Mechanistic modeling of the long-term dynamics of viral markers to predict the outcome of combination therapy in chronic HBV and HDV infections

Selma El Messaoudi [1] , Annabelle Lemenuel-Diot [2], Jérémie Guedj [1]

[1] IAME, Université Paris Cité, Inserm, F-75018 Paris, France; [2] Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel

Background. Nearly 300 million people worldwide are chronically infected with Hepatitis B virus (HBV). One important specificity of HBV is that virus can persist lifelong through different mechanisms, including i) integration of the virus into the host’s genome, ii) production of an envelope antigen (HBeAg) responsible for immune tolerance and iii) production of a large amount of subviral particles bearing the surface antigen (HBsAg) that act as a decoy for the immune response¹. In addition, about 2% of HBV infected individuals are coinfected with HDV, a “parasite virus” that requires HBsAg to replicate. HBV/HDV coinfection is responsible for the most severe form of viral hepatitis².

Two types of treatments are currently available against HBV, namely nucleoside analogs (NUC, such as lamivudine) and pegylated-interferon (Peg-IFN). These treatments are rarely curative as they do not act on the persistence of the virus, and need therefore to be taken lifelong to avoid relapse. Nonetheless, the combination of NUC or Peg-IFN with several new anti-HBV molecules are assessed in clinical development to increase the chance to achieve cure³. In the case of HDV, Peg-IFN is recommended but not approved, and showed overall a limited antiviral efficacy and a poor tolerance. In that context, bulevirtide⁴, an entry inhibitor, has shown promising antiviral effect against HDV RNA in clinical trials. On the basis of these results, it has been administered for compassionate use and has recently received a market authorization in Europe.  However, its effect on the long run to achieve cure is unknown and the benefit of the combination with peg-IFN remains controversial⁵.

While mathematical models have been previously proposed in the context of HBV and/or HDV infections, they essentially focused on short-term treatment. Here we aimed to use these models to characterize the benefit of combination therapy in the long run. For that purpose, we relied on two unique set of data where HBV or HBV/HDV infected patients received monotherapy or combination treatment for one year, and where several virological markers were measured longitudinally, allowing us to provide a detailed picture of effect of antiviral treatment.

Objectives.

In this work, we characterized the impact of antiviral treatments in chronic HBV infection and its coinfection with HDV on viral replication in two distinct projects:   

1. First, we aimed to develop a mechanistic model of HBV infection integrating specific markers of viral replication (HBsAg, HBeAg) to characterize the antiviral response to lamivudine and Peg-IFN.
2. Second, we investigated the antiviral efficacy of bulevirtide alone and in combination with Peg-IFN and evaluated the benefit of different treatment strategies to achieve viral clearance.

Methods.

1. We used data from two multi-arms clinical trials including more than 1300 patients^6,7. Patients were treated either with Peg-IFN, lamivudine or the combination for 48 weeks, and the levels of HBV DNA, HBsAg and for positive patients, HBeAg were sampled. Viral markers during monotherapies only were included in the viral dynamic analysis. With this very rich information, we were able to develop a biological model integrating features of HBV replication and interaction with the host. Our framework included two populations of infected cells producing all viral markers at different production rates: I₁ cells were transcriptionally very active and could evolve to a latent state I₂, that were characterized with the presence of integrated DNA. After inclusion of the most significant drug effects⁸, we used parameters estimated on monotherapies to simulate virological outcomes with the combination.
2. We relied on data from the largest real-world dataset to date with a total of 183 patients, included in two combined real-world studies, namely the French Early Access Program and ANRS HD EP01 BuleDelta study. In both cohorts, patients could receive either bulevirtide 2 mg alone or in combination with Peg-IFN for 48 weeks and the levels of HDV RNA and ALT were sampled. Here, given the nature of the data (i.e. compassionate use of bulevirtide, and real-world setting), and to avoid identifiability issues, a classic viral dynamic model was used to characterize the dynamics of HDV RNA and ALT levels during treatment, accounting for treatment discontinuation. Finally, the model was used to simulate the virological response (defined as decline >2logs or undetectable HDV RNA) and cure (viral elimination⁹) with bulevirtide ± Peg-IFN administered for 1 to 3 years.

Results.

1. The effect on blocking viral production was higher in lamivudine (epsilon>99%) in comparison to Peg-IFN (epsilon<95%) in both HBeAg-status. However, Peg-IFN induced an enhancement of all the loss rates of infected cells, especially in HBeAg-positive patients. Using the model, we were able to predict an effect of the combination of 99.99% and we could reproduce the rates of undetectable HBV DNA after one year of combination therapy (95%PI = [67;78], observed=75% and 95%PI = [90;96], observed=95% in HBeAg-positive and HBeAg-negative, respectively). The model could also reproduce the virological decline of HBsAg and HBeAg in combination therapy.
2. We estimated that Bulevirtide had an efficacy on blocking cell infection of 90.3%, while Peg-IFN blocked viral production with an efficacy estimated to 92.4%, albeit with large inter-individual variabilities. We predicted that the synergism between bulevirtide and Peg-IFN was associated with a more rapid viral decline (~90% of virological response) in comparison to bulevirtide monotherapy (~60%). The model was also used to predict the probability to achieve a cure of viral infection, with a rate of 8% and 19% and these rates could reach 42% and 67% after 3 years with monotherapy and combination, respectively. However, a high rate of dropouts was estimated in patients treated with Peg-IFN, inducing a plateau in the rates of virological response after 2 years of treatment with combination.

Conclusion. We first developed a new tool to predict the benefit of combination therapy in HBV. By characterizing the long-term response of available treatments, and accounting for the dynamics of viral markers targeted by new molecules, our approach proposed a framework of analysis that can be used to evaluate more precisely the efficacy of new anti-HBV drugs on viral replication. Then, in a context of an orphan disease associated with poor prognosis and where limited data are available, our analysis demonstrated for the first time that Peg-IFN strongly enhances the kinetics of viral decline in patients treated with bulevirtide, and could improve the chance to achieve cure. Overall, this work contributes to the characterization of combination therapies with anti-HBV and anti-HDV agents and provides useful tools for the development of new antiviral agents.

References

1. Allweiss L, Dandri M. The Role of cccDNA in HBV Maintenance. Viruses. 2017;9(6):E156. doi:10.3390/v9060156
2. Caviglia GP, Ciancio A, Rizzetto M. A Review of HDV Infection. Viruses. 2022;14(8):1749. doi:10.3390/v14081749
3. Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: From discovery to regulatory approval. Hepatology. 2017;66(4):1296-1313. doi:10.1002/hep.29323
4. Degasperi E, Anolli MP, Lampertico P. Bulevirtide-based treatment strategies for chronic hepatitis delta: A review. J Viral Hepat. 2023;30 Suppl 1:26-32. doi:10.1111/jvh.13811
5. Jachs M, Schwarz C, Panzer M, et al. Response-guided long-term treatment of chronic hepatitis D patients with bulevirtide-results of a “real world” study. Aliment Pharmacol Ther. 2022;56(1):144-154. doi:10.1111/apt.16945
6. Marcellin P, Lau GKK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351(12):1206-1217. doi:10.1056/NEJMoa040431
7. Lau GKK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352(26):2682-2695. doi:10.1056/NEJMoa043470
8. Desmée S, Mentré F, Veyrat-Follet C, Guedj J. Nonlinear Mixed-effect Models for Prostate-specific Antigen Kinetics and Link with Survival in the Context of Metastatic Prostate Cancer: A Comparison by Simulation of Two-stage and Joint Approaches. AAPS J. 2015;17(3):691-699. doi:10.1208/s12248-015-9745-5
9. Dixit NM, Layden-Almer JE, Layden TJ, Perelson AS. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature. 2004;432(7019):922-924. doi:10.1038/nature03153

Reference: PAGE 32 (2024) Abstr 11105 [www.page-meeting.org/?abstract=11105]

Oral: Lewis Sheiner Student Session