This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This study is a prospective cohort study comparing memory and executive functioning in two groups of youth, age 9 years to 19 years at study entry: one group will be youth with perinatally acquired Human Immunodeficiency Virus (HIV)-1 infection and the other group will be perinatally HIV-1 exposed but uninfected youth. All youth enrolled will be currently participating in PHACS AMP. At least 275 evaluable participants (200 HIV-1 infected participants and 75 HIV-1 exposed, uninfected participants) will be enrolled. Participants will be followed for two years and will receive study evaluations within six months of initiation of their AMP 2.5 and 4.5 year study visits. The improved survival of children infected perinatally with HIV, and the aging of the cohort into adulthood, raises clinical and public health issues related to their ability to assume productive independent lives as adults. Existing literature suggests that these youth may have developmental cognitive deficits that have the potential to affect their day-to-day functioning. In adults with HIV, impairments in memory, particularly prospective memory (ProM), and executive functioning (EF) are among the most significant predictors of poor functional outcomes. We hypothesize that children and youth with perinatally-acquired HIV will experience similar effects. In fact, children and adolescents, who are in the process of learning both academic and nonacademic skills, and at a time of rapid change in EF, may show an even greater impact of memory and EF deficits on everyday living than adults, who usually have acquired basic life skills. Understanding the impact on academic functioning, a primary task of adolescence and critical for adult success, is particularly important. To date, no well-controlled studies of perinatally infected children or youth have included comprehensive assessments of retrospective memory or EF, or any measures of ProM. Furthermore, the studies that have assessed memory or EF have not examined their association with academic or adaptive outcomes or medication adherence. The purpose of this study is to fill this significant gap in our knowledge by examining retrospective memory, ProM and EF in a large, well-characterized sample of perinatally infected children and adolescents and matched controls age 9 years to 19 years at study entry. The study goals include an evaluation of the presence and pattern of memory and EF deficits in HIV-infected children compared to controls and their relationship with HIV disease severity, the interrelationship of change in these functions with normal development and changes in disease severity, and whether memory and EF predict medication nonadherence and academic or adaptive problems. Well-standardized measures of memory and EF will be used, and two measures of ProM will be included, one previously used with children and one an adaptation for children of an adult measure of ProM with known associations with HIV. In addition to focusing on functional domains about which we have limited information for this population, the study will represent the first longitudinal research in this area. This will allow us to begin to disentangle developmental and HIV-related changes, both disease progression and improvement with treatment. The linkage of this protocol with PHACS AMP enables us to examine and control for important covariates and to conduct exploratory analyses without additional expense and with minimal burden for research participants. Detailed medication information maintained by PHACS may also allow exploratory examination of changes related to specific drug classes, including CNS penetrance, if sufficient variability in regimens exists in our sample. We anticipate that the study will not only elucidate the developmental cognitive impact of perinatally acquired HIV infection but also will have implications for predicting poor functional outcomes in perinatally infected youth as they approach adulthood. Both memory and EF domains are critically involved in performance of daily activities and in achieving academic and occupational competence. Thus, the study has the potential to have significance for evaluation of infected youth and support the inclusion of memory and EF testing in neuropsychological assessments as standard of care for this population. It would enable care providers and schools to target intervention resources more effectively towards youth with cognitive deficits. The research findings would also set the stage for future studies in the areas of cognitive and adherence intervention, prediction of increased risk behaviors, and central nervous system effects of perinatal HIV by further clarifying developmental patterns of retrospective and ProM and EF associated with the disease. Finally, the study has the potential to contribute an innovative measure of ProM to the pediatric literature. All participants in the study will be monitored from the time of the consent until the final study visit is completed. Untoward effects identified as 1) those related to the participant including social harms, psychological distress, and serious life threatening events such as suicide attempts, 2) those related to the study staff, and (3) those related to the neighborhood/community, if applicable, will be monitored. All untoward effects will be addressed, evaluated, and guidance provided to minimize similar risks in others.
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