Low cerebrospinal fluid concentrations of the nucleotide HIV reverse transcriptase inhibitor, tenofovir.

TitleLow cerebrospinal fluid concentrations of the nucleotide HIV reverse transcriptase inhibitor, tenofovir.
Publication TypeJournal Article
Year of Publication2012
AuthorsBest, BM, Letendre, SL, Koopmans, P, Rossi, SS, Clifford, DB, Collier, AC, Gelman, BB, Marra, CM, McArthur, JC, J McCutchan, A, Morgello, S, Simpson, DM, Capparelli, EV, Ellis, RJ, Grant, I
Corporate AuthorsCHARTER Study Group
JournalJ Acquir Immune Defic Syndr
Date Published2012 Apr 01
KeywordsAdenine, Adult, CHARTER, Cohort Studies, Female, HIV Reverse Transcriptase, Humans, Internal, Male, Middle Aged, Organophosphonates, Reverse Transcriptase Inhibitors, Tenofovir

BACKGROUND: Tenofovir is a nucleotide HIV reverse transcriptase inhibitor whose chemical properties suggest that it may not penetrate into the central nervous system in therapeutic concentrations. The study's objective was to determine tenofovir's penetration into cerebrospinal fluid (CSF).METHODS: CNS HIV Antiretroviral Therapy Effects Research is a multicenter observational study to determine the effects of antiretroviral therapy on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within an hour of each other from subjects taking tenofovir between October 2003 and March 2007. All samples were assayed by mass spectrometry with a detection limit of 0.9 ng/mL.RESULTS: One hundred eighty-three participants (age 44 ± 8 years; 83 ± 32 kg; 33 females; CSF protein 44 ± 16 mg/dL) had plasma and CSF samples drawn 12.2 ± 6.9 and 11 ± 7.8 hours post dose, respectively. Median plasma and CSF tenofovir concentrations were 96 ng/mL [interquartile range (IQR) 47-153 ng/mL] and 5.5 ng/mL (IQR 2.7-11.3 ng/mL), respectively. Thirty-four of 231 plasma (14.7%) and 9 of 77 CSF samples (11.7%) were below detection. CSF to plasma concentration ratio from paired samples was 0.057 (IQR 0.03-0.1; n = 38). Median CSF to wild-type 50% inhibitory concentration ratio was 0.48 (IQR 0.24-0.98). Seventy-seven percent of CSF concentrations were below the tenofovir wild-type 50% inhibitory concentration. More subjects had detectable CSF HIV with lower (≤ 7 ng/mL) versus higher (>7 ng/mL) CSF tenofovir concentrations (29% versus 9%; P = 0.05).CONCLUSIONS: Tenofovir concentrations in the CSF are only 5% of plasma concentrations, suggesting limited transfer into the CSF, and possibly active transport out of the CSF. CSF tenofovir concentrations may not effectively inhibit viral replication in the CSF.

Alternate JournalJ. Acquir. Immune Defic. Syndr.
PubMed ID22217676
PubMed Central IDPMC3299895
Grant ListU10 HD031318-15 / HD / NICHD NIH HHS / United States
5U10 HD031318 / HD / NICHD NIH HHS / United States
U10 HD031318 / HD / NICHD NIH HHS / United States
UL1 RR029887 / RR / NCRR NIH HHS / United States
N01 MH022005 / MH / NIMH NIH HHS / United States