乙肝病毒 rtA181T/sW172 非终止突变可能比 rtA181T/sW172*突变增加阿德福韦酯和恩替卡韦耐药突变体的耐药倍数。

Hepatitis B virus rtA181T/sW172non-stop mutation may increase resistance fold to adefovir- and entecavir-resistant mutants compared to rtA181T/sW172* mutation.

机构信息

Research Center for Clinical and Translational Medicine, Beijing 302 Hospital, Beijing 100039, China; Clinical Medical School, Guilin Medical University, Guilin 541004, Guangxi Zhuang Autonomous Region, China.

Research Center for Clinical and Translational Medicine, Beijing 302 Hospital, Beijing 100039, China.

出版信息

Antiviral Res. 2018 Jun;154:26-34. doi: 10.1016/j.antiviral.2018.04.003. Epub 2018 Apr 6.

DOI:10.1016/j.antiviral.2018.04.003

PMID:29630974

Abstract

The study aimed to characterize rtA181T/sW172stop () and rtA181T/sW172non-stop mutations of hepatitis B virus (HBV). Total of 22,009 patients who visited Beijing 302 Hospital from 2007 to 2016 were enrolled. These patients all received nucleos(t)ide analogues (NAs) treatment and their serum samples were collected for sequence analysis of HBV reverse-transcriptase (RT) and S regions. The rtA181T mutation was detected in 5.37% (1182/22,009) of the patients' samples. The rtA181T-causative sW172, sW172non-stop (sW172 L/S), and mixed sW172*/non-stop mutations occupied 82.91%, 7.70%, and 9.39%, respectively. The patients with rtA181T/sW172non-stop mutants had a higher HBV DNA level compared to those with rtA181T/sW172* mutants. 44.33% (524/1182) rtA181T-positive samples were detected with signature drug-resistant mutations, including 325 with adefovir-resistant mutation rtA181V/N236T, 57 with lamivudine-resistant mutation rtM204V/I, 99 with entecavir-resistant mutation rtM204V/I plus rt184/202/250 substitution(s), and 43 with multidrug-resistant mutation rtA181V/N236T + rtM204V/I ± rt184/202/250 substitution(s). The rtA181T/sW172non-stop mutation had a higher ratio of coexistence with adefovir-resistant mutation compared to rtA181T/sW172* mutation (42.86% vs. 24.59%, P < 0.05). rtA181T/sW172S + rtN236T and rtA181T/sW172L + rtN236T mutants exhibited higher HBV DNA production and adefovir resistance fold than that of rtA181T/sW172* + rtN236T mutant (98.02% and 85.5% vs. 42.1% in HBV DNA production, and 7.38-fold and 5.49-fold vs. 3.69-fold in half maximal effective concentration of wild-type strain); rtA181T/sW172L + rtS202G + rtM204V strain exhibited higher HBV DNA production and entecavir resistance fold than that of rtA181T/sW172* + rtS202G + rtM204V strain (50.98% vs. 34.49%, 524.00-fold vs. 69.33-fold). In conclusion, rtA181T/sW172non-stop mutation may increase resistance fold of adefovir- and entecavir-resistant mutants compared to rtA181T/sW172* mutation and might influence clinical presentation of NAs-treated patients.

摘要

本研究旨在研究乙型肝炎病毒（HBV）rtA181T/sW172 停止突变（）和 rtA181T/sW172 不停顿突变。共纳入 2007 年至 2016 年期间在北京 302 医院就诊的 22009 例患者。这些患者均接受核苷（酸）类似物（NAs）治疗，并采集其血清样本进行 HBV 逆转录酶（RT）和 S 区序列分析。在 22009 例患者的样本中检测到 5.37%（1182/22009）的患者存在 rtA181T 突变。导致 rtA181T 的 sW172、sW172 不停顿（sW172L/S）和混合 sW172*/不停顿突变分别占 82.91%、7.70%和 9.39%。与 rtA181T/sW172突变相比，携带 rtA181T/sW172 非停止突变的患者 HBV DNA 水平更高。在 1182 例 rtA181T 阳性样本中，检测到 44.33%（524/1182）存在特征性耐药突变，其中 325 例存在阿德福韦耐药突变 rtA181V/N236T，57 例存在拉米夫定耐药突变 rtM204V/I，99 例存在恩替卡韦耐药突变 rtM204V/I 加 rt184/202/250 取代（s），43 例存在多药耐药突变 rtA181V/N236T+rtM204V/I±rt184/202/250 取代（s）。与 rtA181T/sW172突变相比，rtA181T/sW172 非停止突变与阿德福韦耐药突变共存的比例更高（42.86% vs. 24.59%，P<0.05）。rtA181T/sW172S+rtN236T 和 rtA181T/sW172L+rtN236T 突变体比 rtA181T/sW172*+rtN236T 突变体产生更高的 HBV DNA 产量和阿德福韦耐药倍数（HBV DNA 产量分别为 98.02%和 85.5%，比 rtA181T/sW172*+rtN236T 突变体高 42.1%，野生型菌株的半数最大有效浓度分别为 7.38 倍和 5.49 倍，比 rtA181T/sW172*+rtN236T 突变体高 3.69 倍）；rtA181T/sW172L+rtS202G+rtM204V 株比 rtA181T/sW172*+rtS202G+rtM204V 株产生更高的 HBV DNA 产量和恩替卡韦耐药倍数（HBV DNA 产量分别为 50.98%和 34.49%，比 rtA181T/sW172*+rtS202G+rtM204V 突变体高 524.00 倍和 69.33 倍）。总之，与 rtA181T/sW172*突变相比，rtA181T/sW172 非停止突变可能增加阿德福韦和恩替卡韦耐药突变体的耐药倍数，并可能影响 NAs 治疗患者的临床表现。