Cognitive impairment in people with HIV infection is an issue of increasing concern.  Prior to the widespread use of ART, HIV-associated dementia (HAD) occurred in almost 50% of people with HIV infection prior to death. ^{[77, 78]} Effective ART has resulted in a dramatic reduction, with HAD now occurring in <2% of individuals. ^{[78, 79]} The current prevalence of cognitive impairment is variable and dependent on the definition used, with estimates of HIV-associated neurocognitive disorder (HAND) affecting up to 30% of people with HIV infection who have suppressed HIV replication on ART. ^{[3, 28, 78-80]} Neurocognitive impairment appears to increase with age, ^{[28, 81-83]} and with the presence of certain co-morbidities such as CVD, metabolic syndrome, co-infection with HCV and sleep and mood disorders. ^[78] Advancing age itself increases susceptibility to HAND, leading to an increase in the proportion of older people with HIV who experience HAD. ^{[28, 81-84]} Neurocognitive impairment may also differ by gender, due to hormonal shifts that occur with ageing. ^{[28, 85]} These impairments may be further exacerbated by a higher frequency of factors associated with neurocognitive impairment namely, drug use, stress, insulin resistance and liver fibrosis. ^[13] As these may become more prevalent and severe with age, they may further exacerbate neurocognitive impairment, and interact with HIV to “accelerate or accentuate cognitive ageing”. ^[13]

The pathogenesis of HAND is underpinned by viral, ART and host factors, as well as premature ageing and neurodegeneration. It has been linked to a combination of immune activation, neuroinflammation, ART neurotoxicity, co-morbidities such as vascular disease and depression, and lifestyle factors including recreational drug use. ^{[3, 78, 86-88]} It is important to consider all potential factors including those not directly related to HIV. ^[78] HIV replication in the CNS has been strongly associated with neuronal damage and the development of HAD. There is also evidence that chronic sustained immune activation in the CNS leads to the production of neurotoxic products, such as nitric oxide, arachidonic acid, and proinflammatory cytokines. ^{[78, 89]}

HIV associated neurocognitive disorder consists of a spectrum of neurocognitive impairment, from asymptomatic to mild cognitive impairment; and HIV-associated dementia. ^[78]  It is characterised by deficits in mental slowness, attention and memory, and impaired executive functioning as well as extra pyramidal features. ^[90-92] The cross-links between premature ageing and neurodegeneration are also important in the consideration of cognitive impairment in people with HIV infection. Cerebrovascular disease can occur because of traditional risk factors or from the metabolic and systemic effects of HIV and ART on endothelial function. ^[78] On brain MRI imaging, white matter hyperintensities are more common in people with HIV infection, increase with age and are associated with increased rates of cognitive impairment. ^{[78, 93]} The neurofibrillary tangles composed of phosphorylated tau, a hallmark of Alzheimer’s Disease, also occur in people with HIV infection ^[94]

The maintenance of cognitive function for the individual translates to better health and quality of life; in the context of HIV, impaired functioning can have significant detriment including lower likelihood of retention in care, poorer health outcomes, and compromised medication adherence. ^{[3, 95, 96]} 111, 110] Other impacts of impaired neuro-functioning include mood and behaviour disorders, and an adverse effect on employment, driving capacity and interpersonal relationships. ^{[78] [3, 78]}

Most guidelines now recommend screening for cognitive impairment only in symptomatic people with HIV infection. ^{[28, 42, 78]} Because of the overlap in clinical presentation, imaging, CSF findings (CSF beta-amyloid) and neuropsychological deficits, differentiation between HAND, Alzheimer’s Disease and vascular dementia can be difficult and expert neurological opinion/geriatric assessment should be sought. Tools for screening and differentiating different causes of cognitive impairment range from bedside screening assessments, formal neuropsychological assessments, biomarker assessments in both plasma and CSF, and the use of neuroimaging techniques. ^{[28, 78]}

It is important to acknowledge that mental health disorders are common in HIV positive patients and can contribute to poor cognitive performance. In turn, a decline in cognitive performance can lead to depressive symptoms. ^{[78, 97, 98]}

The cornerstone of the clinical management of HIV-associated cognitive impairment is ART, and if the patient is not on ART, it should be initiated to prevent ongoing neuronal damage from uncontrolled viral replication. ^[78] There is sparse evidence that specific ART regimens correlate with improvement in cognitive function, and in general, standard first line ART regimens are recommended. ^[78] The exception is the avoidance of efavirenz, on the basis of results of cohort studies suggesting poorer cognitive function in those receiving efavirenz-based ART. ^{[78, 99, 100]} If HIV RNA is not detected in CSF, then reassessment for other contributing factors should take place. ^[78] A change in ART regimen in patients with cognitive impairment and documented CSF virus escape (presence of HIV RNA in CSF when virologically suppressed in plasma) should be based on current and historic drug-resistance profiles of CSF and plasma virus, and/or potential ART neurotoxicity, and the ability of ART to penetrate the central nervous system. ^[78] Other non-pharmacological interventions are encouraged – including exercise, managing stress and low mood, sleeping well and instituting a healthy diet, as well as smoking, drug and alcohol cessation. ^{[78, 99]}

Key recommendations

1. Screening for and assessment of cognitive impairment in people with HIV infection should be performed if the person is symptomatic (self-reported or family members).
2. This assessment may be difficult in people with co-morbidities that may be responsible for, or contribute to, cognitive impairment, such as cerebrovascular disease, neurodegenerative conditions, HCV co-infection, and mood and sleep disorders.
3. Once mood disorders are either excluded or optimised, and cognitive impairment is suspected, formal assessment by a neuropsychologist or referral to a neurologist is recommended.
4. Ancillary investigations to aid clinical assessment include imaging (MRI brain), blood investigations (i.e. syphilis serology, plasma HIV RNA), and lumbar puncture to investigate for CSF virus escape. Further investigations and functional imaging may take place with specialist referral.
5. If CSF HIV RNA is detected after lumbar puncture, antiretroviral drug resistance testing should be performed to help guide possible change in ART regimen.
6. The optimal ART regimen in the context of suspected or confirmed cognitive impairment is based on best clinical practice, with a regimen that accommodates past and/or present available genotype susceptibility results, and possibly CNS penetrance of the medication. Expert assistance may be required.
7. There is no specific ART regimen that is recommended for people with HIV infection who have cognitive impairment, with the exception of avoidance of efavirenz.
8. Non-pharmacological interventions to consider and encourage include smoking and recreational drug cessation, alcohol reduction, exercise, and healthy eating and sleep hygiene practices.