CMV viremia and mortality in hospitalized HIV-infected children

住院 HIV 感染儿童的 CMV 病毒血症和死亡率

基本信息

批准号：
9764423
负责人：
Jennifer Ann Slyker
金额：
$ 20.28万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764423
关键词：
Acute Acute Lung Injury Admission activity Adult Adverse event Affect Africa African Antiviral Agents Archives Blood specimen CD8-Positive T-Lymphocytes Cessation of life Child Childhood Clinical Clinical Trials Critical Illness Critically ill children Cytomegalovirus Cytomegalovirus Infections DNA Data Diagnosis Disease Eligibility Determination Enrollment Enzyme-Linked Immunosorbent Assay Flow Cytometry Frequencies Ganciclovir HIV HIV Infections Hematology Highly Active Antiretroviral Therapy Hospitalization Hospitals Immune Immune response Immunocompetent Immunologics Immunology procedure Immunosuppression Impairment Individual Infant Inflammation Inflammatory Response Interleukin-6 Intervention Intervention Studies Intervention Trial Kenya Laboratories Malnutrition Measures Modeling New Agents Organ Outcome Outcome Study Peripheral Blood Mononuclear Cell Plasma Pneumonia Population Prevalence Procedures Prophylactic treatment Randomized Clinical Trials Recovery Regimen Research Design Risk Factors Safety Sepsis Specimen T-Lymphocyte Therapy trial Valganciclovir Viral Viral Load result Viremia antiretroviral therapy clinical database co-infection cohort conventional therapy data warehouse high risk immune activation immunoregulation immunosuppressed improved improved outcome inflammatory marker insight mortality mortality risk novel strategies novel therapeutics outcome forecast pediatric human immunodeficiency virus reconstitution response senescence seropositive side effect therapy design treatment response trial design valacyclovir virology

项目摘要

African children diagnosed with HIV infection late in disease have a mortality rate often exceeding 20%, and there is an urgent need for novel strategies to improve their prognosis. Cytomegalovirus (CMV) infection, and plasma CMV viral load are risk factors for accelerated HIV progression. Additionally, CMV reactivation occurs in up to a third of critically ill non-immunosuppressed patients, and is associated with mortality. CMV viremia may contribute to poor outcomes in the critically ill through end organ disease, acute lung injury, augmented inflammatory responses, and immunomodulation. We propose to study CMV viremia in a cohort of children diagnosed with HIV infection while critically ill. Our aims are to determine the impact of CMV viremia on mortality and duration of hospitalization (Aim 1), response to antiretroviral therapy initiation (Aim 2), and Immune activation and inflammation (Aim 3). We hypothesize CMV viremia will affect ~50% of children and will be associated with mortality, impaired immunologic recovery post ART, and elevated immune activation and inflammation. Results will inform whether an interventional trial of CMV suppression in this population is warranted, and will inform trial study design. The study will be conducted using archived specimens and data from a cohort of 181 severely ill Kenyan children enrolled in the Pediatric Urgent Start of HAART (PUSH) Study. Children were diagnosed with HIV in hospital, started on antiretroviral therapy (ART), and followed longitudinally with serial plasma and PBMC specimens stored over 24 weeks. We will use quantitative PCR to assess CMV DNA levels and determine the prevalence and duration of CMV viremia. Multivariable regression models will be used to assess the relationship between CMV viremia and clinical outcome (mortality or continued hospitalization at 15 days), response to ART (change in HIV viral load, CD4 percent, and percentage of naïve T cells), and immunologic parameters (levels of plasma inflammatory markers and change in percentage of activated, senescent T cells) while controlling for HIV disease stage. By defining the relationships between CMV viremia, ART response inflammation, and mortality among severely ill HIV-infected children, our study may provide the rationale for a trial of CMV prophylaxis as a strategy to reduce the high mortality rate in this population. !

非洲儿童在疾病晚期被诊断出感染艾滋病毒，死亡率往往超过 20%，迫切需要新的策略来改善巨细胞病毒（CMV）感染的预后。血浆 CMV 病毒载量是加速 HIV 进展的危险因素。此外，还会发生 CMV 重新激活。高达三分之一的非免疫抑制危重患者患有巨细胞病毒病毒血症，并且与死亡率相关。可能会因终末器官疾病、急性肺损伤、增强我们建议在一组儿童中研究 CMV 病毒血症。在病情危重时被诊断出感染了 HIV，我们的目的是确定 CMV 病毒血症对患者的影响。死亡率和住院时间（目标 1）、抗逆转录病毒治疗启动反应（目标 2）以及免疫激活和炎症（目标 3）我们勇敢地面对 CMV 病毒血症将影响约 50% 的儿童。与死亡率、ART 后免疫恢复受损以及免疫激活升高相关结果将告知是否对该人群进行 CMV 抑制干预试验。是有保证的，并将为试验研究设计提供信息。该研究将使用来自 181 名重病肯尼亚人的存档标本和数据进行参加儿科紧急启动 HAART (PUSH) 研究的儿童儿童被诊断出感染艾滋病毒。医院，开始抗逆转录病毒治疗 (ART)，并使用系列血浆和 PBMC 进行纵向随访我们将使用定量 PCR 来评估 CMV DNA 水平并确定保存超过 24 周的样本。多变量回归模型将用于评估 CMV 病毒血症的患病率和持续时间。 CMV 病毒血症与临床结果（死亡率或 15 天持续住院治疗）之间的关系，对 ART 的反应（HIV 病毒载量、CD4 百分比和初始 T 细胞百分比的变化）和免疫学参数（血浆炎症标志物水平和活化、衰老 T 细胞百分比的变化）同时控制 HIV 疾病阶段通过定义 CMV 病毒血症与 ART 之间的关系。我们的研究可能会提供重病艾滋病毒感染儿童的炎症反应和死亡率试验 CMV 预防作为降低该地区高死亡率的策略的理由人口。！