Virologic analysis of tenofovir resistance in a patient with chronic hepatitis B experiencing viral breakthrough during combination treatment with tenofovir disoproxil fumarate and entecavir.

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 rt (reverse transcriptase) 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 entecavir resistance (rtL180M, 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 may experience tenofovir resistance in addition to lamivudine or entecavir resistance. In addition, HBV DNA levels fluctuated during tenofovir alafenamide (TAF) and lamivudine therapy in our patient, although treatment was switched from lamivudine, TDF and ETV to lamivudine and TAF combination therapy in April 2018. In conclusion, three mutations (CN/SI) plus entecavir resistance (rtL180M, rtM204V, 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. This article is protected by copyright. All rights reserved.