Optimal treatment of HIV-associated neurocognitive disorders: myths and reality. A critical review

Abstract

Background: The aim of this study was to review the clinical data on the effectiveness of the pharmacotherapy of HIV-associated neurocognitive disorders (HANDs).

Methods: A literature search of PubMed was performed (from January 1996 to October 2018) using the terms: 'HIV-associated neurocognitive disorders', 'HIV-associated dementia', 'mild neurocognitive disorder (MND)', 'asymptomatic neurocognitive impairment (ANI)', 'adjuvant therapies', 'antiretroviral treatment (cART)', 'neurotoxicity', 'cART intensification', 'fluid markers', 'cerebrospinal fluid', 'protease inhibitors', 'nonnucleoside reverse transcriptase inhibitor', 'nucleoside reverse transcriptase inhibitors', and 'integrase strand transfer inhibitors'. Additional references were identified from a review of literature citations. All English language clinical studies of adjunctive therapies and neuronal markers were selected in order to evaluate a closer relationship between the early involvement and the onset of cognitive decline. We identified 407 relevant studies, of which 248 were excluded based on abstract analysis. Finally, we analyzed 35 articles, organizing the results by cART, adjuvant and neuronal markers (total of 7716 participants).

Results: It is important to inform clinicians about the importance of accurate phenotyping of HIV patients, incorporating an array of markers relevant to HAND pathophysiology, in order to assess the individual's risk and potential response to future personalized antiretroviral treatment.

Conclusion: So far, no clinical trials of HAND therapies are effective beyond optimal suppression of HIV replication in the central nervous system. Combination of validated neuronal markers should be used to distinguish between milder HAND subtypes and improve efficiency of clinical trials, after strict control of confounders.

Keywords: HIV-associated neurocognitive disorders (HAND); active antiretroviral therapy (cART); central nervous system; confounders; neuronal markers.

Figure1.

Schematic Representation of HAND neuropathogenesis. A Schematic model demonstrating the key steps (activated macrophages, microglial cells) of HAND pathogenesis as well as potential targets of current therapies such as anti-inflammatory (minocycline), NMDAR antagonists/anti-excitotoxic (memantine), antioxidants agents (selegiline). HAND, HIV-associated neurocognitive disorder; NMDAR, -N-methyl-D-aspartate receptor.