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( Jeong-ju Yoo ),( Eun-sook Park ),( Ah Ram Lee ),( Doo Hyun Kim ),( Sung Hyun Ahn ),( Hee Woo Sim ),( Soree Park ),( Hong Seok Kang ),( Ju Hee Won ),( Yea Na Ha ),( Gu-choul Shin ),( So Young Kwon ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Aims: Tenofovir disoproxil fumarate (TDF) is the most potent nucleoside analog for the treatment of chronic hepatitis B virus (HBV) infection. Genotypic resistance to tenofovir has not yet been reported. This study aimed to characterise HBV mutations that confer tenofovir resistance. Methods: Two consecutive patients with viral breakthrough during treatment with TDF-containing regimens were prospectively enrolled. The gene encoding HBV reverse transcriptase (RT) was sequenced. Nine HBV clones harbouring a series of mutations in the RT gene were constructed by site-directed mutagenesis. Drug susceptibility of each clone was determined by Southern blot analysis and real-time PCR. Relative frequency of mutants were evaluated by ultra-deep sequencing. Results: (Please understand that actual mutation site numbers were replaced by bold, underlined alphabetical letters since they are now confidential due to embargo policy.) Seven mutations (rtSaaaC [C], rtHbbbY [Y], rtDcccE [E], rtVdddL, rtLeeeM, rtMfffV, and rtLgggI) were commonly found in viral isolates from both patients after viral breakthrough; C, Y, and E were novel mutations. An HBV mutant harbouring all three mutations (CYE) was resistant to tenofovir. The IC<sub>50</sub> values for wild-type HBV and the CYE mutant were 3·8 ± 0·6 μM and 14·1 ± 1·8 μM, respectively. Ultra-deep sequencing showed that CYE mutant was dominant than any other mutant in both patients. All tenofovir-resistant mutants had similar susceptibility to a core inhibitor, NVR 3-778 (IC<sub>50</sub> < 0·4 μM) compared with wild-type (IC<sub>50</sub> = 0·4). Conclusions: Our study reveals that a novel triple mutation (CYE) is associated with tenofovir-resistance. These results demonstrate that tenofovir-resistant HBV mutants can emerge, although the genetic barrier is high. A novel core inhibitor might be a potential rescue therapy for tenofovir-resistant HBV.