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

• 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
• 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

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. !

在疾病晚期被诊断出感染艾滋病毒的非洲儿童的死亡率往往超过20%， 迫切需要新的策略来改善其预后。巨细胞病毒（CMV）感染，以及 血浆CMV病毒载量是加速HIV进展的危险因素。此外，CMV再激活发生 在多达三分之一的非免疫抑制重症患者中，与死亡率相关。CMV病毒血症 可能通过终末器官疾病、急性肺损伤、增强的 炎症反应和免疫调节。我们建议在一组儿童中研究CMV病毒血症 被诊断为艾滋病毒感染，而病情危重。我们的目的是确定CMV病毒血症对 死亡率和住院时间（目标1），抗逆转录病毒治疗开始后的反应（目标2），以及 免疫激活和炎症（目的3）。我们假设CMV病毒血症将影响约50%的儿童， 与死亡率、ART后免疫恢复受损和免疫激活升高相关， 炎症结果将告知是否在该人群中进行CMV抑制的干预性试验， 并将告知试验研究设计。 这项研究将使用来自181名肯尼亚重症患者的存档标本和数据进行 参加儿科紧急开始HAART（PUSH）研究的儿童。年，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），并纵向随访系列血浆和PBMC 保存超过24周的标本。我们将使用定量PCR来评估CMV DNA水平，并确定 CMV病毒血症的患病率和持续时间。多变量回归模型将用于评估 CMV病毒血症与临床结局（15天死亡率或继续住院）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） 同时控制艾滋病病毒感染阶段。通过定义CMV病毒血症、ART 反应炎症和死亡率之间的严重疾病的艾滋病毒感染的儿童，我们的研究可以提供 将CMV预防试验作为一种策略来降低这种疾病的高死亡率的基本原理， 人口 !