Developments in Neuroprotection for HIV-Associated Neurocognitive Disorders (HAND)

Abstract

Purpose of review: Reducing the risk of HIV-associated neurocognitive disorders (HAND) is an elusive treatment goal for people living with HIV. Combination antiretroviral therapy (cART) has reduced the prevalence of HIV-associated dementia, but milder, disabling HAND is an unmet challenge. As newer cART regimens that more consistently suppress central nervous system (CNS) HIV replication are developed, the testing of adjunctive neuroprotective therapies must accelerate.

Recent findings: Successes in modifying cART regimens for CNS efficacy (penetrance, chemokine receptor targeting) and delivery (nanoformulations) in pilot studies suggest that improving cART neuroprotection and reducing HAND risk is achievable. Additionally, drugs currently used in neuroinflammatory, neuropsychiatric, and metabolic disorders show promise as adjuncts to cART, likely by broadly targeting neuroinflammation, oxidative stress, aerobic metabolism, and/or neurotransmitter metabolism. Adjunctive cognitive brain therapy and aerobic exercise may provide additional efficacy. Adjunctive neuroprotective therapies, including available FDA-approved drugs, cognitive therapy, and aerobic exercise combined with improved cART offer plausible strategies for optimizing the prevention and treatment of HAND.

Keywords: Brain; HAND; HIV; HIV-associated neurocognitive disorders; Neuroprotection; Treatment.

Fig. 1

Proposed sites of neuroprotective drug effects in HIV neuropathogenesis. Multiple steps in HIV neuropathogenesis are potentially targetable for neuroprotection. Acute HIV infection results in (1) structural damage to the gut mucosal barrier and translocation of immune-activating microbial products into the systemic circulation, (2) transendothelial migration of HIV-infected immune cells into the CNS, and (3) HIV replication within perivascular/parenchymal macrophages and microglia and trafficking T lymphocytes. Amplification of pro-inflammatory and oxidative processes in infected and non-infected activated glial cells is associated with release of toxic metabolic products, including reactive oxygen species, pro-inflammatory cytokines, HIV proteins, and excitotoxic neurotransmitters. Abbreviations: INSTIs—integrase strand transfer inhibitors; DMF—dimethyl fumarate; SSRIs—selective serotonin re-uptake inhibitors