Efficacy of switching to telbivudine in chronic hepatitis B patients treated previously with lamivudine

Background: Telbivudine showed greater antiviral suppression than lamivudine in phase II and III clinical trials. Aims: The present phase IIIb, randomized, double‐blind, multicentre global trial assessed the antiviral efficacy and safety of telbivudine switch in chronic hepatitis B (CHB) patients who exhibited persistent viraemia under lamivudine therapy. Methods: HBeAg‐positive and HBeAg‐negative adult patients (N=246) with persistent viraemia [hepatitis B virus (HBV) DNA>3 log₁₀ copies/ml] under lamivudine treatment for 12–52 weeks were randomized (1:1) to continue lamivudine 100 mg/day or switch to telbivudine 600 mg/day for 1 year. Primary endpoint was the reduction in serum HBV DNA levels from baseline at Week 24. Results: The mean reduction in serum HBV DNA levels from baseline with telbivudine was significantly higher than lamivudine at Week 24 (?1.9 ± 0.18 vs. ?0.9 ± 0.27 log₁₀ copies/ml; P<0.001) and maintained through 1 year. The rate of treatment failure was significantly lower (P<0.001) for patients who switched to telbivudine (5%) compared with those who continued lamivudine (20%) after 52 weeks of treatment. In the telbivudine group, treatment failure occurred in only five patients with >24 weeks of prior lamivudine treatment, all associated with pre‐existent lamivudine‐resistant mutations. Genotypic resistance rates were higher in patients continuing lamivudine compared with those who switched to telbivudine with <24 weeks of lamivudine exposure. Both treatments were well tolerated with similar safety profiles. Conclusions: Early (≤24 weeks) switch to telbivudine improves virological outcomes in CHB patients with persistent viral replication under lamivudine treatment.     

替比夫定治疗慢性乙型肝炎37例近期疗效观察

目的研究替比夫定（LdT）对慢性乙型肝炎治疗近期疗效和安全性。方法慢性乙型肝炎患者口服替比夫定。患者包括初次使用替比夫定患者21例和阿德福韦酯原发治疗失败后换用替比夫定患者16例两组。治疗前后测定基线HBVDNA水平、HBVM、肝肾功能、肌酸肌酶。结果两组患者治疗1月、3月、6月后ALT较治疗前明显下降（P〈0.05）,两组之间治疗前后ALT比较没有显著性差异（P〉0.05）。两组患者治疗1月log值下降幅度无明显差异（P〉0.05）,治疗3月、6月后log值下降幅度差异有统计学意义（P〈0.05）。初次用药与更换用药在HBVDNA转阴和HBeAg血清转换方面在治疗6月内差异无统计意义（P〉0.05）。结论替比夫定治疗慢性乙型肝炎,可迅速减少肝损伤和降低HBVDNA病毒载量,3、6月时初次用药降低病毒载量优于阿德福韦酯原发治疗失败后更换用药者。     

比较替比夫定与拉米夫定治疗慢性乙型肝炎疗效的Meta分析

目的评价替比夫定与拉米夫定对比治疗慢性乙型肝炎（CHB）的疗效。方法检索2007年4月至2010年8月万方数据、维普资讯、中国生物医学文献数据库,根据纳入标准、排除标准,对入选的6篇随机对照试验（RCT）的研究结果,采用RevMan5.0.2软件进行分析。结果与对照组相比,替比夫定能更显著地提高HBV DNA转阴率、HBeAg转阴率、HBeAg血清转换率和ALT复常率：相对危险度（RR）分别为1.39[95%CI（1.26～1.54）,Z=6.45,P〈0.00001]、1.46[95%CI（1.16～1.84）,Z=3.24,P=0.001]、1.47[95%CI（1.12～1.92）,Z=2.77,P=0.006]和1.15[95%CI（1.09～1.22）,Z=4.88,P〈0.00001];且降低耐药率：优势比（OR）为0.31[95%CI（0.20～0.48）,Z=5.15,P〈0.00001];而两组不良事件发生率的差异无统计学意义[OR=1.36,95%CI（0.84～2.20）,Z=1.27,P=0.20]。结论采用替比夫定与拉米夫定对比治疗CHB患者,能更显著地降低HBV DNA,提高HBeAg血清转阴率、转换率和ALT复常率,降低耐药率,且不增加药物不良反应。     

替比夫定治疗慢性乙型肝炎的研究进展

替比夫定是一种新型的抗HBV作用的核苷类似物,其HBeAg血清学转换率高、起效早,耐药发生率低。了解替比夫定的药理作用,选择合适的病例进行治疗,在治疗过程中及时监测,根据第24周时患者的HBVDNA水平来指导后期的治疗,有助于达到长期抑制HBV的目的。     

替比夫定治疗HBeAg阳性慢性乙型肝炎48周疗效观察

目的观察比较替比夫定与拉米夫定治疗HBeAg阳性慢性乙型肝炎48周的疗效。方法73例患者按就诊顺序分别纳入治疗组（30例）和对照组（43例）。治疗组每天口服替比夫定600mg,对照组每天口服拉米夫定100mg,疗程均为48周。治疗前和治疗4、12、24、48周分别检测血清HBVDNA定量、血清HBV标志物、ALT水平。比较2组48周时HBVDNA水平、HBVDNA阴转率、HBeAg血清转换率、ALT复常率。结果2组HBVDNA水平随治疗时间延长均有所下降,治疗4周时下降最明显,治疗48周时治疗组平均下降水平大于对照组（P=0．001）。治疗组HBVDNA的阴转率为93．3％,高于对照组（69．3％）,P〈0．05,差异有统计学意义。48周时治疗组HBeAg血清转换率为33.3％,对照组为25．5％（P=0．472）,2组之间差异无统计学意义。2组间ALT复常率差异无统计学意义。结论替比夫定治疗HBeAg阳性慢性乙型肝炎48周的疗效优于拉米夫定。     

Diagnosis and management of pre-core mutant chronic hepatitis B

Chronic hepatitis due to pre-core hepatitis B virus (HBV) mutants presents as hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). HBeAg-negative CHB represents a late phase in the natural course of chronic HBV infection that develops after HBeAg loss and seroconversion to anti-HBe. It is usually associated with pre-core stop codon mutation at nucleotide 1896 (mainly selected in non-A HBV genotypes), but also with other pre-core changes or with mutations in the basic core promoter region (mainly in HBV genotype A). In chronic HBV infections, pre-core mutants can be detected both in patients with HBeAg-negative CHB and in inactive hepatitis B surface antigen (HBsAg) carriers. The diagnosis of HBeAg-negative CHB is based on HBsAg positivity, HBeAg negativity, and mainly on increased alanine aminotransferase (ALT) and serum HBV-DNA levels and exclusion of other causes of liver disease. The differential diagnosis between patients with CHB and inactive HBsAg carriers can be made only by close follow-up of aminotransferase activity and viraemia levels, although the cut-off level of serum HBV DNA has not been definitely determined. IgM anti-HBc levels have also been suggested as an index that increases the diagnostic accuracy for transient hepatitis flares, while liver biopsy confirms the diagnosis and evaluates the severity of the liver disease. Interferon-alpha (IFN-alpha) and lamivudine are the two drugs that have been tried, mainly in the management of HBeAg-negative CHB. A 12-month course of IFN-alpha achieves sustained biochemical remission in about 20% of patients, which has been associated with improvement in the long-term outcome of this subset. A 12-month course of lamivudine is rather ineffective, maintaining remission in less than 15% of patients after cessation of therapy. Long-term lamivudine is associated with progressively increasing rate of virological and subsequent biochemical breakthroughs due to YMDD mutants, with approximately 30% of patients remaining in remission in the third year of therapy. Several other antiviral agents are currently being evaluated in this setting with combined regimens being the most reasonable step for the near future.     

Clinical outcomes of chronic hepatitis B patients with persistently detectable serum hepatitis B virus DNA during lamivudine therapy

BACKGROUND AND AIM: A small proportion of chronic hepatitis B patients have persistently detectable serum hepatitis B virus (HBV) DNA despite lamivudine therapy. The incidence and clinical outcomes of patients who persistently have detectable serum HBV-DNA during lamivudine therapy was investigated. METHOD: We enrolled 221 chronic hepatitis B patients who underwent lamivudine therapy for more than 6 months. Among them, 180 were HBeAg positive. Serum HBV-DNA, HBeAg, anti-HBe and alanine aminotransferase (ALT) levels were serially monitored. The study groups were defined, using a hybridization assay, as patients with reductions in serum HBV-DNA below the detectable level (group I) or patients with persistently detectable serum HBV-DNA (group II) during the initial 6 months of lamivudine therapy. RESULTS: The incidence of patients who had persistently detectable HBV-DNA was 7.7%. After the first year, the rates of viral breakthrough, HBeAg loss and serum ALT normalization of group I versus group II were 21% versus 63%, 38% versus 0%, and 71% versus 28%, respectively (P < 0.001). The log(10) reduction of serum HBV-DNA at 6 months was -4.58 log(10) for group I and -1.97 log(10) for group II (P < 0.001, bDNA assay). There were no pretreatment lamivudine-resistant mutants in group II. CONCLUSION: Lamivudine had little effect on serum HBV-DNA suppression, viral breakthrough suppression and rate of HBeAg loss and ALT normalization in chronic hepatitis B patients with persistently detectable serum HBV-DNA during the initial 6 months of therapy. Early termination of lamivudine therapy is advocated for these patients.     

替比夫定治疗慢性乙型重型肝炎的近期疗效观察

目的观察替比夫定治疗慢性乙型重型肝炎的临床疗效。方法随机将60例慢性乙型重型肝炎患者分为2组,对照组30例采用常规综合治疗,治疗组30例常规综合治疗的基础上加用替比夫定600mg,每日一次口服。观察两组在治疗前及后在2周、4周、12周的HBVDNA,治疗前后肝功能,PTA,评估临床疗效。结果治疗组HBVDNA阴转率2,4,12周分别为33.0%,80.0%,83.3%,对照组分别为0%,3.3%,10.0%两组比较差异有统计学意义（P均〈0.01）。治疗4周后,与对照组比较在TBil降低（P〈0.01）、PTA升高（P〈0.01）方面有统计学意义,治疗组总有效率67.7%,对照组40.0%（P〈0.05）。结论替比夫定有较强的抗HBVDNA活性,且起效快,能显著改善肝功能,适合重型肝炎患者使用。     

Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B

Lamivudine has demonstrated efficacy for the treatment of hepatitis B e antigen-negative chronic hepatitis B (e-CHB). However, treatment withdrawal after 1 year has been associated with a high rate of relapse while long-term treatment is associated with increasing risks of drug resistance. We report our treatment experience of 50 Chinese-Canadian patients with e-CHB. All patients received lamivudine for 2 years. Treatment was withdrawn at month 24 in patients who had undetectable hepatitis B virus (HBV) DNA by PCR and normal aminotransferases during the second year of therapy. All patients had HBV genotype B or C. Biochemical response at months 6, 12 and 24 was 74%, 71% and 66%, respectively. HBV DNA was undetectable at months 6, 12 and 24 by hybrid capture and PCR assays in 100%, 92% and 86%; and 94%, 88% and 74% patients, respectively. The cumulative rates of genotypic resistance (GR) after 1 and 2 years were 15% and 25%, respectively. Four (44%) patients with GR experienced a hepatitis flare. The probability of clinical and virological relapse 6, 12, and 18 months after treatment withdrawal were 12% and 30%, 18% and 50%, and 30% and 50%, respectively. Reinstitution of lamivudine resulted in prompt virological and biochemical responses. Our study demonstrates that a sustained response can be achieved after a 2-year course of lamivudine in a subset of patients with e-CHB.     

替比夫定治疗HBeAgeAg阳性慢性乙型肝炎疗效的预测指标

目的探讨替比夫定治疗HBeAg阳性慢性乙型肝炎（CHB）48周的疗效及其预测指标。方法采用替比夫定（LdT）600 mg/d治疗78例HBeAg阳性CHB患者48周,从性别、年龄、ALT和HBV DNA基线、早期病毒学应答（治疗12周时HBV DNA转阴）为预测因素,分析其对治疗48周疗效的影响。结果性别、年龄与治疗8～48周时HBV DNA转阴无相关性（P〉0.05）;5 ULN≤ALT≤10 ULN组治疗24、36及48周时HBV DNA转阴率高于2 ULN≤ALT≤5 ULN组（P〈0.05,P〈0.01）;HBV DNA 106～105拷贝/ml组治疗48周时ALT复常率和HBV DNA转阴率高于HBV DNA〉107拷贝/ml组（P〈0.05）;早期病毒学应答组治疗48周时HBeAg阴转率ALT复常率和HBV DNA转阴率也高于非应答组（治疗12周时HBV DNA≥500拷贝/ml）（P〈0.05）。结论 ALT、HBV DNA基线、早期病毒学应答可能可以作为预测替比夫定抗HBV疗效的指标     

Mutations in the hepatitis B virus polymerase gene associated with antiviral treatment for hepatitis B

Significant advances have been made, during the last 5 years, in the treatment of chronic hepatitis B. Several new antiviral agents: lamivudine, famciclovir, lobucavir and adefovir, have been shown to be safe and effective in inhibiting hepatitis B virus (HBV) replication. These compounds can be administered orally and are well tolerated. However, virus clearance is uncommon after short courses (<6 months) of therapy. Lamivudine and famciclovir have been evaluated in Phase III clinical trials in patients with chronic hepatitis B as well as in liver transplant recipients. Unfortunately, drug-resistant mutants involving the HBV polymerase gene, leading to breakthrough infection, have been reported in some patients who have received long courses (≥ 12 months) of treatment. The incidence, clinical outcome and biological significance of these mutants will be reviewed.     

Four years of lamivudine treatment in Chinese patients with chronic hepatitis B

BACKGROUND AND AIMS: This study assessed the efficacy and safety of up to 4 years of lamivudine treatment and the clinical relevance of the emergence of YMDD-variant hepatitis B virus (HBV). METHODS: Fifty-eight Chinese adult patients with chronic hepatitis B (CHB) were randomized to lamivudine 100 mg/day for up to 5 years and were monitored for YMDD-variant HBV, hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg and detectable antibody to HBeAg) and serum alanine aminotransferase (ALT) concentrations. Four-year data are reported here. RESULTS: The rate of HBeAg seroconversion increased with extended therapy and also with higher baseline ALT concentrations. YMDD-variant HBV was detected in 67% (39/58) of patients at some point during treatment. After 4 years, a total of 47% (27/58) of patients achieved HBeAg seroconversion. Thirty-three per cent (13/39) of patients with YMDD-variant HBV achieved HBeAg seroconversion; this increased to 57% (8/14) in patients with moderately elevated (>2-5 x upper limit of normal) pre-treatment ALT concentrations. The proportion of patients that achieved normal serum ALT increased from 29% (17/58) at baseline to 69% (31/45) following 4 years of treatment. That included 68% (23/34) of patients with YMDD-variant HBV and 73% (8/11) of those without the variant. All patients receiving lamivudine had reduced serum concentrations of HBV-DNA compared with baseline, despite the emergence of YMDD-variant HBV in 39 patients. Lamivudine was generally well tolerated; there was little change in the number or type of drug-related adverse events in the fourth year of the study. CONCLUSIONS: Despite the emergence of YMDD-variant HBV, Chinese patients showed increased HBeAg seroconversion and improvement in ALT levels with an increased duration of treatment with lamivudine.     

Measurement of hepatitis B virus core-related antigen is valuable for identifying patients who are at low risk of lamivudine resistance.

OBJECTIVE: The clinical usefulness of hepatitis B virus core-related antigen (HBVcrAg) assay was compared with that of HBV DNA assay in predicting the occurrence of lamivudine resistance in patients with chronic hepatitis B. PATIENTS: Of a total of 81 patients who were treated with lamivudine, 25 (31%) developed lamivudine resistance during a median follow-up period of 19.3 months. RESULTS: The pretreatment positive rate of HBe antigen, or pretreatment levels of HBVcrAg or HBV DNA did not differ between patients with and without lamivudine resistance. Levels of both HBVcrAg and HBV DNA decreased after the initiation of lamivudine administration; however, the level of HBVcrAg decreased significantly more slowly than that of HBV DNA. The occurrence of lamivudine resistance was significantly less frequent in the 56 patients whose HBV DNA level was less than 2.6 log copy/ml at 6 months of treatment than in the remaining 25 patients. The cumulative rate of lamivudine resistance was as high as 70% within 2 years in the latter group, while it was only 28% in the former group. Lamivudine resistance did not occur during the follow-up period in the 19 patients whose HBVcrAg level was less than 4.6 log U/ml at 6 months of treatment, while it did occur in 50% of the remaining patients within 2 years. CONCLUSION: These results suggest that measurement of HBV DNA is valuable for identifying patients who are at high risk of developing lamivudine resistance, and that, conversely, measurement of HBVcrAg is valuable for identifying those who are at low risk of lamivudine resistance.     

替比夫定与拉米夫定对慢性乙型肝炎患者血清抗原蛋白影响的对照研究

目的:观察和比较替比夫定、拉米夫定对慢性乙型肝炎患者的疗效以及对血清乙肝抗原蛋白水平的影响。方法:采用1∶1随机、对照设计。共入组慢性乙型肝炎患者100例,随机分为替比夫定组50例,拉米夫定组50例;对照观察两组临床疗效及不良反应;并动态监测患者血清HBsAg、HBeAg水平的变化。结果:治疗1年时,替比夫定组患者血清HBV DNA PCR法检测不到的比率、ALT复常率均较拉米夫定组稍高,但无统计学意义;HBeAg阴转率及血清学转化率以及病毒突破率分别为34%、28%和8%,均优于拉米夫定组的16%、12%和22%,差异均有显著性意义(P分别为0.0377、0.0455和0.0498)。两组患者治疗后血清抗原蛋白HBsAg及HBeAg水平均有不同程度的下降,但替比夫定组患者治疗1个月时,血清HBsAg和HBeAg水平较基线下降分别为(30.2±16.1)S/N和(80.8±12.9)S/CO,均高于拉米夫定组的(7.8±12.4)S/N和(10.9±27.9)S/CO,差异有统计学意义;至治疗12个月时,其降幅差异更为明显,分别达到(146.7±32.5)S/N和(202.3±62.8)S/CO及(68.4±39.5)S/N和(90.4±52.8)S/CO,差异有非常显著的统计学意义;替比夫定不良反应轻微,与拉米夫定类似。结论:替比夫定较拉米夫定具有更强地抑制HBV DNA复制能力以及较少的耐药率和病毒反跳率;同时替比夫定能更强地抑制病毒抗原蛋白的表达,可能与较高的HBeAg血清学转换率有关。     

泛昔洛韦和拉米夫定治疗慢性乙肝的短期疗效对比研究

比较和评价泛昔洛韦和拉米夫定短期治疗慢性乙肝的疗效.将101例慢性乙肝患者,随机分为泛昔洛韦组(A组)1500mg/日分三次(4个月)、拉米夫定组(B组)100mg/日和对照组(C组).结果显示,治疗4个月时①A、B和C组ALT的复常率分别为74.0%、82.5%和63.3%.②A和B组HBV DNA的阴转率为64.5%和90.0%均显著高于C组(16.5%),P＜0.001;B组明显高于A组,P=0.017.③A和B组HBeAg血清转化率达27.3%和25.8%,高于C组(13.0%),但P＞0.05.④A组HBV DNA阴转的20例患者,在停药后2、4和6月时其持续应答率分别为65.0%、45.0%和25.0%.表明泛昔洛韦和拉米夫定对慢性乙肝均有治疗效果,拉米夫定的抗病毒作用和疗效明显优于泛昔洛韦.     

替比夫定联合双环醇治疗HBeAg阳性慢性乙型肝炎患者的疗效分析

目的研究替比夫定联合双环醇片治疗HBeAg阳性慢性乙型肝炎(CHB)患者的疗效和安全性。方法选择133例未应用其他抗病毒药物的HBeAg阳性CHB患者,随机分两组接受治疗。试验组67例,每日口服替比夫定600 mg,同时每日服用双环醇片75 mg;对照组66例,仅给予每日口服替比夫定600 mg,两组均连续用药104周。观察治疗前后血清ALT水平及病毒学指标方面的改变。结果两组血清均明显下降,试验组更为显著(P<0.01)。治疗12周时,两组患者在HBeAg转阴率及血清学转换方面比较,差异均无统计学意义,随治疗时间延长,在治疗24、52、104周各时间点,实验组HBeAg转阴率及血清学转换均高于对照组,差异均有统计学意义。两组HBV DNA水平均出现明显下降,但各治疗时间点HBV DNA下降水平及检测不到比率比较,差异无统计学意义(P>0.05)。治疗52周时,治疗组和对照组各出现2例和3例耐药,耐药率分别为4.69%和7.81%,两组比较,差异无统计学意义(P>0.05),治疗104周时,治疗组耐药5例,对照组耐药13例,耐药率分别为7.81%和20.31%,两组比较,差异有统计学意义(P<0.05)。2组均未发生与研究药物相关的不良反应。结论替比夫定与双环醇片联合应用治疗HBeAg阳性CHB在肝功能及病毒学方面取得较好疗效且安全。     

Evolution of hepatitis B virus precore/basal core promoter gene in HBeAg‐positive chronic hepatitis B patients receiving lamivudine therapy

Aim: Lamivudine is effective in hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B, but the relapse rate after cessation of treatment is high. The evolution of viral genome may contribute to the viral replication under antiviral pressure of lamivudine. We therefore determined the evolution of hepatitis B virus (HBV) precore/basal core promoter and polymerase genes in HBeAg‐positive chronic hepatitis B patient during lamivudine therapy. Method: Thirteen patients with HBeAg‐positive chronic hepatitis who had received short‐term lamivudine therapy (mean, 30 weeks) during 1999–2001 were enrolled. The precore/basal core promoter region and polymerase gene were amplified and directly sequenced before, during and post lamivudine treatment. Result: HBeAg loss or seroconversion occurred in 11, but eight relapsed after stopping therapy and five had reversion of HBeAg. Before treatment, basal core promoter mutation was found in 1. In the first 3 months of therapy, a rapid decline of serum HBV DNA level accompanied with basal core promoter mutation appeared in 11 of 13 patients (vs. before therapy; P=0.003). However, this mutant was replaced by wild‐type virus in four of eight patients who relapsed after treatment. There was no significant change of precore sequences before and during therapy. Conclusions: Lamivudine therapy may result in the rapid development of basal core promoter mutation of HBV, but this mutation may revert to wild type gradually after cessation of therapy.