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Cerebrospinal Fluid Concentrations of Key Antiretrovirals Increase With Age
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19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle
Mark Mascolini
Concentrations of tenofovir and efavirenz rose more sharply with age in cerebrospinal fluid (CSF) than in blood in a CHARTER cohort study of 259 people with a median age in the mid-40s [1]. Atazanavir levels remained stable with age in CSF while falling in plasma.
As people 50 and older account for a swelling proportion of HIV populations worldwide, concern grows over the impact of age-related structural and functional changes on antiretroviral concentrations in CSF and blood plasma. CHARTER Study researchers hypothesized that antiretroviral concentrations in CSF and plasma will increase with age and that these increases will be greater in CSF than plasma.
The study involved 259 people who had stored CSF and/or plasma samples and were taking tenofovir, efavirenz, atazanavir, fosamprenavir, or lopinavir. The investigators excluded people with drug levels below the limit of quantitation and people who reported poor adherence. For the whole study group, median age stood at 44 years (interquartile range [IQR] 38 to 48), 78% were men, and 43% Caucasian. Median HIV duration was 11 years (IQR 7 to 16), and current and nadir CD4 medians were 421 (IQR 246 to 586) and 118 (IQR 22 to 200). While 58% of the study group had undetectable HIV RNA in plasma, 83% had an undetectable load in CSF.
Tenofovir concentrations rose more steeply with age in CSF than in plasma. Efavirenz levels rose sharply in CSF among people older than 55 and less steeply though more steadily with age in plasma. Atazanavir concentrations remained stable with age in CSF while declining slightly in plasma, results suggesting a relative increase in CSF with age. Lopinavir and fosamprenavir levels did not change significantly with age in either plasma or CSF. Ritonavir concentrations did not significantly affect atazanavir or fosamprenavir levels.
Multivariate analysis identified age as the most influential factor affecting antiretroviral concentration, though nadir CD4 count and duration of current regimen also had an impact. Including samples with drug levels below assay quantitation limits or samples from nonadherent people did not change these results.
Lower antiretroviral concentrations were associated with worse neurocognitive function, a finding that may reflect worse virologic control with lower drug levels. Higher antiretroviral concentrations were also associated with worse neurocognitive function, a result that may point to greater neurotoxicity with higher drug levels. People with intermediate antiretroviral concentrations had the best neurocognitive function.
The CHARTER team concluded that the impact of aging on antiretroviral penetration of the central nervous system (CNS) varies by drug class, though older age is generally associated with greater antiretroviral exposure in CNS.
Lack of an association between age and protease inhibitor concentrations suggested to these researchers that age-related changes of active efflux transporter expression or activity do not play a major role in determining concentrations.
Reference
1. Croteau D, Best B, Clifford D, et al. Older age is associated with higher ARV concentrations in CSF in HIV+ individuals. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 592.
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