阿德福韦治疗拉米夫定耐药慢性乙型肝炎患者的耐药率及耐药株进化情况

目的观察阿德福韦单药长期治疗拉米夫定耐药CHB患者的耐药率,以及阿德福韦耐药相关性HBV变异及耐药株的动态变化。方法23例发生YMDD变异的CHB患者停用拉米夫定,口服阿德福韦10mg,1次/d,治疗68～116周,从患者基线和阿德福韦单药治疗后不同时间点的血清中抽提HBV DNA,采用直接PCR产物测序法进行耐药变异分析;对其中1例发生阿德福韦耐药患者的一系列血清进行基因克隆分析其HBV耐药株的进化情况。结果阿德福韦单药治疗48周的耐药率为4.3%;96周的耐药率为10.5%。HBV耐药株进化分析结果显示:阿德福韦单药治疗后,YMDD变异株比例逐渐下降而rtA181S变异株出现并逐渐增多,随着治疗时间的延长,又出现了rtA181S N236T联合变异株。阿德福韦变异株(rtA181S和rtA181S N236T联合变异株)对继起的阿德福韦联合拉米夫定治疗病毒学应答较差,并出现了1例阿德福韦与拉米夫定多药耐药联合变异株(rtM204I rtN236T)。结论拉米夫定耐药的CHB患者,换用阿德福韦单药长期治疗后,耐药率逐渐增加并可选择出多药耐药联合变异株。     

应用ntPCR-RFLP技术检测乙型肝炎病毒阿德福韦耐药变异

目的建立一种简便、快速、实用的乙型肝炎病毒（HBV）阿德福韦（ADV）耐药变异-rtN236T变异及rtA181V变异的快速检测方法。方法根据GenBank收录的HBV基因全序设计巢式PCR引物，使野生株rt236NPCR产物中含有DraⅠ酶切位点（5′-TTTAAA-3′），而变异株rt236T无此限制性酶切位点；使野生株rt181APCR产物中含有BlpⅠ酶切位点（5′-GCTNAGC-3′），而变异株rt181V无此限制性酶切位点。选取4份应用ADV治疗1年以上出现HBVDNA反跳的临床耐药慢性乙型肝炎患者血清，经PCR扩增、限制性内切酶酶切及凝胶电泳，进行限制性片段长度多态性（RFLP）分析。并选择经该方法鉴定的野生株及变异株各1例进行HBVRT区基因序列分析。结果建立的ntPCR-RFLP方法可以检测到10^2copies／L的HBVDNA；RFLP分析结果与DNA测序结果一致，4份血清标本中检测到1份rtN236T变异，2份rtA181V变异。结论应用ntPCR-RFLP方法检测HBV阿德福韦耐药变异具有灵敏、特异、简便的优点，适用于HBV耐药变异的监测。     

阿德福韦酯治疗慢性乙型肝炎的耐药性分析

目的 探讨阿德福韦酯治疗慢性乙型肝炎耐药性产生的原因.方法 从阿德福韦酯Ⅲ期临床试验中筛选出30例原发治疗失败或继发耐药患者,应用巢式逆转录聚合酶链反应扩增HBVRT区,比对RT区核苷酸及氨基酸序列,找出变异位点.结果 30株阿德福韦酯治疗失败者中有21株HBV表现出原发性耐药,其中5株具有多态性位点rtN118H(23.8%,5/21).另外9株发生继发性耐药,继发耐药毒株在RT保守区(C结构域rtM207V)和非保守区多个区域均有变异.没有发现典型的nN236T和rtA181V/T突变.结论 多态性位点rtN118H与阿德福韦酯原发耐药可能有关.HBV RT C结构域rtM207V变异及其他处于非保守区的变异可能与HBV继发性耐药有关,天然耐药准种的存在可能是HBV对阿德福韦酯迅速耐药(继发性)的基础.上述结论 有待进一步表型验证实验加以证实.     

应用巢式聚合酶链反应-限制性片段长度多态技术检测乙型肝炎病毒阿德福韦耐药变异-rtN236T变异

目的 建立一种简便、快速、实用的乙型肝炎病毒（HBV）阿德福韦（ADV）耐药变异-rtN236T变异的快速检测方法。方法 根据GenBank收录的HBV基因全序设计巢式PCR引物，使野生株（rt236N）PCR产物中含有DraⅠ酶切位点（5’TITAAA3’），而变异株（rt236T）无此限制性酶切位点。选取4份应用ADV治疗1年以上出现HBV DNA反跳的临床耐药慢性乙型肝炎患者血清，经PCR扩增、DraⅠ酶切、3％琼脂糖凝胶电泳，进行限制性片段长度多态性（RFLP）分析。并选择经该方法鉴定的野生株及变异株各1例进行HBV RT区基因序列分析。结果 自4份血清标本中检测到1例rtN236T变异。所建立的ntPCR-RFLP方法灵敏度高，可以检测到10^3copies／L的HBV DNA；特异性强，其RFLP分析结果与DNA测序结果一致。结论 应用ntPCR-RFLP方法检测rtN236T变异具有灵敏、特异、简便的优点，适用于ADV耐药变异的临床监测工作。     

拉米夫定耐药慢性乙型肝炎患者改用阿德福韦酯单药治疗后发生耐药及处理

目的 探讨拉米夫定耐药慢性乙型肝炎患者改用阿德福韦酯治疗后发生耐药的临床过程及挽救治疗疗效.方法 回顾性分析15例慢性乙型肝炎患者拉米夫定耐药后,在阿德福韦酯单药治疗期间出现的病毒学突破,采用基因测序法检测到HBV聚合酶基因阿德福韦酯相关突变位点,接受挽救治疗措施.结果 15例拉米夫定耐药患者经中位时间为16个月的阿德福韦酯单药治疗,14例出现与阿德福韦酯耐药相关的rtA181T/V和(或)rtN236T突变,1例出现rtM204I+rtL180M+rtA181T联合突变.耐药后15例患者均给予挽救性治疗措施,其中7例接受拉米夫定联合阿德福韦酯治疗的患者,3个月时HBV DNA平均下降(2.2±0.6)lg拷贝/mL,6个月时,5例HBV DNA低于检测限;另3例接受恩替卡韦治疗患者,6个月时HBV DNA水平下降2.8～3.5 lg拷贝/mL.结论 拉米夫定联合阿德福韦酯是拉米夫定耐药慢性乙型肝炎患者改用阿德福韦酯单药治疗发生阿德福韦酯耐药后的有效挽救治疗措施.     

抗乙型肝炎病毒药物阿德福韦酯的耐药性研究进展

阿德福韦酯为核苷类抗乙型肝炎病毒(HBV)新药,是一种逆转录酶抑制剂,对HBV 野生株及对拉米夫定耐药的HBV变异株均有抑制活性。应用阿德福韦酯治疗2年的耐药变异率为1．6％,其耐药与HBV P基因D区的rtN236T变异有关,该变异株对阿德福韦酯的敏感性下降,伴随HBV DNA升高和(或)丙氨酸氨基转移酶反跳。对阿德福韦酯耐药的 HBV对拉米夫定仍有反应,联合用药有望减少阿德福韦酯耐药的发生。对治疗前、后的血清HBV DNA多聚酶区以套式聚合酶链反应扩增后进行序列分析,是目前监测阿德福韦酯耐药的常用方法。     

阿德福韦酯相关性HBV潜在耐药变异位点研究进展

目前阿德福韦酯仍是我国临床治疗慢性乙型肝炎的一线抗病毒药物之一。但是,长期接受阿德福韦酯治疗可能导致HBV耐药性变异,目前公认的与之相关的HBV耐药变异位点为rtA181V/T和rtN236T。此外,尚有报道rtQ215S/P/H、rtV214A、rtN238H、rtI233V、rtN118H、rtM207V、rtA200V和rtL180M等位点变异与HBV对阿德福韦酯耐药相关,但其重要性尚须进一步明确。     

阿德福韦酯抗乙型肝炎病毒的耐药研究进展

阿德福韦酯是继拉米夫定后抗乙型肝炎病毒(HBV)的又一种核苷类似药物,属于逆转录酶抑制剂。阿德福韦酯抗HBV的耐药变异率低,目前发现的耐药位点主要为rtN236T和rtA181V/T。如果阿德福韦酯发生耐药,可导致HBV DNA的反弹及肝功能异常,因此对阿德福韦酯耐药的预防及耐药的处理显得尤为重要。目前对耐药的基础研究主要在分子水平,而临床研究包括联合用药,药物替代疗法和免疫调节等。     

阿德福韦酯抗病毒治疗对乙型肝炎病毒核酸序列及体外转录水平的影响

阿德福韦酯(ADV)能有效抑制HBV复制,且对拉米夫定耐药株有效,是一种新型核苷类抗病毒药物,其耐药相关变异有rtN236T和A181V突变.我们采用HBV全基因组克隆及体外转染的方法,观察了4例慢性乙型肝炎(CHB)患者在使用ADV抗病毒治疗的不同时期HBV全基因组序列及HBV病毒株体外转录水平的变化.     

LAM耐药后ADV序贯治疗再耐药HBV变异株的动态变化

目的:观察阿德福韦酯(ADV)单药序贯治疗拉米夫定(LAM)耐药慢性乙型肝炎(CHB)出现再耐药患者HBV变异株的动态变化.方法:28例初始LAM治疗的CHB患者, 出现LAM耐药后换用ADV单药序贯治疗再次出现不充分病毒学应答或病毒学突破. 采用实时荧光定量PCR检测DNA, 分析HBV DNA动态变化; 采用直接PCR产物测序法检测耐药变异,分析变异模式变化. 对其中2例患者系列血清进行基因克隆分析其HBV耐药株动态变化.结果:28例入选患者HBV DNA载量随耐药变异株的消长而波动: 基线为(7.65±1.04)Log10copies/mL, LAM疗程中最低值中位数为3.68 Log10copies/mL; 出现病毒学突破或/和耐药变异时为(6.87±1.16) Log10copies/mL, 患者换用ADV后最低值中位数为3.78 Log10copies/mL; 患者出现耐药变异模式改变或再次病毒学突破时为(6.04±0.93) Log10copies/mL. 治疗基线及两次病毒突破3个时点HBV DNA载量均数逐渐下降, 且两两之间差异均有统计学意义. 28例患者LAM治疗后24例发生rtM204I/V伴或不伴rtL180M等变异, 4例无耐药变异; 换用ADV单药序贯治疗出现病毒学突破后, 进行测序检测耐药发现: LAM耐药变异13例(包括3例多重耐药), ADV耐药变异11例(包括3例多重耐药), 无耐药变异7例. 其中11例ADV耐药患者: rtA181V变异6例、rtA181T变异3例、rtN236T变异和rtA181V+rtN236T联合变异各1例. 对2例患者血清TA克隆发现ADV耐药准种出现和LAM耐药准种消失的过程, 同时发现对ADV耐药的rtI233M变异和对替诺福韦耐药的rtA194T变异.结论:ADV单药序贯治疗LAM耐药CHB出现再耐药患者HBV变异株动态变化存在5种形式, 且克隆分析可观察耐药株动态变化过程和发现预存的耐药准种.     

Pooled analysis of amino acid changes in the HBV polymerase in patients from four major adefovir dipivoxil clinical trials

BACKGROUND/AIMS: The rtA181V and rtN236T mutations have been associated with resistance to adefovir dipivoxil (ADV). Recent reports have proposed other ADV resistance (ADV-R) mutations. The aims of this study were to confirm the role of rtA181V and rtN236T in clinical resistance to ADV and to screen for other potential ADV-R mutations. METHODS: Patients from ADV studies (n=998) were screened for viral breakthrough and/or insufficient HBV DNA suppression after at least 48 weeks of ADV therapy [virologic failure, VF]. McNemar's exact test was used to test for differences in the proportion of patients with switches from consensus amino acid (AA) at baseline to non-consensus AA at VF and vice versa. RESULTS: Data obtained from 172 paired HBV polymerase sequences demonstrated that only positions rt181 and rt236 had significantly more changes among patients with VF after adjusting for multiple comparisons (p<0.0005). When tested separately, the mutations rtA181V and rtN236T were statistically significant (p<0.0005); no other AA position was associated with VF. Patients who had HBV DNA breakthrough were more likely to develop ADV-R mutations than patients with insufficient HBV DNA suppression (36% vs. 5%). CONCLUSIONS: rtA181V and rtN236T were the only HBV polymerase mutations significantly associated with virologic failure to adefovir dipivoxil.     

Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure

BACKGROUND/AIMS: Recent clinical observations reported the occurrence of amino acid substitutions at position 181 of the HBV polymerase, associated with a viral breakthrough under lamivudine or adefovir therapy. In this study, we characterized the main variants harboring the rtA181T/V mutation isolated from 10 consecutive patients who developed lamivudine and/or adefovir resistance. METHODS: We performed a clonal analysis of the HBV polymerase gene amplified by PCR from serum samples during viral breakthrough. The main mutants were then tested after transfection of Huh7 cells for their resistance profile to nucleoside analogs. RESULTS: Clonal analysis revealed the co-localization on the same HBV genome of rtA181T/V with rtN236T, but not with rtM204V/I mutations following lamivudine, adefovir or lamivudine+adefovir breakthrough. In cell culture, the rtA181T/V mutation induced a decreased susceptibility to lamivudine (<10-fold), adefovir (2- to 8-fold) and tenofovir (2- to 3-fold). Interestingly, the association of rtA181T with rtN236T on one clinical isolate genome increased the resistance to these three drugs. All the tested mutants remained sensitive to entecavir. CONCLUSIONS: Our observations suggest that a single amino acid change at position rt181 may induce cross-resistance to lamivudine and adefovir. These data emphasize the clinical relevance of genotypic and phenotypic analysis in the management of antiviral drug resistance.     

Hepatitis B e antigen‐suppressing mutations enhance the replication efficiency of adefovir‐resistant hepatitis B virus strains

Summary. Hepatitis B e antigen (HBeAg) negative hepatitis B virus (HBV) infections caused by precore (PC) or basal core promoter (BCP) mutations are associated with disease progression and complications. PC or BCP mutations may enhance the replication capacity of distinct drug‐resistance‐associated polymerase mutations, but their effect on adefovir‐resistant HBV mutants is unclear. Importantly, BCP mutations were an independent risk factor for virological breakthrough in lamivudine‐resistant patients treated with adefovir. We aimed at addressing the functional consequences of PC and BCP mutations on the replication and drug susceptibility of adefovir‐resistant HBV mutants. Therefore, HBV constructs with wild type (WT) or adefovir‐resistant rtN236T, rtA181V and rtA181T mutations, with or without concomitant PC or BCP mutations, were analysed in vitro using molecular assays. The adefovir‐resistant polymerase mutations rtN236T, rtA181V and rtA181T showed a drastically reduced viral replication compared with WT. Interestingly, additional PC or BCP mutations enhanced the reduced replication efficacy of adefovir‐resistant constructs and restored HBV replication to WT level. HBV rtA181T mutants displayed abolished hepatitis B surface antigen (HBsAg) secretion, owing to a sW172* stop codon in the overlapping envelope gene. All rtN236T‐ or rtA181V/T‐containing constructs, regardless of concomitant PC or BCP mutations, were resistant to adefovir, but remained susceptible to telbivudine, entecavir and tenofovir. In conclusion, adefovir drug resistance mutations reduced viral replication, which can be significantly increased by additional HBeAg‐suppressing PC or BCP mutations. Because increased HBV replication in HBeAg‐negative patients has been associated with an unfavourable clinical course, close monitoring appears indispensable during adefovir treatment in HBeAg‐negative patients.     

阿德福韦耐药乙型肝炎病毒毒株生物学特性的研究

目的 体外研究阿德福韦(ADV)耐药相关变异对于HBsAg产生及HBV复制等生物学特性的影响.方法 收集12例在ADV治疗过程中出现病毒学突破的慢性乙型肝炎患者血清,对其HBV反转录(RT)区进行PCR扩增和测序分析.对其中4例患者的HBV进行全基因扩增、测序、序列分析及克隆.将优势株的HBV全基因插入PHY106载体,构建成1.1拷贝HBV基因组表达载体,进而转染Huh7细胞,ELISA法检测细胞培养上清液中HBsAg及HBeAg水平,了解不同ADV耐药相关变异类型对HBsAg分泌的影响.抽提转染细胞内病毒核心颗粒HBV DNA,实时荧光定量PCR方法 检测HBV DNA水平.将rtA181T/sW172*变异株与rtA181非变异株质粒按不同比例混合,共转染Huh7细胞,检测上清液中HBsAg及细胞内病毒核心颗粒HBV DNA水平.结果在12例出现病毒学突破的患者中,10例出现ADV耐药相关位点变异,以rtA181变异为主,其中5例有rtA181T变异,4例为rtA181T/S+rtN236T变异.将含rtA181T/sW172*变异的质粒转染细胞后,上清液中不能检测到HBsAg,而含其他变异类型的质粒转染细胞后,上清液中HBsAg和细胞内病毒核心颗粒HBV DNA水平与非变异株相似;含不同变异的HBV临床分离株转染后的细胞内核心病毒颗粒HBV DNA水平未见明显差异.将rtA181T/sw172*变异株及rtA181非变异株的质粒共转染后.随着rtA181非变异株比例的增加,上清液中HBsAg水平也逐渐增高,但细胞内核心病毒颗粒HBV DNA水平无明显差异.结论 rtA181变异是ADV耐药相关性变异的主要类型,rtA181T变异较多见.rtA181T/sW172*变异株可引起HBsAg分泌障碍,但rtA181非变异株可纠正rtA181T/sW172*变异株的HBsAg分泌障碍.不同类型的ADV耐药相关变异对HBV的复制能力无显著影响.     

Establishment of a new quantitative detection approach to adefovir-resistant HBV and its clinical application

AIM:To establish the more feasible and sensitive assessment approach to the detection of adefovir (ADV) resistance-associated hepatitis B virus (HBV) quasispecies.METHODS: Based on the characteristics of rtA181V/T and rtN236T mutations, a new approach based on real-time fluorescent quantitative polymerase chain reaction (RT-PCR) was established for the detection of ADV-resistant HBV quasispecies, total HBV DNA, rtA181 and rtN236 mutations in blood samples from 32 chronic hepatitis B (CHB) patients with unsa...     

HBV反转录酶区rtA181S变异与阿德福韦酯耐药相关性研究

目的：分析HBV反转录酶（RT）区rtA181S变异与阿德福韦酯（ADV）耐药的相关性。方法应用直接测序法筛选分析大样本慢性HBV感染者rtA181S变异的检出频率,并对1例接受ADV单药治疗失败的慢性乙型肝炎患者血清中HBV RT区基因进行克隆测序,分析相关变异形式。用XhoⅠ和SphⅠ双酶切pGEM-Teasy RT及pTriEx-HBV（C）载体后再连接,构建1.1倍HBV野生株和耐药株的重组质粒,转染人肝癌细胞系HepG2细胞,5 h后分别加入不同浓度的 ADV（0、0.033、0.100、0.330、1.000、3.300μmol/L）。隔天换药,4 d后收集细胞上清,采用实时荧光定量PCR法检测不同药物浓度作用下细胞培养上清中的HBV DNA载量,并分析其表型耐药特点。结果9830例慢性HBV感染者的12000个血清样本中,有46例样本检出rtA181S变异（单独或与其他耐药变异联合出现）,在653例中检出经典的rtN236T/A181V变异。其中随访的1例在接受ADV治疗19个月后出现了病毒学和生化学突破,直接测序检出rtA181S＋N236T变异,克隆测序分析显示在24个克隆中11个（45.83%）为野生型,6个（25.00%）为rtN236T变异型,5个（20.83%）为rtA181S变异型,1个（4.16%）为rtA181V变异型,1个（4.16%）为rtA181S＋N236T变异型。在体外实验中,rtN236T、rtA181S和rtA181S＋N236T变异株的相对复制力分别是野生株的91.35%、29.90%和68.53%。表型耐药分析显示rtN236T、rtA181S和rtA181S＋N236T变异株对ADV的灵敏性分别为野生株的1/4.41、1/3.05和1/5.43。结论 rtA181S是一种ADV耐药相关变异,可单独或联合其他变异引起患者耐药。但与经典ADV耐药变异相比,rtA181S变异引起的ADV耐药相对较弱,临床检出率较低。     

ADV初治耐药与LAM耐药者再耐药时HBV-RT区的变异特征

目的:研究阿德福韦酯(adefovir,ADV)初治耐药和ADV用于挽救治疗拉米夫定(lamivudine,LAM)耐药者再耐药时HBV毒株RT区变异特征的差异性.方法:我院就诊的ADV初治耐药者73例,ADV用于挽救治疗LAM耐药者后再耐药者34例,共计107例,在HBVDNA突破时采用PCR方法扩增HBV-RT区基因,对PCR产物直接测序,用Chromas2.0软件分析HBV-RT区基因的核苷酸和氨基酸差异、变异模式,同时使用Clustalx1.81.msw进行基因型分析.结果:在107例患者中,存在rtA181V变异36例,rtA181T变异43例,rtN236T变异47例,rtM204I/V±rtL180M变异20例,其他相关变异如rtA181S/C、rtH/N238S/T/R/A/K、rtV214I/A、rtQ215H共12例.ADV初治组检测到rtA181V/T变异27例(36.99%)、rtN236T变异14例(19.18%)、rtA181V/T+rtN236T变异28例(38.36%),rtA181T/V和rtN236T以外的变异4例(5.48%).其中发生rtA181V和rtA181T变异患者分别有33.3%、64.5%合并rtN236T变异(P=0.0091);ADV挽救治疗LAM耐药者再耐药,检测到rtA181V/T变异21例(61.76%)、rtN236T变异2例(5.88%)、rtA181V/T+rtN236T变异3例(8.82%),rtA181T/V和rtN236T以外的变异8例(23.53%).其中发生rtA181V患者25%合并rtN236T变异,而rtA181T变异患者未检测到rtN236T变异(P=0.2311).20例(58.83%)患者合并rtM204I/V变异,这20例患者中12例(35.29%)合并rtA181V/T和/或rtN236T变异的多重耐药变异.有12例未检测到rtA181T/V和rtN236T变异,但检查到rtA181S/C(2例)、rtV214I/A(3例)、rtQ215H(1例)、rtH/N238S/T/R/A/K(6例)等ADV耐药相关变异,其中ADV挽救治疗LAM耐药患者8例,ADV初治患者4例,两组间存在统计学差异(P=0.0169).结论:ADV初治耐药主要发生rtA181V/T和rtN236T变异,ADV挽救治疗LAM耐药再耐药主要发生rtA181V/T变异,且后者耐药模式更复杂.     

Tenofovir monotherapy is effective in hepatitis B patients with antiviral treatment failure to adefovir in the absence of adefovir-resistant mutations

BACKGROUND/AIMS: We sought to identify mutations associated with treatment failure to adefovir (ADV) and to determine virologic response to tenofovir (TDF) alone and in combination with emtricitabine (FTC) in these patients. METHODS: Serum samples prior to and after the change in treatment to TDF/TDF+FTC from 13 patients were analyzed by direct sequencing and clonal analysis. RESULTS: ADV-resistant mutations, rtA181V and rtN236T, were detected on direct sequencing in 3 of 8 patients who had virologic breakthrough. Among patients with suboptimal virologic response, rtA181T, rtI233V, and rtN236T were present on clonal analysis in 3 patients. Ten patients received TDF, 8 achieved virologic response. One had ADV-resistance at baseline and persistence of ADV-resistant mutations during TDF treatment, addition of FTC resulted in a further decrease in HBV DNA. Another patient had no ADV-resistance at baseline, and selection of ADV-resistant mutations during TDF treatment. All 3 patients who received TDF+FTC had undetectable HBV DNA within 3-12 months including 2 who had ADV-resistance at baseline. CONCLUSIONS: TDF monotherapy is effective for patients with virologic breakthrough or suboptimal response to ADV, but combination therapy with a nucleoside analogue should be considered in patients with ADV-resistance. No novel mutations were detected.     

Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation

BACKGROUND/AIMS: The susceptibility of adefovir-resistant hepatitis B virus (HBV) mutants is only reduced by 3-10-fold in in vitro studies, suggesting that virologic breakthrough and clinical deterioration are unlikely. The aim of this study was to describe the clinical course of patients with adefovir-resistant HBV infection. METHODS: Testing for adefovir-resistant mutations was performed on patients who had a suboptimal response or virologic breakthrough on adefovir. Adefovir-resistant mutations were detected using a line probe assay and direct sequencing of the HBV P-gene. RESULTS: Eight male patients with pre-existing lamivudine resistance or breakthrough (mean age 47+/-13 years) were found to have adefovir-resistant mutations rtA181V/T or rtN236T. Baseline median ALT was 66 IU/L (range, 27-1161) and median HBV DNA 7.9 log10 copies/ml (range, 6-8.3). At the time of adefovir resistance (mean of 20+/-9 months), HBV DNA increased to > or = 5 log10 copies/ml in 7 patients. After detection of adefovir resistance, hepatic decompensation occurred in 2 patients, 1 of whom died. Salvage therapy with lamivudine, entecavir or tenofovir was given to 7 patients and a reduction in HBV DNA by > or = 3 log10 was seen in 3 patients. CONCLUSIONS: In conclusion, adefovir resistance can be associated with significant viral rebound and hepatic decompensation which may be fatal.