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。     

拉米夫定耐药后阿德福韦酯治疗应答欠佳患者乙型肝炎病毒耐药变异模式

目的 观察拉米夫定(LAM)耐药后单用或联合阿德福韦酯(ADV)治疗应答欠佳患者HBV耐药变异模式. 方法收集15例LAM耐药后采用ADV治疗病毒学应答欠佳患者的血清,对HBV聚合酶逆转录区进行聚合酶链反应、扩增、克隆、测序,分析与耐药相关的变异模式.组间HBV DNA水平比较采用t检验.结果 单用ADV组检测出A181T+N236T、A181V和A181T 等模式的ADV耐药变异,而联合治疗组中主要检测出M204V+L180M、M204V+L180M+L229V、M204I+L80I和M204V+L180M+V207I等LAM耐药变异模式.另外,在联合治疗组的3份血清中,20%的克隆上同时出现对LAM和恩替卡韦耐药的变异,分别为M204I+L80I+T184I(2/10)、M204V+L180M+T184S(2/10)和M204V+L180M+G173L+S202G(2/10).两组中各有1份未检测出已知耐药变异的血清,在它们的测序结果中发现所有克隆均出现1269L变异,且其中单用组中所有克隆均出现P109S变异.联合治疗组和单用ADV组患者血清HBV DNA水平分别为(3.86±0.85)log10拷贝/ml和(5.71±0.94)log10拷贝/ml,差异有统计学意义(t=3.947,P<0.01).结论 LAM耐药后ADV治疗病毒学应答欠佳的患者中,单用ADV治疗容易筛选出A181T+N236T和A181V/T等ADV耐药变异模式,而联合ADV治疗组仍以M204V+L180M、M204V+L180M+L229V、M204I+L80I和M204V+L180M+V207I等LAM耐药变异模式为主.联合治疗时由于LAM的持续使用可选择出恩替卡韦耐药变异模式T184I/S和S202G;对于部分患者,1269L和P109S变异可能影响ADV治疗应答.     

个性化疼痛护理在缓解妇科腹腔镜术后非切口性疼痛中的疗效观察

[目的]探讨个性化疼痛护理对妇科腹腔镜术(LS)后非切口性疼痛中的缓解作用。[方法]选择我院接受妇科LS术的病人96例,随机分成观察组和对照组各48例,观察组病人在手术期间给予个性化的疼痛护理,对照组仅给予常规护理。护理前后利用数字评分法(VAS)疼痛评分对两组病人的疼痛情况进行评价,并进行护理满意度调查。[结果]观察组病人非切口性疼痛发生率、重度疼痛率和疼痛持续时间分别为41.7%、4.2%和4.4h±3.9h,对照组分别为72.9%、25.0%和16.2h±5.8h,两组比较差异有统计学意义(P<0.05);两组病人术前VAS评分相比,差异无统计学意义(P>0.05),观察组术后12h和术后24hVAS评分明显低于对照组,差异有统计学意义(P<0.05);观察组护理满意度为91.7%,对照组护理满意度为68.8%,两组差异均有统计学意义(P<0.05)。[结论]个性化疼痛护理对妇科LS术后非切口性疼痛具有显著的缓解作用,可提高病人对护理服务的满意度。     

恩替卡韦或其联合阿德福韦酯补救治疗拉米夫定联合阿德福韦酯应答不佳的慢性乙型肝炎

目的 对拉米夫定(LAM)初治耐药后,LAM联合阿德福韦酯(ADV)应答不佳的慢性乙型肝炎患者,分别采用恩替卡韦(ETV)单药或ETV联合ADV进行补救治疗,比较两种补救方案的疗效.方法 对LAM初治耐药后应用LAM联合ADV应答不佳的40例患者,分别应用ETV 1.0 mg/d(14例)及ETV 0.5 mg/d联合ADV 10mg/d (26例)两种方案进行补救治疗,至少观察48周,定期监测HBV DNA、肝肾功能、HBV标志物等指标.根据资料不同分别采用t检验Wilcoxon检验或x2检验.结果 两组患者采用补救治疗前的基线情况差异无统计学意义.分别采用两种补救方案治疗后,两组患者HBV DNA水平均有下降,但ETV联合ADV组下降幅度较大.补救治疗24周时,ETV 1,0mg组有28.6％％(4例)达到HBV DNA转阴,ETV联合ADV组则有80.8％ (21例)达到HBV DNA转阴,x2=8.469,P=0.004,差异具有统计学意义;48周时,ETV1.0mg组仍仅有4例患者HBV DNA转阴,而ETV联合ADV组全部26例患者均达到HBV DNA转阴.补救治疗24周时,ETV 1.0mg组有42.9％(6例)患者ALT复常,ETV联合ADV组有92.3％ (24例)患者ALT复常,x 2=9.337,P=0.002,差异具有统计学意义;48周时,ETV 1.0mg组有57.1％(8例)患者ALT复常,而ETV联合ADV组所有患者均达到ALT复常.补救治疗48周时,ETV 1.0mg组有1例患者发生HBeAg血清学转换,ETV联合ADV组有4例患者发生HBeAg血清学转换.结论 对于LAM耐药后LAM联合ADV应答不佳的慢性乙型肝炎患者,采用ETV联合ADV的补救方案较ETV单药1.0mg的方案更为有效,可以实现更好的病毒学及生物化学应答.     

Efficacy of 3 years of adefovir monotherapy in chronic hepatitis B patients with lamivudine resistance

AIM:To study the effect of rescue monotherapy with adefovir(ADV) in patients with chronic hepatitis B(CHB) who developed drug resistance to lamivudine(LAM).METHODS:A total of 76 treated CHB patients with resistance to LAM were enrolled in the present study.The patients’ baseline characteristics,such as age,gender,blood tests and hepatitis B virus(HBV) DNA were collected;therapy duration and the response of each patient were also recorded.ADV monotherapy was set as the observation group A.Twenty-four patients with LAM resistance,who were set as group B,accepted combined therapy with LAM + ADV.Patients were followed up at 0,12,24,52,104 and 156 wk.Hepatitis B surface antigen status,hepatitis B e antigen(HBeAg)/anti-HBe status,HBV DNA level and biochemical indexes were monitored.Sequencer of HBV polymerase gene was performed on the ABI 3730 automated sequencer.If no desired effects had been achieved during the course of treatment,patients’ choices were also taken into account.The control group was tested at the same time.RESULTS:In the two groups,27 cases developed viral breakthrough after LAM treatment response.The remaining 49 cases underwent biochemical rebound accompanied by rtM204I/V or rtL180M mutation.In group A,52 cases finished 156 wk of ADV monotherapy;of whom,36 cases were HBeAg positive and 16 HBeAg negative.In patients whose baseline HBV DNAs were 10 3-10 5 copies/mL,88.8% of patients’ HBV DNAs were lower than the lower test limit(10 3 copies/mL) after 12 to 156 wk of ADV treatment.In patients whose baseline HBV DNAs were ≥ 10 6 copies/mL,41.1%-47.0% of patients’ HBV DNAs were lower than the lower test limit after the same course of ADV therapy(χ 2 were 4.35-5.4,41.1%-47.0% vs 88.8% group 10 3-10 5 copies/mL,P < 0.01).In group A,seroconversion of HBeAg developed in 8 of 36 cases(22.2%).In group B,24 cases finished 156 wk of LAM + ADV;of whom,17 cases were HBeAg positive and 7 HBeAg negative.In patients whose baseline HBV DNAs were 10 3-10 5 copies /mL,81.8% of patients’ HBV DNAs were lower than the lower test limit(10 3 copies/mL) after 12 to 156 wk of treatment.In the patients whose baseline HBV DNAs were ≥ 10 6 copies/mL,46.1%-53.8% of patients’ HBV DNAs were lower than the lower test limit after the same course of LAM + ADV therapy(χ 2 were 4.1-5.0,46.1%-53.8% vs 81.8% group 10 3-10 5 copies/mL,P < 0.05-0.01).In group B,4 of 17 cases(23.5%) developed seroconversion of HBeAg.Treatment outcomes in groups A and B were comparable.CONCLUSION:In both group A and B,the ratios of virological response have similar efficacy in patients with lower baseline HBV DNAs.     

Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient

BACKGROUND/AIMS: In contrast to lamivudine, adefovir dipivoxil (ADV) therapy is associated with delayed and infrequent selection of drug resistant hepatitis B virus (HBV). METHODS: A 52 year-old man was treated with lamivudine for an HBV recurrence on his liver graft. A viral breakthrough was observed and the patient received ADV. Serum HBV DNA decreased rapidly and lamivudine was discontinued while ADV monotherapy was maintained. Serum HBV DNA levels remained suppressed until a second breakthrough was observed. Lamivudine was then reintroduced together with ADV, and serum HBV DNA became undetectable by polymerase chain reaction. RESULTS: Sequence analyses of the HBV polymerase gene revealed a sequential selection of lamivudine resistance mutations L180M+M204V, followed by a reversion to wild-type, and subsequently the selection of a novel adefovir resistance mutation N236T. Phenotypic analyses in cell culture assays demonstrated that the HBV isolates at the time of ADV breakthrough had reduced susceptibility to ADV. This mutant remained sensitive to lamivudine, entecavir and emtricitabine in vitro. CONCLUSIONS: We describe the first case of sequential selection of lamivudine and adefovir resistant strains of HBV in a liver transplantation patient. The selection of the N236T polymerase mutant was associated with resistance to ADV but remained sensitive to lamivudine in vitro and in vivo.     

阿德福韦酯治疗拉米夫定失效慢性乙型肝炎的疗效分析

慢性乙型肝炎(CHB)治疗的关键是抗病毒,拉米夫定(LAM)的5年耐药发生率约为70%,耐药的发生严重影响CHB的治疗效果及其预后.由于阿德福韦酯(ADV)与LAM无交叉耐药位点而被用于LAM失效的CHB的挽救治疗.本研究对ADV作为LAM失效CHB的挽救治疗药物在临床应用的疗效及其耐药发生方面进行探讨.     

乙型肝炎病毒rtN238H变异与阿德福韦酯耐药的相关性研究

目的阐明乙型肝炎病毒（HBV）多聚酶/逆转录酶区rtN238H变异对临床产生阿德福韦（ADV）耐药的影响。方法分析了1789例慢性乙型肝炎患者rtN238H变异的发生频率及其与ADV用药的关系;从典型病例患者血清中克隆获得HBV rtN238H变异株并通过回复定点突变获得对应的野生株,分别构建pTriEx-HBV1.1重组表达载体,瞬时转染HepG2细胞。给予转染细胞不同浓度ADV处理,用DNase消化游离DNA后,对上清中成熟病毒颗粒中的HBV DNA进行裂解定量以评价病毒的复制力。结果在1789例乙型肝炎患者中rtN238H变异为181例（10.1%）,其中HBV B基因型感染为151例（83.4%）,C基因型感染为30例（16.6%）;ADV经治和未治患者分别为130例（71.8.%）和51例（28.2%）,其中对ADV治疗产生临床应答（含部分应答）的占82.3%（107/130）,无应答或出现病毒学反跳的占17.7%（23/130）,但与野生株相比,rtN238H变异株对ADV的敏感性和病毒复制力无明显的改变。结论 rtN238H是HBV自然发生的多态性变异,对ADV敏感性和复制力无直接的影响。     

加用阿德福韦酯治疗拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者

我们采用阿德福韦酯联合拉米夫定对29例拉米夫定耐药患者进行48周抗病毒治疗,现报道如下.     

拉米夫定和阿德福韦酯抗乙型肝炎病毒耐药位点检测及临床意义

目的对应用拉米夫定或阿德福韦酯治疗后耐药的慢性乙型肝炎患者给予联合治疗,观察治疗前后乙型肝炎病毒（HBV）变异模式的变化及对疗效的影响。方法在142例对拉米夫定耐药患者中,给予72例拉米夫定联合阿德福韦酯、70例给予恩替卡韦联合阿德福韦酯冶疗,在72例对阿德福韦酯耐药患者中,给予36例联合拉米夫定、另36例联合恩替卡韦治疗,各组均治疗48 w,测定和比较治疗前后所有患者HBV DNA聚合酶逆转录区相关变异位点变化。结果在拉米夫定初治发生耐药的患者中,发生M204V和IL180M变异率分别为98.6%（140/142）和56.3%（80/142）,接受拉米夫定联合阿德福韦酯治疗患者HBV DNA阴转率为86.1%,与恩替卡韦联合阿德福韦酯治疗患者（97.1%）比,无显著性差异;在阿德福韦酯初治发生耐药的患者中,A181V和N236T变异频率分别为63.9%（46/72）和52.8%（38/72）,接受阿德福韦酯联合拉米夫定治疗患者HBV DNA阴转率为52.8%,显著低于阿德福韦酯联合恩替卡韦组（77.8%,P〈0.05）;在阿德福韦酯联合拉米夫定治疗的36例患者中,19例（52.8%）HBV DNA阴转,在阿德福韦酯联合恩替卡韦治疗的36例患者中,28例（77.8%）患者HBV DNA阴转,差异具有显著性（x2=4.963,P〈0.05）。结论以rtM204变异为主的拉米夫定耐药在联合阿德福韦酯进行挽救治疗后疗效确定;以rtA181变异为主的阿德福韦酯耐药患者在接受阿德福韦酯联合恩替卡韦治疗后的疗效优于联合拉米夫定。     

乙型肝炎病毒对阿德福韦耐药的研究进展

核苷（酸）类似物类抗HBV药物的问世是慢性乙型肝炎治疗史上的里程碑之一。这类药物的广泛应用在为慢性乙型肝炎患者带来福音的同时,也带来了较为严重的耐药问题。由于HBV的复制需通过逆转录机制,而HBV聚合酶缺乏校正的功能,因此,HBV比其他DNA病毒更容易发生变异。随着治疗时间的延长,对核苷类药物耐药的变异株被选择出来，且逐渐成为优势毒株，在临床上表现为HBVDNA水平的反弹，有些患者会出现病情的加重。阿德福韦自2002年上市以来已广泛应用于临床，随着时间的延长，HBV对阿德福韦的耐药率也逐渐增加，引起了人们的广泛重视。[第一段]     

阿德福韦耐药乙型肝炎病毒株的快速检测和动态观察

目的设计PCR联合限制性片段长度多态性（PCR—RFLP）快速检测HBV阿德福韦耐药变异（rtN236T）的方法以及观察阿德福韦耐药毒株的动态变化情况。方法7例乙型肝炎患者在阿德福韦单药治疗过程中出现病毒突破或应答不完全。对其系列血清标本的HBVDNA逆转录酶部分区域进行直接或克隆后测序，设计和应用PCR—RFLP方法对rt236位点的变异情况进行检测。采用Hamming距离法计算HBV部分逆转录酶区域的基因多样性。结果l例患者出现rtA18IV变异，3例为rtN236T变异。建立了基于限制性内切酶DraI或HpaI的PCR—RFLP方法检测rtN236T变异：可以检测至少10％的弱势毒株，特异性为100％。在病毒突破前8个月可以检测到耐药毒株；该耐药毒株后来成为优势毒株。1例患者停用阿德福韦3个月后野生毒株取代耐药毒株重新成为优势株。1例患者在病毒突破后继续服用阿德福韦，rtN236T突变被一个新的突变株（rtN236V）替代。拉米夫定耐药患者的HBV逆转录酶有更明显的基因多样性。结论建立了PCR—RFLP快速检测rtN236T变异的方法；阿德福韦耐药毒株可以表现为不同的转化过程。     

拉米夫定联合阿德福韦酯治疗乙型肝炎肝硬化的病毒学应答

拉米夫定(LAM)抗HBV治疗可阻止乙型肝炎肝硬化病程进展,延长生存期,但需长期用药.而长期用药可发生病毒耐药变异使治疗失败[1].     

A low viral load predicts a higher initial virologic response to adefovir in patients with Lamivudine-resistant chronic hepatitis B

Background/Aims

Adefovir (ADV) is the preferred drug for treating lamivudine (LAM)-resistant hepatitis B. However, not all patients who face virologic breakthrough during LAM treatment respond to ADV. The aim of this study was to determine the factors associated with efficacy of ADV in LAM-resistant hepatitis B patients.

Methods

The medical records of 231 patients who received ADV due to LAM-resistance were reviewed. Efficacy was assessed by the initial virologic response (IVR), defined as hepatitis B virus (HBV) DNA not being undetectable by real-time PCR at 6 months of ADV treatment.

Results

Seventy patients (30%) achieved IVR. While ''add-on'' modality, hepatitis B e antigen (HBeAg) negativity, and low baseline HBV DNA levels were associated with IVR in univariate analysis, multivariate analysis revealed HBeAg status and the DNA level to be the significant factors. The probability of IVR achievement increased sharply per each log₁₀ copies/mL decrement in the baseline viral load, which was 133 times in patients who had HBV DNA <10⁵ copies/mL compared with those who had ≥10⁸ copies/mL.

Conclusions

Factors associated with the IVR were HBeAg negativity and a low baseline viral load. Therefore, when virologic breakthrough with genotypic resistance emerges during LAM therapy, ADV treatment should be considered immediately before further increases in viral load. Additional long-term follow-up data are warranted.     

拉米夫定、阿德福韦酯治疗一例患者后乙型肝炎病毒P基因序列的演变与分析

目的 了解对拉米夫定(LAM)和阿德福韦酯(ADV)临床耐药慢性乙型肝炎患者治疗前后HBV P基因序列变化.方法 选择患者治疗前、LAM治疗后1年、更换ADV治疗后1年3个时间点标本,采用一步法扩增HBV株P基因,随机挑选5个克隆进行测序,分析核苷酸和氨基酸的变化.结果 治疗前和ADV治疗1年后血清所有克隆的HBV均为B基因型,LAM治疗1年后血清所有克隆的HBV均为C基因型.LAM治疗后1年,5个克隆中有4个发生rtM204I变异,并伴随rtI91L(A区)、rtS256C(E区)双突变,还有10个氨基酸发生变异.ADV治疗1年后,所有克隆的HBV均转为无YMDD突变的病毒株,spacer domain区发生27～183个碱基缺失,同时有21个氨基酸发生变异,未见rtN236T和rtA181V/T相关变异.与治疗前序列对比,有15个氨基酸发生替代.结论 核甘(酸)类似物治疗慢性乙型肝炎过程中,HBV是否发生基因型转换有待证实,spacer domain区大片段碱基缺失可能与HBV对ADV耐药相关.     

Clonal evolution of hepatitis B virus polymerase gene mutations during lamivudine-adefovir combination treatment

AIM: To identify hepatitis B virus polymerase gene mutations during antiviral therapy using lamivudine-adefovir sequential monotherapy followed by lamivudine-adefovir combination therapy.METHODS: The patient cohort included four adult chronic hepatitis B patients who had undergone sequential monotherapy, first with lamivudine (LMV) and then, after developing viral breakthrough, with adefovir (ADV) therapy. All of the patients had non-response or viral breakthrough after LMV-ADV sequential monotherapy, which resulted in the switching of their antiviral regimen to LMV-ADV combination therapy. Eleven serum samples from the four patients who showed non-response to rescue LMV-ADV combination therapy were collected sequentially at a time before the antiviral treatment and then during the LMV monotherapy, ADV monotherapy, and LMV-ADV combination therapy. For the genotypic analysis, the whole 1310-bp polymerase gene region was amplified, cloned and sequenced.RESULTS: All patients had been previously treated with 100 mg of LMV once daily for a 15- to 26-mo period. The emergence of resistance mutations to LMV, such as rtM204V/I and/or rtL180M, were found in all patients. Their antiviral regimens were switched to ADV monotherapy as the second line treatment. All patients had viral breakthrough or non-response after the LMV-ADV sequential monotherapy. ADV-resistant mutations were detected after 13 to 19 mo of LMV-ADV sequential monotherapy. The rtA181V/T mutations were predominantly identified during the ADV treatment in the LMV-resistant patients. Twenty-seven of 38 clones were combined with an amino acid change at rt181; three clones had mutations in rt236 and one clone had a combined mutation. The rtA181V/T mutations were not suppressed by the LMV-ADV combination therapy. Thirty-nine of 64 clones showed an rtA181V/T mutation and six clones showed combined mutations in rt181 and rt236. Mutations in rt204 re-emerged during the combination treatment. The rt181 and rt204 mutations did not co-exist in one clone.CONCLUSION: Add-on lamivudine therapy with adefovir for adefovir resistance may not suppress the pre-existing adefovir-resistant mutation that develops during lamivudine-adefovir sequential monotherapy.     

拉米夫定联合阿德福韦酯与换用恩替卡韦单药治疗拉米夫定应答不佳患者的疗效对比

目的 观察分别利用拉米夫定和阿德福韦酯联合治疗与换用恩替卡韦单药治疗拉米夫定应答不佳慢性乙型肝炎患者的临床疗效.方法 80例拉米夫定应答不佳的慢性乙型肝炎患者采用随机数字表法分为联合组和单药组,联合组服用拉米夫定100 mg/d和阿德福韦酯10mg/d;单药组服用恩替卡韦0.5 mg/d,观察两组患者治疗48周时的疗效.结果 治疗48周后,联合组的HBV DNA应答率、HBeAg转换率、ALT复常率分别为90.0％、40.0％和95.0％,远高于单药组的70.0％、15.0％和80.0％,两组比较差异均有统计学意义(P＜0.05).治疗48周后,联合组未出现病毒学突破病例;单药组共有2例患者出现病毒学突破.结论 对于拉米夫定应答不佳的慢性乙型肝炎患者,加用阿德福韦酯联合治疗的疗效优于换用恩替卡韦单药治疗,且可降低病毒耐药的发生率.     

拉米夫定联合阿德福韦酯治疗失代偿期乙型肝炎肝硬化的临床观察

目的研究拉米夫定（LAM）联合阿德福韦酯（ADV）治疗失代偿期乙型肝炎肝硬化的临床疗效。方法92例失代偿期乙型肝炎肝硬化患者在综合护肝及对症治疗基础上,联合组30例给予拉米夫定100mg/d和阿德福韦酯10mg/d口服;LAM组28例给予拉米夫定100mg/d口服;34例给予阿德福韦酯10mg/d口服。在治疗前和治疗6个月时观察肝功能、HBVM以及血清HBVDNA水平的变化。结果拉米夫定和阿德福韦酯联合组与拉米夫定组和阿德福韦酯组HBVDNA阴转率分别为80%、53.6%和41.2%,联合组明显优于单用组（P〈0.05）;肝功能Child-Pugh计分分别为7.0±1.1、7.7±1.2和7.8±1.3,联合组明显优于单用组（P〈0.05）。结论拉米夫定联合阿德福韦酯抗病毒治疗失代偿期乙型肝炎肝硬化优于单用拉米夫定或阿德福韦酯治疗。     

阿德福韦酯治疗拉米夫定耐药慢性乙型肝炎的临床研究

目的研究阿德福韦酯片对拉米夫定耐药慢性乙型肝炎患者的疗效和安全性。方法采用多中心、随机，双盲双模拟、拉米夫定对照的临床试验，选择拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者209例，按1：1的比例随机分为阿德福韦酯组105例，拉米夫定组104例。完成24周和48周治疗时，检测血清HBV DNA水平、乙型肝炎病毒血清学标志物及肝功能变化。结果治疗24周时阿德福韦酯组血清HBV DNA水平，平均下降2．40log10，病毒应答率为59．0％，丙氨酸氨基转移酶（ALT）复常率为54．3％，均显著高于拉米夫定组；治疗48周时阿德福韦酯组血清HBV DNA水平，平均下降2．71log10病毒应答率为61．9％，ALT复常率为54．3％，显著优于拉米夫定组；阿德福韦酯组治疗后血清HBeAg阴转率、HBeAg血清转换率及不良事件发生率与拉米夫定组相比，差异无统计学意义。未发生与研究药物相关的严重不良反应。结论阿德福韦酯片治疗拉米夫定耐药慢性乙型肝炎，可在病毒学及生物化学方面取得较好疗效，且安全性良好。     

拉米夫定和阿德福韦酯初始联合与恩替卡韦单药治疗慢性乙型肝炎的疗效和安全性比较

目的 观察拉米夫定(LAM)和阿德福韦酯(ADV)初始联合与恩替卡韦(ETV)单药治疗慢性乙型肝炎的疗效,并比较两者的安全性.方法 选择我院2007年6月-2008年1月符合抗病毒治疗的未曾使用核苷(酸)类似物的初治慢性乙型肝炎患者120例,分为联合组60例和单药组60例,联合组应用LAM 100 mg,ADV 10 mg,每日1次;单药组应用ETV 0.5 mg,每日1次.分别在基线、12、24、48、96周时留取血清,采用全自动分析生物化学仪检测肝功能、肾功能、血生物化学指标;采用化学发光法定量检测HBsAg和HBeAg;采用实时荧光定量PCR检测HBV DNA水平;采用PCR产物直接测序法检测病毒耐药基因.组间比较采用配对t检验,率的比较采用χ2检验.结果 (1)联合组54例,单药组50例完成了48周随访,联合组51例,单药组48例完成了96周随访.两组治疗前性别、年龄、血清ALT、血肌酐、HBV DNA、HBsAg水平及HBeAg阳性率,差异无统计学意义,具有可比性.(2)两组在治疗12周和24周时,HBV DNA＜300拷贝/ml和HBV DNA＜1000拷贝/ml的比率,差异无统计学意义.治疗12周时,单药组和联合组HBV DNA下降＜1 log10拷贝/ml的分别为3.7%(2/54)和18.0%(9/50),两组比较,χ2=5.556,P＜0.05,差异有统计学意义.(3)治疗48周时,单药组和联合组的ALT复常率、HBVDNA＜1000拷贝/ml的比率、HBeAg血清转换率以及与基线比较HBV DNA下降绝对值,差异均无统计学意义.联合组与单药组HBV DNA＜300拷贝/ml的患者分别为90.7%(49/54)和76.0%(38/50),两组比较,χ2=4.125,P＜0.05,差异有统计学意义.(4)治疗96周时,HBV DNA＜300拷贝/ml、HBV DNA＜1000拷贝/ml患者比率和HBeAg血清转换率,联合组分别为96.1%(49/51)、98.0%(50/51)、41.7%(15/36),单药组分别为79.2%(38/48)、87.5%(42/48)、16.7%(6/36),两组比较,χ2值分别为6.639、4.180、5.445,P值均＜0.05,差异有统计学意义;但两组患者与基线比较HBV DNA和HBsAg下降绝对值以及ALT复常率差异无统计学意义.(5)治疗96周时,联合组未见病毒学突破和耐药发生,而单药组累计发生病毒学突破4例,其中3例(6.3%,3/48)检测到ETV相关耐药基因变异位点,2例患者在基线时存在LAM相关耐药基因变异位点(rtL180M+M204V).(6)治疗48、96周时,联合组与单药组患者血肌酐水平及治疗前后血肌酐升高水平差异无统计学意义.在治疗期间,两组均无血清肌酐水平超过正常上限或由于肌酐升高0.5 mg/dl而调整剂量的患者.结论 LAM和ADV初始联合治疗,在减少病毒学突破和耐药发生,以及提高HBeAg血清转换率方面优于ETV单药治疗.

Abstract：

Objective To compare the efficacy and safety of Lamivudine (LAM) plus Adefovir dipivoxil (ADV) combination therapy and Entecavir(ETV) monotherapy for chronic hepatitis B patients.Methods 120 patients with chronic hepatitis B managed in a single-centre clinical practice (median 96 weeks)were split into 2 cohorts,one was treated with de-novo combination Lamivudine (100 mg/day) plus Adefovir (10 mg/day) (LAM+ADV),thc other with Entecavir (0.5 mg/day) monotherapy.Serum levels of ALT,creatinine,HBsAg,HBeAg and HBV viral load,together with genotypic resistence were analyzed at 0,12,24,48,96 weeks,respectively.HBV DNA was determined by real-time PCR.HBsAg and HBeAg were assessed by chemiluminescence.Serum levels of ALT and creatinine were detected by automatic biochemical analyzer.HBV genotypic resistence was tested by direct sequencing.Results (1) At the time point of 96 weeks,a total of 99 patients(51 cases in combination therapy cohort and 48 case in monotherapy cohort) were compared.The baseline characteristics as for HBV viral load,median age,serum levels of ALT and creatinine were compatible between combination therapy cohort and monotherapy cohort.(2) The rates of HBV DNA ＜300 copies/ml and HBV DNA ＜ 1000 copies/ml had no significant difference between LAM + ADV and ETV cohorts by the 12 and 24 weeks (P ＞ 0.05).(3) At the time point of 48 weeks,the rates of HBV DNA＜1000copies/ml,HBeAg seroconversion,and ALT normalization were similar in both cohorts,though the rate of HBV DNA ＜ 300 copies/ml was obviously higher in combination therapy cohort than that of monotherapy cohort (90.7% vs 76%,P ＜ 0.05).(4) At the time point of 96 weeks,the rates of HBV DNA ＜ 300 copies/ml (96.1% vs 79.2%),HBV DNA ＜ 1000 copies/ml (98% vs 87.5%) and the HBeAg seroconversion (41.7% vs 16.7%) were markedly higher in combination therapy cohort than those of monotherapy cohort statistically (P ＜ 0.05 for all).The mean values of decreases for HBV viral loads and HBsAg levels were smilar in both cohorts at 48 and 96 weeks.(5) Elevated serum creatinine not be found in both cohorts at the end of treatment.(6) No virological breakthrough occurred in combination therapy cohort at the end of treatment.Four patients in monotherapy cohort were found with virological breakthrough at 96 weeks and three cases among were confirmed to be of variants associated with ETV resistance (rtLl80M + T184L + M204V).Conclusions Present study suggests that Lamivudine plus Adefovir dipivoxil de-novo combination therapy was more efficacious than Entecavir monotherapy for CHB patients and the tolerance is compatible.