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Background and Aim Methods Results Conclusions Hepatitis B virus (HBV) reactivation could develop after withdrawal following a finite course of nucleoside analog (NA) therapy, leading to virological and clinical relapses. The genetic heterogeneity in the HBV surface and polymerase genes during finite NA therapy has not been carefully studied.Seven chronic HBV‐infected patients experiencing relapses following entecavir (ETV; n = 5; Patients 1 to 5) or tenofovir disoproxil fumarate (TDF; n = 2; Patients 6 and 7) withdrawal were included. Sera obtained before treatment and at relapses were retrieved and submitted for DNA extraction and amplicon‐specific deep sequencing.ETV‐treated patients had a longer time‐to‐relapse than that of TDF‐treated patients (P = 0.0357). No drug‐resistance related polymerase mutation was detected during relapses, except for a low percentage (1.4%) of rtM204I mutation in Patient 1. Two surface truncation mutations (sW216*; 40.9% and sW182*; 4.7%) detected before treatment in two TDF‐treated patients (Patients 6 and 7, respectively) were overtaken by the wild types during subsequent drug‐withdrawal‐related relapses. The simultaneous presence of sG44E (T‐cell epitope) and sE164G (B‐cell epitope) mutations was associated with failure of HBV e antigen (HBeAg) seroclearance in ETV‐treated patients.In conclusion, HBV genome continues to evolve during the courses of finite antiviral therapies. Pre‐existing surface truncation mutations can be overtaken by the wild types after relapses. The sG44E/sE164G mutations are associated with failure of HBeAg seroclearance. [ABSTRACT FROM AUTHOR]