Modeling hepatitis D virus kinetics during bulevirtide monotherapy: challenges and solutions.

The entry inhibitor Bulevirtide (BLV) was recently approved in Europe for treatment of chronic hepatitis D virus (HDV) infection, which is considered the most severe viral hepatitis infection. Theory indicates that models that account for free virus and infected cells, but do not include target cell dynamics (historically called the two-equation model) are limited to predicting a monophasic viral decline for antiviral agents that act only to block viral entry/infection. We investigated herein a recently published two-equation type model against clinical data obtained from patients with HDV treated with BLV monotherapy for up to 96 weeks using non-linear mixed effects modelling (NLME). We found that (i) although the model parameters had a relative standard error (RSE) < 50% suggesting that they were 'precisely estimated', the fits failed to reproduce the non-monophasic HDV kinetic patterns observed in most patients leading to incorrect predictions of the duration of treatment needed to reach a theoretical cure boundary, defined as less than 1 virion in the entire patient extracellular body fluid. (ii) The model cannot explain viral breakthrough, and (iii) the model wrongly predicts that viral load will remain at the same level once treatment is stopped. Lastly, we showed that including target cell dynamics in the model can explain not only monophasic viral decline during treatment but also non-monophasic HDV decline patterns such as biphasic, flat-partial response and viral breakthrough. Including target cell dynamics also predicts a viral rebound once BLV is stopped as observed in clinical studies.