核苷（酸）类药物经治HBV患者耐药突变与疾病进展的关系

发布时间：2018-04-13 11:35

本文选题：乙型肝炎病毒 + 恩替卡韦　；参考：《宁波大学》2017年硕士论文

【摘要】：目的:用直接测序法检测本地区使用核苷(酸)类似物(nucleoside/nucleotide analogues,NUCs)治疗的慢性乙型肝炎病毒(hepatitis B virus,HBV)感染的患者体内HBV逆转录酶(reverse transcriptase,RT)区基因耐药突变位点,分析其与临床疾病进展的关系;并分析恩替卡韦(entecavir,ETV)耐药突变模式及临床特征。方法:第一部分:收集2014年1月1日至2016年12月31日宁波市第二医院门诊或住院的NUCs经治的慢性HBV感染相关肝脏疾病患者血清标本共414例,扩增HBV全长RT区,纯化PCR产物直接测序后检测14个耐药位点(rtV173、rtL180、rtA181、rtT184、rtS202、rtM204,rtV207、rtS213、rtV214、rtQ215、rtN236、rtP237、rtN/H238和rtM250)的变异情况,进一步分析其流行特点,及与不同临床疾病状态的关系。第二部分:从第一部分收集到的样本中筛选出ETV耐药变异位点(T184、S202和/或M250)耐药的样本,分析其耐药突变模式及与临床特点的关系。结果:414例样本中有143例样本检测到HBV基因组RT区耐药突变,其中B基因型35例(35/143,24.5%),C基因型107例(107/143,74.8%),D基因型1例(1/143,0.7%)。14个耐药突变位点中共检测到11个耐药突变位点(rtV173、rtL180、rtA181、rtT184、rtS202、rtM204,rtV207、rtS213、rtV214、rtN236和rtM250)。rtA181位点变异C基因型发生率高于B基因型(p=0.011),rtS213位点变异B基因型高于C基因型(p=0.017、0.013)。rtV214位点变异发生率肝硬化组发生率高于慢性肝炎组(p=0.004)。在143例耐药的样本中,共筛选出ETV耐药样本17例,共检出8种耐药模式,以rtL180+rtM204V+rtS202G/I和rtL180+rtM204V+rtT184A/G/I/S模式为主,分别占41.18%和11.77%,T184A/G/I/S、S202G/I、M250V/I三个耐药位点在B、C基因型的分布无统计学差异(P=0.128、1.000、0.074)。C基因型患者T184A/G/I/S、S202G/I发生率高于M250V/I(p=0.005)。rtT184A/G/I/S位点突变的患者其ALT水平、肝硬化比例较其他模式高,有统计学意义(p=0.000、0.011)。结论:1、检测标本HBV基因型主要为B基因型和C基因型,以C基因型为主。2、NUCs相关耐药突变以rtM204常见,其次为rtL180;C基因型更易出现rtA181位点突变,B基因型更易出现rtS213位点突变;rtV214位点突变可能与疾病进展有关。3、ETV耐药突变模式以rtS202G/I为主,其次为rtT184A/G/I/S,且多在rtL180+rtM204V基础上发生。ETV耐药位点rtT184A/G/I/S的突变可能与患者炎症程度及疾病进展有关。
[Abstract]:Objective: to detect the HBV reverse transcriptase reverse transcriptase (RT) gene mutation site in patients with chronic hepatitis B virus (HBV) infection treated with nucleoside / nucleotide nucleotide NUCsin our region by direct sequencing.To analyze the relationship between ETV and the progress of clinical diseases, and to analyze the pattern and clinical characteristics of drug resistance mutation of entecavirr ETV.Methods: the first part: from January 1, 2014 to December 31, 2016, serum samples of patients with chronic HBV infection associated liver diseases treated with NUCs from outpatient or inpatient department of Ningbo second Hospital were collected and the full-length HBV RT region was amplified.The second part: from the samples collected in the first part, we screened out the samples of ETV resistance mutation site (T184S202 and / or M250), and analyzed the mutant pattern of drug resistance and its relationship with clinical characteristics.Results one hundred and forty-four samples of HBV were found to be resistant to drug resistance in RT region.The incidence of mutation at the locus p0.017, 0.013, rtV214 was higher in the cirrhosis group than in the chronic hepatitis group, which was higher than that in the chronic hepatitis group.Out of 143 drug resistant samples, 17 ETV resistant samples were screened, and 8 drug resistant patterns were detected, mainly rtL180 rtM204V rtS202G/I and rtL180 rtM204V rtT184A/G/I/S.ConclusionThe HBV genotypes were mainly genotype B and genotype C, and rtM204 was the most common mutation in drug resistance.Secondly, rtL180TV-C genotype was more prone to rtA181 locus mutation; rtS213 locus mutation rtV214 mutation might be related to disease progression. RtS202G/I was the main drug resistant mutation pattern in rtL180TV-C genotype.The second was RTT 1844 A / R / I / S, and the mutation of .ETV resistance site rtT184A/G/I/S on the basis of rtL180 rtM204V may be related to the degree of inflammation and progression of the disease.
【学位授予单位】：宁波大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R512.62

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