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Neurocognitive Impairment in HIV: Underrecognized and Increasing


Neurological manifestations of HIV are at least as common as they were before the introduction of HAART. The challenge is that they are milder, and more difficult to recognize. But early treatment is essential.

The advent of the highly-active antiretroviral therapy (HAART) era has dramatically reduced the incidence of severe and life-threatening neurological complications of the virus such as encephalitis and HIV-associated dementia. However, it has not meant the end of neurocognitive impairment.1

In fact, neurological manifestations are as common as if not more common than before the HAART era, says Scott Letendre, MD, associate professor of medicine at the University of California-Diego and an expert in HIV-associated neurological disorders. They are, however, generally milder. The most common is HIV-associated neurocognitive disorder (HAND), which affects an estimated 30- 60% of patients, according to Dr. Letendre.

“In some ways, this can be more problematic for the clinician because more severe conditions are easier to recognize and diagnose,” he adds. With the milder forms, in many cases “you don’t find it unless you look for it.”

Unfortunately, he notes, neurocognitive problems may be viewed as expected in people living with HIV disease because they often have a history of other conditions that can affect the brain such as substance abuse disorders, concurrent infections such as hepatitis C virus (HCF) or syphilis, or other diagnoses, including depression. As a result, clinicians do not always consider HAND.

Increasing Incidence

Several reasons are behind the increased prevalence of HAND, says Dr. Letendre. Particularly relevant is the aging of the HIV population, given that age itself is a risk factor for neurocognitive impairment. However, Dr. Letendre observes, people with HIV tend to develop age-related conditions earlier than the general population.

This is likely related to the chronic inflammation the virus causes and to the attendant vascular damage, he explains, which is also implicated in the high rates of cardiovascular and cerebrovascular disease seen in this population. Certain vascular markers and risk factors, including resting magnetoencephalography, hypertension, hypercholesterolemia, and prior cardiovascular disease, are associated with HAND.2,3

There may also be some correlation between neurocognitive impairment and HAART.4
Risk Factors for HAND

Risk factors for neurocognitive impairment include older age, abdominal obesity,10 higher HIV-1 genetic diversity,6 a history of substance abuse,5 and HCV infection.9

But the most important risk is late diagnosis and treatment, says Dr. Letendre. That’s according to a study from his group that compared cognitive functioning in 200 HIV-positive and 50 uninfected military personnel.

The researchers found no difference in cognitive ability between the two groups. Since military personnel are tested every six to 12 months for HIV and receive immediate treatment, and since they do not demonstrate other risk factors for neurocognitive impairment such as drug use, hepatitis C, or learning disabilities, this clearly supports the fact that earlier diagnosis and treatment are important in preventing HAND, he says. Yet national surveillance finds that about a third of HIV-infected individuals present with an AIDS-defining illness or CD4+ count less than 350.11

“We need to better implement the national plan for early diagnosis and treatment if we are to reduce the risk of cognitive problems,” he says.

That’s why it is important that clinicians monitor their patients’ neurocognitive functioning. In late 2012, the Mind Exchange Working Group (which Dr. Letendre chairs) released recommendations for the screening, diagnosis, and management of HAND that recommended a baseline screening before initiating ART, then screening every six-to-12 months in high-risk individuals and every 12-to-24 months in those at lower risk. The group defined high-risk patients as those who:

•    Demonstrate clinical worsening of HIV disease
•    Have a history of low nadir CD4 count (eg, <200 cells/ μL)
•    Are not receiving ART
•    Do not achieve virologic suppression despite continuous ART
•    Develop new or worsened neurologic symptoms or signs

Diagnosing Neurocognitive Impairment

A key step in identifying neurocognitive impairment is assessing the patient’s daily functioning and identifying any coexisting or preexisting conditions that may be contributing, says Dr. Letendre.

“What we ultimately care about is how well patients are functioning every day,” he explains. “Are they having problems remembering appointments? Taking their medications? Working?” Problems with work, including losing a job, are “sentinel events,” he said. Other clues include problems driving, shopping, paying bills, and cooking meals.

Don’t rely on patient self-reporting alone, he adds. “I think a lot of our patients live with these problems but sublimate them. They figure that it’s a normal part of aging.”

The most common form of HAND is asymptomatic neurocognitive impairment (ANI), which affects about a third of HIV-infected individuals. However, according to Dr. Letendre even “asymptomatic” patients may actually have greater impairment than it appears.

“It depends how you ask,” he says. “If you just say, ‘How are you doing?’ then everyone will be asymptomatic.” But careful probing often uncovers more. One study from his group showed that even patients initially diagnosed with ANI can have performance deficits, “suggesting that ANI may be a much less benign condition than is widely perceived.”

In addition, there is some evidence that ANI portends progression to the more symptomatic form, as those with ANI are 2.2 times more likely to progress to the more severe forms over three years than those with normal cognitive functioning, Dr. Letendre says.

The issue of screening for HAND is controversial, given that existing assessment tools have limited sensitivity. The Mind Exchange recommendations include an algorithm for screening and diagnosing HAND, although the group noted that no single tool is appropriate across all practice settings. Dr. LeTendre suggests starting with the International HIV Dementia Scale screening test or the Montreal Cognitive Assessment, which demonstrate sensitivity rates between 60% and 80%, and which is free to use.

The European AIDS Clinical Society also provides an algorithm for screening, diagnosis, and management of HIV-associated neurocognitive impairment in its most recent clinical guidelines.

Managing HAND

One reason for the debate over screening and diagnosis is that there is no proven treatment for HAND. However, the Mind Exchange group highlighted several treatment practices that can be helpful. Early diagnosis is a crucial step in identifying patients at risk, as well as those in need of more frequent monitoring or specific interventions including medication adherence checks.

Neurocognitive impairment may also be a marker for or associated with other infections, including syphilis, HCV, toxoplasmosis, and cytomegalovirus (CMV).

Nearly all individuals infected with HIV have antibodies to CMV, Dr. Letendre says, but because they rarely develop the severe complications that occurred in the pre-HAART era, they rarely receive treatment. Yet this virus has been linked in the general population to a risk for vascular and cognitive disease, as well as for age-related immune senescence.

“I think the data is really bearing out that this is going to be important,” he adds, although clinical trials are needed to establish whether, in the absence of overt end-organ disease, treating reactivating CMV achieves improvements in neurocognitive function.  The same is true of toxoplasmosis, which the evidence suggests may contribute to neurocognitive impairment even in its quiescent state.

The message, according to Dr. Letendre, is that just because these infections no longer cause the severe damage seen in the pre-HAART era doesn’t mean they shouldn’t be treated. Future clinical trials will identify those conditions that require treatment in order to prevent neurocognitive outcomes.

His group is also exploring the idea that certain HAART medications may help prevent or increase the risk of HAND. For instance, he notes, some therapies, such as darunavir and etravirine, are better able than others to penetrate the blood brain barrier, reach the central nervous system, and eliminate the virus.

“The flip side is that some medications may be worse than others, with emerging evidence that some drugs do cause toxicity in the nervous system,” he adds.

This doesn’t mean that clinicians should switch patients who are already well controlled on HAART to alternative options. In fact, HAART is currently the only recommended “treatment” for HAND, although other drugs, including minocycline, memantine, selegiline, lithium, valproic acid, lexipafant, CPI 1189, peptide T, nimodipine, and psychostimulants, have been evaluated but do not demonstrate consistent benefits.4

However, if HAND persists despite well-controlled HIV, the Mind Exchange group wrote, clinicians should consider HAART neurotoxicity.4

The final message? Diagnose HIV infection early, treat it effectively, assess neurocognitive function regularly in people living with HIV, and be aware of the magnitude of cognitive impairment in this population and its significant impact on their quality of life.



1. Rosca EC, Rosca O, Simu M

et al. HIV-associated neurocognitive disorders: a historical review. The Neurologist (2012) 18(2):64-67.
2. Becker JT, Fabrizio M, Sudre G et al Potential utility of resting-state magnetoencephalography as a biomarker of CNS abnormality in HIV disease. J Neurosci Methods (2012) 206(2):176-182.
3. Wright EJ, Grund B, Robertson K et al Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons. Neurology (2010) 75(10):864-873.
4. Mind Exchange Working G. Assessment, diagnosis, and treatment of HIV-associated neurocognitive disorder: a consensus report of the mind exchange program. Clin Infect Dis. (2013) 56(7):1004-1017.
5. Weber E, Morgan EE, Iudicello JE et al Substance use is a risk factor for neurocognitive deficits and neuropsychiatric distress in acute and early HIV infection. J Neurovirol. (2013) 19(1):65-74.
6. Hightower GK, Wong JK, Letendre SL et al Higher HIV-1 genetic diversity is associated with AIDS and neuropsychological impairment. Virology (2012) 433(2):498-505.
7. Ellis RJ, Badiee J, Vaida F et al CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS (2011) 25(14):1747-1751.
8. Munoz-Moreno JA, Fumaz CR, Ferrer MJ et al Nadir CD4 cell count predicts neurocognitive impairment in HIV-infected patients. AIDS Res Hum Retroviruses (2008) 24(10):1301-1307.
9. Tozzi V, Balestra P, Lorenzini P et al Prevalence and risk factors for human immunodeficiency virus-associated neurocognitive impairment, 1996 to 2002: results from an urban observational cohort. J Neurovirol. (2005) 11(3):265-273.
10. McCutchan JA, Marquie-Beck JA, Fitzsimons CA et al Role of obesity, metabolic variables, and diabetes in HIV-associated neurocognitive disorder. Neurology (2012) 78(7):485-492.
11. Centers for Disease Control and Prevention. Vital signs: HIV testing and diagnosis among adults--United States, 2001-2009. MMWR Morb Mortal Wkly Rep. (2010) 59(47):1550-1555.

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