CROI 2016 Abstract eBook

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Poster Abstracts

membrane transporters (MDR1; MRP2, 4, 7; OAT1; NPT1; ENT1, 3; CNT2, 3) with the intracellular concentrations of TFV-DP and FTC-TP in peripheral blood mononuclear cells (PBMC) and red blood cells (RBC). Methods: HIV-negative and HIV-positive participants were enrolled in a pharmacokinetic (PK) study of daily TFV/FTC (plus efavirenz in HIV-positive) over 30 days. This analysis focused on day 30 PK. Human genomic DNA samples were genotyped for 19 SNPs using PCR-pyrosequencing methods. Blood was collected at 1, 2, 4, 8, and 24 hours and Css(ave) was determined for PBMC with non-compartmental methods (AUC (0-24) /tau). For RBC, the 2 hour post-dose sample was used for the analyses. Associations were evaluated graphically to determine grouping for heterozygotes. PK outcomes were log transformed for normality. T-tests were used for univariate analyses with no adjustment for multiple comparisons. For PK outcomes that demonstrated significance (p<0.05) in the univariate analysis, multivariable linear regression was utilized to adjust for race. Results: Day 30 data were available from thirty-one adults (19 men, 13 HIV-positive). In univariate analysis, significant relationships were identified between CNT2 and ENT3 with TFV-DP, and MDR1 with FTC-TP(Table). After adjusting for race, TFV-DP in PBMC was 24% lower (95% CI: 5.1%,38.8%; p=0.025), 27% lower (7.0%,43.3%; p=0.013), and 26% lower (1.3%,44%; p=0.041) in CNT2_ rs1060896, CNT2_rs11854484, and ENT3_ rs1099976 homozygous variant carriers, respectively; TFV-DP in RBC was 46% higher (7.6, 99.1;p=0.017) according to ENT1_ rs324148 variant carriage; and FTC-TP was 24% higher (5.1%, 38.8%; p=0.017) in those with 0 or 1 copies of the MDR1 (1236/2677/3435)-CGC haplotype versus 2 copies of the CGC haplotype. Conclusions: This study found novel associations between TFV-DP in PBMC and RBC with SNPs in CNT2, ENT3 and ENT1, respectively, as well as SNPs in MDR1 for FTC-TP. We hypothesize that polymorphisms in these transporters are a source of PK variability for TFV-DP and FTC-TP in PBMC and RBC in vivo, and that accurate prediction of individual PK will require accounting for these pharmacogenetic profiles.

446 CYP2B6 Genotype Effects on Neurocognitive Impairment in HIV+ Patients on Efavirenz

Qing Ma 1 ; Jennifer Iudicello 2 ; Xia Liu 3 ; Donald Franklin 2 ; Igor Grant 4 ; Robert Heaton 4 ; Fujie Zhang 3 ; Scott R. Letendre 2 ; for the CHARTER and China neuroAIDS Study Groups 1 Univ at Buffalo, State Univ of New York, Buffalo, NY, USA; 2 Univ of California San Diego, San Diego, CA, USA; 3 China CDC, Beijing, China; 4 Univ of California San Diego, La Jolla, CA, USA Background: 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. Methods: 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). Results: 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). Conclusions: 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. 447 Multispecies ARV Distribution in Intestinal Tissue by Mass Spectrometry Imaging (MSI) Elias P. Rosen 1 ; CorbinThompson 1 ; Craig Sykes 1 ; Lourdes Adamson 2 ; Michelle Mathews 1 ;Yuri Fedoriw 1 ; Paul Luciw 2 ; J.Victor Garcia 1 ; Ramesh Akkina 3 ; Angela Kashuba 1 1 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2 Univ of California Davis, Davis, CA, USA; 3 Colorado State Univ, Fort Collins, CO, USA Background: Methods to accurately evaluate drug distribution within tissues are needed to design effective eradication strategies. Here, we characterize the spatial distribution of emtricitabine (FTC), tenofovir (TFV), and raltegravir (RAL) within the upper and lower intestine (ileum and colorectum) and evaluate differences between ARV accumulation in three animal models for HIV infection using MSI. Methods: Iliac (IL) and colorectal (CR) tissue was removed at necropsy from uninfected rhesus macaques (NHP, n=3) and from two humanized mouse models (BLT, n=3; hu- HSC-Rag, n=3) dosed to steady-state with FTC+TFV+RAL. MSI of snap frozen cryosections (10mm) were analyzed using an infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) source. Response was calibrated by ARV standards on blank tissue, with a limit of detection of 250 fg/voxel (24 ng/g tissue). Serial sections of tissue were utilized to validate MSI results by LC-MS/MS, and stained to correlate observed ARV response with CD3, CD4, and CD8+ cells). LC-MS/MS concentrations are reported in micrograms/g tissue. Results: All ARVs were observed to penetrate NHP intestinal tissues, increasing in concentration from FTC to TFV to RAL for both IL (1.0±1.0, 2.2±1.2, 6.5±4.8, respectively) and CR (2.8±2.6, 4.0±3.7, 71.4±9.2, respectively). Relative to plasma, tissue concentrations for FTC, TFV, and RAL were 3.7±1.1, 3.4±0.6, 3.8±0.2 log units higher, respectively, in IL

Poster Abstracts

171

CROI 2016