Human immunodeficiency virus enters the central nervous system (CNS) early after systemic infection, and may cause neural injury and associated neurocognitive impairment through multiple direct and indirect mechanisms. An international conference of multidisciplinary neuroAIDS experts convened in 2005 to propose operationalized research criteria for HIV-related cognitive and everyday functioning impairments. The resulting classification system, known as the Frascati criteria, defined three types of HIV-associated neurocognitive disorder (HAND): asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia (HAD). Consideration of comorbid conditions that can influence neurocognitive performance, such as developmental disabilities, non-HIV forms of CNS compromise (neurological and systemic), severe psychiatric conditions, and substance use disorders, is essential to differential diagnosis. Since the introduction of combination antiretroviral therapy (ART), rates of severe HAND (i.e., HAD) have greatly declined, although the milder forms of HAND remain quite prevalent, even in virally suppressed people living with HIV (PLWH). Beyond ART, clinical management of HAND includes behavioral interventions focused on neurocognitive and functional improvements. This chapter covers a range of HAND-related topics, such as the neuropathological mechanisms of HIV-related CNS injury, assessment and diagnostic systems for neurocognitive and everyday functioning impairment in HIV, treatment and protective factors, aging with HIV, HAND in international settings, and ongoing challenges and controversies in the field. Future needs for progress with HAND include advances in early detection of mild cognitive deficits and associated functional impairment in PLWH; biomarkers that may be sensitive to its underlying pathogenesis; and differential diagnosis of HAND versus age-related, non-HIV-associated disorders.
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