HIV-associated neurocognitive disorder

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] , Cogstat ^[10]

but there is no one tool which can be used across all settings. ^[11] Some tests are sensitive to moderate but not to mild cognitive decline.^[12] The Mini Mental Status Exam (MMSE)^[13] 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.^[14] 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).^[15]  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).^[16]  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.^[17] 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,^[18] other CNS disease,^[19] low T cell nadir,^[20] longer duration of HIV infection ^[21]

 drug and alcohol use,^[22]  and hepatitis C infection.^[23]. Additionally, the risk of HAND increases as the CD4+ counts decline below 350cells/uL and with higher plasma viral load ^[24]

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

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?
• Do you have any difficulty paying attention ( e.g. foollowing conversations of movies)?
• 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:

• Have you noticed any changes in the person's behaviour?
• 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

More than 20% 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).^{[25] [26]}

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.^[27]  Once diagnosed and treated, improvement in HAND may be seen within 12 weeks, continuing up to 18 months.^[28] 

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).^[29] 

The CNS penetration effectiveness (CPE) score was proposed in order to rank HIV drug penetration and efficacy in the CNS ^[30]. Although currently the CPE score is limited by its categorical scoring, unclear weighting of each criterion (pharmacokinetic, chemical properties, etc.), and lack of consideration of toxic effects or drug interactions, some clinicians continue to take the CPE score into consideration at least in patients that have symptomatic CNS disease as studies have shown regimes with higher CPE scores to be associated with lower cerebrospinal fluid viral loads ^[31].

TABLE 7: Central nervous system penetration effectiveness scores 2010 ( updated according to Letendre, 2014)

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.

A value of 1, 2, 3or 4 is assigned to the different antiviral substances (first line). The CPE values of a cART regimen are summed up to arrive at the CPE score. A higher the score stands for better penetration into the CNS.

THE ONE SIGNIFICANT THING THAT PEOPLE LIVING WITH HIV CAN DO IS TO MAINTAIN ADHERENCE TO cART.

Changes in medication adherence may be one sign that a person is developing some cognitive changes. Additionally decline in medication adherence can be difficult for someone experiencing signs and symptoms of HAND. Strategies should be developed with the person and a caregiver, if they have support of a caregiver to improve medication adherence as HAND may fluctuate over months with some people improving, some deteriorating and the majority remaining stable ^[32]

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,^{[33] [34]} This may lead to drug-resistant HIV, resulting in their current medication regime becoming ineffective.^{[35] [36]}  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/

Positive Life NSW, has information available on their website www.positivelife.org.au