CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

445 COMPARING TFV-DP & FTC-TP IN PBMC, RBC, NEUTROPHILS, & PLATELETS WITH F/TDF VS F/TAF

Jenna Yager 1 , Jose R. Castillo-Mancilla 1 , Cricket McHugh 1 , Kristina M. Brooks 1 , Mustafa E. Ibrahim 1 , Ryan P. Coyle 1 , Bethany M. Johnson 1 , Laura Roon 1 , Jia-Hua Zheng 1 , Lane R. Bushman 1 , Jennifer J. Kiser 1 , Peter L. Anderson 1 1 University of Colorado Anschutz Medical Campus, Aurora, CO, USA Background: Emtricitabine (FTC) plus tenofovir alafenamide (F-TAF) or tenofovir disoproxil (F-TDF) undergo cell-specific conversion, resulting in differential pharmacokinetics (PK) of tenofovir-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) across cell types. The selective cleavage of TAF via cathepsin A allows for more targeted delivery of TFV to cell types expressing that enzyme, such as peripheral blood mononuclear cells (PBMC). The PK of TFV-DP and FTC-TP has been evaluated in PBMC and red blood cells (RBC) measured with dried blood spots (DBS), but not in other major blood cell types, such as neutrophils and platelets. Methods: Paired DBS, PBMC, neutrophils, and platelets were obtained from HIV-negative individuals receiving F-TDF for PrEP, or directly observed F-TAF in the TAF-DBS study that evaluated 33%, 67% and 100% of daily dosing (NCT02962739). DBS, PBMC, neutrophils, and platelets were isolated fromwhole blood using a stepwise ficoll and centrifugation process. TFV-DP and FTC-TP were determined using a validated LC-MS/MS assay. Concentrations in fmol or pmol/10 6 cells were converted to fmol or pmol/µL to normalize across varying cell sizes. Results: Five F-TDF and 29 F-TAF participants had all cell types available. Median TFV-DP in DBS for F-TDF was 1676 (791-1895) fmol/punch consistent with daily dosing (TFV-DP in DBS for F-TAF was dependent on 33%, 67%, or 100% dosing). Table shows concentrations in fmol or pmol per 10 6 cells, per punch(es), and per µL in PBMC, DBS, RBC, neutrophils and platelets. The rank order of FTC-TP (pmol/µL) by cell type was PBMC>neutrophils>platelets>RBC and was the same for F-TAF versus F-TDF. The rank order for TFV-DP (fmol/µL) was PBMC>neutrophils>platelets>RBC for F-TAF versus RBC>PBMC~neutrophils>platelets for F-TDF. Conclusion: FTC-TP was preferentially loaded in PBMC and neutrophils and was similar for F-TAF vs F-TDF. Despite the lower TFV dose, F-TAF produced higher TFV-DP in PBMC, neutrophils, and platelets whereas F-TDF produced higher TFV-DP in RBC. The presence (PBMC/neutrophils/platelets) or absence (RBC) of cathepsin A likely explains these findings. RBC loading with TDF is likely driven by the higher plasma TFV, as well as its disoproxil, tenofovir- monoester intermediates, in portal blood. These findings show that tenofovir prodrug moieties influence cell loading in vivo, providing insights into cell type differences important for using drug concentrations to monitor adherence and characterizing cell-specific drug effects.

446 UTILITY OF MINIMALLY INVASIVE SPECIMENS TO INFORM ARV ADHERENCE TEST DEVELOPMENT Richard Haaland 1 , Amy Martin 1 , MelkamMengesha 1 , Chuong Dinh 1 , Jeffrey Fountain 1 , Davis Lupo 1 , LaShonda Hall 2 , Christopher Conway-Washington 2 , Colleen F. Kelley 2 1 CDC, Atlanta, GA, USA, 2 Emory Center for AIDS Research, Atlanta, GA, USA Background: Antiretroviral drug (ARV) efficacy in treatment and prevention of HIV infection is currently dependent on high levels of adherence to daily oral dosing regimens. Rapid point of care (POC) tests to measure ARV levels could be used to track and improve individual adherence. This study sought to define the utility of urine, dried blood spots, and buccal swabs as minimally invasive specimens amenable to development of POC tests for ARVs. Methods: Urine, buccal swabs, and peripheral blood were collected from 35 HIV-negative men who have sex with men aged 18-49 years enrolled in a clinical trial examining the pharmacokinetics of a single dose of 4 ARVs with a pharmacologic booster. Specimens were collected up to 96 hours following a single oral dose of tenofovir alafenamide (TAF)/emtricitabine (FTC)/elvitegravir (EVG)/cobicistat (COBI)/ and darunavir (DRV). Drug concentrations were measured by high performance liquid chromatography-mass spectrometry with a lower limit of quantification of 10 ng/mL for urine, plasma and blood spots and 2 ng/mL for buccal swabs. Results: FTC was detectable in all urine specimens collected 48 hours following a single dose and TFV and DRV were detectable in all urine specimens collected 24 hours post dose. TFV, FTC and DRV remained detectable in most urine specimens collected at least 72 hours post dose. EVG was not detectable in urine, and COBI was only measurable up to 8 hours post dose. Urine ARV concentrations showed modest correlation with those in plasma for FTC (r=0.510, p<0.001), DRV (r=0.555, p<0.001), and COBI (r=0.431, p<0.001). FTC, EVG and DRV were detectable in all DBS collected up to 24 hours post dose, and FTC and DRV remained detectable in most DBS collected up to 48 hours post dose. COBI was only detectable in DBS up to 8 hours post dose. ARV concentrations in DBS correlated with plasma concentrations for FTC (r=0.941, p<0.001), EVG (r=0.867, p<0.001) and DRV (r=0.917, p<0.001), but not COBI. FTC and COBI were detectable up to 8 hours post dose in buccal swabs, while DRV was detectable in most buccal swab specimens up to 24 hours post dose. TFV was not detectable in plasma, DBS or buccal swabs. Conclusion: Development of POC tests to detect ARV drugs fromminimally invasive specimens may be attractive to assess adherence. Our results suggest that POC assays targeting TFV, FTC or DRV in urine or FTC, EVG or DRV in whole blood may provide the most reliable indicators of ARV adherence. 447 REAL-LIFE MANAGEMENT OF DRUG-DRUG INTERACTIONS BETWEEN ANTIRETROVIRALS AND STATINS Perrine Courlet 1 , Francoise Livio 1 , Susana Alves Saldanha 1 , Alexandra Scherrer 2 , Manuel Battegay 3 , Matthias Cavassini 1 , Marcel Stoeckle 3 , Laurent A. Decosterd 1 , Catia Marzolini 3 , for the Swiss HIV Cohort Study 1 Lausanne University Hospital, Lausanne, Switzerland, 2 University Hospital Zurich, Zurich, Switzerland, 3 University Hospital Basel, Basel, Switzerland

Poster Abstracts

CROI 2020 156