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.

Meta-analysis of factors affecting prevalence estimates of HIV-associated neurocognitive disorder in sub-Saharan Africa

“…1 The growing burden of HAND justifies a quintessential global response to address this important mental health challenge among people living with HIV (PLWHIV). 2 Before ART was introduced in 1996, 20-30% of people with advanced HIV infection displayed symptoms of severe HAND 3,4 , with death occurring within 6 months 5 . In the ART era, the prevalence of HAND varies between 19% and 64%, averaging globally at about 50%.…”

Blood–Brain Barrier Impairment in Patients Living with HIV: Predictors and Associated Biomarkers

“…Our univariate analysis shows a lower prevalence of BBB alteration among participants treated with integrase inhibitors (INSTI), compared with patients treated with other classes of antiviral drugs (protease inhibitors or non–nucleoside reverse transcriptase inhibitors). Integrase inhibitors (Raltegravir, Elvitegravir, Dolutegravir and Bictegravir) are commonly used as first-line cART regimen, in association with other classes of antivirals, such as two nucleoside reverse transcriptase inhibitors [ 27 ]. Moreover, other elements can influence the therapy response, such as HIV DNA, substance abuse, pharmacogenetics, adherence to antiretrovirals and demographic factors, e.g., age and ethnicity [ 28 ].…”

Microglia: The Real Foe in HIV-1-Associated Neurocognitive Disorders?

“…HAND still represents an unresolved multifactorial complication of HIV, even in the modern cART (traditional three-drug regimen) era that often achieves the suppression of HIV replication to levels below the limit of detection of currently used assays. Indeed, recent studies have demonstrated that no clinical trials of HAND treatments are efficient beyond the optimal suppression of HIV replication in the CNS [ 11 , 12 ]. Whereas some studies have indicated a reduction in cognitive impairment due to cART, patients with a controlled viral load who discontinue treatment with antiretrovirals have shown an improvement in cognitive functions and a reduction in neuronal damage [ 12 , 13 ].…”

“…Indeed, recent studies have demonstrated that no clinical trials of HAND treatments are efficient beyond the optimal suppression of HIV replication in the CNS [ 11 , 12 ]. Whereas some studies have indicated a reduction in cognitive impairment due to cART, patients with a controlled viral load who discontinue treatment with antiretrovirals have shown an improvement in cognitive functions and a reduction in neuronal damage [ 12 , 13 ].…”