The Chronicity of HIV Infection Should Drive the Research Strategy of NeuroHIV Treatment Studies: A Critical Review

Abstract

HIV infection has become a chronic illness when successfully treated with combined antiretroviral therapy (cART). The long-term health prognosis of aging with controlled HIV infection and HIV-associated neurocognitive disorder (HAND) remains unclear. In this review, we propose that, almost 20 years after the introduction of cART, a change in research focus is needed, with a greater emphasis on chronicity effects driving our research strategy. We argue that pre-emptive documentation of episodes of mild neurocognitive dysfunction is needed to determine their long-term prognosis. This strategy would also seek to optimally represent the entire HAND spectrum in therapeutic trials to assess positive and/or negative treatment effects on brain functions. In the first part of the paper, to improve the standard implementation of the Frascati HAND diagnostic criteria, we provide a brief review of relevant quantitative neuropsychology concepts to clarify their appropriate application for a non-neuropsychological audience working in HIV research and wanting to conduct randomized clinical trials on brain functions. The second part comprises a review of various antiretroviral drug classes and individual agents with respect to their effects on HAND, while also addressing the question of when cART should be initiated to potentially reduce HAND incidence. In each section, we use recent observational studies and randomized controlled trials to illustrate our perspective while also providing relevant statistical comments. We conclude with a discussion of the neuroimaging methods that could be combined with neuropsychological approaches to enhance the validity of HIV neurology (neuroHIV) treatment effect studies.

Utility of Using the Montreal Cognitive Assessment (MoCA) as a Screening Tool for HIV-Associated Neurocognitive Disorders (HAND) In Multi-Ethnic Malaysia

“…In contrast, the demographically corrected rates were in agreement with international HAND prevalence rates in treated and virally suppressed HIV-positive populations [27–31]. Of note the rate of low performance in the HIV-negative sample was determined by design when building the normative formula to have optimal sensitivity and specificity to at least mild level of cognitive impairment [32]. …”

Methamphetamine potentiates HIV-1gp120-induced microglial neurotoxic activity by enhancing microglial outward K + current

“…It is widely accepted that HIV-1 infection has become a chronic illness with very low levels of viral replication and chronic immune activation when successfully treated with combined anti-retroviral therapy (cART) (Gates and Cysique, 2016; Jaeger and Nath, 2012; Watkins and Treisman, 2015). Despite this promising success, HAND remains prevalent in the HIV-1-infected population (Alfahad and Nath, 2013; Heaton et al, 2011; Simioni et al, 2010).…”

HIV-1 Glycoprotein 120 Enhancement of N-Methyl-D-Aspartate NMDA Receptor-Mediated Excitatory Postsynaptic Currents: Implications for HIV-1-Associated Neural Injury

“…Although the introduction of combination antiretroviral therapy (cART) has significantly decreased the incidence of HAD, the milder forms of HAND remains prevalent even in the era of cART (Heaton et al, 2010; Heaton et al, 2011; Alfahad and Nath, 2013). The causes for continuing high rates of HAND in the cART era are uncertain, but multifactorial mechanisms have been proposed including, but not limited to, incomplete viral suppression in the central nervous system (CNS) due to poor CNS penetration of some commonly used antiretroviral drugs, presence of drug-resistant viral stain, possible neurotoxicity of cART and the possibility that even very low levels of viral replication in the CNS could induce neural injury or dysfunction due to a prolonged exposure to neuro-inflammatory responses and neurotoxic viral proteins(Heaton et al, 2011; Jaeger and Nath, 2012; Gates and Cysique, 2016). Among the viral proteins is HIV-1 envelope glycoprotein 120 (gp120) that has been implicated as having neurotoxic effects in the CNS(Zhang et al, 2011; Hoefer et al, 2015).…”