Neurological disorders strikingly high among HIV/AIDS patients

"They assumed [it] would go away, but that's not the case."

New research suggests that roughly half of HIV patients might have some neurocognitive impairment, although most of this might be asymptomatic or mild.

"Neurocognitive impairment in HIV remains a problem even though we have treatments that allow people to live longer and healthier lives," says David J. Moore, PhD, assistant professor of psychiatry at the University of California, San Diego (UCSD).

"Most of the impairments are relatively mild, but they do have an impact on people's daily functioning: their ability to drive, ability to maintain employment, and those kinds of things," Moore says. "So our research group program is dedicated to trying to figure out what's going on and what are some of the underlying factors."

HIV dementia was one of the alarming changes that took place in AIDS patients prior to the advent of highly active antiretroviral therapy (HAART), but it fell off the general HIV community's radar once the potent new drugs made it possible for people to live longer and healthier.

"Once people saw the antiretrovirals were working and allowing people to live longer and healthier lives they assumed neurocognitive disease would go away," Moore says. "But that's not the case."

Research has shown that HIV infection ages the human brain by about 15 years,1 says Amanda Brown, PhD, assistant professor in the department of neurology and co-director of translational research in neuro-AIDS at the Johns Hopkins University in Baltimore, MD. Brown also is the National Institutes of Mental Health (NIMH) development co-director of the Johns Hopkins Internship in Brain Sciences.

"It didn't matter what age you were, your brain looked 15 years older," Brown says.

Brown's research provides a possible answer to why this happens. Her study shows that osteopontin, an inflammatory marker, stimulates HIV-1 replication. High levels of osteopontin are present in the central nervous system of HIV-infected people despite antiretroviral therapy. Inflammatory macrophages play a role in HIV dementia.2

"Osteopontin was discovered as an early t-cell activation marker," Brown says. It's been found to be highly expressed in many neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease."

Another recent study found that HIV neuromedical factors, including lower CD4 nadir and detectable HIV RNA were associated with white matter damage in the brain.3

"What we were trying to do is look in detail at MRI data from brain scans of patients in the CHARTER study, and we conducted some analyses that provided different measures of integrity of the brain," says Terry L. Jernigan, PhD, professor of cognitive science, psychiatry, and radiology, University of California, San Diego. Jernigan also is the director of the UCSD Center for Human Development.

"We wanted to know if there was a pattern of clinical markers that predict who is going to have better or worse brain integrity," Jernigan explains. "The result of this was not surprising even in the context of how complex HIV disease is: there was a pattern associated with indices of impairment of the brain's integrity, and one factor most consistently related to evidence of brain tissue volume lost."

The white matter compartment of the brain is particularly vulnerable to HIV disease, she adds.

"The volume of white matter compartment was particularly lower in individuals who had a history of severe immunosuppression," Jernigan says. "If in the course of HIV illness you were severely immunosuppressed, you had more brain matter loss."

Deterioration or changes in white brain matter can lead to difficulties in concentration and psychomotor slowing, she adds.

"People will feel they are not able to respond as quickly doing a complicated motor task," Jernigan says. "Those kinds of symptoms are commonly reported by patients who have some sort of damage to cerebral white matter."

One pattern noted was that HIV subjects who had a lower nadir CD4 cell count had little more brain volume loss, even if their current CD4 cell count was higher, than did people who had a nadir CD4 and current CD4 cell count that were closer together, Jernigan says.

"Those whose CD4 cell count had recovered had more brain volume loss," she adds. "It's a puzzling finding, and we are unsure what that might be telling us."

Aging can impact white matter volume, as well, but Jernigan and co-investigators controlled for that in their analysis.

Another finding in the study was that HIV-positive people who also are infected with hepatitis C had some inflammatory changes in their white matter that were associated with comorbid HIV/HCV infection, Jernigan notes.

"That suggested there was a heightened inflammatory response in the brain, a heightened immune response," she says. "HIV alone was associated with an increase in that, but HCV increased that further."

What HIV patients experience as neurocognitive decline is probably related to damage that occurs when they are severely immunosuppressed, Jernigan notes.

"So going forward we will want to work very hard to prevent those severe episodes of immunosuppression," she adds.

With HAART, neurological health is far better than what it had been since the treatments have reduced the amount of brain damage that occurs in HIV patients, Jernigan says.

"But because patients will have to take these treatments for a very long time they could have subtle effects on the brain, and we need to understand those," she explains. "In other words, things are much better but there does seem to be some continuing problems with the brain."

One reason for this might be the fact that HIV can hide in the brain, using it as a reservoir. Many drugs do not cross the blood-brain barrier.

Some drug combinations can cross that barrier, but in light of findings that HIV can enter the brain within 15 days, some damage is done before treatment is initiated, Brown says.

This could explain why some recent research suggests that neurocognitive decline is very common in HIV-infected populations, although much of it is unrecognized by patients and clinicians because it's asymptomatic.

Half of the HIV-infected subjects enrolled in a study that looked at the neurocognitive impact of substance use were diagnosed with HIV-associated neurocognitive disorder (HAND), a new study shows.3

"The latest criteria for cognitive disorders associated with HIV includes a milder form, which we refer to as asymptomatic," says Desiree A. Byrd, PhD, an assistant professor of pathology and psychiatry at the Mount Sinai School of Medicine in New York, NY.

"They are suffering from neurocognitive problems but their daily activities are not impacted," she explains. "For example, they are not forgetting to pay bills or cooking and burning food."

In Byrd's study, the findings regarding the impact of substance use were surprising: HIV neurocognitive effects were similar in HIV patients with and without historic substance abuse.4

"I was very surprised by the outcome," Byrd says. "These were not a group of active substance users; the findings might have been different if that was the situation, but most of our group had abused substances in the past."

The study divided subjects into three groups, including those who reported no substance use, those who reported past drug or alcohol dependence, and those who admitted past substance use, but did not consider themselves dependent.

"We had participants estimate the amount they had used over their lifetimes," Byrd says.

This study is a cross-sectional study that looks at one point in time. So it would be interesting to look at the neurocognitive status of patients over time since HAND can fluctuate, she notes.

"So perhaps people with substance use have a worst course," she adds.

A positive result of the study is that it suggests that prior substance use does not need to be exclusion criteria in HIV and neurocognitive research, Byrd says.

"One message for HIV researchers is that they do not need to exclude HIV participants from cognition studies because of a history of substance use," she says. "You'd be excluding an important part of the HIV cohort."

What may have an impact, according to another recent study, is a family history of dementia.

"HIV-infected people who endorsed having a history of dementia in their families had higher neurocognitive disorder scores than those without a family history," Moore says.

Family history is a risk factor for HAND, Moore's study finds.5

"Our study basically shows that if you have this risk, which is probably a genetic susceptibility risk, then you are more likely to show worse performance," he explains. "I think this is one of many susceptibility factors for possible development of neurocognitive impairment in HIV-infected people."

The proportion of people who had neurocognitive impairment was 53% in the group with a family history of dementia, and it was 47% in the group that did not have that history, he adds.

"It was a significant effect," he says.

In light of these recent neurological findings regarding HIV patients, clinicians could focus on several positive changes:

• The first would be to use neurocognitive screeners, even if these are not optimal. One would be the International HIV Dementia Scale, Moore suggests.

• "Another thing is that having a low CD4 count seems to be a biological factor associated with cognitive impairment," Moore says. "So you should treat people earlier and prevent them from getting a very low CD4 count."

This strategy possibly could prevent patients' CD4 counts from falling very low, he adds.

• A third strategy is to use antiretroviral drugs with higher central nervous system (CNS) penetration, Moore says.

"Some HIV medications have a high CNS penetration and can cross the blood brain barrier better," he says.

References

  1. Ances BM, Vaida F, Yeh MJ, et al. HIV and aging independently affect brain function as measured by functional magnetic resonance imaging. J Infect Dis 2010:201(3):336-340.
  2. Brown A, Islam T, Adams R, et al. Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals. J Neuroviral 2011;17(4):382-392.
  3. Jernigan TL, Archibald SL, Fennema-Notestine C, et al. Clinical factors related to brain structure in HIV: the CHARTER study. J Neuroviral 2011;17(3):248-257.
  4. Byrd DA, Fellows RP, Morgello S, et al. Neurocognitive impact of substance use in HIV infection. JAIDS 2011;58(2):154-162.
  5. Moore DJ, Arce M, Moseley S, et al. Family history of dementia predicts worse neuropsychological functioning among HIV infected persons. J Neuropsy & Clin Neurosci 2011;23(3):316-323