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.

项目摘要尽管现代的抗逆转录病毒疗法（ART），患有艾滋病毒（PLWH）的人约有50％心血管疾病的风险增加。虽然持续性的全身感染似乎可以预测这种风险，但降低治疗的HIV感染中感染和心血管风险的最佳策略仍然不确定。该提议的总体假设是不对称的巨细胞病毒（CMV）复制是一种治疗的HIV感染中心血管风险的重要介质。这个假设得到了以下事实的支持 CMV在血管内皮中复制，似乎在动脉粥样硬化中起作用。固体器官移植受者。此外，超过90％的PLWH具有无症状CMV共同感染，CMV 治疗的PLWH的脱落水平高于一般人群，CMV的替代标记为与治疗的HIV中的血管疾病和心肌梗死风险有关，并治疗无症状CMV 在较早的试验中复制减少了最强烈预测的炎症途径（即STNFR2）治疗的艾滋病毒中的血管疾病。但是，尚无研究评估是否治疗无症状的CMV复制在处理过的PLWH中，可减少内皮功能障碍的血管感染和标记。我们的建议通过利用由亨特博士领导的单独资助的安慰剂控制的临床试验来解决这些问题 ACTG中180个抑制Art抑制的PLWH的新型CMV末端抑制剂Lettermovir（A5383）。目标1意志确定48周的LETEROMOVIR是否减少了FDG-PET/CT评估的血管感染 92名参与者的子集。 AIM 2将评估LETEROMOVIR是否会减少内皮的血浆标记功能障碍和AIM 3将表征Leteromovir Therapy改变的血浆蛋白质组学特征使用改良的APATMER分析，并将这些变化与血管炎症的并发变化相关联。这些研究还受益于拥有完善专业知识和悠久历史的强大MPI团队合作包括Drs。亨特（HIV免疫病发生，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）；由蛋白质组学和生物信息学的组成的团队专业知识（Ganz和Olshen博士）；以及世界上最大的艾滋病毒疗法临床试验网络（ACTG）。总的来说，这些研究将首次检验的艾滋病毒感染，更广泛地在人类中 - 在严格的背景下，无症状CMV复制在血管疾病中的潜在因果作用设计临床试验。如果成功，这项研究可能有助于激励Leteromovir的未来3阶段试验以减少心血管事件以及治疗的HIV感染的其他并发症。