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Background <p>Low-level viremia (LLV) during nucleos(t)ide analogue therapy for chronic hepatitis B (CHB) is clinically relevant, but its biological basis in children remains unclear. We investigated the clinical features of pediatric LLV and sought host factors linking incomplete virological suppression to stress adaptation and profibrotic signaling.</p> Methods <p>Children with CHB who initiated entecavir therapy between 2019 and 2024 were retrospectively enrolled. LLV and maintained virological response (MVR) were defined by serum HBV DNA at week 48. Longitudinal trajectories were analyzed using generalized estimating equation models. Public liver transcriptomic datasets were integrated to identify CHB-associated host candidates, which were prioritized by machine learning and validated in pediatric samples. Functional studies were performed in an entecavir-based LLV-like HepG2.2.15 model.</p> Results <p>Among 109 children with CHB, 27.5% developed LLV. Compared with the MVR group, LLV was associated with higher baseline HBV pregenomic RNA (HBV pgRNA) and smaller declines in HBV DNA, aminotransferases, and APRI, with the earliest divergence at week 12. Integrated transcriptomic and machine-learning analyses identified 5,080 differentially expressed genes enriched in oxidative stress- and DNA damage-related pathways and prioritized RRM2B as a candidate host factor. RRM2B was elevated in pediatric LLV samples and correlated positively with HBV pgRNA. In vitro, low-dose entecavir induced an LLV-like state characterized by increased RRM2B, reactive oxygen species, γ-H2AX, and PI3K/AKT signaling. RRM2B silencing further suppressed HBV DNA replication, reduced oxidative stress and DNA damage, and attenuated LLV-like hepatocyte-derived TGF-β1 secretion and subsequent profibrotic activation of LX-2 cells.</p> Conclusions <p>RRM2B is associated with pediatric LLV and may be involved in stress-related and profibrotic host responses under conditions of incomplete virological suppression.</p>

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RRM2B is associated with low-level viremia during entecavir therapy in pediatric chronic hepatitis B and promotes profibrotic signaling in vitro

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Yuanzhen Zhang,
  • Aoxue Tan,
  • Tingting Wu,
  • Yunan Chang,
  • Xiaorong Peng,
  • Kai Zhu,
  • Qiqin Tang,
  • Hongmei Xu

摘要

Background

Low-level viremia (LLV) during nucleos(t)ide analogue therapy for chronic hepatitis B (CHB) is clinically relevant, but its biological basis in children remains unclear. We investigated the clinical features of pediatric LLV and sought host factors linking incomplete virological suppression to stress adaptation and profibrotic signaling.

Methods

Children with CHB who initiated entecavir therapy between 2019 and 2024 were retrospectively enrolled. LLV and maintained virological response (MVR) were defined by serum HBV DNA at week 48. Longitudinal trajectories were analyzed using generalized estimating equation models. Public liver transcriptomic datasets were integrated to identify CHB-associated host candidates, which were prioritized by machine learning and validated in pediatric samples. Functional studies were performed in an entecavir-based LLV-like HepG2.2.15 model.

Results

Among 109 children with CHB, 27.5% developed LLV. Compared with the MVR group, LLV was associated with higher baseline HBV pregenomic RNA (HBV pgRNA) and smaller declines in HBV DNA, aminotransferases, and APRI, with the earliest divergence at week 12. Integrated transcriptomic and machine-learning analyses identified 5,080 differentially expressed genes enriched in oxidative stress- and DNA damage-related pathways and prioritized RRM2B as a candidate host factor. RRM2B was elevated in pediatric LLV samples and correlated positively with HBV pgRNA. In vitro, low-dose entecavir induced an LLV-like state characterized by increased RRM2B, reactive oxygen species, γ-H2AX, and PI3K/AKT signaling. RRM2B silencing further suppressed HBV DNA replication, reduced oxidative stress and DNA damage, and attenuated LLV-like hepatocyte-derived TGF-β1 secretion and subsequent profibrotic activation of LX-2 cells.

Conclusions

RRM2B is associated with pediatric LLV and may be involved in stress-related and profibrotic host responses under conditions of incomplete virological suppression.