乙型肝炎病毒核苷（酸）类似物耐药研究进展

doi:10.3877/cma.j.issn.1674-1358.2018.01.001

核苷（酸）类似物耐药问题是慢性乙型肝炎抗病毒治疗中的重要问题之一。随着核苷（酸）类似物耐药研究的不断进展，耐药检测新技术逐渐被研发，对病毒变异的机制了解更加精确且全面。核苷（酸）类似物新的可疑耐药位点不断被提出，但这些位点的临床意义尚待进一步明确。尤其是慢性乙型肝炎患者应用核苷（酸）类似物抗病毒治疗的过程即是病毒与机体相互作用的过程逐渐被认知，在此过程中病毒准种及全基因组序列存在动态演变。核苷（酸）类似物耐药仅为此相互作用过程的表现之一，应将核苷（酸）类似物耐药放在机体免疫与病毒相互作用的整体背景下进行研究。

关键词: 肝炎、乙型、慢性, 肝炎病毒、乙型, 耐药

Nucleos(t)ide analogues resistance is still one of the most important questions in management of patients with chronic hepatitis B. New techniques to detecting resistant mutations were developed, showing the resistance more precisely and comprehensively. New possible variants related to nucleos(t)ide analogues resistance were identified, but the clinical significance still need to be verified. The researches on nucleos(t)ide analogues resistance as one of the manifestations in dynamic interaction between HBV and host immunity during nucleos(t)ide analogues therapy were realized. And nucleos(t)ide analogues resistance in the background of virus-host interaction should be understanded.

Key words: Chronic hepatitis B, Hepatitis B virus, Resistance

表1 已获得广泛认可的NAs耐药位点与部分尚处于研究阶段的NAs耐药位点

NAs种类	耐药变异	对该变异的认识现状
LAM	rtM204V/I ± rtL180M	广泛认可的耐药变异^[1,23]
	rtA181T	广泛认可的耐药变异^[1,23]
	L80I	待确认的补偿变异^[24]
	rtS117F	待确认的补偿变异^[25]
	rtL229	待确认的补偿变异^[26]
	rtM204Q	待确认的耐药变异^[27]
	rtQ267H	待确认的补偿变异^[29]
	rtL269	待确认的补偿变异^[30]
ADV	rtA181T/V	广泛认可的耐药变异^[1,23]
	rtN236T	广泛认可的耐药变异^[1,23]
	rtA181S	待确认的耐药变异^[28]
	rtQ215H	有争议的耐药变异^[31,32]
	rtI233V	有争议的耐药变异^{[33,34,35,36,37]}
LdT	rtM204V/I ± rtL180M	广泛认可的耐药变异^[1,23]
	rtA181T	广泛认可的耐药变异^[1,23]
ETV	rtM204V/I ± rtL180M基础上 + rtI169、rtT184、rtS202或rtM250任一个或多个位点变异	广泛认可的耐药变异^[1,23]
	rtI163V	待确认的耐药变异^[38]
	rtA186T	待确认的耐药变异^[38]
TDF	rtA194T	待确认的耐药变异^[39]
	rtP177G	待确认的耐药变异^[40]
	rtF249A	待确认的耐药变异^[40]
	rtA181T + rtN236T	待确认的耐药变异^[41]

表1 已获得广泛认可的NAs耐药位点与部分尚处于研究阶段的NAs耐药位点

NAs种类	耐药变异	对该变异的认识现状
LAM	rtM204V/I ± rtL180M	广泛认可的耐药变异^[1,23]
	rtA181T	广泛认可的耐药变异^[1,23]
	L80I	待确认的补偿变异^[24]
	rtS117F	待确认的补偿变异^[25]
	rtL229	待确认的补偿变异^[26]
	rtM204Q	待确认的耐药变异^[27]
	rtQ267H	待确认的补偿变异^[29]
	rtL269	待确认的补偿变异^[30]
ADV	rtA181T/V	广泛认可的耐药变异^[1,23]
	rtN236T	广泛认可的耐药变异^[1,23]
	rtA181S	待确认的耐药变异^[28]
	rtQ215H	有争议的耐药变异^[31,32]
	rtI233V	有争议的耐药变异^{[33,34,35,36,37]}
LdT	rtM204V/I ± rtL180M	广泛认可的耐药变异^[1,23]
	rtA181T	广泛认可的耐药变异^[1,23]
ETV	rtM204V/I ± rtL180M基础上 + rtI169、rtT184、rtS202或rtM250任一个或多个位点变异	广泛认可的耐药变异^[1,23]
	rtI163V	待确认的耐药变异^[38]
	rtA186T	待确认的耐药变异^[38]
TDF	rtA194T	待确认的耐药变异^[39]
	rtP177G	待确认的耐药变异^[40]
	rtF249A	待确认的耐药变异^[40]
	rtA181T + rtN236T	待确认的耐药变异^[41]

[1]	参加乙型肝炎耐药讨论会专家. 核苷和核苷酸类药物治疗慢性乙型肝炎的耐药及其管理[J/CD]. 中华实验和临床感染病杂志(电子版),2012,6(6):643-650.
[2]	杨松，成军. 乙型肝炎病毒核苷(酸)类似物耐药检测方法的进展[J]. 中华传染病杂志,2009,27(11):697-700.
[3]	Tadokoro K, Suzuki F, Kobayashi M, et al. Rapid detection of drug-resistant mutations in hepatitis B virus by the PCR-Invader assay[J]. J Virol Methods,2011,171(1):67-73.
[4]	Gauthier M, Bonnaud B, Arsac M, et al. Microarray for hepatitis B virus genotyping and detection of 994 mutations along the genome[J]. J Clin Microbiol,2010,48(11):4207-4215.
[5]	Jardi R, Rodriguez-Frias F, Tabernero D, et al. Use of the novel INNO-LiPA line probe assay for detection of hepatitis B virus variants that confer resistance to entecavir therapy[J]. J Clin Microbiol,2009,47(2):485-488.
[6]	Hu Y, Zhang WL, Xie SL, et al. An improved reverse dot hybridization for simple and rapid detection of adefovir dipivoxil-resistant hepatitis B virus[J]. Genet Mol Res,2012,11(1):53-60.
[7]	Jia S, Wang F, Li F, et al. Rapid detection of hepatitis B virus variants associated with lamivudine and adefovir resistance by multiplex ligation-dependent probe amplification combined with real-time PCR[J]. J Clin Microbiol,2014,52(2):460-466.
[8]	Sun A, Pu W, Zhou C, et al. A nanoscale mutation-sensitive on/off switch based assays for the detection of hepatitis B virus lamivudine-resistant mutations[J]. J Nanosci Nanotechnol,2015,15(5):3939-3943.
[9]	Margeridon-Thermet S, Shulman NS, Ahmed A, et al. Ultra-deep pyrosequencing of hepatitis B virus quasispecies from nucleoside and nucleotide reverse-transcriptase inhibitor (NRTI)-treated patients and NRTI-naive patients[J]. J Infect Dis,2009,199(9):1275-1285.
[10]	Rodriguez C, Chevaliez S, Bensadoun P, et al. Characterization of the dynamics of hepatitis B virus resistance to adefovir by ultra-deep pyrosequencing[J]. Hepatology,2013,58(3):890-901.
[11]	Mese S, Arikan M, Cakiris A, et al. Role of the line probe assay INNO-LiPA HBV DR and ultradeep pyrosequencing in detecting resistance mutations to nucleoside/nucleotide analogues in viral samples isolated from chronic hepatitis B patients[J]. J Gen Virol,2013,94(Pt 12):2729-2738.
[12]	Zhou B, Dong H, He Y, et al. Composition and interactions of hepatitis B virus quasispecies defined the virological response during telbivudine therapy[J]. Sci Rep,2015,5:17123.
[13]	Yin F, Wu Z, Fang W, et al. Resistant mutations and quasispecies complexity of hepatitis B virus during telbivudine treatment[J]. J Gen Virol,2015,96(11):3302-3312.
[14]	Zhang XX, Li MR, Cao Y, et al. Dynamics of genotypic mutations of the hepatitis B virus associated with long-term entecavir treatment determined with ultradeep pyrosequencing: a retrospective observational study[J]. Medicine(Baltimore),2016,95(4):e2614.
[15]	Lai MW, Yeh CT. The oncogenic potential of hepatitis B virus rtA181T/surface truncation mutant[J]. Antivir Ther,2008,13(7):875-879.
[16]	Yeh CT, Chen T, Hsu CW, et al. Emergence of the rtA181T/sW172^* mutant increased the risk of hepatoma occurrence in patients with lamivudine-resistant chronic hepatitis B[J]. BMC Cancer,2011,11:398.
[17]	Tong Y, Liu B, Liu H, et al. New universal primers for genotyping and resistance detection of low HBV DNA levels[J]. Medicine(Baltimore),2016,95(33):e4618.
[18]	Kim BK, Revill PA, Ahn SH. HBV genotypes: relevance to natural history, pathogenesis and treatment of chronic hepatitis B[J]. Antivir Ther,2011,16(8):1169-1186.
[19]	Inoue J, Ueno Y, Wakui Y, et al. Four-year study of lamivudine and adefovir combination therapy in lamivudine-resistant hepatitis B patients: influence of hepatitis B virus genotype and resistance mutation pattern[J]. J Viral Hepat,2011,18(3):206-215.
[20]	Amini-Bavil-Olyaee S, Vucur M, Luedde T, et al. Differential impact of immune escape mutations G145R and P120T on the replication of lamivudine-resistant hepatitis B virus e antigen-positive and -negative strains[J]. J Virol,2010,84(2):1026-1033.
[21]	Ohkawa K, Takehara T, Kato M, et al. Supportive role played by precore and preS2 genomic changes in the establishment of lamivudine-resistant hepatitis B virus[J]. J Infect Dis,2008,198(8): 1150-1158.
[22]	Herbers U, Amini-Bavil-Olyaee S, Mueller A, et al. Hepatitis B e antigen-suppressing mutations enhance the replication efficiency of adefovir-resistant hepatitis B virus strains[J]. J Viral Hepat,2013,20(2):141-148.
[23]	European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection[J]. J Hepatol,2012,57(1):167-185.
[24]	Warner N, Locarnini S, Kuiper M, et al. The L80I substitution in the reverse transcriptase domain of the hepatitis B virus polymerase is associated with lamivudine resistance and enhanced viral replication in vitro[J]. Antimicrob Agents Chemother,2007,51(7):2285-2292.
[25]	Lin CL, Chien RN, Hu CC, et al. Identification of hepatitis B virus rtS117F substitution as a compensatory mutation for rtM204I during lamivudine therapy[J]. J Antimicrob Chemother,2012,67(1):39-48.
[26]	Ji D, Liu Y, Li L, et al. The rtL229 substitutions in the reverse transcriptase region of hepatitis B virus (HBV) polymerase are potentially associated with lamivudine resistance as a compensatory mutation[J]. J Clin Virol,2012,54(1):66-72.
[27]	Liu Y, Xu Z, Wang Y, et al. rtM204Q may serve as a novel lamivudine-resistance-associated mutation of hepatitis B virus[J]. PLoS One,2014,9(2):e89015.
[28]	Liu Y, Li X, Xin S, et al. The rtA181S mutation of hepatitis B virus primarily confers resistance to adefovir dipivoxil[J]. J Viral Hepat,2015,22(3):328-334.
[29]	Qin B, Zhang B, Zhang X, et al. Substitution rtq267h of hepatitis B virus increases the weight of replication and lamivudine resistance[J]. Hepat Mon,2013,13(10):e12160.
[30]	Ahn SH, Kim DH, Lee AR, et al. Substitution at rt269 in hepatitis B virus polymerase is a compensatory mutation associated with multi-drug resistance[J]. PLoS One,2015,10(8):e0136728.
[31]	Micco L, Fiorino S, Loggi E, et al. Polymorphism rtQ215H in primary resistance to adefovir dipivoxil in hepatitis B virus infection: a case report[J]. BMJ Case Rep,2009,1(1):287.
[32]	Amini-Bavil-Olyaee S, Herbers U, Mohebbi SR, et al. Prevalence, viral replication efficiency and antiviral drug susceptibility of rtQ215 polymerase mutations within the hepatitis B virus genome[J]. J Hepatol,2009,51(4):647-654.
[33]	Geipel A, Glebe D, Will H, et al. Hepatitis B virus rtI233V mutation and resistance to adefovir[J]. N Engl J Med,2014,370(17):1667-1668.
[34]	Sirma H, Schildgen O. More on hepatitis B virus rtI233V mutation and resistance to adefovir[J]. N Engl J Med,2014,371(5):482-483.
[35]	Schildgen O, Olotu C, Funk A, et al. Selection and counterselection of the rtI233V adefovir resistance mutation during antiviral therapy[J]. J Clin Microbiol,2010,48(2):631-634.
[36]	Curtis M, Zhu Y, Borroto-Esoda K. Hepatitis B virus containing the I233V mutation in the polymerase reverse-transcriptase domain remains sensitive to inhibition by adefovir[J]. J Infect Dis,2007,196(10):1483-1486.
[37]	Liu Y, Xin S, Ye X, et al. Increased occurrence of mutant rtI233V of HBV in patients receiving adefovir therapy[J]. Antivir Ther,2016,21(1):9-16.
[38]	Hayashi S, Murakami S, Omagari K, et al. Characterization of novel entecavir resistance mutations[J]. J Hepatol,2015,63(3):546-553.
[39]	Amini-Bavil-Olyaee S, Herbers U, Sheldon J, et al. The rtA194T polymerase mutation impacts viral replication and susceptibility to tenofovir in hepatitis B e antigen-positive and hepatitis B e antigen-negative hepatitis B virus strains[J]. Hepatology,2009,49(4):1158- 1165.
[40]	Qin B, Budeus B, Cao L, et al. The amino acid substitutions rtP177G and rtF249A in the reverse transcriptase domain of hepatitis B virus polymerase reduce the susceptibility to tenofovir[J]. Antiviral Res,2013,97(2):93-100.
[41]	Villet S, Pichoud C, Billioud G, et al. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure[J]. J Hepatol,2008,48(5):747-755.
[42]	Locarnini S. Hepatitis B viral resistance: mechanisms and diagnosis[J]. J Hepatol,2003,39 (Suppl) 1:S124-132.
[43]	Daga PR, Duan J, Doerksen RJ. Computational model of hepatitis B virus DNA polymerase: molecular dynamics and docking to understand resistant mutations[J]. Protein Sci,2010,19(4):796-807.
[44]	Schildgen O, Sirma H, Funk A, et al. Variant of hepatitis B virus with primary resistance to adefovir[J]. N Engl J Med,2006,354(17):1807-1812.
[45]	Walsh AW, Langley DR, Colonno RJ, et al. Mechanistic characterization and molecular modeling of hepatitis B virus polymerase resistance to entecavir[J]. PLoS One,2010,5(2):e9195.
[46]	Zhu Y, Curtis M, Snow-Lampart A, et al. In vitro drug susceptibility analysis of hepatitis B virus clinical quasispecies populations[J]. J Clin Microbiol,2007,45(10):3335-3341.
[47]	Baldick CJ, Eggers BJ, Fang J, et al. Hepatitis B virus quasispecies susceptibility to entecavir confirms the relationship between genotypic resistance and patient virologic response[J]. J Hepatol,2008, 48(6):895-902.
[48]	Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus[J]. Elife,2012,1(1):e00049.
[49]	Buti M, Tsai N, Petersen J, et al. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection[J]. Dig Dis Sci,2015,60(5):1457-1464.
[50]	Kitrinos KM, Corsa A, Liu Y, et al. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B[J]. Hepatology,2014,59(2):434-442.
[51]	Chan HL, Chan CK, Hui AJ, et al. Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA[J]. Gastroenterology,2014,146(5):1240-1248.
[52]	Liu W, Song H, Chen Q, et al. Multidrug resistance protein 4 is a critical protein associated with the antiviral efficacy of nucleos(t)ide analogues[J]. Liver Int,2016,36(9):1284-1294.
[53]	Murakami E, Tsuge M, Hiraga N, et al. Effect of tenofovir disoproxil fumarate on drug-resistant HBV clones[J]. J Infect,2016,72(1):91-102.
[54]	Thai H, Campo DS, Lara J, et al. Convergence and coevolution of hepatitis B virus drug resistance[J]. Nat Commun,2012,3:789.
[55]	Warner N, Locarnini S. The antiviral drug selected hepatitis B virus rtA181T/sW172^* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound[J]. Hepatology,2008,48(1):88-98.
[56]	Sloan RD, Ijaz S, Moore PL, et al. Antiviral resistance mutations potentiate hepatitis B virus immune evasion through disruption of its surface antigen a determinant[J]. Antivir Ther,2008,13(3):439-447.
[57]	Ahn SH, Park YK, Park ES, et al. The impact of the hepatitis B virus polymerase rtA181T mutation on replication and drug resistance is potentially affected by overlapping changes in surface gene[J]. J Virol,2014,88(12):6805-6818.
[58]	Chen CH, Lee CM, Tung WC, et al. Evolution of full-length HBV sequences in chronic hepatitis B patients with sequential lamivudine and adefovir dipivoxil resistance[J]. J Hepatol,2010,52(4):478-485.
[59]	Yang S, Xing H, Wang Q, et al. De novo entecavir+adefovir dipivoxil + lamivudine triple-resistance mutations resulting from sequential therapy with adefovir dipivoxil, and lamivudine[J]. Ann Clin Microbiol Antimicrob,2016,15:24.
[60]	Ninomiya M, Kondo Y, Niihori T, et al. Sequential analysis of amino acid substitutions with hepatitis B virus in association with nucleoside/nucleotide analog treatment detected by deep sequencing[J]. Hepatol Res,2014,44(6):678-684.
[61]	Lee GH, Inoue M, Toh JK, et al. Two-step evolution of the hepatitis B drug-resistant mutations in a patient who developed primary entecavir resistance[J]. Liver Int,2013,33(4):642-646.
[62]	Bhattacharya D, Lewis MJ, Lassmann B, et al. Combination of allele-specific detection techniques to quantify minority resistance variants in hepatitis B infection: a novel approach[J]. J Virol Methods,2013,190(1-2):34-40.
[63]	Mello FC, Lago BV, Lewis-Ximenez LL, et al. Detection of mixed populations of wild-type and YMDD hepatitis B variants by pyrosequencing in acutely and chronically infected patients[J]. BMC Microbiol, 2012,12:96.
[64]	Yang S, Zheng JM, Wang XY, et al. PCR product pyrosequencing for detecting HBV resistance to adefovir[J]. Int J Infect Dis,2010,14(S2):S65.
[65]	Zhou B, Dong H, He Y, et al. Composition and interactions of hepatitis B virus quasispecies defined the virological response during telbivudine therapy[J]. Sci Rep,2015,5:17123.

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Progress in hepatitis B virus resistance to nucleos(t)ide analogues

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Progress in hepatitis B virus resistance to nucleos(t)ide analogues