A Semi‐mechanistic Model to Characterize the Long‐Term Dynamics of Hepatitis B Virus Markers During Treatment With Lamivudine and Pegylated Interferon

Abstract

Antiviral treatments against hepatitis B virus (HBV) suppress viral replication but do not eradicate the virus, and need therefore to be taken lifelong to avoid relapse. Mathematical models can be useful to support the development of curative anti-HBV agents; however, they mostly focus on short-term HBV DNA data and neglect the complex hostpathogen interaction. This work aimed to characterize the effect of treatment with lamivudine and/or pegylated interferon (Peg-IFN) in 1,300 patients (hepatitis B envelope antigen (HBeAg)-positive and HBeAg-negative) treated for 1 year. A mathematical model was developed incorporating two populations of infected cells, namely I 1 , with a high transcriptional activity, that progressively evolve into I 2 , at a rate tr , representing cells with integrated HBV DNA that have a lower transcriptional activity. Parameters of the model were estimated in patients treated with lamivudine or Peg-IFN alone (N = 894), and the model was then validated in patients treated with lamivudine plus Peg-IFN (N = 436) to predict the virological response after a year of combination treatment. Lamivudine had a larger effect in blocking viral production than Peg-IFN (99.4-99.9% vs. 91.8-95.1%); however, Peg-IFN had a significant immunomodulatory effect, leading to an enhancement of the loss rates of I 1 (×1.7 in HBeAg-positive patients), I 2 (> ×7 irrespective of HBeAg status), and tr (×4.6 and ×2.0 in HBeAg-positive and HBeAg-negative patients, respectively). Using this model, we were able to describe the synergy of the different effects occurring during treatment with combination and predicted an effect of 99.99% on blocking viral production. This framework can therefore support the optimization of combination therapy with new anti-HBV agents.Chronic hepatitis B virus (CHB) infection is a leading cause of liver disease, including cirrhosis and hepatocellular carcinoma. In 2021, nearly 300 million people were chronically infected worldwide, resulting in more than 800,000 deaths. 1 To reduce disease progression, antiviral treatments rely on two therapeutic classes, nucleoside analogs (NUCs) and pegylated interferons (Peg-IFNs), which are

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

“…Second, we could not identify an effect of Peg-IFN on the clearance of infected cells, as found in some HBV studies. 27 Whether this is a genuine effect or simply reflects a lack of power to identify it, will need to be studied. Consequently, the dynamics of ALT was predicted to be similar between the two treatment groups as a reflection of our data ( Figs.…”

“…Mathematical models have been largely used to decipher and predict the outcome of treatments against hepatitis B, C, or D. [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] In the case of HCV, these tools provided important insights regarding treatment duration and the time needed to cure viral infection, i.e. achieve a sustained virological response.…”

A multiscale model of the action of a capsid assembly modulator for the treatment of chronic hepatitis B

“…Our model adapts the multiscale model of CHB developed by Goncalves et al [36] to study the CAM RG7907 to include both the dynamics of ALT and uninfected hepatocytes. While multiscale models have been used in modeling chronic hepatitis C infection [22][23][24] and are beginning to be developed for CHB [36,[58][59][60], many previous modeling studies of CHB have not included the intracellular viral life cycle [29,30,43,[61][62][63]. Multiscale models, such as the model presented in this work or developed elsewhere [36,59], offer unique insight into the intracellular and extracellular dynamics of HBV via the ability to explicitly model distinct mechanisms of action for novel small-molecule antiviral therapies.…”