Raltegravir Cerebrospinal Fluid Concentrations in HIV-1 Infection

Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing this drug.Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma.Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0-126.0). The median plasma raltegravir concentration was 448 ng/ml (range, 37-5180). CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations.Approximately 50% of the CSF specimens exceeded the IC(95) levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry

Raltegravir concentrations in plasma (A) and CSF (B) in relation to the time after the previous dose.

<p>Results for individual subject evaluations and repeat subject evaluations are indicated by the matching color of squares (plasma) and circles (CSF) coded for each subject. A: The horizontal grey fill plots IC₉₅ range of 9.0–15.0 ng/ml, while the lower dashed horizontal line within this zone shows the lower limit of quantitation (LLQ) for plasma of 10.0 ng/ml. B: The one CSF measurement of raltegravir below the LLQ is plotted as if equal to 1.9 ng/ml (orange circle). The size of the symbols in B. also varies with the CSF:albumin ratios at the time of sampling as shown by the grey circles in the key: the largest circles show the one sample with ratio >10, the next largest the 5 samples for albumin ratios from 7.5–10, the next the 10 samples with ratios from 5–7.4, and the smallest the 9 samples for ratios <5. The dashed horizontal line within this zone shows the LLQ for CSF of 2.0 ng/ml.</p

Longitudinal data from patient with three samples over the course of her illness (see text).

<p>A: CSF raltegravir concentrations fell as the patient recovered. B: Plasma raltegravir concentrations were variable despite similar times of sampling (shown in hours after dosing adjacent to symbols). C: Decline in the albumin ratio with recovery. D: Similar decline in the CSF albumin concentrations. E: HIV-1 RNA treatment response was parallel in plasma and CSF, with higher levels in the latter. F: Rapid blood CD4+ T cell recovery.</p