Planning grant for CMV suppression to reduce mortality in hospitalized, HIV-exposed children

摘要 越来越多的证据表明，在严重疾病期间检测巨细胞病毒(CMV)病毒血症可能 确定结果不佳的高风险个体的子集。巨细胞病毒感染与病毒血症的关系 在美国和欧洲，有免疫能力的成年人在重症监护病房中被发现死亡，在 在肯尼亚住院的艾滋病毒携带者儿童(CLHIV)和暴露于艾滋病毒的未感染儿童(HEU)。在中国的一次审判 HIV阴性的患有严重脓毒症的成年人发现，随机接受更昔洛韦预防可降低 CMV重新激活和减少对氧的依赖，表明CMV之间存在潜在的因果联系 复制和结果。总之，这些数据表明抑制CMV病毒血症可能会改善患者的预后 重病患者，我们的目标是在HIV暴露(CLHIV和 HEU)肯尼亚儿童，巨细胞病毒流行率接近100%，重症住院死亡率 儿童约占30%。拟议的试验将招募患有CMV病毒血症1000IU/ml的24个月大的儿童， 并将随机安排儿童接受标准护理或抗病毒治疗，以抑制CMV病毒血症。 主要终点是6个月的全因死亡率、中性粒细胞减少的风险和死亡的综合结果。 或在15天后继续住院。肺和肠道损伤的临床和血液生物标志物，以及 病理研究将告知干预效果的机制。 这项建议汇集了一个由临床和科学专家组成的国际团队，以开发一种随机的 该试验将确定使用抗病毒疗法抑制CMV病毒血症是否安全并减少 高度脆弱儿童的死亡率和其他有害后果。这个规划期将是最好的 让团队和现场做好准备，以实施拟议的随机对照试验。在目标1中，我们将最终确定协议和所有研究 工具，包括统计分析和数据管理计划、数据安全和监测计划 数据安全和监测委员会(DSMB)和章程、招聘和同意的发展 材料、病例报告表(CRF)和临床试验的详细拨款建议预算。在《目标2》中我们将 召集研究人员、临床和科学顾问以及主要政府和社区 利益攸关方，并制定多地点试验协调和结果的角色和责任计划 传播。在目标3中，我们将最后确定《操作手册》(MOP)，并准备实施 临床试验方案。如果干预被发现是安全和有效的，合作团队是理想的 准备与肯尼亚设施和政策制定者合作，制定进一步的试验和/或扩大干预规模。

ABSTRACT Increasing evidence suggests the detection of cytomegalovirus (CMV) viremia during serious illness may identify a subset of individuals at elevated risk for poor outcomes. Associations between CMV viremia and mortality have been found in immunocompetent adults admitted to intensive care in the US and Europe, and in children living with HIV (CLHIV) and HIV-exposed uninfected (HEU) children hospitalized in Kenya. A trial in HIV-negative adults with severe sepsis found that randomization to ganciclovir prophylaxis reduced the risk of CMV reactivation and decreased oxygen dependency, suggesting a potential causal link between CMV replication and outcomes. Together these data suggest suppression of CMV viremia may improve outcomes in severely ill patients, and our goal is to conduct a randomized controlled trial (RCT) in HIV-exposed (CLHIV and HEU) children in Kenya, where CMV prevalence nears 100% and inpatient mortality rates for severely ill children are ~30%. The proposed trial will enroll children aged <24 months, with CMV viremia >1000 IU/ml, and will randomize children to receive either standard of care or antiviral therapy to suppress CMV viremia. Primary endpoints will be 6-month all-cause mortality, risk of neutropenia, and the combined outcome of death or continued hospitalization at 15 days. Clinical and blood biomarkers of lung and intestinal injury, and pathological investigations will inform mechanisms of intervention efficacy. This proposal brings together an international team of clinical and scientific experts to develop a randomized trial which will determine whether suppression of CMV viremia using antiviral therapy is safe and reduces mortality and other deleterious outcomes in highly vulnerable children. This Planning Period will optimally prepare the team and sites to conduct the proposed RCT. In Aim 1 we will finalize the protocol and all study instruments, including the statistical analysis and data management plans, data safety and monitoring plan (DSMP), data safety and monitoring board (DSMB) and charter, development of recruitment and consent materials, case report forms (CRFs), and a detailed grant proposal budget for the clinical trial. In Aim 2 we will convene the study investigators, clinical and scientific advisors and key government and community stakeholders, and to develop a roles and responsibilities plan for multisite trial coordination and results dissemination. In Aim 3 we will finalize the Manual of Operations (MOP) and prepare the sites to implement the clinical trial protocol. If the intervention is found to be safe and effective, the collaborative team is ideally poised to work with Kenyan facilities and policymakers to develop further trials and/or scale the intervention.