HBV rtA181位点突变的病毒学特点及临床耐药研究

A retrospective study on the viral characteristics and antiviral therapeutic regimens effect in chronic hepatitis B patients with rtA181 mutations

目的 回顾性研究HBV rtA181位点突变模式与临床核苷（酸）类似物耐药的关系及挽救治疗效果.方法 核苷（酸）类似物治疗过程中发现HBV rtA181位点突变的45例慢性乙型肝炎或肝硬化患者,检测其血清HBV DNA水平,PCR产物直接测序检测HBV变异模式及基因型,收集突变前用药史及突变后的挽救治疗方案及疗效相关资料.结果 HBV rtA181位点共发现三种突变形式,其突变率分别为rtA181T 66.67％ （30/45）,rtA181V 31.11％ （14/45）,rtA181S 2.22％ （1/45）,rtA181T多见于HBV C基因型患者（P＜0.05）;涉及rtA181的HBV突变模式共发现13种,多位点联合突变率为57.78％ （26/45）,其中rtA181与rt236位点联合突变率为40.00％ （18/45）,与rt204位点联合突变率为22.2％ （10/45）,多位点突变患者较单位点突变患者有病毒载量分布更高的趋势,但差异无统计学意义（P＞0.05）,多位点突变与基因型及突变形式无关（P＞0.05）;发生rtA181突变的患者97.78％ （44/45）有拉米夫定（LAM）和（或）阿德福韦酯（ADV）治疗史,另外1例有替比夫定（LdT）治疗史.其后的挽救治疗采用加用或换用恩替卡韦（ETV）、LAM联合ADV以及LdT联合ADV均能在一个月内将HBV DNA降低2个lg值,继续随访效果最显著的方法为加用或换用ETV.结论 HBVrtA181位点突变模式多样,与LAM、ADV或LdT长期单药或序贯治疗有关,加用或换用ETV可取得显著的挽救治疗效果.

Objective To investigate the mutation patterns of hepatitis B virus in chronic hepatitis B patients with rtA181 mutations.Methods Forty-five chronic hepatitis or cirrhosis patients undergoing nucleos（t）ide analogues treatment were found HBV rtA181 locus mutation.Their serum HBV DNA levels were detected,HBV P gene was amplified and PCR products were sequenced to analyze genotype as well as mutation patterns.The information of medication history,salvage regimen and efficacy were collected.Results Three mutation forms of HBV rtA181 were found in 45 cases which were rtA181T 66.67% （30/ 45）,rtA181V 31.11% （14/45） and rtA181S 2.22% （1/45） respectively.The rate of HBV genotype C was higher than that of genotype B in rtA181T carriers （P 〈 0.05）.Thirteen kinds of patterns involved rtA181 of HBV mutations were found.Multi-site rtA181 mutations occurred 57.78% （26/45）.rtA181 combined with rt236 occurred 40.00% joint （18/45）,rtA181 combined with rtM204 mutation occurred 22.2% （10/45）,and the patients with multi-site rtA181 mutations seemed have higher viral load distribution,but the difference was not statistically significant （P 〉 0.05）.Nor the rtA181 mutation form either the HBV genotype correlated with multi-site rtA181 mutation （P 〉 0.05）; Most of patients （97.78%,44/45） with rtA181 mutation had lamivudine and （or） adefovir treatment history,the other one only had telbivudine antiviral treatment previously.Some kinds of subsequent salvage antiviral treatment strategy obtained 2 lg HBV DNA decrease in a month,such as plusing or switching to entecavir,lamivudine ＆amp; adefovir,and telbivudine ＆amp; adefovir.Long follow-up study indicated plusing （or） switching to entecavir can achieve significant sustained response of the salvage treatment to rtA181 mutation.Conclusions HBV rtA181 mutation patterns varied,correlated with long-term lamivudine,adefovir or telbivudine monotherapy or sequential treatment.The subsequent salvage therapy should be focused on plusing or switching to entecavir.