Natural history of serum HBV‐RNA in chronic HBV infection

Abstract

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 log copies mL ) patients, followed by HBeAg+IA (5.73 ± 1.16 log copies mL ), HBeAg-IA (4.52 ± 1.25 log copies mL ) and IC (2.96 ± 0.40 log copies mL ) 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.

Serum Hepatitis B Virus RNA: A New Potential Biomarker for Chronic Hepatitis B Virus Infection

“…Huang et al reported that serum HBV pgRNA weakly correlated with cccDNA in untreated CHB patients with a correlation coefficient of 0.363 ( P < 0.001), which is similar to the result of Gao et al ( r = 0.25, P < 0.01), who quantified serum polyadenylated HBV RNA by RACE–quantitative PCR . In a CHB natural history study, Wang et al found a moderate overall correlation between serum 3.5‐kb RNA and intrahepatic cccDNA ( r = 0.596, P < 0.001) among all of the recruited patients; however, when classifying the patients into immune‐tolerant, HBeAg‐positive immune active, inactive carrier, and HBeAg‐negative immune active phases, the correlation disappeared in all phases . For patients under NA treatment, Wang et al found no significant correlation between serum HBV RNA and cccDNA copy numbers .…”

“…(33) In a CHB natural history study, Wang et al found a moderate overall correlation between serum 3.5kb RNA and intrahepatic cccDNA (r = 0.596, P < 0.001) among all of the recruited patients; however, when classifying the patients into immune-tolerant, HBeAg-positive immune active, inactive carrier, and HBeAg-negative immune active phases, the correlation disappeared in all phases. (52) For patients under NA treatment, Wang et al found no significant correlation between serum HBV RNA and cccDNA copy numbers. (21) In addition, Gao et al reported that serum HBV polyA RNA had no correlation with intrahepatic cccDNA at 96 weeks after NA treatment.…”

“…(33) Despite there being no correlation between cccDNA and serum HBV pgRNA, the latter strongly correlates with intrahepatic HBV pgRNA, as well as with the ratio of intrahepatic HBV pgRNA to cccDNA, which reflects intrahepatic viral transcription activity. (21) In addition to the intrahepatic viral replicative markers, serum HBV pgRNA correlated with liver injury or histopathology, (21,52) which raises the question of whether the serum HBV RNA, or at least part of them, are released through hepatocyte destruction.…”

Serum Hepatitis B Virus RNA as a Potential Diagnostic Biomarker During Chronic Hepatitis B Virus Infection

“…Serum HBV RNA levels correlate to intrahepatic pgRNA, liver histopathology, and cccDNA, supporting a potential utility for serum pgRNA in indirectly monitoring cccDNA activity during NA treatment. However, the use of this marker during NA treatment in predicting clinical outcomes remains undemonstrated, although the following model of pgRNA utility during NA treatment could be extrapolated: a subject with undetectable HBV DNA but consistently elevated pgRNA presumably has active cccDNA transcription occurring (Fig.…”

Pregenomic RNA: How to assist the management of chronic hepatitis B?

“…In addition, other studies have also suggested that nucleocapsid maturation may not be dependent on DNA synthesis . Similar to the production of Dane virion, the nucleocapsid‐packaged pgRNA may also be enveloped and released from hepatocytes to produce pgRNA virion (Figure ), but its infectivity requires extensive experimental evidence.…”