Central nervous system (CNS) complications continue to occur among adults aging with HIV. For example, neurocognitive impairment occurs in 30-50% of persons with HIV (PWH). With advancing age, cognitive and mood disorders such as depression increase in frequency and in severity. While research to date has focused on the biological mechanisms associated with the aging of the CNS (e.g., amyloid-related pathology), few studies have focused on aging and prescribed, potentially neurotoxic drugs influence the effects of HIV and antiretroviral therapy (ART) on cognition and depression. Studies of neurotoxicity of ART drugs and prescribed drugs in older PWH have largely been limited by small sample sizes, suboptimal neurocognitive characterization, and relatively short follow-up. This proposal will address these limitations by using data and specimens from nearly 20,000 comprehensive medical and neurobehavioral assessments collected over more than 20 years. CNS complications, such as neurocognitive impairment and major depression disorder, are a key area for multidisciplinary studies of HIV and aging in order to characterize the interactions between HIV, comorbid diseases, and their treatment and to gain insights into the pathogenesis of these complications that may inform therapeutics. The overarching hypothesis is that prescribed drug-related neurotoxicity increasingly contributes to the incidence and persistence of CNS complications in PWH as they age. To address this, the proposed project is organized into three aims: 1) Determine how age and concomitantly prescribed drugs modify the relationships between ART drugs and neurocognitive performance or depression using a longitudinal database of more than 20,000 comprehensive assessments and advanced analytical methods; 2) Determine how age and concomitantly prescribed drugs modify the dose-effect relationships between ART drugs and NC performance and depression using physiologically-based pharmacokinetic modeling; and 3) Explore the mechanisms by which concomitant drugs modify ART neurotoxicity using a novel high-throughput, inducible human pluripotent stem cell culture method and extracellular vesicle characterization. The completion of this proposal will provide valuable data on how aging interacts with prescribed drugs to increase the risk of ART neurotoxicity and CNS complications. The results may also inform future interventions to prevent and treat CNS complications in older PWH.

Public Health Relevance

Polypharmacy is an increasingly common problem among aging persons with HIV (PWH), particularly since it could worsen toxicity from antiretroviral therapy and the adverse effects of comorbid diseases. This application proposes to systematically evaluate the influence of aging and concomitant drugs on ART neurotoxicity and its effects on cognition and depression and to explore the molecular and cellular mechanisms. The identification and validation of pharmacological factors affecting ART neurotoxicity, cognition, and depression would have substantial public health relevance and could support early intervention and treatment optimization.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG063659-02
Application #
10149896
Study Section
HIV Comorbidities and Clinical Studies Study Section (HCCS)
Program Officer
Mackiewicz, Miroslaw
Project Start
2020-05-01
Project End
2025-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228