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Low Tenofovir Concentrations in Cerebrospinal Fluid
Brookie Best*1, S Letendre1, P Koopmans2, D Clifford3, A Collier4, B Gelman5, J McArthur6, D Simpson7, E Capparelli1, R Ellis1, and the CHARTER Group
1Univ of California, San Diego, US; 2Radboud Univ Nijmegen Med Ctr, The Netherlands; 3Washington Univ, St Louis, MO, US; 4Univ of Washington, Seattle, US; 5Univ of Texas Med Branch, Galveston, US; 6Johns Hopkins Univ, Baltimore, MD, US; and 7Mt Sinai Sch of Med, New York, NY, US
Background: HIV neurocognitive impairment (HNCI)
remains highly prevalent despite the use of combination ART (cART). Ongoing
viral replication due to poor distribution of ART into the central nervous
system (CNS) may contribute to HNCI. Tenofovir (TFV) is a potent and
widely-used nucleotide HIV reverse transcriptase inhibitor but its chemical
properties suggest that it may not penetrate into the CNS in therapeutic
concentrations. The study objective was to determine TFV penetration into
cerebrospinal fluid (CSF).
Methods: CHARTER is an ongoing, North American,
multi-center, observational study to determine the effects of ART on
HIV-associated neurological disease. Single random plasma and CSF samples were
drawn within an hour of each other from subjects taking TFV between October
2003 and March 2007. Plasma and CSF samples were assayed by mass spectrometry
with a detection limit of 1 ng/mL. Data were analyzed with summary statistics
and linear regression.
Results: From 117 participants (age 44±8 years; 83±39
kg; 18 females; CSF protein 62±134 mg/dL) samples were drawn 11.5±7.4 hours
post-dose. Of the total, 19 subjects took a NNRTI and 100 took a
ritonavir-boosted protease inhibitor (PI). The median plasma and CSF TFV
concentrations after a median 8.5 months (IQR 3.8 to 16.9) of therapy were 96
ng/mL (IQR <1 to 243) and 5 ng/mL (IQR 2.2 to 8.2), respectively. Of 63 subjects,
8 (13%) had CSF samples, and of 115, 20 (17%) had plasma samples that were
below detection (<1 ng/mL). The CSF/plasma concentration ratio from paired
samples drawn within 1 hour of each other was 0.04 (IQR 0.007 to 0.08; n
= 26). The CSF/IC50 ratio was 0.02 (IQR 0.01 to 0.04) using published
wild type IC50 against HIV-1 (0.7 µM or 201 ng/mL). No CSF samples
had concentrations that exceeded the TFV wild type IC50. Plasma
concentrations did not correlate strongly with CSF concentrations (r2
= 0.14).
Conclusions: TFV concentrations in the CSF are only
4% of plasma concentrations, suggesting limited active or passive transfer into
the CSF, and possibly active transport out of the CSF. CSF concentrations do
not exceed the wild type IC50 of TFV, and may not provide enough protection
against viral replication in the CSF.
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