An intriguing shift in cognitive abilities

A team of researchers at the University of California at San Diego (UCSD) has been studying HIV-related brain issues for many years. In past studies the UCSD team has documented the presence of mild HIV neurocognitive impairment in some ART users. These studies were generally cross-sectional in nature; that is, they assessed participants at one point in time. Now the UCSD researchers have conducted a more meaningful study: They monitored neurocognitive changes in more than 300 HIV-positive people for at least four years. The researchers found that some participants who initially had mild, symptom-free brain injury were at significantly increased risk for subsequently developing symptoms of HIV-related neurocognitive impairment.

Caution for readers

Some readers may understandably find these results distressing. However, later in this report, we explain the findings from the UCSD study and place them in context. Furthermore, it is important to note that not every HIV-positive person will develop neurocognitive impairment (caused by HIV) in the present era. Also in this issue of TreatmentUpdate, we present research findings about ways that scientists are exploring to try to remedy HIV-related brain injury. Readers should note that preliminary results from a Canadian study that is in progress suggest that is possible to reverse the decline in neurocognitive functioning that can sometimes occur with HIV. However, before we discuss that study, we first deal with the San Diego research.

Study details

Researchers analysed data collected from 347 HIV-positive participants who were part of a large observational study called the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER). The 347 participants underwent extensive assessment of neurocognitive functioning every six months, in addition to regular HIV and immunologic assessments. Also, researchers performed spinal taps (lumbar punctures) so as to get a sample of the fluid that surrounds the brain and spinal cord. This fluid is called CSF (cerebrospinal fluid).

On average participants were monitored for four years.

At the start of the study, the 347 participants were distributed as follows:

• symptom-free neurocognitive impairment – 121 people
• neurocognitively normal – 226 people

Researchers asked participants to rate their ability to carry out their daily activities. Among participants who were employed, researchers asked them about changes in their productivity, the accuracy and quality of their work and the effort required to produce such work. All of these assessments by participants were called self-reports.

Psychologists know that self-reports are not always accurate for at least the following reasons:

• denial
• loss of insight
• alteration of behaviour to avoid challenges

Mindful of these issues, the CHARTER team also developed its own assessments of daily functioning, called performance-based measures.

Here is the average profile of participants at the start of the study:

• age – 43 years
• gender – 82% men, 18% women
• years of education – 13
• having been diagnosed with substance use in the past – 70%
• having been diagnosed with major depression in the past – 50%
• CD4+ count – 440 cells/mm³
• currently taking ART – 70%
• proportion of participants with viral load in the blood less than 50 copies/ml – 43%
• proportion of participants with viral load in CSF less than 50 copies/ml – 68%
• estimated time living with HIV – 10 years
• proportion of participants with hepatitis C virus (HCV) co-infection – 24%

Results—Overall

Using any of three metrics—self-reports, performance-based measures, or a combination of both—researchers found that having symptom-free neurocognitive impairment was significantly associated with an increased risk for the future development of symptoms of such impairment.

Results—Participants with low viral loads

When researchers restricted their analysis only to people whose viral load in the blood at the start of the study was less than 50 copies/ml, the increased risk for developing symptoms of neurocognitive impairment was still found and was statistically significant.

Researchers continued to focus on participants who had a low viral load (less than 50 copies/ml) and found that among this subset, self-reports did not achieve a statistically meaningful relationship in their ability to predict the decline of the brain. Perhaps this is because of reasons previously mentioned (see Study details).

Several factors

Also, after the researchers took into account IQ levels, lowest-ever CD4+ count and years of education, having symptom-free neurocognitive impairment was still associated with an increased risk for developing symptoms of this problem.

A closer look

According to the study team, the proportion of participants who eventually developed symptoms of impaired neurocognitive functions entered the study with the following neurocognitive status:

• symptom-free impairment at the start of the study – 50%
• normal neurocognitive functioning – 22%

In general, the researchers found that people who had symptom-free neurocognitive impairment at the start of the study were more likely to develop symptoms of such impairment. Some participants became somewhat disabled as a result of this worsening impairment.

Researchers found that, overall, participants whose neurocognitive functions declined during the course of the study tended to have the following profile:

• “were older, had less education, were more often female, were more likely to have [been diagnosed] with a substance use disorder [at some point in their life], had greater than [minimal] comorbidity…”

Points to consider

1. The results from the present study show that some HIV-positive people who have initially symptom-free neurocognitive impairment have an increased risk—between two-and six-fold—for the subsequent development of symptoms of such impairment.

2. The results of the present study, while important, may not apply to all HIV-positive people for at least the following reasons:

• a relatively small number of participants was analysed
• the issue of disability (caused by neurocognitive impairment) was not fully explored by the study team. There was no information on whether or not symptoms of disability changed over time.
• the parent study—CHARTER—focused on HIV-related neurologic disease. It is possible that because of this focus, it could have inadvertently attracted participants who were concerned about, and perhaps in some cases possibly prone to, neurocognitive issues. A larger, longer and more geographically diverse study is needed to confirm the findings reported. Such a study would be expensive, would require highly motivated participants and would likely take several years to complete.

3. Gender – in the present study women were nearly threefold more likely to develop symptoms of neurocognitive impairment. This may have occurred because women in the study had lower levels of education and were more vulnerable to substance use than men. Future studies need to take gender-related factors into account when assessing neurocognitive functions.

What to do?

The study researchers, highly experienced in studying HIV-related brain issues, propose that people who have symptom-free neurocognitive impairment should receive more monitoring since they are at heightened risk for HIV-related disability.

The findings from the present study should be viewed as preliminary and intriguing. Furthermore, readers should note that while about 51% of people with initially symptom-free neurocognitive impairment declined, so did 22% of participants who were initially graded as neurocognitively normal.

An external view

American neuroscientists Steven Albert, PhD, and Eileen Martin, PhD, who reviewed the study’s findings made the following comment:

“Could it be that the development of cognitive impairment and associated disability is a feature of HIV infection more generally, despite [ART], viral suppression, and medical care?”

In the present study, the average age of participants who were initially assessed as being neurcognitively normal was 43 years, most were high school graduates and their IQs were in the normal range.

Based on this observation, the U.S. neuroscientists asked this troubling question:

“With longer follow-up, will most CHARTER participants who were initially diagnosed as cognitively normal also develop neurocognitive impairment and associated disability in their 40s and 50s?”

It is not clear how, if at all, the results from the present study apply to other groups of HIV-positive people, such as the following:

• people who have not used substances
• people who have never developed AIDS

In other parts of this issue of TreatmentUpdate, we report interventions that researchers are studying to reduce the risk of developing neurocognitive impairment or even reverse such impairment.

—Sean R. Hosein

REFERENCES:

1. Grant I, Franklin DR Jr, Deutsch R, et al. Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology. 2014 Jun 10;82(23):2055-62.
2. Albert SM, Martin EM. HIV and the neuropsychology of everyday life. Neurology. 2014 Jun 10;82(23):2046-7.