Longitudinal profile of plasma pregenomic RNA in patients with chronic hepatitis B infection on long-term nucleoside analogues and its interaction with clinical parameters

Mak, Lung-Yi; Anderson, Mark; Stec, Michael; Chung, Matthew Shing-Hin; Wong, Danny Ka-Ho; Hui, Rex Wan-Hin; Seto, Wai-Kay; Cloherty, Gavin; Yuen, Man-Fung

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Original Article

Longitudinal profile of plasma pregenomic RNA in patients with chronic hepatitis B infection on long-term nucleoside analogues and its interaction with clinical parameters

Lung-Yi Mak^1,2, Mark Anderson³, Michael Stec³, Matthew Shing-Hin Chung¹, Danny Ka-Ho Wong^1,2, Rex Wan-Hin Hui¹, Wai-Kay Seto^1,2, Gavin Cloherty³, Man-Fung Yuen^1,2

¹Department of Medicine, Queen Mary Hospital, The University of Hong Kong
²State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
³Abbott Laboratories, Abbott Diagnostics Division, Abbott Park, IL, USA

Correspondence :

Man-Fung Yuen ,
Tel: +852 28162863, Fax: +852 22553984, Email: mfyuen@hkucc.hku.hk

Received: August 27, 2024 Revised: December 6, 2024 Accepted: December 21, 2024

ABSTRACT

Background
Plasma pregenomic hepatitis B virus RNA (pgRNA) is a novel biomarker in chronic hepatitis B infection (CHB). We aimed to describe the longitudinal profile of pgRNA and factors influencing its levels in CHB patients on nucleoside analogue (NUC).
Methods
Serial plasma samples from 1354 CHB patients started on first-line NUC were evaluated. Time of NUC initiation was taken as baseline (year 0), followed by 1-year, 3-year and 5-year of NUC therapy. pgRNA was measured by Research Use Only RealTime HBV RNA v2.0 (0.2 mL) (Abbott Diagnostics) with lower limit of detection of 0.8 log U/mL (~20 copies/mL).
Results
Among 1354 subjects (median age at baseline 49.8 (interquartile range [IQR] 40.2-57.3) years, 65.2% male, 16.1% HBeAg-positive, 28.6% cirrhotic), baseline median HBV RNA was 3.68 (IQR 2.42-5.19) log U/mL. Upon NUC therapy, median pgRNA levels were 2.45 (IQR 1.82-3.62), 2.23 (IQR 1.67-3.05) and 2.14 (IQR 1.48-2.86) log U/mL at 1, 3 and 5 years respectively, with the corresponding log U/mL reductions of 0.82, 1.20 and 1.54. Undetectable/ unquantifiable pgRNA was achieved in 13.5%, 15.9% and 20.1% of patients at 1, 3 and 5 years respectively. Older age, male sex, HBeAg-negativity and high PAGE-B score were associated with lower pgRNA.
Conclusion
Plasma pgRNA declines are modest under NUC therapy, with only 16.3% achieving RNA undetectability after 5 years of first-line NUC indicating cccDNA silencing has not been achieved in the majority of patients. Clinical characteristics should be taken into consideration when interpreting the plasma pgRNA level.

KeyWords: HBV biomarkers, cirrhosis, aging, nucleoside analogue