HIV dementia persists, but now it’s a chronic disease
Researchers find similarities to Alzheimer’s disease
Highly active antiretroviral therapy (HAART) has not eliminated HIV dementia, but it has changed the problem from one that strikes with severity and quickly leads to death to a process of slow, chronic cognitive decline, according to new research. "What’s been observed is there appears to be less of the old AIDS dementia, at least among patients with access to the newer antiretroviral therapies," says Dawn McGuire, MD, medical director of the Western NeuroAIDS Program at the HIV Institute for Treatment and Research in San Francisco. "But there appears to be as much or possibly an increased frequency of the more insidious cognitive dysfunction, and that’s very troubling," says McGuire, who is a co-author on a new study that details how AIDS dementia has evolved into a more protracted disorder.
The study found that HIV-1 associated dementia now represents more subtle neurotoxicity than it did prior to HAART.1 A decade ago, researchers at the University of California - San Francisco discovered a soluble factor produced from HIV-infected monocyte/macrophages, which meant these blood cells would become activated and enter and exit the brain, causing brain damage.
"It wasn’t the virus itself that caused brain damage, and that changed everybody’s thinking, because we thought it was the virus," says Lynn Pulliam, PhD, MS, professor of medicine and laboratory medicine at UCSF and chief of microbiology and director of research at the VA Medical Center in San Francisco. Pulliam is senior author on the recent study. Prior to HAART, the inflammatory cells caused immediate cell death. Now that HIV patients routinely are treated with antiretroviral drugs, the cells still may become activated, but instead of causing immediate cell death they cause apoptosis, which can be reversed, Pulliam says. "In 1997, it turned out the inflammatory products from monocyte/macrophages were not quite as toxic as they were in 1991," she adds.
Pulliam and colleagues have continued to follow HIV-infected patients on HAART and found that the soluble factors no longer caused cell death at all and do not appear to be toxic. "So I looked at more subtle changes in neural cells, things that were not as overt in a microscope, such as proteases that may be triggered in a subtle way to go toward apoptosis and cell death," Pulliam says. "It turns out they do trigger proteases and alter neuronal function." This meant that the toxicity still exists, although it’s far more subtle than it was even five years ago. "Ten years ago, AIDS patients with AIDS dementia died within six months; five years ago, they lived a little longer," Pulliam says. "Now I believe they will live even longer, but there will be problems."
Another offshoot of the research has been the discovery that there are some similarities between the latest form of AIDS-associated dementia and Alzheimer’s disease. This includes the elevation of a monocyte/macrophage subset, CD69, in both dementias. "Clinically they are very different, and if you look at the brain under a microscope they are very different," McGuire says. "But they share a common inflammatory pathway, which is very complex." This suggests that some of the treatments now being used and studied for use with Alzheimer’s disease patients might also benefit patients who have AIDS dementia. "These pathways, so far as they are understood, appear to be affected by anti-inflammatory drugs and antioxidants," McGuire says.
Also, investigators are beginning to look at both Alzheimer’s disease and AIDS populations to see if AIDS accelerates the dementing process among older patients who may also have Alzheimer’s disease, Pulliam says.
From a clinician’s perspective, the findings suggest that HIV-infected patients should be observed and screened for cognitive problems, including the usual symptoms and signs: difficulties with new learning, difficulties retaining information, problems with concentration, clumsiness in walking or dexterity, difficulties with word finding, concentration and memory complaints, and hesitation in speech, McGuire says. "These are classic symptoms of HIV chronic impairment, of subcortical dementia, although memory problems are slightly different on testing than those associated with Alzheimer’s disease," McGuire explains. "Alzheimer’s patients can’t form new memories, and with HIV dementia they can form new memories but can’t access them very easily."
Mistaking dementia for depression
Some HIV physicians may be missing signs of cognitive impairment because they assume that if their patients are depressed, the cognitive problems are due to the depression. Also, clinicians expect that if a patient has AIDS dementia, then it will occur when the patient has a low CD4 cell count and high viral load, and this is no longer the case, McGuire says. "I think with close testing they would find that a majority of these patients who’ve had HIV for a number of years actually have some dementia," McGuire says.
Not all HIV patients will develop dementia, but those who do develop it typically will have been infected for six to 10 years, and they might attribute their symptoms to depression, anxiety, or aging, McGuire says. "Take subjective complaints of memory problems seriously," she advises. "It’s reasonable to try a trial of an antidepressant if there are other clinical signs of depression, but do not hesitate to have the patient undergo psychometric testing." At present, the best treatment appears to be to keep the patient as healthy as possible under HAART, because there are no fully studied treatments for AIDS dementia, McGuire says.
Last year, Pulliam published her finding that a synthetic antioxidant, CPI-1189, reversed all toxic soluble factors produced from monocyte/ macrophages from AIDS dementia patients. Clinical trials in AIDS dementia patients were just completed, and there was a positive effect. "I am conducting a study with a potent antioxidant that is a product derived from olive oil and potentially can be produced for pennies a day," McGuire says. "At the end of this small study I’m doing, I hope to have some lab evidence that it is reducing free radical damage, and if that’s the case, I’m going to lobby for funds and collaborative investigations to look into this."
In the laboratory, at least, both antioxidants and anti-inflammatories appear to be very successful in delaying the cognitive damage in brain cells with AIDS-associated dementia, Pulliam says.
Reference
1. Kusdra L, McGuire D, Pulliam L. Changes in monocyte/macrophage neurotoxicity in the era of HAART: implications for HIV-associated dementia. AIDS 2002; 16:31-38.
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