患病率为 6.2% 与未感染艾滋病毒的人相比，感染者的年龄几乎要年轻 10 岁，传统的心血管风险也较低。 尽管HIV病毒被抑制到<200拷贝/mL，但主要是女性。 马拉维的一项病例对照研究发现，青少年卒中（≤45 岁）的主要危险因素 222 名 PWH 和 503 名患有急性卒中的人群对照，调整后的比值比为 5.57 (2.43-12.8)。 然而，这些研究都没有将不完美的依从性视为中风的危险因素。 关于 ART 治疗成功的研究主要集中于完美或近乎完美的依从策略 将 HIV 病毒载量抑制至临床相关阈值以下，目前临床定义为 <200 拷贝/mL。 然而，根据南非和乌干达的一项队列研究，实践中对 A​​RT 的坚持往往并不完美 表明尽管大多数被归类为病毒抑制，但几个人的依从性 一项针对 64 名病毒抑制参与者的研究证实了这一点，其中 47% 的参与者的病毒水平受到抑制。 尽管前两个月的依从率为 93%，但可检测到的病毒血症在 0-50 拷贝/mL 之间 (82%-98%) 使用未公布的药丸计数表明细胞内替诺福韦浓度较低。 干血斑 (DBS) 上的二磷酸盐 (TFV-DP) 是一种客观药物浓度生物标志物，表明 过去 8 周的累积依从性与 2 倍高的病毒血症几率相关 20-200 拷贝/mL。 研究病毒抑制的中风患者 ART 依从性的不完美提供了一个机会 这项探索性研究将获得对减少中风的潜在可改变因素的新见解。 关于中风与 ART 依从性之间关联的初步数据以及新的测试方法 用于识别和预测病毒抑制的感染者中风的候选蛋白质组生物标志物。 检验以下假设：不完美的 ART 依从性足以将 HIV 病毒载量抑制至 <200 拷贝/mL 不足以将病毒血症控制在该阈值以下，并且与导致中风的炎症有关。