Abstract
Hepatitis B virus (HBV) infection remains a significant global health burden, primarily due to its chronic complications, including acute exacerbation, cirrhosis, hepatocellular carcinoma (HCC), and related sequelae. Acute exacerbation of chronic hepatitis B (CHB-AE) is common and often represents the earliest clinical manifestation. The Hepatitis B virus X protein (HBx) (17-kDa) is not only essential for viral replication but also plays a role in the development of HCC. To investigate the role of HBx mutation in CHB-AE progression, we enrolled 33 hospitalized CHB-AE patients and 31 patients with HBV-related liver failure (controls) from mainland China between January 2017 and June 2018. Single mutation 36 of HBx was significantly more prevalent in CHB-AE patients (p < 0.05), whereas Joint Mutation 1 was more frequent in HBV-related liver failure patients (p < 0.05). HBx mutations, including Single mutation 36 and Joint Mutations 2 and 3, were significantly associated with high HBV DNA levels (p < 0.05), while Joint mutation 1 predominated in the low HBV DNA group (p < 0.01). Age-stratified analysis showed that Single mutation 36 and Joint Mutation 2 were more common in younger patients (<35 years old) (p < 0.05), whereas Joint mutation 1 was more frequent in older age (≥35 years old) (p < 0.05). Moreover, antiviral therapy markedly reduced the prevalence of Joint mutation 1 from 82.98% in treatment-naïve patients to 29.41% in treatment-experienced patients (p < 0.0001). These findings suggest that specific HBx mutations are associated with viral replication levels, disease progression, and patient demographics. Such mutations may serve as molecular markers for disease severity and potential therapeutic targets in both CHB-AE and HBV-related liver failure.