Development of a ribavirin dosing regimen in transplant recipients with chronic hepatitis E virus infection: a population pharmacokinetic and -dynamic model

Objectives The optimal ribavirin dosing regimen for the treatment of chronic hepatitis E virus (HEV) infection in solid organ transplant (SOT) is unknown. We modelled ribavirin plasma concentrations versus virologic response and haemoglobin concentrations. Patients and methods Data were collected in a retrospective, multicentre study of adult SOT recipients with chronic HEV infection treated with ribavirin between September 2009 and November 2019. Population pharmacokinetic and pharmacodynamic analyses were conducted using nonlinear mixed-effects modelling. Simulations were performed to select the most suitable RBV dosing regimen considering efficacy and safety. Results In total, 107 chronically HEV-infected SOT recipients with 305 ribavirin plasma levels, 592 viral load and 443 haemoglobin concentrations were included. Sustained virologic response was achieved in 68.2% of the subjects. Owing to a low IC₅₀, the decline in viral load was independent of ribavirin concentration and dose, whereas haemoglobin decreased with increasing ribavirin concentration and dose. A model-supported ribavirin dose for 180 days of 600 mg/day and kidney function (eGFR) ≥ 60 mL/min/1.73 m², 400 mg/day and eGFR 30-59 mL/min/1.73 m² and 200 mg/day and eGFR ≤30 mL/min/1.73 m² showed good efficacy and low toxicity. Conclusions This study constitutes a valuable first step in determining the optimal ribavirin treatment regimen for chronic HEV infections in SOT recipients. Our model suggests a lower dose of ribavirin and longer treatment duration compared to the suggested dosing regimen in the EASL Clinical Practice Guidelines on HEV infection. Implementing our dosing regimen in clinical practice will allow for lower toxicity rates, improved tolerability and equal efficacy in chronically HEV-infected SOT recipients.