| Publication Abstract Display | | Type: Poster | | Title: CYP2B6 genotype affects global neurocognitive impairment in HIV-positive patients receiving Efavirenz: A CHARTER and China neuroAIDS study. | | Authors: Ma Q, Iudicello J, Liu X, Franklin D, Grant I, Heaton R, Zhang F, Letendre S, for the CHARTER group and the China NeuroAIDS Team | | Date: 02-22-2016 | | Abstract:Blood-brain barrier active efflux transporters of the ATP-binding cassette (ABC) gene family and CYP enzymes are involved in distribution and elimination of antiretroviral drugs in the brain and periphery. Single nucleotide polymorphisms (SNPs) in CYP2B6 and ABCB1 have been associated with peripheral exposure of efavirenz. The impact of genetic profiles of transporters and CYP2B6 on central nervous system (CNS) exposure of efavirenz or on neurocognitive (NC) performance has not been assessed.
Adult HIV-positive patients receiving efavirenz (EFV)-containing cART for at least six months (n=44 from CHARTER, n=23 from China neuroAIDS) were included. Single random plasma or paired plasma and CSF samples were collected and analyzed using LC/MS-MS methods. Standardized comprehensive neurocognitive testing was performed. SNPs in the following genes were extracted from an SNP array: ABCB1, ABCC4, and CYP2B6. Results are expressed as median and interquartile range (IQR).
The median EFV plasma and CSF concentrations were 2335 ng/mL (1707-3510) and 13.6 ng/mL (5.9-19.1), respectively. CSF-to-plasma ratios ranged from 0.00003 to 0.073 (median 0.0053, IQR 0.0023-0.0082). CSF concentrations significantly correlated with plasma levels (Pearson rho = -0.28, P = 0.04). ABCB1 3435 C>T (rs1045642) had no significant impact on CSF concentrations [TT 12.9 (4.96-18.5) vs. CC/CT 13.8 (10.7-15.5) ng/mL, p = 0.391]. CYP2B6 516G>T (rs3745274) TT carriers had significantly higher plasma and CSF concentrations [TT 27.2 (12.6-33.6), GT 15.6 (2.63-20.3), GG 7.45 (3.27-19.3) ng/mL, p = 0.047]. Significantly higher incidence of global neurocognitive impairment was noted among CYP2B6 TT carriers (81% vs. 26%, p=0.02).
The interpatient variability of CNS exposure of EFV is large. CYP2B6 516G>T is associated with plasma and CSF concentrations as well as global neurocognitive impairment, suggesting the relationship between genetic factors and CNS exposure may be one of the underlying mechanisms for the development of NC impairment. |
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