Exploring the impact of aging on the brains of HIV-positive and HIV-negative people

• A French study compared neurocognitive function between people with and without HIV
• HIV-positive participants were more likely to have some degree of neurocognitive impairment
• However, most participants with impairment experienced mild or no symptoms

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.

The situation today

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.

Will aging increase the risk for brain degeneration in people with HIV?

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.

A study in France – ANRS EP58 HAND 55–70

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.

Study details

Scientists at six major hospitals in France recruited HIV-positive people who met the following criteria:

• were between 55 and 70 years of age
• had a viral load less than 50 copies/mL for the 24 months before they entered the study
• had a CD4+ count of at least 200 cells/mm³ for the past 12 months before they entered the study

The scientists stated that people in the following groups were not enrolled:

• people with confusion
• people with a history of brain disease
• people with major psychiatric syndromes
• people who had an injury to their senses (taste, touch, smell and so on)
• people who were in prison
• people who had undergone extensive neuropsychological evaluation in the past six months
• people who were not fluent in French

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:

• 55 to 59 years
• 60 to 64 years
• 65 to 70 years

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:

• be “active smokers and cannabis consumers”
• have “increased rates of cardiovascular and chronic kidney disease”
• be “less physically active”
• live alone
• be gay, bisexual or other men who had sex with men (MSM)

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:

• HIV-positive people – 36%
• HIV-negative people – 24%

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)

• HIV-positive people – 25%
• HIV-negative people – 19%

Mild neurocognitive disorder (MND); this can cause a mild to moderate degree of interference in daily functioning

• HIV-positive people – 11%
• HIV-negative people – 5%

Dementia

• HIV-positive people – 1 participant (0.5%)
• HIV-negative people – 3 participants (0.3%)

Bear in mind

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:

• “more severely [neurologically] impaired patients may have died at earlier ages, leaving increasingly mildly affected patients represented in the older cohorts”

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:

• the recommended combinations of ART have changed over time
• the timing of initiation of ART has changed over the years

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.

Alzheimer’s disease—no increased risk

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.”

For the future

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.”

Notes on neurocognitive impairment and HIV

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:

• substance use
• nutritional deficiencies, including vitamin B₁₂ deficiency
• traumatic brain injury
• obstructive sleep apnea, disturbed sleep
• psychiatric illnesses: anxiety disorders, major depression, bipolar disorder
• risk factors for stroke and premature aging of blood vessels in the brain: diabetes, higher-than normal blood pressure, abnormal cholesterol levels

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.

Not a one-way street

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.

How HIV-related brain injury is classified today

Scientists who study the brain today divide HIV-related brain injury into the following three categories:

• Asymptomatic neurocognitive impairment (symptom-free neurocognitive impairment) – In such cases, testing detects subtle or mild degradation of, or decline in, memory and thinking processes not seen in people of the same age who have a similar level of education. This decline is not sufficiently serious to affect a person’s ability to engage in everyday activities.
• Mild neurocognitive disorder (MND) – Testing detects at least a modest decline in memory and thinking processes. Memory and thinking processes are functioning below what would be seen in healthy people of the same age and educational level. In cases of MND, the ability to carry out everyday activities is usually only somewhat affected.
• HIV-related dementia – Testing reveals a severe decline in clear thinking and memory and a moderate to severe decrease in the ability to carry out activities of everyday living.

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 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

REFERENCES:

1. Makinson A, Dubois J, Eymard-Duvernay S, et al. Increased prevalence of neurocognitive impairment in aging people living with human immunodeficiency virus: The ANRS EP58 HAND 55–70 Study. Clinical Infectious Diseases. 2020; in press.
2. Clifford DB. Thinking about getting older with human immunodeficiency virus. Clinical Infectious Diseases. 2020; in press.
3. Koenig S, Gendelman HE, Orenstein JM, et al. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science. 1986;233(4768):1089-1093.
4. Saloner R, Heaton RK, Campbell LM, et al. Effects of comorbidity burden and age on brain integrity in HIV. AIDS. 2019 Jun 1;33(7):1175-1185.
5. Saylor D, Dickens AM, Sacktor N, et al. HIV-associated neurocognitive disorder—pathogenesis and prospects for treatment. Nature Reviews Neurology. 2016 Apr;12(4):234-248.
6. Navia BA, Jordan BD, Price RW. The AIDS dementia complex: I. Clinical features. Annals of Neurology. 1986 Jun;19(6):517-524.
7. Brew BJ, Barnes SL. The impact of HIV central nervous system persistence on pathogenesis. AIDS. 2019 Dec 1;33:S113-S121.
8. Henderson LJ, Johnson TP, Smith BR, et al. Presence of Tat and transactivation response element in spinal fluid despite antiretroviral therapy. AIDS. 2019 Dec 1;33:S145-S157.
9. Abreu, C, Shrik EN, Queen SE, et al. Brain macrophages harbor latent, infectious simian immunodeficiency virus. AIDS. 2019 Dec 1;33:S189-S196.
10. Spudich S, Robertson KR, Bosch RJ, et al. Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance. Journal of Clinical Investigation. 2019;129(8):3339-3346.
11. Clifford DB. Is successful HIV therapy a Pyrrhic victory for the brain? Journal of Clinical Investigation. 2019;129(8):3052-3053.
12. Solomon IH, Chettimada S, Misra V, et al. White matter abnormalities linked to interferon, stress response, and energy metabolism gene expression changes in older HIV-positive patients on antiretroviral therapy. Molecular Neurobiology. 2019; in press.
13. Chaganti J, Marripudi K, Staub LP, et al. Imaging correlates of the blood-brain barrier disruption in HIV-associated neurocognitive disorder and therapeutic implications. AIDS. 2019;33(12):1843-1852.
14. Davies O, Haynes BI, Casey SJ, et al. Clinical and neuroimaging correlates of cognition in HIV. Journal of NeuroVirology. 2019; in press.