Highly active antiretroviral therapy (HAART) has resulted in a marked rise in survival rates among HIV-infected persons. To what extent the brain compartment benefits from such treatment, particularly in the setting of advanced, even stable, disease, remains unclear. Recent studies suggest that cerebral injury and neurocognitive impairment can persist or unfold in the setting of HAART and stable disease. The frequency, spectrum and extent of neurological injury, its relationship to cognitive functioning and responsiveness to antiretroviral therapies thus remain important yet unresolved issues. The HIV MRS consortium has identified regional and cellular abnormalities specific to different stages of HIV-associated cognitive impairment (AIDS dementia complex, ADC) as well as an in vivo model of brain injury that suggests basal ganglia and neuronal events may be critical to the development of ADC. It has also identified potential host (e.g. age, plasma MCP-1, CSFIP-10, CSF fractalkine) and viral factors (CSF HIV RNA) at baseline that may increase the risk for neurocognitive impairment (NCI) or its further decline. This is a five-year multicenter longitudinal study of cerebral injury (as measured by MRS) and NCI in 310 HIV-positive subjects with a history of advanced immunosuppression (nadir CD4<100/mL) on HAART. The study will fill an important gap in the literature by implementing MRS in a prospective design in order to identify subjects at risk for NCI. We will examine the pattern and dynamics of regional injury by MRS among 250 neurologically asymptomatic (NA) and 60 ADC subjects. The majority of subjects will be enrolled from three well characterized existing prospective cohorts, including two ACTG studies (N= 210) and from the brain bank studies UCLA NNAB and UCSD CNTN (N= 100). Subjects will be stratified by CD4 count at entry, <200 or >200 cells/ml. The brain bank subjects will be further divided into virologically suppressed and nonsuppressed groups. The primary aims are: 1) to identify NA subjects at risk for brain injury as measured by MRS and examine host (e.g. age, chemokines) and viral factors (HIV RNA) at baseline that may increase the risk for subsequent neurological injury and NCI; 2) to determine whether the emergence of basal ganglia and neuronal factors predict the onset of NCI or its progression; 3) to examine dynamic relationships between neurologic function, biomarkers that reflect changing virologic and immunologic activity and changes in treatment. Multivariate longitudinal models and variable selection will be used to study the neurological effects of HIV infection as a dynamic system of interrelated factors. Detection of brain injury among NA subjects on HAART and at risk for ADC will have critical ramifications for overall health outcome and early therapeutic intervention.
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