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.     

拉米夫定联合阿德福韦酯治疗慢性乙型肝炎的临床研究

目的:观察拉米夫定联合阿德福韦酯治疗慢性乙型肝炎的临床疗效.方法:选取84例慢性乙型肝炎患者,随机分为拉米夫定组42例,给予拉米夫定100 mg/d、拉米夫定联合阿德福韦酯治疗组42例,给予拉米夫定100 mg/d、阿德福韦酯10 mg/d.均给予常规护肝及支持对症治疗.在治疗24、48周时观察两组患者肝功能、HBeAg阴转率和HBeAg血清转换率,比较两组ALT复常情况和不良反应发生情况.结果:治疗后两组患者HBV DNA均较基线值降低,且随治疗时间延长降低更明显;治疗24周时两组患者HBV DNA阴转率相似,治疗48周时B组与A组相比差异具有显著性;两组患者治疗后HBeAg阴转率、HBeAg血清转换率未见统计学差异;B组患者治疗48周时ALT复常率与A组相比差异具有显著性;两组均未见严重不良事件.结论:拉米夫定联合阿德福韦酯与单用拉米夫定相比可以有效治疗慢性乙型肝炎,值得临床推广.     

拉米夫定改善慢性乙型重型肝炎的疗效

目的观察拉米夫定治疗慢性乙型重型肝炎的疗效。方法Ⅰ组为治疗组,对20例慢性乙型重型肝炎在采用综合治疗的基础上,加用拉米夫定抗病毒治疗;Ⅱ组为对照组,32例慢性重型肝炎患者仅采用综合治疗,观察两组患者接受不同治疗方法3个月前后血清总胆红素(TB il)、凝血酶原活动度(PTA),统计学分析Ⅰ组治疗前后及两组治疗后均值差异,计算两组的有效率和病死率(有效判定标准:TB il<60μmol/L,PTA>40%),对两组有效率和病死率差异进行χ2检验。结果Ⅰ组治疗后TB il显著降低,与Ⅰ组治疗前相比较差异有统计学意义(P<0.05),与Ⅱ组治疗后相比较,差异有统计学意义(P<0.05)。Ⅰ组治疗后PTA显著升高,与Ⅰ组治疗前相比较,差异有统计学意义(P<0.05),与Ⅱ组治疗后相比较,差异有统计学意义(P<0.05)。I组有效率显著高于Ⅱ组(χ2=13.66,RR=0.03,P<0.01),I组病死率显著低于Ⅱ组(χ2=16.90,RR=10.11,P<0.01)。结论拉米夫定能改善慢性乙型重型肝炎的疗效。     

Lamivudine treatment in HBeAg-negative chronic hepatitis B patients with low level viraemia

BACKGROUND: Our aim was to determine the short-term natural course of viraemia and the response to lamivudine treatment in HBeAg-negative chronic hepatitis B patients with a persistently low hepatitis B virus (HBV)-DNA level. METHODS: A total of 55 patients were included. Group 1 consisted of 37 patients with low-level viraemia and high serum alanine aminotransferase (ALT) levels and further randomized to two groups: group 1a (n=19) patients received 1 year of lamivudine therapy and group 1b (n=18) patients were untreated controls. Group 2 consisted of 18 inactive carriers who were followed as controls of untreated low viraemic chronic hepatitis B patients. HBV DNA was longitudinally determined by real-time polymerase chain reaction assay. RESULTS: A female predominance in group 2 was observed while males were predominant in group 1. Mean age and baseline HBV-DNA levels did not differ between group 1 and 2 patients while group 1 patients had a higher histological score (P<0.01). Of group 1a patients, 44% had complete ALT normalization at end of treatment, whereas 21% untreated group 1b patients had normal ALT at the end of the follow-up. No change in histological activity was observed in group 1a patients at the end of treatment. HBV-DNA levels did not significantly change from baseline to end-of-treatment/observation period in patient groups. The viraemia course was not different across the groups. CONCLUSIONS: Low viraemic HBeAg-negative patients with high ALT present with minimal/mild histological activity. Inactive carriers cannot be differentiated from low viraemic patients with high ALT based on HBV DNA determination. Although lamivudine treatment can be effective in some cases, observation rather than a prompt treatment attempt seems to be more logical because of mild histological changes and low response rate to treatment in these patients.     

Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B.

High viral and/or antigen load may be an important cause of the T cell hyporesponsiveness to hepatitis B virus (HBV) antigens that is often observed in patients with chronic HBV infection. Reduction of viral and antigen load by lamivudine treatment represents an ideal model for investigating this hypothesis. HLA class II restricted T cell responses and serum levels of HBV-DNA, HBsAg, and HBeAg were studied before and during lamivudine treatment in 12 patients with hepatitis B e antigen positive chronic active hepatitis B to assess possible correlations between viral and/or antigen load and vigor of the T cell response. Cell proliferation to HBV nucleocapsid antigens and peptides and frequency of circulating HBV nucleocapsid-specific T cells were assessed to characterize CD4-mediated responses. A highly significant enhancement of the CD4-mediated response to HBV nucleocapsid antigens was already detectable in most patients 7-14 d after the start of lamivudine treatment. This effect was dramatic and persistent in 10 patients but undetectable in 2. It occurred concomitant with a rapid and marked reduction of viremia. Interestingly, lamivudine also enhanced the responses to mitogens and recall antigens, showing that its effect was not limited to HBV-specific T cells. In conclusion, an efficient antiviral T cell response can be restored by lamivudine treatment in patients with chronic hepatitis B concurrently with reduction of viremia, indicating the importance of viral load in the pathogenesis of T cell hyporesponsiveness in these patients. Since lamivudine treatment can overcome T cell hyporeactivity, combining lamivudine with treatments directed to stimulate the T cell response may represent an effective strategy to induce eradication of chronic HBV infection.     

Lamivudine as an alternative therapy for interferon-resistant chronic hepatitis B and the characteristics of hepatitis B virus: a case report

A 27-year-old man who had been diagnosed as having chronic hepatitis B suffered disease exacerbation with marked reactivation of hepatitis B virus (HBV). Treatment with interferon (IFN) did not improve his condition, and his serum HBV DNA level increased to over 10 000 pg/ml during IFN administration. Following replacement with lamivudine, there was a substantial reduction in HBV DNA to an undetectable level, and liver function parameters subsequently improved to within the normal range. Quantitative analysis of the precore mutant HBV DNA, which is a variant that cannot express hepatitis B e antigen due to a G-to-A point mutation in the precore region of the viral genome, revealed that the amount present was greater than for the precore wild-type HBV DNA in the serum taken before IFN treatment. This case suggests that lamivudine would be an appropriate alternative to IFN, particularly in patients infected with HBV containing an excess of precore mutants resistant to IFN therapy.     

拉米夫定联合愈肝颗粒治疗慢性乙型肝炎近期疗效研究

目的:研究拉米夫定(3-TC)联合中药愈肝颗粒对慢性乙型肝炎(CHB)的治疗作用。方法:64例CHB患者随机分为治疗组、对照组,治疗组采用3-TC和愈肝颗粒联合治疗,对照组单用3-TC,疗程6个月,治疗前、后分别检测血清肝功能、乙肝标志物、HBV-DNA,并记录治疗期间发生的不良事件。结果:治疗6个月后治疗组HBeAg转阴率和HbeAg/抗HBe血清转换明显高于对照组,治疗组HBV-DNA转阴率与对照组差异无显著性意义(P>0.05),治疗组血清ALT下降值显著高于对照组(P<0.01)。结论:采用3-TC与愈肝颗粒联合治疗CHB有良好的疗效。     

拉米夫定联合中药对乙型肝炎患者表面抗原定量的影响

目的观察拉米夫定联合自拟小柴胡加减汤对肝郁脾虚型慢性乙型肝炎患者乙型肝炎病毒表面抗原(HBsAg)定量及乙型肝炎病毒(HBV)DNA载量的影响。方法将74例慢性乙型肝炎患者分为对照组34例,治疗组40例,治疗组给予拉米夫定联合中药汤剂治疗、对照组给予拉米夫定治疗,治疗6个月,观察患者HBsAg定量、HBV DNA载量的变化。结果 (1)治疗6个月后,两组HBsAg定量比较,差异无统计学意义(P>0.05);治疗组与对照组HBsAg定量治疗后差值比较,差异无统计学意义(P>0.05)。(2)治疗3个月后,两组HBV DNA定量分级情况、HBV DNA定量阳性结果、两组治疗前后HBV DNA阳性结果对比,差异均无统计学意义(P>0.05)。治疗6个月后,两组HBV DNA定量分级情况对比,差异有统计学意义(P<0.05)。治疗组与对照组HBV DNA阳性结果对比,差异有统计学意义(P<0.05)。对照组治疗后与治疗前HBV DNA阳性结果对比,差异无统计学意义(P>0.05)。治疗组治疗后与治疗前HBV DNA阳性结果对比,差异有统计学意义(P<0.05)。结论小柴胡加减汤联合拉米夫定可抑制乙型肝炎病毒复制。     

Lamivudine therapy for decompensated liver cirrhosis related to hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection is the major cause of chronic liver disease worldwide. Although the clinical course of HBV infection varies widely, the prognosis of decompensated liver cirrhosis is quite poor and the 5-year survival rate has been estimated to be only 14-35%. While the ultimate treatment of decompensated cirrhosis is orthotopic liver transplantation (OLT), recent studies have suggested that lamivudine can also improve the clinical outcomes in this group of patients. Lamivudine rapidly suppresses HBV replication and can improve several parameters of liver function tests and afford prolonged periods of pretransplantation survival. However, the proportion of clinical improvement as defined by a decrease in Child-Pugh score as well as the prolonged survival rate varied widely from study to study. These discrepancies might result from differences in the severity of cirrhosis at entry, the presence of active viral replication or inflammation, and the proportions of patients who received OLT during the study period. Overall, about half of the patients achieved a clinical improvement with lamivudine therapy. However, data are still lacking on whether lamivudine can prolong survival before OLT and even replace OLT. Most of the deaths or clinical improvement occurred or started to occur within the first 6 months of treatment. Therefore, OLT should be actively considered in patients with risk factors for early mortality or those without clinical improvement within the first 6 months of lamivudine treatment.     

阿德福韦酯治疗拉米夫定耐药性HBeAg阳性慢性乙型肝炎的疗效及安全性分析

目的观察并分析阿德福韦酯（ADV）治疗拉米夫定（LAM）耐药性乙肝病毒e抗原（HBeAg）阳性慢性乙型肝炎的疗效及安全性。方法选择2006年6月至2007年6月期间来自我院的76例LAM耐药性HBeAg阳性慢性乙型肝炎患者,分别采用ADV及LAM继续治疗。治疗1年后,分别观察两组的血清丙氨酸转氨酶（ALT）、HBeAg、乙肝病毒（HBV）DNA变化情况,并进行安全性分析。结果治疗1年后,两组患者HBeAg转阴率比较,差异无统计学意义（P〉0．05）,而ADV组的血清ALT复常率明显高于LAM组,差异有统计学意义（P〈0．05）。ADV组HBVDNA水平明显下降,且显著低于LAM组治疗后HBVDNA水平,差异有统计学意义（P〈0．05）。两组均未见严重不良反应。结论ADV治疗LAM耐药性HBeAg阳性慢性乙型肝炎具有良好的临床疗效及安全性。     

Entecavir monotherapy for lamivudine-refractory chronic hepatitis B

Evaluation of: Sherman M, Yurdaidin C, Simsek H et al. Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical and serology outcomes through 96 weeks. Hepatology 48, 99–108 (2008).

This article evaluates the efficacy, safety and resistance profile of entecavir treatment in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B lamivudine-refractory patients. A total of 286 patients were randomized and treated with entecavir 1 mg (n = 141) or continued lamivudine 100 mg (n = 145). At week 52, 77 entecavir-treated patients with a protocol-defined virologic response continued blinded therapy for up to 96 weeks. Cumulative proportions of all treated patients who achieved confirmed efficacy end points were also analyzed. It was shown that with 2 years of treatment, 30% of all entecavir-treated patients achieved HBV DNA of less than 300 copies/ml by PCR and 85% had alanine aminotransferase normalization (vs 1 and 29% of lamivudine-treated patients; p < 0.0001). HBeAg seroconversion was achieved by 17% of all entecavir-treated patients (24 out of 141) versus 6% of all lamivudine-treated patients (8 out of 1450; p < 0.0011) and was sustained in 11 patients (7.8%) 6 months after treatment discontinuation. However, entecavir treatment was associated with an increasing rate of drug resistance. Therefore, entecavir monotherapy does not appear to be the treatment of choice for lamivudine-refractory HBV patients and either a combination of potent antivirals with nonoverlapping resistance patterns or the use of newer nucleotides as monotherapy (e.g., tenofovir) could be helpful in the management of this difficult population.     

拉米夫定治疗慢性乙型肝炎伴AFP增高8例临床观察

目的：观察拉米夫定治疗慢性乙型肝炎伴AFP增高的临床疗效。方法：口服拉米夫定100mg/天，6个月后进行第一阶段评定，接连第二阶段仍以拉米夫定攻固，结果：8例病人经6个月治疗后HBV－DNA全转阴，AFP，ALT随HBV－DNA阴转而逐渐恢复正常，但是第二阶段治疗时有2例HBV－DNA复阳，其中一例YMDD变异。结论：拉米夫定治疗慢性乙型肝炎1伴AFP增高疗效显著，但是用药时间不宜过长，长期服用出现病毒耐药和变异。     

310例接受拉米夫定治疗的慢性乙型肝炎患者HBV RT区全长测序及结果分析

目的对接受拉米夫定(LAM)治疗慢性乙型肝炎(CHB)患者HBV P基因RT区全长测序并分析结果。方法选择接受拉米夫定治疗6个月以上的慢性乙型肝炎患者310例,收集LAM治疗后患者的血清,采用直接PCR产物基因测序法对HBV RT区碱基进行测序,后对测序数据用Chromas 223软件进行分析,找出HBV P基因RT区基因的变异位点和相应的氨基酸,进一步分析HBV耐药突变模式。结果 1)310例患者出现位点变异的有135例(43.5%),变异位点24个;2)基础变异位点和频率:rtM204 v/I 111例(82.20%),rtS213T 8例(5.92%),rtC256S 4例(2.96%),3位点差异有统计学意义(P0.05);3)变异模式和频率:rtM204I 39例(28.89%),rtM204V+rtL108M 25例(18.51%),rtM204V+rt204I+rtL180M 11例(8.15%),rtM204I+rtL180M 6例(4.44%),rtM204V+rtL180M+rtV173L/M 5例(3.70%),rtS213T 5例(3.70%),rtM204V+rtL180M+rtV207M/L/I 4例(2.96%),rtM204V 4例(2.96%)等;4)rtM204V还可伴随rtT184 I/S/M、rtA181T、rtC256S、rtS213T、rtL229V等位点变异。结论拉米夫定长期治疗可引起主要耐药位点rtM204 v/I突变,并常有rtL180M、rtV173L、rtS213T、rtC256S、rtV207M/L等一系列补偿性耐药位点伴随;单位点突变除rtM204I一种外,还存在rtS213T、rtM204V等突变模式;联合突变模式多数包含rtM204位点,但也存在rtS213T+rtL187I、rtC256S+rtF221Y等突变模式。     

慢性乙肝和乙肝后肝硬化肝脏形态的变化

目的 探讨慢性乙肝和乙肝后肝硬化肝脏MRI形态的变化.方法 对慢性乙肝患者32例、乙肝后肝硬化患者17例及无肝脏疾病的患者(对照组)18例行MR轴位T1W、T2W及动态增强扫描,观察肝脏形态.结果 肝脏表面不规则、肝脏边缘变钝、胆囊窝扩大、肝脏右后切迹征及再生结节能提示肝硬化(P＜0.05),以其中任一种阳性诊断肝硬化,敏感度为99.85％,以其中任两种同时阳性诊断肝硬化,特异度为98.80％～99.96％;上述指标与炎症活动度无关(P＞0.05);肝脏边缘变钝提示早期肝硬化(P＜0.05),其余各指标在对照组和慢性乙肝不同分期、分级间差异无统计学意义(P均＞0.05).结论 MRI显示的肝脏形态变化能提示乙肝后肝硬化,与肝炎症活动度无关.     

Treatment of chronic hepatitis B

Hepatitis B virus (HBV) infection is the leading cause of chronic liver disease and hepatocellular carcinoma worldwide. Approximately 350 million individuals are infected with HBV and >500,000 deaths per year can be attributed to HBV. Although universal vaccination has reduced HBV incidence in many countries, it still remains a major public health problem, especially in parts of Asia and Africa. Improved understanding of HBV virology and virus-host interactions has revolutionized chronic hepatitis B therapy in the past two decades. Development of oral nucleoside/nucleotide analogues heralds a new era of safe and effective treatment of this disease. On the basis of these advances, new guidelines for the treatment of chronic hepatitis B have been issued. Successful long-term treatment of chronic hepatitis B may rest on combination therapy that is based on molecular approaches targeting various stages of the HBV life-cycle. In this review, we summarize the current modalities and highlight important issues in the treatment of chronic hepatitis B monoinfection.     

Current therapies for chronic hepatitis B virus infection

Patients who are chronically infected with the hepatitis B virus are at an increased risk of developing cirrhosis, hepatic decompensation and hepatocellular carcinoma. Therapeutic intervention offers the only means of interrupting this progression. Currently there are three licensed agents for the treatment of chronic hepatitis B virus infection. These are interferon-alpha, an immunomodulator, and two synthetic nucleos(t)ide analogs, namely lamivudine (Epivir, GlaxoSmithKline) and adefovir dipivoxil (Hepsera, Gilead Sciences). This review aims to summarize current experience with these drugs in the treatment and management of patients with chronic hepatitis B virus infection, their efficacy, and current problems of drug resistance. An outline of future treatment perspectives is also included.