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.     

Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients

Three-hundred and twenty-four patients were enrolled in an open-label, multicenter, international study in which pre- and post-liver transplantation (LT) patients with recurrent chronic hepatitis B (CHB) and evidence of lamivudine-resistant HBV were treated with adefovir dipivoxil 10 mg once daily. In the pre- and post-LT cohorts, 128 and 196 patients were treated for a median duration of 18.7 and 56.1 weeks, respectively. In patients who received 48 weeks of treatment, 81% of the pre-LT and 34% of the post-LT cohort achieved undetectable serum hepatitis B virus (HBV) DNA (Roche Amplicor Monitor polymerase chain reaction [PCR] assay lower limit of quantification [LLQ] < 400 copies/mL) with a median change in serum HBV DNA from baseline of -4.1 log(10) and -4.3 log(10) copies/mL, respectively. Serum alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 76%, 81%, 50%, and 83% of pre-LT patients and 49%, 76%, 75%, and 20% of post-LT patients. The Child-Pugh-Turcotte (CPT) score improved in over 90% of patients in both cohorts. Genotypic analysis of 122 HBV baseline samples revealed that 98% of these patients had lamivudine-resistant mutant HBV. No adefovir resistance mutations were identified in patients after 48 weeks of therapy. One-year survival was 84% for pre-LT and 93% for post-LT patients (Kaplan-Meier analysis). Treatment-related adverse effects associated with adefovir dipivoxil in this setting were primarily mild to moderate in severity. In conclusion, 48 weeks of adefovir dipivoxil resulted in significant improvements in virologic, biochemical, and clinical parameters in CHB patients pre- and post-LT with lamivudine-resistant HBV.     

阿德福韦酯治疗HBeAg阳性的中国慢性乙型病毒性肝炎患者52周的多中心临床研究

目的评价阿德福韦酯（ADV）片10mg／d治疗HBeAg阳性的中国慢性乙型病毒性肝炎患者52周的疗效和安全性。方法采用多中心、随机、双盲、安慰剂平行对照的研究设计。第一阶段480例患者按3：1的比例随机进入ADV组（360例）或安慰剂组（120例）治疗12周；第二阶段所有患者均接受开放的ADV治疗28周；第三阶段则原接受ADV治疗的患者重新按2：1的比例随机接受ADV治疗（AAA组）或安慰剂治疗（AAP组）；而第一阶段服用安慰剂的患者（PAA组）将继续接受ADV治疗。根据不同的组别，患者分别口服ADV10mg或安慰剂1片，1日1次。主要疗效评估指标为血清HBV DNA的变化情况。次要疗效评估指标为丙氨酸转氨酶（ALT）的复常率与HBeAg转阴率、HBeAg的血清转换率。结果12周时，AAA组和AAP组HBV DNA中位数水平较基线分别降低3．4lg拷贝／ml和3．3lg拷贝／ml；40周时，三组血清HBV DNA中位数水平降低程度相似，较基线降低了4．O～4．6lg拷贝／ml；52周时，PAA组和AAA组HBV DNA中位数水平较基线分别降低5．0lg拷贝／ml和4．5lg拷贝／ml，而AAP组HBV DNA中位数水平则恢复到接近基线水平；PAA组和AAA组患者分别有30．3％和28．4％的患者HBV DNA转阴，而AAP组HBV DNA转阴率从40周的19．3％（23／119）降低到0．8％（1／119）；PAA组和AAA组ALT复常率分别为69．2％（74／107）和78．6％（176／224），而AAP组的ALT复常率由40周时的74．3％（81／109）下降为52周的21．1％（23／109）；PAA组和AAA组HBeAg转阴率分别为20％（24／119）和13％（30／237），血清转换率分别为17％（20／116）和8%（19／232），而AAP组的HBeAg转阴率和血清转换率分别从40周的14％（16／114）和11％（12／112）降低到52周时的9％（10／114）和4％（5／112）。45例血清HBV DNA水平较治疗最低水平增高≥1lg的患者中未发现与ADV耐药相关的基因突变。安全性方面，各组至少发生1个与药物相关不良事件的发生率为5％～11％，大多为轻、中度。研究期间各治疗组血清肌酐及血磷值平均水平同基线相比无变化。结论阿德福韦酯片10mg／d剂量服用52周，可以安全、有效地治疗中国HBeAg阳性的慢性乙型肝炎患者，未发现与ADV耐药相关的病毒基因突变。     

Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B

BACKGROUND AND AIMS: Adefovir dipivoxil possesses potent in vitro and in vivo antiviral activity in wild-type hepatitis B. This study assessed the safety and efficacy of adefovir dipivoxil alone and in combination with lamivudine compared with ongoing lamivudine therapy in patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant hepatitis B virus (HBV). METHODS: Fifty-nine hepatitis B e antigen (HBeAg)-positive patients with genotypic evidence of lamivudine-resistant HBV, serum alanine aminotransferase (ALT) level > or =1.2 times the upper limit of normal, and serum HBV DNA level > or =6 log(10) copies/mL despite ongoing treatment with lamivudine were randomized to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine daily. The primary end point was the time-weighted average change from baseline in serum HBV DNA level (DAVG) up to week 16. RESULTS: Rapid reductions in serum HBV DNA level were seen by 4 weeks in all recipients of adefovir dipivoxil; DAVG(16) was -0.07 in the lamivudine group compared with -2.45 and -2.46 log(10) copies/mL in the adefovir dipivoxil/lamivudine and adefovir dipivoxil monotherapy groups, respectively (P < 0.001). Median change from baseline in serum HBV DNA level at week 48 was 0.0, -3.59, and -4.04 log(10) copies/mL in the lamivudine, adefovir dipivoxil/lamivudine, and adefovir dipivoxil groups, respectively. ALT level normalized in 10 of 19 (53%) and 9 of 18 (47%) recipients of adefovir dipivoxil/lamivudine and adefovir dipivoxil, respectively, compared with 1 of 19 (5%) recipients of lamivudine. Three patients receiving adefovir dipivoxil or adefovir dipivoxil/lamivudine and none receiving lamivudine monotherapy were HBeAg negative at week 48 and one became hepatitis B surface antigen negative. CONCLUSIONS: These data, limited to patients with compensated liver disease, indicate that adefovir dipivoxil alone or in combination with ongoing lamivudine therapy provides effective antiviral therapy in patients with lamivudine-resistant HBV.     

Adefovir dipivoxil is a new drug for treatment of chronic hepatitis B

Adefovir dipivoxil is a new nucleotide analog derived from adenosin-monophosphate. At the 10 mg/day dose significantly decreases HBV DNA in serum, activity of transaminases, and leads to better histology results in liver assessment of adults with hepatitis B in the phase of active viral replication. Treatment with Adefovir dipivoxil is a long term treatment (48 weeks), it is well tolerated, and side effects are moderate and reversible. It can be administered to HBeAg positive patients, to patients with HBV mutant unable to create HBeAg if positive HBV DNA in serum, and to patients with lamivudine resistant HBV mutant.     

阿德福韦酯治疗慢性乙型肝炎72例疗效观察

目的 对比观察阿德福韦酯及苦参素治疗慢性乙型肝炎(慢乙肝)的近期疗效.方法 132例患者随机分为2组,治疗组72例,对照组60例.在应用甘草酸二铵注射液、益肝灵降酶保肝治疗基础上,对照组患者用苦参素0.2 g,3/d,口服;治疗组患者用阿德福韦酯10 mg,1/d,口服,疗程均为24周.2组患者的性别、年龄、病程、ALT、病毒载量,治疗前比较无显著差异(P>0.05).结果 治疗结束时,2组患者临床症状均有明显改善,ALT复常率及HBeAg阴转率无显著差异(P>0.05),HBV DNA有效率及HBV DNA阴转率,有显著统计学差异(P<0.005).结论 阿德福韦酯治疗慢乙肝,抑制HBV DNA的疗效明显优于苦参素.     

阿德福韦酯治疗HBeAg阳性慢性乙型肝炎101例临床观察

目的观察阿德福韦酯治疗HBeAg阳性慢性乙型肝炎和拉米夫定治疗无效的慢性乙型肝炎患者,单药连续144周治疗,停药后监测96周疗效和药物安全性。方法初始治疗69例,拉米夫定治疗无效再治疗32例共101例,采用单药阿德福韦酯(ADV)10mg,每日1次口服,连续治疗144周,疗程结束继续监测到240周。结果阿德福韦酯初治组和复治组经144周连续治疗和停药后监测至240周血清ALT累积复常率分别为91.3%和90.6%,血清HBV DNA转阴率分别为88.4%和84.3%,HBeAg转阴率分别为34.7%和28.1%,HBeAg/HB-eAb血清转换率分别为55.0%和53.1%,HBsAg/HBsAb血清学转换均在停药后不同时间段发生,初治组为7.2%,复治组为6.3%。经144周连续治疗和停药后随访期间血、尿常规和肾功能,均无与治疗相关的异常发现。结论阿德福韦酯单药10mg每日1次口服治疗HBeAg阳性慢性乙型肝炎患者,有显著抑制HBV DNA复制,对拉米夫定治疗无效患者,可获得同样疗效,长期服药无明显耐药性,安全性好。     

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。     

阿德福韦酯治疗乙型肝炎肝硬化合并乙型肝炎病毒相关性肾炎的近期疗效

目的 观察阿德福韦酯治疗乙型肝炎肝硬化合并乙型肝炎病毒相关性肾炎的近期疗效.方法 选择6例乙型肝炎肝硬化合并乙型肝炎病毒相关性肾炎患者,定量PCR测得血清HBVDNA＞105拷贝/ml,肾组织HBV DNA阳性,肝功能Child-Pugh分级均为A级,在常规治疗基础上加用阿德福韦酯10 mg/d 1年.于治疗后1、3、6个月复查血常规、尿蛋白定量、肝肾功能、血清HBV标志物变化情况.结果 治疗后3、6个月血清HBV DNA转阴的分别有2例和5例,HBeAg转阴的分别有1例和4例,抗HBe转阳的均只有1例;ALT复常的分别有5例和6例,总胆红素复常的分别有4例和5例.治疗6个月后尿蛋白量＜0.3 g/d的2例,尿蛋白量较治疗前下降＞50%的3例.巩固治疗1年时完全缓解3例,部分缓解2例. 结论 阿德福韦酯治疗乙型肝炎肝硬化合并乙型肝炎病毒相关性肾炎近期安全有效.     

Treatment strategies using adefovir dipivoxil for individuals with lamivudine-resistant chronic hepatitis B

AIM: To investigate retrospectively the long-term efficacy of various treatment strategies using adefovir dipivoxil (adefovir) in patients with lamivudine-resistant chronic hepatitis B.METHODS: We included 154 consecutive patients in two treatment groups: the “add-on” group (n = 79), in which adefovir was added to ongoing lamivudine treatment due to lamivudine resistance, and the “switch/combination” group (n = 75), in which lamivudine was first switched to adefovir and then re-added later as needed. The “switch/combination” group was then divided into two subgroups depending on whether participants followed (group A, n = 30) or violated (group B, n = 45) a proposed treatment strategy that determined whether to add lamivudine based on the serum hepatitis B virus (HBV) DNA levels (< 60 IU/mL or not) after 6 mo of treatment (roadmap concept).RESULTS: The cumulative probability of virologic response (HBV DNA < 60 IU/mL) was higher in group A than in the “add-on” group and in group B (P < 0.001). In contrast, the cumulative probability of virologic breakthrough was lower in the “add-on” group than in group B (P = 0.002). Furthermore, the risk of virologic breakthrough in the multivariate analysis was significantly lower in the “add-on” group than in group A (hazard ratio = 0.096; 95%CI, 0.015-0.629; P = 0.015).CONCLUSION: The selective combination of adefovir with lamivudine based upon early treatment responses increased the odds of virologic breakthrough relative to the use of uniform combination therapy from the beginning of treatment.     

Short-term overlap lamivudine treatment with adefovir dipivoxil in patients with lamivudine-resistant chronic hepatitis B

AIM： To evaluate the efficacy of short-term overlap lamivudine therapy with adefovir in patients with lamivudine-resistant and naive chronic hepatitis B, we compared patients receiving overlap therapy with those receiving adefovir alone. METHODS： Eighty patients who had received lamivudine treatment for various periods and had a lamivudineo resistant liver function abnormality were enrolled. Forty of these patients received adefovir treatment combined with lamivudine treatment for ≥ 2 mo, while the other 40 received adefovir alone. We assessed the levels of hepatitis B virus （HBV） DNA at 0, 12 and 48 wk and serum alanine aminotransferase （ALT） levels after 0, 12, 24 and 48 wk of adefovir treatment in each group. RESULTS： We found serum ALT became normalized in 72 （87.5%） of the 80 patients, and HBV DNA decreased by ≥ 2 Ioglo copies/mL in 60 （75%） of the 80 patients at the end of a 48-wk treatment. HBV DNA levels were not significantly different between the groups. The improvements in serum ALT were also not significantly different between the two groups. CONCLUSION： These findings suggest short-term overlap lamivudine treatment results in no better virological and biological outcomes than non-overlap adefovir monotherapy.     

阿德福韦酯治疗对α-干扰素无应答的慢性乙型肝炎的临床观察

目的 观察阿德福韦酯治疗对α-干扰素无应答的CHB患者的疗效。方法 27例对α-干扰素无应答的CHB患者，口服阿德福韦酯10mg，1次／日，随访至18个月，观察肝功能、乙型肝炎病毒标记物及HBVDNA的变化情况。结果 27例患者在6个月、12个月和18个月时HBVDNA阴转率分别为18．5％、29．6％和44．4oA；ALT复常率分别为88．9%、92．6％和85．2%；HBeAg血清学转换率分别为7．4％、14．8％和25．9％。结论 阿德福韦酯治疗对α-干扰素无应答的CHB患者的疗效随疗程的延长逐渐增加。     

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.     

Surgical treatment of HCC in a patient with lamivudine-resistant hepatitis B cirrhosis with adefovir dipivoxil

We describe a 77-year-old woman with chronic hepatitis B who became resistant to lamivudine. She was started on adefovir (10 mg daily) while still continuing lamivudine therapy. Four mo later her liver function improved and serum Hepatitis B virus (HBV)-DNA level became undetectable. Three years after the start of additional adefovir treatment, hepatocellular carcinoma (HCC) was detected and the patient underwent a successful hepatectomy. Our findings suggest that the addition of adefovir to ongoing lamivudine therapy cannot completely suppress hepatocarcinogenesis, but is useful for improving liver function in patients with lamivudine-resistant HBV-related cirrhosis, allowing HCC surgery.     

恩替卡韦联合阿德福韦酯对拉米夫定耐药乙肝肝硬化的疗效

目的 研究恩替卡韦（ENT）联合阿德福韦酯（ADV）治疗对拉米夫定耐药乙型肝炎肝硬化的临床疗效.方法 选取98例对拉米夫定耐药乙型肝炎肝硬化患者分为代偿期和失代偿期,两组患者均给予恩替卡韦（0.5 mg/d,qd）和阿德福韦酯（10 mg,qd）治疗.两组患者分别在治疗前、治疗24周和48周收集患者的血清样本检测HBV DNA阴转率、ALT复常率、评估Child-Pugh评分和与药物相关的不良反应.结果 治疗24周、48周时两组患者的HBV DNA阴转率、HBeAg阴转率、ALT复常率与治疗前相比均得到显著改善,治疗24周和48周时,两组HBeAg阴转率、HBV DNA阴转率、ALT复常率比较,差异有统计学意义（P＜0.05）.Child-Pugh评分与治疗前相比得到改善,但差异无统计学意义（P＞0.05）,治疗24周和48周时,两组Child-Pugh评分比较差异有统计学意义（P＜0.05）.未见不良反应和病毒学突破.结论 恩替卡韦联合阿德福韦酯治疗乙型肝炎肝硬化可以有效抑制乙肝病毒复制,延缓疾病进展,安全性良好.