Among nucleos(t)ide analogue therapies for hepatitis B virus (HBV) treatment, entecavir (ETV) and tenofovir disoproxil fumarate (TDF)/tenofovir alafenamide are associated with the lowest rate of drug resistance. ETV is a drug requiring at least three substitutions in the reverse transcriptase (RT) domain to develop resistance, which is a rare occasion in treatment‑naïve patients. However, pre‑existing or acquired single mutations in the RT domain could lead to a virological breakthrough, after viral suppression. The present case report describes a 58‑year‑old female patient with hepatitis B virus (HBV) and high viral load who started HBV treatment with ETV. After 85 weeks of treatment, HBV‑DNA declined to 0 IU/ml and remained undetectable for 3 years. However, after that period of time, the HBV‑DNA rebounded, followed by the rise of liver enzymes (aspartate aminotransferase and alanine transaminase). Only the substitution M204I was detected in the HBV polymerase region. The patient was then switched to TDF treatment, achieving normalization of the liver enzymes and a decline in HBV‑DNA levels. The present case report suggests that nucleoside‑naïve patients should be cautiously monitored for resistance, even more than biochemically (transaminases, bilirubin) and virologically (HBV‑DNA), even if complete HBV suppression is achieved.
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