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

TL;DR

This study explores how alcohol use affects the metabolism of a drug used to treat HIV, suggesting alcohol may reduce drug effectiveness in liver cells.

Contribution

The study provides new evidence linking alcohol use to altered pharmacokinetics of tenofovir alafenamide via CES1 inhibition in hepatocytes.

Findings

Higher alcohol use correlated with lower plasma TFV clearance and PBMC TFV-DP clearance, though not statistically significant.

Alcohol may inhibit CES1-mediated TAF hydrolysis in hepatocytes, potentially shifting drug metabolism to PBMCs.

Observed changes in drug clearance suggest alcohol could impact treatment efficacy for HIV patients.

Abstract

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.

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.

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.

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.

All Authors: No reported disclosures

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