乙肝病毒rtCYE/rtCYEI突变可能导致有限的替诺福韦耐药性：对大量中国患者样本的分析
Hepatitis B virus rtCYE/rtCYEI mutations may contribute limited tenofovir resistance: Analysis of a large sample of Chinese patients.
作者信息
Si Lan-Lan, Fan Zhen-Ping, Liu Wen-Hui, Chen Rong-Juan, Chen Xue-Yuan, Ji Dong, Li Le, Chen Chun, Liao Hao, Wang Jun, Xu Dong-Ping, Zhao Jun, Liu Yan
机构信息
Graduate School, Guangzhou Medical University, Guangzhou 511436, Guangdong Province, China.
Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China.
出版信息
World J Hepatol. 2025 Aug 27;17(8):107456. doi: 10.4254/wjh.v17.i8.107456.
BACKGROUND
Whether rtS106C+H126Y+D134E/rtS106C+H126Y+D134E+L269I (rtCYE/rtCYEI) mutations in the hepatitis B virus (HBV) reverse-transcriptase (RT) region are associated with tenofovir disoproxil fumarate (TDF) resistance is controversial.
AIM
To evaluate the presence of the rtCYE/rtCYEI mutations in a large cohort of Chinese patients with chronic HBV infection.
METHODS
A total of 28236 patients who underwent drug resistance testing at the Fifth Medical Center of Chinese PLA General Hospital from 2007 to 2019 were enrolled. All patients received nucleoside/nucleotide analogues (NAs) therapy, and serum samples were collected for sequence analysis of the HBV RT domain with mutation analysis.
RESULTS
The detection rates of a single mutation of rtS106C, rtH126Y, rtD134E, and rtL269I were 8.21%, 3.20%, 2.55% and 61.49% in 23718 genotype C patients, and 1.31%, 1.76%, 0.21%, and 92.33% in 4266 genotype B patients, respectively. The combined mutations of rtCYE/rtCYEI were only detected in 12 genotype C patients, accounting for 0.042% of all patients. These 12 patients had received NA treatments except TDF before testing. Among them, 6 patients had coexisting rtCYE/rtCYEI and lamivudine-resistance mutations, and 2 patients had coexisting rtCYE/rtCYEI and adefovir-resistance mutations. Compared with the wild-type (WT) strain, the replication capacity of rtCYE/rtCYEI mutants from representative patients decreased by 41.1%-71.8%, and TDF susceptibility reduced by less than 2-fold, but rtCYEI+rtA181V/N236T mutants exhibited a 6.2-/9.9-fold decrease in TDF susceptibility. Molecular modeling showed that rtCYE/rtCYEI mutants had a slight decrease in binding energy to TDF compared to the WT strain. In the clinic, emergence of the rtCYE/rtCYEI mutations was not specifically associated with TDF treatment.
CONCLUSION
HBV rtCYE/rtCYEI mutations have a limited effect on TDF susceptibility and are not sufficient to cause TDF resistance.
背景
乙型肝炎病毒（HBV）逆转录酶（RT）区域中的rtS106C+H126Y+D134E/rtS106C+H126Y+D134E+L269I（rtCYE/rtCYEI）突变是否与富马酸替诺福韦二吡呋酯（TDF）耐药相关存在争议。
目的
评估大量中国慢性HBV感染患者中rtCYE/rtCYEI突变的存在情况。
方法
纳入2007年至2019年在中国人民解放军总医院第五医学中心接受耐药检测的28236例患者。所有患者均接受核苷/核苷酸类似物（NAs）治疗，并采集血清样本进行HBV RT结构域的序列分析及突变分析。
结果
在23718例C基因型患者中，rtS106C、rtH126Y、rtD134E和rtL269I单突变的检出率分别为8.21%、3.20%、2.55%和61.49%；在4266例B基因型患者中，其检出率分别为1.31%、1.76%、0.21%和92.33%。rtCYE/rtCYEI的联合突变仅在12例C基因型患者中检测到，占所有患者的0.042%。这12例患者在检测前除TDF外均接受过NAs治疗。其中，6例患者同时存在rtCYE/rtCYEI和拉米夫定耐药突变，2例患者同时存在rtCYE/rtCYEI和阿德福韦耐药突变。与野生型（WT）毒株相比，代表性患者的rtCYE/rtCYEI突变体的复制能力下降了41.1%-71.8%，对TDF的敏感性降低了不到2倍，但rtCYEI+rtA181V/N236T突变体对TDF的敏感性下降了6.2/9.9倍。分子模拟显示，与WT毒株相比，rtCYE/rtCYEI突变体与TDF的结合能略有下降。在临床上，rtCYE/rtCYEI突变的出现与TDF治疗并无特异性关联。
结论
HBV rtCYE/rtCYEI突变对TDF敏感性的影响有限，不足以导致TDF耐药。
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