Effect of Peg-IFN on the viral kinetics of patients with HDV infection treated with bulevirtide

Abstract

Background & aims: Bulevirtide 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 pegylated-interferon (Peg-IFN) are unknown.

Methods: We used mathematical modelling to analyze the viral kinetics in two French observational cohorts of 183 patients receiving bulevirtide with or without Peg-IFN for 48 weeks.

Results: The efficacy of bulevirtide in blocking cell infection was estimated to 90.3%, whereas 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 (>2 log of decline or undetectability) at week 48 of 86.9% (95% prediction interval [PI] = [79.7-95.0]), compared with 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 with 18.8% (95% PI = [11.6-29.0]) with bulevirtide + Peg-IFN. Mathematical modelling suggests that after 144 weeks 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.

Conclusions: In 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 implications: Bulevirtide 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 patients with CHD. Clinical trials are now warranted to confirm those predictions.

Keywords: Antiviral treatment; Bulevirtide; Hepatitis delta virus; Peg-IFN; Viral kinetics.

Graphical abstract

Fig. 1

Flowchart of the viral kinetics study. BLV, bulevirtide; Peg-IFN, pegylated interferon.

Fig. 2

Patient treatments and observations. (A) Number of patients treated with BLV alone (black), BLV + Peg-IFN (red), Peg-IFN alone (orange) and off-treatment (blue). (B) Corresponding proportion of observations. Black bars correspond to detectable HDV RNA, gray bars represent undetectable HDV RNA, white bars represent the proportion of unavailable data at each time. BLV, bulevirtide; Peg-IFN, pegylated interferon.

Fig. 3

Viral and biochemical kinetics observed during 48 weeks of treatment with BLV alone (BLV) or in combination with Peg-IFN (BLV + Peg-IFN). ALT, alanine transaminase; BLV, bulevirtide; Peg-IFN, pegylated interferon.

Fig. 4

Long-term viral and biochemical kinetics predicted by the mathematical model in patients receiving BLV (black), BLV + Peg-IFN for 144 weeks (red), and BLV + Peg-IFN for 48 weeks, followed by BLV alone afterwards (yellow). The plain line and its shaded area represent the median prediction of 500 simulated data sets and its 95% prediction interval. ALT, alanine transaminase; BLV, bulevirtide; Peg-IFN, pegylated interferon.

Fig. 5

Viral and biochemical response rate predicted by the mathematical model in patients receiving BLV (black), BLV + Peg-IFN (red), and BLV + Peg-IFN for 48 weeks, followed by BLV alone (yellow), without taking into account treatment discontinuation (per-protocol analysis) (A) and when taken account treatment discontinuation (intention-to-treat analysis) (B). The diamond and its associated line represent the median prediction of 500 simulated data sets and its 95% prediction interval. ALT, alanine transaminase; BLV, bulevirtide; Peg-IFN, pegylated interferon.