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Background & Aims: Although the advent of ultra-deep sequencing technology allows for the analysis of heretofore undetectable minor viral mutants, a limited amount of information is currently available regarding the clinical implications of hepatitis B virus (HBV) genomic heterogeneity. Methods: To characterize the HBV genetic complexity in association with various clinical settings, we performed ultra-deep sequencing of full-genome HBV in the liver of 23 liver transplant recipients, including 4 acute, 14 chronic-naïve, and 5 chronic nucleos(t)ide analogue (NA)-treated cases. Dynamic changes of the G1896A pre-core mutant were examined in the serum of 22 chronic-naïve non-transplant patients before and after entecavir administration.Results: The overall viral complexity was significantly lower in acute than chronic cases. Four of eight (50%) HBeAg-negative cases showed a substantially low prevalence of the G1896A pre-C mutant in the liver tissues, suggesting that other mutations were involved in their HBeAg seroconversion. Interestingly, liver tissues in 4 of 5 (80%) of the anti-HBe-positive cases receiving NA had extremely low levels of the G1896A pre-C mutant (0.0%, 0.0%, 0.1%, and 1.1%). Consistently, dynamic change analysis of the G1896A pre-C mutant demonstrated that entecavir administration significantly reduced the proportion of the G1896A pre-C mutant in 16 of 22 cases, irrespective of their HBeAg/Ab serostatus, suggesting the high sensitivity of the G1896A pre-C mutant to NA.Conclusions: Our findings illustrate the strong advantage of deep sequencing as a tool for dissecting the pathophysiology of HBV infection and provide a rationale for future application of this technology to predict the therapy outcome. none provided |