HIV-Associated Neurocognitive Disorder (HAND) is the umbrella construct for cognitive impairment attributable to HIV infection, and remains common in the era of combination antiretroviral therapy even as its most severe form has become rare. The Frascati research criteria (Antinori 2007) stratify HAND into Asymptomatic Neurocognitive Impairment (ANI), Mild Neurocognitive Disorder (MND), and HIV-Associated Dementia (HAD), graded by neuropsychological performance and functional impact. DSM-5-TR captures these presentations under Major or Mild Neurocognitive Disorder Due to HIV Infection, while ICD-11 places them within neurocognitive disorders due to a known etiology. The clinical bottom line is that HAND is a diagnosis of exclusion in a patient with HIV: rule out opportunistic CNS infection, neurosyphilis, substance effects, depression, and medication toxicity before attributing impairment to HIV itself. Early identification matters because viral suppression, cardiovascular risk reduction, and treatment of comorbid depression and substance use are the levers that move outcomes.

Cognitive impairment remains prevalent among people with HIV (PWH) despite effective viral suppression, though the severity profile has shifted away from frank dementia toward milder forms.

Prevalence and shift in severity

• Across cohorts in the cART era, an estimated 30-50% of PWH meet Frascati criteria for some form of HAND, with ANI the most common and HAD now uncommon (<5%).^[1-2]
• HAD prevalence fell from roughly 10-15% in the pre-cART era (1990s) to 2-4% in contemporary cohorts; ANI and MND now account for the majority of cases.^[1,3]
• Frascati-based prevalence estimates have been criticized for inflation due to normative comparison methods; studies applying multivariate normative correction or excluding ANI yield lower symptomatic-HAND rates of 15-25%.^[4]

Age, sex, and demographic patterns

• Median age of HAND onset has shifted upward as the HIV population ages; cognitive impairment in older PWH reflects an interaction between HIV-related and age-related vascular and neurodegenerative processes.^[2,42]
• Sex ratio largely tracks the underlying HIV epidemic in a given region; some cohorts report higher cognitive impairment burden in women, attributed in part to socioeconomic and comorbidity factors.^[6]
• Black and Hispanic PWH in the United States carry a higher cognitive impairment burden, mediated by later diagnosis, lower nadir CD4, and structural determinants of health.^[6]

Risk factors

• Low nadir CD4 count (typically <200 cells/mm^3) is the most reproducible HIV-specific predictor of HAND.^[1-2]
• Detectable plasma or cerebrospinal fluid HIV RNA, longer duration of untreated infection, and prior AIDS-defining illness raise risk.^[1,3]
• Cardiovascular risk factors (hypertension, diabetes, dyslipidemia, smoking), hepatitis C coinfection, methamphetamine and other stimulant use, heavy alcohol use, and major depression are independently associated with worse cognitive performance in PWH.^[4,6]
• APOE ε4 carriage may modestly increase risk, though evidence is mixed and effect sizes smaller than in idiopathic Alzheimer disease.^[7]

HAND reflects indirect neuronal injury from chronic CNS immune activation rather than direct neuronal infection; HIV enters the CNS early and persists in long-lived myeloid cells even when plasma viremia is suppressed.^[1,8]

Neuroinvasion and CNS reservoir

• HIV crosses the blood-brain barrier within days to weeks of primary infection via a "Trojan horse" mechanism in infected monocytes and CD4+ T cells.^[1,8]
• Productive infection in the CNS occurs primarily in perivascular macrophages and microglia; neurons themselves are not productively infected.^[8]
• The CNS functions as a viral reservoir; compartmentalized viral evolution and occasional CSF viral escape (detectable CSF HIV RNA despite suppressed plasma virus) contribute to ongoing injury.^[8-9]

Mechanisms of neuronal injury

• Viral proteins gp120, Tat, Nef, and Vpr exert direct neurotoxicity through excitotoxic glutamate signaling, oxidative stress, and mitochondrial dysfunction.^[8]
• Chronic microglial activation produces proinflammatory cytokines (TNF-α, IL-1β, IL-6), chemokines, and quinolinic acid, driving synaptodendritic injury more than neuronal loss.^[1,8]
• Astrocyte dysfunction impairs glutamate clearance and blood-brain barrier integrity.^[8]

Imaging and pathology

• Structural MRI shows frontal and subcortical atrophy, with caudate volume loss correlating with motor and processing-speed deficits; cerebral white matter hyperintensities are common.^[2,10]
• Magnetic resonance spectroscopy demonstrates reduced N-acetylaspartate (neuronal marker) and elevated myo-inositol and choline (glial activation) in basal ganglia and frontal white matter.^[10]
• Functional MRI and diffusion tensor imaging show altered Default Mode Network connectivity and reduced white-matter integrity even in virally suppressed PWH.^[10]
• Historic neuropathology of HIV encephalitis (multinucleated giant cells, microglial nodules) is now rare; current pathology in suppressed PWH shows microglial activation and synaptic loss without florid encephalitis.^[8]

Genetic and host factors

• Polymorphisms in MCP-1, TNF-α, and chemokine receptor genes modulate susceptibility, though no single variant has a large clinical effect.^[7]
• APOE ε4, common cardiovascular risk loci, and host factors driving inflammaging contribute to the cognitive phenotype in aging PWH.^[2,7]

Two overlapping frameworks coexist in research and clinical practice: the Frascati research criteria (Antinori et al., 2007), which subdivide HAND by severity, and DSM-5-TR, which folds HIV-related impairment into Major or Mild Neurocognitive Disorder Due to HIV Infection.^[11-12]

Frascati criteria

• ANI: performance ≥1 standard deviation below demographically adjusted norms in at least two cognitive domains, without functional impairment in everyday activities.^[11]
• MND: same neuropsychological threshold as ANI plus mild interference with activities of daily living (work, household, social functioning), reported by patient or informant.^[11]
• HAD: performance ≥2 standard deviations below norms in at least two domains plus marked functional impairment; conforms to historical "AIDS dementia complex."^[11]
• All three require HIV diagnosis, exclusion of delirium and pre-existing causes, and that impairment not be better explained by comorbid medical, psychiatric, or substance-related conditions.^[11]

DSM-5-TR Major or Mild Neurocognitive Disorder Due to HIV Infection:

• Evidence of significant (Major) or modest (Mild) decline from prior performance in one or more cognitive domains, supported by clinical concern and objective testing, typically performance ≥2 SD (Major) or 1-2 SD (Mild) below norms.^[12]
• Documented HIV infection by laboratory testing.^[12]
• Cognitive impairment not better explained by another medical condition, mental disorder, or substance.^[12]
• Major NCD requires interference with independence in everyday activities; Mild NCD preserves independence but requires greater effort or compensatory strategies.^[12]

ICD-11 placement

• ICD-11 codes HIV-related cognitive impairment under 6D8 Neurocognitive disorders due to a disease classified elsewhere, cross-referenced to HIV disease in chapter 01; mild and dementia-level severity are specified.^[5]
• ICD-11 does not formally adopt the ANI category, reflecting ongoing debate about whether asymptomatic, test-defined impairment should constitute a disorder.^[4-5]

The contemporary phenotype is a slowly progressive subcortical-frontal pattern dominated by deficits in attention, processing speed, executive function, and learning efficiency, with relative sparing of language and primary memory storage.^[1-2]

Cognitive domains affected

• Attention and working memory: difficulty sustaining concentration, slowed mental tracking, errors on serial sevens or digit-span backward.^[1-2]
• Processing speed: slowed completion of timed tasks (Trail Making A, Symbol Digit Modalities Test).^[2]
• Executive function: impaired set-shifting, planning, response inhibition; classically affected on Trail Making B and Wisconsin Card Sorting.^[2]
• Learning and memory: encoding and retrieval inefficiency that improves with cuing or recognition, contrasting with the storage failure of Alzheimer disease.^[1-2]
• Motor function (in more advanced disease): slowed fine motor speed, gait instability, tremor; legacy "AIDS dementia complex" emphasized this triad.^[1]

Behavioral and neuropsychiatric features

• Apathy is the most common and most disabling neuropsychiatric feature, often disproportionate to mood disturbance.^[1-2]
• Depression, irritability, and emotional lability are common and contribute independently to functional impairment.^[2,6]
• Personality change, social withdrawal, and reduced spontaneity may precede measurable cognitive decline.^[1]
• Frank psychosis is uncommon in contemporary HAND; when present, consider opportunistic infection, substance use, or primary psychiatric illness.^[1]

Course

• Onset is insidious over months to years; abrupt cognitive change should prompt search for an alternative cause.^[1-2]
• Many patients show a fluctuating or static course on cART; a subset progress despite virologic suppression, particularly with poor CSF antiretroviral penetration or persistent immune activation.^[2,9]
• Improvement after cART initiation is well described, particularly in those with detectable plasma virus at baseline.^[3]

Red flags suggesting a non-HAND etiology

• Rapid (weeks) cognitive decline.^[1]
• Focal neurologic signs, new seizures, or new headache pattern.^[1]
• Fever or systemic illness.^[1]
• CD4 <200 cells/mm^3 with new neurologic symptoms; broaden the workup for opportunistic CNS disease before attributing to HAND.^[1,14]

Because cognitive complaints in PWH have a wide differential and HAND is itself a diagnosis of exclusion, the workup is organized around three buckets: opportunistic and HIV-related CNS disease, medical and toxic mimics, and primary psychiatric or neurodegenerative disease.^[1,14] Opportunistic and HIV-related CNS disease (especially when CD4 <200):

• Progressive Multifocal Leukoencephalopathy (JC virus): subacute focal deficits, asymmetric white-matter lesions on MRI without mass effect, positive CSF JC virus PCR.^[14]
• CNS toxoplasmosis: ring-enhancing lesions, often multiple; serum Toxoplasma IgG positive in most cases.^[14]
• Cryptococcal meningitis: headache, fever, elevated opening pressure, CSF cryptococcal antigen positive.^[14]
• CMV encephalitis or ventriculitis, primary CNS lymphoma (single homogeneously enhancing periventricular lesion, EBV-positive CSF), and tuberculous meningitis round out the advanced-immunosuppression differential.^[14]
• CSF viral escape: detectable CSF HIV RNA with suppressed plasma HIV RNA producing new or worsening cognitive symptoms.^[9]

Medical and toxic mimics

• Neurosyphilis: always test RPR/VDRL and confirm with treponemal assay; consider lumbar puncture when neurologic symptoms and reactive serology coexist.^[14]
• Hepatitis C with hepatic encephalopathy or HCV-related cognitive effects.^[14]
• Hypothyroidism, B12 deficiency, hyponatremia, hypercalcemia, uremia.^[14]
• Substance use: methamphetamine, cocaine, alcohol, cannabis, MDMA, opioids, and benzodiazepines all produce cognitive effects that can mimic or compound HAND.^[2,47]
• Medication effects: efavirenz (neuropsychiatric and cognitive effects), anticholinergic burden, sedating psychotropics, opioids.^[15]

Primary psychiatric and neurodegenerative disease

• Major depressive disorder produces "pseudodementia" with attentional and executive complaints; effort-validity testing and response to antidepressant treatment help differentiate.^[1-2]
• Anxiety disorders and PTSD impair attention and working memory.^[2]
• Alzheimer disease and other neurodegenerative dementias: amnestic-storage pattern, hippocampal atrophy, characteristic biomarkers (CSF Aβ42/tau, amyloid PET) help distinguish in older PWH.^[2]
• Vascular cognitive impairment: especially important in PWH with cardiovascular comorbidity; MRI shows confluent white-matter disease and lacunes.^[2,42]
• Delirium: always consider in hospitalized PWH with acute change; HAND does not present acutely.^[1]

Evaluation rests on a structured history with collateral, a focused neurologic and mental status exam, validated cognitive screening followed by formal neuropsychological testing when feasible, and targeted laboratory and imaging work to exclude alternative causes.^[1,14]

History and collateral

• Symptom timeline, functional change at work and home, driving safety, medication adherence, and instrumental ADLs.^[1-2]
• HIV history: nadir CD4, current CD4 and viral load, duration of cART, regimen history, adherence, prior AIDS-defining illnesses.^[1]
• Comorbidity review: cardiovascular risk factors, hepatitis C, syphilis, prior opportunistic CNS disease, head injury, seizure history.^[14]
• Substance use history including methamphetamine, cocaine, alcohol, cannabis, MDMA, and benzodiazepines.^[2,47]
• Psychiatric history with attention to depression, suicidality, prior cognitive screens.^[2,6]

Examination

• Mental status exam with explicit assessment of attention, processing speed, set-shifting, and recall with cuing.^[1-2]
• Neurologic exam for focal signs, frontal release signs, gait, fine motor speed.^[1]
• General medical exam including funduscopy and lymphadenopathy.^[14]

Cognitive screening and formal testing

• Brief screens: MoCA outperforms MMSE for the subcortical-frontal pattern of HAND but lacks sensitivity for ANI.^[16]
• HIV-specific screens: International HIV Dementia Scale (IHDS) and the HIV Dementia Scale; both screen for HAD but miss milder impairment.^[16]
• Formal neuropsychological battery covering attention, processing speed, learning and memory, executive function, motor speed, and language; required to formally meet Frascati criteria.^[11,16]
• Functional assessment: Patient's Assessment of Own Functioning Inventory (PAOFI), Lawton IADL, and informant-based measures.^[11]

Laboratory workup

• HIV RNA (plasma) and CD4 count; CSF HIV RNA if cognitive decline despite plasma suppression.^[1,9]
• RPR/VDRL with confirmatory treponemal assay; TSH; B12; CBC; comprehensive metabolic panel; hepatitis C antibody and HCV RNA if positive; toxoplasma IgG; cryptococcal antigen if CD4 <200.^[14]
• Urine drug screen and detailed substance-use review.^[2]

Neuroimaging

• MRI brain with and without contrast is the imaging study of choice; CT is acceptable when MRI is contraindicated.^[14]
• Imaging is essential when CD4 <200, focal signs are present, headache is new, or cognitive decline is rapid, to exclude PML, toxoplasmosis, lymphoma, and other space-occupying disease.^[14]

Lumbar puncture

• Indicated when imaging or clinical picture suggests opportunistic infection, when neurosyphilis is suspected, or when cognitive decline progresses despite plasma viral suppression (to assess CSF escape).^[9,14]
• Routine LP is not required for stable, suppressed PWH with mild cognitive complaints and a benign exam.^[14]

What NOT to order

• Routine amyloid PET or CSF Alzheimer biomarkers are not first-line in younger PWH; reserve for older patients with an amnestic-cortical phenotype.^[2]
• Electroencephalography is not diagnostic of HAND and is reserved for suspected seizures or encephalopathy.^[14]

Suppressive cART is the foundation of HAND management; everything else is adjunctive or aimed at comorbid contributors.^[1,9] No agent has been shown to reverse established HAD in cART-treated, virologically suppressed patients, and no neuroprotective adjunct has met the bar for guideline-level recommendation.^[9,17]

Pharmacotherapy

• Initiate or optimize combination antiretroviral therapy in any patient with HAND who is not already on a suppressive regimen.^[1,9]
• Regimen choice is driven by virologic, resistance, tolerability, and drug-interaction considerations rather than CNS penetration alone. The CNS Penetration Effectiveness (CPE) score correlates with CSF viral suppression but has not consistently translated into better neurocognitive outcomes, and higher-CPE regimens carry a possible signal of neurotoxicity.^[9,17-18]
• Suspected CSF escape (cognitive decline with detectable CSF HIV RNA despite plasma suppression) is managed by intensifying or modifying cART guided by CSF and plasma resistance testing, in consultation with HIV specialty care.^[9]
• Treat comorbid depression with an SSRI; sertraline 50 mg PO QD and escitalopram 10 mg PO QD are reasonable first-line choices given favorable interaction profiles with most antiretrovirals.^[19]
• Review every psychotropic for interactions with ritonavir-, cobicistat-, and integrase-inhibitor-containing regimens; pimozide and high-dose quetiapine combined with strong CYP3A4 inhibitors are particularly hazardous.^[19]
• Psychostimulants (methylphenidate) have low-quality evidence for fatigue and attentional symptoms in HIV and may be considered case by case after substance-use review.^[17]

Psychotherapy

• Cognitive rehabilitation and computerized cognitive training show modest, mostly short-term gains in attention and processing speed in PWH; evidence is low certainty and benefits attenuate after the intervention ends.^[21]
• Cognitive behavioral therapy for depression and insomnia is effective in PWH and addresses major modifiable contributors to subjective cognitive complaints.^[19]
• Motivational interviewing and contingency-management approaches for substance use have moderate evidence in HIV populations and indirectly support cognition by reducing methamphetamine, alcohol, and cocaine exposure.^[2]

Neuromodulation

• No neuromodulation modality (rTMS, tDCS, ECT) has guideline-level support for HAND specifically; ECT remains indicated for severe comorbid depression in PWH using standard criteria.^[19]

Adjunctive

• Aggressive management of vascular risk: blood pressure, LDL, glycemic control, and smoking cessation, since cerebrovascular disease is a major driver of cognitive decline in aging PWH.^[9,42]
• Treat hepatitis C with direct-acting antivirals when coinfected; HCV cure is associated with modest cognitive improvement.^[22]
• Address obstructive sleep apnea, which is underdiagnosed in PWH and contributes to attention and memory complaints.^[19]
• Encourage exercise and Mediterranean-style diet; observational evidence in PWH parallels the broader dementia-prevention literature.^[34]
• Trialed but not recommended: selegiline, minocycline, memantine, lithium, valproate, and statins for HAND specifically; none have shown convincing cognitive benefit in randomized trials.^[17]

No agent reverses established HIV-associated dementia in suppressed patients; viral suppression plus vascular and psychiatric comorbidity management is the evidence-supported strategy.^[9,17]

The harms picture in HAND is driven less by the disorder itself than by the long-term consequences of HIV, antiretroviral exposure, and a high burden of comorbidity. Evidence quality is also constrained by inconsistent diagnostic criteria, short follow-up, and selection bias in cART-era cohorts.

Common adverse effects and harms picture

• Antiretroviral neuropsychiatric effects, most prominent with efavirenz (vivid dreams, depression, suicidal ideation) and to a lesser extent dolutegravir and rilpivirine ^[31,33].
• Polypharmacy-related cognitive blunting from anticholinergics, benzodiazepines, opioids, and gabapentinoids, which is often the proximate cause of cognitive complaints in middle-aged people with HIV ^[32].
• Stigma and labeling effects: an ANI diagnosis in an otherwise functional patient can affect employment, insurance, and self-concept without changing management ^[4,18].

Serious or rare adverse effects

• Misattribution of opportunistic CNS disease (cryptococcal meningitis, CNS lymphoma, PML, neurosyphilis) to HAND, delaying life-saving treatment ^[10-11].
• Drug-drug interactions between ART (especially ritonavir-boosted protease inhibitors and cobicistat) and psychotropics, increasing levels of midazolam, certain SSRIs, and antipsychotics ^[34].
• Increased risk of suicide, particularly around HIV diagnosis and with efavirenz exposure ^[35].

Monitoring and discontinuation considerations

• Cognitive screening at HIV diagnosis and at least annually is recommended by EACS, with more frequent screening if symptoms emerge or regimen changes ^[36].
• Abrupt ART discontinuation produces viral rebound and risks accelerated cognitive decline; deprescribing other CNS-active drugs should be staged and monitored ^[37].

Limitations of the evidence base

• Most prevalence estimates rely on the Frascati criteria, which have been criticized for overdiagnosing ANI by classifying healthy individuals as impaired on the basis of statistical cutoffs alone ^[18,38].
• Cohorts overrepresent men who have sex with men in high-income settings; data from sub-Saharan Africa, women, and older adults are comparatively thin ^[39].
• Randomized trials of cognitive interventions are small, short, and use heterogeneous neuropsychological endpoints, limiting pooled inference ^[28-29].

Cognitive trajectories in HIV differ meaningfully by age, sex, perinatal exposure, and comorbid substance use, and these subgroups should not be evaluated against the same normative expectations.

Pediatric and perinatally-infected adults

• Children with perinatal HIV show developmental delay, executive dysfunction, and slowed processing speed, with severity inversely related to nadir CD4 and timing of ART initiation ^[40].
• Young adults living with perinatally-acquired HIV carry a higher burden of neurocognitive impairment than behaviorally-infected peers and should be assessed with developmentally normed instruments ^[41].

Geriatric

• HIV-positive adults over 50 carry double the prevalence of cognitive impairment of age-matched HIV-negative controls, with additive vascular and amyloid contributions ^[12,42].
• Distinguishing HAND from early Alzheimer's disease in this group is increasingly relevant; CSF amyloid-beta and tau, and amyloid PET when available, help adjudicate ^[43].

Perinatal and pregnancy

• Cognitive complaints in pregnancy in women with HIV are frequently multifactorial, including sleep disruption, depression, and ART regimen changes ^[44].
• Dolutegravir is preferred in pregnancy after the resolution of earlier neural tube defect concerns; efavirenz is avoided when alternatives exist due to neuropsychiatric burden ^[45].

Comorbid substance use

• Methamphetamine use accelerates HAND progression and amplifies dopaminergic injury in the striatum ^[46].
• Chronic alcohol use, opioid use disorder, and stimulant use all worsen HAND independently of viral load and must be addressed in parallel ^[47].

Cultural and global considerations

• Neuropsychological norms developed in high-income settings overestimate impairment in sub-Saharan African cohorts; locally-validated instruments such as the International HIV Dementia Scale should be used ^[48].
• Access to ART, viral load monitoring, and second-line regimens shapes the global epidemiology of HAD, which remains more prevalent in resource-limited settings ^[49].

HAND in the cART era is more often a chronic, fluctuating condition than a progressive dementia. Trajectories cluster into stable, improving, and declining phenotypes, with the decliner group carrying excess mortality.

Natural history

• Among virally suppressed patients, roughly 20-25 percent improve, 50-60 percent remain stable, and 15-20 percent decline over 2-3 years of follow-up ^[50].
• Conversion from ANI to symptomatic HAND (MND or HAD) occurs at 2-6 percent per year and is predicted by detectable viral load, low nadir CD4, and depression ^[13].

Predictors of poor outcome

• Low nadir CD4, longer duration of untreated infection, ongoing viremia, hepatitis C coinfection, and cerebrovascular disease ^[12,50].
• Depression and stimulant use are independently associated with cognitive decline and reduced ART adherence ^[27,46].

Mortality

• HAD remains independently associated with all-cause mortality, with hazard ratios in cART-era cohorts roughly 2-3 times that of cognitively intact peers ^[51].
• Excess mortality is driven by non-AIDS events (cardiovascular, malignancy, suicide) rather than opportunistic infection in well-resourced settings ^[51].

Acute cognitive change in a patient with HIV is a neurologic emergency until proven otherwise. The differential is broader and more dangerous than in HIV-negative patients of the same age.

Red flags requiring urgent workup

• Subacute cognitive decline over days to weeks, fever, focal neurologic signs, seizures, or new headache require imaging, lumbar puncture, and infectious workup before psychiatric attribution ^[10-11].
• New psychosis, mania, or catatonia in a patient with HIV should prompt evaluation for CNS opportunistic infection, neurosyphilis, ART-related neuropsychiatric effects, and immune reconstitution inflammatory syndrome ^[52].

Suicide risk

• Suicide risk peaks around the time of HIV diagnosis, after disclosure events, and with efavirenz exposure; screening with a validated instrument is part of routine HIV care ^[35].

Hospitalization criteria

• Inability to manage ART adherence safely at home, active suicidality, severe behavioral disturbance, or suspected opportunistic CNS disease warrant inpatient care ^[52].
• Comanagement with infectious disease and neurology is standard in tertiary settings ^[36].

Several core questions in HAND remain unresolved despite three decades of research, and the most useful clinical posture is to know what is debated rather than to pretend the debates are settled.

Is the Frascati ANI category clinically meaningful?

• Critics argue that ANI, defined by neuropsychological performance one standard deviation below norms without functional impact, captures statistical noise and overestimates true HAND prevalence ^[18,38].
• Defenders point to longitudinal data showing ANI predicts symptomatic progression, mortality, and functional decline, and treat it as a marker of subclinical disease ^[13].

Does CNS-targeted ART matter?

• The CHARTER analyses found regimens with higher CNS-penetration-effectiveness scores reduced CSF HIV RNA but produced inconsistent cognitive benefit ^[17].
• Major guidelines (DHHS, EACS) do not endorse selecting ART by CPE score for cognitive indications; the topic remains contested ^[36].

Is HAND a single entity or a syndromic family?

• Some authors propose splitting HAND into vascular, neurodegenerative, and inflammatory subtypes with distinct biomarker signatures ^[53].
• Others argue that the cART-era phenotype is dominated by shared vascular and metabolic mechanisms and that fine-grained subtyping is premature ^[54].

Diagnostic overlap with Alzheimer's disease in aging cohorts:

• As people with HIV live into their 70s and 80s, the contribution of Alzheimer pathology to cognitive impairment is rising, and the field lacks consensus on how to apportion etiology ^[42-43].
• CSF amyloid and tau biomarkers behave differently in HIV than in pure Alzheimer disease, complicating interpretation ^[43].

Failed neuroprotective trials

• Trials of memantine, selegiline, minocycline, lithium, and intranasal insulin have been uniformly negative or inconclusive, raising the question of whether neuroprotection is achievable once viral suppression is in place ^[29-30].

• The Frascati criteria stratify HAND into asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia, based on neuropsychological performance and functional impact ^[3].
• HIV-associated dementia is now uncommon in the cART era, but milder forms (ANI and MND) remain common, with combined prevalence estimates of roughly 30-50 percent in cohort studies ^[1].
• HAND is classically a subcortical pattern: impaired processing speed, attention, executive function, and motor slowing, with relative preservation of language and recognition memory ^[7].
• HIV-associated dementia meets DSM-5-TR criteria for Major Neurocognitive Disorder Due to HIV Infection; ANI and MND map to the mild form, with ANI requiring no functional impact ^[4].
• Low nadir CD4 count, detectable plasma or CSF viral load, hepatitis C coinfection, and cardiovascular disease are the strongest predictors of HAND progression ^[12,50].
• Efavirenz is associated with vivid dreams, depression, and suicidal ideation, and is now generally avoided when alternatives are available ^[31,35].
• The International HIV Dementia Scale is a brief screening tool validated for low-resource settings; MoCA is preferred when normative data permit ^[15,48].
• New focal neurologic signs, fever, or rapid cognitive decline in a patient with HIV mandate imaging and lumbar puncture to exclude opportunistic infection, neurosyphilis, CNS lymphoma, and PML, not HAND ^[10-11].
• Combination antiretroviral therapy is the only intervention that reliably reduces incidence and severity of HAND; CNS-penetration optimization is not endorsed by major guidelines ^[17,36].
• Memantine, selegiline, minocycline, and lithium have all failed in HAND neuroprotection trials ^[29-30].
• Cognitive complaints in middle-aged people with HIV are frequently driven by depression, polypharmacy, sleep disorders, and substance use rather than HAND itself; treat the modifiable contributors first ^[27,32].
• Suicide risk peaks around HIV diagnosis and with efavirenz exposure, independent of cognitive status ^[35].
• Children with perinatal HIV show developmental delay and executive dysfunction proportional to nadir CD4 and delayed ART initiation ^[40].

No external funding. No conflicts of interest declared. Peer-review status: pending.