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. 2025 Apr;60(4):469-478.
doi: 10.1007/s00535-025-02211-5. Epub 2025 Jan 22.

Usefulness of serum HBV RNA levels for predicting antiviral response to entecavir treatment in patients with chronic hepatitis B

Masanari Kosaka  1 , Hatsue Fujino  2 , Masataka Tsuge  3 , Kenji Yamaoka  1 , Yasutoshi Fujii  1 , Shinsuke Uchikawa  1 , Atsushi Ono  1 , Eisuke Murakami  1 , Tomokazu Kawaoka  1 , Daiki Miki  1 , Clair Nelson Hayes  1 , Seiya Kashiyama  4 , Sho Mokuda  5 , Shinichi Yamazaki  6 , Shiro Oka  1
Affiliations

Usefulness of serum HBV RNA levels for predicting antiviral response to entecavir treatment in patients with chronic hepatitis B

Masanari Kosaka et al. J Gastroenterol. 2025 Apr.

Abstract

Background: Hepatitis B virus (HBV) RNA is an important serum biomarker of hepatic covalently closed circular DNA (cccDNA) transcriptional activity; however, its clinical characteristics remain unclear. This study evaluated the clinical utility of HBV RNA levels in patients with chronic hepatitis B (CHB).

Methods: We studied 87 CHB patients with serum HBV DNA levels ≥ 5.0 log IU/mL who initiated entecavir (ETV) treatment between 2000 and 2018. Serum HBV RNA levels were measured at three-time points: before ETV treatment, at 12 weeks, and at 48 weeks after starting ETV treatment. Clinical markers associated with the antiviral effects of ETV treatment were analyzed.

Results: Serum HBV RNA levels decreased in both HBeAg-positive and -negative patients during the observation period. In HBeAg-positive patients, multivariable analysis showed that lower HBV RNA levels at 48 weeks of ETV treatment were independently associated with HBeAg seroconversion. Additionally, lower baseline HBV RNA levels significantly predicted virologic response in those patients. In contrast, among HBeAg-negative patients, lower HBV core-related antigen (HBcrAg) levels and the FIB-4 index were independently associated with virologic response. In HBeAg-positive patients, those with higher baseline HBV RNA levels showed a more significant reduction in hepatitis B surface antigen levels.

Conclusion: Serum HBV RNA levels predicted HBeAg seroconversion and early HBV DNA reduction in HBeAg-positive patients, while HBcrAg was significantly associated with virologic response in HBeAg-negative patients. These findings highlight the different predictive roles of HBV RNA and HBcrAg based on HBeAg status, which may provide individualized treatment strategies.

Keywords: Entecavir; HBV DNA; HBV RNA; HBeAg seroconversion; HBsAg.

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Conflict of interest statement

Declarations. Conflict of interest: All authors declare that they have no affiliations with or involvement in any organization with any financial or non-financial interests in the subject matter or materials discussed in this manuscript. Ethical approval and informed consent: All the participants provided written informed consent. This study was approved by the Ethics Committee of Hiroshima University, Hiroshima, Japan (Approved ID: E2016-0704). This study was conducted in accordance with the principles of the Declaration of Helsinki. All authors declare that they have no affiliations with or involvement in any organization with any financial or non-financial interests in the subject matter or materials discussed in this manuscript.

Figures

Fig. 1
Fig. 1
Correlation between hepatitis B virus (HBV) RNA levels and other HBV-related markers before entecavir (ETV) treatment. Correlations between HBV RNA levels, a hepatitis B surface antigen (HBsAg), b HBV DNA levels, and c hepatitis B core-related antigen (HBcrAg) levels in patients with chronic hepatitis B (CHB), indicated using scatter plots. The data points are distinguished based on hepatitis B e-antigen (HBeAg) status: circles represent HBeAg-positive patients, and triangles represent HBeAg-negative patients
Fig. 2
Fig. 2
Changes in hepatitis B virus (HBV) RNA levels during entecavir (ETV) treatment. Changes in HBV RNA levels in a hepatitis B e-antigen (HBeAg) -positive and b HBeAg-negative patients at baseline and 12 and 48 weeks following ETV treatment initiation.
Fig. 3
Fig. 3
Changes of log reduction in hepatitis B surface antigen (HBsAg) by hepatitis B virus (HBV)-RNA levels. a In hepatitis B e-antigen (HBeAg)-positive patients, HBsAg decreased significantly in patients with high baseline HBV-RNA levels from 1 to 5 years following treatment initiation. b In HBeAg-negative patients, HBsAg reduction remained insignificant at baseline HBV-RNA level up until 5 years
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