Abstract Chronic hepatitis B contributes significantly to global morbidity and mortality, especially in low- and middle-income countries. Hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B virus DNA (HBV DNA), and anti-hepatitis B core antibody (anti-HBc) are conventional biomarkers used for diagnosis and disease monitoring. However, their utility is often limited in certain clinical contexts. This limitation is particularly evident in patients with pre-core (PC) or basal core promoter (BCP) HBV genome mutations, and those on long-term nucleos(t)ide analogue (NA) therapy. Assessing viral transcriptional activity, principally driven by covalently closed circular DNA (cccDNA), is critical to disease management but is not adequately addressed by conventional biomarkers. Hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) are promising non-invasive surrogate markers that may overcome these limitations. Many investigations have shown that HBcrAg associates with intrahepatic viral activity and cccDNA transcription, even in patients with undetectable HBV DNA following antiviral therapy. Furthermore, serum HBV RNA, mainly derived from pregenomic RNA, provides insight into active replication and virological relapse after treatment cessation. Recent evidence also suggests that the concurrent use of HBcrAg and HBV RNA may improve clinical decision-making, particularly in predicting safe discontinuation of NA therapy and assessing viral reactivation risk. This narrative review summarizes evidence on the diagnostic and prognostic value of HBcrAg and HBV RNA in chronic HBV management. We also explore their clinical applications, implementation challenges, and the future research needed to enable their integration into routine clinical practice and to contribute to global hepatitis B elimination initiatives.
Mardian et al. (Fri,) studied this question.