Does
Antiretroviral Therapy Improve Neurocognitive Performance in People with HIV?
 | Data
from 2 recent studies provided conflicting evidence about whether antiretroviral
therapy can improve mental functioning in HIV patients with neurocognitive impairment,
and whether drugs that penetrate the blood-brain barrier lead to better outcomes. |
By
Liz Highleyman  | AIDS
dementia complex (also known as AIDS-related dementia and HIV-associated dementia)
is a condition in people with AIDS that results in the loss of cognitive capacity,
affecting the ability to function in a social or occupational setting. |
|
While
the advent of effective combination
ART reduced the rate of severe AIDS-related dementia, milder impairment of
neurocognitive functioning -- for example memory loss or difficulty with thinking
and concentration -- remain common. It remains unclear whether antiretroviral
drugs need to cross the blood brain barrier -- which protects the central
nervous system (CNS) from toxins and other harmful agents -- in order to improve
cognitive functioning in people with HIV. Study
1 In
the first study, published in the May
27, 2009 advance online issue of Neurology, researchers at the University
of California at San Diego sought evaluated the time course of cognitive changes
in 37 individuals with HIV-associated neurocognitive disorders who started combination
ART. Neuropsychological function was assessed at baseline and at 12, 24, 36, and
48 weeks of therapy. Results  | Cognitive
improvement began soon after ART initiation. | | 13%
of participants showed improvement at week 12, but more common at weeks 24 and
36, and reached 41% by week 48. | | Fewer
than 5% of participants experienced significant worsening of neurocognitive function. | | In
a multivariate analysis, independent predictors of neuropsychological improvement
were more severe impairment at baseline and use of drugs with better CNS penetration
index. | | Larger
decreases in viral load were associated with neuropsychological improvement only
in a univariate analysis, but was no longer significant in the multifactor analysis. |
"Clinically
meaningful neuropsychological improvement seemed to peak around 24-36 weeks after
combination antiretroviral therapy initiation and was prolonged over the 1-year
study period," the researchers concluded. "This study also provides
new evidence that benefit may be maximized by choosing antiretroviral medications
that reach therapeutic concentrations in the CNS." Department
of Psychiatry, Division of Biostatistics and Bioinformatics, Department of Family
and Preventive Medicine, Department of Medicine, and Department of Neurosciences,
University of California at San Diego, San Diego, CA; Brain Sciences, University
of New South Wales, Sydney, Australia. Study
2 In
the second study, described in the July
17, 2009 issue of AIDS, the AIDS Clinical Trials Group (ACTG) 736 Study
Team assessed whether antiretroviral regimens with good CNS penetration could
control HIV in cerebrospinal fluid (CSF) and improve cognitive performance. 
This
study included 101 patients with advanced HIV disease who were starting or changing
to a new potent antiretroviral regimen; data for 79 participants were analyzed.
Participants underwent neurological and neuropsychological testing at study entry
and at weeks 24 and 52 after starting a new regimen.
Antiretroviral regimens
were categorized as having strong or weak CNS penetration effectiveness (CPE),
with a score of at least 2 or less than 2. Drugs with minimal penetration were
given a score of 0 while those with good penetration were given a score of 1,
and the scores for all drugs in the regimen were added to derive the CPE.
Results Suppression
of HIV RNA in the CSF was more likely when the regimen's CPE rank was 2 or higher
than when it was less than 2. The likelihood of plasma viral load suppression,
in contrast, was not affected by CPE rank.
Among participants with impaired
neuropsychological performance at study entry, those taking regimens with a CPE
score of at least 2 actually had lower neurocognitive performance scores over
the course of the study. "In
this study, antiretrovirals with good CNS penetration were associated with poorer
neurocognitive performance," the study authors wrote. "A larger controlled
trial is required before any conclusions regarding the influence of specific antiretrovirals
on neurocognitive performance should be made."
The investigators were
unable to explain these unexpected findings -- though they suggested that drugs
that penetrate the brain may have unrecognized toxicities in the CNS -- indicating
that further research is needed in this area.
Department of Neurology,
University of Washington School of Medicine, Seattle, WA. 7/14/09 References LA
Cysique, F Vaida, S Letendre, and others. Dynamics of cognitive change in impaired
HIV-positive patients initiating antiretroviral therapy. Neurology. May
27, 2009 [Epub ahead of print]. CM
Marra, Y Zhao, DB Clifford, and others. Impact of combination antiretroviral therapy
on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 23(11):
1359-1366. July 17, 2009.
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