Prediction of cccDNA dynamics in hepatitis B patients by a combination of serum surrogate markers

Quantification of intrahepatic covalently closed circular DNA (cccDNA) is a key for evaluating an elimination of hepatitis B virus (HBV) in infected patients. However, quantifying cccDNA requires invasive methods such as a liver biopsy, which makes it impractical to access the dynamics of cccDNA in patients. Although HBV RNA and HBV core-related antigens (HBcrAg) have been proposed as surrogate markers for evaluating cccDNA activity, they do not necessarily estimate the amount of cccDNA. Here, we employed a recently developed multiscale mathematical model describing intra- and intercellular viral propagation and applied it in HBV-infected patients under treatment. We developed a model that can predict intracellular HBV dynamics by use of extracellular viral markers, including HBsAg, HBV DNA, and HBcrAg in peripheral blood. Importantly, the model prediction of the amount of cccDNA in patients over time was confirmed to be well correlated with the data for quantified cccDNA by paired liver biopsy. Thus, our method combining classic and emerging surrogate markers enables us to predict the decay dynamics of cccDNA in patients undergoing treatment.Author summary: Chronic hepatitis B (CHB) poses a major global health issue due to the persistence of covalently closed circular DNA (cccDNA) in the liver, which acts as a template for ongoing viral replication. Current therapies, such as PEG IFN-α, could reduce cccDNA levels but rarely achieve complete elimination. In this study, we developed and applied a multiscale mathematical model that combines data from in vitro, in vivo, and clinical studies to predict the dynamics of cccDNA in CHB patients during treatment. Our model uses extracellular viral markers—HBV DNA, HBsAg, and HBcrAg—to estimate cccDNA levels, potentially reducing the reliance on invasive liver biopsies. We demonstrated that our model may predict cccDNA turnover under treatment and can suggest options such as prolonging the duration of treatment to patients who get a large reduction in cccDNA to achieve a complete cure. This approach provides a new tool for personalizing CHB treatment strategies, aiming to achieve a complete cure by targeting and monitoring cccDNA dynamics more effectively.