The extent to which antiretroviral therapy protects against neurocognitive complications remains uncertain. Historical data indicate that the advent of the first antiretroviral (AZT) was associated with reduction in diagnosis of AIDS-associated dementia. However, not all investigators have reached the same conclusion.
The advent of potent antiretroviral combination therapies holds with it the promise of reducing viral load to unmeasurable or very low levels. Studies are under way to determine whether such viral load reductions are associated with neurocognitive improvement. Preliminary observations indicate that reduction of viral load in the CSF may be more specifically associated with neurocognitive improvement than reduction in plasma load. If correct, this would raise questions about the differential efficacy of new antiretrovirals. In other words, the possibility arises that agents may be extremely potent in lowering peripheral viral load but, because of their poor
penetration into the central nervous system, they may not be equally effective with regard to CNS complications.
Research is also ongoing to test drugs that may impact the putative mechanisms of neural injury. For example, a treatment trial is currently under way with the NMDA blocker memantine to determine whether reducing activity at glutamatergic receptor sites may be associated with neurocognitive improvement. A trial of peptide T, which putatively competes with viral envelope protein gp120 at neural receptor sites (e.g., receptor sites for VIP and possibly chemokine receptor sites), produced mixed results. Overall, it appeared that peptide T did not yield neurocognitive improvement; however, an analysis based on a subset of definitely impaired HIV-infected individuals did suggest some benefit. Thus, the question of peptide T's effectiveness remains unresolved. Pentoxyfylline, which blocks the action of TNF-a, was not promising in improving neurocognitive functioning in a preliminary trial.
profile reminiscent of''subcortical'' dementias such as those associated with Huntington's disease, Parkinson's disease, and white matter dementias. One of the fundamental substrates of the cognitive impairment is neural injury, including loss of dendritic spines and synaptic simplification. The mechanism of injury may involve the toxic effects of viral products such as gp120 as well as inflammatory mechanisms involving perhaps abnormal expression of various lymphokines. Protective factors may also be important, although the role of FGF and other trophic factors has yet to be established. Alhough they are usually mild in nature, HIV-associated neurocognitive disturbances can have substantial effects on day-to-day life, including employment, and day-to-day tasks such as medication management and driving skills. The presence of impairment is also associated with earlier mortality. Currently available antiretroviral drug combinations have increased survival of patients with HIV, but their potential to avert or improve neurocognitive complications is not conclusively established.
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