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Introduction: Human immunodeficiency virus (HIV) is a neurotropic virus that enters the central nervous system (CNS) early in the course of infection. Although antiretroviral drugs are able to eliminate the majority of the HIV virus in the bloodstream, however, no specific treatment currently exist for CNS infections related to HIV. This is mainly attributed to the poor penetrability of antiretroviral therapy across the blood-brain barrier (BBB), and the protective nature of the BBB. Therefore, in order to increase the efficacy of anti-HIV drugs, novel drug delivery methodologies that can exhibit activity in the CNS are most needed and warranted., Areas Covered: In this review article, the authors discussed the challenges with delivering drugs to the brain especially under HIV infection pathophysiology status. Also, they discussed the approaches currently being investigated to enhance brain targeting of anti-HIV drugs. A literature search was performed to cover advances in major approaches used to enhance drug delivery to the brain., Expert Opinion: If drugs could reach the CNS in sufficient quantity by the methodologies discussed, mainly through intranasal administration and the utilization of nanotechnology, this could generate interest in previously abandoned therapeutic agents and enable an entirely novel approach to CNS drug delivery.