Beyond HAND: Practical approaches to cognitive assessment in ageing people with HIV

When I see patients like the 64-year-old woman I presented at CROI, someone who has lived with HIV for more than three decades, is virally suppressed, yet struggles with memory and social isolation, a single diagnostic label does not guide what she may need clinically. The HIV population is profoundly heterogeneous. It includes long-term survivors who lived through the era before effective therapy, as well as people who acquired HIV perinatally and are now reaching middle age. These overlapping generations have different biological, social and neurobehavioural trajectories. A single diagnostic framework is reductionist.

What I suggested at CROI is that we need to be more proactive and not wait for dementia-level symptoms before acting. The number of people with HIV aged 50 years and older has tripled globally since 2000. A reactive approach is no longer adequate. Brain health will likely become more pervasive in culture, and trend towards proactive, systematic approaches embedded in routine HIV care.

The World Health Organization (WHO) definition I highlighted conceptualises brain health as a continuous state of attaining and maintaining optimal neurological function across the life course. This perspective is fundamentally different from a retrospective diagnostic label such as HAND, which is applied after cognitive impairment has already occurred. Reframing in this way encourages earlier intervention, more personalised care and a broader focus on modifiable contributors to cognitive ageing.

Q. How does the ‘treatable traits’ framework change the way clinicians should assess and manage cognitive concerns in older adults living with HIV?

The treatable traits framework shifts clinicians away from asking whether a patient meets criteria for HAND and towards asking which specific, modifiable factors are driving that person’s cognitive trajectory.

In practice, the answer is almost always plural. In the case described, three traits were prominent.

• The first was vascular risk, including hypertension, diabetes and hyperlipidaemia, which directly influence subcortical vascular disease.
• The second was sleep. Untreated sleep apnoea, insomnia and central nervous system (CNS)-sedating medications are under-recognised contributors to cognitive impairment.
• The third was social isolation, including loss of community and environmental barriers to leaving the home. These factors independently predict depression and future dementia.

I would also emphasise medication deprescribing. Trials are underway testing whether removing anticholinergics causally improves cognition, and that is the type of evidence base the field needs.

Q. What role should emerging tools such as cerebrospinal fluid biomarkers, neuroimaging and computational phenotyping play in distinguishing HIV-related pathology from age-associated neurological disease?

I consider cerebrospinal fluid biomarkers and neuroimaging ideally reserved for specific triggers. These include rapid decline, focal findings or unresolved diagnostic uncertainty after a basic workup. Indiscriminate use delays care and wastes resources. In research, tools such as MRI-based brain age, EEG metrics and epigenetic clocks are promising for distinguishing HIV-related pathology from age-associated disease. The field must make these models interpretable, validate them against real outcomes and show that improving the biomarker improves the patient. We are not there yet, but computational phenotyping could help to change trial design and personalise care.

Q. In practical terms, how can clinicians implement personalised interventions to ensure that increased lifespan with antiretroviral therapy is matched by improved neurological healthspan?

In practical terms, clinicians can implement personalised interventions to ensure that increased lifespan on antiretroviral therapy (ART) is matched by an improved neurological healthspan. While brain health does require clinical training, comfort with longitudinal care and the trust of the patient, it does not require neurologists to lead.

Neurologists can play a key role in training the HIV workforce, and my laboratory is personally invested in supporting regional clinics as well as Ryan White providers. There is also a global community of neurologists working in neuroHIV who are committed to brain health for people with HIV.

We discussed a framework for primary care that covers five domains:

First, there are pre-clinic investments that allow people, over time, to feel comfortable flagging concerns.

Second, clinicians should review viral load, CD4 history and ART history.

Third, medications should be examined with a focus on CNS-active medications, especially when an individual is taking three or more, alongside a review of substance use.

Fourth, mental health and sleep quality should be addressed.

Fifth, the visit should include a physical examination with a validated bedside cognitive tool. None of these components require specialty training.

I suggested using a tiered escalation structure:

• Tier 1 consists of proactive and longitudinal brain health. This includes managing risk factors, explaining the rationale to patients and targeting what is modifiable.
• Tier 2 includes lumbar puncture or neuroimaging for specific clinical indications.
• Tier 3 involves referral to neurology or neuropsychology when needed.

A key insight from the Lancet Commission in 2024 is that up to 45% of dementia risk may be modifiable. What remains unknown is how much of the modifiable risk identified by the Lancet Commission applies to people with HIV, and to what degree.