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Cases of AIDS were first recognized in the early 1980s in North America and Europe. A key observation in those early years was that previously healthy young men had unexpectedly developed severe immune deficiency. As a result, bacteria, fungi and parasites would become opportunistic—take advantage of weakened immunity—and ravage major organ systems, including the brain.
However, in the early years of the pandemic there was no obvious cause for the cluster of brain issues that some people with HIV developed. This cluster of issues included challenges with concentrating, performing calculations, memory and thinking clearly. Eventually scientists were able to identify HIV infection as the underlying cause of these problems. As there was no effective HIV treatment in those early days, symptoms would steadily grow worse and additional problems could appear, including difficulty coordinating muscles and movement, severe changes in personality and, in extreme cases, dementia.
Fast forward to the present and the widespread availability of potent combination HIV therapy (ART) in Canada and other high-income countries has dramatically changed the landscape of AIDS. ART helps to suppress HIV to very low levels commonly called “undetectable,” and continued adherence helps to keep HIV levels suppressed. This allows the immune system to begin to effect repairs, generally raising CD4+ cell counts to within the normal range and keeping AIDS-related infections at bay. As a result, scientists expect that many ART users will have a near-normal life expectancy.
Studies in the current era using extensive neuropsychological testing have found that low-grade brain injury, called neurocognitive impairment, is relatively common among HIV-positive people. The good news is that in most cases of neurocognitive impairment in HIV-positive people who have an undetectable viral load thanks to ART, individuals are usually symptom free or experience only minor impairment. What’s more, studies have found that HIV-related dementia is relatively rare in Canada and other high-income countries in people who maintain an undetectable viral load.
Note that in general, most of the studies of neurocognitive impairment in the current era have involved relatively young HIV-positive people. Large, longitudinal studies are needed with older ART users.
As HIV-negative people age, their risk for neurocognitive decline generally increases. The same trend should be expected in HIV-positive people. What’s more, some neuroscientists think that the neurocognitive decline in HIV-positive people might be faster and more intense than in HIV-negative people because of HIV’s known impact on the brain.
To begin to explore the issue of aging and neurocognitive function, scientists in France conducted a well-designed study called ANRS EP58 HAND 55–70. They enrolled 200 HIV-positive and 1,000 HIV-negative people between the ages of 55 and 70 years: each HIV-positive participant was randomly matched with 5 HIV-negative participants on the basis of age, gender and education level. All HIV-positive people in the study had a suppressed viral load (less than 50 copies/mL) and at least 200 CD4+ cells/mm3 in their blood samples thanks to ART. All participants underwent extensive neuropsychological testing.
The scientists found that about 36% of the HIV-positive participants and 24% of the HIV-negative participants had some degree of neurocognitive impairment. After taking many factors into account in their statistical analysis, they found that HIV infection was associated with an increased risk of neurocognitive impairment. However, the vast majority of people with such neurocognitive impairment were either symptom-free (asymptomatic) or had mostly mild symptoms.
Later in this CATIE News bulletin we help to put these findings into context and highlight important non-HIV factors that can affect neurocognitive functioning.
Scientists at six major hospitals in France recruited HIV-positive people who met the following criteria:
The scientists stated that people in the following groups were not enrolled:
HIV-positive participants were recruited sequentially during routine clinical visits. The study protocol ensured that about one-third of participants were in each of the following age categories:
HIV-negative people were used as a comparison or control group and were recruited from a pre-existing cohort called Constance. People in Constance had been randomly selected from the population.
The French scientists then matched the data from each HIV-positive person with the data from five HIV-negative people of similar age, the same gender and the same educational background.
Rates of cardiovascular disease and diabetes were similar in the HIV-positive and HIV-negative groups.
In comparing data from the two groups of participants, the scientists found that overall, HIV-positive people were more likely to:
Each person in the study underwent a neurocognitive assessment once. This was therefore a cross-sectional study with data collected at one time point.
According to the scientists, the overall distribution of neurocognitive impairment was as follows:
The scientists stated that “most [neurocognitively] impaired individuals were asymptomatic.” They also calculated the distribution of different classifications of neurocognitive impairment, with the following results:
Asymptomatic neurocognitive impairment (ANI)
Mild neurocognitive disorder (MND); this can cause a mild to moderate degree of interference in daily functioning
Dementia
Some issues with the present study:
Age
In this study, scientists found that 36% of HIV-positive people aged between 55 and 70 years had some degree of neurocognitive impairment. This is a somewhat higher prevalence than what was found in earlier studies of people with a suppressed viral load. However, those earlier studies tended to enrol younger people.
The overall distribution of neurocognitive impairment in the French study is similar to what was reported in other large studies with HIV-positive people.
Survival bias
One important issue to keep in mind when thinking about the French study is a factor scientists call survival bias. Neurology professor David Clifford, MD (Washington University, St. Louis, Missouri), has much experience studying HIV’s effect on brain health. He explained survival bias in the French study in this way:
Thus, the study’s conclusion that most older people with HIV have only mild neurocognitive impairment may be inadvertently biased. While this conclusion is true about the people in this study, it may not be true for all HIV-positive people.
Professor Clifford raised other issues about the French study, such as these:
These and other unmeasured factors could have had an impact on the distribution and intensity of neurocognitive impairment among HIV-positive people in the study. Such factors need to be taken into account in a future larger study that monitors the brain health of HIV-positive people over a period of years.
According to Professor Clifford, “the elephant in the room related to serious, age-related cognitive decline [among people with HIV] is Alzheimer’s disease (AD). While the prevalence of AD in the general population rises above age 70, it is logical that if there were an acceleration of AD related to HIV, it should be emerging in this population as [HIV-positive people] approach 70. That was not seen.” In support of this finding, Professor Clifford noted that “there are actually only a very few case reports of documented AD in any HIV-positive patients.”
Professor Clifford stated, “Finding a marked increase in neurocognitive impairment in aging [HIV-positive people] is a sobering task, and calls on healthcare providers to prepare additional support and therapy for the associated disability that this population suffers.”
He noted that there are some reassuring signals from the French study: “The majority of disabilities identified were asymptomatic or caused only minor disability.” Among HIV-positive people, “only 1 patient in 200 had dementia. Further, the mix of [neurocognitive impairment] did not worsen with successively older cohorts, up to age 70.”
Professor Clifford added that the outcome of the French study “emphasizes significant and ongoing disabilities that we have yet to reverse and which are associated with HIV. Our HIV clinics will need to expand services to protect and support these patients appropriately. Meanwhile, prospective studies will be required to understand the details of interactions with HIV, its treatment, and associated conditions as patients enter the later years of their lives.”
Many factors can affect brain health. Other scientists who study HIV’s impact on the brain have noted that the following issues can affect a person’s neurocognitive abilities.
Age
A well-designed study in Hawaii found that HIV-positive people who are over the age of 50 are twice as likely as their younger counterparts to develop HIV-related dementia. A second American study of HIV-positive people found that older age was associated with worse neuropsychological assessments. However, scientists caution that older people in the second study tended to have higher than normal blood pressure, excess weight, elevated levels of cholesterol and a previous diagnosis of AIDS. It is therefore possible that the supply of oxygen and nutrients to the brain was reduced in these people because of cardiovascular disease. Thus, it is plausible that in that second study, cardiovascular disease could have contributed to older participants’ neurocognitive impairment, not just their age. We discuss the importance of cardiovascular disease below.
Cardiovascular disease
Several studies have found that the presence of cardiovascular and metabolic diseases in HIV-positive people contributes to poor neurocognitive performance. Diabetes, narrowing of the arteries, higher than normal levels of cholesterol and tobacco use can all weaken the health of the brain and lead to poorer neurocognitive performance.
Other factors
Additional issues identified by neuroscientists that can affect brain health independently of HIV include the following:
Thus, before one can assume that forgetfulness is caused by HIV-related injury to the brain, many other issues first have to investigated and ruled out.
In the current era, a premature decline in neurocognitive functioning does not mean that improvement cannot eventually occur. It can be helpful if doctors evaluate patients for underlying issues and address any issues they find. There are anecdotal reports of HIV-positive people recovering from mild to moderate neurocognitive impairment and premature neurocognitive impairment after underlying cardiovascular and metabolic factors were diagnosed and treated. Some hospitals in large cities have neurocognitive rehabilitation programs for people affected by HIV infection and other conditions.
There are also studies underway testing different interventions to try to reverse mild to moderate neurocognitive impairment. Results from these studies should be available in several years.
Scientists who study the brain today divide HIV-related brain injury into the following three categories:
All three categories now make up what researchers call HAND – HIV-associated neurocognitive disorder. Rates of HAND in studies conducted in the current era vary between 15% and 55%. However, it is important to note that the vast majority of people living in high-income countries who have HAND today are either not experiencing symptoms or their symptoms are mild.
Resources
A Mind of Her Own – Positive Side
Brain fitness leads to improvement for some HIV-positive people – CATIE News
Exercise found to improve memory – CATIE News
Exercise and the brain – TreatmentUpdate 203
Good for the brain—advice from neuroscientists – TreatmentUpdate 203
Menopause and HIV—their impact on cognition – TreatmentUpdate 203
—Sean R. Hosein
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