Spontaneous HBeAg seroconversion and loss of hepatitis B virus DNA after acute flare due to development of drug resistant mutants during entecavir monotherapy

Aims: Patients with chronic hepatitis B virus (HBV) infection under entecavir (ETV) treatment develop resistant mutants with viral rebound. Here, we report an interesting case of spontaneous loss of HBV‐DNA and seroconversion following an acute flare after the development of ETV‐resistant mutants. This patient received ETV after lamivudine breakthrough. Methods: Cloning and sequence analysis of the HBV reverse transcriptase (RT) region were performed with seven samples during ETV therapy. In addition, two full‐length HBV genomes derived from samples before and after the emergence of ETV resistance were sequenced. Results: ETV resistant mutants appeared at week 228, with virological and biochemical rebound at the same time. Unexpectedly, HBeAg seroconversion occurred 8 weeks later. The viral load decreased and became undetectable from week 252. Analysis of HBV isolates in the patient at week 124 revealed that wild‐type HBV was predominant at that time and ETV resistant mutants were not found among 20 clones. Interestingly, a new mutant type with rtL180M+rtT184L was found alongside rtL180M+rtT184L+rtM204V/I at week 228 and appeared to develop independently, according to the sequence analysis. In contrast to the previously identified ETV resistant mutants, it did not carry the rtM204V/I mutations. Conclusion: The data presented here indicates that the flare following the emergence of ETV resistant mutants may reflect immune‐mediated control of HBV infection, leading to a spontaneous loss of HBV‐DNA and seroconversion.