A total of 119 CSF-plasma pairs were obtained from 75 subjects. Most subjects provided either one (n = 52) or two (n = 14) specimen pairs. The remaining 9 subjects provided 3 (n = 5), 4 (n = 1), 5 (n = 1), 6 (n = 1), and 9 (n = 1) pairs. Subjects were predominantly middle-aged (median age of 44 years; interquartile range [IQR], 39 to 51) white (57%) men (78%) with AIDS (77%). The median CD4+ cell count at the time of sampling was 413/mm3 (IQR, 279 to 542), with 11% of values falling below 200/mm3. The median nadir CD4+ cell count was 105/mm3 (IQR, 15 to 227). Disease severity based on the 1993 Centers for Disease Control and Prevention classification system was categorized as C for 56%, B for 30%, and A for 14%. HIV RNA was at or below the detection limit (1.70 log10 copies/ml) in 57% of plasma and 88% of CSF specimens.
The median duration of FPV use was 9.5 months (IQR, 3.1 to 20.1). Concurrent antiretrovirals included nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) in all subjects, a non-NRTI in 13%, an additional protease inhibitor other than ritonavir in 11%, and one fusion inhibitor in 1%. The self-reported FPV dose before sampling was taken with food at 83% of the sampling time points. Adherence information was available for 85 sampling time points, and adequate adherence was reported for 75 (87%).
APV concentrations in plasma and CSF are displayed in , and aggregate data are summarized in , including both overall results and results by FPV dosing schedule. APV was not detected in four CSF specimens, while the corresponding plasma had detectable APV. The median CSF APV concentrations with and without RTV (including both FPV dosing schedules) were 26.1 ng/ml (IQR, 16.9 to 45.8) (not shown in table) and 23.4 ng/ml (IQR, 10.7 to 41.5), respectively. The data for the timing of CSF sampling were evenly distributed over the dosing intervals, and the median postdose sampling intervals (± standard deviation [SD]) were 7.2 ± 5.2 h for CSF and 6.9 ± 5.2 h for plasma. APV was detectable in all but four CSF specimens. CSF fractional penetrance (i.e., the amount of drug reaching the CSF compartment) was 1.2% of the median total plasma APV concentration (IQR, 0.8% to 1.8%). APV concentrations in CSF correlated with those in plasma (rho = 0.61; P < 0.0001) () with persistent statistical significance in subgroups with (rho = 0.63; P < 0.0001) and without (rho = 0.57; P = 0.005) RTV. Further, correlations remained consistently strong when correlative analyses were performed using postdose sampling interval quartiles ranging from 0.5 to 5, 5 to 7, 7 to 12, and 12 to 23 h. The correlation weakened slightly for the shortest postdose sampling interval range of 0.5 to 5 h, but the coefficient (rho = 0.30) was greater than 0.25 although not statistically significant (P = 0.123). APV concentrations in plasma and CSF correlated with the postdose sampling interval (rho = −0.25 [P = 0.0054] and −0.29 [P = 0.0019], respectively). The CSF-to-plasma ratio did not change significantly across the dosing interval (rho = −0.12; P = 0.22). RTV-boosted FPV regimens were associated with higher plasma concentrations of APV compared to FPV without RTV (t = 1.61; P = 0.058) but not with higher CSF concentrations (t = 1.07; P = 0.15). These results were not substantially different when the analyses were performed with inclusion of a single time point for subjects with multiple CSF-plasma pairs.
Fig 1 Amprenavir concentrations by fosamprenavir dosing schedule in plasma (dark shading) and CSF (light shading) by postdose sampling time. The horizontal solid line represents the median IC50 (5.6 ng/ml) and the horizontal dashed line the IC50 99th percentile (more ...)
Summary of amprenavir concentrations and sampling by fosamprenavir dosing schedule
Correlation between amprenavir CSF and plasma concentrations.
APV concentrations in CSF exceeded the median IC50 for wild-type HIV-1 in 97.3% of specimens with detectable APV by a median of 4.4-fold (IQR, 2.9 to 7.9), while 73.9% of the same specimens had concentrations above the 99th percentile of the IC50 range. Higher APV concentrations in plasma were not associated with undetectable HIV RNA levels in plasma (t = 0.42; P > 0.34). Overall, higher APV concentrations in CSF were not associated with undetectable HIV RNA in CSF (t = 1.5; P = 0.15). Of note, all HIV RNA levels in CSF were undetectable when HIV RNA levels in plasma were undetectable. In the subgroup of subjects who had detectable HIV RNA levels in plasma, detectable HIV RNA levels in CSF trended toward an association with lower APV concentrations in CSF (mean, 24.5 versus 37.5 ng/ml [t = −1.8; P = 0.08]). This association was present (β = 0.04; P = 0.08) in multivariable analyses that accounted for APV concentrations in plasma, duration of FPV therapy, and postdose sampling time. Classification and regression trees showed that all of the detectable HIV RNA levels in CSF occurred in subjects who had APV concentrations in CSF below 53.5 ng/ml. This equated to a CSF-to-IC50 ratio of 9.6. In other words, all detectable HIV RNA levels in CSF occurred in subjects whose APV concentrations in CSF exceeded the 50% inhibitory concentration by less than 9.6-fold. This categorical expression of CSF APV concentrations was statistically significantly associated with detectable HIV RNA levels in CSF (β = −12.5; P = 0.01) in multivariable analyses that accounted for APV concentrations in plasma, duration of FPV therapy, and postdose sampling time.
FPV dosing schedules were associated with different CSF and plasma APV concentrations as well as CSF-to-plasma and CSF-to-IC50 ratios as shown in and . While FPV at 700 mg BID with RTV resulted in the highest median CSF APV concentration, the other FPV dosing schedules did not substantially differ. However, FPV at 1,400 mg BID without RTV had the highest CSF-to-plasma ratio, with trends toward significance (). FPV at 1,400 mg BID without RTV appeared to be associated with lower plasma APV concentrations, although the differences compared to other dosing schedules were not statistically significant.
CSF-to-plasma ratios of amprenavir concentrations by fosamprenavir dosing schedule, including only the first time point for subjects with multiple time points. QD, once daily.