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HIV-Associated Neurocognitive Disorders (HAND) is a serious menifestation of HIV in‐ fection in the central nervous system (CNS), and encompassess a wide spectrum of cog‐ nitive, behavioral, and motor deficits [1-3]. While the implementation of combination antiretroviral therapy (ART) has dramatically increased the life expectancy and led to significant improvements in the clinical presentation and progression of HAND, an esti‐ mated 50% of HIV-infected patientscontinue to suffer from implications of HAND in the ART era, with as much as 20% of these exhibiting symptoms of HIV-associated dementia (HAD), the most severe form of HAND [3-6]. The brain regions affected in patients with HAND has changed in the ART era in parallel to the changes observed in the clinical picture; a more subtle and insidious cortical damage mainly in the hippocampus and the temporal cortex is observed, in contrast to the overt subcortical damage seen before ART [7-10]. The underlying causes of these changes are not fully elucidated; however, exami‐ nation of the post-mortem tissue reveals the persistence of synaptic and dendritic dam‐ age in the affected brain regions [3, 11]. Emerging evidence suggests that controlling viral replication in the periphery or in the CNS may not be sufficient to control the un‐ derlying neuropathological processes that culminate in the development of HAND. The impact of HAND on the quality of life, adherence to drug regimens, and co-morbidities especially in an aging HIV population with decreased cognitive reserves, is of major con‐ cern. In this chapter, we will examine the major factors that continue to impact the CNS of HIV-infected individuals, and introduce new challenges in the successful treatment of HAND.

Persistence of HIV-Associated Neurocognitive Disorders in the Era of Antiretroviral Therapy