Nithya Srinivas
As of the year 2015, 36.7 million people worldwide were living with HIV infection. While the introduction of highly active antiretroviral therapy (HAART) has greatly reduced the morbidity and mortality of HIV infection, there is still no cure for this disease. In the central nervous system (CNS), HIV RNA in the cerebrospinal fluid (CSF) has been found even in patients who otherwise have viral suppression in the plasma. Further, HIV infection in the brain may lead to the development of
more » ... opment of HIV-associated neurocognitive disorders (HAND). Milder forms of cognitive decline in HAND remain highly prevalent in people taking HAART and this may be a function of ineffective antiretroviral (ARV) distribution in the brain tissue. However, existing methods only measure ARV pharmacokinetics (PK) in the CSF and are insufficient to explain brain distribution of ARVs. Therefore, the goal of this project was to conduct a comprehensive analysis of ARV penetration into the brain tissue in preclinical models, evaluate the role of drug transporters in modulating ARV brain tissue disposition across species, and develop a model to predict disposition of one ARV (efavirenz [EFV]) in human brain tissue using PK data from preclinical models and determine the relationship between model-predicted drug exposure in the brain and neurocognitive impairment in a cohort of HIV-positive participants. In the first aim of the study, the brain tissue concentration and brain tissue:plasma penetration ratio of six ARVs were determined across two humanized mouse models and one nonhuman primate (NHP) model by LC-MS/MS. ARV brain tissue:plasma concentrations were only preserved across all three species for raltegravir, and showed no differences based on infection status or sex (in the NHPs). In the NHPs, ARV concentrations in the CSF were >6-fold lower than brain tissue. The CSF concentrations were poorly predictive of the brain tissue concentrations for all ARVs except EFV (r=0.91, p<0.001). Mass-spectrometry imaging could only detect EFV distribution [...]
doi:10.17615/17px-yx97 fatcat:czrxewvnw5be3iyomatcnuqbp4