title: Total raltegravir concentrations in cerebrospinal fluid exceed the 50-percent inhibitory concentration for wild-type HIV-1.
abstract: HIV-associated neurocognitive disorders continue to be common. Antiretrovirals that achieve higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV and improved cognition. The objective of this study was to measure total raltegravir (RAL) concentrations in CSF and to compare them with matched concentrations in plasma and in vitro inhibitory concentrations. Eighteen subjects with HIV-1 infection were enrolled based on the use of RAL-containing regimens and the availability of CSF and matched plasma samples. RAL was measured in 21 CSF and plasma pairs by liquid chromatography-tandem mass spectrometry, and HIV RNA was detected by reverse transcription-PCR (RT-PCR). RAL concentrations were compared to the 50% inhibitory concentration (IC(50)) for wild-type HIV-1 (3.2 ng/ml). Volunteers were predominantly middle-aged white men with AIDS and without hepatitis C virus (HCV) coinfection. The median concurrent CD4(+) cell count was 276/μl, and 28% of CD4(+) cell counts were below 200/μl. HIV RNA was detectable in 38% of plasma specimens and 4% of CSF specimens. RAL was present in all CSF specimens, with a median total concentration of 14.5 ng/ml. The median concentration in plasma was 260.9 ng/ml, with a median CSF-to-plasma ratio of 0.058. Concentrations in CSF correlated with those in with plasma (r(2), 0.24; P, 0.02) but not with the postdose sampling time (P, >0.50). RAL concentrations in CSF exceeded the IC(50) for wild-type HIV in all specimens by a median of 4.5-fold. RAL is present in CSF and reaches sufficiently high concentrations to inhibit wild-type HIV in all individuals. As a component of effective antiretroviral regimens or as the main antiretroviral, RAL likely contributes to the control of HIV replication in the nervous system.
authors.affiliation: HIV Neurobehavioral Research Center, University of California-San Diego, 220 Dickinson, Suite B, #8208, San Diego, CA 92103, USA. dcroteau@ucsd.edu
authors.forename: David
authors.initials: D
authors.lastname: Croteau
authors.forename: Scott
authors.initials: S
authors.lastname: Letendre
authors.forename: Brookie M
authors.initials: BM
authors.lastname: Best
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Ellis
authors.forename: Sheila
authors.initials: S
authors.lastname: Breidinger
authors.forename: David
authors.initials: D
authors.lastname: Clifford
authors.forename: Ann
authors.initials: A
authors.lastname: Collier
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gelman
authors.forename: Christina
authors.initials: C
authors.lastname: Marra
authors.forename: Gilbert
authors.initials: G
authors.lastname: Mbeo
authors.forename: Allen
authors.initials: A
authors.lastname: McCutchan
authors.forename: Susan
authors.initials: S
authors.lastname: Morgello
authors.forename: David
authors.initials: D
authors.lastname: Simpson
authors.forename: Lauren
authors.initials: L
authors.lastname: Way
authors.forename: Florin
authors.initials: F
authors.lastname: Vaida
authors.forename: Susan
authors.initials: S
authors.lastname: Ueland
authors.forename: Edmund
authors.initials: E
authors.lastname: Capparelli
authors.forename: Igor
authors.initials: I
authors.lastname: Grant
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000097:blood / Q000134:cerebrospinal fluid* / Q000627:therapeutic use; D002853:Chromatography, Liquid; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019438:Ritonavir / Q000097:blood / Q000134:cerebrospinal fluid* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry
chemical_list: D019380:Anti-HIV Agents; D019438:Ritonavir