571. Effects of alcohol use on tenofovir alafenamide metabolites among persons with HIV: Implications from a pharmacokinetic model

Abstract Background Tenofovir alafenamide (TAF) is used to treat hepatitis B virus and HIV. TAF undergoes intracellular hydrolysis by carboxylesterase 1 (CES1) in the liver and cathepsin A in peripheral blood mononuclear cells (PBMCs), followed by phosphorylation to the active moiety, tenofovir-diphosphate (TFV-DP). Evidence in hepatocytes suggests ethanol inhibits TAF hydrolysis to TFV via CES1 inhibition, reducing active TFV-DP in the liver. Methods QUANTI-TAF (NCT04065347) was an observational pharmacokinetic (PK) study where PWH received TAF/emtricitabine (FTC)-based antiretroviral therapy. We evaluated a subset of 20 PWH who self-reported high (n=10) or no (n=10) alcohol use. Plasma TFV, intracellular TFV-DP concentrations in PBMCs, and phosphatidylethanol (PEth [biomarker for alcohol use]) in dried blood spots (DBS) were quantified using validated LC-MS/MS at 0, 4, 8, and 12 weeks. An oral absorption 2-compartment PK model was used to evaluate if PEth category (< 50 ng/mL, low [n=9]; 50-200 ng/mL, moderate [n=5]; and ≥200 ng/mL, high [n=6]) was associated with apparent clearance (CL/bioavailability [F]) of plasma TFV and PBMC TFV-DP. Results A total of 20 virally suppressed PWH were evaluated. Median (IQR) DBS PEth concentrations were 131 ng/mL (62-309). Mean (SD) plasma TFV CL/F generally decreased as PEth category increased, although non-significantly (low: 25.77 L/h [±5.55]; moderate: 25.54 L/h [±1.95]; high: 22.34 L/h [±3.63]; ANOVA p=0.18), Figure 1A. In PBMCs, TFV-DP CL/F also generally decreased as PEth category increased (low: 0.2064 L/h [±0.12]; moderate: 0.1664 L/h [±1.12]; high: 0.09697 L/h [±0.06]; ANOVA p=0.16), Figure 1A. When moderate and high PEth categories were combined, there was also a difference in CL/F values for plasma TFV (p=0.06) and PBMC TFV-DP (p=0.08), Figure 1B. Conclusion Alcohol use was associated with lower TFV CL/F in plasma, and TFV-DP CL/F in PBMCs, potentially driven by inhibition of CES1-mediated TAF hydrolysis to TFV in hepatocytes. We believe these observed changes in CL/F are likely driven by changes to F. We hypothesize that increased TFV-DP in PBMCs represents a shunting of TAF delivery from hepatocytes (CES1) to PBMCs. Alcohol use could contribute to metabolic differences in TFV conversion from TAF, which could have implications for treatment. Disclosures All Authors: No reported disclosures