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07.08.2020 | Original Article | Ausgabe 6/2020

Hepatology International 6/2020

Hepatitis B virus X gene mutants emerge during antiviral therapy and increase cccDNA levels to compensate for replication suppression

Hepatology International > Ausgabe 6/2020
Chih-Lang Lin, Rong-Nan Chien, Yu-De Chu, Kung-Hao Liang, Ya-Hui Huang, Po-Yuan Ke, Kwang-Huei Lin, Yang-Hsiang Lin, Chau-Ting Yeh
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s12072-020-10079-1) contains supplementary material, which is available to authorized users.
YHL and CTY are co-corresponding authors.

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Hepatitis B virus (HBV) X gene (HBx) mutants can develop during the natural course of chronic HBV infection. However, little is known about whether the emergence of HBx mutants during long-term antiviral therapy is an adaptation of HBV to antiviral stress. This study was to identify HBx mutants that emerged in patients experiencing Lamivudine resistance or suboptimal treatment.


Forty-six Lamivudine-resistant patients and 46 patients with suboptimal treatment responses to Entecavir were enrolled in this study. HBx mutants were identified by sequence analysis and their roles in the HBV replication cycle were characterized.


We show that deletion/truncation/insertion mutations were only detected in the Lamivudine resistance group, while synonymous mutations were found in both groups. Follow-up analyses revealed that five patients in the Lamivudine group developed hepatocellular carcinoma, while patients in the Entecavir group did not. These mutants were characterized by a significant decrease in transactivation of the pre-S1 promoter, and varying effects on transactivation of the X promoter. Co-transfection of HBx-mutant plasmid and HBV replication-competent clone into HepG2 cells resulted in increased nuclear-to-cytoplamic HBV core antigen, HBV-DNA ratios, and nuclear covalently closed circular DNA (cccDNA). Antiviral drug sensitivity assays revealed that these mutants exhibited a compensatory effect to counteract antiviral drug suppression, resulting in elevated secretory HBV-DNA levels.


Our study demonstrates that HBx mutants can emerge during Lamivudine or Entecavir therapy. These mutants exhibit altered transactivation of the HBV pre-S1 and X promoters, leading to increased cccDNA levels to compensate for replication suppression.

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