What drives the dynamics of HBV RNA during treatment?

Hepatitis B virus RNA (HBV RNA)-containing particles are encapsidated pre-genomic RNA (pgRNA) detectable in chronically infected patients in addition to virions (HBV DNA) that have been suggested as a marker of the treatment efficacy. This makes promising the use of core protein allosteric modulators, such as RG7907, which disrupt the nucleocapsid assembly and profoundly reduce HBV RNA. Here, we developed a multiscale model of HBV extending the standard viral dynamic models to analyse the kinetics of HBV DNA and HBV RNA in 35 patients treated with RG7907 for 28 days. We compare the predictions with those obtained in patients treated with the nucleotide analog tenofovir. RG7907 blocked 99.3% of pgRNA encapsidation (range: 92.1%-99.9%) which led to a decline of both HBV DNA and HBV RNA. As a consequence of its mode of action, the first phase of decline of HBV RNA was rapid, uncovering the clearance of viral particles with half-life of 45 min. In contrast, HBV DNA decline was predicted to be less rapid, due to the continuous secretion of already formed viral capsids (t_1/2  = 17 ± 6 h). After few days, both markers declined at the same rate, which was attributed to the loss of infected cells (t_1/2  ≅ 6 ± 0.8 days). By blocking efficiently RNA reverse transcription but not its encapsidation, nucleotide analog in contrast was predicted to lead to a transient accumulation of HBV RNA both intracellularly and extracellularly. The model brings a conceptual framework for understanding the differences between HBV DNA and HBV RNA dynamics. Integration of HBV RNA in viral dynamic models may be helpful to better quantify the treatment effect, especially in viral-suppressed patients where HBV DNA is no longer detectable.