CNS-Targeted Antiretroviral Strategies: When Are They Needed and What to Choose

Abstract

Recent studies support the idea that residual cerebrospinal fluid HIV RNA in the setting of plasma viral suppression is associated with compartmental immune activation but the link to neuronal damage is debated. Some authors have reported an incomplete antiviral efficacy in macrophage-derived cells but targeted antiretroviral regimen switches have not been performed. Additionally, improvements in neurocognition using drugs with better central nervous system penetration or maraviroc (associated with favorable immunological properties) have been observed in pilot studies. Trials evaluating specific interventions for cardiovascular health (including brain white matter abnormalities) and neurotoxicity of antiretrovirals are warranted. Central nervous system-targeted antiretroviral strategies are needed in patients with uncontrolled cerebrospinal HIV replication, and they may be suggested in subjects with low CD4 nadir, individuals carrying drug-resistant viruses, and those with compartmental immune activation.

Cerebrospinal fluid HIV-1 escape according to different thresholds and underlying comorbidities

“…A patient presenting with plasma HIV-RNA below 20 copies/mL and a CSF HIV-RNA of 21 copies/mL would be categorized, by all definitions, as a CSF-E. What may be the clinical and scientific consequences of adopting such a low-threshold definition? A CSF-E diagnosis triggers a remarkable time and resource-consuming clinical workout, a tailored follow-up and primarily it should prompt to reassess and eventually modify the ongoing cART, aiming at a better CNS-targeted combination in terms of penetration and efficacy [7]. According to definition C, we observed a substantially high prevalence of primary asymptomatic CSF-E; current knowledge suggests no relevant worsening over time but a significantly higher immune activation; [8] however, additional biomarkers able to exclude associated CNS damages may be helpful in avoiding unnecessary treatment changes.…”

HIV-1-Associated Neurocognitive Disorders: Is HLA-C Binding Stability to β2-Microglobulin a Missing Piece of the Pathogenetic Puzzle?

“…It would be reasonable to use antiretroviral drugs with high CNS penetration/effectiveness score, such as darunavir, abacavir or raltegravir ( 108 , 109 ), to reduce the risk of HAND. However, some antiretroviral drugs are potentially neurotoxic: they may increase the production of Aβ protein by neurons and reduce its microglial phagocytosis, leading to the deposition of amyloid plaques in the CNS ( 68 , 110 ).…”

Current and Future Therapeutic Strategies for Lentiviral Eradication from Macrophage Reservoirs

“…Functional imaging techniques such as PET-CT to measure translocator protein (TSPO) expression offer a more accurate picture of CNS activation. Use of [11C]-PK11195 PET in HIV chronically infected patients, who lacked any neurologic or cognitive symptoms, was able to identify microglial activation in spite of undetectable CSF and plasma viral loads (Calcagno et al, 2018;Garvey et al, 2014).…”

“…It has been recently identified using brain magnetic resonance spectroscopy that intensification of maraviroc therapy can lead to improved neuronal integrity markers and reduction of CSF inflammation. Additionally, a similar drug still under development, Cenicriviroc, also showed potential for the reduction of CNS activation (Calcagno et al, 2018).…”

“…Two possible explanations for continued and slowly progressive cognitive decline include the release of neurotoxic secretions by infected macrophages as well as direct or indirect toxicity from antiretroviral therapy. One specific NNRTI, efavirenz, has been linked with lower neurocognitive performance in several studies (Calcagno et al, 2018).…”