Publication Abstract Display
Type: Published Abstract
Title: Darunavir concentrations in CSF exceed the median inhibitory concentration.
Authors: Letendre S, Rossi S, Best B, Way L, Ueland S, Grant I, Ellis RJ, Capparelli E, and the HNRC Group
Year: 2009
Publication: 49th Interscience Conference on Antimicrobial Agents & Chemotherapy
Volume: A1-1312 Issue: Pages: 45
Abstract:Background: HIV-associated neurocognitive disorders continue to be highly prevalent in domestic and international settings. Antiretrovirals (ARVs) that achieve higher concentrations in CSF are associated with better control of HIV and improved neuropsychological performance. The objective of this study was to measure darunavir (DRV) in CSF and compare the findings to concentrations in matched total and unbound concentrations in blood and in vitro inhibitory concentrations. Methods: 16 HIV-infected participants (pts) were evaluated at the UCSD HIV Neurobehavioral Research Center between May 2006 and February 2009 and were selected based on use of DRV-containing regimens and the availability of CSF and blood plasma stored at -70oC since collection. Total DRV was measured in 29 CSF and matched blood plasma specimens by HPLC (plasma) or LC/MS (CSF). Unbound DRV was measured in plasma specimens by ultrafiltration and HPLC. The lower limit of detection of each assay was 5 ng/mL. Concentrations were compared to the median inhibitory concentration (IC50) for wild-type HIV (2.4 ng/mL). HIV RNA was measured by RT-PCR (limit of quantitation 50 copies/mL). Descriptive and bivariate statistics were calculated using standard methods. Results: Pts were mostly middle-aged (median 48 years) white (62%) men (88%) with AIDS (100%) who did not have HCV co-infection (81%). Median CD4 count at assessment was 197/µL and 52% were below 200/µL. HIV RNA was detectable in 38% of blood and 10% of CSF specimens. Median duration of DRV was 7.5 months. DRV was present in all CSF specimens with a median concentration of 56.9 ng/mL (IQR 39.6, 81.4). The median CSF-to-plasma ratio was 1.4% (IQR 0.9%, 1.8%) for total DRV concentrations and 9.4% for unbound DRV concentrations (IQR 6.8%, 14.2%). CSF concentrations were more strongly correlated with unbound DRV concentrations in plasma (r = 0.61, p = 0.0005) than total DRV concentrations (r = 0.50, p = 0.005), although this difference did not reach statistical significance (z = 0.57, p > 0.10). DRV concentrations in CSF exceeded the IC50 of wild-type HIV in all specimens by a median of 23.7-fold (IQR 16.5, 33.9). Conclusions: Darunavir was present in CSF specimens and exceeded the wild-type IC50 in all individuals. DRV compares well to other better penetrating protease inhibitors. DRV concentrations in CSF did not correlate significantly better with unbound DRV concentrations in blood, supporting that factors other than plasma protein binding determine distribution across the blood-brain barrier. Darunavir should contribute to control of HIV replication in the nervous system as a component of effective antiretroviral regimens.

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