C16 HIV-Associated neurocognitive disorders (HAND)


HIV is a neurotropic virus which invades the central nervous system (CNS) from the time of primary infection. HIV-associated dementia (HAD) is an AIDS defining illness (ADI), and milder or asymptomatic forms of HIV-associated neurocognitive disorders (HAND) are increasingly recognised. On the other hand, neurological symptoms and cognitive impairment in HIV-infected individuals may also be the result of opportunistic infections and malignancies affecting the CNS. In addition, medical and psychosocial morbidities are increasingly recognised as confounding factors. As biological specimen is often not available from patients with neurological disorders, a careful clinical approach is important to establish the correct diagnosis and allow appropriate treatment.

Before the advent of highly active antiretroviral therapy (HAART), it has been estimated that neurocognitive impairment occurred in 30% to 50% of all individuals infected with HIV.[1-3] The epidemiology of HAND has changed dramatically since the introduction of HAART in the mid-1990s. The incidence of HAD has decreased while the overall prevalence of HAND has increased as people living with HIV/AIDS (PLWHA) now have a longer life expectancy, while neurocognitive impairment due to HIV may not always recover completely despite HAART.[4][Further Reading A][Further Reading B]

Classification of HAND

The American Academy of Neurology (AAN) AIDS Task Force has defined in 1997 two levels of neurocognitive disorders, namely minor cognitive motor disorder (MCMD) and HIV-associated dementia (HAD). In 2007, the National Institute of Mental Health (NIMH) and the National Institute of Neurological Diseases and Stroke (NINDS) convened a working group composing of experts in the field and proposed an updated research nosology for HAND.[5][6][Box 16.1] A spectrum of neuropsychological impairment ranging from HAD to MND (mild neurocognitive disorder) to ANI (asymptomatic neurocognitive impairment) is defined based on the performance on cognitive testing and whether activities of daily living (ADL) is impaired.

HAND now consists predominantly of milder forms of cognitive impairment. In one study of individuals with HIV infection, 2.4% was diagnosed with HAD, while the prevalence of MND and ANI were 11.7% and 32.7% respectively.[7]

Box 16.1. NIMH and NINDS updated research nosology for HIV-associated neurocognitive disorders [6]

HIV-associated asymptomatic neurocognitive impairment (ANI)
Acquired impairment in cognitive functioning, involving at least two ability domains, documented by performance of at least 1.0 SD below the mean for age-education-appropriate norms on standardised neuropsychological tests. The cognitive impairment does not interfere with everyday functioning.

HIV-1-assocaited mild neurocognitive disorder (MND)
Acquired impairment in cognitive functioning, involving at least two ability domains, documented by performance of at least 1.0 SD below the mean for age-education-appropriate norms on standardised neuropsychological tests. The cognitive impairment produces at least mild interference in daily functioning.

HIV-associated Dementia (HAD)
Marked acquired impairment in cognitive functioning, involving at least two ability domains; typically the impairment is in multiple domains, especially in learning of new information, slowed information processing, and defective attention/concentration. The cognitive impairment must be ascertained by neuropsychological testing with at least two domains 2 SD or greater than demographically corrected means, and produces marked interference with day-to-day functioning (work, home life, social activities).

The pattern of cognitive impairment should not meet criteria for delirium (e.g., clouding of consciousness is not a prominent feature)
There should not be evidence of another, pre-existing cause for the dementia (e.g., other CNS infection, CNS neoplasm, cerebrovascular disease, pre-existing neurologic disease, or severe substance abuse compatible with CNS disorder).
If dementia persists after 1 month on remission of major depression, a reassessment should be conducted to reassess for dementia.

Cognitive impairment and implications of HAND

Patients with HAND mainly show a subcortical pattern of cognitive impairment with deficits in speed of information processing, working memory, prospective memory, and learning and recalling information. They may also display simple motor slowness and difficulties in problem solving, fluency as well as cognitive flexibility. On the other hand, their visual-spatial and verbal skills tend to be preserved. They may also show a pattern of retrieval deficits,[2] i.e., a pattern of performance characterised by poor free recall but normal ability in recognising words presented to them earlier from a word list. Before the availability of HAART, individuals with HAND tended to show deficits in motor skills, mental speed and verbal fluency. In the post-HAART era, impairments in learning, memory and executive function predominated instead, which suggests a shift from the prior subcortical deficits to a cognitive profile with increased cortical/frontal deficits.[8] In general, they tend to show a “spotty” profile of frontal-subcortical neurocognitive impairment.[9]

HAD has been recognised to be associated with poorer survival. The adverse impact to survival has also been found to affect HIV-infected individuals who display relatively mild neurocognitive disturbance. In addition, patients with HAND are more likely to have poorer medication adherence, which is related to impairment in cognitive domains such as executive functioning, problem solving, learning, memory, attention and working memory. They are also more likely to report deterioration in their work performance and have a higher likelihood of unemployment. Their self-care ability may become impaired and their quality of life adversely affected.

Clinical diagnosis and assessments [Algorithm 16]

Clinical Presentation

The main clinical features of HAD, the most severe form of HAND, include cognitive impairment (including problem with memory, concentration, mental processing speed and comprehension), motor dysfunction (such as gait unsteadiness, incoordination, abnormal tone and tremor) and behavioural abnormality (e.g. apathy, depression and agitation). The memory impairment may result in tendency for missing appointments, losing personal items, repetition of items during conversation, and difficulty in learning a new process. They may find it difficult to focus on more complicated tasks and mental tasks, tend to take longer to complete. They may also become more easily distractible and their social behaviour may become altered. Sometimes, the patient may have little insight in their cognitive impairment and it could be their family members and friends who first notice the problems. It should be recognised that patients with milder forms of HAND generally have mild or no symptoms and they may not volunteer the symptoms during consultation due to lack of awareness, insight or attribution to other causes.

Clinicians should have a high index of suspicion and be alert to the presence of clues suggesting presence of HAND. They should routinely ask about cognitive, behaviour or motor symptoms from the patients and their significant others or from direct observation during consultation. This is especially so in certain settings where the risk for HAND is increased, including older age, low nadir CD4+T lymphocyte count, previous CNS infection, hepatitis C virus (HCV) coinfection, high cardiovascular risk, and not being currently on HAART. Although the majority of patients with HAND show stable neurocognitive functioning,[10] those with ANI may have a higher risk of developing symptomatic HAND in the long run.[11] The predictors of deterioration include being off HAART, having higher disease severity and presence of depressive symptoms. Considering the potential implications of HAND, early identification of asymptomatic or mildly symptomatic individuals is of paramount importance.

(b) Making a diagnosis

HAND is a diagnosis by exclusion and patients with HIV infection often have complex medical and social histories that may include more than one risk factor for neurocognitive impairment. In addition, patients on long-term HAART may also suffer from neurotoxicity or cerebrovascular complications related to their medications. Clinicians have to be aware of these possibilities in order to make the correct diagnosis and provide appropriate treatment for their patients.[Box 16.2] A number of laboratory tests and other assessments should be performed to rule out other treatable causes of neurocognitive impairment.

  • Laboratory blood tests: Complete blood count, electrolytes and creatinine, liver function, thyroid function, vitamin B12 and folate level, or syphilis serology.
  • Toxicology tests if substance use is suspected (e.g., opioids, ethanol, amphetamines).
  • Brain imaging studies: Computerised tomography (CT) scan or magnetic resonance imaging (MRI) to rule out space-occupying masses and other lesions.
  • Cerebral spinal fluid (CSF) examination to rule out other infections of the CNS and to detect HIV virological breakthrough.
  • Screening for depression using instrument such as
    • Centre for Epidemiologic Studies Depression Scale (CES-D)
    • The Hamilton Rating Scale for Depression
    • Depression Anxiety and Stress Scale
    • The Patient Health Questionnaire (PHQ-9)

Box 16.2. Confounding factors to the diagnosis of HAND

  • HIV-related opportunistic disease affecting the central nervous system
  • Co-infection with hepatitis C virus (HCV)
  • Medication side effects (e.g. HAART-related neurotoxicity)
  • Depression
  • Ageing
  • Developmental cognitive disability (e.g. mental retardation, specific learning difficulties)
  • Non-HIV-related neurologic condition (e.g. stroke, epilepsy, multiple sclerosis)
  • History of traumatic brain injury
  • History of alcohol or other substance use disorder

(c) Neurocognitive Assessment

Neuropsychological (NP) testing is the gold standard for evaluating the presence and level of neurocognitive impairment.[Box 16.3] Such testing should cover multiple ability domains (see appendix), with at least one test in each domain. The results of NP testing have to be compared against a demographically comparable HIV seronegative group, or published normative data that are demographically adjusted (for age, education, gender, and/or ethnicity, as appropriate for the test).

In settings where formal NP testing is not available, a number of validated screening tools are available for identifying and staging HAND. These include International HIV Dementia Scale, Montreal Cognitive Assessment, grooved pegboard and trail making test part B. These tools can each be completed in about ten minutes, require only minimal training for administration and can be used in clinics for initial screening for HAND. Cogstate, a computerised brief cognitive test battery, is also a sensitive screening tool. It should be noted that the Mini Mental State Examination (MMSE) is sensitive tool to screen for cortical dementia (e.g. Alzheimer’s disease) but not for the detection of HAND and hence is not recommended.

(d) Changes on Neuroimaging

Neuroimaging studies have provided substantial information on the anatomical and functional changes in the brain of patients with HAND. CT and especially MRI demonstrate white matters abnormalities in both subcortical and cortical regions and with progressive disease there is cerebral atrophy with widened cortical sulci, dilated ventricles, and reduced gray and white matter volumes.[1, 12] White matter abnormalities are more readily seen on MRI as ill-defined areas of increased T2-weighted signal intensity, often symmetrical, especially in the periventricular region. In addition, abnormalities in the metabolite ratios in the brain are demonstrated on magnetic resonance spectroscopy (MRS), which reveals a pattern of elevated choline, myoinositol and sometimes creatine level with reduction in N-acetylaspartate in the frontal areas and basal ganglia. Apart from the above, the potential of diffusion tension imaging (DTI), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) in HAND research and possibly management is increasingly recognised in recent years.

Box 16.3. Neuropsychological tests for assessment of HAND

  Neuropsychological Tests
Fluency Controlled Oral Word Association Test (FAS)
Category Fluency
Action Fluency
Design Fluency Tests
Executive functions Stroop Colour and Word Test
Trail making Test – Part B
Colour Trails – II
Wisconsin Card Sorting Test
Tower of London
Speed of information processing WAIS-III Digit Symbol Subtest
WAIS-III Symbol Search Subtest
Symbol Digit Modalities Test
Trail making Test – Part A
Colour Trails – I
Attention/working memory WAIS-III Digit Span Subtest
WAIS-III Letter-Number Sequencing Subtest
WMS-III Spatial Span Subtest
Paced Auditory Serial Addition Test
Verbal and visual learning & memory Verbal
Hong Kong List Learning Test 2nd Edition
Chinese Auditory Verbal Learning Test
Hopkins Verbal Learning Test- Revised
WMS-III Visual Reproduction I&II
Brief Visuospatial Memory Test – Revised
Rey-Osterreith Complex Figure Test
Motor skills Grooved Pegboard
Finger Tapping Test
Timed Gait
Screening Tools HIV Dementia Scale
Modified HIV Dementia Scale
International HIV Dementia Scale
Montreal Cognitive Assessment
NOTE: WAIS-III is the Third Edition of the Wechsler Adult Intelligence Scale; WMS-III is the Third Edition of the Wechsler Memory Scale

Clinical management [Algorithm 16]

The best approach to minimise the impact of HAND is prevention by identifying and engaging HIV infected individuals into care and initiating HAART early before profound immunodeficiency develops. They should be counselled on lifestyle modification to reduce their cardiovascular risk and avoid substance use. Patients with mood disturbance should receive psychotherapy, psychosocial support and medical therapy as appropriate.

Patients with symptomatic HAND who are not on HAART should have initiation of treatment as soon as possible after assessment for other opportunistic infection and comorbidities. For patients who are already on HAART, the regimen should be optimised, with guidance by genotypic resistance testing, to achieve full virological suppression in the plasma. CSF examination for HIV RNA level should be performed to determine if residual replication is present in the CNS in otherwise virologically fully suppressed patients. A CSF Penetration Effectiveness (CPE) score system [13] has been developed to compared the ability of different antiretroviral agents to penetrate the CNS and to facilitate construction of what is sometimes termed a “neuroHAART” regimen.[Box 16.4] However, prospective studies on the utility of the CPE score ranking in constructing HAART regimen to improve the neurocognitive outcome have yielded conflicting results. If the viral load is already fully suppressed in the plasma and CSF, the patient should be reassessed for alternative causes of neurocognitive impairment, including neurotoxicity from antiretroviral medications. Patients with HAND should also receive medication adherence management and be referred for cognitive rehabilitation and support of activities of daily living when needed.

Box 16.4. Revised CNS Penetration-Effectiveness ranks 2010, updated in 2014 [13]

  4 3 2 1
Nucleoside reverse transcriptase inhibitor (NRTI) Zidovudine (ZDV) Abacavir (ABC) Lamivudine (3TC) Tenofovir (TDF)
    Emtricitabine (FTC) Stavudine (d4T)  
      Didanosine (ddI)  
Non-nucleoside reverse transcriptase inhibitors (NNRTI) Nevirapine (NVP) Efavirenz (EFV) Rilpivirine (RPV)  
    Etravirine (ETV)    
Protease inhibitor (PI) Indinavir/r (IDVr) Darunavir/r (DRVr) Atazanavir (ATV) Nelfinavir (NFV)
    Fosamprenavir/r (fAPVr) Atazanavir/r (ATVr) Ritonavir (RTV)
    Indinavir (IDV) Fosamprenavir (FPV) Saquinavir (SQV)
    Lopinavir/r (LPVr)   Saquinavir/r (SQVr)
Entry/Fusion Inhibitors   Maraviroc (MRV)   Enfuvirtide (ENF)
Integrase Inhibitor (INSTI) Dolutegravir (DTG) Raltegravir (RAL)    
/r-ritonavir boosting

Algorithm 16. Approach to the management of HAND

Algorithm 16. Approach to the management of HAND


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  9. Woods SP., Rippeth JD, Frol AB, Levy JK, Ryan E, Soukup VM, Hinkin CH., Lazzaretto D, Cherner M, Marcotte TD, Gelman BB, Morgello S, Singer EJ, Grant I, Heaton RK. Interrater reliability of clinical ratings and neurocognitive diagnoses in HIV. J Clin Exp Neuropsychol 2004;26(6):759-778. link
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Further Reading

  1. Paul RH, Sacktor NC, Valcour V, Tashima, KT (Eds). HIV and the brain: new challenges in the modern era. New York: Humana Press; 2009. link
  2. Eggers C, Arendt G, Hahn K, Husstedt IW, Maschke M, Neuen-Jacob E, Obermann M, Rosanktanz T, Maschke M, Schielke E, Straube E; German Association of Neuro-AIDS und Neuro-Infectiology (DGNANI). HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment. J Neurol 2017;264:1715-1727. link