Lamivudine for chronic hepatitis B

Lamivudine (Epivir, GlaxoSmithKline) was approved by the US Food and Drug Administration for the treatment of adult patients with chronic hepatitis B in 1998, and has since been shown to be of benefit to selected patients with chronic hepatitis B. Drug resistance is the main issue encountered during therapy, with lamivudine resistant mutants emerging at a rate of approximately 15 to 30% per year of therapy. These mutants are associated with relapse of hepatitis, and occasionally hepatic decompensation. Despite this, therapeutic indications and guidelines for lamivudine therapy have now been drawn up, which indicate that lamivudine will be the first line therapy for hepatitis B e antigen-positive chronic hepatitis B patients, although its role in hepatitis B e antigen-negative patients remains controversial.     

Comparison of the Efficacy of Lamivudine Plus Adefovir Versus Entecavir in the Treatment of Lamivudine-Resistant Chronic Hepatitis B: A Systematic Review and Meta-Analysis

Background

Hepatitis B virus infection remains 1 of the major health threats worldwide. Currently, lamivudine plus adefovir combination therapy or entecavir monotherapy is usually used for the treatment of patients with lamivudine-resistant chronic hepatitis B (CHB). However, there are few systematic comparisons between the efficacy of lamivudine plus adefovir and the efficacy of entecavir in the treatment of these patients.

Objective

The goal of this systematic study and meta-analysis was to assess the efficacy of lamivudine plus adefovir compared with entecavir for the treatment of patients with lamivudine-resistant CHB.

Methods

A comprehensive literature search of PUBMED, Web of Science, WANFANG database, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Review, were screened to obtain citations from January 1990 to January 2012 in this study. Data analysis was done by using the Review Manager Software 5.1.

Results

Eight studies were suitable for analysis. A total of 696 patients with lamivudine-resistant CHB were studied and grouped according to treatment: 341 patients in the entecavir group and 355 patients in the lamivudine plus adefovir group. The results found that the rates of undetectable hepatitis B virus DNA levels, alanine aminotransferase normalization, hepatitis B e antigen loss, and hepatitis B e antigen seroconversion were not significantly different between the lamivudine plus adefovir group and the entecavir group. Moreover, the rate of adverse reactions was also not significantly different between the 2 groups. However, virologic breakthrough for the patients with lamivudine resistance was higher in the entecavir group than in the lamivudine plus adefovir group.

Conclusions

For these CHB patients with lamivudine resistance, lamivudine plus adefovir was a better treatment option than entecavir alone.     

Antivirals for the treatment of chronic hepatitis B: current and future options

Despite effective vaccination programmes, new hepatitis B virus (HBV) infections remain common and there are many millions of individuals already infected. Therapeutic agents are needed to reverse existing liver disease and prevent future disease progression. This article reviews recently published clinical data on the two currently available antivirals for the treatment of chronic hepatitis B infection, lamivudine and adefovir dipivoxil. Lamivudine, a nucleoside analogue, is currently the only licensed antiviral for the treatment of chronic hepatitis B in Asia. Extensive clinical trials have shown that lamivudine is effective and well tolerated in a wide range of patients. YMDD variants have been identified in some patients with reduced sensitivity to lamivudine after extended therapy. Adefovir dipivoxil, a nucleotide analogue, will soon be commercially available in Asia. Adefovir dipivoxil 10 mg is well tolerated and is as effective as lamivudine in reducing serum HBV DNA and alanine aminotransaminase levels and increasing seroconversion in patients with hepatitis B e antigen. No adefovir-resistant mutants have been reported during 48-week clinical trials. The addition of adefovir dipivoxil to ongoing lamivudine therapy, in patients with YMDD variants and a reduced response to lamivudine, leads to significant inhibition of viral replication and improvement in liver function after 1 year of therapy.     

血清乙肝病毒E抗原水平预测拉米夫定疗效研究

目的使用拉米夫定治疗乙型肝炎表面抗原(HBeAg)阳性慢性乙型肝炎患者,观察治疗前和治疗中HBeAg水平对血清HBeAg转阴率的影响,分析血清乙肝病毒E抗原水平对拉米夫定疗效的预测作用。方法入选HBeAg阳性慢性乙型肝炎患者261例,根据治疗前血清HBeAg水平分为3组,A组204例,HBeAg水平≥1.0;B组31例,1.0>HBeAg水平≥0.1;C组26例,HBeAg水平<0.1。给予拉米夫定治疗1年后观察各组HBeAg血清转阴率。A组患者治疗12周后,根据HBeAg水平是否<1.0分为两组,观察两组患者治疗1年后HBeAg血清转阴率。结果 HBeAg阳性慢性乙型肝炎患者,拉米夫定治疗前血清HBeAg水平越低,治疗1年后HBeAg血清转阴率越高。拉米夫定治疗12周后,血清HBeAg水平降至1.0以下的患者血清HBeAg转阴率较高。结论拉米夫定治疗前和治疗12周HBeAg水平可预测HBeAg血清转阴率,HBeAg水平可作为抗病毒治疗对象的选择和疗效判断的指标。     

Efficacy of alpha interferon therapy for lamivudine resistance in chronic hepatitis B

OBJECTIVES: The occurrence of lamivudine resistance is often associated with the clinical breakthrough, which is characterised by the reappearance of hepatitis B virus (HBV) DNA in serum and the elevation of aminotransferases. We evaluated the efficacy of alpha interferon for clinical breakthrough in patients receiving lamivudine therapy. PATIENTS: Six chronic hepatitis B patients receiving lamivudine were enrolled in the study. RESULTS: Under lamivudine therapy, clinical breakthroughs occurred in between fifteenth and thirty-fourth month of lamivudine therapy. HBV DNA reappeared, and alanine aminotransferase was elevated. Genotypic analysis showed M552V, M552I and L528M mutations. After determining the clinical breakthrough, standard alpha interferon-2b was given for 6 months. Lamivudine was also maintained. In only one patient, HBV DNA became negative by polymerase chain reaction, and serum alanine transaminase level was normal at the end of therapy. CONCLUSION: Alpha interferon added to lamivudine is generally ineffective in the treatment of lamivudine resistance.     

乙型肝炎病毒YMDD自然变异与抗病毒治疗后变异特点

目的了解未经拉米夫定抗病毒治疗的慢性乙型肝炎（CHB）患者和经拉米夫定治疗后的CHB患者乙型肝炎病毒基因组P区多聚酶YMDD变异情况，观察其特点。方法选择未接受过抗病毒治疗的CHB患者119例和经拉米夫定治疗后无明显效果的CHB患者30例，采用荧光标记杂交双探针聚合酶链反应熔解曲线法（FH—PCR—MC）对其血浆标本进行YMDD基因序列突变检测。结果119例未接受过抗病毒治疗的患者，变异检出率为19．3％（23／119），23例出现自然变异毒株的患者，其体内病毒均为变异株与野生株共生，且变异株为非优势株，变异株在总病毒量中所占的比例均在50％以下，变异类型以YVDD为主（20例）。30例经拉米夫定治疗的患者变异检出率为56．7％（17／30），17例阳性患者有11例患者体内病毒完全为变异毒株，仅6例患者为变异株与野生株共生，且变异株为优势株者占83．3％（5／6）；在变异类型上YVDD占8例，居多；YVDD与YIDD同时阳性占3例。结论未经抗病毒治疗的CHB患者存在YMDD自然变异毒株，且变异株皆与野生株共生，变异株为非优势株。经拉米夫定治疗后的变异多数为完全变异，少数为变异株与野生株共生，且变异株大多为优势株。     

拉米夫定在慢性乙型肝炎患儿外周血Th17细胞变化的研究

目的研究拉米夫定在慢性乙型肝炎(下称慢性乙肝)患儿外周血Th17细胞变化的特征及意义。方法选取该院慢性乙肝患儿45例作为慢性乙肝组,另选取23例健康儿童作为健康对照组。慢性乙肝组患儿给予拉米夫定治疗1年。抽取健康对照组、慢性乙肝组治疗前及治疗1年后外周静脉血,检测血清中乙型肝炎病毒表面标志物(HBV-M)、乙型肝炎病毒核酸定量(HBV-DNA)、丙氨酸氨基转移酶(ALT)及外周血中Th17细胞特征。结果经拉米夫定治疗,慢性乙肝患儿ALT、HBV-DNA载量明显降低,其中26例患儿出现HBV-DNA转阴,4例出现HBeAg转阴。慢性乙肝组治疗前Th17细胞频率明显高于健康对照组(P0.05),经拉米夫定治疗1年后外周血Th17细胞频率较治疗前显著降低,但仍高于健康对照组(P0.05)。治疗后HBV-DNA转阴患儿较未转阴患儿的Th17细胞频率明显降低。结论拉米夫定治疗儿童慢性乙肝能有效抑制病毒复制,且可降低患儿外周血中Th17细胞的频数。     

Lamivudine therapy for Japanese patients with cirrhosis B

OBJECTIVE: The aim of this study was to investigate the emergence of YMDD mutants in patients with chronic hepatitis B during lamivudine therapy and to compare the emergence patterns of YMDD mutants in cirrhotic and noncirrhotic patients. METHODS: Eighteen cirrhotic and 37 noncirrhotic patients with chronic hepatitis B were studied. The emergence of YMDD mutants was determined before, as well as at 1, 3, 6, 9 and 12 months after treatment using a highly sensitive method based on polymerase chain reaction. RESULTS: Although YMDD mutants were elicited early, the emergence of YMDD mutants was not always associated with breakthrough hepatitis. YMDD mutants appeared in cirrhotic and noncirrhotic patients: in 22 and 8% at 1 month, 13 and 21% at 3 months, 46 and 19% at 6 months, 30 and 19% at 9 months, and 83 and 27% at 12 months, respectively. CONCLUSION: YMDD mutants emerge more frequently in cirrhotic than noncirrhotic patients during the early period on lamivudine treatment. The highly sensitive method may be useful for monitoring the development of YMDD mutants in patients with chronic hepatitis B during lamivudine therapy.     

拉米夫定对前C区变异乙肝的治疗与乙肝病毒基因分型的研究

目的：探讨前C区变异的乙型肝炎患者基因型与拉米夫定疗效的关系。方法：随机选择80例HbeAg阴性、血清丙氨酸氨基转氨酶异常的慢性乙型病毒性肝炎患者，检测其HBV基因分型，并给予拉米夫定治疗。于治疗后第1，3，6，9，12个月分别检测患者肝功能及乙肝病毒定量变化，治疗9个月后再次检测乙肝病毒基因分型。结果：前C区变异乙型肝炎患者HBV基因分型：B型6．25％，C型26．25％，D型52．5％，E型8．75％，CD混合型5％，F型1．25％。HbeAg阴性乙型肝炎患者口服拉米夫定HBVYMDD突变株（YIDD／YVDD）多发生于HBV基因型D型、C型。前C区变异多发生于HBV基因型D型。结论：前C区变异多发生于HBV基因型D型，C型、D型对拉米夫定疗效依次降低。     

Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection

Adefovir dipivoxil (Hepsera^®, Gilead Sciences) is a prodrug of adefovir, with potent antiviral activity against hepatitis B virus. Adefovir dipivoxil therapy, 10 mg daily for 48 weeks, is effective in hepatitis B e antigen-positive and -negative chronic hepatitis B. In hepatitis B e antigen-negative chronic hepatitis B, adefovir dipivoxil was recently found to maintain its efficacy even after 3 years of therapy. Adefovir dipivoxil is effective in patients with compensated or decompensated chronic viral B liver disease, and in pre- and post-transplant hepatitis B virus patients who develop resistance to lamivudine (Epivir^®, GlaxoSmithKline). It is well-tolerated and safe even after the third year of long-term therapy, and is associated with low rates of viral resistance. All these characteristics make adefovir dipivoxil an important drug for the treatment of hepatitis B virus infection and an excellent candidate for long-term maintenance therapy in chronic viral B liver disease.     

拉米夫定治疗儿童慢性乙型肝炎的疗效

目的探讨拉米夫定治疗儿童慢性乙型肝炎的临床疗效及安全性。方法将218例慢性乙型肝炎患儿按不同的治疗方法分为拉米夫定组(治疗组)116例和对照组102例。对照组采用常规治疗,如一般护肝、降酶、退黄等治疗。治疗组在对照组治疗的基础上采用拉米夫定片(100mg/片)3～100mg.kg-1.d-1口服。观察2组患儿治疗后12、24、52个月HBV DNA阴转、HBeAg阴转、ALT复常及临床疗效、不良反应等情况。结果治疗组总有效率明显高于对照组(P<0.05)。治疗组患儿治疗后24、52个月HBV DNA、HBeAg阴转率及ALT复常率均明显高于对照组(均P<0.01)。2组患儿均未发生不良反应。结论拉米夫定治疗儿童慢性乙型肝炎有较好的疗效,是治疗儿童慢性乙型肝炎较理想的药物。     

Peginterferon–α2a (40 kDa) (Pegasys®) for hepatitis B

Chronic hepatitis B virus is a serious and life threatening disease afflicting 350 million people worldwide, despite the availability of effective vaccines. Thus far, current monotherapy with conventional interferon-α, lamivudine and adefovir dipivoxil remains unsatisfactory. In addition, the use of conventional interferon-α needs to be administered subcutaneously three-times weekly and is associated with frequent adverse events. Although nucleoside/nucleotide analogs such as lamivudine and adefovir dipivoxil are well tolerated and can normalize serum alanine aminotransaminase rapidly, 1-year therapy with either lamivudine or adefovir dipivoxil results in low hepatitis B e antigen seroconversion rates. In hepatitis B e antigen-negative patients, most would relapse after lamivudine has been discontinued. Peginterferon-α2a, an immunomodulatory agent, is a new drug that has just completed Phase III clinical trials for the treatment of both hepatitis B e antigen-positive and -negative chronic hepatitis B virus infection. The advantage of peginterferon-α2a in achieving sustained virologic response over nucleoside/nucleotide analogs is particularly obvious in the hepatitis B e antigen-negative group. In both studies, sustained off-treatment response is superior to the use of monotherapy with lamivudine, and concomitant use of lamivudine and pegnterferon-α2a does not have advantages over the use of peginterferon-α2a alone. These recent data put peginterferon-α2a as the antihepatitis B virus therapy of choice, especially in young and motivated patients with chronic hepatitis B virus infection. However, despite the superiority of peginterferon-α2a over currently licensed nucleoside/nucleotide analogs, more research needs to be conducted in order to find the most optimal treatment regimen in our fight against chronic hepatitis B virus infection.     

Peginterferon-alpha2a (40 kDa) (Pegasys) for hepatitis B

Chronic hepatitis B virus is a serious and life threatening disease afflicting 350 million people worldwide, despite the availability of effective vaccines. Thus far, current monotherapy with conventional interferon-alpha, lamivudine and adefovir dipivoxil remains unsatisfactory. In addition, the use of conventional interferon-alpha needs to be administered subcutaneously three-times weekly and is associated with frequent adverse events. Although nucleoside/nucleotide analogs such as lamivudine and adefovir dipivoxil are well tolerated and can normalize serum alanine aminotransaminase rapidly, 1-year therapy with either lamivudine or adefovir dipivoxil results in low hepatitis B e antigen seroconversion rates. In hepatitis B e antigen-negative patients, most would relapse after lamivudine has been discontinued. Peginterferon-alpha2a, an immunomodulatory agent, is a new drug that has just completed Phase III clinical trials for the treatment of both hepatitis B e antigen-positive and -negative chronic hepatitis B virus infection. The advantage of peginterferon-alpha2a in achieving sustained virologic response over nucleoside/nucleotide analogs is particularly obvious in the hepatitis B e antigen-negative group. In both studies, sustained off-treatment response is superior to the use of monotherapy with lamivudine, and concomitant use of lamivudine and pegnterferon-alpha2a does not have advantages over the use of peginterferon-alpha2a alone. These recent data put peginterferon-alpha2a as the antihepatitis B virus therapy of choice, especially in young and motivated patients with chronic hepatitis B virus infection. However, despite the superiority of peginterferon-alpha2a over currently licensed nucleoside/nucleotide analogs, more research needs to be conducted in order to find the most optimal treatment regimen in our fight against chronic hepatitis B virus infection.     

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分析

目的 探讨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疗效.方法 68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,治疗组22例,给予拉米夫定100 mg/d联合阿德福韦酯10 mg/d口服;对照A组23例,给予阿德福韦酯10 mg/d口服;对照B组23例,给予拉米夫定100 mg/d口服,治疗6个月.治疗前后都观察肝功能、血清乙型肝炎病毒脱氧核糖核酸(HBV DNA)水平以及变化.结果 拉米夫定和阿德福韦酯联合治疗组与对照A组和对照B组HBVDNA阴转率分别为81.8%、47.8%和43.5%,联合治疗组明显优于对照组A组及B组(P<0.05);肝功能Child-Pugh评分分别为(6.8±1.4)分、(7.2±61.5)分和(7.4±1.9)分,联合治疗组明显优于两个对照组(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独使用拉米夫定或阿德福韦酯治疗,且不易产生耐药性,并可起互补作用,患者能长期稳定病情.     

乙肝病毒的YMDD变异与血清标志物关系的分析研究

目的观察拉米夫定治疗慢性乙型肝炎患者YMDD变异前、后血清乙肝标志物的变化情况.方法检测37例拉米夫定YMDD变异患者治疗前、变异后以及20例YMDD变异患者继续治疗6个月时血清HBV-DNA、HBeAg、前S1蛋白、ALT等指标的水平.结果YMDD变异组治疗后的HBV-DNA、ALT含量及前S1蛋白阳性率明显低于治疗前自身对照组,而HBeAg阳性率则无显著变化;YMDD变异组患者继续治疗6个月时与刚变异时比较HBV-DNA含量显著降低,而前S1蛋白、ALT含量则无显著性差异.结论乙肝病毒的YMDD变异的患者拉米夫定治疗前、变异后血清乙肝标志物HBV-DNA、前S1蛋白、ALT等水平变化显著;尽管发生了HBV聚合酶变异,这些病人在拉米夫定作用下仍显现持续HBV-DNA抑制.     

拉米夫定联合水飞蓟宾治疗对E抗原阳性的慢性乙型肝炎患者相关血液指标的影响

目的：应用拉米夫定联合水飞蓟宾治疗 E 抗原阳性的慢性乙型肝炎,通过治疗前后的相关血液指标变化判断疗效,为个体化治疗提供依据。方法选取 E 抗原阳性慢性乙型肝炎患者226例,按肝功能损伤程度分为轻度组55例、中度组94例和重度组77例,均给予口服拉米夫定100 mg,每日1次及服用水飞蓟宾70 mg,每日3次,疗程6个月。分别对治疗前后的相关血液指标进行分析。结果治疗6个月后,轻度组及中度组患者血清 ALT 复常率、E 抗原阴转率及 HBV-DNA 阴转率有不同程度的改善,而重度组上述指标则均显著提高（P ＜0．05）。结论拉米夫定联合水飞蓟宾治疗更能有效抑制 HBV-DNA 的复制,明显促进血清 ALT 复常率及提高 E 抗原阴转率,尤其是肝功能损伤程度重者;在一定程度上提高治疗慢性乙型肝炎的疗效。     

Histological improvements after a three-year lamivudine therapy in patients with chronic hepatitis B in whom YMDD mutants did not or did develop

OBJECTIVE: The long-term effects of lamivudine and the influence of YMDD mutants on the histology of chronic hepatitis B are not known. METHODS: 3-year lamivudine therapy was given to 16 patients with chronic hepatitis B. YMDD mutants did not develop in 9 patients (group A), while they appeared in the remaining 7 patients (group B). RESULTS: Biochemical and virological responses were invariably achieved in the 9 patients without YMDD mutants, while virological breakthroughs with or without biochemical relapses occurred in all 7 patients with such mutants. All 16 patients accomplished histological improvement, with the total histology activity index (HAI) score decreasing from 11.3 +/- 3.0 to 4.1 +/- 1.7 (p < 0.001). The total HAI score decreased from 11.6 +/- 3.8 to 3.4 +/- 1.3 in the 9 patients in group A (p < 0.001). Although to a significantly lesser extent (p < 0.02), the total HAI score also decreased in the 7 patients in group B from 10.9 +/- 1.0 to 5.0 +/- 1.7 (p < 0.001). CONCLUSION: The results obtained indicate that 3-year lamivudine therapy can induce histological improvements, regardless of the appearance of YMDD mutants accompanied by virological breakthroughs and biochemical relapses.     

实时荧光聚合酶链反应技术检测乙型肝炎病毒YMDD变异的研究

目的采用实时荧光聚合酶链反应(PCR)技术检测慢性乙型肝炎(CHB)患者在使用拉米夫定过程中,乙型肝炎病毒(HBV)YMDD变异的发生情况,并研究影响变异发生的相关因素,为临床预测和判断HBV YMDD变异提供一定的依据。方法选择50例CHB患者作为拉米夫定治疗组,30例CHB患者作为对照组。采用实时荧光PCR方法分别检测两组在用药期间HBV YMDD变异的发生情况,同时采用荧光定量PCR方法检测治疗组在用药前后HBV DNA水平。结果治疗组在用药52周时的变异率24.0%,明显高于对照组52周时的变异率3.3%(P<0.05);治疗组在用药52周时的变异率24.0%,明显高于用药26周时的变异率4.0%(P<0.05);治疗前HBV DNA水平较高组(28例)患者在用药52周时的变异率(35.7%)明显高于HBV DNA水平较低组(22例)患者的变异率(9.1%)(P<0.05);治疗组中未变异的38例患者在用药52周时的HBV DNA阴转率(65.8%)明显高于变异的12例患者的HBV DNA阴转率(16.7%)(P<0.05)。结论拉米夫定可导致HBV YMDD变异的产生,并且该变异的发生率随着拉米夫定的用药时间的延长而增加;HBV YMDD变异的发生同血清HBV DNA水平相关。     

Influence of the hepatitis B e antigen/anti-HBe status on the response to lamivudine

OBJECTIVE: The optimal therapeutic regimen of lamivudine for chronic hepatitis B is not agreed upon, especially with reference to hepatitis B e antigen (HBeAg) or the corresponding antibody (anti-HBe) in sera of patients. METHODS: We analyzed 249 Japanese patients with chronic HBV infection who were treated with lamivudine for more than 12 months. HBeAg was detected in sera from 117 of them (47%). HBV DNA sequences in serum samples from the pretreatment period and during therapy were amplified by polymerase chain reaction, and analyzed for mutations. RESULTS: Lamivudine normalized serum levels of alanine aminotransferase at 6 and 12 months, and suppressed serum HBV DNA to levels undetectable by the bDNA method in most patients. Lamivudine suppressed HBV DNA levels to a greater extent in patients with anti-HBe than HBeAg. In patients treated with lamivudine for 5 years, HBV mutants with mutations in the precore region and core promoter reverted to the wild-type in some of them within 1 year. CONCLUSION: Lamivudine induces a better response in patients without than in those with HBeAg. It initially selects the wild-type HBV from among precore or core promoter mutants.