阿德福韦酯治疗拉米夫定耐药的慢性乙型肝炎的疗效观察

目的 观察阿德福韦酯（ADV）治疗拉米夫定（LAM）耐药的慢性乙型肝炎的临床疗效和安全性。方法 随机将81例拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者分为ADV治疗组41例,以ADV联合LAM治疗12周,停用LAM再继续应用ADV治疗36周和LAM治疗组40例,继续应用LAM。结果 ADV治疗组患者在治疗24周和48周时HBV DNA水平下降明显优于LAM组,差异有统计学意义（P〈0．05）;ADV组治疗24周和48周时,血清HBeAg阴转率分别为31．7％和34．1％,血清HBeAg／抗-HBe转换率为24．4％和22．0％,丙氨酸氨基转移酶复常率为56．1％和68．3％,均显著优于LAM组（P〈0．05）。治疗中无不良反应发生。结论 ADV能有效安全地治疗LAM耐药性慢性乙型肝炎患者。     

阿德福韦酯治疗拉米夫定耐药慢性乙型肝炎的临床观察

目的观察拉米夫定治疗慢性乙型肝炎发生病毒基因变异后,单用或联合阿德福韦酯治疗的疗效以及安全性。方法 35例拉米夫定治疗失败的慢性乙型肝炎患者接受阿德福韦酯治疗,另30例患者采用拉米夫定联合阿德福韦酯治疗,观察2年。结果联合组与阿德福韦酯治疗组比,在治疗2年时,ALT复常率和HBVDNA阴转率均明显高于阿德福韦酯治疗组(P0.05);阿德福韦酯治疗无严重不良反应发生。结论阿德福韦酯联合拉米夫定治疗拉米夫定治疗失败的慢性乙型肝炎患者,远期疗效优于单用阿德福韦酯组。     

阿德福韦酯联合拉米夫定治疗拉米夫定耐药慢性乙型肝炎32例临床观察

目的探讨ADV联合LAM治疗LAM耐药CHB患者的临床疗效。方法选择LAM耐药的HBeAg阳性CHB患者62例,随机分为ADV+LAM(A组)32例,予ADV10mg/d联合LAM100mg/d口服;ADV组(B组)30例,给予ADV10mg/d口服,观察12、24、48、72和96周治疗时血清肝功能,HBVDNA水平,HBV血清学标志及不良反应。结果治疗72、96周A组ALT复常率分别为71.9%、81.2%,B组分别为56.7%、63.3%(P0.05);治疗72、96周A组HBVDNA水平为3.14±1.26lgcopies/ml,B组为4.38±1.42lgcopies/ml(P0.05);治疗72、96周A组HBVDNA转阴率分别为84.3%、90.6%,B组分别为73.3%、66.7%(P0.05);治疗96周A组新的耐药变异率为0%,B组为23.1%(P0.05);治疗96周A组HBeAg转阴率为56.3%,B组为43.3%(P0.05)。两组均未发现与药物相关的不良反应。结论 ADV联合LAM治疗LAM耐药CHB患者较换用ADV治疗有显著的抗病毒效果,能有效减少新的HBV耐药变异的发生,安全性良好。     

阿德福韦酯对拉米夫定耐药的HBV抑制作用观察

为了解阿德福韦酯对拉米夫定耐药的HBV的抑制作用,我院自2005年起对37例拉米夫定耐药的慢性乙型肝炎患者使用阿德福韦酯进行抗病毒治疗,取得了比较满意的治疗效果,现报告如下.     

阿德福韦酯联合拉米夫定治疗拉米夫定治疗失效的慢性乙型肝炎疗效分析

目的观察拉米夫定治疗慢性乙型肝炎发生乙型肝炎病毒耐药后,单用或联用阿德福韦酯治疗的疗效以及安全性。方法27例拉米夫定耐药的慢性乙型肝炎患者被随机分为拉米夫定联合阿德福韦酯治疗组和单用阿德福韦酯治疗组。联合组口服阿德福韦酯10mg／d和拉米夫定100mg／d,单用组给予阿德福韦酯10mg／d,并均给予常规护肝及对症、支持治疗,疗程24月。观察6、9、12、18、24月时两组患者的肝功能、HBVDNA、病毒耐药突变率。两组间均数比较采用t检验,多组间均数比较采用方差分析,计数资料比较采用x。检验。结果治疗6、9和12月时,拉米夫定联合阿德福韦酯治疗组AⅡ复常率分别为37．O％、51．8％和74．0％,单用阿德福韦酯治疗组分别为31．5％、47．3％和57．9％,两组间差异有统计学意义（p值均〈0．05）,且随着疗程的延长,联合组患者肝功能指标复常率均明显升高;治疗12月时,两组患者HBVDNA水平均较治疗前明显下降,但差异无统计学意义（P〉0．05）。随着疗程的延长,拉米夫定联合阿德福韦酯治疗组HBVDNA转阴率不断升高（P〈0．05）,与单用阿德福韦酯治疗组比亦有明显差异（P〈0．05）;患者血清HBeAg转阴率及HBeAg／抗-HBe转换率随着治疗疗程的延长均增加,但两组问差异无统计学意义;24月时两组病毒耐药突变率差异无统计学意义;两组均未发现与药物有关的严重不良反应发生。结论阿德福韦酯联合拉米夫定治疗对拉米夫定耐药的慢性乙型肝炎患者有效。     

阿德福韦酯联合拉米夫定治疗拉米夫定耐药的慢性乙型肝炎患者48周疗效观察

目的 观察阿德福韦酯（ADV）联合拉米夫定（LAM）治疗LAM耐药的慢性乙型肝炎患者的临床疗效。方法 2011年1月～2013年6月我科诊治的对LAM耐药的慢性乙型肝炎患者85例,43例接受ADV组治疗,42例接受ADV联合LAM治疗,观察治疗48 w时的疗效。结果 在治疗24 w和48 w时,联合治疗组患者肝功能指标改善情况优于阿德福韦治疗组（P<0.05）;在治疗24 w和48 w时,联合治疗组患者血清HBV DNA阴转率分别为54.7%（23/42）和92.8%（39/42）,显著高于阿德福韦治疗组[分别为37.2%（16/43）和67.4%（29/43）,P<0.05];在治疗48 w时,联合治疗组血清HBeAg阴转率为24.1%（7/29）,显著高于阿德福韦组的[3.2%（1/31）,P<0.05]。结论 ADV联合LAM治疗LAM耐药的慢性乙型肝炎患者有较好的临床疗效。     

阿德福韦酯治疗拉米夫定耐药慢性乙型肝炎临床观察

阿德福韦酯(ADV)对拉米夫定耐药变异株具有显著的抑制作用,临床推荐拉米夫定耐药患者的优选治疗.现就阿德福韦酯治疗拉米夫定耐药的20例慢性乙型肝炎患者近期疗效报道如下.     

阿德福韦酯联合拉米夫定治疗拉米夫定耐药慢性乙型肝炎59例临床观察

目的 探讨阿德福韦酯(ADV)联合拉米夫定(LAM)治疗LAM耐药慢性乙型肝炎(CHB)患者的临床疗效.方法 选择LAM耐药的HBeAg阳性的CHB患者114例,随机分成两组:ADV +LAM(A组)59例,予ADV10mg/d联合LAM 100 mg/d口服;ADV组(B组)55例,予ADV 10 mg/d 口服.分别观察完成24、48、96和144周治疗时血清肝功能,HBV DNA水平,HBV血清学标志及不良反应.结果 治疗96、144周A组ALT复常率较B组显著升高(P＜0.05);治疗96、144周A组HBV DNA水平较B组显著下降(P＜0.05);治疗96、144周A组HBV DNA转阴率较B组显著升高(P＜0.05);治疗96、144周A组新的耐药变异率显著低于B组(P＜0.05);治疗96、144周A组HBeAg转阴率显著高于B组(P＜0.05).两组均未发现与药物相关的不良反应.结论 ADV联合LAM治疗LAM耐药CHB患者有显著的抗病毒效果,能有效减少HBV耐药变异的发生,安全性良好.     

阿德福韦酯联合拉米夫定治疗拉米夫定耐药慢性乙型肝炎的临床观察

目的 观察阿德福韦酯联合拉米夫定治疗拉米夫定耐药慢性乙型肝炎临床疗效.方法 首先在充分告知符合研究对象的患者(80例)病情后根据患者的意愿选择分为:(1)对照组(单药治疗组,n=38例),在拉米夫定应用基础上重叠阿德福韦酯治疗12周后,停用拉米夫定,单独使用阿德福韦酯治疗132周;(2)观察组(联合治疗组,n=42例),出现拉米夫定耐药后联合应用阿德福韦酯144周.每3个月检测患者的HBV-DNA、HBV-M、肝功能、肾功能及血常规等.结果 144周疗程结束后联合治疗组患者HBV-DNA转阴率明显优于对照组,疗效差异有统计学意义(P＜0.01),HbeAg在两组间未见明显差异(P>0.05),联合治疗组治疗后肝功能复常率较单药治疗组高(P<0.05).结论 阿德福韦酯联合拉米夫定治疗拉米夫定耐药慢性乙型肝炎有较好的疗效.     

阿德福韦酯联合拉米夫定治疗拉米夫定耐药慢性乙型肝炎疗效观察

目的探讨阿德福韦酯（ADV）联合拉米夫定（LAM）治疗LAM耐药慢性乙型肝炎（CHB）患者的临床疗效及安全性。方法选择LAM耐药的HBeAg阳性CHB患者102例随机分为3组,ADV＋LAM组（A组）38例,给予ADV10mg/d联合LAM100 mg/d口服;ADV组（B组）42例,ADV10mg/d口服;LAM组（C组）22例,LAM 100mg/d口服,分别于完成24、48和72周治疗时,观察血清HBV DNA水平、HBV血清学标志、肝功能及不良反应。结果治疗24、48、72周A、B组HBV DNA水平较C组均显著下降（P〈0.01）,HBV DNA阴转率较C组显著升高（P〈0.05,P〈0.01）,治疗24、48、72周A组和72周B组ALT复常率较C组均显著升高（P〈0.05,P〈0.01）;治疗48、72周A组HBV DNA水平较B组显著下降（P〈0.05）,治疗72周HBV DNA阴转率和ALT复常率较B组显著升高（P〈0.05,P〈0.01）。三组血清HBeAg阴转率及血清转换率间差异无统计学意义（P〉0.05）。治疗期间A组新的耐药变异率低于C组（P〈0.05）,均未发现与药物相关的严重不良反应。结论ADV联合LAM治疗LAM耐药CHB患者具有显著的抗病毒和临床疗效,且安全性良好。     

Efficacy of adefovir dipivoxil in the treatment of lamivudine-resistant hepatitis B virus genotype C infection.

BACKGROUND AND AIMS: Adefovir dipivoxil (ADV) is a nucleotide analogue that is known to be effective for lamivudine-resistant hepatitis B virus (HBV) mutants as well as wild-type HBV. The aim of this study is to assess the efficacy of ADV against lamivudine-resistant genotype C HBV mutants. METHODS: Thirty-five patients with breakthrough hepatitis due to lamivudine-resistant HBV received ADV 10 mg daily with discontinuation of lamivudine. Quantitative HBV DNA, HBeAg, liver function test including alanine aminotransferase (ALT) was checked every 4-12 weeks to evaluate the efficacy of ADV. RESULTS: ADV was administered for a median of 48 weeks (range: 24-120 weeks). The rate of serum HBV DNA loss was 68.6%, 80.0%, 84.0%, and 88.2% at weeks 12, 24, 36, and 48, respectively. The rate of serum HBeAg seroconversion was 8.3% and 14.3% at weeks 24 and 48, respectively. The rate of serum ALT normalization at week 48 was 70.6%. Within 32 weeks after stopping ADV therapy, serum HBV DNA levels increased to a median of 378.9 pg/ml in 88.9% of patients, who were treated for a median of 40 weeks. Moreover, in some patients, the ALT level increased to more than five times the upper limit of normal. CONCLUSIONS: Administration of ADV is an effective option for the treatment of patients with lamivudine-resistant genotype C HBV infection.     

膦甲酸钠联合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 观察膦甲酸钠联合阿德福韦酯治疗拉米夫定耐药的慢性乙型肝炎患者的疗效和安全性.方法 选择拉米夫定耐药的慢性乙型肝炎患者70例,随机分为联合组(膦甲酸钠和阿德福韦酯组)36例,对照组(阿德福韦酯组)34例,完成4周和12周治疗时,分别检测血清HBV DNA水平和肝功能变化.结果 在治疗4周和12周时,联合组肝功能恢复及病毒应答率,均显著高于对照组.两组均未发生与研究药物相关的严重不良反应.两组不良事件发生率无统计学差异.结论 膦甲酸钠联合阿德福韦酯治疗拉米夫定耐药的慢性乙型肝炎,可在生物化学及病毒学方面取得较好疗效,且安全性好.     

Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants

BACKGROUND: The recurrence of chronic hepatitis B after liver transplantation results in increased risk for graft failure and death of patients. Lamivudine has been shown to be effective in the treatment of chronic hepatitis B, but resistance to this agent is common after prolonged administration. METHODS: One patient with chronic hepatitis B virus (HBV) infection developed resistance to lamivudine after 15 months of treatment. The resistance was confirmed by mutation in the HBV DNA polymerase gene. The patient was treated subsequently with adefovir dipivoxil for 7 months. RESULT: HBV DNA and HBsAg were tested negative, but HBeAb and HBsAb were positive. CONCLUSION: This study provides an evidence that adefovir dipivoxil can be effective in the treatment of lamivudine-resistant HBV mutants.     

Long-term outcomes of add-on adefovir dipivoxil therapy to ongoing lamivudine in patients with lamivudine-resistant chronic hepatitis B

Aim: Add-on adefovir dipivoxil (ADV) therapy has been a standard rescue treatment for patients with lamivudine (LAM)-resistant chronic hepatitis B, but the overall benefits of long-term add-on ADV therapy are still limited. The aim of this study was to evaluate the long-term efficiency of add-on ADV treatment and to explore predictive factors associated with it. Methods: A total of 158 patients with LAM-resistant chronic hepatitis B were included in this retrospective, multicenter, nationwide study in Japan. After confirming LAM resistance, ADV was added to LAM treatment. Three types of events were considered as outcomes: virological response, hepatitis B e antigen (HBeAg) clearance and alanine aminotransferase (ALT) normalization. Virological response was defined as serum hepatitis B virus (HBV) DNA levels of less than 3 log copies/mL. Baseline factors contributing to these outcomes were examined by univariate and multivariate analyses. Results: The median total duration of ADV treatment was 41 months (range, 6–84). The rate of virological response was 90.8% at 4 years of treatment; HBeAg clearance and ALT normalization were achieved by 34.0% and 82.7%, respectively, at the end of follow up. Each outcome had different predictive factors: baseline HBV DNA and albumin level were predictive factors for virological response, history of interferon therapy and ALT level for HBeAg clearance, and sex and baseline albumin level for ALT normalization. Conclusion: Long-term add-on ADV treatment was highly effective in LAM-resistant chronic hepatitis B patients in terms of virological and biochemical responses. Lower HBV replication and lower albumin level at baseline led to better outcomes.     

阿德福韦酯治疗慢性乙型肝炎85例不良反应观察

目的观察阿德福韦酯治疗慢性乙型肝炎的不良反应。方法 2007年12月至2012年2月慢性乙型肝炎患者共120例,排除失代偿性肝病、原发性或继发性泌尿系统疾病。所有病例治疗前无尿常规及肾功能异常。其中单一使用常规剂量阿德福韦酯治疗的初治病例85例（A组）,其余35例患者予以拉米夫定或恩替卡韦治疗（B组）。治疗过程中起初12周每4周复查血尿常规及肝肾功能,之后每12周复查血尿常规、肝肾功能、血磷、血清肌酸激酶及淀粉酶等。结果 A组9例（10.59%）出现尿常规异常,包括蛋白尿、镜下血尿等,其中一过性异常5例（5.88%）,持续异常4例（4.71%）。B组有1例（2.86%）一过性尿蛋白阳性。两组尿检异常率及持续尿检异常率对比差异均无统计学意义（P〉0.05）。A组5例（5.88%）尿素氮（BUN）升高,B组1例（2.86%）BUN升高,均为一过性,两组对比差异无统计学意义（P〉0.05）。无血清肌酐（SCr）升高病例,未见其他不良反应。结论常规剂量阿德福韦酯治疗慢性乙型肝炎安全性良好。少数病例出现持续性尿检异常,可考虑换药。     

Viral response at 6 months is associated with treatment outcome of adefovir add-on therapy for lamivudine-resistance

Background and Aim: Adefovir add‐on therapy is recommended for patients infected with lamivudine‐resistant hepatitis B virus (HBV). We aimed to describe the long‐term treatment outcome and predictors for good response of adefovir add‐on therapy. Methods: A total of 559 chronic hepatitis B (CHB) patients who had been treated for at least 12 months with adefovir add‐on therapy due to resistance to lamivudine were retrospectively included. Complete virologic response (CVR) was defined as serum HBV DNA < 9 IU/mL. Viral responses at 6 months were classified as PCR negativity, partial virologic response (PVR, HBV DNA < 2000 IU/mL), or inadequate virologic response (IVR, HBV DNA ≥ 2000 IU/mL). Results: The median duration of follow‐up was 31.5 months (range, 12–56). The cumulative probabilities of CVR during adefovir add‐on therapy were 58%, 70%, 78%, and 80% at 12, 24, 36, and 43 months, respectively. The cumulative rates of resistance to adefovir were 0.4%, 0.8%, and 3.1% at 12, 24, and 36 months, respectively. The only baseline factor associated with CVR (hazard ratio 0.83, 95% confidence interval 0.62–0.91, P ≤ 0.001) and resistance to adefovir (hazard ratio 1.925, 95% confidence interval 1.13–3.30, P = 0.017) was serum HBV DNA level. Comparison of the cumulative rates of CVR and resistance to adefovir according to viral response at 6 months showed significant differences among the three groups (P < 0.0001 and P = 0.0005, respectively). Conclusions: Pre‐treatment HBV DNA level and viral response at 6 months is associated with treatment outcome for adefovir‐add on therapy in lamivudine resistance.     

拉米夫定联合阿德福韦酯治疗HBeAg阳性慢性乙型肝炎患者48周临床观察

我国现有慢性乙型肝炎（CHB）患者约2000万例,其中HBeAg阳性CHB患者近60%,常常表现为ALT持续或间歇升高,HBV复制活跃,肝组织重度炎症坏死,与HBeAg阴性患者相比,有较高的肝硬化比率[1]及较快速的病情进展[2]。而持续的高病毒载量又与肝细胞癌（HCC）直接相关[3],那么最大限度地长期抑制HBV,减轻肝细胞炎症坏死及纤维化,延缓和减少肝脏失代偿、肝硬化、HCC及其并发症的发生,从而改善生存质量和延长生存时间[4]成为CHB治疗的总体目标。核苷和核苷     

Development of HCC in patients receiving adefovir dipivoxil for lamivudine‐resistant hepatitis B virus mutants

Aim: To identify factors for the development of hepatocellular carcinoma (HCC) in the patients who receive adefovir add‐on lamivudine for treatment of lamivudine‐resistant hepatitis B virus (HBV) mutants. Methods: A total of 247 patients who developed lamivudine‐resistant HBV mutants, with an increase of HBV DNA ≥ 1 log copies/mL, received adefovir dipivoxil 10 mg add‐on lamivudine 100 mg daily during a median of 115 weeks (range: 25–282 weeks). They were followed for the development of HCC by imaging modalities every 3?6 months. Results: HCC developed in 18 of the 247 (7.3%) patients. Eight factors were in significant association with the development of HCC by the univariate analysis. They included age, cirrhosis, platelet counts, levels of bilirubin, aspartate aminotransferase (AST), alanine aminotransferase and α‐fetoprotein, as well as YMDD mutants at the start of adefovir dipivoxil. By the multivariate analysis, AST levels, YIDD mutants, cirrhosis and age were independent factors for the development of HCC. By the Kaplan‐Meier analysis, AST levels ≥ 70 IU/L, YIDD mutants, cirrhosis and age ≥ 50 years increased the risk of HCC (P = 0.018, P = 0.035, P = 0.002 and P = 0.014, respectively). HCC developed more frequently in the patients with than without cirrhosis at the start of adefovir (10/59 [16.9%] vs. 8/188 [4.3%], P = 0.002). Conclusion: HCC can develop in cirrhotic patients receiving adefovir add‐on lamivudine. Hence, the patients with baseline AST ≥ 70 IU/L and YIDD mutants would need to be monitored closely for HCC.     

阿德福韦酯治疗HBeAg阳性慢性乙型肝炎临床研究

目的评价阿德福韦酯（ADV）治疗HBeAg阳性慢性乙型肝炎患者48周的疗效和安全性。方法试验按两个阶段进行。第一阶段患者随机进入安慰剂组（A组,20例）或ADV组（B组,34例）双盲治疗12周;第二阶段患者均接受开放的ADV治疗36周。结果治疗12周时,A组和B组HBVDNA总有效率分别为33．3％、76．5％;12周后,随着疗程延长,HBVDNA转阴率、HBeAg转阴率、HBeAg血清转换率、ALT复常率均增加。结论ADV（10mg,1／d,48周）能安全有效地治疗HBeAg阳性慢性乙型肝炎。     

Adefovir plus lamivudine are more effective than adefovir alone in lamivudine-resistant HBeAg- chronic hepatitis B patients: A 4-year study

Background and Aim:  Adefovir dipivoxil (ADV) is effective in lamivudine (LAM)-resistant hepatitis B e antigen-negative (HBeAg^-) chronic hepatitis B (CHB). However, it is unclear whether LAM treatment should be continued in these patients. We aimed to compare the long-term efficacy of adding ADV to ongoing LAM treatment versus switching to ADV monotherapy in LAM-resistant HBeAg^- CHB.
Methods:  Sixty LAM-resistant patients with HBeAg^- CHB were randomly assigned (3:1) to combination therapy (10 mg ADV once daily plus ongoing LAM at 100 mg once daily [ n  = 45]) or 10 mg ADV monotherapy once daily ( n  = 15). Virological and biochemical responses were defined as hepatitis B virus (HBV)–DNA <400 copies/mL and as normalization of alanine aminotransferase levels, respectively.
Results:  The median follow-up time was 53 months (range 20–60 months). A virological response was observed in 38/45 (84.4%) and 11/15 (73.3%) patients in the ADV/LAM and ADV monotherapy groups, respectively ( P  = 0.56). Biochemical response rates were higher in the ADV/LAM group than in the ADV monotherapy group (90.9% vs 57.1%, respectively; P  = 0.01). In the ADV/LAM group, serum HBV–DNA remained undetectable in all patients who achieved a virological response ( n  = 38). In the ADV monotherapy group, virological breakthrough occurred in four of the 11 patients who achieved a virological response (36.4%; P  < 0.001 vs the ADV/LAM group, log–rank test). In addition, two patients in each group who did not achieve a virological response eventually developed ADV resistance.
Conclusions:  Adding ADV to LAM is more effective than switching to ADV monotherapy in LAM-resistant patients with HBeAg^- CHB.