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Efavirenz and Emtricitabine Concentrations Consistently Exceed Wild-type IC50 in Cerebrospinal Fluid: CHARTER Findings
Brookie Best*1, S Letendre1, E Capparelli1, R Ellis1, S Rossi1, P Koopmans2, I Grant1, and the CHARTER Group
1Univ of California, San Diego, US and 2Radboud Univ Nijmegen Med Ctr, Nijmegen, The Netherlands
Background: Persistent HIV replication sub-therapeutic
concentrations of ARV in the nervous system may put patients at risk for HIV-associated
neurocognitive disorders (HAND). Emtricitabine (FTC) is commonly used but its
concentrations in cerebrospinal fluid (CSF) have not been measured.
Concentrations of efavirenz (EFV) in CSF are uncertain since they were detectable
in one study (n = 10), but undetectable in another (n = 11). This study’s
objective was to determine concentrations of EFV and FTC in CSF.
Methods: CHARTER is an ongoing, multi-center,
observational study to determine the effect of ART on HAND. Single, random
plasma and CSF samples were drawn within an hour of each other from subjects taking
FTC or EFV. Samples were assayed by high-performance liquid chromatography (HPLC)
(EFV plasma, detection limit 39 ng/mL) or liquid chromatography/mass
spectrophotometry (LC/MS) (EFV CSF, limit <0.1 ng/mL; FTC plasma/CSF, limit 1
ng/mL). Data were analyzed by drug with summary statistics and linear regression.
Results: For EFV, 77 participants (44±8 years; 20 females)
had samples drawn 12.7±5.4 hours post-dose. Median EFV concentration was 2209
ng/mL in plasma (IQR 1316 to 4386) and 13.3 ng/mL in CSF (IQR 4 to 21.1). After
extraction with methyl tert-butyl ether, the lower limit of detection decreased
to <0.1 ng/mL. Without this high degree of assay sensitivity, EFV could not
be measured in CSF. The CSF/plasma ratio was 0.005 (IQR 0.002 to 0.007; n = 66).
The CSF/wild type IC50 (0.51 ng/mL) ratio was 26 (IQR 8 to 41). Two
values (2.6%) were below the IC50. For FTC, 21 participants (45±8
years; 4 females) had samples drawn 10.9±8.2 hours post-dose. Median FTC concentration
was 261 ng/mL (IQR 96 to 720) in plasma and 109 ng/mL in CSF (IQR 84 to 196). The
CSF/plasma ratio was 0.43 (IQR 0.29 to 0.89). The CSF/wild-type IC50
(70 ng/mL) ratio was 1.6 (IQR 1.2 to 2.8). CSF/plasma ratios correlated with
time post dose (r2=0.34). Median ratios drawn <12 and >12
hours post dose were 0.36 (IQR 0.21 to 0.45; n = 14) and 0.89 (IQR 0.72 to
1.34; n = 7), respectively.
Conclusions: EFV CSF concentrations were only 0.5%
of plasma concentrations, consistent with the unbound fraction in blood and suggesting
limited active transport out of the CSF. FTC CSF/plasma ratios ranged from 36%
to nearly equal over the dose interval. Concentrations of FTC and EFV in CSF exceed
the wild-type IC50 in most individuals and may inhibit HIV replication
in the nervous system.
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