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HIV-associated brain dysfunction in the era of HAART - Editorials, Reasons for hope, but continued concern
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NEUROLOGY Aug 4 2009;73:338-339
Ronald A. Cohen, PhD, ABPP, ABCN and Assawin Gongvatana, PhD
From the Department of Psychiatry and Human Behavior, Brown University, Providence, RI.
Address correspondence and reprint requests to Dr. Ronald Cohen, Department of Psychiatry and Human Behavior, Brown University, Providence, RI 02906 rcohen@lifespan.org
Studies conducted following the advent of highly active antiretroviral therapy (HAART) over a decade ago demonstrated dramatic neurocognitive improvements among HIV-infected people,1 leading to initial optimism that brain dysfunction secondary to HIV might be eradicated. Yet neurocognitive disturbances continue to occur,2,3 and may be continuing to evolve in the HAART era,4 with the possibility that the proviral DNA remains despite treatment.5 There are still many important questions about the relationship between HIV-associated neurocognitive impairments and antiretroviral (ARV) treatment.
The study by Cysique and colleagues6 provides insights into the timeline and biomarkers associated with cognitive changes following ARV initiation. Rapid cognitive improvements occurred within the first 12 weeks, which continued more gradually throughout the 48-week study period. The results provide a preliminary reference for the degree and rate of cognitive change that might be expected, and point to the potential value of short-term cognitive improvements as an independent marker of treatment outcome. Clinicians may then consider adjustment to treatment regimens if expected cognitive improvements are not observed despite suppressed viral load.
The largest improvement was found in patients with the greatest baseline impairment. This is not surprising since people with greater impairment to begin with have more room for improvement. Notably, the results indicate that HIV-associated cognitive impairment is treatable and may not reflect permanent structural damage to the brain, such as is presumed to occur in brain disorders like Alzheimer disease.
The CNS penetration capacity of the treatment regimen was found to be predictive of neurocognitive improvement. This observation seems logical, though it is surprising that other factors such as nadir CD4, duration of infection, or current viral load did not exert greater influence. It remains unclear whether statistical artifacts such as multicollinearity between the CNS penetration index and the other biomarkers resulted in the penetration index being retained as the only significant predictor. Regardless of this issue, a complex interaction seems to exist among these factors, which varies based on the specific clinical cohort and other study-specific factors.
The current cohort consisted of ARV-naive individuals and those who failed previous treatment regimens. One might expect the groups to show different cognitive responses to treatment, since the latter group is likely to have longer duration of illness. This issue is notable given evidence that disease history variables such as nadir CD4 predict cognitive function and structural brain abnormalities.7,8 The authors found that ARV experience did not significantly predict the degree of cognitive improvement. Such finding, suggesting reversible cognitive impairment despite chronic HIV disease, would have implication regarding our understanding of the neuropathologic mechanism of HIV. Unfortunately, interpretation of the results was complicated by the small sample size, and the fact that the statistical model already contained a number of explanatory variables. Future studies that are adequately powered are necessary to facilitate better understanding of the interaction between treatment and disease history on the brain.
The study raises a number of intriguing questions. Despite clinically significant and apparently rapid cognitive improvements produced by HAART, treated patients continue to show brain metabolite and neuronal abnormalities.9,10 Furthermore, reduced brain volumes have been related to HIV disease history variables,8 but not with current disease status or treatment regimen. To date, most findings regarding the influence of HIV disease history are from cross-sectional analyses, and these factors have not been adequately studied longitudinally. Factors tied to disease history and brain metabolic status may have more of an influence on baseline cognitive status than on the extent of improvement that is possible with treatment. Yet it would seem that these factors should set an upper limit on the amount of improvement that is likely to occur with treatment. It is highly unlikely that HAART would produce a rapid increase in cortical or subcortical volume, or reverse cognitive impairments associated with these structural changes, unless volume reductions reflect something other than cerebral tissue loss.
The methodologic approach taken by the investigators in this study may provide a means to sorting out these issues. For example, the results from the current study suggest that neurocognitive improvements peaked at about 48 weeks, whereas CD4 and viral load appear to stabilize sooner. The degree to which a lag exists between immunologic/virologic control and neurocognitive improvement would seem to be important to understanding the neurobiological factors enabling functional recovery. Presumably, during this period metabolic changes are occurring in the brain, such as a reduction in cerebral inflammation that enables recovery to occur.7,8 Recent advances in structural and functional neuroimaging (e.g., diffusion tensor imaging, functional MRI), as well in vivo measurement of brain metabolic function (magnetic resonance spectroscopy), should greatly facilitate efforts to better understand the temporal dynamics of the neural recovery process in HIV.
Dr. Cohen is funded by the NIH [#R01 MH074368 (PI), #HL084178-01 (Co-investigator), #NS036524 and S1 (Co-investigator), #DK075119 (Co-investigator), and #R01HL089311 (Co-investigator)] and serves on the editorial boards of the Journal of the International Neuropsychological Society, The Clinical Neuropsychologist, and Brain Imaging and Behavior. Dr. Gongvatana reports no disclosures.
REFERENCES
1. Cohen RA, Boland R, Paul R, et al. Neurocognitive performance enhanced by highly active antiretroviral therapy in HIV-infected women. AIDS 2001;15:341-345.
2. McArthur JC. HIV dementia: an evolving disease. J Neuroimmunol 2004;157:3-10.
3. Sacktor N, McDermott MP, Marder K, et al. HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol 2002;8: 136-142.
4. Brew BJ. Evidence for a change in AIDS dementia complex in the era of highly active antiretroviral therapy and the possibility of new forms of AIDS dementia complex. AIDS 2004;18 suppl 1:S75-S78.
5. Shiramizu B, Gartner S, Williams A, et al. Circulating proviral HIV DNA and HIV-associated dementia. AIDS 2005;19:45-52.
6. Cysique LA, Vaida F, Letendre S, et al. Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology 2009;73:342-348.
7. Munoz-Moreno JA, Fumaz CR, Ferrer MJ, et al. Nadir CD4 cell count predicts neurocognitive impairment in HIV-infected patients. AIDS Res Hum Retroviruses 2008;24:1301-1307.
8. Cohen R, Jaroslaw Harezlak J, Tate D, et al, and the HIV Neuroimaging Consortium. Cortical and subcortical volumes on magnetic resonance imaging associated with HIV history and current disease status. CROI; Montreal, Canada; 2009.
9. Paul RH, Yiannoutsos CT, Miller EN, et al. Proton MRS and neuropsychological correlates in AIDS dementia complex: evidence of subcortical specificity. J Neuropsychiatry Clin Neurosci 2007;19:283-292.
10. Chang L, Lee PL, Yiannoutsos CT, et al. A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age. Neuroimage 2004;23:1336-1347.
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