Natural history of serum HBV-RNA in chronic HBV infection

Virus-like particles encapsulating HBV-RNA represent a serum biomarker for assessing viral replication activity in clinical practice. However, baseline levels of serum HBV-RNA and their associations with viral replicative intermediates and liver disease in phases of chronic hepatitis B remain unknown. In this cross-sectional study, 102 patients were categorized into immune-tolerant (IT), HBeAg-positive immune active (HBeAg+IA), inactive carrier (IC) and HBeAg-negative immune active (HBeAg-IA) phases. HBV-RNA in serum samples and in 66 paired liver biopsies were quantified and correlated with serum ALT levels, histopathological scores and the levels of other viral replicative intermediates. Mean levels of serum HBV-RNA differed among phases, with the highest levels among IT (6.78 ± 0.83 log₁₀ copies mL^-1 ) patients, followed by HBeAg+IA (5.73 ± 1.16 log₁₀ copies mL^-1 ), HBeAg-IA (4.52 ± 1.25 log₁₀ copies mL^-1 ) and IC (2.96 ± 0.40 log₁₀ copies mL^-1 ) patients. Serum HBV-RNA levels correlated with HBV DNA in all phases, although correlations with other viral replicative intermediates weakened or disappeared when cases were stratified into phases. Distinct compositions of viral products were found among phases: the ratio of HBsAg to serum HBV-RNA was highest in IC patients, while the ratio of serum HBV-RNA to intrahepatic HBV-RNA and the ratio of intrahepatic HBV-DNA to intrahepatic HBV-RNA were significantly higher in IT patients. In conclusion, baseline levels of HBV-RNA and the composition of viral replicative intermediates differ significantly across the natural course of chronic HBV infection. These findings shed light on the nature of viral replication and pathogenesis of disease among different phases of chronic HBV infection.