HIV-Associated Neurocognitive Disorder

HIV-associated neurocognitive disorder is a spectrum of cognitive, motor and behavioural impairment caused by HIV infection of the central nervous system. It ranges from asymptomatic neurocognitive impairment to mild neurocognitive disorder and HIV-associated dementia.

In the era of antiretroviral therapy, milder forms affect about 20 to 40% of people with HIV, and HIV-associated dementia affects under 5%. Risk factors are low nadir CD4 count, late diagnosis, older age, poor adherence, hepatitis C, substance use and vascular risk.

Classification. Asymptomatic neurocognitive impairment (abnormal tests without functional decline), mild neurocognitive disorder (mild functional decline) and HIV-associated dementia (marked decline).

Course. Untreated, progressive over months. With antiretroviral therapy, many stabilise or improve, but milder impairment may persist despite viral suppression.

Pathophysiology.

HIV-infected monocytes enter the brain and infect macrophages and microglia, whose release of viral proteins, cytokines and neurotoxins injures neurons and synapses without direct neuronal infection.

Persistent immune activation and a central nervous system viral reservoir contribute to chronic impairment.

• Subcortical pattern: slowed thinking and motor speed, poor attention, impaired memory retrieval, executive dysfunction.
• Apathy, depression, irritability and social withdrawal.
• Motor signs: slowed movements, tremor, gait imbalance, hyperreflexia, frontal release signs.
• In advanced disease, mutism, incontinence, paraparesis and severe dementia.

Red flags.

• Focal neurological signs, seizures or headache (opportunistic infection or lymphoma).
• Fever, reduced consciousness or rapid decline over days.
• Neurological worsening soon after starting antiretrovirals (immune reconstitution inflammatory syndrome).

• Diagnosis of exclusion, with documented HIV infection, neuropsychological testing showing impairment in at least 2 domains, and no other cause.
• Brain MRI: diffuse atrophy and white matter hyperintensities; exclude opportunistic infection (toxoplasmosis, progressive multifocal leukoencephalopathy, cryptococcus) and lymphoma.
• Plasma HIV RNA and CD4 count; cerebrospinal fluid analysis with HIV RNA (to detect escape) and tests for infection.
• Exclude syphilis, B12 deficiency, thyroid disease, hepatitis C, depression, substance use, sleep disorders and drug effects.
• Screen for drug resistance when viral load is detectable.

Differential diagnosis. Opportunistic infection, primary central nervous system lymphoma, neurosyphilis, depression, substance use, Alzheimer disease, vascular cognitive impairment, drug toxicity (efavirenz) and metabolic encephalopathy.

• Start or optimise antiretroviral therapy at once to achieve full viral suppression (HIV RNA under 50 copies/mL), with regimen selection based on resistance testing.
• Dolutegravir 50 mg orally once daily (50 mg twice daily with rifampicin or other strong inducers) with tenofovir alafenamide 25 mg and emtricitabine 200 mg orally once daily. Maximum dolutegravir 100 mg daily. Monitor HIV RNA at 4 and 12 weeks then 6 monthly, CD4 count, renal function, liver function, weight and mood or sleep disturbance. Avoid tenofovir alafenamide when creatinine clearance is under 30 mL/min; separate dolutegravir from antacids, iron and calcium by 2 hours before or 6 hours after; use caution in hepatic impairment; acceptable in pregnancy and breastfeeding with specialist advice.
• Persistent impairment despite viral suppression: review for central nervous system escape (cerebrospinal fluid viral load), drug resistance and comorbid conditions; adjust the regimen with specialist advice.
• Stop or avoid neurotoxic drugs (efavirenz) and treat comorbidities: depression, sleep apnoea, substance use, hepatitis C and vascular risk.
• Cognitive rehabilitation, occupational therapy, and carer and adherence support (pill boxes, reminders).
• Treat depression: sertraline 50 mg orally once daily, increased by 50 mg every 1 to 2 weeks as needed to 100 to 200 mg daily. Maximum 200 mg daily. Monitor mood and suicidal thoughts, sodium, bleeding and serotonin toxicity. Reduce dose (or use alternate days) in hepatic impairment; avoid with monoamine oxidase inhibitors; check for interactions with antiretrovirals.
• Immune reconstitution inflammatory syndrome: corticosteroids by specialist advice.

Monitoring. Repeat cognitive screening yearly in all people with HIV and at 3 to 6 months after any change; viral load at the intervals given in Management.

Referral and escalation. HIV physician and neurology; neuropsychology and psychiatry; urgent admission for focal signs or rapid decline.

Special groups. Older adults: combined vascular and age related cognitive risk. Pregnancy: use dolutegravir based regimens with specialist advice.