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 nave 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. !
More than a fifth of children diagnosed with HIV in hospital die within 6 months of admission. Cytomegalovirus (CMV) and other co-infections may contribute to this high mortality rate, and treatment or prophylaxis may provide an interventional strategy to reduce mortality. The proposed study will utilize blood specimens and data collected as part of a recently completed clinical trial in Kenya to evaluate the association between CMV viremia and survival, response to antiretroviral therapy, and inflammation in critically ill children.
