MLPA结合RT-PCR快速检测乙型肝炎病毒拉米夫定及阿德福韦耐药
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摘要
乙型肝炎病毒(hepatitis B virus，HBV)耐药的产生成为长期治疗慢性乙型肝炎成功与否的主要障碍。目前检测HBV耐药的方法多种多样，但都因存在一些缺陷，其临床应用受到限制，例如灵敏度低、耗时长、成本高等缺点。在本论文中，我们建立了一种可以同时检测HBV拉米夫定(lamivudine, LAM)及阿德福韦(adefovir, ADV)耐药突变株(rtM204V, rtM204I, rtA181T, rtA181V, rtN236T)的多重连接探针-实时荧光PCR(multiplex ligation-dependent probe real-time PCR, MLP-RT-PCR)方法。该方法结合了多重连接探针扩增(multiplex ligation-dependent probe amplification，MLPA)技术的灵敏、特异、高通量和实时PCR方便快捷、实时检测的特点。通过检测临床116例慢性乙肝患者DNA样本对MLP-RT-PCR方法进行了方法性能评价，其中检测出LAM耐药突变41例(35.3%)，ADV耐药突变17例(14.7%)及两者共同耐药突变5例(4.3%)。检测结果与金标准直接测序方法比较，MLP-RT-PCR检测rtM204V、rtM204I、rtA181T、rtA181V和rtN236T的符合率分别为95.7%(111/116)、98.3%(114/116)、99.1%(115/116)、98.3%(114/116)和99.1%(115/116)。MLP-RT-PCR方法检测低比例突变株的灵敏度比直接测序方法更高，能够检测0.1%以上的rtM204V、rtM204I、rtA181T和rtN236T突变株，1%以上的rtA181V突变株。MLP-RT-PCR发现了4例低比例临床突变株，并进一步被TA克隆测序方法确证。MLP-RT-PCR能够快速、灵敏检测HBV多重耐药突变位点，为临床提供了一种成本低廉、检测快速的乙型肝炎耐药检测方法。
Drug-resistant mutations of hepatitis B virus (HBV) are the major obstacles tosuccessful therapy for chronic hepatitis B. Although there are many methods to detect theantiviral drug-resistant mutations of HBV, their applications are restricted because of theshortcomings such as low sensitivity, time required and high cost. Here a multiplexligation-dependent probe real-time PCR (MLP-RT-PCR) method was developed to detectlamivudine (LAM) and adefovir (ADV) resistant HBV mutants (rtM204V/I, rtA181V/T andrtN236T) simultaneously. The new method combined the high-throughout of multiplexligation-dependent probe amplification (MLPA) with the rapid and sensitive detection ofreal-time PCR. In this report, the MLP-RT-PCR was evaluated by detecting drug-resistantmutants in116patients with chronic hepatitis B. By MLP-RT-PCR analysis, LAM-resistantmutations were detected in41patients (35.3%), ADV-resistant mutations were detected in17patients (14.7%), LAM and ADV-resistant mutations were detected in5patients (4.3%).Based on the results of MLP-RT-PCR, the mutations rtM204V, rtM204I, rtA181T, rtA181Vand rtN236T were95.7%(111/116),98.3%(114/116),99.1%(115/116),98.3%(114/116),and99.1%(115/116), respectively, in concordance with those of direct sequencing. TheMLP-RT-PCR assay was more sensitive than direct sequencing when detecting mutationswith low percentage.The channels for rtM204V, rtM204I, rtA181T and rtN236T detectedmutants whose percentage were over0.1%, while the channels for rtA181V detectedmutants whose percentage was over1%. Four samples containing the low percentage(<10%) mutants were identified by MLP-RT-PCR and further confirmed by clonalsequencing. MLP-RT-PCR is a rapid and sensitive method that enables the detection ofmulti-drug-resistant HBV mutations in clinical practices.
Drug-resistant mutations of hepatitis B virus (HBV) are the major obstacles tosuccessful therapy for chronic hepatitis B. Although there are many methods to detect theantiviral drug-resistant mutations of HBV, their applications are restricted because of theshortcomings such as low sensitivity, time required and high cost. Here a multiplexligation-dependent probe real-time PCR (MLP-RT-PCR) method was developed to detectlamivudine (LAM) and adefovir (ADV) resistant HBV mutants (rtM204V/I, rtA181V/T andrtN236T) simultaneously. The new method combined the high-throughout of multiplexligation-dependent probe amplification (MLPA) with the rapid and sensitive detection ofreal-time PCR. In this report, the MLP-RT-PCR was evaluated by detecting drug-resistantmutants in116patients with chronic hepatitis B. By MLP-RT-PCR analysis, LAM-resistantmutations were detected in41patients (35.3%), ADV-resistant mutations were detected in17patients (14.7%), LAM and ADV-resistant mutations were detected in5patients (4.3%).Based on the results of MLP-RT-PCR, the mutations rtM204V, rtM204I, rtA181T, rtA181Vand rtN236T were95.7%(111/116),98.3%(114/116),99.1%(115/116),98.3%(114/116),and99.1%(115/116), respectively, in concordance with those of direct sequencing. TheMLP-RT-PCR assay was more sensitive than direct sequencing when detecting mutationswith low percentage.The channels for rtM204V, rtM204I, rtA181T and rtN236T detectedmutants whose percentage were over0.1%, while the channels for rtA181V detectedmutants whose percentage was over1%. Four samples containing the low percentage(<10%) mutants were identified by MLP-RT-PCR and further confirmed by clonalsequencing. MLP-RT-PCR is a rapid and sensitive method that enables the detection ofmulti-drug-resistant HBV mutations in clinical practices.
引文
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6Yoshida S, Hige S, Yoshida M, Yamashita N, Fujisawa S, Sato K, Kitamura T, Nishimura M, Chuma M, Asaka M,Chiba H. Quantification of lamivudine-resistant hepatitis B virus mutants by type-specific TaqMan minor groove binderprobe assay in patients with chronic hepatitis B. Ann. Clin. Biochem.2008.45:59–64.
7Lole KS, Arankalle VA. Quantitation of hepatitis B virus DNA by real-time PCR using internal amplification controland dual TaqMan MGB probes. J. Virol. Methods.2006.135:83–90.
8Hua R, Tanaka Y, Fukai K, Tada M, Seto M, Asaoka Y, Ohta M, Goto T, Kanai F, Kato N, Yoshida H, Kawabe T,Yokosuka O, Omata M. Rapid detection of the hepatitis B virus YMDD mutant using TaqMan-minor groove binderprobes. Clin. Chim. Acta.2008.395:151–154
9Chieochansin T, Chutinimitkul S, Payungporn S, Theamboonlers A, Tangkijvanich P, Komolmit P, Poovorawan Y.Rapid detection of lamivudine-resistant hepatitis B virus mutations by PCR-based methods. Tohoku. J. Exp. Med.2006.210:67–78.
1Allen MI, Deslauriers M, Andrews CW, Tipples GA, Walters KA, Tyrrell DL, Brown N, Condreay LD. Identificationand characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group.
2Hepatology.1998.27:1670–1677.Borroto-Esoda K, Miller MD, Arterburn S. Pooled analysis of amino acid changes in the HBV polymerase in patientsfrom four major adefovir dipivoxil clinical trials. J. Hepatol.2007.47:492–498.
3Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negativechronic hepatitis B. N. Engl. J. Med.2005.352:2673–2681.
4Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of40nucleic acidsequences by multiplex ligation-dependent probe amplification. Nucleic. Acids. Res.2002.30:e57.
5Bunyan DJ, Skinner AC, Ashton EJ, et al. Simultaneous MLPA-based multiplex point mutation and deletion analysis
6of the dystrophin gene. Mol. Biotechnol.2007.35:135–140.Bergval I, Sengstake S, Brankova N, Levterova V, Abadía E, Tadumaze N, et al. Combined species identification,genotyping, and drug resistance detection of Mycobacterium tuberculosis cultures by MLPA on a bead-based array. PLoS.One.2012.7:e43240
7Bergval IL, Vijzelaar RN, Dalla Costa ER, Schuitema AR, Oskam L, Kritski AL, Klatser PR, Anthony RM.Development of multiplex assay for rapid characterization of Mycobacterium tuberculosis. J. Clin. Microbiol.2008.46:689–699.
8Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology2009;137:1593–608.
9Tillmann HL. Antiviral therapy and resistance with hepati-tis B virus infection. World J Gastroenterol2007;13(1):125–40.
10Locarnini S, Bowden S. Drug resistance in antiviral therapy. Clin Liver Dis2010;14(3):439–59.
1Werle-Lapostolle B, Bowden S, Locarnini S et al. Persistence of cccDNA during the natural history of chronic hepatitisB and decline during adefovir dipivoxil therapy.Gastroenter-ology2004;126:1750–8.
2Amini-Bavil-Olyaee S, Vucur M, Luedde T, Trautwein C, Tacke F. Differential impact of immune escape mutationsG145R and P120T on the replication of lamivudine-resistant hepatitis B virus e antigen-positive and–negative strains. J3Virol2010;84:1026–33.
Zhou T, Saputelli J, Aldrich CE, Deslauriers M, Condreay LD, Mason WS. Emergence of drug-resistant populations ofwoodchuck hepatitis virus in woodchucks treated with the antiviral nucleoside lamivudine. Antimicrob AgentsChemother1999;43:1947–54.
4Amini-Bavil-Olyaee S, Vucur M, Luedde T, Trautwein C, Tacke F. Differential impact of immune escape mutationsG145R and P120T on the replication of lamivudine-resistant hepatitis B virus e antigen-positive and–negative strains. JVirol2010;84:1026–33.
5Sheldon J, Soriano V. Hepatitis B virus escape mutantsinduced by antiviral therapy. J Antimicrob Chemother2008;61:766–8.
Sloan RD, Ijaz S, Moore PL, Harrison TJ, Teo CG, Tedder RS. Antiviral resistance mutations potentiate hepatitis Bvirus immune evasion through disruption of its surface antigen a determinant. Antivir Ther2008;13:439–47.
1Bartholomeusz A, Tehan BG, Chalmers DK. Comparisons of the HBV and HIV polymerase, and antiviral resistancemutations. Antivir Ther2004;9:149–60.
2Yeh CT, Chien RN, Chu CM, Liaw YF. Clearance of the original hepatitis B virus YMDD-motif mutants withemer-gence of distinct lamivudine resistant mutants during pro-longed lamivudine therapy. Hepatology2000;31:1318–26.
Angus P, Vaughan R, Xiong S et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novelmutation in the HBV polymerase. Gastroenterology2003;125:292–7.
4Bartholomeusz A, Locarmini S, Ayves A et al. Molecular modelling of hepatitis B virus polymerase and Adefovirresistance identifies three clusters of mutations. Hepatology2004;40:246A
5Bartholomeusz A, Locarmini S, Ayves A et al. Mechanistic basis for hepatitis B virus resistance to acyclic nucleosidephosphonate analogues, Adefovir and Tenofovir. Hepatol-ogy2005;42:594A.
6Bartholomeusz A, Locarnini SA. Antiviral drug resistance: clinical consequences and molecular aspects. Semin LiverDis2006;26:162–70
Zoulim F. Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis Bvirus infection. Antiviral Res2004;64:1–15.
1Lai CL, Dienstag J, Schiff E et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapyforpatients with chronic hepatitis B. Clin Infect Dis2003;36:687–96.
2Lok AS, Lai CL, Leung N et al. Long-term safety of lamivu-dine treatment in patients with chronic hepatitisB.Gastro-enterology2003;125:1714–22.
3Tenney DJ, Levine SM, Rose RE et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additionalsubstitutions in virus already resistant to Lamivudine.Antimicrob Agents Chemother2004;48:3498–507.
4Holomán J, Glasa J. EASL clinical practice guidelines. JHepatol2009;51:821–2.
5Lok AS, McMahon BJ. Chronic hepatitis B: update2009.Hepatology2009;50:661–2
6Qin B,Zhang B, Zhang X,He T,Xu W,Fu L. Tu C. Substitution Rtq267h of Hepatitis B Virus Increases the Weight ofReplication and Lamivudine Resistance.Hepat Mon.2013October;13(10):e12160
7Ono SK, Kato N, Shiratori Y et al. The polymerase L528M mutation cooperates with nucleotide binding-sitemuta-tions, increasing hepatitis B virus replication and drug resistance. J Clin Invest2001;107:449–55.
8Allen MI, Deslauriers M, Andrews CW et al. Identification and characterisation of mutations in hepatitis B virusresis-tant to lamivudine. Lamivudine Clinical Investigation Group.Hepatology1998;27:1670–7
9Ling R, Mutimer D, Ahmed M et al. Selection of mutations in the hepatitis B virus polymerase during therapy oftrans-plant recipients with lamivudine. Hepatology1996;24:711–13.
10Tipples GA, Ma MM, Fischer KP, Bain VG, Kneteman NM,Tyrrell DL. Mutation in HBV RNA-dependent DNApoly-merase confers resistance to lamivudinein vivo. Hepatology1996;24:714–17
11Delaney WE IV, Yang H, Westland CE et al. The hepatitis B virus polymerase mutation rtV173L is selected duringlami-vudine therapy and enhances viral replication in vitro. JVirol2003;77:11833–41.
Nakanishi H, Kurosaki M, Asahina Y et al. Polymerase domain B mutation is associated with hepatitis relapse duringlong-term lamivudine therapy for chronic hepatitis B. Intervirology2005;48:381–8.
13Pai SB, Bozdayi AM, Pai RB et al. Emergence of a novel mutation in the FLLA region of hepatitis B virus duringlamivudine therapy. Antimicrob Agents Chemother2005;49:2618–24
14Yatsuji H, Noguchi C, Hiraga N et al. Emergence of a novel lamivudine-resistant hepatitis B virus variant with asubstitution outside the YMDD motif. Antimicrob Agents Chemother2006;50:3867–74.
15Fu L, Cheng YC. Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in L (K) SddC3TC) resistance. Biochem Pharmacol1998;55:1567–72.
Melegari M, Scaglioni PP, Wands JR. Hepatitis B virus mutants associated with3TC and famciclovir administra-tionare replication defective. Hepatology1998;27:628–33.
17Ogata N, Fujii K, Takigawa S, Nomoto M, Ichida T, Asakura H. Novel patterns of amino acid mutations in the hepatitisB virus polymerase in association with resistance to lami-vudine therapy in Japanese patients with chronic hepatitis B. JMed Virol1999;59:270–6.
18Warner N, Locarnini S, Kuiper M et al. The L80I substitu-tion in the reverse transcriptase domain of the hepatitis Bvirus polymerase is associated with lamivudine resistance and enhanced viral replication in vitro. Antimicrob AgentsChemother2007;51:2285–92.
Lei J, Wang Y, Wang L, Zhang S, Chen W, Bai Z, Xu L. Profile of hepatitis B virus resistance mutations againstnucleoside/nucleotide analogue treatment in Chinese patients with chronic hepatitis B. Virology Journal2013,10:313.
1Tillmann HL. Antiviral therapy and resistance with hepati-tis B virus infection. World J Gastroenterol2007;13(1):125–40.
2Westland C, Delaney WT, Yang H et al. Hepatitis B virus genotypes and virologic response in694patients in phase IIIstudies of adefovir dipivoxil. Gastroenterology2003;125:107–16.
3Yuen MF, Lai CL. Adefovir dipivoxil in chronic hepatitis B infection. Expert Opin Pharmacother2004;5:2361–7.
4Lacombe K, Ollivet A, Gozlan J et al. A novel hepatitis B virus mutation with resistance to adefovir but not toteno-fovir in an HIV-hepatitis B viurs-co-infected patient. AIDS2006;20:1–3.
5Villeneuve JP, Durantel D, Durantel S et al. Selection of a hepatitis B virus strain resistant to adefovir in a liver
6trans-plantation patient.J Hepatol2003;39:1085–9.Fung SK, Andreone P, Han SH et al. Adefovir-resistant hepatitis B can be associated with viral rebound and hepaticdecompensation. J Hepatol2005;43:937–43.
7Hadziyannis SJ, Tassopoulos NC, Heathcote EJ et al. Long-term therapy with adefovir dipivoxil for HBeAg-negativechronic hepatitis B. N Engl J Med2005;352:2673–81
8Schildgen O, Sirma H, Funk A et al. Variant of hepatitis B virus with primary resistance to adefovir. N Engl J Med2006;354:1807–12.
9Curtis M, Zhu Y, Borroto-Esoda K. Hepatitis B virus con-taining the I233V mutation in the polymerasereverse-transcriptase domain remains sensitive to inhibition by adefovir. J Infect Dis2007;196:1483–6.
Villet S, Pichoud C, Trepo C et al. Selection of the A181T/V substitution in HBV chronically infected patients whodeveloped a resistance to lamivudine and/or adefovir. Hepatology2006;44:555A.
11Lee Y-S, Chung Y-H, Ryu SH et al. Hepatitis B virus with rtL80V/I mutation associates with poor response toade-fovir dipivoxil therapy (Abstract965). Hepatology2005;42:575A.
12Locarnini S, Qi X, Arerburn S et al. Incidence and predictors of emergence of adefovir resistant HBV during four yearsof adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B (CHB).J Hepatol2005;42: A36.
13Tenney DJ, Rose RE, Baldick CJ et al. Long-term monitoring shows hepatitis B virus resistance to entecavir innucleoside-na ve patients is rare through5years of therapy. Hepatology2009;49:1503–14.
Villet S, Ollivet A, Pichoud Cet al. Stepwise process for the development of entecavir resistance in a chronic hepatitisB virus infected patient. J Hepatol2007;46:531–8.
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2Tenney DJ, Oliver AJ, Rose RE et al. Hepatitis B virus resis-tance to entecavir in volves novel changes in the viralpolymerase.Hepatology2003;40:245A.
3Colonno R, Rose R, Levine S et al. Entecavir two year resis-tance update: no resistance observed in nucleoside na vepatients and low frequency resistance emergence in lami-vudine refractory patients (Abstract962). Hepatology2005;42:573A.
4Lai CL, Gane E, Liaw YF et al. Globe Study Group.2-Year GLOBE trial results: telbivudine is superior to lamivudinein patients with chronic hepatitis B. Gastroenterology2009;136:486–95.
5Ladner S, Miller T, Otto M, King R. The hepatitis B virus M539V polymerase variation responsible for3TC resis-tancealso confers cross-resistance to other nucleoside ana-logues. Antivir Chem Chemother1998;9:65–72.
6Chin R, Shaw T, Torresi J et al. In vitro susceptibilities of wild-type or drug-resistant hepatitis B virus tobeta-D-2,6-diaminopurine dioxolane and2-fluoro-5-methyl-beta-L-arab inofuranosyluracil. Antimicrob AgentsChemother2001;45:2495–501
7Locarnini S. Primary resistance, multidrug resistance, and cross-resistance pathways in H BV as a consequence oftreatment failure. Hepatol Int2008;2:147–51
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1Gish RG. Clinical trial results of new therapies for HBV: implications for treatment guidelines. Semin Liver Dis2005;25:29–39
2Locarnini S, Warner N. Major causes of antiviral drug resis-tance and implications for treatment of hepatitis B virusmonoinfection and coinfection with HIV. Antivir Ther2007;12: H15–23.
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4Brunelle MN, Jacquard AC, Pichoud C et al. Susceptibility to antivirals of a human HBV strain with mutationscon-ferring resistance to both lamivudine and adefovir. Hepa-tology2005;41:1391–8
5Villet S, Pichoud C, Villeneuve JP et al. Selection of a multiple drug-resistant hepatitis B virus strain in aliver-transplanted patient. Gastroenterology2006;131:1253–61
6Warner N, Locarnini S. The antiviral drug selected hepatitis B virus rtA181T/sW172mutant has a dominant negativesecretion defect and alters the typical profile of viral rebound. Hepatology2008;48:88–98.
Villet S, Pichoud C, Billioud Get al. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. JHepatol2008;48:747–55
1Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of40nucleic acidsequences by multiplex ligation-dependent probe amplification. Nucleic. Acids. Res.2002.30:e57.
2White SJ, Vink GR, Kriek M, Wuyts W et al.Two-color multiplex ligation-dependent probe amplification: detectinggenomic rearrangements in hereditary multiple exostoses. Hum.Mutat.2004,24,86–92
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1Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of40nucleic acidsequences by multiplex ligation-dependent probe amplification. Nucleic. Acids. Res.2002.30:e57.
1Reijans M, Dingemans G, Klaassen CH, Meis JF, Keijdener J, Mulders B, Eadie K, van Leeuwen W, van Belkum A,Horrevorts AM, Simons G. RespiFinder: a new multiparameter test to differentially identify fifteen respiratory viruses. J.Clin. Microbiol.2008.46:1232–1240.
1Wang Z, Huang Y, Wen S, Zhou B, Hou J. Hepatitis B virus genotypes and subgenotypes in China. Hepatol. Res.2007.37: S36–41.
1PasS D，NoPPomPanth S，EijkA V，eta1．Quantification of the newly detected lamivudine resistant YSDD variants ofHepatitis B virus using molecular beacons.J Clin Virol,2005,2:166-172．
2Hong SP, Kim NK, Hwang SG, Chung HJ, Kim S, Han JH, Kim HT, Rim KS, Kang MS, Yoo W, Kim SO. Detection ofhepatitis B vi-rus YMDD variants using mass spectromet-ric analysis of oligonucleotide fragments. J Hepatol2004,40:837–844
3Paik YH, Han KH, Hong SP, Lee HW, Lee KS, Kim SO, Shin JE, Ahn SH, Chon CY, Moon YM. The clinical impact ofearly de-tection of the YMDD mutant on the out-comes of long-term lamivudine therapy in patients with chronichepatitis B. Antivir Ther2006,11,447–455.
1Reijans M, Dingemans G, Klaassen CH, Meis JF, Keijdener J, Mulders B, Eadie K, van Leeuwen W, van Belkum A,Horrevorts AM, Simons G. RespiFinder: a new multiparameter test to differentially identify fifteen respiratory viruses. J.Clin. Microbiol.2008.46:1232–1240.
1Shaw T, Bartholomeusz A, Locarnini S. HBV drug resistance: mechanisms, detection and interpretation. J. Hepatol2006.44:593–606
2Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, MaJ, Arterburn S, Xiong S, Currie G, Brosgart CL. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronichepatitis B. N. Engl. J. Med.2005.352:2673–2681.
1Choi YJ, Kim HS, Lee SH, Park JS, Nam HS, Kim HJ, Kim CJ, Jeong DJ, Park KS, Baek KA. Evaluation of peptidenucleic acid array for the detection of hepatitis B virus mutations associated with antiviral resistance. Arch. Virol.2011.156:1517–1524
2Liu Y, Wang C, Zhong Y, Li X, Dai J, Ren X, et al. Genotypic resistance profile of hepatitis B virus (HBV) in a largecohort of nucleos(t)ide analogue-experienced Chinese patients with chronic HBV infection. J. Viral. Hepat.2011.18:e29–39.
1Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology2009;137:1593–608.
2Tillmann HL. Antiviral therapy and resistance with hepati-tis B virus infection. World J Gastroenterol2007;13(1):125–40.
3Locarnini S, Bowden S. Drug resistance in antiviral therapy. Clin Liver Dis2010;14(3):439–59.
4Werle-Lapostolle B, Bowden S, Locarnini S et al. Persistence of cccDNA during the natural history of chronic hepatitisB and decline during adefovir dipivoxil therapy.Gastroenter-ology2004;126:1750–8.
5Amini-Bavil-Olyaee S, Vucur M, Luedde T, Trautwein C, Tacke F. Differential impact of immune escape mutationsG145R and P120T on the replication of lamivudine-resistant hepatitis B virus e antigen-positive and–negative strains. JVirol2010;84:1026–33.
1Zhou T, Saputelli J, Aldrich CE, Deslauriers M, Condreay LD, Mason WS. Emergence of drug-resistant populations ofwoodchuck hepatitis virus in woodchucks treated with the antiviral nucleoside lamivudine. Antimicrob AgentsChemother1999;43:1947–54.
2Werle-Lapostolle B, Bowden S, Locarnini S et al. Persistence of cccDNA during the natural history of chronic hepatitisB and decline during adefovir dipivoxil therapy.Gastroenter-ology2004;126:1750–8.
3Amini-Bavil-Olyaee S, Vucur M, Luedde T, Trautwein C, Tacke F. Differential impact of immune escape mutationsG145R and P120T on the replication of lamivudine-resistant hepatitis B virus e antigen-positive and–negative strains. JVirol2010;84:1026–33.
4Sheldon J, Soriano V. Hepatitis B virus escape mutantsinduced by antiviral therapy. J Antimicrob Chemother2008;61:766–8.
5Sloan RD, Ijaz S, Moore PL, Harrison TJ, Teo CG, Tedder RS. Antiviral resistance mutations potentiate hepatitis Bvirus immune evasion through disruption of its surface antigen a determinant. Antivir Ther2008;13:439–47.
6Bartholomeusz A, Tehan BG, Chalmers DK. Comparisons of the HBV and HIV polymerase, and antiviral resistancemutations. Antivir Ther2004;9:149–60.
7Yeh CT, Chien RN, Chu CM, Liaw YF. Clearance of the original hepatitis B virus YMDD-motif mutants withemer-gence of distinct lamivudine resistant mutants during pro-longed lamivudine therapy. Hepatology2000;31:1318–26
1Angus P, Vaughan R, Xiong S et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novelmutation in the HBV polymerase. Gastroenterology2003;125:292–7.
2Bartholomeusz A, Locarmini S, Ayves A et al. Molecular modelling of hepatitis B virus polymerase and Adefovirresistance identifies three clusters of mutations. Hepatology2004;40:246A
3Bartholomeusz A, Locarmini S, Ayves Aet al. Mechanistic basis for hepatitis B virus resistance to acyclic nucleosidephosphonate analogues, Adefovir and Tenofovir. Hepatol-ogy2005;42:594A.
4Bartholomeusz A, Locarnini SA. Antiviral drug resistance: clinical consequences and molecular aspects. Semin LiverDis2006;26:162–70
5Zoulim F. Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis Bvirus infection. Antiviral Res2004;64:1–15.
6Lai CL, Dienstag J, Schiff E et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapyforpatients with chronic hepatitis B. Clin Infect Dis2003;36:687–96.
7Lok AS, Lai CL, Leung N et al. Long-term safety of lamivu-dine treatment in patients with chronic hepatitisB.Gastro-enterology2003;125:1714–22.
8Tenney DJ, Levine SM, Rose RE et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additionalsubstitutions in virus already resistant to Lamivudine.Antimicrob Agents Chemother2004;48:3498–507
9Holomán J, Glasa J. EASL clinical practice guidelines. JHepatol2009;51:821–2
1Lok AS, McMahon BJ. Chronic hepatitis B: update2009.Hepatology2009;50:661–2
2Qin B,Zhang B, Zhang X,He T,Xu W,Fu L. Tu C. Substitution Rtq267h of Hepatitis B Virus Increases the Weight ofReplication and Lamivudine Resistance.Hepat Mon.2013October;13(10):e12160.
3Ono SK, Kato N, Shiratori Yet al. The polymerase L528M mutation cooperates with nucleotide binding-site muta-tions,increasing hepatitis B virus replication and drug resistance. J Clin Invest2001;107:449–55.
4Allen MI, Deslauriers M, Andrews CW et al. Identification and characterisation of mutations in hepatitis B virusresis-tant to lamivudine. Lamivudine Clinical Investigation Group.Hepatology1998;27:1670–7.
5Ling R, Mutimer D, Ahmed M et al. Selection of mutations in the hepatitis B virus polymerase during therapy oftrans-plant recipients with lamivudine. Hepatology1996;24:711–13
6Tipples GA, Ma MM, Fischer KP, Bain VG, Kneteman NM,Tyrrell DL. Mutation in HBV RNA-dependent DNApoly-merase confers resistance to lamivudinein vivo. Hepatology1996;24:714–17
7Delaney WE IV, Yang H, Westland CE et al. The hepatitis B virus polymerase mutation rtV173L is selected duringlami-vudine therapy and enhances viral replication in vitro. JVirol2003;77:11833–41.
8Nakanishi H, Kurosaki M, Asahina Y et al. Polymerase domain B mutation is associated with hepatitis relapse duringlong-term lamivudine therapy for chronic hepatitis B. Intervirology2005;48:381–8.
9Pai SB, Bozdayi AM, Pai RB et al. Emergence of a novel mutation in the FLLA region of hepatitis B virus duringlamivudine therapy. Antimicrob Agents Chemother2005;49:2618–24
10Yeh CT, Chien RN, Chu CM, Liaw YF. Clearance of the original hepatitis B virus YMDD-motif mutants withemer-gence of distinct lamivudine resistant mutants during pro-longed lamivudine therapy. Hepatology2000;31:1318–26.
11Yatsuji H, Noguchi C, Hiraga Net al. Emergence of a novel lamivudine-resistant hepatitis B virus variant with asubstitution outside the YMDD motif. Antimicrob Agents Chemother2006;50:3867–74
12Fu L, Cheng YC. Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in L (K) SddC(TC) resistance. Biochem Pharmacol1998;55:1567–72.
13Melegari M, Scaglioni PP, Wands JR. Hepatitis B virus mutants associated with3TC and famciclovir administra-tionare replication defective. Hepatology1998;27:628–33.
Ogata N, Fujii K, Takigawa S, Nomoto M, Ichida T, Asakura H. Novel patterns of amino acid mutations in the hepatitisB virus polymerase in association with resistance to lami-vudine therapy in Japanese patients with chronic hepatitis B. JMed Virol1999;59:270–6.
15Warner N, Locarnini S, Kuiper M et al. The L80I substitu-tion in the reverse transcriptase domain of the hepatitis Bvirus polymerase is associated with lamivudine resistance and enhanced viral replication in vitro. Antimicrob AgentsChemother2007;51:2285–92.
16Delaney WE IV, Yang H, Westland CE et al. The hepatitis B virus polymerase mutation rtV173L is selected duringlami-vudine therapy and enhances viral replication in vitro. JVirol2003;77:11833–41.
Lei J, Wang Y, Wang L, Zhang S, Chen W, Bai Z, Xu L. Profile of hepatitis B virus resistance mutations againstnucleoside/nucleotide analogue treatment in Chinese patients with chronic hepatitis B. Virology Journal2013,10:313.
1Westland C, Delaney WT, Yang H et al. Hepatitis B virus genotypes and virologic response in694patients in phase IIIstudies of adefovir dipivoxil. Gastroenterology2003;125:107–16.
2Yuen MF, Lai CL. Adefovir dipivoxil in chronic hepatitis B infection. Expert Opin Pharmacother2004;5:2361–7.
3Lacombe K, Ollivet A, Gozlan J et al. A novel hepatitis B virus mutation with resistance to adefovir but not toteno-fovir in an HIV-hepatitis B viurs-co-infected patient. AIDS2006;20:1–3
4Villeneuve JP, Durantel D, Durantel S et al. Selection of a hepatitis B virus strain resistant to adefovir in a livertrans-plantation patient.J Hepatol2003;39:1085–9
5Fung SK, Andreone P, Han SH et al. Adefovir-resistant hepatitis B can be associated with viral rebound and hepaticdecompensation. J Hepatol2005;43:937–43
Hadziyannis SJ, Tassopoulos NC, Heathcote EJ et al. Long-term therapy with adefovir dipivoxil for HBeAg-negativechronic hepatitis B. N Engl J Med2005;352:2673–81.
1Schildgen O, Sirma H, Funk A et al. Variant of hepatitis B virus with primary resistance to adefovir. N Engl J Med2006;354:1807–12.
2Curtis M, Zhu Y, Borroto-Esoda K. Hepatitis B virus con-taining the I233V mutation in the polymerasereverse-transcriptase domain remains sensitive to inhibition by adefovir. J Infect Dis2007;196:1483–6.
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