Older age is associated with higher antiretroviral concentrations in cerebrospinal fluid in HIV-infected individuals.

Type: Poster
Title: Older age is associated with higher antiretroviral concentrations in cerebrospinal fluid in HIV-infected individuals.
Authors: Croteau D, Letendre S, Best B, Clifford D, Gelman B, Marra C, McArthur J, McCutchan JA, Simpson D, Grant I
Date: 03-05-2012
Abstract:Background: Nearly 25% of HIV-infected individuals in the US are currently over age 50 and HIV prevalence rate in this age group is expected to double by 2015. Age-related systemic and central nervous system (CNS) changes have the potential to result in greater CNS exposure to antiretrovirals (ARVs), which has remained largely unexplored. Methods: HIV-infected individuals were selected based on having had ARV concentrations previously measured in blood plasma and cerebrospinal fluid (CSF) by LC/MS/MS. The analysis targeted 3 drugs (tenofovir, efavirenz, and atazanavir), one from each of the traditional ARV classes. Subjects with undetectable drug concentrations in plasma were excluded. Univariable and multivariable methods, including generalized additive models (GAM), were used to evaluate associations with age. Neurocognitive functioning (NCF) was determined using standardized comprehensive testing and summarized by the global deficit score. A decision tree approach (CART) was used to explore non-linear relationships between ARV concentrations and NCF. For each of the plasma and CSF drug concentrations, cut-offs that achieved optimum NCF classifications were derived. Results: 204 HIV-infected individuals (including 36 contributing samples for 2 ARV) provided CSF (n=162) and plasma (n=230) specimens. Tenofovir CSF (n=44) concentrations increased more steeply with age than plasma (n=44). Efavirenz concentrations increased markedly in CSF (n=66) in subjects older than 55 with a less steep and steadier increase with age for plasma (n=77) concentrations. Plasma (n=109) atazanavir concentrations slightly declined with age while CSF (n=58) concentrations remained stable, suggesting a relative increase in CSF with age based on CSF/plasma ratio increase. Non-linear relationships between ARV CSF concentrations and NCF were observed. CART analysis revealed that the group with intermediate ARV concentrations had the best NCF. Conclusions: The effect of aging on ARV exposure in the CNS varies by drug. In general, older age was associated with greater ARV exposure in the CNS. Lower ARV concentrations were associated with worse NCF, which may be due to suboptimal virologic control. Higher ARV concentrations were also associated with worse NCF, which may indicate drug neurotoxicity. More data in older HIV-infected individual are needed to validate these findings.