Tenofovir disoproxil fumarate (TDF) is widely used to treat hepatitis B virus (HBV) patients worldwide. We previously reported a patient with CHB and
cirrhosis in whom viral breakthrough occurred during combination
therapy with TDF and
entecavir (ETV) against ETV-resistant virus. A recent Korean report showed that two patients with viral breakthrough during treatment with TDF-containing regimens were found to carry five
reverse transcriptase (rt) mutations ([rt]S106C[C], rtH126Y[Y], rtD134E[E], rtM204I/V, and rtL269I [I]), with the C, Y, E, and I mutations being associated with
tenofovir resistance. We report the
clinical course up to September 2019 in our patient, and compare the HBV mutations to those of the two Korean patients. Four mutations (rtS106C, rtD134N/S[N/S], rtM204V, and rtL269I) plus ETV resistance (rtL180M and rtS202G) existed when she developed viral breakthrough during ETV and TDF combination
therapy in April 2013. Moreover, three mutations (rtS106C, rtD134N, and rtL269I) existed at baseline. Our patient's father is Korean. Considering these factors, patients with these three or four mutations (CYEI or CN/SI) at baseline could experience
tenofovir resistance in addition to
lamivudine (
LAM) or ETV resistance. In addition, HBV
DNA levels fluctuated during
tenofovir alafenamide (TAF) and
LAM therapy in our patient, although treatment was switched from
LAM, TDF, and ETV to
LAM and TAF combination
therapy in April 2018. In conclusion, three mutations (CN/SI) plus ETV resistance (rtL180M, rtM204V, and rtS202G) can cause
tenofovir resistance. Long-term
therapy with
tenofovir against ETV-resistant virus has the potential to induce viral breakthrough and resistance, necessitating careful follow-up.