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

项目摘要 抗逆转录病毒疗法（ART）极大地改变了艾滋病毒感染者（PWH）的健康状况。较新 具有更强的病毒抑制的ART方案可能允许自满蔓延，因为依从性不佳， 尽管依从性不佳，但宽恕方案仍能实现抑制病毒载量。反过来，不完美 依从性可能导致持续的病毒复制低于临床相关的抑制阈值， 炎症和过早衰老。越来越多的数据表明，潜在的炎症在很大程度上 尽管病毒受到抑制，但威尔斯亲王医院仍继续发展非传染性疾病， 显示出与没有艾滋病毒的人相比，显著的NCD，艾滋病毒相关中风的风险增加了2倍。 HIV相关卒中与主要死亡率、发病率和医疗保健经济负担相关。的 目前的研究人员发现，在南非病毒载量受到抑制的PWH患者中， 与没有艾滋病毒的人相比。PWH几乎年轻10岁，传统的心血管风险较低 尽管病毒抑制至<200拷贝/mL，但主要是女性。此外，艾滋病毒 在马拉维的一项病例对照研究中发现， 222例PWH和503例对照人群急性卒中，校正比值比为5.57（2.43-12.8）。 然而，这些研究中没有一项将不完全依从性作为中风的风险因素进行研究。 关于ART治疗成功的研究主要集中在完美或接近完美的坚持策略上 将HIV病毒载量抑制到临床相关阈值以下，目前定义为<200拷贝/mL。临床 然而，在实践中，对ART的坚持往往是不完美的，南非和乌干达的一项队列研究表明， 这表明，尽管大多数参与者被归类为病毒抑制， PWH的类别较差。这一点在一项对64名病毒抑制参与者的研究中得到了证实，其中47%的参与者都是病毒抑制者。 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/毫升之间 (82%-98%）使用未公布的药丸计数。其他研究表明，细胞内较低浓度的替诺福韦 干血斑（DBS）上的二磷酸盐（TFV-DP），一种客观的药物浓度生物标志物， 在前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。 研究病毒抑制性PWH伴卒中患者的不完善ART依从性， 对减少中风的潜在可变因素的新见解。这项探索性研究将获得重要的 关于中风和ART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病毒抑制PWH患者卒中的识别和预测。我们将 检验不完全ART依从性足以将HIV病毒载量抑制至<200拷贝/mL的假设 不足以控制低于该阈值的病毒血症，并且与导致中风的炎症有关。

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.