Circulating HBV RNA: From biology to clinical applications

Chronic HBV infection can hardly be cured due to the persistence of an intrahepatic pool of viral covalently closed circular DNA (cccDNA) transcription template, which is refractory to current antivirals. The direct analyses of cccDNA quantity and transcriptional activity require an invasive biopsy. Recently, circulating HBV RNA has been identified as a promising noninvasive surrogate marker of cccDNA and can be used for monitoring disease progression and predicting prognosis of patients with chronic HBV infection. To better understand this surrogate biomarker of cccDNA, we reviewed the current knowledge about the molecular characteristics and potential clinical applications of circulating HBV RNA. Specifically, we summarized the reported species and existing forms of circulating HBV RNA and discussed their biogenesis and the capacity of de novo infection by RNA virions. Moreover, we described the potential applications of circulating HBV RNA in different clinical scenarios, such as classifying the phases of chronic HBV infection, analyzing sustained on-treatment and off-treatment outcomes of treated patients, as well as predicting HCC development. Perspectives on future research of circulating HBV RNA were also proposed in this review.