HIV-associated neurocognitive disorder

Denise Cummins: Sydney District Nursing, Community Health, Sydney Local Health District

HIV-associated neurocognitive disorder (HAND) is an umbrella term used to describe neurodegenerative disease caused by human immunodeficiency virus (HIV)-1 infection and may affect more than 30% of people with HIV[1] regardless of virological suppression. The central nervous system acts as a reservoir for HIV with neuronal damage occurring both at the time of initial HIV infection and throughout the chronic phase.[2] Although there is a decreasing incidence of HIV-associated dementia, milder forms of cognitive impairment have increased, regardless of HIV virological suppression and immune recovery. Cognitive impairment is the most common central nervous system complication in people with HIV.[3]

There are three categories of HAND, each associated with an increasing level of impairment:

  • Asymptomatic neurocognitive impairment (ANI) shows HIV-associated impairment in cognitive function, but everyday functioning is not affected.
  • Mild neurocognitive disorder (MND) is characterised by HIV-associated impairment in cognitive function where interference in everyday functioning is displayed.[4] [5]
  • HIV-associated dementia (HAD) shows marked impairment in cognitive function, especially in learning of new information, information processing, and attention or concentration.[6]

Prevalence rates: ANI 30%, MND 20-30% and HAD 2-8%.[7] [8]

Screening and diagnosis

There are several screening tools for HAND, such as the Montreal Cognitive Assessment, and the International Dementia Scale [9] but there is no one tool which can be used across all settings. [10] Some tests are sensitive to moderate but not to mild cognitive decline.[11] The Mini Mental Status Exam (MMSE)[12] is not useful in this context as HIV cognitive impairment affects the sub-cortex of the brain but the MMSE can be used to screen for other forms of cognitive impairment such as that caused by Alzheimer's disease. If clinical neurological examination is not freely available, asking people with HIV and their caregivers about changes to their activities of daily living is a useful starting point.

No known biological markers have been identified to support a definitive diagnosis of HAND.[13] The gold standard for HAND diagnosis is formal neuropsychological tests completed by a specially trained clinical neuropsychologist with or without radiological tests such as magnetic resonance imaging (MRI).[14]  Therefore, multiple detection methods such as clinical review, functional review and neurological imaging are necessary. The diagnosis of HAND is also often made through a process of excluding other conditions (e.g. excluding new opportunistic infections, progressive multifocal leukoencephalopathy and cryptococcal meningitis).[15]  This approach presents challenges for clinicians as there are a number of confounding and comorbid conditions such as depression or alcohol-related brain damage that may complicate the diagnosis. Further, people with HIV may downplay their signs and symptoms, or their caregivers may attribute behaviours to other causes such as ageing or poor mental health.

As people with HIV age, they may be at risk of other neurologic disorders associated with ageing such as vascular dementia and Alzheimer's disease.[16] Thus, the complexities around neurological health for people with HIV may be increasing.

Predictors of HAND

Studies suggest predictors of HAND include: past history of AIDS-defining central nervous system (CNS) disease,[17] other CNS disease,[18] low T cell nadir,[19] drug and alcohol use,[20] low education level,[21] and hepatitis C infection.[22]

General (non-HAND) cognitive impairment risk factors

Ageing and vascular risk factors such as smoking, hypertension, diabetes, hypercholesterolaemia and hyperlipidaemia should be considered, as they would in the non-HIV population.

Signs and symptoms

Signs and symptoms of HAND experienced by people with HIV that can indicate changes in cognition over time may be a new behaviour (e.g. poorer memory) or may be so subtle that they are missed or people with HIV attribute the changes to something else, such as being tired or busy. If the person has always misplaced keys, this is their usual behaviour. It is more important to take note of new changes in behaviour.

Signs and symptoms of MND and HAND include noting a change in the person’s behaviour and cognition, affecting the person’s ability to perform activities of daily living such as preparing meals, managing finances, remembering doctor’s appointments and driving ability. It may also affect a person’s social relationships and the ability to retain employment or work at a higher level.

The important areas affected are: motor skills, memory, concentration and social engagement. In addition, executive function can also be affected whereby the person may experience changes in their ability to plan, organise and to solve complex or new problems (Table 6). 

Table 6: Areas affected by HIV-associated neurocognitive disorder (HAND) and nursing strategies

Area affected

Signs and symptoms

Strategies

Motor skills

 

Increasing fatigue

Unsteady gait

Increased clumsiness

Fine motor coordination

Slowed motor speed

Driving deficits

Difficulty typing, texting

Provide information slowly

Give ample opportunity for response

May need assistance to complete activities

 

Memory

Forgetting dates (e.g. birthdays), where placed keys, phone

Memory affecting cooking and shopping

Missing appointments and medications

Forgetting to send emails and issues for meetings

Write down instructions relating to important information and check understanding

Encourage use of memory aids (e.g. diaries, calendars, Post-It notes)

Repeat and write down new information

Provide reminders of appointments

Encourage a routine

Pay more deliberate attention to what the person is trying to remember

Concentration

How the person becomes receptive to stimuli and how he or she begins to process information Problems include:

Difficulty taking simple information and following directions

Difficulty keeping track of conversations

May have to re-read things

Difficulty completing activities

Difficulty following plots of movies and books

Becoming mentally fatigued easily

 

Present information in small amounts at a time

Present information in a manner that is clear, simple and concrete

Limit distractions (e.g. TV)

Provide prompts and reorient to task if distracted

Determine the time of day at which the person is most alert and encourage completion of difficult tasks at that point

Behavioural (social) changes

The person can experience one of two areas of behaviour change:

1: Apathy and listlessness

    Withdrawal

    Lack of motivation

    Impulsivity and disinhibition

 

2: Hypomania

Change in personality

Increased agitation, aggression and irritability  (e.g. stealing, swearing,  overfamiliarity)

Emotional lability

Identify the person’s change of mood, ask if he or she is aware of changes; are there any reasons for becoming withdrawn

Arrange a psychiatric assessment to exclude depression

If not depression assist the person to have small achievable goals

Check in with the person frequently to encourage engagement with the service

Identify changes in mood Ask the person what he or she has noticed, whether there are any specific reasons for increased irritability for example

Arrange a psychiatric review ( possible prescription of medications)

Develop strategies to reduce elevated mood or irritability

 

Refer to other services to support changes in mood outcomes to life

 

 

Executive function

The person may experience difficulty in:

Initiation of a task

Planning

Problem-solving

Cognitive flexibility

Decision-making

Concept formation and abstraction

Judgment

Feedback utilisation and monitoring behaviour

Encourage client to work through problems with a trusted person and to write down alternative solutions for later referral

Try to break complex tasks down into smaller components

Provide a structure or plan where possible

Guide client through complex decisions step-by-step

 


It is important to ask the people with HIV (and a caregiver, if they have one) questions relating to changes either may have noticed. A vital question to start the conversation can simply be:  “Have you noticed any changes?”

Questions to ask people with HIV:

  • Are you slower in your thinking than you used to be?
  • Are you more forgetful than you used to be?
  • Is it harder to organise things?
  • Are you able to find pleasure in the things you used to enjoy?
  • Tell me any changes you have noticed.

Questions to ask their caregivers:

  • Is the person more forgetful?
  • Has his or her personality changed?
  • Is the person finding it harder to organise his or her life?

Treatment of HAND

20-38% of people with HIV will develop cognitive impairment regardless of optimal therapy and virological suppression. Before combination antiretroviral therapy (ART) with diagnosis of AIDS, median survival after a dementia diagnosis was 6 months. Since antiretroviral therapy there has been a decrease in neuropsychiatric diagnosis, incidence of dementia has halved and survival time increased to 48 months’ survival with AIDS dementia complex (as it was known then).[23] [24]

Medication adherence can be difficult for someone experiencing signs and symptoms of HAND.

Following initiation of treatment or changes in treatment, people with HIV should show improvements; however, for various reasons some people may be left with some form of deficit or their deficit may worsen. The reasons for this result are varied: some people with HIV will experience improvements.  Antiretroviral medication can cross the blood–brain barrier to varying degrees, and some drugs have increased anti-HIV activity in the CNS. Regardless of whether the person is treatment naive or experienced with antiretroviral medications, the option of adding an antiretroviral medication that will have enhanced coverage in the CNS should be considered in the choice of medications.[25]  Once diagnosed and treated, improvement in HAND may be seen within 12 weeks, continuing up to 18 months.[26] 

Some people with HIV, however, may notice increased deficits. Reasons for this may include poor penetration across the blood-brain barrier; a legacy effect (damage before initiation of antiretroviral therapy) which may cause continuing neurocognitive decline; potential for resistance with reseeding of systematic compartment 10% escaped to cerebrospinal fluid (some people with HIV, although viral load is controlled in the plasma, will still have detectable virus in the CSF, and this, over time, may be linked to less effective control by antiretroviral therapy in CSF affecting the brain, and additionally affecting immune activation in the CSF with cognitive dysfunction); toxicity from antiretroviral therapy and inadequacy of antiretroviral agents with low level replication occurring (Table 7).[27] 

TABLE 7: Central nervous system penetration effectiveness scores 2010

Drug class

4

3

2

1

NRTIs

Zidovudine

Emtricitibine

Abacavir

Lamivudine

Stavudine

Didanosine

 

Tenofovir

Zalcitabine

NNRTIs

Nevirapine

Delavirdine

Efavirenz

Etravirine

 

PIs

Indinavir

Darunavir-r

Fosasmprenavir-r

Indinavir

Lopinavir-r

Atazanavir-r

Atazanavir

Fosamprenavir

 

Nelfinavir

Ritonavir

Saquinavir-r

Saquinavir

Tipranavir

Fusion/entry inhibitors

 

Maraviroc

 

Enfuvirtide

Integrase inhibitors

 

Raltegravir

 

 

NNRTI – non-nucleoside reverse transcriptase inhibitors; NRTI – nucleoside reverse transcriptase inhibitors; PI – protease inhibitors; -r – boosted with ritonavir

Source: Letendre SL, Ellis RJ, Ances BM, et al.  Neurologic complications of HIV disease and their treatment. Top HIV Med 2010;18:45-55.

Significance of early recognition of HAND

There are several reasons why early recognition of HAND is important:

People with HIV with cognitive impairment have been shown to be less adherent to HIV medication regimes,[28] [29] This may lead to drug-resistant HIV, resulting in their current medication regime becoming ineffective.[30] [31]  Morbidity and mortality can then be affected as the person experiences poor health outcomes secondary to impaired adherence.  For those who can maintain a single-dose daily regimen, this should help adherence.

As people with HIV are ageing and may have a longer duration of HIV infection the overall prevalence of neurocognitive impairment has increased especially in its milder forms.

Increased potential for many people with HIV who are otherwise controlled to become disabled through neurological impairment.

The interval between initial infection of CNS and development of HAD represents a window of opportunity to detect early and treat, therefore reducing potential clinical progression.

What to do

Regularly review your clients. Ask questions about changes they may have noticed. Be aware of risk factors for HAND and other general cognitive impairment and assist the person to reduce these risk factors, e.g. cease smoking, reduce cholesterol and triglycerides, treat hypertension and modify diet. Annual assessment and monitoring may be beneficial.

Conclusion

HAND continues to represent substantial personal, societal and economic burdens and may place an increasing obligation on Australian resources, especially as people with HIV age. Early recognition and treatment is paramount and can have a positive impact on quality of life and health outcomes for those living with HIV.

See:
https://fightdementia.org.au/about-dementia-and-memory-loss/about-dementia/types-of-dementia/aids-related-dementia/

1.
Clifford DB,  Ances BM. HIV-associated neurocognitive disorder. Lancet Infectious diseases 2013; 13: 976-86. 
2.
Nabha L, Duong L, Timpone J. HIV associated neurocognitive disorders: perspectives on management strategies. Drugs 2013; 73(9): 893-905, June. 
3.
Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J. Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2008; 69(18): 1789-99. 
4.
Robertson KR, Su Z, Margolis DM, Krambrink A, Havlir DV, Evans S, Skiest, D.J. For the A5170 Study Team.  Neurocognition effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 2010; 74: 1260-1266. 
5.
Skinner S, Adewale AJ, DeBlock L, Gill MJ, Power C. Neurocognitive screening tools in HIV/AIDS: comparative performance among patients exposed to antiretroviral therapy. British HIV Association HIV Medicine 2009;10; 246-252 
6.
Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J. Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2008; 69(18): 1789-99. 
7.
McArthur J, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. Annals of  Neurology 2010;67:699–714. 
8.
Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J. Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2008; 69(18): 1789-99. 
9.
Sacktor NC, Wong M, Nakasujja N, Skolasky RL, Selnes OA, Musisi S, Robertson K, McArthur JC, Ronald A, Katabira E. 2005. The International HIV Dementia Scale: a new rapid screening test for HIV dementia. AIDS Sep 2; 19(13):1367-74. 
10.
Achappa B, Priyadarshni S, Madi D, Bhaskaran U, Ramapuram JT, Rao, S, Chowta M, Mahalingam S.  Neurocognitive dysfunction among HIV positive patients using International HIV dementia scale. Asian Journal of Medical Sciences 2014; Oct-Nov Vol 5 Issue 4 61-64. 
11.
Atluri VSR, Kurapati KRV, Samikkannu T, Nair MPN. Biomarkers of HIV Associated Neurocognitive Disorders. JSM Biomarkers 2014; 1(1):1002. 
12.
Folstein MF, Folstein SE, McHugh PR.1975.  Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 1975 Nov; 12(3):189-98. 
13.
Atluri VSR, Kurapati KRV, Samikkannu T, Nair MPN. Biomarkers of HIV Associated Neurocognitive Disorders. JSM Biomarkers 2014; 1(1):1002. 
14.
Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre S L, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC,  Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA,  Abramson I,  Gamst A,  Fennema-Notestine C,  Jernigan T, Wong J, Grant I. CHARTER Group. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 2010; 75(23): 2087-96. 
15.
Nabha L, Duong L, Timpone J. HIV associated neurocognitive disorders: perspectives on management strategies. Drugs 2013; 73(9): 893-905, June. 
16.
del Palacio M, Alvarez S, Munoz-Fernandez, MA. HIV-1 infection and neurocognitive impairment in the current era. Rev Med Virol 2012; 22(1): 33-45, Jan. 
17.
Fabiani S, Pinto B, Bruschi F.  Toxoplasmosis and neuropsychiatric diseases: can serological studies establish a clear relationship? Neurological  Science.  2013; 34(4):417-25. doi: 10.1007/s10072-012-1197-4, April. 
18.
Valcour VG, Shikuma CM, Watters MR, Sacktor NC. Cognitive impairment in older HIV-1-seropositive individuals:  prevalence and potential mechanisms. AIDS. 2004;18 (Suppl 1:S79 – 86). 
19.
Ellis  RJ,  Badiee J,  Vaida F, Letendre S,   Heaton RK,   Clifford D,  Collier AC,  Gelman B, McArthur J, Morgello S, McCutchan JA,  Grant I.  CHARTER Group. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS 2011;10: 25(14): 10.1097/QAD.0b013e32834a40cd, Sept 10. 
20.
Fiala M, Eshleman A J, Cashman J, et al. Cocaine increases human immunodeficiency virus type 1 neuroinvasion through remodeling brain microvascular endothelial cells. Journal of Neurovirology 2005; 11, 281–29110.1080/13550280590952835 
21.
De Ronchi D, Faranca I, Berardi D. Risk factors for cognitive impairment in HIV-1-infected persons with different risk behaviors. Archives of Neurology. 2002; 59(5):812-8. 
22.
Schouten J, Wit FW, Stolte IG, et al. Comorbidity and ageing in HIV-1 infection: the AGEhIV Cohort Study. Oral abstract. AIDS 2012: XIX International AIDS Conference: Abstract THAB0205. Presented 2012, July 26. 
23.
McArthur J, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. Annals of  Neurology 2010;67:699–714. 
24.
Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J. Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2008; 69(18): 1789-99. 
25.
Letendre SL, FitzSimons C, Ellis RJ, Clifford D, Collier AC, Gelman B, Marra C, Macarthur J, McCutchan JA, Morgello S, Simpson D, Vaida F, Heaton R, Grant I, and the CHARTER Group. Correlates of CSF Viral Loads in 1,221 volunteers of the CHARTER cohort. 17th Conference on Retroviruses and Opportunistic Infections, 2010. 
26.
Cystique LA, Vaida F, Letendre S, Gibson S, Cherner M, Woods SP,  McCutchan JA,  Heaton RK, Ellis RJ. Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology 2009; 73(5), 342-8. 
27.
In a conversation with Dr. Bruce Brew, 2012. 
28.
Robertson KR, Su Z, Margolis DM, Krambrink A, Havlir DV, Evans S, Skiest, D.J. For the A5170 Study Team.  Neurocognition effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 2010; 74: 1260-1266. 
29.
Skinner S, Adewale AJ, DeBlock L, Gill MJ, Power C. Neurocognitive screening tools in HIV/AIDS: comparative performance among patients exposed to antiretroviral therapy. British HIV Association HIV Medicine 2009;10; 246-252 
30.
Robertson KR, Su Z, Margolis DM, Krambrink A, Havlir DV, Evans S, Skiest, D.J. For the A5170 Study Team.  Neurocognition effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 2010; 74: 1260-1266. 
31.
Skinner S, Adewale AJ, DeBlock L, Gill MJ, Power C. Neurocognitive screening tools in HIV/AIDS: comparative performance among patients exposed to antiretroviral therapy. British HIV Association HIV Medicine 2009;10; 246-252