替诺福韦酯对阿德福韦酯应答不佳患者的挽救治疗研究进展

阿德福韦酯(adefovir dipivoxil,ADV)作为常用抗HBV治疗药物,与拉米夫定(lamivudine,LAM)、替比夫定和恩替卡韦无交叉耐药,且价格相对低廉,长期以来用于初治患者和LAM耐药患者的挽救治疗。然而由于ADV耐药基因屏障较低且临床用药剂量较低,临床长期应用累积了较多ADV应答不佳患者。替诺福韦酯(tenofovir disoproxil fumarate,TDF)作为ADV应答不佳患者的挽救治疗方案之一,对ADV初治应答不佳患者和LAM耐药的ADV应答不佳患者的临床疗效略有差异。然而多项体外研究显示TDF对ADV耐药病毒株抑制作用减弱。ADV应答不佳的患者换用TDF是否会引起或加重肾损害值得临床关注。本文就TDF对ADV应答不佳患者挽救治疗的国内外研究进展作综述,为提高耐药HBV感染防治的管理提供帮助。     

阿德福韦酯联合苦参素治疗经阿德福韦酯应答不佳的慢性乙型肝炎的临床研究

目的 观察阿德福韦酯联合苦参素治疗经阿德福韦酯治疗2年后应答不佳的慢性乙型肝炎的疗效.方法 选取初始接受阿德福韦酯治疗,经两年治疗后所有患者血清HBV DNA水平维持在1.0×104copies/mL～9.9×105copies/mL之间的慢性乙型肝炎患者75例.分为联合组和单用组,联合组(39例)给予阿德福韦酯(10 mg,1次/d,口服)和苦参素(住院期间苦参素针0.6静脉滴注1次/d,出院后改苦参素胶囊0.3,口服,3次/d).单用组(36例)继续给予阿德福韦酯(10 mg,1次/d,口服)治疗.观察治疗26周、52周时的应答情况.结果 两组患者在治疗26周、52周时,联合组ALT复常率显著高于单用组,差异有显著性(P＜0.05).联合治疗26周、52周后,HBV DNA阴转率均明显高于单用组(30.7%vs 8.3%、53.8%vs22.2%),差异有显著性(P＜0.05).第52周时,两组患者的HBeAg血清学转换率有显著性差异(28.2%vs7.7%,P＜0.05).结论 对于经过阿德福韦酯抗病毒治疗应答不佳者,阿德福韦酯联合苦参素治疗显示良好的协同效果.     

Efficacy and safety of adefovir dipivoxil 20 mg daily in HBeAg-positive patients with lamivudine-resistant hepatitis B virus and a suboptimal virological response to adefovir dipivoxil 10 mg daily

BACKGROUND/AIMS: Some patients receiving adefovir at the approved dose of 10 mg daily for chronic hepatitis B have a "suboptimal" virological response characterized by a slow and moderate decrease in viral replication. METHODS: We assessed the efficacy and safety of adefovir 20 mg daily in patients with hepatitis B e antigen-positive chronic hepatitis B resistant to lamivudine and a suboptimal virological response to adefovir 10 mg daily add-on. RESULTS: No amino acid substitutions known to confer adefovir resistance were found in these patients. In the five treated patients, the switch from 10 mg to 20 mg of adefovir daily significantly improved antiviral efficacy (-1.78+/-0.28 log international units/mL versus -3.73+/-0.51 log international units/mL, respectively, p=0.0039), and alanine aminotransferase levels normalized in all but one of the patients. No signs of renal dysfunction occurred. CONCLUSIONS: These results suggest: (i) that suboptimal responses to adefovir 10 mg daily are due to underdosing; and (ii) that increasing the adefovir dose to 20 mg daily is beneficial and safe in patients with lamivudine-resistant HBV and a suboptimal response to adefovir 10 mg daily, especially when alanine aminotransferase levels are elevated and/or the liver disease is severe or rapidly progressive. Careful monitoring of renal function is necessary.     

A placebo-controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection

Adefovir dipivoxil (bis-POM PMEA) is an adenine nucleotide analogue with activity against retroviruses and herpesviruses, and in vitro activity against hepatitis B virus (HBV). This study was conducted to evaluate its safety and antiviral activity in patients with chronic HBV infection. Twenty patients (13 co-infected with human immunodeficiency virus, HIV) were randomized in a phase I/II, double-blind, placebo-controlled study. Patients who had been hepatitis B surface antigen (HBsAg)/hepatitis B e antigen (HBeAg) positive for > or = 6 months, with elevated hepatic transaminases and serum HBV DNA > or = 50 pg ml-1, were randomized to adefovir dipivoxil 125 mg (n = 15) or placebo (n = 5) as a single, daily, oral dose for 28 days. Antiviral activity was assessed by changes in serum HBV DNA (using the Digene Hybrid Capture assay) and HBeAg/hepatitis B e antibody (HBeAb) status. HBV DNA levels fell rapidly by > 1 log10 in all active drug recipients (median fall 1.8 log10 pg ml-1) but increased by 0.01 log10 pg ml-1 in controls (P = 0.002). Reductions were sustained during treatment. HBV DNA returned to baseline over 1-6 weeks following discontinuation of active drug. HBeAg became transiently undetectable in one patient on treatment and, in another, sustained seroconversion to HBeAb occurred 12 weeks after treatment ended. Liver transaminase elevations > 300 U l-1 were observed in three patients during therapy (leading to protocol-specified treatment discontinuation or dose reduction) and in four patients during follow-up. On-treatment transaminase elevations were associated with HIV status, occurring in three of six HIV-uninfected patients compared with none of nine who were HIV infected. In addition, a slower return to baseline of serum HBV DNA levels was observed in the non-HIV-infected patients. Treatment for chronic hepatitis B as a once-daily oral dose was well tolerated and associated with significant and sustained reductions in serum HBV DNA levels during treatment. Transaminase elevations, which may be related to the therapeutic effect, were observed during and after treatment. Further studies are warranted to investigate the safety, and optimum dose and duration, of adefovir dipivoxil treatment for chronic hepatitis B.     

慢乙肝患者基因变异位点检测及阿德福韦酯疗效观察

目的探讨乙型肝炎病毒基因突变的类型及位点,观察阿德福韦酯的临床疗效。方法 43例慢性乙型肝炎位点变异患者服用阿德福韦酯10mg/d,48周,观察治疗前后临床指标的变化。结果变异位点为rtL180M/M204V、rtM204I、rtL180M/M204I28例,单独与联合变异并存;G1896A变异7例,V214A、V173L变异4例,G1896A、L180M、M204I、M204V联合变异4例。阿德福韦酯对HBV变异株有明显的抑制作用,HBVDNA由治疗前与治疗后24周、48周HBVDNA、ALT复常率显著改善（P值均〈0.01）。药物安全性良好。结论阿德福韦酯对位点变异慢乙肝患者有一定疗效。     

阿德福韦酯治疗e抗原阳性慢性乙型肝炎的疗效预测因素研究

目的探讨阿德福韦酯治疗HBeAg( )慢性乙型肝炎的疗效预测指标,为个体化治疗提供依据。方法于2004年10月至2005年12月在北京大学第一医院等5所医院进行该研究,选取连续应用阿德福韦酯治疗48周的HBeAg( )慢性乙型肝炎患者共140例,采用Logistic回归分析阿德福韦酯治疗48周的疗效预测指标。结果基线血清丙氨酸转氨酶(ALT)、HBV DNA水平和24周时HBV DNA阴转为48周HBV DNA阴转的预测指标;研究中基线ALT≥134.5U/L、HBV DNA≤6.57lg拷贝/mL和24周HBV DNA阴转者治疗至48周时的HBV DNA阴转率(93.3%)、HBeAg阴转率(60%)、HBeAg血清转换率(40%)均较高。治疗24周时HBV DNA未阴转者继续治疗至48周时仍有47.8%的患者发生HBV DNA阴转、8.6%的患者发生HBeAg血清转换。结论慢性乙型肝炎患者应用阿德福韦酯治疗前HBV DNA低水平、ALT高水平且24周时HBV DNA阴转是48周疗效较好的预测指标;治疗24周时HBV DNA未阴转者不应放弃治疗。     

阿德福韦酯治疗HBeAg阳性慢性乙型肝炎病毒学应答的预测因素分析

目的 探讨阿德福韦酯(ADV)治疗HBeAg阳性慢性乙型肝炎(CHB)患者病毒学应答的预测因素.方法 对203例HBeAg阳性CHB患者采用ADV 10 mg/d治疗48周,PCR-限制性片段长度多态性检测TNF-α-238及TNF-α-308位点基因多态性,ELISA测定基线血清TNF-α水平,荧光定量PCR或HBV S基因直接测序法检测HBV基因型、亚型,Logistic回归分析影响ADV应答的因素.结果 203例患者ADV治疗24周和48周时HBV DNA转阴率、ALT复常率、HBeAg转阴率及转换率、联合应答率分别为31.5%(64/203)、59.1%(120/203)、15.8%(32/203)、8.9%(18/203)、13.3%(27/203)和58.6%(119/203)、78.3%(159/203)、29.6%(60/203)、16.7%(34/203)、25.6%(52/203).HBV基因型B、TNF-α-308G/A基因型、较高水平基线ALT及较低载量基线HBV DNA易于24周时HBV DNA转阴[OR=0.405,95%CI(0.191～0.859),P=0.019;OR=0.292,95%CI(0.132～0.643),P=0.002;OR=0.933,95%CI(0.989～0.997),P＜0.01;OR=2.089,95%CI(1.412～3.092),P＜0.01];24周HBV DNA高转阴率、较高水平基线ALT有利于48周时HBV DNA转阴[OR=0.029,95%CI(0.007～0.126),P＜0.01;OR=0.995,95%CI(0.991～0.999),P=0.016].结论 HBeAg阳性CHB患者ADV治疗24周病毒学应答的预测因素是HBV基因型、TNF-α-308基因型、基线ALT水平及HBV DNA载量;48周的预测因素是24周HBV DNA转阴率、基线ALT水平.

Abstract：

Objective To investigate the predictive factors of virological response in HBeAg-positive chronic hepatitis B (CHB)patients treated with adefovir dipivoxil (ADV).Methods A total of 203 HBeAg-positive CHB patients treated with ADV (Mingzheng)10 mg once daily for 48 weeks were recruited.The gene polymorphisms at positions-238 and-308 in tumor necrosis factor (TNF)-α promoter region were determined by the restriction fragment length polymorphism assay of products amplified using polymerase chain reaction (PCR-RFLP).The serum levels of TNF-a at baseline were measured by enzyme linked immunosorbent assay (ELISA).Hepatitis B virus (HBV)genotypes were tested by real-time fluorescent quantitative PCR and HBV subgenotypes were tested by HBV S gene sequencing.Factors related to ADV response were determined by Logistic regression analysis.Results The HBV DNA negative rate,alanine aminotransferase (ALT)normalization rate,HBeAg loss rate and seroconversion rate,and combined response rate at week 24 and 48 of treatment in 203 patients were 31.5% (64/203),59.1% (120/203),15.8% (32/203),8.9% (18/203),13.3% (27/203)and 58.6% (119/203),78.3% (159/203),29.6% (60/203),16.7% (34/203),25.6% (52/203),respectively.HBV DNA negative rate at week 24 was higher in patients with HBV genotype B,that was higher in patients with TNF-α-308G/A genotype,and that was higher in patients with higher baseline ALT level or lower baseline HBV DNA level [OR = 0.405,95 % CI (0.191 - 0.859),P =0.019;OR=0.292,95%CI(0.132-0.643),P=0.002;OR=0.933,95%CI(0.989-0.997),P＜0.01 ;OR=2.089,95%CI (1.412-3.092),P＜0.01].Meanwhile,HBV DNA negative rate at week 48 were higher in patients with higher HBV DNA negative rate at week 24 or higher baseline ALT level [OR=0.029,95%CI(0.007-0.126),P＜0.01;OR= 0.995,95%CI(0.991-0.999),P=0.016].Conclusions HBV genotype,TNF-α-308 genotype,baseline levels of ALT and HBV DNA are predictors of virological response at week 24 in HBeAg-positive CHB patients treated with ADV.And the HBV DNA negative rate at week 24 and baseline ALT level are predictors of virological response at week 48.     

Hepatitis B virus genotypes and the response to lamivudine therapy

Hepatitis B virus (HBV) can be classified into eight major genotypes (A-H) that have mainly a geographic distribution. The HBV genotype may influence disease progression, HBeAg seroconversion rates, response to antiviral treatment. The aim of study was to analyze the distribution and frequency of genotypes in patients with chronic hepatitis B. Response to lamivudine 100 mg daily therapy was examined in respect to genotype. Sixty six patients (45 (68,2%) male, 21 (31,8%) female) with chronic hepatits B were enrolled. HBV genotypes were assigned before treatment with INNO-LiPA HBV Genotyping, Innogenetics, N. V., Ghent assay, which is a line probe test based on the reverse hybridization principle. In baseline and after 12 months of treatment serological markers of HBV infection, alanine aminotransferase (ALT) activities and HBV DNA serum levels were tested. Patients with chronic hepatitis B were infected predominantly with genotype A. HBV genotype distribution was: 78,8% for genotype A, 13,6% for genotype D, 1,5% for mixed infection with genotypes A and D. Distribution of genotypes A and D was asymmetrically regardless of sex, HBeAg status, ALT and HBV DNA levels. Four (6,1%) specimens had indeterminate A results by LiPA. There were no significant differences between patients with genotypes A and D regarding age and sex. There were also no significant differences between these two groups regarding rates of HBeAg and anti-HBe positivity, ALT activity and viral load. Twenty months of lamivudine (100 mg daily) therapy resulted in significant decreases in serum HBV DNA and ALT activities in patients with genotype A as well as with genotype D. After 12 months of treatment there were no statistical differences in HBeAg seroconversion rates, ALT activities, viral loads, frequency of HBeAg and anti-HBe between genotypes A and D.     

阿德福韦酯治疗HBeAg阴性慢性乙型肝炎疗效与HBV基因型的关系

目的探讨阿德福韦酯（ADv）治疗HBeAg阴性慢性乙型肝炎（chronic hepatitis B,CHB）的疗效与HBv基因型的关系。方法选择71例HBVDNA〉1×10^4copies／ml、ALT〉2倍正常值上限、TBIL正常的HBeAg阴性cHB患者,其中B基因型40例,C基因型31例,所有患者均口服ADV 10mg,1／d,治疗52周,动态观察治疗过程中HBV DNA和ALT水平的变化。结果在治疗12、24、52周时,B基因型患者ALT变化、血清HBVDNA水平下降≥2log。完全抑制比例与C基因型患者相比差异无统计学意义（P〉0．05）。结论ADV能有效抑制HBeAg阴性CHB患者HBV复制,促进肝功能好转,其疗效与HBV基因型B或C型无关。     

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.     

阿德福韦酯治疗不同HBV基因型感染慢性乙型肝炎患者48周疗效分析

目的观察阿德福韦酯初始治疗慢性乙型肝炎患者48周疗效及其与HBV基因型的关系。方法 75例慢性乙型肝炎患者接受国产阿德福韦酯治疗48周,观察治疗期间ALT、AST、HBV DNA、HBeAg等指标变化,并检测患者HBV基因型。结果在75例中检出B基因型49例（65.3%）,C基因型22例（29.3%）,B/C基因型4例（5.3%）;治疗48周时ALT复常率和HBV DNA转阴率分别为58.7%和50.7%,HBeAg消失率为34.9%,HBeAg血清转换率为1.5%;在治疗12周时,B基因型组ALT复常率和HBV DNA阴转率分别为26.5%和38.8%,48周时为55.1%和53.1%,在治疗12周时,C基因组ALT复常率和HBV DNA阴转率为13.6%和31.8%4,8周为59.1%和36.4%（P〉0.05）。结论基线HBV DNA〉1×105copies/ml的慢性乙型肝炎患者初始采用ADV治疗,HBeAg血清学转换率较低,ADV治疗的疗效与HBV基因型无关。     

Resistant mutants induced by adefovir dipivoxil in hepatitis B virus isolates

AIM:To investigate the loci of adefovir dipivoxil(ADV)-induced resistance in hepatitis B virus(HBV)isolates and optimize the management of ADV-treated patients.METHODS:Between June 2008 and August 2010,a cross-sectional control study was conducted comprising 79 patients with chronic HBV infection-related liver disease who had been administered ADV monotherapy.Patients underwent liver imaging.Serum DNA extracts were analyzed for HBV DNA levels,genotypes,and serology markers,and deep sequencing of the HBV P gene was performed.RESULTS:ADV-resistant patients were found either with a single mutated locus,or with coexisting mutated loci.The most prevalent mutations were rt A181T,rt V214A,and rt N236T.Twenty-six patients had more than two mutated loci.The mutants were distributed among the patients without any significant affinity for gender,age,end-stage of liver disease,complications of non-alcoholic fatty liver disease,or HBV DNA levels.Patients with the rt A181T mutant were primarily infected with genotype C and e-antigen negative HBV,while patients with the rt N236T mutant were primarily infected by genotype B HBV(χ2=6.004,7.159;P=0.023,0.007).The duration of treatment with ADV was shorter in the single mutant group compared with the multi-mutant group(t=2.426,P=0.018).CONCLUSION:Drug-resistant HBV mutants are complex and diverse.Patients should receive the standard and first-line antiviral treatment,strictly comply with medication dosage,and avoid short-term withdrawal.     

Hepatitis B virus with the rtL80V/I mutation is associated with a poor response to adefovir dipivoxil therapy

Background/Aims: Lamivudine (LAM) resistance is frequently associated with various types of genomic changes in hepatitis B virus (HBV)‐DNA including YMDD mutations (rtM204V/I). We intended to examine the effects of these genotypic variants on the antiviral efficacy of adefovir dipivoxil (ADV) therapy. Methods: A total of 97 chronic hepatitis B (CHB) patients with YMDD mutants who had been treated with ADV for >12 months were analysed. Mutations of the entire polymerase domain of HBV were determined by direct sequencing. Results: All the 97 patients had genotype C HBV associated with rtM204V/I mutations; 63 (65%) rtM204I, 27 (28%) rtM204V and seven (7%) both. The rtL80V/I and rtL180M variants were identified in 66 (68%) and 67 (69%) patients respectively. The rtM204I and rtM204V variants were strongly associated with rtL80V/I and rtL180M respectively (P<0.01). There was no difference in antiviral response at 12 months after ADV therapy between patients in relation to the type of YMDD mutation or the presence of rtL180M. However, interestingly, after ADV therapy for 12 months, patients with rtL80V/I achieved a much smaller reduction in serum HBV‐DNA titre than those without it (mean, ?3.43 vs. ?4.43 log₁₀ copies/ml; P=0.018). In addition, patients with rtL80V/I had lower rates of undetectable HBV‐DNA (20 vs. 26%), alanine aminotransferase normalization (70 vs. 81%) and HBeAg loss (16 vs. 26%) than those without it, although none of these differences was statistically significant. Conclusions: These results provide evidence that rtL80V/I variants of HBV may be associated with a poor antiviral response to ADV in CHB patients with YMDD mutants.     

Hepatitis B virus genotypes in Europe

There are eight genotypes of hepatitis B virus (HBV). Most genotypes can be further divided into subgenotypes. HBV genotypes influence the course of disease and treatment, and show geographic preferences. In Europe, A and D are the main genotypes found. Genotype A is more prevalent in northern Europe, where genotype D is mainly found in countries surrounding the Mediterranean Sea and in Eastern Europe. Subgenotype A2 is the dominant subgenotype in Europe, but the geographic prevalence of the four subgenotypes found in genotype D is not yet clear. On treatment with interferon HBV, genotype A, compared to genotype D, showsbetter virological response and in a large proportion of patients, even development of anti-HBs. However, in the first year of treatment with lamivudine, higher rates of emergence of YMDD variants are observed in genotype A. This work summarizes the current knowledge on HBV genotypes in countries with low and intermediate HBV carriership from Europe.     

Hepatitis B virus taxonomy and hepatitis B virus genotypes

Hepatitis B virus (HBV) is a member of the hepadnavirus family. Hepadnaviruses can be found in both mammals (orthohepadnaviruses) and birds (avihepadnaviruses).The genetic variability of HBV is very high. There are eight genotypes of HBV and three clades of HBV isolates from apes that appear to be additional genotypes of HBV. Most genotypes are now divided into subgenotypes with distinct virological and epidemiological properties. In addition, recombination among HBV genotypes increases the variability of HBV. This review summarises current knowledge of the epidemiology of genetic variability in hepadnaviruses and, due to rapid progress in the field,updates several recent reviews on HBV genotypes and subgenotypes.     

Biphasic clearance kinetics of hepatitis B virus from patients during adefovir dipivoxil therapy.

In a recent phase II clinical study, 13 chronic hepatitis B-infected patients treated daily with 30 mg adefovir dipivoxil for 12 weeks displayed a median 4.1-log10 decrease in plasma hepatitis B virus (HBV)-DNA levels. The decline of viral load during therapy displayed a biphasic kinetic profile that was modeled to determine the efficacy of inhibition of viral production, as well as kinetic constants for the clearance of free virus and the loss of infected cells. Viral production was suppressed with an efficacy of 0.993 +/- 0.008, indicating that only 0.7% of viral production persisted during therapy. The initial, faster phase of viral load decline reflects the clearance of HBV particles from plasma with a half-life of 1.1 +/- 0.3 days, translating to a 48% daily turnover of the free virus. The second, slower phase of viral load decline closely mirrors the rate-limiting process of infected cell loss, with a half-life of 18 +/- 7 days. The duration of therapy required to completely eliminate the virus from plasma or suppress it to levels sufficient to induce seroconversion is a function of the half-life of the free virus, the half-life of infected cells, and the efficacy of inhibition of virus production from infected cells. These quantitative analyses provide a more detailed picture of the dynamics of HBV infection and therapy, and can be used to compare the efficacy of various doses and inhibitors of HBV replication for the treatment of HBV infections.     

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.