Neurocognitive disorders may be rising in aging patients with HIV

Neurocognitive disorders typically present as patients age, but these conditions pose special challenges in patients with HIV.

“There are two schools of thought with regard to the study and treatment of HIV and aging,” Ronald J. Walent, RN, PhD, assistant adjunct professor in the department of physiological nursing at the University of California in San Francisco, said in an interview. “One is that some HIV pathology can be explained as accelerated processes of aging. The other involves concentrating on HIV as a disease process on its own even though conditions may look similar to conditions we see in older adults without HIV. For that second school, though things are happening to HIV populations that generally happen much later in non-HIV populations, it is really due to HIV pathology, and not an accelerated natural process.”

Victor Valcour, MD, an internist and geriatrician at the Memory and Aging Center at University of California at San Francisco, agreed with Walent and said more study on the topic of neurocognitive impairment in patients with HIV is warranted.

David E. Vance, MD, said even patients who have high ART adherence levels can experience neurological problems. Photo by Siddiqi Ray

“When we started our first cohort of HIV patients who were older than age 50 in Honolulu back in 2001, it was not of great interest to people,” Valcour said. “Now there is a lot of interest.”

Clinicians and researchers in all specialties have begun to brace for the complications that will arise as the boom of HIV populations that survived the early wave of the disease through the ART era grow older.

A silent epidemic

In a presentation made during the International AIDS Conference earlier this year, Valcour called HIV-associated cognitive impairment a “silent epidemic” that is often “out of sight and out of mind” in the clinical setting.

According to Valcour, two kinds of HIV-associated impairment dominate the diagnoses: HIV mild neurocognitive disorder and HIV asymptomatic neurocognitive impairment.

“Together about half of patients who have HIV will have abnormal testing and fall into one of these areas,” he said. “The flip side to that is about 50% of people will test perfectly fine on neurocognitive tests. That may be an indicator as to why it is somewhat of a silent epidemic.”

Valcour cited findings published by Robertson and colleagues in 2008 using data from the AIDS Clinical Trials Group. Among patients who were changing therapy or starting therapy, approximately 39% of them tested in an impaired range when they began treatment, according to Valcour.

“Unfortunately, after these patients were on treatment for 48 weeks, of the people who were healthy, 20% developed impairment over that time,” Valcour said.

Valcour said that when HIV enters the brain, beyond memory loss, there are complications related to concentration, mental slowing, motor skills and behavior.

Neurocognitive disorders

Recent research from a Canadian cohort of 1,651 individuals indicated that 24.5% of patients with HIV and 41% of patients with AIDS were identified as having one or more neurologic disorders. Symptomatic distal sensory polyneuropathy accounted for 10% of those disorders, and HIV-associated neurocognitive disorder accounted for 6.2%.

Patients with at least one neurologic disorder had a mortality rate of 17.6%, compared with 8.0% among patients without neurologic disease. The AIDS-related death rate was 9.7% in patients with neurologic disorders vs. 3.2% in patients without neurologic complications.

There were 53 recognized neurologic disorders recognized in the cohort that ranged from neuropathy to dementia.

Valcour noted that dementia is often considered an age-related disorder, but that the frequency of this particular type of cognitive impairment increases with age, which makes it difficult for HIV clinicians dealing with older patients to separate out where HIV-related impairment ends and those associated with aging, such as Alzheimer’s disease, begins.

David E. Vance, PhD, MGS, associate professor at the Edward R. Roybal Center for Translational Research in Aging and Mobility at the University of Alabama at Birmingham told Infectious Disease News that milder forms of neurocognitive impairment may not be easy to recognize, especially as these problems can present in younger patients with HIV.

Valcour said that less than 1% of HIV-negative patients younger than 60 years experience dementia, but that the rate effectively doubles with each 5-year increment, from 3% to 5% by age 65 up to the 30%-50% range among individuals aged 80 to 90 years. He said that dementia may occur more rapidly and more frequently in HIV-positive populations, but the clinical data are as yet unclear on the issue.

Findings from Beau Ances, MD, PhD, assistant professor of neurology at the Washington University School of Medicine in St. Louis, and colleagues indicated that functional brain demands among 26 individuals with HIV were equivalent to those of 25 HIV-negative controls who were 15 to 20 years older.

Valcour believes that future research may confirm these and other indicators that individuals with HIV may develop dementia faster and more frequently than the general population, but that, at the moment, the lack of evidence is simply a matter of cohort numbers. “We do not have many people over 70 yet,” Valcour said. “We may be able to see changes when we get more HIV populations in that age group.”

Ances told Infectious Disease News that HIV may lead to changes that are similar to what is seen in Alzheimer’s disease. “Patients who have thinking problems have certain markers that we usually see for Alzheimer’s, so the questions are whether HIV leads to accelerated aging in the brain, and whether patients with HIV are more susceptible to Alzheimer’s.”

Ances said that there are no definitive answers to these questions, largely because patients with HIV are just starting to reach the age where these issues would be raised. The issue is further complicated because there is no definitive diagnosis for Alzheimer’s. However, he noted that the amyloid A-beta-42 in the brain and cerebrospinal fluid may be a biomarker for Alzheimer’s, and that patients with HIV in their 40s and 50s — which is generally too young for Alzheimer’s to develop — have deposits of this amyloid.

“This raises the question of whether we should give ART regimens that have higher or lower penetration in the brain,” Ances said. “The jury is still out.”

Neurotoxicity

Scott Letendre, MD, an associate professor of medicine in the HIV Neurobehavioral Research Center at the University of California, San Diego, believes that many researchers may be too cautious in interpreting data about ART penetration into the brain. He said that although many of these data are from retrospective or observational studies rather than randomized prospective trials, the recent findings are more consistent than some physicians acknowledge. The issue of neurotoxicity cannot be dismissed, however.

“The neurotoxicity issue in the brain, early on, was mainly focused on stavudine and didanosine, which are not widely used at this point,” he said. “We are starting to see evidence of longer-term side effects of efavirenz, which is certainly a cause for concern — the problem with neurotoxicity is limited to certain drugs.”

Ances said a large amount of literature indicates that ART may be toxic to the peripheral nerves and cause neuropathy, and it is not a great leap to think that similar dynamics may be happening in the brain.

“We are left with this quandary that it may be good to get into the brain and fight the virus, but it may also be bad for the brain because it affects certain things at the cellular level, particularly in the mitochondria,” he said. “There is a trade-off to be made.”

Letendre urged caution in interpreting the literature. He said that many of the findings from 5 or more years ago on neurotoxicity and penetration in the brain were based on studies that did not have methodological consistency, and should therefore be interpreted carefully.

Letendre tempered his comments by saying that clinicians should be aware of penetration levels when designing regimens for patients who may have complicated risk profiles.

Walent noted that metabolic complications arising from long-term ART also can contribute to neurocognitive problems, and can complicate treatment options.

As people age, the liver’s capacity to detoxify and process medication decreases. Walent said that aging also affects kidney function and the elimination of drug metabolites. These are critical considerations when prescribing medication of any kind, particularly ART.

Vance echoed Walent’s point, noting that continued use of ART creates higher cortisol levels. “This hormone can be problematic,” he said. “In particular, it is not a friend to the brain.”

Another contributor to neurocognitive problems is the mental and emotional stress associated with HIV. (See perspective, at right, for more on this issue).

HIV populations have higher rates of substance abuse and smoking than the general population, which many researchers see as evidence of a circular cause-and-effect phenomenon. Similar observations have been made about associations between HIV and mental illness.

Reservoirs in the brain

Vance said that despite the neurotoxicity discussion, the fact remains that even patients who have high ART adherence levels and who are reaching goals for HIV RNA and CD4 counts experience neurological problems, in part due to reservoirs of the virus in the brain.

Valcour agreed. “Sequestered reservoirs appear to be active in some way, and we are particularly concerned about monocytes,” Valcour said. “Chronic immune activation even in T-cells also may be particularly concerning as well.”

As evidence that reservoirs with HIV may be active, Valcour noted that HIV DNA can still be detected within blood cells of patients with suppressed viral loads. He and colleagues examined 30 individuals in Bangkok, half of whom had dementia at study outset and none of whom had ever received ART. Those with dementia had higher levels of DNA in their monocytes. After a year of successful treatment in terms of plasma and viral load, the patients who did not have dementia had undetectable HIV DNA in their monocytes, whereas patients with dementia were more likely to still have detectable. DNA in their monocytes, according to Valcour.

“This leads me to think that even with the treatment we have, we are not adequately treating in terms of the brain,” he said. “This monocyte reservoir is an active marker that seems to predict who is at risk for cognitive impairment.”

Advice for clinicians

Valcour said that there may be concerns that are unique to HIV patients with neurocognitive disorders.

“My Alzheimer’s patients usually are accompanied by a caregiver or loved one to help, but it is not uncommon for me to see HIV patients alone, making diagnosis more difficult,” he said.

Vance said that some fine-tuning is required in terms of ART and neurocognitive disorders, but that the problem is on the radar. He suggested that until those details are worked out, clinicians should simply be aware of the possibility of impairment.

“If it takes a few more seconds to do a neuropsychological test, we should do it,” he said. “If the problem seems to be impacting the everyday functioning of your patient, it is worth investigating.”

Walent urged clinicians to separate population-level data from individual patients.

“In this population we can see these trends — more cardiovascular disease, bone disease, neurocognitive impairment at a younger age among HIV populations than in the general population — but that is not necessarily happening in every individual,” he said. “Some patients may have a decrease in bone density, but others do not. We need to remember to look at HIV population trends with an eye to how they may apply to each individual.”

Valcour brought the matter back to basics. In addition to appropriate medical evaluation, he encouraged simple solutions such as physical and mental exercise. “Patients should remain physically and cognitively stimulated,” he said. “With so many challenges from aging, the infection and the treatment, the importance of physical exercise in maintaining the health of our patients cannot be overstated.”

This is also true as patients deal with metabolic complications resulting from prolonged ART use, Walent said.

“Long-term treatment may cause various types of metabolic dysregulation,” Walent said. “ART occasionally gets a bad rap, because of side effects that can be difficult to manage, but it is keeping many individualss alive with an acceptable quality of life. Sometimes the treatment seems worse than the ailment, but given the course of disease progression in untreated HIV, even our imperfect therapies are preferable.” — by Rob Volansky

For more information:

• Ances BM. J Infect Dis. 2010; 201:336-340.
• Robertson K. AIDS. 2007; 21: 1915-1921.
• Valcour VG. Journal of Leukocyte Biology. 2010;87:621-626.
• Vivithanaporn P. Neurology. 2010;75:1150-1158.

What other psychological issues do aging individuals with HIV face?

Depression

We have seen a lot of individuals with HIV functioning in fragile social groups, which may not last for the long-term. It is quite possible that as these patients age, they will have less support and, consequently, be more susceptible to depression.

Many of our patients fall into three broad categories with regard to social networks: Those who have support from family and friends; those who have mainly friend-centered networks; and those who are mostly isolated.

Obviously, the isolated group is of the biggest concern, but the other two groups are not necessarily immune to depression. Even HIV-positive individuals with a network of family and friends may not have disclosed to everyone in their circle, and they therefore may not get the kind of support they need. Among the cohort with friend-centered networks, many of the ‘friends’ are drug buddies or other such influences that may not be positive.

Among the New York populations that we deal with, more than 70% of our older patients with HIV live alone; by comparison, it is estimated that about 38%-40% of older adults who do not have HIV live alone. The combination of the stresses of the disease and a lack of informal social support could pose larger problems. On top of this, many of those isolated individuals rely on community-based systems of support, but even though this aging, isolated HIV-positive population is growing, as are their needs, the economic downturn has left many of those community centers marginalized or without resources.

We have seen evidence that ART can have a positive effect on depression. In non-HIV populations, depression is often linked to health status, so the more we can keep comorbid conditions to a minimum, the less likely patients will be to experience depression. However, this issue is often complicated in HIV populations. A key factor is also the high rate of substance abuse, which often co-occurs with other mental health issues or may be a form of self-medication. The stigma and social isolation of HIV can also exacerbate any mental health the substance use issues faced by the client.

Something else to consider is that individuals who have had episodes of depression are more likely to have another episode of depression. An HIV diagnosis can certainly trigger this.

A final piece of the puzzle is summed up by an article I read with the title: ‘HIV is not my biggest problem.’ We are seeing a lot of infections among low-income and minority populations who have a whole host of serious life concerns other than HIV. They deal with crime, unemployment, lack of health care and racial issues that put them at further risk across the board, keep them from treatment and cause ongoing disruption to whatever networks they have.

– Mark Brennan, PhD

Senior research scientist, AIDS Community Research Initiative of America