HIV emerged as a major threat to world health over 30 years ago, and has challenged scientists and clinicians to combat its vast and devastating effects. Although the virus is recognised for its direct effect on the cellular immune system through depletion of infected CD4 lymphocytes, it also has broad effects on the nervous system, including evidence for direct pathology in the brain, spinal cord, and peripheral nerves.1 This primary HIV-associated neurocognitive disorder, combined with a unique range of opportunistic infections and malignant disease, constitutes neuroAIDS.
Development of combined antiretroviral therapy (cART) has changed HIV to a chronic disease with a life expectancy approaching population norms for patients who comply with treatment.2 The main issues remaining for neuroAIDS include the implications of persistent low levels of HIV, ongoing inflammatory responses, potential therapeutic toxicity, and interactions between ageing and neurodegeneration caused by the virus.3, 4, 5, 6 A functional cure for HIV infection will need the virus to be silenced in all body compartments, including the brain.7
HIV is more prevalent in developing countries than in developed countries. Because treatment is often delayed, a heavy disease burden persists in these settings because of neurological opportunistic infections, especially cryptococcal and tubercular meningitis, toxoplasma encephalitis, and progressive multifocal leukoencephalopathy.8, 9 These complications mostly stop after stable cART has been achieved. Additionally, peripheral neuropathy can affect the quality of life of patients with HIV, but is reduced when treatment with non-neurotoxic antiretrovirals is started early after infection.10 These important neuroAIDS topics are reviewed elsewhere.8, 9, 10 We restrict this Review to HIV-associated neurocognitive disorder.3, 4, 5
Far short of the quest for cure, progress towards elimination of HIV-associated neurological disability has been discouraging.11, 12 Cross-sectional studies continue to show that about half of all treated patients with HIV have cognitive impairment, which represents little improvement compared with the pre-cART era. However, a silver lining of modern treatment is that more severe forms of neurocognitive impairment are rare, although milder forms remain. Establishment of the causes, prognosis, and optimum cART regimen for patients with HIV-associated neurocognitive disorder remains a major goal. An understanding of existing HIV-associated neurocognitive disorder definitions is essential. A consensus research definition13 of HIV-associated neurocognitive disorder includes the subclassifications asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia (table).
Key messages
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Neurocognitive ability is impaired in most patients with HIV
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Severe dementia rarely develops in patients on effective combined antiretroviral therapy
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Most patients with mild neurocognitive impairment are clinically stable
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Comorbid disorders contribute to neurocognitive impairment but do not fully explain it
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Typical HIV disease biomarkers (viral load or CD4) are no longer closely associated with impairment
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Cardiovascular disease and inflammatory markers are associated with impairment
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Neuroimaging and cerebrospinal fluid studies could provide new mechanisms to improve our understanding of HIV-associated neurocognitive disorder
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Optimum HIV therapy is necessary, but not sufficient, to avert cognitive impairment
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Neither higher CNS-penetrating combined antiretroviral therapy nor adjuvant treatments have proven to be effective to reverse HIV-associated neurocognitive disorder
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Treatment to address inflammation and cardiovascular risks seems to be a rational approach