By
Liz Highleyman
Antiretroviral
drugs that cross the blood-brain barrier and fight HIV
within the brain may help prevent AIDS-related dementia
and milder forms of neurocognitive impairment.
Scott
Letendre from the University of California at San Diego
and colleagues have previously
published data on how well various antiretroviral drugs
penetrate the brain. At ICAAC, the HIV Neurobehavioral Research
Center Study Group augmented this research with findings
for 2 drugs approved since the initial work.
The
raltegravir analysis included 22 paired blood plasma and
CSF samples from 18 individuals taking raltegravir-containing
regimens. Most (94%) were men, 89% were white, and the median
age was 46 years. Most (89%) had an AIDS diagnosis and 12%
had hepatitis C coinfection. The median CD4 count (at the
time of raltegravir measurement) was 276 cells/mm3, and
just over one-quarter had < 200 cells/mm3.
The
darunavir analysis included 29 paired plasma and CSF samples
from 18 patients taking darunavir-containing regimens. This
group was slightly more diverse, with 88% being men and
62% being white. The average age was 48 years and 19% had
hepatitis C. Reflecting the population of highly treatment-experienced
patients who typically use darunavir, the median CD4 count
was lower, at 197 cells/mm3, with about half having <
200 cells/mm3.
Combined Results
 |
The
median CSF raltegravir concentration was 14.5 ng/mL,
while the median plasma concentration was 260.9 ng/mL.
|
|
Raltegravir
concentrations in CSF exceeded the 50% inhibitory concentration
(IC50) for wild-type (non-mutated) HIV, with a median
level 4.3 times the IC50. |
|
Raltegravir
CSF concentrations had a positive correlation with plasma
levels. |
|
62%
of raltegravir recipients had undetectable plasma viral
load and 95% had undetectable CSF viral load. |
|
The
median CSF darunavir concentration was 56.9 ng/mL, while
the median total plasma concentration was 4094 ng/mL
and the median unbound plasma concentration was 542
ng/mL (darunavir tends to bind with blood proteins,
which interferes with ability to cross the blood-brain
barrier). |
|
Darunavir
concentrations in CSF also exceeded the IC50 for wild-type
HIV, with a median level 20.7 times the IC50. |
|
Darunavir
CSF concentrations also had a positive correlation with
total plasma concentrations, but the association with
unbound plasma levels was not significantly stronger. |
|
62%
of darunavir recipients had undetectable plasma viral
load and 90% had undetectable CSF viral load. |
Based
on these findings, the researchers concluded that both raltegravir
and darunavir "are in the therapeutic range for inhibition
of wild-type HIV" and "should contribute to control
of HIV replication in the nervous system" as a component
of effective antiretroviral therapy.
It
should be noted, however, that studies to date have produced
conflicting
data on this issue, with some indicating that regimens
that fully suppress plasma HIV are protective against neurocognitive
problems even if they do not enter the central nervous system
(brain and spinal cord). Furthermore, drug levels in the
CSF do not necessarily reflect concentrations in brain tissue.
10/16/09
References
S
Letendre, B Best, S Breidinger, and others. Raltegravir
concentrations in CSF exceed the median inhibitory concentration.
49th Interscience Conference on Antimicrobial Agents and
Chemotherapy (ICAAC 2009). San Francisco. September 12-15,
2009. Abstract A-1311.
S.
Letendre, S Rossi, B Best, and others. Darunavir concentrations
in CSF exceed the median inhibitory concentration. ICAAC
2009. Abstract A-1312.
