Antiretroviral Monocyte Efficacy Score Linked to Cognitive Impairment in Hiv

Abstract

Background Monocytes transmigrating to the brain play a central role in HIV neuropathology. We hypothesized that the continued existence of neurocognitive impairment (NCI) despite potent antiretroviral (ARV) therapy is mediated by the inability of such therapy to control this monocyte/macrophage reservoir. Methods Cross-sectional and longitudinal analyses were conducted within a prospectively enrolled cohort. We devised a monocyte efficacy (ME) score based on the anticipated effectiveness of ARV medications against monocytes/macrophages using published macrophage in vitro drug efficacy data. We examined, within an HIV neurocognitive database, its association with composite neuropsychological test scores (NPZ8) and clinical cognitive diagnoses among subjects on stable ARV medications unchanged for >6 months prior to assessment. Results Among 139 subjects on ARV therapy, higher ME score correlated with better NPZ8 performance (r=0.23, P<0.01), whereas a score devised to quantify expected penetration effectiveness of ARVs into the brain (CPE score) did not (r=0.12, P=0.15). In an adjusted model (adjusted r2=0.12), ME score (β=0.003, P=0.02), CD4+ T-cell nadir (β=0.001, P<0.01) and gender (β=−0.456, P=0.02) were associated with NPZ8, whereas CPE score was not (β=0.003, P=0.94). A higher ME score was associated with better clinical cognitive status (P<0.01). With a range of 12.5–433.0 units, a 100-unit increase in ME score resulted in a 10.6-fold decrease in the odds of a dementia diagnosis compared with normal cognition (P=0.01). Conclusions ARV efficacy against monocytes/macrophages correlates with cognitive function in HIV-infected individuals on ARV therapy within this cohort. If validated, efficacy against monocytes/macrophages may provide a new target to improve HIV NCI.

Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

“…used in vitro effective concentration in acutely infected macrophages (EC50) to calculate a "monocyte efficacy score" (ME score: 1/EC50*1000): surprising results were observed with tenofovir being 17 times more efficacious than abacavir (50 versus 3). [182] In 139 patients the composite score was nicely associated with neurocognitive performance and with presence of HAND or minor motor cognitive disorder.…”

Monocytes Mediate HIV Neuropathogenesis: Mechanisms that Contribute to HIV Associated Neurocognitive Disorders

“…Regimens that better target cells of the monocyte lineage are important to eradicating both peripheral and CNS viral reservoirs, as they are the major source of virus production in the brain. A scale has been developed to assess the efficacy of antiretroviral regimens to inhibit HIV infection of monocytes/macrophages[152]. cART regimens with higher monocyte efficacy scores more effectively inhibited the in vitro infection of monocytes and macrophages as compared to treatments with lower scores.…”

“…cART regimens with higher monocyte efficacy scores more effectively inhibited the in vitro infection of monocytes and macrophages as compared to treatments with lower scores. HIV seropositive people receiving antiretroviral regimens with lower monocyte efficacy scores had a significantly higher likelihood of cognitive impairment[152]. This occurred even in individuals who had undetectable plasma viral loads.…”

Evidence-based perspectives on the implementation of screening for neurocognitive impairment in HIV

“…62 Similarly, the monocyte efficacy score grades drugs on their ability to achieve high intracellular concentrations in the macrophage-monocyte cell line, which includes microglia. 63 To date, there have been inconsistent findings regarding the effects of drugs with different CNS penetrations. 46,62,[64][65][66][67][68][69][70] The inevitable biases that emerge in these observational studies make their findings difficult to interpret.…”