Selection of an entecavir-resistant mutant despite prolonged hepatitis B virus DNA suppression, in a chronic hepatitis B patient with preexistent lamivudine resistance: successful rescue therapy with tenofovir

BACKGROUND AND OBJECTIVE: Entecavir has potent activity against hepatitis B virus. Drug resistance has not been reported in nucleoside-naïve patients and is low in lamivudine-refractory patients. METHODS AND RESULTS: A 43-year-old man was treated with lamivudine for hepatitis B e antigen-positive chronic hepatitis B. A viral breakthrough owing to a drug-resistant mutant was observed and entecavir 1 mg daily was added. After the viral load had been near the lower detection range of the PCR assay for 30 weeks, lamivudine was discontinued. The serum hepatitis B virus DNA remained low until a second viral breakthrough was observed after 45 weeks of entecavir monotherapy. Treatment was switched from entecavir to tenofovir disoproxil 245 mg daily, which resulted in a decline below 1000 copies/ml. Sequence analysis revealed the presence of rtL180M and rtM204V lamivudine-resistant-associated mutations at the start of entecavir treatment. During entecavir treatment, the rtS202G mutation was selected. Retrospective analysis revealed that during lamivudine treatment three other mutations had been selected as well, namely rtE1D, rtV207L, and rtI220L. CONCLUSION: We describe the first case of entecavir resistance in a lamivudine-resistant patient with good initial suppression of viral replication for 70 weeks. On the basis of the data from cross-resistance and sensitivity testing in vitro and treatment outcomes, tenofovir proves to be a good treatment option for entecavir-resistant patients.