Utility of a High-Sensitivity HBV RNA Assay for Monitoring HBV Carriers Receiving Nucleos(t)ide Analogue Therapy

Chronic hepatitis B virus (HBV) infection is a dynamic condition with distinct phases, and accurate monitoring is essential for optimal disease management. Although conventional HBV biomarkers in serum such as HBV DNA, HBsAg, and HBcrAg are widely used, these markers have limitations in fully capturing viral activity, especially during nucleos(t)ide analogue (NA) therapy. Recently, HBV RNA has emerged as a novel biomarker reflecting the transcriptional activity of covalently closed circular DNA (cccDNA), yet its clinical relevance remains underexplored.

This study analyzed 168 serum samples collected from 124 patients with chronic HBV infection who were undergoing nucleos(t)ide analogue (NA) therapy. Serum HBV RNA levels were quantified using the high-sensitivity cobas® HBV RNA assay. The relationship between HBV RNA and other viral markers (HBV DNA, HBsAg, and HBcrAg) was evaluated. In addition, we assessed the potential of HBV RNA as a criterion for NA discontinuation by applying the Japan Society of Hepatology (JSH) scoring system for NA cessation.

A strong correlation was found between HBV RNA and HBcrAg (r = 0.84), suggesting that HBV RNA may reflect intrahepatic cccDNA activity. HBV RNA levels declined earlier than HBsAg and HBcrAg during NA treatment. Notably, HBcrAg remained ≥ 3.0 log U/mL in many patients even when HBV RNA was undetectable. In the scoring analysis, all patients with HBV RNA levels ≥ 1.0 log copies/mL were assigned to higher-risk groups for virological relapse, indicating the need to continue NA therapy in these individuals. Importantly, undetectable HBV RNA alone did not consistently correlate with a low risk of relapse.

HBV RNA is a promising marker for detecting early suppression of viral replication during NA therapy. However, HBV RNA undetectability alone may not be sufficient to guide NA discontinuation.