Aetiology

Causes of altered mental status among people living with HIV include acutely presenting conditions (which often represent HIV-related opportunistic infections or associated systemic illness, or ischaemic stroke), and more progressive (and often previously documented) neurocognitive disorders or psychological comorbidities.

The incidence of specific HIV-related conditions is usually dependent upon the degree of immunosuppression and whether the underlying HIV infection is being actively treated with antiretroviral therapy (ART).

HIV-associated conditions

Include HIV-associated neurocognitive disorder (HAND), drug adverse effect, or therapy-related immune reconstitution inflammatory syndrome (IRIS).

HIV-associated neurocognitive disorder

Represents a spectrum of progressive neurocognitive impairment ranging from asymptomatic neurocognitive impairment (ANI) to HIV-associated dementia (HAD):[14][23]​​

By definition, these conditions are only diagnosed if the impairment is not occurring as part of a delirium secondary to infection or drug effects, and cannot be explained by alternative aetiologies.[14]

Drug adverse effect or therapy-related IRIS

ART may induce cognitive or psychiatric problems directly as an adverse effect or indirectly through their effect on the immune system. The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is associated with the development of neuropsychiatric adverse effects, especially in the first weeks of treatment.[24][25][26][27][28]​ Rates of similar neuropsychiatric adverse effects are significantly lower with other NNRTI agents such as nevirapine, etravirine, and rilpivirine.[29][30]​

The integrase inhibitor raltegravir has been associated with infrequent neuropsychiatric adverse effects, and dolutegravir may be associated with insomnia and other central nervous system (CNS) effects.[31][32][33][34][35][36]

Patients receiving ART may develop IRIS as a consequence of the reaction of a restored immune system to infectious agents. Commonly implicated infectious agents include Mycobacterium tuberculosis or M avium complex, although other causes (e.g., herpes simplex virus [HSV], varicella zoster virus [VZV], progressive multifocal leukoencephalopathy [human polyomavirus 2, also known as John Cunningham virus [JCV]], cytomegalovirus [CMV], cryptococcal infection and Toxoplasmosis gondii) are also recognised triggers.[37][38][39]

CNS opportunistic infections and tumours

HIV-related opportunistic infections (OIs) arise as a consequence of impaired immunity in advanced stages of HIV infection, usually in the setting of CD4 <200 cells/mm³.[23]​ These illnesses tend to occur most often in people with untreated HIV infection or those with poor adherence to ART. The risk of OI, and neurological involvement, increases in people with HIV as the CD4 count declines.

Common manifestations include:

  • Encephalitis due to infection with Toxoplasma gondii, HSV, or, rarely, VZV or cytomegalovirus

  • Meningitis due to infection with Cryptococcus neoformans or  M tuberculosis

  • PML due to infection with human polyomavirus 2 (also known as JCV)

  • Epstein-Barr virus-positive primary CNS lymphoma

Non-opportunistic infections such as bacterial causes of meningitis (including neurosyphilis), must be considered in patients presenting with acute neurological deterioration and infectious signs or symptoms.

Non-HIV-associated conditions

Comprise systemic comorbidities and psychiatric comorbidities.

Systemic comorbidities

Concomitant nutritional deficiency (e.g., folate, vitamin B12, vitamin D) may cause cognitive impairment, which may be seen in the setting of malnutrition in advanced HIV/AIDS.[40] People with advanced HIV infection are at an increased risk of ischaemic stroke compared with people without HIV.[41] The underlying pathogenesis varies and includes cerebral emboli secondary to cardiac disease, accelerated atherosclerosis, or cerebral vasculitis as a consequence of syphilis or amfetamine/cocaine use.

People living with HIV with concomitant hepatitis C infection have higher rates of cognitive impairment.[40][42]​​ Thyroid disease and hypogonadism are more common in people with HIV, and can represent an underlying cause of altered mental status.[40][43][44][45]

Psychiatric comorbidities

Psychiatric comorbidities are highly prevalent in people living with HIV and can contribute to cognitive difficulties.[40] These include:[23][40]​​

  • Depression

  • Anxiety

  • Alcohol and substance use disorders

  • Cognitive impairment due to polypharmacy from prescription medications, in particular those with anticholinergic properties and psychotropic medications

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