Clinical significance of serum HBV RNA measurement in chronic hepatitis B patients

In the era of antiviral therapy with potent nucleos(t)ide analogues (NAs), serum HBV DNA is reduced to a level below the lower limit of detection in most chronic hepatitis B (CHB) patients, but the loss of serum HBV DNA only indicates that reverse transcription of virus is effectively inhibited and cannot truly reflect the transcriptional activity of covalently closed circular DNA (cccDNA) in hepatocytes. In addition, some patients, although with almost depleted or residual, silent cccDNA in liver tissue, were still positive for serum HBsAg after long-term treatment due to the integration of HBV DNA fragments. How to truly evaluate the presence and transcriptional activity of cccDNA in hepatocytes is still a problem that needs to be solved urgently. Serum HBV RNA comes from cccDNA transcript in liver tissue and is released into blood circulation as virus-like HBV RNA particles, since it is not effectively transformed to rcDNA. Therefore, in patients receiving the treatment with NAs, serum HBV RNA can qualitatively reflect the transcriptional activity of cccDNA in liver tissue. At present, most scholars think it is hard to achieve "complete cure" of CHB with current therapies. Therefore, we put forward a ladder-like improvement pattern from "partial cure" to "para-functional cure" and "clinical cure" (or "functional cure"). "Partial cure" based on the elimination or silence of cccDNA and persistently negative HBV RNA should be used to predict the risk of recurrence or virological rebound after drug withdrawal, and a low serum level of HBsAg combined with these two criteria should be used as the criteria for "quasi-clinical cure". The clinical significance of serum HBV RNA measurement needs to be addressed in multi-cohort clinical trails and/or improved in the real world studies