Background &amp; AimsBulevirtide is a first-in-class entry inhibitor antiviral treatment for chronic hepatitis D. The viral kinetics during bulevirtide therapy and the effect of combining bulevirtide with Peg-IFN are unknown.MethodsWe used mathematical modeling to analyze the viral kinetics in two French observational cohorts of 183 patients receiving bulevirtide with or without Peg-IFN for 48 weeks.ResultsThe efficacy of bulevirtide in blocking cell infection was estimated to 90.3%, while Peg-IFN blocked viral production with an efficacy of 92.4%, albeit with large inter-individual variabilities. The addition of Peg-IFN to bulevirtide was associated with a more rapid virological decline, with a rate of virological response (&gt;2 log of decline or undetectability) at week 48 of 86.9% (95% PI = [79.7;95.0]), compared to 56.1% (95% PI = [46.4;66.7]) with bulevirtide only. The model was also used to predict the probability to achieve a cure of viral infection, with a rate of 8.8% (95% PI = [3.5;13.2]) with bulevirtide compared to 18.8% (95% PI = [11.6;29.0]) with bulevirtide+Peg-IFN. Mathematical modeling suggests that after 144 weks of treatment, the rates of viral cure could be 42.1% (95% PI= [33.3;52.6]) with bulevirtide and 66.7% (95% PI= [56.5;76.8]) with bulevirtide+Peg-IFN.ConclusionsIn this analysis of real-world data, Peg-IFN strongly enhanced the kinetics of viral decline in patients treated with bulevirtide. Randomized clinical trials are warranted to assess the virological and clinical benefit of this combination, and to identify predictors of poor response to treatment.Impact and ImplicationBulevirtide has been approved for Chronic HDV infection by regulatory agencies in Europe based on its good safety profile and rapid virological response after treatment initiation, but the optimal duration of treatment and the chance to achieve a sustained virological response remain unknown. The results presented in this study have a high impact for clinicians and investigators as they provide important knowledge on the long-term virological benefits of a combination of peg-IFN and bulevirtide in CHD patients. Clinical trials are now warranted to confirm those predictions.Read less <