Impact of Treating Asymptomatic CMV Replication on Cardiovascular Risk in Treated HIV Infection

治疗无症状 CMV 复制对 HIV 感染治疗者心血管风险的影响

基本信息

批准号：
10449260
负责人：
PETER W HUNT
金额：
$ 72.61万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449260
关键词：
AIDS clinical trial group Address Aging Antiviral Agents Aortitis Atherosclerosis Bioinformatics Biological Biological Assay Biological Markers Blood Vessels CD8-Positive T-Lymphocytes Cancer Patient Cardiology Cardiovascular system Clinical Clinical Trials Clinical Trials Design Clinical Trials Network Coagulation Process Collaborations Controlled Clinical Trials Cytomegalovirus Development Disease Endothelial Cells Endothelin-1 Endothelium Event Foundations Funding Future Ganciclovir General Population Genital Genitalia HIV HIV Infections Heart Transplantation Hematopoietic Stem Cell Transplantation Herpesviridae Human Immunocompromised Host Immunoglobulin G In Vitro Incidence Inflammation Inflammatory Infrastructure Intervention Longterm Follow-up Mediating Mediator of activation protein Modernization Morbidity - disease rate Mucous Membrane Myocardial Infarction Organ Outcome P-Selectin PET/CT scan Participant Pathogenesis Pathway Analysis Pathway interactions Persons Pharmaceutical Preparations Placebo Control Placebos Plasma Play Proteins Proteome Proteomics Recording of previous events Recovery Risk Risk Factors Role Sampling Smooth Muscle Myocytes Solid Stroke Surrogate Markers Symptoms T-Lymphocyte TNF gene Testing Therapeutic Clinical Trial Thrombosis Time Toxic effect Transplant Recipients Valganciclovir Vascular Diseases Vascular Endothelium Viral X-Ray Computed Tomography antiretroviral therapy aptamer atherogenesis atherosclerosis risk base cardiovascular disorder risk cardiovascular effects cardiovascular risk factor co-infection differential expression endothelial dysfunction experience fluorodeoxyglucose positron emission tomography heart disease risk immune activation inflammatory marker inhibitor macrophage monocyte multimodality novel organ transplant recipient phase III trial placebo controlled trial post-transplant atherosclerosis prevent proteomic signature seropositive systemic inflammatory response terminase treatment effect vascular inflammation

项目摘要

PROJECT SUMMARY Despite modern antiretroviral therapy (ART), people living with HIV (PLWH) have an approximately 50% increased risk of cardiovascular disease. While persistent systemic inflammation appears to predict this risk, the optimal strategies to reduce inflammation and cardiovascular risk in treated HIV infection remain undefined. The overarching hypothesis of this proposal is that asymptomatic cytomegalovirus (CMV) replication is an important mediator of cardiovascular risk in treated HIV infection. This hypothesis is supported by the fact that CMV replicates in vascular endothelium and appears to play a role in atherosclerosis in immunocompromised solid-organ transplant recipients. Furthermore, over 90% of PLWH have asymptomatic CMV co-infection, CMV shedding levels are higher in treated PLWH than in the general population, surrogate markers of CMV are associated with vascular disease and myocardial infarction risk in treated HIV, and treating asymptomatic CMV replication in an earlier trial reduced the inflammatory pathways (i.e., sTNFR2) that most strongly predict vascular disease in treated HIV. Yet, no study has assessed whether treating asymptomatic CMV replication in treated PLWH reduces vascular inflammation and markers of endothelial dysfunction. Our proposal addresses these issues by leveraging a separately funded placebo-controlled clinical trial led by Dr. Hunt of the novel CMV terminase inhibitor letermovir in 180 ART-suppressed PLWH in the ACTG (A5383). Aim 1 will determine whether 48 weeks of letermovir reduces vascular inflammation as assessed by FDG-PET/CT in a subset of 92 participants. Aim 2 will assess whether letermovir reduces plasma markers of endothelial dysfunction and Aim 3 will characterize the plasma proteomic signatures that are altered by letermovir therapy using a modified aptamer assay and relate these changes to concurrent changes in vascular inflammation. These studies also benefit from a strong MPI team with complementary expertise and a long history of collaboration including Drs. Hunt (HIV immunopathogenesis, clinical trials), Tawakol (cardiology, FDG-PET/CT imaging), and Hsue (HIV cardiology, clinical trials); a team of co-Is with proteomics and bioinformatics expertise (Drs. Ganz and Olshen); and the largest HIV therapeutics clinical trials network in the world (ACTG). Collectively, these studies will test for the first time treated HIV infection – and more broadly in humans - a potential causal role of asymptomatic CMV replication in vascular disease in the context of a rigorously designed clinical trial. If successful, this study could help motivate a future Phase 3 trial of letermovir to reduce cardiovascular events among other complications in treated HIV infection.

项目概要尽管采用现代抗逆转录病毒疗法 (ART)，但艾滋病毒感染者 (PLWH) 的感染率仍高达 50% 虽然持续的全身炎症似乎预示着这种风险，在治疗艾滋病毒感染时减少炎症和心血管风险的最佳策略仍不清楚。该提案的总体假设是无症状巨细胞病毒（CMV）复制是一种这一假设得到以下事实的支持： CMV 在血管内皮细胞中复制，似乎在免疫功能低下的动脉粥样硬化中发挥作用此外，超过 90% 的 PLWH 患有无症状的 CMV 合并感染，即 CMV。接受治疗的 PLWH 的脱落水平高于一般人群，CMV 的替代标志物是与接受治疗的 HIV 患者的血管疾病和心肌梗死风险相关，以及治疗无症状的 CMV 早期试验中的复制减少了最有力预测的炎症途径（即 sTNFR2）然而，尚无研究评估是否可以治疗无症状 CMV 复制。在 PLWH 中，可减少治疗后的血管炎症和内皮功能障碍的标志物。通过利用由 Hunt 博士领导的单独资助的安慰剂对照临床试验来解决这些问题新型 CMV 终止酶抑制剂莱特莫韦用于 ACTG 中 180 名 ART 抑制的 PLWH（A5383）。确定 48 周的莱特莫韦是否可以减轻血管炎症（通过 FDG-PET/CT 评估）目标 2 将评估莱特莫韦是否会降低内皮细胞的血浆标记物。功能障碍和 Aim 3 将表征莱特莫韦治疗改变的血浆蛋白质组学特征使用改良的适体测定并将这些变化与血管炎症的并发变化联系起来。这些研究还受益于强大的 MPI 团队，他们具有互补的专业知识和悠久的历史合作包括 Hunt 博士（HIV 免疫发病机制、临床试验）、Tawakol（心脏病学、FDG-PET/CT）成像）和 Hsue（HIV 心脏病学、临床试验）；专业知识（Ganz 博士和 Olshen 博士）；以及世界上最大的 HIV 治疗临床试验网络 (ACTG)。总的来说，这些研究将首次测试经过治疗的艾滋病毒感染——更广泛地在人类中—— 在严格的背景下，无症状巨细胞病毒复制在血管疾病中的潜在因果作用如果成功，这项研究可能有助于推动莱特莫韦未来的 3 期试验，以减少治疗艾滋病毒感染的心血管事件和其他并发症。