PubMedZhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology2026-07-27
[Distribution of serum HBV RNA in the natural history of chronic HBV infection and factors influencing HBV RNA negativity: a retrospective study stratified by HBeAg status].
Li Y J YJ, Deng J H JH, Yan Z L ZL, Yang L P LP et al.
Objective: To characterize the distribution of serum hepatitis B virus (HBV) RNA in patients with HBV infection according to different HBeAg statuses and natural history stages, to analyze factors associated with HBV RNA negativity, and to observe dynamic changes in HBV RNA after six months of follow-up in patients treated with nucleos(t)ide analogues (NAs). Methods: This was a single-center, retrospective, real-world cohort study. A total of 1 184 patients with chronic HBV infection who attended the Fourth People's Hospital of Qinghai Province between October 2023 and October 2025 and underwent HBV RNA testing were enrolled. Baseline characteristics and HBV RNA levels were compared after stratification by hepatitis B e antigen (HBeAg) status. Patients were classified into five stages of the natural history of chronic HBV infection according to the Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2022 Edition), and HBV RNA levels were compared across stages. Two-way ANOVA was performed for HBV RNA levels using HBeAg status and baseline high-sensitivity HBV DNA status as grouping factors. Logistic regression was used to analyze factors associated with HBV RNA negativity, and a receiver operating characteristic (ROC) curve was plotted based on a multivariate model in the HBeAg-negative population. Among patients receiving NAs therapy who completed six months of follow-up, HBV RNA levels at baseline and at six months were compared, and ΔHBV RNA was compared after stratifying by baseline high-sensitivity HBV DNA status. Depending on data type, intergroup comparisons were performed using the χ2 test, Mann-Whitney U test, or Kruskal-Wallis H test; pre- and post-treatment comparisons were performed using the Wilcoxon signed-rank test; and ΔHBV RNA was compared between groups using the Mann-Whitney U test. Results: Among the enrolled patients, 461 were HBeAg-positive and 723 were HBeAg-negative. HBV RNA levels in the HBeAg-positive group were higher than those in the HBeAg-negative group (P<0.001). HBV RNA levels differed significantly across natural history stages (P<0.001). Two-way ANOVA showed a statistically significant main effect of HBeAg status on HBV RNA levels with a large effect size (F=923.869, P<0.001, partial η2=0.444). The main effect of baseline high-sensitivity HBV DNA status on HBV RNA levels was also statistically significant but with a small effect size (F=3.981, P=0.046, partial η2=0.003). No significant interaction was observed between the two factors (P>0.05). Multivariate logistic regression showed that HBeAg negativity (OR=16.028, 95% CI: 9.910-25.924), lower hepatitis B surface antigen (HBsAg) level (OR=0.561, 95% CI: 0.475-0.663), and lower alanine aminotransferase (ALT) level (OR=0.995, 95%CI:0.992-0.999) were associated with HBV RNA negativity. In the HBeAg-negative subgroup, HBsAg and ALT remained independently associated factors, and the model achieved an AUC of 0.658 (95%CI: 0.618-0.698), indicating modest discriminative ability. Follow-up analysis showed an overall decline in HBV RNA after six months of treatment. Stratified analysis revealed that in the group with negative baseline high-sensitivity HBV DNA, HBV RNA decreased significantly after treatment (P< 0.001); in the group with positive baseline high-sensitivity HBV DNA, HBV RNA showed a decreasing trend, but the difference was not statistically significant (P>0.05). No significant difference in ΔHBV RNA was observed between the two groups (P>0.05). Conclusion: Serum HBV RNA levels in patients with chronic HBV infection are closely associated with HBeAg status, and HBeAg was an important factor influencing HBV RNA levels. HBV RNA negativity is independently associated with HBeAg negativity, lower HBsAg levels, and lower ALT levels. In the HBeAg-negative population, conventional clinical indicators have only modest discriminative ability for identifying HBV RNA negativity. HBV RNA may serve as a complementary biomarker to assess residual viral transcriptional activity.
