Total raltegravir concentrations in cerebrospinal fluid exceed the 50-percent inhibitory concentration for wild-type HIV-1.
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.
Croteau
David
D
HIV Neurobehavioral Research Center, University of California-San Diego, 220 Dickinson, Suite B, #8208, San Diego, CA 92103, USA. dcroteau@ucsd.edu
Letendre
Scott
S
Best
Brookie M
BM
Ellis
Ronald J
RJ
Breidinger
Sheila
S
Clifford
David
D
Collier
Ann
A
Gelman
Benjamin
B
Marra
Christina
C
Mbeo
Gilbert
G
McCutchan
Allen
A
Morgello
Susan
S
Simpson
David
D
Way
Lauren
L
Vaida
Florin
F
Ueland
Susan
S
Capparelli
Edmund
E
Grant
Igor
I
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
D019380:Anti-HIV Agents; D019438:Ritonavir