HIV-Associated Neurocognitive Disorder¶

VERSION: 1.1 CREATED: February 2, 2026 REVISED: February 2, 2026 STATUS: Revised per checker/rebuilder v1.1

DIAGNOSIS: HIV-Associated Neurocognitive Disorder (HAND)

ICD-10: B20 (Human immunodeficiency virus [HIV] disease), F02.80 (Dementia in other diseases classified elsewhere without behavioral disturbance), F02.81 (Dementia in other diseases classified elsewhere with behavioral disturbance), R41.81 (Age-related cognitive decline), R41.840 (Attention and concentration deficit), R41.3 (Other amnesia), F06.8 (Other specified mental disorders due to known physiological condition)

CPT CODES: 96116 (Neurobehavioral status exam), 96132 (Neuropsychological testing), 70553 (MRI brain with/without contrast), 70551 (MRI brain without contrast), 70450 (CT head without contrast), 85025 (CBC), 80053 (CMP), 86360 (CD4 count), 87536 (HIV viral load), 86689 (HTLV antibody), 89051 (CSF cell count), 84157 (CSF protein), 82945 (CSF glucose), 87536 (CSF HIV RNA), 86592 (RPR/VDRL), 87389 (HIV antigen/antibody), 84443 (TSH), 82607 (B12), 80307 (urine drug screen), 82746 (Folate), 83036 (HbA1c), 96127 (Brief emotional/behavioral assessment), 95816 (EEG), 78608 (PET brain)

SYNONYMS: HIV-associated neurocognitive disorder, HAND, HIV dementia, HIV-associated dementia, HAD, AIDS dementia complex, ADC, HIV encephalopathy, minor neurocognitive disorder due to HIV, MND, asymptomatic neurocognitive impairment, ANI, neuroAIDS, HIV cognitive impairment, HIV-related cognitive decline, HIV-associated mild neurocognitive disorder, HIV brain disease, subcortical dementia due to HIV

SCOPE: Evaluation and management of the HIV-associated neurocognitive disorder (HAND) spectrum including asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD) per Frascati criteria. Covers ART optimization with emphasis on CNS penetration effectiveness (CPE score), exclusion of opportunistic infections, neuropsychological testing, management of comorbid depression and substance use, and monitoring for disease progression. Settings: ED (acute presentations), HOSP (inpatient evaluation), OPD (outpatient longitudinal management). Excludes CNS opportunistic infections as primary diagnosis (see separate templates for PML, CMV encephalitis, toxoplasmosis, cryptococcal meningitis), acute HIV seroconversion encephalitis, and pediatric HIV neurocognitive impairment.

DEFINITIONS:

Asymptomatic Neurocognitive Impairment (ANI): Acquired impairment in >=2 cognitive domains (>=1 SD below normative mean) without functional impairment; Frascati criteria
Mild Neurocognitive Disorder (MND): Acquired impairment in >=2 cognitive domains (>=1 SD below normative mean) with mild functional impairment; Frascati criteria
HIV-Associated Dementia (HAD): Acquired marked impairment in >=2 cognitive domains (>=2 SD below normative mean) with marked functional impairment in ADLs; Frascati criteria
CNS Penetration Effectiveness (CPE) Score: Ranking system for antiretroviral CNS penetration (1 = low, 4 = high); higher total CPE score associated with better CSF viral suppression
Frascati Criteria: International consensus criteria (Antinori et al., 2007) for diagnosing HAND spectrum based on neuropsychological performance and functional status

PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting

═══════════════════════════════════════════════════════════════ SECTION A: ACTION ITEMS ═══════════════════════════════════════════════════════════════

1. LABORATORY WORKUP¶

1A. Essential/Core Labs¶

Test	Rationale	Target Finding	ED	HOSP	OPD	ICU
HIV-1/2 antigen/antibody (4th generation) (CPT 87389)	Confirm HIV diagnosis if not previously documented; baseline for new presentations	Reactive; document	STAT	STAT	ROUTINE	-
CD4 count (CPT 86360)	Immune status determines HAND risk stratification; CD4 <200 increases risk of HAD and opportunistic infections; CD4 nadir is strongest predictor of HAND	CD4 >500 goal; document nadir	STAT	STAT	ROUTINE	-
HIV-1 RNA viral load (plasma) (CPT 87536)	Plasma virologic control; detectable viral load associated with worse neurocognitive outcomes; assess ART adherence	Undetectable (<20 copies/mL)	STAT	STAT	ROUTINE	-
CBC with differential (CPT 85025)	Anemia (ZDV), infection, hematologic abnormalities; macrocytosis may indicate medication effect or B12/folate deficiency	Normal; document baseline	STAT	STAT	ROUTINE	-
CMP (BMP + LFTs) (CPT 80053)	Metabolic encephalopathy; hepatic dysfunction (hepatitis co-infection); renal function for ART dosing; electrolyte abnormalities	Normal; document baseline	STAT	STAT	ROUTINE	-
RPR/VDRL (CPT 86592)	Neurosyphilis co-infection common in HIV population; treatable cause of cognitive decline; higher rate of neurosyphilis in HIV+ patients	Nonreactive; if reactive, obtain LP for neurosyphilis	STAT	STAT	ROUTINE	-
TSH (CPT 84443)	Hypothyroidism is reversible cause of cognitive impairment; efavirenz and immune reconstitution can affect thyroid	Normal (0.4-4.0 mIU/L)	URGENT	ROUTINE	ROUTINE	-
Vitamin B12 (CPT 82607)	B12 deficiency common in HIV; causes cognitive impairment and myelopathy; reversible	>400 pg/mL	URGENT	ROUTINE	ROUTINE	-
Folate (CPT 82746)	Folate deficiency contributes to cognitive decline; TMP-SMX prophylaxis may mask deficiency	Normal	-	ROUTINE	ROUTINE	-
Hepatitis B surface Ag/Ab/core Ab (CPT 87340)	Co-infection screening; hepatitis affects ART selection; hepatic encephalopathy in differential	Negative or immune	STAT	STAT	ROUTINE	-
Hepatitis C antibody + RNA if positive (CPT 86803)	HCV co-infection prevalence 25-30% in HIV; HCV independently causes neurocognitive impairment; treatable	Negative; if positive, obtain HCV RNA and initiate treatment	STAT	STAT	ROUTINE	-
Urinalysis (CPT 81003)	UTI as cause of acute cognitive worsening; tenofovir nephrotoxicity screening	Normal	STAT	STAT	ROUTINE	-
Urine drug screen (CPT 80307)	Substance use is major confounder and comorbidity in HAND evaluation; methamphetamine, cocaine, and opioids cause neurocognitive impairment; must be excluded before HAND diagnosis	Negative; positive result requires addressing substance use before attributing deficits to HAND	STAT	STAT	ROUTINE	-

1B. Extended Workup (Second-line)¶

Test	Rationale	Target Finding	ED	HOSP	OPD	ICU
HIV genotype/resistance testing (CPT 87901)	If virologic failure suspected; resistance mutations affect ART optimization for CNS-penetrating regimen	Wild-type preferred; document resistance mutations for CNS-penetrating ART selection	-	ROUTINE	ROUTINE	-
HbA1c (CPT 83036)	Diabetes independently impairs cognition; metabolic syndrome common with ART (PIs); vascular risk factor	<7%	-	ROUTINE	ROUTINE	-
Lipid panel (CPT 80061)	Cardiovascular risk factors contribute to vascular cognitive impairment; PI-associated dyslipidemia	Per guidelines	-	ROUTINE	ROUTINE	-
Testosterone (AM, total and free) (CPT 84403)	Hypogonadism common in HIV; causes fatigue, depression, and cognitive symptoms; treatable	Normal for age	-	ROUTINE	ROUTINE	-
Vitamin D, 25-OH (CPT 82306)	Deficiency common in HIV; associated with cognitive decline; TDF and efavirenz may worsen	>30 ng/mL	-	ROUTINE	ROUTINE	-
Thiamine (Vitamin B1) (CPT 84425)	Wernicke encephalopathy if alcohol use; nutritional deficiency common in HIV	Normal	URGENT	ROUTINE	ROUTINE	-
Ammonia (CPT 82140)	Hepatic encephalopathy if liver disease (HBV/HCV co-infection, cirrhosis)	<35 micromol/L	URGENT	ROUTINE	-	-
Toxoplasma IgG (CPT 86777)	Baseline serostatus; if positive, at risk for reactivation with CD4 <100; mass lesion in differential	Document serostatus; negative reduces toxoplasmosis risk	-	ROUTINE	ROUTINE	-
Cryptococcal antigen (serum) (CPT 86641)	Screen if CD4 <100; cryptococcal meningitis causes cognitive impairment; may be subclinical	Negative; positive requires LP and treatment	-	ROUTINE	ROUTINE	-
CMV IgG (CPT 86644)	Baseline serostatus; CMV encephalitis risk if CD4 <50	Document serostatus	-	ROUTINE	ROUTINE	-
Depression screening (PHQ-9) (CPT 96127)	Depression prevalence 20-40% in HIV; major confounder in cognitive assessment; treatable; must be addressed before HAND diagnosis	PHQ-9 <5; >=10 requires treatment	-	ROUTINE	ROUTINE	-

1C. Specialized Testing (Selected Patients)¶

Test	Rationale	Target Finding	ED	HOSP	OPD	ICU
ART drug levels (therapeutic drug monitoring)	If CNS penetration or adherence concerns; especially for dolutegravir, darunavir CSF levels in suspected CNS escape	Therapeutic range	-	EXT	EXT	-
Serum ceruloplasmin/copper (CPT 82390)	Wilson disease if <50 years with movement disorder and cognitive decline	Normal	-	EXT	EXT	-
ANA, dsDNA (CPT 86235)	Autoimmune process in differential; HIV can cause false-positive ANA	Negative	-	EXT	EXT	-
Paraneoplastic panel	If subacute onset with concern for HIV-associated malignancy (lymphoma)	Negative	-	EXT	EXT	-
JC virus antibody (serum) (CPT 86255)	PML risk stratification; positive serostatus with CD4 <200 increases PML risk	Document serostatus	-	ROUTINE	ROUTINE	-
Autoimmune encephalitis panel (serum)	If subacute cognitive decline with psychiatric features, seizures; immune reconstitution may trigger autoimmune processes	Negative	-	EXT	EXT	-

2. DIAGNOSTIC IMAGING & STUDIES¶

2A. Essential/First-line¶

Study	Timing	Target Finding	Contraindications	ED	HOSP	OPD	ICU
MRI brain with and without contrast (CPT 70553)	Initial evaluation of all suspected HAND; contrast to evaluate for OI, lymphoma, or other enhancing lesions	HAND: cerebral atrophy (esp. caudate, basal ganglia), white matter hyperintensities, no enhancing lesions; ring-enhancing lesions indicate toxoplasmosis vs lymphoma; multifocal white matter lesions without enhancement indicate PML	Pacemaker, metal, severe renal disease (gadolinium)	URGENT	ROUTINE	ROUTINE	-
CT head without contrast (CPT 70450)	Emergent evaluation if MRI unavailable; acute mental status change; mass effect evaluation before LP	Mass lesion, hydrocephalus, hemorrhage; less sensitive than MRI for HAND-specific changes	None	STAT	STAT	-	-

2B. Extended¶

Study	Timing	Target Finding	Contraindications	ED	HOSP	OPD	ICU
MRI spectroscopy (MRS) (CPT 76390)	Research/specialized centers; differentiating HAND from other dementias; monitoring treatment response	HAND: elevated choline/creatine (inflammation), reduced N-acetylaspartate/creatine (neuronal loss), elevated myoinositol (gliosis); pattern may precede structural changes	Same as MRI	-	EXT	EXT	-
FDG-PET brain (CPT 78608)	Diagnostic uncertainty; differentiate HAND from AD or FTD; atypical presentations	HAND: subcortical hypometabolism (basal ganglia, thalamus); AD: temporoparietal; FTD: frontal	Per PET	-	-	EXT	-
CT chest/abdomen/pelvis	If concern for systemic OI, lymphoma, or other HIV-associated malignancy as cause of CNS symptoms	Lymphadenopathy, masses, infections	Contrast allergy, renal disease	-	ROUTINE	-	-
EEG (CPT 95816)	If seizures suspected, subclinical seizure activity, or NCSE in acute cognitive decline	HAND: generalized slowing; focal abnormalities indicate structural lesion; seizure activity requires treatment	None	-	ROUTINE	ROUTINE	-

2C. Neuropsychological Testing¶

Study	Timing	Indication	Findings	ED	HOSP	OPD	ICU
Bedside cognitive screen (MoCA or MMSE) (CPT 96116)	All patients at initial evaluation; MoCA preferred (more sensitive for subcortical deficits)	Screening; MoCA more sensitive than MMSE for HAND (subcortical pattern)	MoCA <26 suggests impairment; HAND pattern: poor recall, psychomotor slowing, executive dysfunction with relatively preserved recognition memory	-	ROUTINE	ROUTINE	-
HIV Dementia Scale (HDS)	Rapid bedside screen validated for HIV; assesses psychomotor speed, memory, construction	Screening specific to HAND	Score <10/16 suggests HAD; <14/16 suggests MND; tests timed writing, memory recall, antisaccade, cube copy	-	ROUTINE	ROUTINE	-
International HIV Dementia Scale (IHDS)	Alternative bedside screen; culturally adapted; less education bias than HDS	Screening in diverse populations	Score <=10/12 suggests HAND; motor speed, psychomotor speed, memory recall	-	ROUTINE	ROUTINE	-
Formal neuropsychological testing (CPT 96132)	Gold standard for HAND diagnosis per Frascati criteria; must test >=5 cognitive domains; quantifies severity across domains	Definitive HAND classification; required for Frascati diagnosis; baseline for monitoring treatment response	Tests >=5 domains: attention/working memory, processing speed, executive function, learning, recall, motor function, verbal fluency; >=1 SD below norms in >=2 domains = ANI/MND; >=2 SD = HAD	-	-	ROUTINE	-
Functional assessment (IADL scale)	Required for Frascati classification; distinguishes ANI (no impairment) from MND (mild) and HAD (marked)	Determine functional impact of cognitive deficits	ANI: no functional impairment; MND: mild difficulty with IADLs; HAD: marked impairment in daily functioning	-	ROUTINE	ROUTINE	-

LUMBAR PUNCTURE¶

Indication: All patients with suspected HAND require LP for CSF HIV RNA quantification, exclusion of opportunistic infections, and biomarker assessment; mandatory for HAD evaluation; strongly recommended for MND; obtain for ANI if clinical concern warrants

Study	Rationale	Target Finding	ED	HOSP	OPD	ICU
Opening pressure (CPT 89050)	Elevated in cryptococcal meningitis, mass lesions; normal in uncomplicated HAND	10-20 cm H2O; elevated requires evaluation for OI	URGENT	URGENT	-	-
Cell count (tubes 1 and 4) (CPT 89051)	Mild CSF pleocytosis (5-20 WBC) can be seen in HIV alone; higher counts suggest OI or co-infection	WBC <20 in HAND; WBC >20 requires aggressive OI investigation	URGENT	URGENT	ROUTINE	-
Protein (CPT 84157)	Mildly elevated (50-100 mg/dL) common in HAND; markedly elevated suggests OI or other pathology	15-45 mg/dL normal; mild elevation expected in HAND	URGENT	URGENT	ROUTINE	-
Glucose (CPT 82945)	Low CSF glucose suggests bacterial/fungal/TB meningitis; normal in HAND	>60% of serum glucose; low requires evaluation for OI	URGENT	URGENT	ROUTINE	-
CSF HIV-1 RNA (quantitative) (CPT 87536)	CSF viral escape (detectable CSF HIV RNA with suppressed plasma viral load) is treatable cause of HAND; guides ART optimization for CNS penetration	Undetectable; if detectable with suppressed plasma VL, this indicates CSF viral escape requiring ART optimization for CNS penetration	URGENT	URGENT	ROUTINE	-
CSF VDRL (CPT 86592)	Neurosyphilis; VDRL is only validated non-treponemal CSF test; high co-infection rate	Nonreactive	-	ROUTINE	ROUTINE	-
Cryptococcal antigen (CSF) (CPT 86641)	Rule out cryptococcal meningitis if CD4 <200 or elevated opening pressure; can present with subacute cognitive decline	Negative; positive requires cryptococcal meningitis treatment	URGENT	URGENT	-	-
CSF meningitis/encephalitis panel (PCR multiplex)	Rule out viral encephalitis (HSV, CMV, VZV, JC virus); especially if acute/subacute presentation	Negative; positive requires targeted treatment	URGENT	URGENT	-	-
JC virus PCR (CSF)	PML if white matter lesions on MRI; CD4 <200; progressive multifocal symptoms	Negative; positive confirms PML diagnosis (sensitivity ~80%)	-	URGENT	ROUTINE	-
CMV PCR (CSF)	CMV encephalitis if CD4 <50; periventricular enhancement on MRI	Negative; positive requires ganciclovir treatment	-	URGENT	-	-
AFB smear and culture, TB PCR	Tuberculous meningitis if endemic area, low CD4, constitutional symptoms	Negative; positive requires TB treatment	-	URGENT	ROUTINE	-
Cytology	CNS lymphoma if mass lesion, EBV+ in CSF; HIV increases lymphoma risk	Normal; abnormal requires oncology referral	-	ROUTINE	-	-
EBV PCR (CSF)	Primary CNS lymphoma marker; elevated CSF EBV DNA with ring-enhancing lesion on MRI	Negative; positive with enhancing lesion requires biopsy or empiric treatment	-	URGENT	-	-
CSF neurofilament light chain (NfL)	Marker of neuronal injury; elevated in active HAND; may track treatment response; research and specialized centers	Low/normal; elevated indicates active neuronal injury	-	EXT	EXT	-
Oligoclonal bands / IgG index (CPT 83916)	Intrathecal immune activation; elevated in HAND but nonspecific; helps distinguish from MS or other inflammatory processes	May show intrathecal synthesis	-	ROUTINE	ROUTINE	-

Contraindications: Elevated ICP without imaging clearance; coagulopathy (INR >1.5, platelets <50K); skin infection at LP site; mass lesion on imaging (obtain CT/MRI before LP if concern)

3. TREATMENT¶

3A. ART Optimization for CNS Penetration¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Dolutegravir (Tivicay)	PO	First-line INSTI with high CPE score (CPE 4); excellent CNS penetration; backbone of CNS-optimized ART regimen	50 mg :: PO :: daily :: 50 mg PO daily; increase to 50 mg BID if INSTI resistance suspected or with rifampin	Hypersensitivity; concurrent dofetilide	Viral load q4-8 weeks until undetectable, then q3-6 months; CD4 q3-6 months; CMP; weight gain monitoring	-	ROUTINE	ROUTINE	-
Tenofovir alafenamide (TAF) / Emtricitabine (Descovy)	PO	NRTI backbone; TAF with moderate CPE; preferred over TDF for renal/bone safety	25/200 mg :: PO :: daily :: 1 tablet PO daily	CrCl <30 (for combined formulation); concurrent use with other tenofovir products	Renal function; lipid panel; HBV status (flare risk if discontinued)	-	ROUTINE	ROUTINE	-
Tenofovir disoproxil fumarate (TDF) / Emtricitabine (Truvada)	PO	Alternative NRTI backbone; TDF has slightly higher CPE than TAF	300/200 mg :: PO :: daily :: 1 tablet PO daily; dose adjust for CrCl <50	CrCl <60 (relative); osteoporosis	Renal function q3-6 months; DEXA if >50 or risk factors; phosphorus	-	ROUTINE	ROUTINE	-
Abacavir (Ziagen)	PO	NRTI with high CPE score (CPE 3); use in CNS-optimized regimens	600 mg :: PO :: daily :: 600 mg PO daily or 300 mg BID	*HLA-B5701 positive** (fatal hypersensitivity reaction -- must test before prescribing); cardiovascular risk (controversial)	HLA-B*5701 mandatory before initiation; hypersensitivity reaction monitoring	-	ROUTINE	ROUTINE	-
Zidovudine (AZT, Retrovir)	PO	NRTI with highest CPE score (CPE 4); use in CNS-escape despite toxicity; historical backbone of HAND treatment	300 mg :: PO :: BID :: 300 mg PO BID; dose adjust for renal impairment	Severe anemia (Hgb <7.5); neutropenia (ANC <750); myopathy	CBC q2-4 weeks initially (anemia, neutropenia); CK if myopathy symptoms; macrocytosis expected	-	ROUTINE	ROUTINE	-
Darunavir/ritonavir (Prezista/Norvir)	PO	PI with moderate CPE; boosted PI for resistant virus; use when INSTI resistance present	800/100 mg :: PO :: daily :: 800 mg darunavir + 100 mg ritonavir PO daily with food; 600/100 mg BID if resistance	Sulfonamide allergy (relative); concurrent drugs with CYP3A4 interactions	LFTs; lipid panel; glucose; drug interactions (extensive CYP3A4 inhibition); GI tolerance	-	ROUTINE	ROUTINE	-
Efavirenz (Sustiva)	PO	NNRTI with high CPE score (CPE 3); historical use in HAND; CNS side effects limit utility due to neuropsychiatric toxicity	600 mg :: PO :: QHS :: 600 mg PO at bedtime on empty stomach	Pregnancy (first trimester -- teratogenic); severe psychiatric disease; concurrent CYP interactions	Neuropsychiatric monitoring (vivid dreams, depression, suicidality, psychosis -- especially first 2-4 weeks); LFTs; lipid panel	-	EXT	EXT	-
Nevirapine (Viramune)	PO	NNRTI with high CPE score (CPE 4); alternative for CNS optimization; hepatotoxicity and rash risk limit use	200 mg :: PO :: daily :: 200 mg PO daily x 14 days lead-in, then 200 mg BID; extended release: 400 mg daily after lead-in	CD4 >250 (women) or >400 (men) for treatment-naive (hepatotoxicity risk); severe hepatic impairment	LFTs at baseline, 2 wks, 4 wks, then q3 months; rash monitoring (SJS risk first 18 weeks); discontinue if LFTs >5x ULN	-	EXT	EXT	-
Maraviroc (Selzentry)	PO	CCR5 antagonist with high CPE score (CPE 3); requires tropism testing; unique anti-inflammatory CNS mechanism relevant to HAND	300 mg :: PO :: BID :: 300 mg PO BID (with CYP3A4 inhibitors: 150 mg BID; with inducers: 600 mg BID)	Non-CCR5-tropic virus (must confirm R5 tropism before use); hepatotoxicity risk	Tropism assay mandatory; LFTs; cough, URI symptoms; CYP3A4 interactions	-	EXT	EXT	-

3B. Treatment of CSF Viral Escape¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
ART regimen intensification (CNS-optimized)	PO	CSF viral escape (detectable CSF HIV RNA with suppressed plasma viral load); neurologic deterioration despite plasma viral suppression	Individualized :: PO :: per resistance profile :: Switch to regimen with highest total CPE score incorporating dolutegravir + 2 high-CPE NRTIs (e.g., DTG/ABC/3TC or DTG + ZDV/3TC); target total CPE >=7-8; guided by resistance profile	Per individual drug contraindications	Repeat LP in 4-8 weeks to confirm CSF viral suppression; plasma VL q4 weeks; neuropsychological retesting at 6-12 months	-	URGENT	ROUTINE	-
Enfuvirtide (Fuzeon) — salvage therapy	SC	Multidrug-resistant CSF viral escape refractory to oral optimization; extensive NRTI/NNRTI/PI/INSTI resistance	90 mg :: SC :: BID :: 90 mg SC BID (injection site rotation)	Hypersensitivity; injection site reactions (nearly universal)	Injection site reactions; pneumonia risk; eosinophilia; CSF VL follow-up	-	EXT	EXT	-

3C. Symptomatic Treatment¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Sertraline	PO	Depression comorbid with HAND (prevalence 20-40%); safe in HIV; minimal drug interactions with ART	25 mg :: PO :: daily :: Start 25 mg daily; increase by 25 mg q1-2 weeks; target 50-200 mg daily	Concurrent MAOIs; caution with ritonavir (increases sertraline levels)	Suicidality monitoring; serotonin syndrome; GI effects; hyponatremia	-	ROUTINE	ROUTINE	-
Escitalopram	PO	Depression/anxiety comorbid with HAND; well tolerated; minimal CYP interactions	5 mg :: PO :: daily :: Start 5-10 mg daily; max 20 mg daily	Concurrent MAOIs; QT prolongation	QTc if risk factors; suicidality monitoring; check interactions with PIs	-	ROUTINE	ROUTINE	-
Mirtazapine	PO	Depression with insomnia and weight loss (common in HIV); appetite stimulation; dual benefit in HIV wasting with depression	15 mg :: PO :: QHS :: Start 15 mg QHS; increase to 30-45 mg; lower dose more sedating	Concurrent MAOIs; caution with CYP3A4 inhibitors (PIs may increase levels)	Weight gain (desired in wasting); sedation; neutropenia (rare)	-	ROUTINE	ROUTINE	-
Bupropion	PO	Depression with fatigue, psychomotor slowing; avoid in seizure risk; may assist with stimulant cessation in comorbid methamphetamine use	150 mg :: PO :: daily :: Start 150 mg XL daily; increase to 300 mg XL daily after 1 week if needed	Seizure disorder; eating disorders; concurrent MAOIs; abrupt alcohol/benzodiazepine withdrawal	Seizure risk; insomnia; anxiety; blood pressure	-	ROUTINE	ROUTINE	-
Methylphenidate	PO	Psychomotor slowing, apathy, and fatigue in HAND; evidence for improved attention and processing speed in HIV cognitive impairment; Hinkin et al., J Clin Exp Neuropsychol 2001	5 mg :: PO :: BID :: Start 5 mg BID (morning and noon); increase by 5-10 mg/week; target 20-40 mg/day in divided doses; avoid evening dosing	Uncontrolled hypertension; cardiac arrhythmias; glaucoma; concurrent MAOIs; active psychosis; substance abuse history (relative)	Heart rate; blood pressure; appetite; insomnia; psychiatric symptoms; abuse potential	-	ROUTINE	ROUTINE	-
Modafinil	PO	Fatigue and excessive daytime sleepiness in HAND; alternative to methylphenidate with lower abuse potential	100 mg :: PO :: QAM :: Start 100 mg QAM; increase to 200 mg QAM after 1 week; max 200 mg daily	Hypersensitivity; cardiac arrhythmias; concurrent CYP3A4 concerns (may reduce PI levels -- monitor)	Blood pressure; interactions with PIs (may reduce darunavir levels); sleep quality; SJS risk (rare)	-	ROUTINE	ROUTINE	-
Memantine (Namenda)	PO	NMDA receptor-mediated neurotoxicity in HIV; moderate-severe HAND; limited but emerging evidence for neuroprotection in HAND; Schifitto et al., Neurology 2007	5 mg :: PO :: daily :: Start 5 mg daily; increase by 5 mg/week to 10 mg BID; max 20 mg/day	Severe renal impairment (CrCl <30)	Confusion; dizziness; constipation; renal function	-	EXT	ROUTINE	-
Trazodone	PO	Insomnia comorbid with HAND; sleep disruption common in HIV; alternative to benzodiazepines (avoid in HAND)	25 mg :: PO :: QHS :: Start 25 mg QHS; titrate to 50-100 mg QHS as needed; max 100 mg QHS for insomnia	Orthostatic hypotension; concurrent MAOIs; priapism risk	Sedation; orthostasis; falls risk	-	ROUTINE	ROUTINE	-
Quetiapine	PO	Agitation, psychosis, or severe behavioral disturbance in HAD; lowest effective dose; use non-pharmacologic interventions first	12.5 mg :: PO :: QHS :: Start 12.5-25 mg QHS; titrate slowly to lowest effective dose; max 100-200 mg for behavioral symptoms in dementia	QT prolongation; metabolic syndrome; Parkinsonism	Caution: metabolic effects compound ART metabolic toxicity; QTc; glucose; lipids; weight; EPS monitoring	-	ROUTINE	ROUTINE	-
Haloperidol	IV/IM	Acute agitation or psychosis in ED/inpatient setting with HAD; short-term use only	2 mg :: IV/IM :: PRN agitation :: 2-5 mg IV/IM PRN; may repeat q30min; max 20 mg/24h; switch to oral atypical ASAP	QT prolongation; Parkinsonism; NMS risk	QTc before and during use; EPS; NMS monitoring; avoid in DLB (not typical in HAND)	STAT	STAT	-	-

3D. Substance Use Treatment (Common Comorbidity)¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Buprenorphine/naloxone (Suboxone)	SL	Opioid use disorder comorbid with HAND; improves ART adherence; minimal cognitive impairment vs. continued illicit use	2/0.5 mg :: SL :: daily :: Induction: 2/0.5 mg SL; increase by 2/0.5-4/1 mg q1-2h to relief; target maintenance 8/2-16/4 mg daily	Concurrent full agonist opioids (precipitated withdrawal); severe hepatic impairment	LFTs; precipitated withdrawal; sedation; check interactions with PIs (buprenorphine levels may increase with ritonavir)	-	ROUTINE	ROUTINE	-
Naltrexone XR (Vivitrol)	IM	Alcohol use disorder comorbid with HAND; alcohol worsens cognitive impairment and ART non-adherence	380 mg :: IM :: monthly :: 380 mg IM gluteal injection monthly; patient must be opioid-free >=7-10 days	Acute opioid use; acute hepatitis; hepatic failure	LFTs; injection site reaction; depression screening; opioid-free confirmation	-	-	ROUTINE	-
Contingency management referral	-	Methamphetamine use disorder (most common stimulant in HIV-HAND population); no FDA-approved pharmacotherapy; CM has strongest evidence	N/A :: - :: - :: Refer to behavioral health program offering contingency management/motivational incentives; combine with cognitive behavioral therapy	None	Adherence; UDS; neurocognitive monitoring for improvement after abstinence	-	ROUTINE	ROUTINE	-

3E. Prophylaxis Against Opportunistic Infections (Concurrent)¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
TMP-SMX (Bactrim DS)	PO	PCP prophylaxis if CD4 <200; toxoplasmosis prophylaxis if CD4 <100 and Toxo IgG+; prevents OIs that worsen cognition	1 DS tablet :: PO :: daily :: 1 DS tablet (160/800 mg) PO daily; alternatives: dapsone, atovaquone if sulfa allergy	Sulfonamide allergy; severe renal impairment; folate deficiency (supplement)	CBC; CMP; rash (SJS rare); hyperkalemia; folate supplementation	-	ROUTINE	ROUTINE	-
Fluconazole	PO	Secondary prophylaxis if prior cryptococcal meningitis; maintenance until immune reconstitution (CD4 >200 x 6 months)	200 mg :: PO :: daily :: 200 mg PO daily until CD4 >200 for >=6 months on suppressive ART	Hepatic disease; QT prolongation; drug interactions (azoles + PIs)	LFTs; drug interactions with ART (especially ritonavir); QTc	-	ROUTINE	ROUTINE	-

4. OTHER RECOMMENDATIONS¶

4A. Referrals & Consults¶

Recommendation	ED	HOSP	OPD	ICU
Infectious disease/HIV specialist for ART optimization with focus on CNS-penetrating regimen and resistance management	-	URGENT	ROUTINE	-
Neurology consultation for HAND diagnosis confirmation, exclusion of other etiologies, and longitudinal cognitive monitoring	-	ROUTINE	ROUTINE	-
Neuropsychology for formal neuropsychological testing (mandatory for Frascati criteria diagnosis); minimum 5 cognitive domains assessed	-	-	ROUTINE	-
Psychiatry for depression, anxiety, PTSD management (prevalence 20-40% in HIV); substance use disorder treatment	-	ROUTINE	ROUTINE	-
Addiction medicine / substance use treatment if active substance use; methamphetamine use is most potent modifier of HAND	-	ROUTINE	ROUTINE	-
Social work for medication adherence support, housing stability, insurance navigation, disability applications; social determinants profoundly affect HAND outcomes	-	ROUTINE	ROUTINE	-
Case management / HIV navigator for ART adherence programs (DOT, pill boxes, pharmacy sync); adherence is the single most modifiable factor in HAND treatment	-	ROUTINE	ROUTINE	-
Occupational therapy for ADL assessment and compensatory strategies in MND/HAD; adaptive equipment; vocational rehabilitation	-	ROUTINE	ROUTINE	-
Speech therapy if language or swallowing difficulties in advanced HAD	-	ROUTINE	ROUTINE	-
Palliative care for advanced HAD with poor prognosis despite optimized ART; goals of care discussions	-	-	ROUTINE	-
Ophthalmology if CD4 <100 for CMV retinitis screening; vision changes in HAND evaluation	-	ROUTINE	ROUTINE	-

4B. Patient/Family Instructions¶

Recommendation	ED	HOSP	OPD
ART adherence is the most important factor in preventing and treating HAND; undetectable viral load = healthiest brain; use pill organizers, alarms, and pharmacy reminders	ROUTINE	ROUTINE	ROUTINE
Cognitive difficulties in HIV are treatable -- ART optimization often improves symptoms over months; do not stop medications	-	ROUTINE	ROUTINE
Avoid alcohol and recreational drugs; substances worsen cognitive impairment independently and reduce ART adherence; methamphetamine is particularly neurotoxic	ROUTINE	ROUTINE	ROUTINE
Report new or worsening memory problems, confusion, difficulty with daily tasks, personality changes, or depression to your HIV provider promptly	-	ROUTINE	ROUTINE
Establish healthcare proxy and advance directives, particularly if diagnosed with HAD; discuss preferences while able to participate	-	ROUTINE	ROUTINE
Keep all follow-up appointments; cognitive monitoring requires regular neuropsychological testing to track changes over time	-	ROUTINE	ROUTINE
Return to ED if sudden confusion, severe headache, fever with cognitive changes, new weakness, seizures, or vision changes (may indicate OI, not just HAND)	ROUTINE	ROUTINE	ROUTINE
Sleep hygiene: maintain consistent sleep schedule; insomnia worsens cognitive function and is treatable	-	ROUTINE	ROUTINE
Exercise regularly (30 min moderate activity, 5 days/week); physical activity improves cognition in HIV; Fazeli et al., J Assoc Nurses AIDS Care 2014	-	ROUTINE	ROUTINE

4C. Lifestyle & Prevention¶

Recommendation	ED	HOSP	OPD
Regular aerobic exercise (30 min, 5 days/week) -- improves neurocognition, cardiovascular health, mood, and immune function in HIV	-	ROUTINE	ROUTINE
Cognitive stimulation activities (reading, puzzles, social engagement, learning new skills); preserves cognitive reserve	-	-	ROUTINE
Mediterranean or MIND diet; cardiovascular risk reduction contributes to brain health; nutritional optimization in HIV	-	-	ROUTINE
Cardiovascular risk factor management (BP <130/80, diabetes control, lipid management); vascular contributions to HAND increasingly recognized	-	ROUTINE	ROUTINE
Tobacco cessation (smoking rate >40% in PLWH); smoking accelerates brain aging and vascular cognitive impairment	-	ROUTINE	ROUTINE
Limit alcohol to <=1 drink/day or abstain; alcohol is directly neurotoxic and worsens HIV-mediated neuroinflammation	-	ROUTINE	ROUTINE
Avoid benzodiazepines and anticholinergics; these worsen cognitive impairment and must be minimized in HAND patients	-	ROUTINE	ROUTINE
Social engagement and peer support groups (PLWH community); social isolation worsens depression and cognitive decline	-	-	ROUTINE
Screen for and treat obstructive sleep apnea; prevalence increased in HIV; untreated OSA worsens cognition	-	-	ROUTINE

═══════════════════════════════════════════════════════════════ SECTION B: REFERENCE (Expand as Needed) ═══════════════════════════════════════════════════════════════

5. DIFFERENTIAL DIAGNOSIS¶

Alternative Diagnosis	Key Distinguishing Features	Tests to Differentiate
CNS opportunistic infection (toxoplasmosis, cryptococcal meningitis, PML, CMV encephalitis)	Acute/subacute onset; focal deficits; fever; low CD4 (<200 typically); enhancing or white matter lesions on MRI	MRI with contrast; LP with OI panel; serum/CSF cryptococcal antigen; CSF JC virus PCR; toxoplasma serology
Depression / Pseudodementia	Depressed mood; "I don't know" responses; subjective complaints often exceed objective deficits; rapid onset; sleep/appetite changes; may not show >=2 domain deficits on testing	PHQ-9; psychiatric evaluation; neuropsychological testing (depression affects effort-dependent tasks but spares recognition); trial of antidepressant with cognitive reassessment
Substance use effects (methamphetamine, cocaine, opioids, alcohol)	Temporal correlation with substance use; positive UDS; may improve with sustained abstinence; methamphetamine causes similar subcortical deficits as HAND	UDS; history; reassess cognition after >=4 weeks abstinence; brain MRI (meth causes white matter changes similar to HAND)
Neurosyphilis	Co-infection common; Argyll Robertson pupils; may be indistinguishable from HAND clinically; posterior column signs in tabes	Serum RPR/VDRL; CSF VDRL; FTA-ABS; treat with IV penicillin and reassess
Hepatic encephalopathy	HBV/HCV co-infection; asterixis; elevated ammonia; fluctuating consciousness; cirrhosis on exam	Ammonia level; LFTs; hepatitis serologies; abdominal imaging
CNS lymphoma (primary)	Ring-enhancing periventricular lesion; progressive focal deficits; CD4 typically <50; EBV-associated	MRI with contrast; CSF EBV PCR; stereotactic biopsy; whole body PET
Medication-induced cognitive impairment	Temporal relation to drug initiation; efavirenz (neuropsychiatric), dolutegravir (insomnia), opioids, benzodiazepines, anticholinergics	Medication timeline; trial discontinuation; drug levels; symptoms reverse with discontinuation
Alzheimer's disease	Cortical pattern (aphasia, apraxia, agnosia); prominent episodic memory loss with poor recognition; older patient; amyloid biomarkers positive	Neuropsychological testing (cortical vs subcortical pattern); amyloid PET or CSF Abeta42/tau; MRI (hippocampal atrophy in AD vs caudate atrophy in HAND)
Vascular cognitive impairment	Stepwise decline; cardiovascular risk factors; strategic infarcts; white matter disease on MRI; may coexist with HAND	MRI (lacunar infarcts, extensive WMH); vascular risk factor assessment; HAND and VCI may be additive
Metabolic encephalopathy (hyponatremia, uremia, hypoglycemia)	Acute/fluctuating; electrolyte abnormalities; renal failure; medication-related	CMP; renal function; glucose; corrects with metabolic correction
Immune reconstitution inflammatory syndrome (IRIS)	Paradoxical worsening after ART initiation (typically 2-8 weeks); new or worsening neurological symptoms; enhancing lesions	Timing correlation with ART start; MRI with contrast; LP; distinguish from OI vs IRIS; may require corticosteroids

Red Flags Requiring Urgent Investigation¶

Red Flag	Concern	Immediate Action
Acute cognitive decline with fever	CNS opportunistic infection; meningitis; sepsis	Urgent imaging followed by LP followed by empiric treatment
New focal neurologic deficit	Mass lesion (toxoplasmosis, lymphoma); stroke; PML	Urgent MRI with contrast; initiate empiric toxoplasmosis treatment if ring-enhancing lesion
Seizure (new-onset)	OI; mass lesion; metabolic; toxicity	CT head followed by labs followed by LP; seizure management
Rapid deterioration after starting ART	IRIS; unmasked OI; medication toxicity	MRI; LP; initiate corticosteroids for IRIS; do not stop ART
CD4 <100 with new headache or confusion	Cryptococcal meningitis; toxoplasmosis; CMV	Serum CrAg; urgent imaging followed by LP; empiric treatment
Visual changes with low CD4	CMV retinitis; PML affecting occipital lobe; optic neuritis	Urgent ophthalmology; MRI

6. MONITORING PARAMETERS¶

Parameter	Frequency	Target/Threshold	Action if Abnormal	ED	HOSP	OPD	ICU
HIV viral load (plasma)	q3-6 months on stable ART; q4 weeks during ART changes	Undetectable (<20 copies/mL)	Detectable: perform adherence assessment, resistance testing, ART modification	-	ROUTINE	ROUTINE	-
CD4 count	q3-6 months until immune reconstitution (CD4 >500 x 2 years); then annually	>500 cells/microL	<200: initiate OI prophylaxis; <100: high risk for OIs affecting cognition	-	ROUTINE	ROUTINE	-
CSF HIV RNA (if initial CSF escape)	4-8 weeks after ART optimization; then q6-12 months if history of CSF escape	Undetectable	Persistent CSF viral escape: perform further ART optimization; initiate salvage regimen; neurology/ID co-management	-	ROUTINE	ROUTINE	-
Cognitive screening (MoCA or HDS)	Every clinic visit or at minimum q6 months	Stable or improving	Decline >=2 points: obtain formal neuropsychological testing; evaluate for new confounders	-	ROUTINE	ROUTINE	-
Formal neuropsychological testing	Baseline; 6-12 months after ART optimization; annually in MND/HAD; q2 years in ANI	Stable or improved; no new domain impairments	Worsening: obtain CSF evaluation for viral escape; imaging; confounder assessment	-	-	ROUTINE	-
Depression screening (PHQ-9)	Every visit	PHQ-9 <5	>=10: initiate/adjust antidepressant; >=20: urgent psychiatric referral; suicidality assessment	-	ROUTINE	ROUTINE	-
Substance use screening	Every visit	Abstinence from neurotoxic substances	Active use: initiate substance use treatment referral; reassess HAND diagnosis after abstinence	-	ROUTINE	ROUTINE	-
ART adherence assessment	Every visit	>95% adherence (pill counts, pharmacy records, self-report)	Suboptimal: identify barriers; case management; DOT; simplify regimen; adherence counseling	-	ROUTINE	ROUTINE	-
Functional status (IADL scale)	q6-12 months	Stable independence	Decline: increase support; OT referral; driving evaluation; reassess HAND severity	-	ROUTINE	ROUTINE	-
MRI brain	Baseline; repeat if clinical worsening, suspected OI, or CSF escape detected	Stable or improved atrophy; no new lesions	New enhancement: perform OI workup; progressive atrophy: evaluate treatment failure; WMH progression: initiate vascular management	-	ROUTINE	ROUTINE	-
Metabolic panel (glucose, lipids, HbA1c)	q6-12 months (ART metabolic effects)	Per guidelines	Metabolic syndrome: initiate cardiovascular risk reduction; address vascular contribution to cognitive impairment	-	ROUTINE	ROUTINE	-

7. DISPOSITION CRITERIA¶

Disposition	Criteria
Outpatient workup (most patients)	Suspected ANI or MND; stable cognition; safe home environment; reliable follow-up; no acute OI concern; CD4 >200 with suppressed viral load
Admit to hospital	New HAD diagnosis with marked functional impairment; suspected CNS OI; acute cognitive decline requiring urgent LP and imaging; CSF viral escape requiring inpatient ART optimization; unsafe home environment; inability to manage medications independently
Discharge from hospital	OI ruled out or treated; ART optimized; stable or improving cognition; safe disposition; follow-up arranged with ID and neurology; medication adherence plan established
Transfer to higher level of care	Suspected CNS OI requiring subspecialty management not available at current facility; need for brain biopsy; refractory CSF viral escape requiring expert HIV management
Assisted living / Supervised care	Advanced HAD with inability to live independently; unable to manage ART adherence without supervision; safety concerns
Long-term care / Skilled nursing	End-stage HAD; 24-hour care needs; severe functional impairment despite ART optimization
Palliative care / Hospice	End-stage HAD unresponsive to ART optimization; goals of care focused on comfort; multiple concurrent OIs with poor prognosis

8. EVIDENCE & REFERENCES¶

Recommendation	Evidence Level	Source
Frascati criteria define HAND classification (ANI, MND, HAD) based on neuropsychological testing in >=5 domains	Expert consensus (international)	Antinori et al. Neurology 2007
HAND prevalence remains 30-50% despite effective ART; ANI is most common form in ART era	Class II evidence	Heaton et al. J Int Neuropsychol Soc 2011
CD4 nadir is strongest predictor of HAND regardless of current CD4	Class II evidence	Ellis et al. Arch Neurol 2011
CSF viral escape occurs in 5-10% of virologically suppressed patients; treatable with CNS-penetrating ART	Class III evidence	Canestri et al. AIDS 2010
Higher CPE score ART regimens associated with better CSF viral suppression	Class II evidence	Letendre et al. Arch Neurol 2008
CPE score does not consistently predict neurocognitive improvement (controversy exists)	Class II evidence (conflicting results)	Marra et al. Neurology 2009
Dolutegravir achieves therapeutic CSF concentrations and has high CPE score	Class II evidence	Letendre et al. Antimicrob Agents Chemother 2014
ART initiation improves neurocognitive function in most patients; greatest benefit in first 6-12 months	Class I evidence (SMART/START substudy)	Wright et al. AIDS 2010
Depression and substance use are major confounders in HAND diagnosis and must be addressed	Expert consensus	Mind Exchange Working Group. Clin Infect Dis 2013
Methamphetamine use compounds HIV neurotoxicity and accelerates HAND progression	Class II evidence	Carey et al. Curr HIV/AIDS Rep 2006
Methylphenidate improves psychomotor speed and attention in HIV cognitive impairment	Class II evidence (RCT)	Hinkin et al. J Clin Exp Neuropsychol 2001
Exercise improves neurocognitive outcomes in people living with HIV	Class II evidence	Fazeli et al. J Assoc Nurses AIDS Care 2014
HCV co-infection independently worsens neurocognitive impairment in HIV	Class II evidence	Clifford et al. Neurology 2005
AAN and EACS recommend neurocognitive screening for all PLWH	Professional society guideline	EACS Guidelines 2023; AAN Practice Parameter
Immune reconstitution inflammatory syndrome (IRIS) can cause paradoxical neurologic worsening after ART initiation	Class III evidence	Johnson & Nath. Curr Treat Options Neurol 2011

NOTES¶

HAND is a diagnosis of exclusion -- all confounders (depression, substance use, metabolic, OIs, medications) must be systematically excluded before attributing cognitive deficits to HIV
The most common form of HAND in the ART era is ANI; HAD has decreased dramatically but MND and ANI remain prevalent
CD4 nadir (not current CD4) is the strongest predictor of HAND; patients with historical deep nadir remain at risk despite immune reconstitution
CSF viral escape is an underrecognized and treatable cause of cognitive decline in virologically suppressed patients -- always check CSF HIV RNA
CPE score is a useful but imperfect guide; clinical response and CSF viral suppression matter more than absolute CPE score
Substance use (especially methamphetamine) is the most potent modifier of HAND and must be addressed alongside ART optimization
ART adherence is the single most important modifiable factor -- simplify regimens, address barriers, involve case management
Depression is both a confounder and comorbidity -- screen at every visit, treat aggressively, and reassess cognitive deficits after treatment
Avoid anticholinergics and benzodiazepines in HAND patients; these worsen cognitive impairment
Frascati criteria require neuropsychological testing in >=5 cognitive domains with standardized norms; bedside screens are insufficient for diagnosis
Aging with HIV: as PLWH age, vascular, metabolic, and neurodegenerative contributions to cognitive impairment increasingly overlap with HAND

CHANGE LOG¶

v1.1 (February 2, 2026) - Added REVISED date line and updated STATUS to "Revised per checker/rebuilder v1.1" - Updated version from 1.0 to 1.1 in frontmatter and header - Relocated LP section from under Section 1 to after Section 2B imaging per style guide - Added "2C. Neuropsychological Testing" subsection header (previously unlabeled) - Replaced all non-directive language ("consider") with direct statements throughout document - Fixed haloperidol structured dosing: added "PRN agitation" frequency field - Fixed trazodone structured dosing: changed starting dose from "25-50 mg" to "25 mg" with titration instructions - Fixed ART regimen intensification dosing: added "per resistance profile" frequency field - Fixed contingency management referral dosing format with proper structured fields - Fixed enfuvirtide row: clarified "salvage therapy" in treatment name - Removed hedging language from efavirenz, nevirapine, and maraviroc indication text - Added OPD ROUTINE coverage to urinalysis (Section 1A) - Converted all "consider" directives to active directive language across all sections - Fixed methylphenidate citation to consistent PMID 11806849 (Hinkin et al., J Clin Exp Neuropsychol 2001) - Replaced arrow symbols with plain language connectors throughout target finding columns

v1.0 (February 2, 2026) - Initial template creation - Comprehensive HAND evaluation covering Frascati criteria (ANI, MND, HAD) - ART optimization section with CPE score considerations and CNS-penetrating regimens - CSF viral escape diagnosis and management - Exclusion of opportunistic infections (toxoplasmosis, PML, cryptococcal meningitis, CMV) - Comorbid depression, substance use (methamphetamine, opioids, alcohol) management - Neuropsychological testing framework including HIV Dementia Scale and formal testing - Symptomatic treatment including methylphenidate, antidepressants, and memantine - 15 evidence references with PubMed links

APPENDIX A: CNS Penetration Effectiveness (CPE) Score Reference¶

CPE Score	Drug Class	Antiretrovirals
4	NRTI	Zidovudine (AZT)
4	NNRTI	Nevirapine
4	INSTI	Dolutegravir
3	NRTI	Abacavir, Emtricitabine
3	NNRTI	Efavirenz, Etravirine
3	PI	Darunavir/r, Indinavir/r, Lopinavir/r
3	CCR5 antagonist	Maraviroc
2	NRTI	Lamivudine, Stavudine, Tenofovir (TDF)
2	NNRTI	Rilpivirine
2	PI	Atazanavir/r, Fosamprenavir/r
2	INSTI	Raltegravir
1	NRTI	Didanosine, Tenofovir alafenamide (TAF)
1	PI	Nelfinavir, Ritonavir (full dose), Saquinavir, Tipranavir
1	INSTI	Elvitegravir, Bictegravir (limited data)
1	Fusion inhibitor	Enfuvirtide (T-20)

Target: Total regimen CPE score >=7-8 for CNS optimization (sum of all drugs in regimen)

Example high-CPE regimen: Dolutegravir (4) + Abacavir (3) + Lamivudine (2) = CPE 9

Note: CPE score is a guide, not a mandate. Clinical response and CSF viral suppression are the definitive measures of CNS treatment success. Some studies show conflicting results regarding CPE and neurocognitive outcomes.

APPENDIX B: Frascati Criteria (HAND Classification Algorithm)¶

Confirm HIV-positive status
Exclude confounders: Depression (PHQ-9), substance use (UDS, >=4 weeks abstinence), delirium, OI, metabolic, medications
Neuropsychological testing: >=5 cognitive domains: attention/working memory, processing speed, executive function, learning, delayed recall, motor function, verbal fluency
Classify by performance and function:

Classification	Neuropsych Performance	Functional Impairment	ICD-10
Normal	Within normal limits	None	--
ANI	>=1 SD below norms in >=2 domains	None	R41.81
MND	>=1 SD below norms in >=2 domains	Mild (some difficulty with IADLs)	F02.80
HAD	>=2 SD below norms in >=2 domains	Marked (significant impairment in ADLs)	F02.80, F02.81

Deficits cannot be explained by confounders alone
Deficits do not meet criteria for delirium

APPENDIX C: HAND Monitoring Schedule¶

Visit Type	Frequency	Components
Initial evaluation	At HAND diagnosis	Full neuropsych testing; LP with CSF HIV RNA; MRI brain; complete labs; depression/substance screening; functional assessment
Post-ART optimization	4-8 weeks after change	CSF HIV RNA (if initial escape); plasma VL; brief cognitive screen; adherence assessment
Early follow-up	3-6 months	Cognitive screening (MoCA/HDS); depression screening; substance use assessment; VL/CD4; functional status
Routine monitoring	q6-12 months (ANI); q3-6 months (MND/HAD)	Cognitive screening; formal neuropsych annually in MND/HAD; VL/CD4; metabolic labs; functional assessment; ART adherence
Triggered evaluation	With any new cognitive decline	Repeat LP (CSF viral escape); MRI (OI/progression); full labs; confounder reassessment; formal neuropsych if >6 months from last