HBV RNA dynamics and cytokine-driven hyperinflammation: a synergistic prognostic axis in hepatitis B-related acute-on-chronic liver failure.

BACKGROUND AND AIMS: The interplay between hepatitis B virus (HBV) replication and host immunity remains poorly defined in hepatitis B-related acute-on-chronic liver failure (HBV-ACLF). This study aimed to investigate the dynamic antagonism between serum HBV RNA and cytokine-driven hyperinflammation, and to evaluate their combined prognostic value.

METHODS

In this prospective cohort study (March 2021-December 2022), 133 patients with HBV-ACLF were enrolled. Serum levels of HBV RNA and Th1/Th2 cytokines (IFN-γ, TNF-α, IL-4, IL-6, IL-10) were measured. Logistic regression analysis was used to identify independent predictors of 12-week prognosis, and to construct and internally validate prognostic models.

RESULTS

Non-survivors (40.6%, 54/133) exhibited significantly lower HBV RNA levels (2.97 ± 1.22 vs. 4.05 ± 1.30 log10copies/mL, p < 0.001) but 1.2-fold higher IFN-γ levels (p < 0.001) compared to survivors. A strong inverse correlation was observed between HBV RNA and IFN-γ (r = -0.326, p < 0.001), suggesting that suppressed viral replication may trigger a Th1-dominant hyperinflammatory state. Multivariate logistic regression identified HBV RNA (AUC = 0.730, optimal cutoff = 3.98 log10 copies/mL) and IFN-γ (AUC = 0.821, optimal cutoff = 496.23 pg/mL) as independent predictors of 12-week mortality. A nomogram incorporating these factors demonstrated superior predictive performance (AUC = 0.917), outperforming the MELD score and achieving comparable accuracy to the COSSH-ACLF II score.

CONCLUSIONS

HBV RNA and Th1 cytokines form a dynamic prognostic axis in HBV-ACLF. Declining HBV RNA, indicative of viral control, paradoxically heralds a cytokine-driven hyperinflammatory state associated with organ failure. This virus-immunity interplay provides a novel stratification tool to guide early immunomodulatory therapy, challenging the traditional focus on viral load alone.