Alterations in Cerebrospinal Fluid Chemokines Are Associated With Maraviroc Exposure and In Vivo Metabolites Measurable by Magnetic Resonance Spectroscopy

Abstract

Background: Cerebrospinal (CSF) fluid biomarkers may be a useful tool for assessing the cerebral effects of antiretroviral therapy. Objective: The aim of the study was to investigate the relationship between 4 CSF chemokines with maraviroc exposure and cerebral metabolite ratios (CMR) measured by magnetic resonance spectroscopy (¹H-MRS) in HIV-infected individuals following maraviroc intensification. Methods: CSF concentration of maraviroc and 4 chemokines (MCP-1, IP-10, MCP-4, and MIP-1β), plasma concentration of maraviroc pre-CSF assessment, and right basal ganglia CMR were assessed in 12 male HIV-infected, neuro-asymptomatic adults after 14 days of antiretroviral therapy intensification with maraviroc 150 mg twice daily. The relationship between CSF analytes with both CMRs and plasma and CSF maraviroc concentrations were examined using Spearman correlation coef-ficient. Results: Twelve subjects completed study procedures with baseline values as follows: mean (SD) age 42 (8) years, CD4+ cell count 503 (199) cells/µL, and plasma HIV RNA <50 copies/mL in most subjects. Mean (range, pg/mL) chemo-kine concentrations were IP-10, 1242 (190-8073); MCP-4, 6.52 (1-18); MCP-1, 702 (201-1618); and MIP-1β, 42 (5-153). IP-10, MCP-4, and MIP-1β were significantly associated with CMRs in the right basal ganglia with (1) lower concentrations of IP-10 correlating with higher N-acetyl aspartate to creatine ratios (NAA/Cr) and (2) higher concentrations of MCP-4 and MIP-1β correlating with higher myoinositol to creatine (mI/Cr) ratios. There were no significant associations with MCP-1. Finally lower concentrations of IP-10 were significantly associated with higher maravi-roc plasma trough concentration (r = –0.629,P = .028) but not CSF concentration (r = –0.308,P = .331). Conclusion: We hypothesize that the relationship between IP-10, MCP-4, and MIP-1β with maraviroc exposure and CMRs may be associated with a direct cerebral effect of maraviroc.

Keywords:

• cerebrospinal fluid
• chemo-kines
• maraviroc
• MR spectroscopy