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Raltegravir Reaches Good Nervous System Levels 4.3 Fold x EC50
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49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), September 12-15, 2009, San Francisco
Mark Mascolini
Raltegravir concentrations in cerebrospinal fluid (CSF) exceeded the median inhibitory concentration (IC50) for wild-type (nonmutant) virus in all 21 evaluated samples from 18 people with HIV [1]. Median raltegravir level in CSF quadrupled the IC50.
Understanding how well new antiretrovirals penetrate the central nervous system is important because HIV-related neurocognitive disorders persist in people otherwise responding well to treatment. Scott Letendre and colleagues at the University of California, San Diego measured levels of the integrase inhibitor raltegravir in 22 paired blood plasma-CSF samples from 18 HIV-infected people taking a raltegravir-containing regimen. The investigators used assays with lower quantitation limits of 2 ng/mL in plasma and 0.25 ng/mL in CSF. Earlier work by other investigators found an 18.4 ng/mL median raltegravir concentration in CSF [2].
In the new study, participants had a median age of 46 years and most were male (94%) and white (89%), with AIDS (83%) and without hepatitis C virus infection (88%) [1]. Median CD4 count when raltegravir levels were measured stood at 276, and 5 people (28%) had a CD4 count under 200. Study participants had taken raltegravir for a median of 4.2 months (interquartile range [IQR] 1.4 to 27.4). They took raltegravir with an average of 3.2 other antiretrovirals, including protease inhibitors in 48%, a nonnucleoside in 38%, maraviroc in 24%, and one or more nucleosides in all but one regimen.
One specimen pair collected more than 24 hours after dosing had raltegravir concentrations of 3.5 ng/mL in plasma and 0.31 ng/mL in blood and was excluded from the analysis. HIV RNA was undetectable in 13 of 21 plasma samples (62%) and 20 of 21 CSF samples (95%). Higher raltegravir levels in plasma were not associated with undetectable HIV RNA in plasma. The same kind of analysis could not be done for CSF because there was only 1 sample with RNA detectable in CSF.
Letendre detected raltegravir in all CSF specimens at a median concentration of 14.5 ng/mL (IQR 9.3 to 26.1, range 6.0 to 94.2). Median plasma concentration of raltegravir was 260.9 ng/mL (IQR 72.0 to 640.4, 17.8 to 4870). Median CSF-to-plasma ratio was 5.8% (IQR 2.1% to 17.8%, range 1.0% to 53.5%). Raltegravir CSF concentrations correlated positively with plasma concentrations (rho = 0.49, P = 0.02) but not with time since raltegravir dosing.
Raltegravir levels exceeded the IC50 for wild-type virus in all 21 CSF samples by a median of 4.3-fold (IQR 2.7 to 7.7, range 1.8 to 27.7).
The researchers conclude that "regimens containing raltegravir should contribute to control of HIV replication in the nervous system as a component of effective antiretroviral regimens."
References
1. Letendre S, Best B, Breidinger S, et al.. Raltegravir concentrations in CSF exceed the median inhibitory concentration. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract A-1311.
2. Yilmaz A, Gisslen M, Spudich S, et al. Raltegravir cerebrospinal fluid concentrations in HIV-1 Infection. PLoS One. 2009;4(9):e6877.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0006877
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