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Article(id=1203057880384626712, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203057879566737430, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2023.02.0138, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1619971200000, receivedDateStr=2021-05-03, revisedDate=null, revisedDateStr=null, acceptedDate=1625587200000, acceptedDateStr=2021-07-07, onlineDate=1764760950418, onlineDateStr=2025-12-03, pubDate=1677513600000, pubDateStr=2023-02-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764760950418, onlineIssueDateStr=2025-12-03, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764760950418, creator=13701087609, updateTime=1764760950418, updator=13701087609, issue=Issue{id=1203057879566737430, tenantId=1146029695717560320, journalId=1189873630562394117, year='2023', volume='48', issue='2', pageStart='123', pageEnd='244', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1764760950222, creator=13701087609, updateTime=1764762101198, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1203062707223241334, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203057879566737430, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1203062707223241335, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203057879566737430, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=138, endPage=142, ext={EN=ArticleExt(id=1203057881693249565, articleId=1203057880384626712, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Characteristics of resistance-associated mutation in treatment-experienced chronic hepatitis B patients with low-level viremia, columnId=1203057881600974876, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=The diagnosis, treatment and prognosis of chronic hepatitis B, runingTitle=null, highlight=null, articleAbstract=

Objective To analyze the genotypic characteristics of resistance-associated mutation in reverse-transcriptase(RT) domain of hepatitis B virus (HBV) in treatment-experienced chronic hepatitis B (CHB) patients with low-level viremia (LLV). Methods CHB patients with LLV, who admitted to the Fifth Medical Center of Chinese PLA General Hospital from September 2007 to August 2019, were retrospectively enrolled. Their serum HBV DNA was extracted, and a nested PCR was used to amplify an HBV RT fragment, 1225 bp in length (nt54-nt1278), containing the HBV RT gene (nt130-nt1161) and S gene (nt155-nt835).PCR products were bidirectionally sequenced, and a molecular evolutionary tree analysis of the RT/S gene sequence was performed with MEGA 4 software, with the Hepacivirus database (http://www.ncbi.nlm.nih.gov/projects/genotyping/formpage.Cgi) with the standard sequence as the reference for HBV genotyping. Results Among the 2096 patients, 82.4% were male, mean age was(45.6±12.0) years, HBV DNA was (2.5±0.5) log10 IU/ml. Lamivudine resistance related mutations accounted for 58.0%, with M204V and L180M+M204V as the main forms; Adefovir dipivoxil resistance associated mutations accounted for 21.2%, with A181V and N36T as the predominant forms; Entecavir resistance associated mutations accounted for 17.9%, with L180M+M204I/V+T184L/A/S/I and L180M+M204V+S202G being the predominant forms; Multidrug resistance accounted for 2.9%, with L180M+M204I/V+A181V and L180M+M204V+A181V+N236T+S202G being the predominant forms. Conclusion Lamivudine and Adefovir resistance are the main drug-resistant mutation genotypes in the treated CHB patients with LLV, which reduces the gene barrier of entecavir resistance and increases the proportion of entecavir resistance. Therefore, the first-line nucleos(t)ide analogues with strong effect and low resistance should be selected for antiviral treatment.

, correspAuthors=Dong Ji, Yan Liu, authorNote=null, correspAuthorsNote=
* Liu Yan, E-mail:
Ji Dong, E-mail:
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目的 分析经治低水平病毒血症（LLV）慢性乙型肝炎（CHB）患者反转录酶（RT）区耐药突变的基因型特征。方法 回顾性研究2007年9月-2019年8月在解放军总医院第五医学中心就诊的经治LLV CHB患者2096例，提取其血清乙型肝炎病毒（HBV）DNA，并采用巢式PCR扩增HBV RT片段，长度为1225 bp（nt54-nt1278），包含HBV RT基因（nt130-nt1161）及S基因（nt155-nt835）。对PCR产物进行双向测序，采用MEGA 4软件对RT/S基因序列进行分子进化树分析，以肝炎病毒数据库（http://www.ncbi.nlm.nih.gov/projects/genotyping/formpage.Cgi）的标准序列为参照进行HBV基因分型。结果 2096例CHB患者中男1727例，女369例，年龄（45.6±12.0）岁，HBV DNA为（2.5±0.5）log10 IU/ml。拉米夫定耐药相关突变1216例，占58.0%，以M204I/V、L180M+M204V为主要形式；阿德福韦耐药相关突变444例，占21.2%，以A181V、N36T为主要形式；恩替卡韦耐药相关突变376例，占17.9%，以L180M+M204I/V+T184L/A/S/I、L180M+M204V+S202G为主要形式；多药耐药60例，占2.9%，以L180M+M204I/V+A181V、L180M+M204V+A181V+N236T+S202G为主要形式。结论 经治LLV的CHB患者耐药突变基因型以拉米夫定和阿德福韦耐药为主，且降低了恩替卡韦耐药的基因屏障，提高了恩替卡韦的耐药比例，抗病毒治疗应选择强效、低耐药率的一线药物。

, correspAuthors=纪冬, 刘妍, authorNote=null, correspAuthorsNote=
刘妍，E-mail：
纪冬，E-mail：
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王建军，医学博士，副主任医师，主要从事慢性乙型肝炎及肝硬化的基础与临床研究

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王建军，医学博士，副主任医师，主要从事慢性乙型肝炎及肝硬化的基础与临床研究

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王建军，医学博士，副主任医师，主要从事慢性乙型肝炎及肝硬化的基础与临床研究

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postcode=null, companyName=null, departmentName=null, remark=2解放军总医院第五医学中心感染病医学部，北京 100039)])], figs=[ArticleFig(id=1203057887787573599, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057880384626712, language=EN, label=Fig. 1, caption=Genotype distribution of drug resistance mutations in the reverse transcriptase domain of patients with CHB in different drug resistant groups, figureFileSmall=4unXZMl4k4wZOK3NbQl3mQ==, figureFileBig=kk166CpAXThNBkEC0/igow==, tableContent=null), ArticleFig(id=1203057887934374251, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057880384626712, language=CN, label=图1, caption=各耐药组CHB患者反转录酶区耐药突变的基因型分布

A. LAM耐药组；B. ADV耐药组；C. ETV耐药组；D. 多药耐药组

, figureFileSmall=4unXZMl4k4wZOK3NbQl3mQ==, figureFileBig=kk166CpAXThNBkEC0/igow==, tableContent=null), ArticleFig(id=1203057888123117946, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057880384626712, language=EN, label=Tab. 1, caption=

Comparison of clinical characteristics among the patients with CHB in different drug resistant groups

, figureFileSmall=null, figureFileBig=null, tableContent=
指标LAM耐药组(n=1216)ADV耐药组(n=444)ETV耐药组(n=376)多药耐药组(n=60)χ2/F/ZP
性别[例(%)]    2.6250.269
 男977(80.3)386(86.9)316(84.0)48(80.0)
 女239(19.7)58(13.1)60(16.0)12(20.0)
年龄(岁，$\bar{x}±s$)44.1±12.348.0±11.147.8±10.744.6±10.72.6840.069
HBV基因型 [例(%)]    5.4090.493
 B型180(14.8)70(15.8)47(12.5)4(6.7)
 C型1027(84.5)371(83.6)326(86.7)56(93.3)
 D型9(0.7)3(0.6)3(0.8)0(0)
HBeAg[例(%)]    12.051<0.001
 阳性431(35.4)122(27.5)142(37.8)19(31.7)
 阴性785(64.6)322(72.5)234(62.2)41(68.3)
TBIL[μmol/L, M(Q1, Q3)]13.6(9.8, 19.2)14(10.4, 20.5)12.8(9.6, 17.7)13.9(9.8, 22.7)6.3720.095
ALT[U/L, M(Q1, Q3)]27(19, 40)28(21, 40)29(21, 43)26(17, 37)6.8380.077
AST[U/L, M(Q1, Q3)]27(22, 39)28(23, 41)28(22, 37)28(21, 36)5.4940.139
), ArticleFig(id=1203057888198615425, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057880384626712, language=CN, label=表1, caption=

各耐药组CHB患者临床特征比较

, figureFileSmall=null, figureFileBig=null, tableContent=
指标LAM耐药组(n=1216)ADV耐药组(n=444)ETV耐药组(n=376)多药耐药组(n=60)χ2/F/ZP
性别[例(%)]    2.6250.269
 男977(80.3)386(86.9)316(84.0)48(80.0)
 女239(19.7)58(13.1)60(16.0)12(20.0)
年龄(岁，$\bar{x}±s$)44.1±12.348.0±11.147.8±10.744.6±10.72.6840.069
HBV基因型 [例(%)]    5.4090.493
 B型180(14.8)70(15.8)47(12.5)4(6.7)
 C型1027(84.5)371(83.6)326(86.7)56(93.3)
 D型9(0.7)3(0.6)3(0.8)0(0)
HBeAg[例(%)]    12.051<0.001
 阳性431(35.4)122(27.5)142(37.8)19(31.7)
 阴性785(64.6)322(72.5)234(62.2)41(68.3)
TBIL[μmol/L, M(Q1, Q3)]13.6(9.8, 19.2)14(10.4, 20.5)12.8(9.6, 17.7)13.9(9.8, 22.7)6.3720.095
ALT[U/L, M(Q1, Q3)]27(19, 40)28(21, 40)29(21, 43)26(17, 37)6.8380.077
AST[U/L, M(Q1, Q3)]27(22, 39)28(23, 41)28(22, 37)28(21, 36)5.4940.139
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经治低水平病毒血症慢性乙型肝炎患者耐药突变的基因型特征
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王建军 1 , 纪冬 1, * , 李乐 2 , 思兰兰 2 , 陈容娟 2 , 李原华 1 , 葛斐林 1 , 姚增涛 2 , 徐东平 2 , 刘妍 2, *
解放军医学杂志 | 慢性乙型肝炎的诊治与预后专题研究 2023,48(2): 138-142
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解放军医学杂志 | 慢性乙型肝炎的诊治与预后专题研究 2023, 48(2): 138-142
经治低水平病毒血症慢性乙型肝炎患者耐药突变的基因型特征
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王建军1, 纪冬1, * , 李乐2, 思兰兰2, 陈容娟2, 李原华1, 葛斐林1, 姚增涛2, 徐东平2, 刘妍2, *
作者信息
  • 1解放军总医院第五医学中心肝病医学部，北京 100039
  • 2解放军总医院第五医学中心感染病医学部，北京 100039

    • 王建军，医学博士，副主任医师，主要从事慢性乙型肝炎及肝硬化的基础与临床研究

通讯作者:

刘妍，E-mail：
纪冬，E-mail：
Characteristics of resistance-associated mutation in treatment-experienced chronic hepatitis B patients with low-level viremia
Jian-Jun Wang1, Dong Ji1, * , Le Li2, Lan-Lan Si2, Rong-Juan Chen2, Yuan-Hua Li1, Fei-Lin Ge1, Zeng-Tao Yao2, Dong-Ping Xu2, Yan Liu2, *
Affiliations
  • 1Department of Liver Diseases, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
  • 2Department of Infectious Diseases, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
出版时间: 2023-02-28 doi: 10.11855/j.issn.0577-7402.2023.02.0138
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摘要
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目的 分析经治低水平病毒血症（LLV）慢性乙型肝炎（CHB）患者反转录酶（RT）区耐药突变的基因型特征。方法 回顾性研究2007年9月-2019年8月在解放军总医院第五医学中心就诊的经治LLV CHB患者2096例，提取其血清乙型肝炎病毒（HBV）DNA，并采用巢式PCR扩增HBV RT片段，长度为1225 bp（nt54-nt1278），包含HBV RT基因（nt130-nt1161）及S基因（nt155-nt835）。对PCR产物进行双向测序，采用MEGA 4软件对RT/S基因序列进行分子进化树分析，以肝炎病毒数据库（http://www.ncbi.nlm.nih.gov/projects/genotyping/formpage.Cgi）的标准序列为参照进行HBV基因分型。结果 2096例CHB患者中男1727例，女369例，年龄（45.6±12.0）岁，HBV DNA为（2.5±0.5）log10 IU/ml。拉米夫定耐药相关突变1216例，占58.0%，以M204I/V、L180M+M204V为主要形式；阿德福韦耐药相关突变444例，占21.2%，以A181V、N36T为主要形式；恩替卡韦耐药相关突变376例，占17.9%，以L180M+M204I/V+T184L/A/S/I、L180M+M204V+S202G为主要形式；多药耐药60例，占2.9%，以L180M+M204I/V+A181V、L180M+M204V+A181V+N236T+S202G为主要形式。结论 经治LLV的CHB患者耐药突变基因型以拉米夫定和阿德福韦耐药为主，且降低了恩替卡韦耐药的基因屏障，提高了恩替卡韦的耐药比例，抗病毒治疗应选择强效、低耐药率的一线药物。

乙型肝炎，慢性  /  低水平病毒血症  /  耐药  /  突变

Objective To analyze the genotypic characteristics of resistance-associated mutation in reverse-transcriptase(RT) domain of hepatitis B virus (HBV) in treatment-experienced chronic hepatitis B (CHB) patients with low-level viremia (LLV). Methods CHB patients with LLV, who admitted to the Fifth Medical Center of Chinese PLA General Hospital from September 2007 to August 2019, were retrospectively enrolled. Their serum HBV DNA was extracted, and a nested PCR was used to amplify an HBV RT fragment, 1225 bp in length (nt54-nt1278), containing the HBV RT gene (nt130-nt1161) and S gene (nt155-nt835).PCR products were bidirectionally sequenced, and a molecular evolutionary tree analysis of the RT/S gene sequence was performed with MEGA 4 software, with the Hepacivirus database (http://www.ncbi.nlm.nih.gov/projects/genotyping/formpage.Cgi) with the standard sequence as the reference for HBV genotyping. Results Among the 2096 patients, 82.4% were male, mean age was(45.6±12.0) years, HBV DNA was (2.5±0.5) log10 IU/ml. Lamivudine resistance related mutations accounted for 58.0%, with M204V and L180M+M204V as the main forms; Adefovir dipivoxil resistance associated mutations accounted for 21.2%, with A181V and N36T as the predominant forms; Entecavir resistance associated mutations accounted for 17.9%, with L180M+M204I/V+T184L/A/S/I and L180M+M204V+S202G being the predominant forms; Multidrug resistance accounted for 2.9%, with L180M+M204I/V+A181V and L180M+M204V+A181V+N236T+S202G being the predominant forms. Conclusion Lamivudine and Adefovir resistance are the main drug-resistant mutation genotypes in the treated CHB patients with LLV, which reduces the gene barrier of entecavir resistance and increases the proportion of entecavir resistance. Therefore, the first-line nucleos(t)ide analogues with strong effect and low resistance should be selected for antiviral treatment.

hepatitis B, chronic  /  low level viremia  /  drug-resistant  /  mutation
王建军, 纪冬, 李乐, 思兰兰, 陈容娟, 李原华, 葛斐林, 姚增涛, 徐东平, 刘妍. 经治低水平病毒血症慢性乙型肝炎患者耐药突变的基因型特征. 解放军医学杂志, 2023 , 48 (2) : 138 -142 . DOI: 10.11855/j.issn.0577-7402.2023.02.0138
Jian-Jun Wang, Dong Ji, Le Li, Lan-Lan Si, Rong-Juan Chen, Yuan-Hua Li, Fei-Lin Ge, Zeng-Tao Yao, Dong-Ping Xu, Yan Liu. Characteristics of resistance-associated mutation in treatment-experienced chronic hepatitis B patients with low-level viremia[J]. Medical Journal of Chinese People’s Liberation Army, 2023 , 48 (2) : 138 -142 . DOI: 10.11855/j.issn.0577-7402.2023.02.0138
正文
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核苷(酸)类似物[nucleos(t)ide analogues，NAs]可强效抑制乙型肝炎病毒(hepatitis B virus，HBV)复制[1-2]，实现完全病毒学应答(CVR)，然而部分患者始终无法获得CVR，美国肝病研究学会(AASLD)将此种情况定义为低水平病毒血症(low-level viremia，LLV)[3]。NAs经治患者中，存在LLV者较易发生病毒耐药，导致抗病毒治疗失败，进一步引发病情进展，导致肝纤维化、肝硬化甚至肝癌的发生，故经治LLV不容忽视，尤其是其中发生药物耐药者。大样本的LLV耐药基因型分析少见报道，本研究通过大样本回顾性调查研究，分析经治的慢性乙型肝炎(CHB)合并LLV患者反转录酶(RT)区耐药突变的基因型特征，以便精准调整治疗策略。
1 资料与方法
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1.1 研究对象
选取2007年9月-2019年8月在解放军总医院第五医学中心就诊的经治LLV CHB患者2096例。其中男1727例，女369例，年龄(45.6±12.0)岁，HBV DNA为(2.5±0.5) log10 IU/ml，谷丙转氨酶(ALT)为(38.7±56.8) U/L，谷草转氨酶(AST)为(39.2±50.8) U/L，总胆红素(TBIL)为(23.9±50.1) μmol/L。其中乙型肝炎e抗原(HBeAg)阳性714例，乙型肝炎e抗体(HBeAb)阴性1382例。参照2005年中华医学会修订的慢性乙肝指南标准进行诊断[4]。经过口服拉米夫定(LAM)、替比夫定(LdT)、阿德福韦(ADV)、恩替卡韦(ETV)等至少一种抗病毒药物或序贯应用多种抗病毒药物治疗至少12个月后仍合并LLV(HBV DNA 20~2000 IU/ml)的患者，排除HBV与丙型肝炎病毒(HCV)、甲型肝炎病毒(HAV)、丁型肝炎病毒(HDV)、戊型肝炎病毒(HEV)或人免疫缺陷病毒(HIV)混合感染。
1.2 方法
提取患者的血清HBV DNA，并使用巢式PCR扩增HBV RT片段，长度为1225 bp(nt54-nt1278)，包含HBV RT基因(nt130-nt1161)及S基因(nt155-nt835)。对PCR产物进行双向测序，用MEGA 4软件对RT/S基因序列进行分子进化树分析，以肝炎病毒数据库(http://www.ncbi.nlm.nih.gov/projects/genotyping/formpage.Cgi)的标准序列为参照进行HBV基因分型：B型301例，C型1780例，D型15例。分析RT区，根据不同的耐药位点，将2096例患者分为LAM耐药组(L180和M204位点，1216例)、ADV耐药组(A181V和N236T位点，444例)、ETV耐药组(L180和M204再加上T184L/A/S/I、S202G和M250等位点，376例)及多药耐药组(LAM/ADV或ADV/ETV耐药位点，60例)，分析各耐药组RT区耐药突变的基因型分布特点。
1.3 统计学处理
应用SPSS 26.0软件进行统计分析。符合正态分布的计量资料以$\bar{x}±s$表示，两组间比较采用t检验，多组比较采用方差分析；非正态分布计量资料以M(Q1，Q3)表示，两组比较采用Mann-Whitney检验，多组比较采用Kruskal-Wallis检验。计数资料以例(%)表示，组间比较采用χ2检验。P<0.05为差异有统计学意义。
2 结果
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2.1 各耐药组CHB患者的临床特征比较
各耐药组CHB患者的性别、年龄、HBV基因型、TBIL、ALT、AST比较差异无统计学意义(P>0.05)。而各耐药组HBeAg阳性率差异有统计学意义，均为HBeAg阳性患者的比例较低，其中ADV耐药组的HBeAg阳性患者比例最低(P<0.05，表1)。
2.2 各耐药组RT区耐药突变的基因型分布
LAM耐药相关突变以M204I/V、L180M+M204V为主要形式，分别占29.5%、29.4%；ADV耐药相关突变以A181V、N236T为主要形式，分别占44.8%、39.4%；ETV耐药相关突变以L180M+M204I/V+T184L/A/S/I、L180M+M204V+S202G为主要形式，分别占39.6%、37.8%；多药耐药相关突变以L180M+M204I/V+A181V、L180M+M204V+N236T+A181V+S202G为主要形式，占76.7%(图1)。
3 讨论
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乙型肝炎是严重危害我国人民健康的疾病，其抗病毒治疗方案最初为干扰素，但不良反应较多，患者依从性不佳[5-6]。自1999年LAM获批上市以来，陆续有ADV、LdT、ETV、替诺福韦(TDF)、丙酚替诺福韦(TAF)等NAs药物上市，该类药物可强效抑制HBV复制，实现CVR；然而有部分患者始终无法获得CVR，临床上可以检测到HBV DNA长期的低病毒载量复制(20~2000 IU/ml)。近年来研究发现，持续或间断的LLV与肝纤维化的进展相关[7-8]，并可显著增高肝硬化患者发生肝癌的概率[9]，甚至造成失代偿期肝硬化患者的死亡风险明显增高[10]。因此，LLV越来越受到重视。
口服NAs可引起病毒耐药，HBV DNA的耐药突变主要体现为基因RT区位点的突变，但目前尚无TDF耐药的报告[11]。在LLV患者中，由于病毒长期存在，药物无法完全清除病毒，在长时间低水平病毒持续刺激下，即使是目前常见的强效、低耐药性的ETV，也存在耐药情况[11-13]。
本研究中LAM耐药患者最多，占58%(1216/2096)，主要原因是LAM是既往最常用的抗病毒药物，应用时间最久，耐药突变最常见，其5年耐药率可达60%~70%，且LAM与LdT耐药位点有交叉，还可增高ETV的耐药率[14]。既往研究发现，LAM耐药后基因变异的主要位点为rtM204V/I和(或)rtL180M[15-16]。在本研究中，LAM耐药相关突变以M204V、L180M+M204V为主要形式，分别占29.5%、29.4%；其他突变形式包括L180I/V+M204V、L180M+M204I/V及L180M+M204I等。
与LAM相比，ADV的耐药率要低得多，长期应用人群的2年和5年耐药率分别为2%和29%[17]。在本研究中，ADV耐药占所有筛选病例的21.2%(444/2096)，以A181V、N236T为主要形式，分别占ADV耐药病例的44.8%、39.4%；A181V+N236T变异占15.8%。有研究表明，A181V变异还可降低患者对LAM、TDF治疗的敏感性，且单个A181V变异可导致LAM与ADV产生交叉耐药[18]，故在进行ADV的挽救治疗时，需特别重视该变异的存在与否。另外，本研究还发现各耐药组的HBeAg阳性患者比例均较低，其中ADV耐药组的HBeAg阳性患者比例最低，提示HBeAg阴性患者可能更容易出现ADV耐药。
ETV耐药的变异位点是在LAM耐药变异位点L180M、M204的基础上，再加上T184、S202及M250中至少一个位点才能导致ETV耐药，所以ETV耐药的基因屏障较高。有研究显示ETV初治患者的耐药率为1.7%，但对已发生LAM变异的患者，再应用ETV治疗后耐药比例明显增大[19]。在本研究中，ETV耐药占所有筛选病例的17.9%(376/2096)，以L180M+M204I/V+T184L/A/S/I、L180M+M204V+S202G为主要形式，分别占39.6%、37.8%；ETV耐药比例的增高主要考虑这部分患者在应用ETV治疗之前就应用了LAM或LdT，然后再换用ETV，先出现的LAM或LdT耐药降低了ETV耐药的基因屏障，所以耐药比例增大。本研究中多药耐药的比例较小，占2.9%(60/2096)，以LAM+ADV耐药的L180M+M204I/V+A181V及ETV+ADV耐药的L180M+M204V+N236T+A181V+S202G为主要形式，分别占61.7%及15.0%。
通过上述LLV耐药基因位点的分析可以发现，既往长期应用LAM、LdT及ADV的患者在LLV耐药中占主要部分，且LAM及LdT的应用降低了ETV的耐药基因屏障，提高了ETV的耐药率，增加了发生耐药后挽救治疗的难度。所以目前提倡初治选择一线药物ETV、TDF或TAF。对于既往应用二线药物LAM、LdT或ADV的患者，即使目前没有耐药，也最好换用一线药物治疗。对于应用一线抗病毒药物治疗后仍存在LLV的患者，目前尚无明确的指导意见。对于接受TAF、TDF或ETV单药治疗的LLV患者，无论ALT水平如何，AASLD 2018版指南均建议维持当前单药治疗，但该建议证据质量等级极低，且推荐等级为酌情[20]，具体情况有待进一步研究。对于应答不佳的CHB患者，我国指南建议采用ETV、TDF或TAF治疗48周，若HBV DNA>2×103 IU/ml，排除依从性和检测误差后，对于采用ETV治疗者，可换用TDF或TAF；对于采用TDF或TAF治疗者，可换用ETV，或两种药物联合使用[21]。目前有研究表明，对于采用ETV治疗的LLV患者，换用TAF治疗后可获得CVR，ALT复常率也明显提高，肝脏硬度也可得到明显改善[22]。
综上所述，对于LLV患者，换用另一种药物治疗可以获得更好的预后，但联合另一种强效抗病毒药物治疗的有效性、长期使用替代治疗方案的安全性及具体机制尚需随机对照研究进一步证实。
基金
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  • 国家自然科学基金创新群体项目(81721002)
  • 国家自然科学基金重点项目(81930110)
  • 国家“十三五”科技重大专项(2018ZX10725506)
  • 首都临床特色应用研究特色课题(Z181100001718034)
  • 解放军总医院医疗大数据与人工智能研发项目(2019MBD-024)
  • 中华社会救助基金会菊梅肝胆病防治能力建设专项基金重点项目(2018JM12603003)
文献
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参考文献 引证文献
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2023年第48卷第2期
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doi: 10.11855/j.issn.0577-7402.2023.02.0138
  • 接收时间：2021-05-03
  • 首发时间：2025-12-03
  • 出版时间：2023-02-28
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  • 收稿日期：2021-05-03
  • 录用日期：2021-07-07
基金
National Natural Science Foundation of China(81721002)
国家自然科学基金创新群体项目(81721002)
National Natural Science Foundation of China(81930110)
国家自然科学基金重点项目(81930110)
National Major Science and Technology Special Project of China(2018ZX10725506)
国家“十三五”科技重大专项(2018ZX10725506)
Capital Characteristic Clinic Project of Beijing Municipal Science and Technology Commission(Z181100001718034)
首都临床特色应用研究特色课题(Z181100001718034)
Medical Big Data and Artificial Intelligence Development Fund of Chinese PLA General Hospital(2019MBD-024)
解放军总医院医疗大数据与人工智能研发项目(2019MBD-024)
Key Project of Jumei Special Fund for Hepatobiliary Disease Prevention and Treatment, China Social Assisstance Foundation(2018JM12603003)
中华社会救助基金会菊梅肝胆病防治能力建设专项基金重点项目(2018JM12603003)
作者信息
    1解放军总医院第五医学中心肝病医学部，北京 100039
    2解放军总医院第五医学中心感染病医学部，北京 100039

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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