Researchers Look to Adjunctive Therapies to Treat NeuroAIDS
by Chael Needle
LifeGuide [Treatment Horizons]
In the years before HAART, HIV-associated neurologic disease typically meant dementia marked by rapid and acute damage. While HAART has improved immune response and slowed down HIV-associated neurologic disease, or neuroAIDS, it has not been found to cure the condition, the nerve damage that can manifest as a loss of attention span, memory, speaking ability, movement, and decision-making skills. No approved treatment exists for neuroAIDS, a condition that is estimated to affect one in five patients with HIV.
Thinking Outside the Antiretroviral Box
Now researchers are looking at molecular targets—proteins released by HIV and chemicals released by human cells reacting to them—as the toxic culprits of neuroAIDS. Recently, researchers at the University of Rochester Medical Center received a $7 million grant from the National Institutes of Mental Health to confirm that two new drug classes can protect the brain from HIV-related nerve damage.
HIV “thus far still seems smarter than Big Pharma and human behavior and we’re still a long ways away from having a strategy to effectively eradicate it either by vaccination or by chemotherapy,” says Dr. Harris A. Gelbard, MD, PhD, a professor in the Department of Neurology at the Medical Center and principal investigator on the new grant. “The best we’ve been able to do (which is an incredible achievement) has been to get most people to be able to live with the virus. But living with it is far from perfect.” That is, HAART is not 100 percent effective and can come with its own side effects, and such conditions as neurologic disease need additional therapies, and ones alternative to (but compatible with) HAART. In addition, successful HAART therapy—suppressed viral load and increased T-cell counts—does not mean neuroAIDS won’t develop.
Researchers learned early on, notes Dr. Gelbard, that many of the antiretrovirals “have poor or incomplete penetrability into the brain, and that the virus gets into the brain early—within days or weeks of infection.” But while the “classic” form of HIV-associated dementia (HAD) abated in the HAART era, the percentage of those who would develop HIV-associated neurologic disease continued to rise.
After HAART stabilized or suppressed viral replication in many of the patients who were in treatment, neuroAIDS researchers began to learn more about HIV’s particular effects on the brain. Dr. Gelbard mentions for instance a reversal of the understanding that neurologic disease, once it began, was a “one-way sort of ticket. You weren’t going to get better. You were just going to keep losing faculties. Well, that wasn’t the case.” Researchers have realized that neurologic disease has a reversible component, though ultimately not wholly reversible. Adjunctive therapies could potentially capitalize on this partial reversibility as well as protect the brain for as long as possible.
Assessing NeuroAIDS
Dr. Giovanni Schifitto, MD, who heads up the clinical trials component of neuroAIDS research at Rochester, as well as sees patients in the neurology clinic and as part of ongoing epidemiological studies, which in part are looking at predictors of progression in both dementia and neuropathy in collaboration with other institutions, says that the tools used for neurologic assessment have not really changed since the pre-HAART era. The minor (mild to moderate) cognitive deficits that patients, even in those whose viral replication is controlled, continue to show on their tests cannot be directly assessed, says Dr. Schifitto. “We cannot take the brain out and check it. So we have to rely on clinical and other noninvasive tools,” such as MRI and other imaging technologies.
“Images are the closest things that we have to look at the brain. The difference compared to before is that in an untreated disease the brain changes are quicker to see and follow and [it’s easier to] predict what is going to happen clinically.” With patients in antiretroviral treatment, structural changes are not going to happen quickly and more sophisticated imaging techniques are used to chart these more subtle changes.
From his personal experience in the clinic, Dr. Schifitto says that patients are typically referred for “formal cognitive assessment when there are complaints from the patient or the family members that things are not going in the right direction.” It’s not standard, he says, for patients to be referred for baseline cognitive batteries, and points to limited resources as one of the reasons that this is not routine.
He also mentions that patients are also referred for psychiatric treatments because of mood disorders when in fact they might be suffering from cognitive impairment; HIV-associated neurologic disorders and other subcortical diseases like Parkinson’s and Huntington’s often present with mood disorders. Dr. Schifitto recommends that patients who are referred for psychiatric assessment be referred for neurologic assessment as well.
Ups & Downs
A “progressive loss of mental faculties” impinges on one’s quality of life of course, notes Dr. Gelbard, limiting one’s ability to be independent. As neuroAIDS often appears like milder forms of Parkinson’s and Alzheimer’s, it seems often manageable at first. This is a gross approximation, says Dr. Gelbard, but living with the disease neurologically is like being seventy-five percent of yourself. “If you are at the limits of your cognitive reserve then you’re easily overwhelmed, aren’t you? So if you have to do all of the things that you normally have to do in the course of the day that involve multitasking then you are going to come up short.
And some of those may have more serious repercussions than others, hence the need for adjunctive therapies.” The burden that neurologic conditions place on you also ups the ante, makes you more overwhelmed cognitively. No one is really sure however if this burden speeds up the progression. “What’s clear is that over the long haul people get worse but without a clearly demarcated, stepwise progression such that ‘one month from now, you’ll lose this much ability; six months from now you’ll lose ten percent more and so until you have nothing left to lose’—it’s not this neat, linear process; [it’s not] like a tree that’s losing its leaves in autumn. Some days you’re better, some days you’re worse. Overall if you look at the big picture between now and five years from now, you’re definitely going downhill. In point of fact, it used to be in the days before HAART, once someone had been diagnosed with neurologic disease pretty much six months from the time of that diagnosis, you were going to be dead. Now it’s much more like four to five years,
or longer.”
NeuroAIDS often goes unnoticed for many patients. “A lot of our patients within [one of his study cohorts] are not working so it’s hard to know what they are missing,” Dr. Schifitto says about a situation where cognition is not being called upon regularly to perform. “If somebody has not been stressed in that sense, then they don’t necessarily realize how much they’re missing.”
Dr. Schifitto reminds that a well-controlled virus does not mean that the virus is under control 100 percent of the time, and that not a lot of virus is needed in the brain to “cause an immune response that can activate cells that release inflammatory products that can damage the brain. So you can imagine having a little inflammation that continues to be there, up and down according to how much the virus is driving this double inflammatory reaction. Over the years it will continue to be a source of damage to the brain so we’re not talking about a big hit in a short period of time; we’re talking about more hits but now for decades.”
Aging itself can play a factor. In addition to HIV, says Dr. Schifitto, patients might have age-related burdens, such as high blood pressure and diabetes, which are two common risk factors for strokes and vascular dementia. Age is another risk factor for Alzheimer’s disease, he adds. These in conjunction with HIV can create multiple hits to the brain. “And it’s possible HIV may accelerate some of those risk factors, too. So we know one of the problems that antiviral drugs do have, like the protease inhibitors, is interfering with glucose tolerance so some of these patients are developing diabetes. We know that some of these drug regimens are increasing cholesterol and triglycerides and so patients need to be taking protective agents to lower cholesterol and triglycerides. The picture is going to be a little more complicated as we on the one hand are struggling and working toward treating things that are just HIV-linked, one way or the other, but we have to take into consideration also other factors that are just part of aging as one of the significant impacts on this population.”
New Candidates
The new grant funds research into drugs that inhibit mixed lineage kinase (MLK), a molecular target first suggested by Stephen Dewhurst, PhD, Dean’s Professor of Microbiology and Immunology at the Medical Center, based on the work of his colleagues, Dr. Gelbard and Sanjay Maggirwar, PhD, assistant professor in the Department of Microbiology and Immunology at the Medical Center. The grant also funds another molecular target, glycogen synthase kinase 3 beta (GSK-3b). Earlier research conducted by Drs. Maggirwar and Gelbard identified an enzyme, GSK-3b, that damages the brain if overactivated by HIV.
GSK-3b research is now focused on valproic acid and lithium, existing epilepsy drugs found to inhibit the enzyme. Dr. Schifitto reports that they have already conducted two studies with valproic acid, one of which was a pharmacokinetic study in humans. “[The study] showed no significant interaction with protease inhibitors and non-nucleosides, particularly Sustiva. That led to a second phase, a small proof of concept trial using both imaging and clinical outcomes. And in that study we showed that there was not an obvious clinical improvement—again these are short studies to get some pilot data on the drug and then apply for a larger study. [Using MRI spectroscopy] we saw some significant improvement in the imaging component of that study.” A grant application to confirm the data of this pilot study and expand the knowledge base of valproic acid was sent to NIH for a larger, multicenter study. The study on lithium is finished but the results have not been reported yet as analysis has not been completed, according to Dr. Schifitto.
“We are now waiting for a third drug, which is an experimental drug manufactured by Cephalon: CEP-1347. This drug has entered some in vitro studies but the animal studies have not been performed yet. We’re waiting for results from the initial animal study, which has been ongoing for the past month.” The animal study, led by Dr. Howard E. Gendelman, is being conducted by the Center for Neurovirology and Neurodegenerative Disorders (CNND) at the University of Nebraska Medical Center, which is partnered on the grant with the University of Rochester. CEP-1347, a mixed lineage kinase 3 (MLK3) inhibitor, has a different mechanism of action than valproic acid and lithium, and Dr. Schifitto reports that they have “some pretty promising, interesting results in vitro; we hope that the animal studies will confirm and extend those results. But we’ll have to wait and see.”
Chael Needle wrote about microbicide candidate, Amphora, in the October issue.
November 2006
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