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

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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.