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 Both symptomatic and asymptomatic neurocognitive impairment in HIV are associated with a higher risk for low/very low viremia and viral failure.

“The HIV landscape has changed quickly during the last 10 years,” Mattia Trunfio, MD, PhD, notes. “Most of the existing work on neurocognitive impairment and medication adherence in HIV pertains to a time when the characteristics of patients were different. The cognitive phenotypes of people with HIV-associated neurocognitive disorders have changed, HIV-associated dementia has become extremely rare, and modern ART regimens are more forgiving, in that the ability to maintain viral suppression despite suboptimal adherence is stronger, at least for some.”

Given this, updated data that examine the relationships between cognitive impairment, adherence to antiretroviral treatment (ART), and viral control are warranted, he continues.

Dr. Trunfio and colleagues conducted an observational study published in AIDS and Behavior that examined the relationship between neurocognitive impairment and viral control in the 2 years before and the 2 years after a neurocognitive assessment. The study included 322 PLWH on ART (68.0% men; 95.3% White). ART adherence among the study population ranged from 87% to 100%.

Physician’s Weekly (PW) spoke with Dr. Trunfio to learn more.

PW: What results from your study are important to emphasize?

Dr. Trunfio: The detection of cognitive issues was associated with a higher risk for experiencing persistently low/very low viremia and viral failure. Compared with people without such issues, the risk for viral failure was higher for those with asymptomatic and symptomatic impairment —5-fold and 10-fold higher, respectively—and persistent low-level viremia—2-fold higher for both asymptomatic and symptomatic impairment.

The probability of worse viral control and therapeutic failure increased as the severity of cognitive impairment increased, which was already relevant in people with “asymptomatic” issues, so it is important to stress that the current “asymptomatic” attribution used by Frascati’s criteria could overlook clinical risks and the real impact of such a condition on daily life activities. Adherence to ART explains part of this relationship, suggesting that among the mechanisms, one is represented by cognitive issues weakening adherence.

Memory issues, as well as issues with visuospatial and sensory perception, motor function, and processing speed, were associated with poorer viral control. This may suggest that weakened adherence can be due to issues in remembering to take medications at a specific time or to refill pills at a specific date, but also to issues in medication management capacity, like correctly interpreting dosing instructions, distinguishing between multiple pills, or adhering to the best intake modalities.

The loop between neurocognitive impairment and viral control is a vicious cycle. That is why it is challenging to precisely estimate the direction and the effect size of all the relationships involved. Cognitive impairment can lead to diminished medication adherence, and consequently, HIV replication eases, especially in anatomical sites where ART pharmacokinetics are hindered, such as the central nervous system; this, in turn, can lead to neuroinflammation and further cognitive decline, triggering a self-perpetuating dangerous cycle.

What is novel about your findings? 

The novelty of our findings lies in the timeframe they refer to. Compared with previous work, our participants are valid representatives of modern cohorts of people with HIV in terms of ART regimens, clinical management, and types of cognitive issues. We assessed viral control, ART adherence, and cognitive impairment simultaneously. Most previous studies have assessed the relationship between only two of these three factors, so it was less easy to make inferences on the underlying mechanisms and causality.

We also enrolled one of the largest study populations. We covered 4 years with more than 3,000 viral load measurements, and we stratified by degrees and type of cognitive issues through an extensive battery of cognitive tests instead of using cognitive screenings or considering only the dichotomic presence or absence of cognitive impairment.

This last point was fundamental to finally providing data specific to people with asymptomatic cognitive impairment (ANI). There is not much work investigating the relationships of ANI with either medication management/adherence or any other aspect of daily life activities.

What are the implications of your findings?

From a clinical perspective, any intervention to improve medication adherence should routinely address cognitive issues. The detection of HIV-associated cognitive impairment should prompt HIV clinicians to consider polypharmacy, which is known to affect adherence, medication adherence and management, and trends of viral suppression over time. Conversely, persistently detectable plasma viremia requires cognitive issues to be considered a cause.

Even though causality in the path from cognitive issues to viral control through adherence requires further evidence, our data clearly show that the likelihood of finding cognitive issues or poorer viral control is significantly higher when the other condition is present. Together with compensatory strategies for mental issues, clinicians can consider different ART options, tailoring the timing of cognitive follow-up and assessing viral load and the potential benefits of long-acting injectable ART.

The second main implication is that any reappraisal of the classification of HIV-associated cognitive disorders, which is currently under debate, must consider that a proportion of individuals with ANI may not be asymptomatic. Our findings, when added to previous knowledge of increased risk for further cognitive decline in people with HIV and ANI, support the need for early diagnosis that must be sensitive to and inclusive of even mild cognitive issues, in line with the approach already undertaken in other fields for cognitive issues related to age and neurodegenerative disorders. Individuals with ANI can experience functional impairment but do not endorse it in self-report. So far, we distinguish ANI from symptomatic impairment based on self-reporting tools, which are not always reliable. This unreliability stems from inconsistencies between subjective cognitive complaints and actual impairment, intersection with mood disorders, and metacognitive deficits, and indeed, a re-evaluation of this point is critical to improving the current Frascati’s criteria.

What would you like to see future research focus on?

We have much to learn and imitate from other models of care in the geriatric and neurology fields. We need to better explore the possibilities and efficacy of interventions that address this vicious cycle: Can we use modern technologies (eg, AI) to improve adherence and medication management or—perhaps, and even better—both adherence and cognitive skills simultaneously? Another question is to which extent improving adherence can ameliorate viral control when we navigate in the gray area of mild episodic forgetfulness and low-level viremia, as well as the other way: To which extent can avoiding episodic viral blips or persistent low-level viremia contribute to favorable cognitive trajectories? All of this remains to be explored.