| Publication Abstract Display | | Type: Published Abstract | | Title: Therapeutic Amprenavir and Abacavir concentrations in CSF from the same individuals. | | Authors: Letendre S, Capparelli E, Best B, Rossi S, Way L, Grant I, Ellis R, the HNRC Group | | Year: 2009 | | Publication: 10th International Workshop on Clinical Pharmacology of HIV Therapy | | Volume: Issue: Pages: | | Abstract:Background: Antiretrovirals (ARVs) that achieve higher concentrations in CSF
are associated with better control of HIV and improved neuropsychological
performance. Few studies have measured concentrations of two or more
ARVs in CSF specimens from the same individuals. Demonstrating that the
concentrations of two ARVs are in the therapeutic range would strengthen
evidence that they are important components of neuroeffective regimens.
Methods & Materials: 46 HIV-infected participants (pts) were evaluated at the
UCSD HIV Neurobehavioral Research Center between February 2005 and
May 2008 and were selected based on use of fosamprenavir (FPV)-
containing regimens and the availability of CSF and blood plasma that had
been stored at -70oC since collection. Amprenavir was measured in 71 CSF
and 75 plasma specimens by HPLC (plasma) or LC/MS (CSF). Abacavir
(ABC) CSF and plasma concentrations were measured in a subset of 15 pts.
The lower limit of detection for both CSF assays was 1 ng/mL. HIV RNA were
measured by RT-PCR (limit of quantitation 50 copies/mL). Concentrations
were compared to the median inhibitory concentration (IC50) for wild-type HIV
from the PhenoSense assay (APV 5.6 ng/mL, ABC 70 ng/mL). Descriptive
and bivariate statistics were calculated using standard methods.
Results: Pts were mostly middle-aged (median 47 years) white (59%) men
(93%). Median CD4 count was 328 with 31% below 200/μL. HIV RNA were
detectable in 41% of blood and 16% of CSF specimens. Median duration of
FPV was 11.3 months. APV was present in all CSF specimens with a median
concentration of 25 ng/mL (IQR 16, 44). The median CSF-to-plasma ratio was
0.013 (IQR 0.009, 0.019). CSF concentrations correlated with plasma
concentrations (rho = 0.64, p < 0.001) but not with post-dose sampling time.
Those taking ritonavir (n = 70) had higher concentrations in plasma (median
2,292 vs. 377, p < 0.001) and CSF (median 27 vs. 7, p = 0.004). ABC
concentrations in CSF and plasma were similar (rho = 0.85, p < 0.001) with a
median CSF-to-plasma ratio of 1.03 (IQR 0.72, 2.77). APV concentrations in
CSF exceeded the IC50 of wild-type HIV in all but 1 CSF specimen by a
median of 4.4-fold (IQR 2.9, 7.8). ABC concentrations in CSF exceeded the
IC50 in 68% with a median CSF-to-IC50 ratio of 2.7 (IQR 0.33, 7.4).
Conclusions: Amprenavir and abacavir are present in CSF and reach
sufficiently high concentrations to inhibit wild-type HIV in nearly all of those
taking fosamprenavir regimens and by about a third taking abacavir
regimens. Among protease inhibitors, ritonavir-boosted fosamprenavir has
better estimated activity in the nervous system, similar to indinavir and
lopinavir. Among NRTIs, abacavir has superior estimated activity in the
nervous system to tenofovir (the median CSF tenofovir-to-IC50 ratio is 0.03).
Regimens containing fosamprenavir and abacavir should contribute to control
of HIV replication in the nervous system as components of effective
antiretroviral regimens. |
return to publications listing
|