Combination antiretroviral therapy (cART) has changed the natural history of HIV infection, a remarkable achievement that allows those individuals that can tolerate and are compliant with the regimen a survival rate that is getting closer to those that are not infected. However, despite this great success, cART has not eliminated HIV-associated neurocognitive disorders (HAND). Because HAND is progressive even in those taking cART, it has been suggested that the residual viral replication may be sufficient to maintain an inflammatory response that leads to neuronal injury. Thus better CNS penetrating agents should be useful. However, several reports suggest that cART itself may be neurotoxic and at least in part responsible for the persistence and progression of cognitive impairment. Adding to this scenario is the increased survival of HIV infected individuals which it means that the HIV infected population is getting older and the interaction cART- aging may be synergistic in terms of CNS injury. Defining the potential central nervous system (CNS) toxicity associated with cART exposure and its interaction with aging, will create the bases for changing current practices such as adjusting cART doses, especially in the elderly who may be more vulnerable to cART effect and investigating the best combinations of ART with least CNS toxicity. Findings from this research would also provide impetus to develop new drugs with a better CNS profile. Therefore, the primary aim of this proposal is to determine whether chronic exposure to cART alters brain structure and function and whether this differs in young versus older HIV infected individuals. The primary hypothesis is that chronic exposure to cART will affect neural function, as assessed by decreased resting cerebral blood flow (measured by arterial spin labeling) and alter white matter integrity as assessed by diffusion tensor imaging metrics [decreased fractional anisotropy (FA) and increased mean diffusivity (MD)]. These effects on brain structure and function will be more pronounced in older as compared to younger HIV infected subjects because the impact of cART on cellular energy homeostasis is expected to be greater in older vs. younger subjects. We have chosen changes in these neuroimaging biomarkers as primary outcomes of CNS injury because of their sensitivity although measurements of cognitive performance will be used as secondary outcomes. To investigate the interaction cART-aging and to estimate the contribution of HIV infection in subjects on stable cART and well controlled viral replication, we propose to establish a cohort of younger (40 subjects <50 years of age) and older (40 subjects e 50 years of age) ART naive subjects starting cART. These subjects will be age-matched to HIV- controls. An additional 30 HIV infected long-term non progressors will be enrolled to measure the effect of residual HIV replication on the brain in the absence of cART. It is expected that it will take 24-30 months to enroll the subjects who will then be followed for two years. Previous neuroimaging studies suggest observable changes within two years thus cART neurotoxicity, should be measurable within the two-year follow-up.

Public Health Relevance

Over a million people are thought to be HIV infected in the US. The availability of effective antiretroviral drugs has greatly enhanced the survival rate of HI infected individuals which is getting closer to the survival rate of those that are not infected. I is projected that by 2015 more than half of all HIV+ individuals in the U.S. will be over the age of 50. However, aging is associated with an increased risk of neurological disorders and there are significant concerns that chronic exposure to antiretroviral drugs may synergize with the aging process leading to brain injury and ultimately to poor mental health. The aims of this study are to investigate this interaction so that more individualized treatment regimens can be developed.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH099921-02
Application #
8652502
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Colosi, Deborah
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
School of Medicine & Dentistry
DUNS #
City
Rochester
State
NY
Country
United States
Zip Code
14627