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目的依托国家“十一五”重大传染病防治科技重大专项,对中国慢性乙型肝炎(乙肝)及乙肝后肝硬化患者核苷(酸)类药物治疗耐药情况进行监测和分析。方法采用网络信息与生物信息技术,建立并初步完善中国乙肝病毒(HBV)耐药网络监测平台,分析当前HBV逆转录酶(RT)区耐药相关基因突变的特点及耐药现状。结果建立了目前国内覆盖面最广的大型HBV基因多功能共享数据库。截至2012年12月,已对267家单位的9 998例乙肝患者进行了基因耐药检测,其中基因型明确的患者有7 551例,B基因型为2 421例,占32.06%(2 421/7 551),C基因型为5 088例,占67.38%(5 088/7 551),D基因型患者为42例,占0.56%(42/7 551)。在检测到原发性耐药相关位点突变及代偿性突变的5 207例(5 207/7 551,68.96%)患者中,C基因型占3 700例(3 700/5 088,72.72%),B基因型占1 482例(1 482/2 421,61.21%),C基因型的构成比明显高于B基因型(P<0.01);在原发性耐药位点突变中,主要耐药突变(rtM204V/I,rtA181T/V,rtN236T)的检出率为43.64%(3 295/7 551),其中M204I、rtA181T(sW172*)和rtA181V突变常见于C基因型(P值均<0.01),而N236T突变却在B基因型中多见(P<0.01)。在恩替卡韦继发性耐药突变的患者中,M204V比M204I更常见(P<0.01)。国内部分地区或医院抗病毒治疗的核苷(酸)药物应用方案纷繁复杂,不够规范,多药耐药的构成比高达1.73%(131/7 551)。结论为实现对乙肝患者耐药数据的实时监控、共享和标准化,本研究建立了我国HBV耐药监测网络平台。目前国内HBV基因突变及其导致的核苷(酸)类药物耐药现状值得关注,其致病相关机制有待进一步研究。
Objective To monitor and analyze the resistance to nucleoside (acid) drug treatment in patients with chronic hepatitis B (Hepatitis B) and Hepatitis B after liver cirrhosis by relying on major scientific and technological projects of national “Eleventh Five-Year” major infectious disease prevention and control. Methods By using network information and bioinformatics techniques, a monitoring platform for HBV resistance network in China was established and initially optimized to analyze the characteristics and drug resistance of resistance-related gene mutations in HBV reverse transcriptase (RT) region. Results The multi-functional shared database of large-scale HBV gene with the most extensive coverage in China was established. As of December 2012, 9,998 hepatitis B patients from 267 units had been tested for genetic resistance, of which 7,551 were genotyped, 2 421 were genotype B, accounting for 32.06% (2 421 / 7 551). The genotype of C was 5 088 cases (67.38% (5 088/7 551)) and 42 genotype D patients (42 cases), accounting for 0.56% (42/7 551). Among the 5 207 patients (5 207/7 551,68.96%) who detected mutations and compensatory mutations in primary resistance-related sites, the C genotype accounted for 3700 cases (3700/5888, 72.72% ), B genotype accounted for 1 482 cases (1 482/2 421, 61.21%), the C genotype was significantly higher than the B genotype (P <0.01); mutations in the primary resistance site, the main The detection rate of resistant mutations (rtM204V / I, rtA181T / V and rtN236T) was 43.64% (3 295/7 551), of which M204I, rtA181T (sW172 *) and rtA181V mutations were common in genotype C (P < 0.01), while N236T mutation was more common in B genotype (P <0.01). M204V was more common than M204I in patients with secondary resistance mutations in entecavir (P <0.01). Nucleotide (acid) drug applications of antiretroviral therapy in some areas or hospitals in China are complicated and not standardized enough, and the composition ratio of multidrug resistance is as high as 1.73% (131/7 551). Conclusion To achieve real-time monitoring, sharing and standardization of drug resistance data of hepatitis B patients, this study established a network platform of HBV drug resistance monitoring in our country. At present, the mutation of HBV gene and the drug resistance status of nucleoside (acid) drugs in our country are worth noting. The related mechanism of HBV remains to be further studied.