Could Cholinesterase Inhibitors and Memantine Alleviate HIV Dementia?

To the Editor: HIV dementia usually responds to highly active antiretroviral therapy (HAART), despite relatively poor penetration of HAART drugs across the blood-brain barrier.1,2 However, patients on HAART can still have significant cognitive deficits,3,4 and HIV dementia appears to be at least somewhat independent of viral load within the central nervous system,5 raising the specter of increasing numbers of long-term HIV survivors disabled by dementia. Part of the solution may be cholinesterase inhibitors (donepezil, galantamine, and rivastigmine), now commonly used to treat Alzheimer's disease. Cholinesterase inhibitors compensate for cholinergic deficiency by inhibiting the breakdown of acetylcholine and can delay nursing home placement by typically 6 months to a year,6 in what on the average is a decade-long progression from initial signs to a locked-in end stage. Galantamine also appears to have some effect in directly stimulating nicotinic cholinergic receptors.6 Symptomatic relief from all 3 agents is modest but real and can be quantified by various instruments assessing patients and their caregivers, who note decreased burden of caregiving with the use of cholinesterase inhibitors. Beyond Alzheimer's disease, cholinesterase inhibitors can also improve cognitive functioning in several other neurologic disorders, including dementia of multiple sclerosis,7 Parkinsonian dementia,8 attention deficit disorder,9 traumatic brain injury,10-13 and vascular dementia.14-16 All of these conditions have many subcortical neuropsychological features in common with typical HIV dementia, such as inattention to detail and difficulty learning, suggesting there would be a similar improvement for HIV dementia. In addition, it is important to note that both multiple sclerosis dementia and HIV dementia have prominent white matter lesions. This is especially the case for HIV-associated progressive multifocal leukoencephalopathy, which was common in the pre-HAART era and now seems to be making a resurgence.17 It is thought that most patients with subcortical dementias who improve with cholinesterase inhibitors have cholinergic afferent fibers passing through lesioned areas,16 creating a state of relative cholinergic deficiency relieved by inhibiting breakdown of acetylcholine. If this is correct, many patients with HIV-induced white matter lesions may have an identical situation. Memantine, a noncompetitive inhibitor of the N-methyl-D-aspartate (NMDA) glutamate receptor, also shows promise for HIV dementia. There is already in vitro and animal data showing memantine neuroprotection against NMDA-mediated neurotoxicity of the HIV gp120 protein,18-20 and clinical trials of memantine for HIV dementia have reportedly begun.21 When used for Alzheimer's disease, memantine significantly attenuates progression from moderate to severe stages22 and has additive effect when coadministered with donepezil.23 Rigorous placebo-controlled multicenter clinical trials of cholinesterase inhibitors and memantine should be expedited, above and beyond what may already be under way. If patients desire to try the medications ahead of randomized controlled studies, HIV clinics could offer small open-label therapeutic trials, carefully monitoring for any drug interactions with HAART. Hopefully, there can be a fast track to determine whether cholinesterase inhibitors and memantine should be a routine part of treatment of HIV dementia. Joseph Martin Alisky, MD, PhD Marshfield Clinic Research Foundation and marshfield Clinic-Thorp Center; Marshfield, WI