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

by Kwang Su Kim, Masashi Iwamoto, Kosaku Kitagawa, Hyeongki Park, Sanae Hayashi, Senko Tsukuda, Takeshi Matsui, Masanori Atsukawa, Kentaro Matsuura, Natthaya Chuaypen, Pisit Tangkijvanich, Lena Allweiss, Takara Nishiyama, Naotoshi Nakamura, Yasuhisa Fujita, Eiryo Kawakami, Shinji Nakaoka, Masamichi Muramatsu, Kazuyuki Aihara, Takaji Wakita, Alan S. Perelson, Maura Dandri, Koichi Watashi, Shingo Iwami, Yasuhito Tanaka

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.