HIV-associated neurocognitive disorder (HAND)


  • HIV is found in brain in macrophages, microglia, and multinucleated giant cells especially of the deep white matter, basal ganglia, and brain stem.
  • HAND injury is primarily to the subcortical white matter


  • HAND refers to HIV-associated neurocognitive disorder and refers to dysfunction of any degree of severity from asymptomatic neurocognitive impairment to mild neurocognitive disorder to HIV-associated dementia (HAD). Distinguishing between classifications along this spectrum is useful for research with limited clinical utility.
  • HIV encephalopathy and AIDS-dementia complex are less used terms that refer to HAD.
  • HAND is subacute decline in cognitive function due to HIV characterized by memory loss, cognitive slowing (withdrawal can be prominent), and gait disturbances (loss of balance, stumbling)
  • Cortical-type dementia is becoming more common with the use of long-term ART; this is characterized by impairments in memory, learning, and executive function. The pathophysiology of this is unclear. Also unclear is whether it is part of the HAND spectrum or related to other cortical dementias.
  • Prevalence 2% for HAD, 12% for mild neurocognitive disorder, and 33% for asymptomatic neurocognitive impairment.
  • Risk factors for HAND include Hx of more severe immunosuppression (nadir CD4 < 200), so earlier treatment to prevent severe immunosuppression may decrease risk.
  • Early Sx: apathy, impaired memory, difficulty with reading and calculation, decreased libido, depressive symptoms, waning interest in work and hobbies causing social withdrawal, occasionally mania or psychosis.
  • Later Sx (HAD): psychomotor slowing, poor memory, slowed movement. At end-stage, patients can be mute, bedbound, and incontinent.
  • Severe HAD may be accompanied by HIV-related myelopathy or neuropathy.
  • Considered a "subcortical dementia" due to absence of signs like aphasia and apraxia seen in "cortical dementias" like Alzheimer disease.
  • Motor symptoms like gait dysfunction, poor balance, and tremor may be present.
  • Severity rated from 0 to 4: 0-normal, 0.5-subclinical, 1-mild, 2-moderate, 3-severe, 4-end stage.
  • When untreated with antiretroviral therapy, mean survival was ~6 months.


  • DDx includes PML, CNS toxoplasmosis, primary CNS lymphoma, CMV encephalitis, neurosyphilis, vitamin B12 or thiamine deficiency, delirium, depression, medication/drug effect, or other causes of dementia.
  • Differs from delirium in that there is no alteration of consciousness or attention.
  • Exam may show frontal release signs, hyperreflexia, and increased tone.
  • Consider OI if focal signs or fever present.
  • Workup once HAND is suspected includes brain MRI, neuropsychological testing, serologic testing as needed to rule out vitamin deficiency and syphilis because the diagnosis is one of exclusion.
  • MRI usually shows atrophy and ill-defined white matter hyperintensities on T2-weighted scans.
  • CSF analysis not essential, but may be needed to rule out OI.
  • CSF findings nonspecific: may be acellular or show a lymphocytic pleocytosis; protein elevated in 65%.
  • The HIV dementia scale is useful to assess degree of HIV dementia and for longitudinal follow-up (see PDF); it is not a diagnostic tool.



  • ART is mainstay of treatment.
  • Drugs with greater CNS penetration, including AZT, d4T, 3TC, ABC, NVP, IDV, and LPV/r, are more effective at decreasing CSF viral load, but evidence is mixed regarding whether this results in clinical benefit.
  • IRIS can occasionally be seen following initiation of ART-usually due to PML.
  • No other adjunctive treatments have proven benefit.

Non-ART therapies

  • Treatment of comorbid depression, mania, or psychosis may be necessary in advanced HAD.
  • HAD patients are sensitive to psychoactive medications.

Selected Drug Comments




ART is only effective treatment for HAD.


Common Practice

  • Perform HIV dementia scale for a baseline disease assessement (see PDF; a score ≤10 suggests HAD) and follow-up assessments (see PDF)
  • Monitor response to ART.
  • If neurologic deterioration, perform brain MRI to rule out IRIS or OI.
  • Neuropsychological testing is more sensitive that the HIV dementia scale but may be harder to access. It is especially valuable for early HAND.


  1. Clifford DB, Ances BM. HIV-associated neurocognitive disorder. Lancet Infect Dis. 2013;13(11):976-86.  [PMID:24156898]

    Comment: Excellent review of current knowledge of HAND.
    Rating: Important

  2. Garvey L, Winston A, Walsh J, et al. Antiretroviral therapy CNS penetration and HIV-1-associated CNS disease. Neurology. 2011;76(8):693-700.  [PMID:21339496]

    Comment: A non-significant association was seen between lower ART CNS penetration effectiveness score and CNS OIs. Lower CNS penetration effectiveness score was associated with higher mortality, though it is unclear whether or not this is a causative association.

  3. Heaton RK, Clifford DB, Franklin DR, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75(23):2087-96.  [PMID:21135382]

    Comment: Though HAD is rare, milder forms of HAND are common even among those on ART.

  4. Cysique LA, Vaida F, Letendre S, et al. Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology. 2009;73(5):342-8.  [PMID:19474412]

    Comment: Neuropsychological improvement peaked 24-36 wks after starting ART; CNS penetration index associated with improvement.

  5. Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008;65(1):65-70.  [PMID:18195140]

    Comment: Drugs with higher CNS penetration associated with lower CSF viral loads.

  6. Kandanearatchi A, Vyakarnam A, Landau S, et al. Suppression of human immunodeficiency virus replication in human brain tissue by nucleoside reverse transcriptase inhibitors. J Neurovirol. 2004;10(2):136-9.  [PMID:15204933]

    Comment: Authors observed statistically significant reduction in rate of viral replication for d4T added 24 hrs prior to infection.

  7. McArthur JC, McClernon DR, Cronin MF, et al. Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol. 1997;42(5):689-98.  [PMID:9392567]

    Comment: Association between plasma HIV RNA and CSF levels of HIV and beta-2-microglobulin suggests that both viral load and CNS immune activation are important determinants of neurological disease.

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Last updated: November 8, 2016