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.     

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。     

Hepatitis B virus-related decompensated liver cirrhosis: benefits of antiviral therapy

Following development of liver cirrhosis in patients with chronic hepatitis B, liver disease may continue to progress and decompensation or hepatocellular carcinoma (HCC) may occur, especially in those with active viral replication. Decompensation may manifest with jaundice, ascites, variceal bleeding or hepatic encephalopathy. Earlier studies have shown that the prognosis of decompensated cirrhosis is usually poor with a 5-year survival rate at 14-35% under conventional standard of care. The approval of oral antiviral agents has greatly improved the prognosis, as demonstrated in several cohort studies and randomized clinical trials involving therapy with lamivudine, adefovir dipivoxil, entecavir, telbivudine, or tenofovir disoproxil fumarate. Oral antiviral agents are effective in restoring liver function and improving survival in patients with decompensated cirrhosis especially if therapy is initiated early enough. These agents are generally well tolerated without significant side effects. However, their preventive effect in HCC development has yet to be convincingly demonstrated. Given their known resistance profiles, entecavir and tenofovir should be considered as the first-line therapy for patients with HBV-related decompensated cirrhosis.     

拉米夫定治疗失代偿期乙肝肝硬化的临床研究

目的观察拉米夫定对失代偿期乙肝肝硬化患者的治疗效果和安全性。方法60例患者Child-Pugh评分、基础情况相当，分为治疗组和对照组各30例，治疗组在常规治疗同时服用拉米夫定，每日100mg，对照组给予常规治疗。结果拉米夫定治疗随访时间中位数为2年2月。所有患者治疗3～6月后症状和体征逐渐改善，腹水消失。拉米夫定治疗组1年内血清HBV-DNA转阴率76．67％（23／30），血清白蛋白和PTA上升、总胆红素均有下降，Child-Pugh评分减少，2年生存率达93．33％，并发症及再次住院率明显下降。拉米夫定治疗出现YMDD变异率：1年为6．67％（2／30），2年为33．33％（10／30），出现病毒变异后及时加用阿德福韦酯的患者肝功能恢复良好。结论拉米夫定治疗能改善失代偿期乙肝肝硬化肝功能和提高生存率。一旦出现YMDD变异，及时加用阿德福韦酯等针对YMDD变异的抗病毒药物可抑制变异的HBV的复制，防止肝功能恶化。     

拉米夫定、阿德福韦酯联合自体骨髓干细胞移植治疗乙肝肝硬化失代偿期患者的疗效观察

目的观察拉米夫定、阿德福韦酯联合自体骨髓干细胞移植治疗乙肝肝硬化失代偿期患者的临床效果。方法77例乙肝肝硬化失代偿期患者随机分为两组。常规对症支持治疗方法下,A组（37例）采用拉米夫定、阿德福韦酯抗病毒治疗,B组（40例）在A组基础上加用自体骨髓干细胞移植治疗。治疗4周后复查各实验室指标、l临床症状和体征情况。结果治疗4周后,B组血浆白蛋白、天门冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）、总胆红素水平、PT、AFP、胆碱酯酶等指标较A组明显改善（P〈0．05）;B组临床症状和体征较A组也明显改善（P〈0．05）。结论采用拉米夫定、阿德福韦酯联合自体骨髓干细胞移植治疗乙肝肝硬化失代偿期患者,可有效避免骨髓干细胞受到患者体内乙肝病毒的感染和损害,帮助骨髓干细胞在肝脏环境内能分化为正常的肝细胞,参与肝脏结构的修复和重构,改善患者的肝功能,提高患者的生活质量。     

Determinants of early mortality and benefits of lamivudine therapy in patients with hepatitis B virus-related decompensated liver cirrhosis

Chronic hepatitis B infection (HBV) is a major health problem worldwide. The prognosis is grave for patients with HBV-related decompensated liver cirrhosis (LC). We evaluated the effectiveness and the determinants of early mortality of lamivudine treatment in patients with HBV-related decompensated LC. Thirty patients with HBV-related decompensated LC and active viral replication were treated with lamivudine 100 mg daily for a median duration of 9 months. Among these patients, five patients died within 3 months. Two patients were lost to follow-up at week 8 and 9. One patient was treated for <6 months. Twenty-two patients were treated over 6 months. Univariate analysis revealed that the total bilirubin (P = 0.008), prothrombin time (P = 0.004), Child-Turcotte-Pugh score (P = 0.005), the model of efd-stage liver disease score (P = 0.004) and stage III hepatic encephalopathy (P = 0.001) were predictive factors of early mortality. Multivariate analysis revealed that the independent factor associated with early mortality was stage III encephalopathy. Among 22 patients, liver function improved markedly after lamivudine therapy. Of the nine hepatitis B e antigen (HBeAg)-positive patients, three had HBeAg seroconversion. Two patients had YMDD mutant and virological breakthrough at 41 and 46 weeks. One of the two had hepatocellular carcinoma and died of hepatic failure at week 125; the other received adefovir and is doing well. Lamivudine appeared to have benefits in viral suppression and significant improvement in liver function in patients with HBV-related decompensated LC. As noted in prior studies, poor baseline liver function is associated with a poor prognosis in Asian patients with decompensated HBV cirrhosis treated with lamivudine.     

Decompensated hepatitis B virus-related cirrhosis successfully treated with lamivudine allowing surgery for hepatocellular carcinoma

A 39-year-old man was diagnosed with hepatitis B virus-related cirrhosis, and because of hepatic exacerbations with icterus and ascites, he had been repeatedly hospitalized. He was treated with lamivudine. Several months later, his ascites disappeared and his liver function was improved from class C to A according to the Child-Pugh classification. Two years later, one small hepatocellular carcinoma was detected, and he underwent a successful hepatectomy. From this case, we consider lamivudine to be useful for improving hepatic function in decompensated liver cirrhosis type B and lamivudine might enable surgical resection of hepatocellular carcinoma.     

Lamivudine treatment enabling right hepatectomy for hepatocellular carcinoma in decompensated cirrhosis

A 69-year-old man was admitted to our hospital in October 2003, for further examination of two liver tumors. He was diagnosed with hepatocellular carcinoma (HCC) arising from decompensated hepatitis B virus (HBV)-related cirrhosis. Long-term lamivudine administration improved liver function dramatically despite repeated treatment for HCC. His Child-Pugh score was 9 points at start of lamivudine treatment, improving to 5 points after 1 year. His indocyanine green at 15 min after injection test score was 48% before lamivudine treatment, improving to 22% after 2 years and to 5% after 4 years. Radiofrequency ablation controlled the HCC foci and maintained his liver function. In April 2009, abdominal computed tomography revealed a tumor thrombus in the right portal vein. Since his indocyanine green test results had improved to less than 10%, we performed a right hepatectomy, which was successful. To our knowledge, there have been no documented reports of patients undergoing successful right hepatectomy for HCC arising from decompensated cirrhosis. The findings observed in our patient indicate the importance of nucleoside analogs for treating HBV-related HCC.     

拉米夫定和阿德福韦酯初始联合及脐血干细胞治疗失代偿期肝硬化临床研究

目的探讨脐带血干细胞输注及拉米夫定（LAM）、阿德福韦酯（ADV）初始联合治疗失代偿期乙型肝炎肝硬化的临床效果。方法选择失代偿期乙型肝炎肝硬化患者56例,给予ADV10mg／d和LAM100mg／d口服,脐带血干细胞细胞悬液[含单个核细胞（15-35）×10^9／t]100ml静脉输注,每周1次,连续3次。治疗后将患者血常规、肝功能（ALT、AST、ALB、TBil、DBil）、病毒血清学指标进行比较。结果56例患者的肝功能（如ALT、AST、TB、ALB）等血清学指标,治疗前后差异有统计学意义（P〈0．05）,血常规（如WBC、PLT等）、HBVDNA载量比较差异有统计学意义（P〈0．05）。结论脐带血干细胞输注及LAM、ADV初始联合治疗失代偿期乙型肝炎肝硬化可迅速显著地抑制HBVDNA的复制,降低病毒载量,有效减轻肝脏的炎性反应,减少肝细胞坏死损伤,促进肝细胞再生,加速肝功能恢复。     

乙型肝炎肝硬化失代偿期初始拉米夫定和阿德福韦酯联合抗病毒治疗的疗效观察

目的研究拉米夫定（LAM）初始联合阿德福韦酯（ADV）治疗乙型肝炎肝硬化失代偿期患者的疗效与安全性。方法30例HBeAg阳性乙型肝炎肝硬化失代偿期患者,分为LAM初始联合ADV治疗组和变异后联合组,疗程均为48周。结果初始联合组与变异后联合组患者ALT与TBil在治疗4、12、24与48周均较基线明显好转（P〈0．05）,治疗4、12周后,两组均无HBVDNA转阴的患者,治疗24周后,分别有4例（40％）初始联合组与4例（20％）变异后联合组患者HBVDNA转阴,但差异无统计学意义。治疗48周后,初始联合组与变异后联合组HBVDNA转阴率分别为90％（9／10）与40％（8／20）,HBeAg／抗-HBe血清转换率分别为60％（6／10）与20％（4／20）,两组间差异均具有统计学意义（P〈0．05）。初始联合组患者Child—Pugh评分在48周时,优于变异后联合组（P〈0．05）。结论ADV初始联合LAM治疗在改善乙型肝炎肝硬化失代偿期患者临床状况及抗病毒方面均明显优于变异后联合治疗。     

阿德福韦酯治疗YMDD变异的失代偿期乙型肝炎肝硬化临床观察

目的观察阿德福韦酯治疗拉米夫定治疗过程中出现YMDD变异的失代偿期乙型肝炎肝硬化的疗效和安全性。方法将28例在拉米夫定治疗过程中出现YMDD变异的失代偿期乙型肝炎肝硬化患者随机分为治疗组15例和对照组13例,两组均在保肝、利胆等常规内科综合治疗基础上继续接受拉米夫定100mg/d口服治疗,治疗组在上述基础上联合阿德福韦酯10mg/d口服,疗程1年。结果对照组1例因出现肝细胞癌死亡,2例因并发上消化道大出血死亡。治疗组1例在治疗一周时因出现血肌酐轻度升高退出。治疗1年时结果显示,治疗组肝功能恢复情况及HBVDNA阴转率均优于对照组(P<0.01),治疗组病死率为0%,对照组为23.08%。结论阿德福韦酯治疗YMDD变异的失代偿期乙型肝炎肝硬化患者有良好的疗效和安全性,能提高患者的生存质量,改善预后。     

Lamivudine treatment of decompensated hepatitis B virus-related cirrhosis

BACKGROUND: Patients with decompensated hepatitis B vires (HBV)-related cirrhosis tend to have low or undetectable HBV replication. However, some patients continue to have high levels of HBV replication and effective suppression of HBV replication with antiviral agents may potentially decrease hepatic necroinflammation and improve or stabilize liver function. This review was to under stand the efficacy and safety of lamivudine in the treatment of decompensated HBV cirrhosis. DATA SOURCES: An English-language literature search (MEDLINE January 1988-July 2005) was performed, and a total of 52 articles/abstracts relevant to the issue were selected. After review of the selected papers, the meaningful results and conclusions were extracted using scientific crite ria. The papers reviewed pertained mainly to the efficacy and safety profiles of lamivudine treatment for decompensated HBV cirrhosis. RESULTS: The ultimate treatment of decompensated HBV cirrhosis is liver transplantation, but lamivudine treatment may lead to rapid suppression of viral replication and improvement of biochemical and clinical parameters, reduced morbidity and hospitalization for complications of liver disease, increased pre-transplant survival as well as reduced need for transplantation. However, viral resistance can develop after prolonged treatment with lamivudine, and breakthrough hepatitis may be fatal in few patients. Adefovir is effective for lamivudine-resistant HBV mutants. CONCLUSIONS: Antiviral therapy with lamivudine for decompensated HBV cirrhosis can be effective. However, some patients may experience a hepatitis flare with the emergence of YMDD mutants resulting in progressive worsening of liver disease, and should be referred for "rescue" therapy with other nucleoside/nucleotide analogues such as adefovir dipivoxil.     

失代偿期肝硬化抗病毒治疗的临床价值

研究拉米夫定治疗失代偿期肝硬化的疗效及安全性。将活动期肝硬化和静止期肝硬化患者分成对照组和治疗组。对照组给予常规综合治疗12月;治疗组除上述治疗外,给予拉米夫定100mg/日,疗程12个月。观察治疗前后肝功能、HBV DNA、HBeAg阴转和病毒变异等。拉米夫定治疗12个月后,患者肝功能明显改善,Ch ild-pugh评分缩短(P<0.05),HBV DNA下降(P<0.05),HBeAg阴转率升高(P<0.05),血清转换率及病毒变异率无统计学意义。失代偿期肝硬化应用拉米夫定治疗可改善肝功能、阻止病情进一步发展;病毒变异率低,未见严重后果发生。     

拉米夫定或阿德福韦酯选择性治疗失代偿性乙型肝炎肝硬化3年临床观察

目的观察拉米夫定或阿德福韦酯选择性治疗乙型肝炎肝硬化失代偿期患者长疗程疗效及治疗方案的选择。方法乙型肝炎肝硬化失代偿期患者65例,HBV DNA5 log10拷贝/mL者服用拉米夫定(100mg/d)或再联用阿德福韦酯(10mg/d);HBV DNA5 log10拷贝/mL者可单用拉米夫定或阿德福韦酯;病毒持续不下降或反弹要求拉米夫定联用阿德福韦酯。观察治疗前后患者临床症状体征、生化指标、病毒学改变情况。结果65例患者中43例生存至研究结束,3年生存率为66.1%。患者治疗后肝功能正常或好转,病情缓解稳定,生活质量改善,HBV DNA下降约3 log10拷贝/mL,Child-Pugh积分下降3。结论拉米夫定或阿德福韦酯选择性治疗乙型肝炎肝硬化失代偿期患者,可延长患者生存时间,改善肝功能,阻止病情进展,提高生活质量。     

拉米夫定治疗慢性乙型肝炎病毒感染的近期疗效

目的评价拉米夫定治疗不同临床类型慢性乙型肝炎病毒（HBV）感染的近期疗效。方法口服拉米夫定150mg,每日1次,连服6个月,治疗慢性乙型肝炎病人40例,肝炎肝硬化18例,慢性重型肝炎10例。观察其临床、生物化学、血清学和病毒学改变。结果（1）慢性乙型肝炎病情缓解。对照组病毒血症持续,27．5％病人于随访期内肝炎复发（P＜0．001）。同时观察拉米夫定联用干扰素治疗病人20例,未见提高疗效。（2）肝炎肝硬化病情渐趋稳定,肝功能好转,Child—Pugh积分下降。（3）慢性重型肝炎除2例服药不足3个月死亡外,余8例病情缓解,随着肝功能改善,生活质量显著好转。结论拉米夫定适用于治疗慢性乙型肝炎,对处于HBV复制状态的肝硬化和重型肝炎也有效。     

拉米夫定治疗30例HBV引起的失代偿性肝病

观察拉米夫定治疗HBV引起的失代偿性肝病的近期疗效。选择18例慢性重型乙型肝炎、12例失代偿性肝硬化患者在综合治疗基础上,口服拉米夫定(100mg/d),观察6个月患者的临床表现、肝功能、病毒学指标、Ch ild-Pugh记分及HBV DNA变化情况。提示拉米夫定能迅速有效地改善多数HBV引起的失代偿性肝病患者的临床症状及肝功能,使患者HBV DNA阴转,可提高HBV引起的失代偿性肝病患者生存率。     

Efficacy of lamivudine in patients with hepatitis B virus precore mutant infection before and after liver transplantation

OBJECTIVE: Hepatitis B virus (HBV) precore mutant infection is associated with a more severe liver disease and a poorer response to interferon. We evaluated the efficacy and tolerance of lamivudine to induce complete and sustained suppression of viral replication in seven patients infected with HBV precore mutant (HBeAg-/HBeAb+/HBV DNA+) (in three patients mutation at codon 1896 was detected by direct sequencing). METHODS: Of the seven patients, five had decompensated HBV cirrhosis in a replicative phase and were liver transplant candidates (Group A) and two patients underwent orthotopic liver transplantation (OLT) for HBV liver cirrhosis and developed recurrent HBV infection in the grafted liver (Group B). Lamivudine 100 mg daily was administered orally for a period of 6-75 wk. RESULTS: After 6-8 wk lamivudine therapy was well tolerated and successfully suppressed HBV replication to an undetectable serum level of HBV DNA by polymerase chain reaction in six patients. In Group A, two patients underwent successful OLT with no evidence of HBV reinfection 2-14 months later. Lamivudine was continued after OLT with no episodes of rejection. Three patients died before a suitable liver could be found (one remained serum HBV DNA+ after 6 wk of lamivudine therapy). In Group B, 9-14 months after lamivudine therapy both patients developed lamivudine resistance (increased liver enzymes, reappearance of serum HBsAg and HBV DNA [by hybridization]). In both patients liver histology had progressed and in both, mutation at codon 552 of the HBV polymerase gene was detected. CONCLUSIONS: Lamivudine is well tolerated in patients with decompensated liver cirrhosis due to HBV precore mutant infection who are liver transplant candidates. In four patients (80%) potent suppression of viral replication was detected, allowing OLT to be performed. However, post-OLT, a resistant mutant developed under lamivudine therapy. Combination therapy with other antiviral agents should be evaluated to discourage the emergence of lamivudine-resistant mutants.     

Beneficial effects of lamivudine in hepatitis B virus-related decompensated cirrhosis

BACKGROUND/AIMS: HBV-related chronic liver disease patients often present with hepatic decompensation and are not eligible for interferon therapy. Whether long-term lamivudine is effective in these patients was prospectively evaluated. METHODS: Eighteen patients with HBV-related decompensated cirrhosis, all with quantitative DNA +ve and 10 HBeAg +ve, were given lamivudine 150 mg/d. RESULTS: Each patient received at least 9 months (mean 17.9) of lamivudine. Three HBeAg+ve patients (30%) seroconverted to anti-HBe and one lost HBsAg during the follow-up. An improvement from baseline in the aspartate aminotransferase (130 vs. 72 IU/l, p<0.04); alanine aminotransferase (111 vs. 58 IU/l, p<0.01) and Child-Pugh score (8.3 vs 6.7, p<0.013) was seen. Lamivudine had no significant side-effects. HBV DNA became undetectable in all patients by 8 weeks of therapy. In three (17%) patients, HBV DNA again became positive at 9, 9 and 27 months. YMDD mutant was, however, detected in only one (6%). A significant reduction was noted in the morbidity and hospitalizations for complications of liver disease before and after starting lamivudine (1.5+/-0.7 vs. 0.6+/-0.7, p<0.002). CONCLUSIONS: In decompensated HBV-related cirrhosis, lamivudine: i) is effective in suppressing HBV DNA and seroconversion to anti-HBe (30%), ii) can achieve significant improvement in clinical and biochemical status of liver functions.     

Fatal hepatic failure after emergence of the hepatitis B virus mutant during lamivudine therapy in a patient with liver cirrhosis

Lamivudine therapy for chronic hepatitis and decompensated liver cirrhosis related to the hepatitis B virus (HBV) resulted in improvement of liver function and inhibition of viral replication. Despite emergence of the HBV mutant, e-antigen seroconversion and improvement of liver function may be achieved with continuation of lamivudine therapy. Although hepatic decompensation has been reported in a few cases after the emergence of lamivudine-resistant mutants, fatal cases of non-transplant patients have only rarely been reported in the literature. Here, we describe a patient with HBV-related liver cirrhosis who died after a breakthrough infection with a lamivudine-resistant mutant. Hepatic failure and mortality developed after flare-up of severe hepatitis after 13 months of lamivudine treatment. Emergence of the HBV mutant with substitution of isoleucine for leucine at residue 426 (L4261) in combination with isoleucine for methionine at residue 550 (M5501) was observed at 10 and 13 months of treatment.     

恩替卡韦治疗乙型肝炎肝硬化失代偿期的Meta分析

目的比较恩替卡韦、拉米夫定、阿德福韦酯治疗乙型肝炎肝硬化失代偿期的疗效。方法计算机检索PubMed、MEDLINE、EBSCO、CNKI、万方数据库、重庆维普等,并追查所有纳入的参考文献。检索年限均从建库到2013年3月。纳入恩替卡韦与拉米夫定或阿德福韦酯比较治疗乙型肝炎肝硬化失代偿期的随机对照试验。采用Jadad评分法评价纳入研究的方法学质量,并用Cochrane协作网提供的RevMan 5.0软件进行Meta分析,并对不同疗程进行亚组分析。结果纳入8个随机对照试验(n=708),Meta分析结果显示:恩替卡韦治疗乙型肝炎肝硬化失代偿期24周HBV DNA转阴率略高于拉米夫定组,差异无统计学意义(P0.05),但明显高于阿德福韦酯组,差异有统计学意义(P0.00001);48周恩替卡韦组HBV DNA转阴率明显高于拉米夫定组和阿德福韦酯组,差异有统计学意义(P0.00001)。48周恩替卡韦组HBeAg血清转换率与拉米夫定组和阿德福韦酯组差异无统计学意义(P0.05)。结论长期的恩替卡韦治疗乙型肝炎肝硬化失代偿期疗效明显优于拉米夫定和阿德福韦酯。