Antonio Gonçalves (1), Annabelle Lemenuel-Diot (2), Lu Gao (3), Lue Dai (3), Ruben Alvarez (2), Joseph Grippo (4), Jérémie Guedj (1)
(1) IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité Paris, France (2) Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel (3) Roche Pharmaceutical Research and Early Development, Disease Therapeutic Area Infectious Diseases, Roche Innovation Center Shanghai (4) Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center New York
Objectives: Current antiviral treatment against Hepatitis B virus (HBV) rely on nucleoside analogues (such as entecavir, ETV) and are largely effective in reducing viral load levels and limiting disease progression. However these treatments do not eradicate virus and therefore they need to be taken lifelong to present virus resurgence. The main obstacle to cure is the fact that the virus is able to escape from the immune response, via the production of a large amount of subviral particles (SVPs) coated with HBs-antigen (HBsAg) that act as a decoy for the immune response [1]. In order to stimulate the immune response, a promising strategy is to use a toll-like receptor 7 (TLR7) agonist. Stimulation of TLR7 receptors indirectly induces the production of IFN-α and cytokines and stimulates antigen presentation [2]. Thereby, TLR7 agonists contribute to the organization of both innate and adaptive immune responses. Here we aimed to use a viral dynamic model to characterize for the first time the antiviral response during treatment with a TLR7 agonist used alone or in combination with ETV.
Methods: We used data collected by Hoffmann-La Roche in a mouse model [3]. A total of 118 animals were analyzed, treated with either a placebo (n=24), ETV (n=6), TLR7 agonist (n=76), or the combination of both (n=12) at various dosing regimen and for period of 6 to 9 weeks of treatment. HBV DNA (viremia), HBsAg (surface antigen) and anti-HBs (antibodies against HBsAg) were weekly measured across all studies. We developed a viral dynamic model that describes the interplay between virions, SVPs and antibodies. Indeed, infected cells produced virions and subviral particles in a large excess. We hypothesized that TLR7 agonist may induce the production of anti-HBs. However, a low amount of anti-HBs may be rapidly occupied by binding to virions and SVPs and forming immune complexes, and such immune complex-associated antibodies can be difficult to detect. The immune complexes may be eliminated and cause an extra decay of their kinetics, or may eventually reform viral particles. We estimated the percentage of reduction of the production on virions and SVPs and the stimulation of anti-HBs levels.
Results: A biological model of chronic hepatitis B, integrating the role of anti-HBsAg in virus elimination, could successfully reproduce all the observed data in both monotherapy and combination groups. With this model, we showed that ETV efficiently blocked HBV DNA production (ε=99.9999%) but had no effect on HBsAg or anti-HBs titers. In contrary, the TLR7 agonist has shown a triple mechanism of action, whereby production of both virions and SVPs were successfully blocked. Production of virions could be reduce 93.80 % for and 99.70% at the dose of 100 mg/kg weekly (QW) and every other day (QOD) respectively, whereas reduction of the production of SVPs could be reduced by 99.70% up to 99.97%. In addition, our model suggested that the treatment led to an increase in anti-HBs concentrations, thereby allowing for further reduction of viremia and HBsAg titers on the long run. Eventually, a model assuming a Loewe additivity of ETV and the TLR7 agonist in reducing virion production could well reproduce the data observed during combination therapy.
Conclusions: The model provides a novel framework to analyze the effect of immunomodulatory drugs that is consistent with destabilization of viral production and stimulation of antibody production, which may contribute as combination partner in the perspective of a cure. Future analyses including other drugs in combination with TLR7 agonist and clinical studies are needed to confirm the potential of this therapeutic class.
References:
[1] Zeisel MB, Lucifora J, Mason WS, Sureau C, Beck J, Levrero M, et al. Towards an HBV cure: state-of-the-art and unresolved questions—report of the ANRS workshop on HBV cure. Gut. 2015;64:1314–26.
[2] Liang TJ, Block TM, McMahon BJ, Ghany MG, Urban S, Guo J-T, et al. Present and future therapies of hepatitis B: From discovery to cure: VIRAL HEPATITIS. Hepatology. 2015;62:1893–908.
[3] Huang Y-H, Fang C-C, Tsuneyama K, Chou H-Y, Pan W-Y, Shih Y-M, et al. A murine model of hepatitis B-associated hepatocellular carcinoma generated by adeno-associated virus-mediated gene delivery. Int J Oncol. 2011;39:1511–9.
Reference: PAGE 27 (2018) Abstr 8629 [www.page-meeting.org/?abstract=8629]
Poster: Drug/Disease Modelling - Infection