Interferon-lamivudine combination is no better than lamivudine alone in anti-HBe-positive chronic hepatitis B

BACKGROUND AND AIMS: Results of studies using lamivudine and interferon combination in the treatment of chronic hepatitis B are not consistent or conclusive. This study aimed to evaluate the efficacy of interferon plus lamivudine use versus single lamivudine in anti-HBe-positive chronic hepatitis B. METHODS: Eighty patients were treated with either lamivudine or lamivudine plus simultaneously started interferon. Patients were assigned in groups according to random allocation rule. Lamivudine was given 150 mg/day for 96 weeks in each group; interferon was administered 10 MU three times a week for 24 weeks in the combination therapy group. RESULTS: Alanine aminotransferase (ALT) normalization was achieved earlier in patients treated with lamivudine alone. At the end of treatment, there was no difference between the groups with respect to HBV DNA negativity, ALT normalization and breakthrough rate. Histological improvement was remarkable in each group, but fibrosis score and necro-inflammatory activity were much lower in lamivudine-treated patients. CONCLUSIONS: Addition of interferon to the lamivudine regimen does not increase the effectiveness of the treatment. Considering the side effects of interferon treatment, this combination seems not to be convenient for anti-HBe-positive chronic hepatitis B.     

Continued lamivudine therapy in patients with chronic hepatitis B

From September 1995 through April 2002, 286 patients with chronic hepatitis B were started on lamivudine at the Toranomon Hospital in Tokyo, Japan, and most of them continued with it. At present, 16 patients received lamivudine for 5 years, 7 of whom for 7 years or longer. YMDD mutants increased gradually and developed in 69% of them during the 7 years on lamivudine. Biochemical and virological responses were achieved in 9 of the 16 patients (56%) at 5 years, and in 4 of the 7 patients (57%) at 7 years. Histological assessments were performed at 3 years in the 16 patients and further at 4 and 7 years in the 7 patients. Necroinflammatory changes improved remarkably with a decrease in the total histological activity score from 11.3 +/- 3.0 to 4.1 +/- 1.7 (p < 0.0001) at 3 years in the 16 patients. Histological improvements continued in 4 of the 7 patients (57%) at 7 years on lamivudine, while the pathology was unchanged in 2 patients (29%) and aggravated in the remaining 1 patient (14%). Severe acute exacerbation of hepatitis developed in 1 patient, who received additional interferon-alpha therapy to cope with it. Based on my experience, the continuation of lamivudine in patients with chronic hepatitis B benefits approximately two thirds of them with persistent virological and biochemical responses accompanied by histological improvements. Breakthrough hepatitis induced by YMDD mutants along the way in a small number of patients needs to be diagnosed promptly by regular monitoring for transaminases and, if it develops, it can be treated with interferon or other antiviral agents.     

大黄蟅虫丸与拉米夫定联合治疗慢性乙型肝炎活动性肝硬化46例临床护理

目的:探讨大黄蟅虫丸与拉米夫定联合治疗慢性乙型肝炎活动性肝硬化的护理方法.方法:将86例慢性乙型肝炎活动性肝硬化患者随机分为实验组46例和对照组40例.对照组行常规治疗,实验组口服大黄蟅虫丸与拉米夫定治疗.观察药物不良反应,观察治疗前后肝功能及第1,3,6,12个月的血清HBV-DNA变化,做好各项护理工作.结果:实验组治疗后肝功能显著改善,血清HBV-DNA转阴率提高,与对照组比较有显著性差异(P<0.05).结论:大黄蟅虫丸与拉米夫定联合治疗慢性乙型肝炎活动性肝硬化,配合精心的护理,效果满意,值得临床推广应用.     

Short-term lamivudine therapy in HBeAg-negative chronic active hepatitis B in Taiwan

Lamivudine treatment in hepatitis B e antigen (HBeAg)-negative and hepatitis B virus (HBV) DNA-positive chronic hepatitis B (CHB) patients is associated with poor sustained response. A previous study has shown that short-term lamivudine therapy in HBeAg-positive patients with alanine aminotransferase (ALT) > 5x upper limit of normal (ULN) could achieve a high HBeAg response rate and low lamivudine resistance rate. We, therefore, prospectively treated 85 HBeAg-negative CHB patients with ALT > 5x ULN by lamivudine for 6-12 months. The mean pretreatment levels were as follows: ALT (normal < 36 U/I) 533 U/I (range: 180-2,418 U/I); total bilirubin (normal < 1.3 mg/dl) 2.0 mg/dl (range: 0.2-29.6 mg/dl), HBV DNA (normal, undetectable) 1.6 x 10(8) copies/ml (range: 1.4 x 10(5)-1.7 x 10(9) copies/ml). After a mean of 7.4 months (6-12 months) treatment, 69 (81%) patients achieved complete response. In a follow-up, 12 months after stopping lamivudine therapy, 33 (39%) patients showed sustained complete response. Patients with sustained response were younger than the relapsed patients (39.7 +/- 11.9 years versus 47.0 +/- 10.3 years; P = 0.005). The emergence of lamivudine-resistant variant HBV was documented in two patients (2%). It is concluded that in HBeAg-negative chronic hepatitis B patients with ALT levels above 5x ULN, a 6-12 month course of lamivudine therapy may achieve sustained an off-treatment response in approximately one-third of patients.     

慢性乙肝病人服用拉米夫定的教育指导

目的探讨服用拉米夫定的慢性乙肝病人的教育指导内容及方式,提高病人用药依从性。方法对护士进行有关服用拉米夫定知识的培训;对病人采用个案和集中的方式进行教育指导;发放拉米夫定教育指导内容测试问卷;建立拉米夫定用药监测和随访记录表。结果所有病人了解用药相关知识,能定期监测和随访,未出现擅自停药现象。结论护理人员对慢性乙肝病人进行系统的教育指导,并注重心理护理,有效利用社会支持系统,可以提高病人用药依从性,保障用药安全。     

拉米夫定治疗慢性乙型肝炎患者乙型肝炎病毒YMDD变异的研究

目的探讨拉米夫定治疗1年后慢性乙型肝炎（CHB）患者发生YMDD基序变异的状况及其检测方法。方法采用荧光定量PCR法检测血清HBV DNA含量，荧光PCR法和变性高效液相色谱法检测HBV YMDD基序变异。结果61例CHB患者经过拉米夫定治疗1年后，40例（65．6％）HBV DNA阴转；在21例HBV DNA阳性患者中，10例为YMDD野生型，11例出现YMDD基序变异，变异率达18．0％（11／61）。在11例基序变异中，完全变异7例（63．6％），部分变异4例（36．4％）。在完全变异型中，YIDD变异型5例，YVDD变异型2例；在部分变异型中，YIDD变异型3例，YVDD变异型1例。结论CHB患者拉米夫定治疗1年后，出现较高的YMDD基序变异率。利用荧光PCR法结合变性高效液相色谱法检测基序变异，经济便捷，可作为CHB患者YMDD基序变异的常规监测。     

Short-term lamivudine for the treatment of chronic hepatitis B

Short-term lamivudine and its withdrawal were evaluated as regards an immunomodulatory therapy of chronic hepatitis B. Lamivudine was given for 3 or 6 months to 23 patients with chronic hepatitis B who were infected with hepatitis B virus (HBV) genotype C, including 15 with hepatitis B e antigen (HBeAg) and 8 without it. It decreased serum levels of alanine aminotransferase (ALT) and HBV DNA in HBeAg-positive patients. Flare-ups of ALT and HBV DNA after treatment were observed in most patients, and 4 of the 12 (33%) patients with 6-month lamivudine treatment remained in remission 6 months after withdrawal of the therapy. In HBeAg-negative patients, however, flare-ups of ALT and HBV DNA were mild. Normalization of ALT and a decrease in serum HBV DNA were accomplished in 6 of the 9 (75%) patients. Breakthroughs or serious side effects were not observed in any patients. Short-term lamivudine is safe and may offer a therapeutic option to patients with chronic hepatitis B.     

Chronic active hepatitis. Prolonged survival without treatment.

A case is presented of a patient with established HBsAg-positive chronic active hepatitis and cirrhosis of at least 14 years duration. The disease, although untreated, has caused the patient relatively little disability. The implications of the patient's prolonged illness are discussed with reference to current knowledge of chronic active hepatitis. It is concluded that corticosteroid therapy may not be a mandatory requirement for all patients with this disease.     

Serum cytokine levels in patients with chronic hepatitis B according to lamivudine therapy

Background: Cytokines are known to play critical roles in the pathogenesis of chronic hepatitis B (CHB). However, the relationship between cytokines and treatment responses to drugs for CHB is not clearly defined yet. We measured the serum cytokine levels of interleukin (IL)‐1α, IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, vascular endothelial growth factor, interferon‐γ, tumor necrosis factor‐ (TNF‐α), macrophage/monocyte chemotactic protein 1, and epidermal growth factor to elucidate the cytokine expression pattern according to the patients' responses to lamivudine. Methods: Fifty‐eight specimens from 27 CHB patients and 98 specimens from healthy individuals were tested for 12 kinds of cytokines. The patients were grouped as: before treatment, ongoing treatment, duringmaintaining remission, and patients with viral breakthrough owing to resistance against lamivudine. The Evidence Investigator (Randox, Antrim, UK), a protein chip analyzer, was used to quantify serum cytokines. Results: Among 12 cytokines, IL‐6, IL‐8, IL‐10, and TNF‐α were significantly elevated in patients with resistance against lamivudine compared with patients maintaining response. IL‐8, IL‐10, and TNF‐α levels also weak to moderate correlated with ALT and HBV‐DNA concentrations. Conclusions: Serum cytokine levels would reflect the pathological differences of the individual treatment phases and may become useful indices in monitoring the treatment response of CHB. J. Clin. Lab. Anal. 25:414–421, 2011. © 2011 Wiley Periodicals, Inc.     

慢性乙型肝炎患者拉米夫定治疗与YMDD变异的相关因素

拉米夫定抗病毒效果显著,而长期应用易发生病毒YMDD变异问题也备受关注[1],常见拉米夫定突变位点为rtM204V/I,突变株病毒因具备一定的复制能力而且对拉米夫定不敏感,从而逐渐取代野生株成为优势株,导致患者对拉米夫定耐药,乙型肝炎病毒(HBV)DNA水平反跳,丙氨酸氨基     

Impact of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B

Lamivudine is a nucleoside analogue with potent inhibitory effects on hepatitis B virus (HBV) replication. Prolonged therapy is required for sustained suppression. However, HBV species with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA-dependent DNA polymerase conferring resistance to lamivudine may emerge after 9-10 months therapy with an incidence of 38 and 67% after 2 and 4 years of lamivudine therapy, respectively. During continued lamivudine therapy, patients with YMDD mutant HBV usually show serum alanine aminotransferase (ALT) and HBV DNA elevations at lower median levels than their baseline. Marked flare of serum ALT or acute exacerbation may occur as the result of CLT-mediated hepatocytolysis directed against YMDD mutants. Although viral clearance with or without emergence of distinct lamivudine-resistant mutants may occur after such exacerbations, 20% of the exacerbations are complicated with decompensation or even fatality. The exacerbations appear to be more severe than those that occur during the natural course of wild-type HBV chronic infection. In addition, some mutations may generate S gene truncation near 'transactivity-on-region'. Thus, the benefit of prolonged lamivudine therapy must be balanced against concern about YMDD mutants. Currently, the most cost-effective strategy is to select patients with stronger endogenous anti-HBV immunity, thereby increasing efficacy and shortening the duration of lamivudine therapy. New drugs and new strategies are needed to better achieve the goals of therapy and minimize the problem of YMDD mutants.     

阿德福韦酯联合拉米夫定治疗慢性乙型肝炎病毒耐药分析

目的 通过研究乙型肝炎患者乙型肝炎病毒(HBV)基因型的分布特点及耐药位点的分布,了解拉米夫定联合阿德福韦酯治疗慢性HBV耐药情况的发生,以探讨其临床意义.方法 选取在我院门诊和住院部就诊的曾经单用过拉米夫定或阿德福韦酯治疗失败的患者,再次使用拉米夫定联合阿德福韦酯治疗2年以上的慢性乙型肝炎患者73例,应用实时荧光聚合酶链式反应(PCR)方法检测HBV DNA分型情况,用连接酶检测反应(LDR)方法检测位点变异情况.结果 73例中14例未能检测出基因型,基因型检出率80.8％(59/73);其余59例标本检测到了基因型,其中B型11例(18.6％)、C型43例(72.9％)、非B非C型5例(8.5％).治疗1年的59例标本中有9例患者检测到了耐药位点,耐药发生率为15.3％,其中B基因型中检出2例(18.2％),C基因型中检出7例(16.3％),非B非C型基因型中未检出;各基因型中变异位点的检出率差异无统计学意义(x2=1.286,P＞0.05).治疗2年的59例患者中有24例患者检测到了耐药位点,耐药发生率40.7％,其中B基因型中检出4例(36.4％),C基因型中检出18例(41.9％),非B非C型基因型中检出2例(3.3％);各基因型中变异位点的检出率差异亦无统计学意义(x2=6.578,P＞0.05).治疗2年后在24例耐药患者中发生相关阿德福韦酯耐药率33.3％(8/24),发生相关拉米夫定耐药率58.3％(14/24),发生联合耐药率8.3％(2/24).结论 兰州地区HBV基因型主要以C基因型分布为主,其次是B型,还有其他基因型存在;不同基因型耐药发生概率相近,突变概率与基因型无关.对单用拉米夫定或阿德福韦酯治疗失败后的患者再次使用两者联合治疗,亦有较高的耐药风险.     

Genetic analysis of patients with chronic active hepatitis.

21 patients with chronic active hapatitis (CAH) and their families were HL-A typed. HL-A8 was significantly increased in frequency. An apparent increased frequency of HL-A1 was shown to be secondary to the increased HL-A8 due to linkage disequilibrium. Genotype analysis revealed a striking increased frequency of homozygosity for HL-A8, 6 of 21 patients (28.5%) vs. 2.8% of controls. Two patients and one normal who were homozygous for both HL-A1 and HL-A8 were found to be homozygous for a mixed lymphocyte culture (MLC) determinant 8a. Homozygous 8a cells were used as test-stimulating cells in one-way MLC reactions to determine the frequency of the expression of the 8a determinant in 17 patients and 49 controls selected for HL-A type. 8a was found to be associated with 50% of HL-A8 haplotypes and was frequent in the patient and control populations of the same HL-A types. These data suggest that susceptibility to CAH is determined by homozygosity for a gene that is in linkage disequilibrium with HL-A8 and more closely associated with the HL-A second locus then with the locus for the major MLC determinant.     

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。     

Long-term follow-up of lamivudine treatment in patients with severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B

BACKGROUND: The long-term efficacy of lamivudine treatment for patients suffering from severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is unknown. METHODS: Consecutive patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B were prospectively recruited from 1999 to 2004 and treated with lamivudine. All patients had alanine aminotransferase (ALT) and serum bilirubin levels 10x and 3x above the upper limit of normal, respectively. HBeAg-positive patients without severe acute exacerbation served as controls. RESULTS: Forty-five patients with severe acute exacerbation and 31 controls were treated with lamivudine for a median of 2.8 (range 1.0-7.1) years and 3.8 (range 3.5-8.4) years, respectively. Compared with controls, patients with severe acute exacerbation had higher HBeAg seroconversion rates (78% versus 52%; P=0.02) and lower risk of virological breakthrough. However, 33% of patients with severe acute exacerbation still developed lamivudine resistance and virological breakthrough by year 5. HBV DNA levels at week 4 and prolonged baseline prothrombin time were independent factors associated with virological breakthrough. All patients with week 4 HBV DNA <3 log10 copies/ml had maintained virological response. Among 15 patients who stopped lamivudine after sustained HBeAg seroconversion for > or =6 months, 11 (73%) had virological relapse at a median of 1.4 (0.2-3.9) years. ALT increased beyond 10x the upper limit of normal in six (38%) patients who stopped lamivudine and two (7%) patients on maintained lamivudine treatment (P=0.02). CONCLUSION: Among patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B treated with lamivudine, virological breakthrough and post-treatment relapse are common despite a high rate of HBeAg seroconversion. Severe hepatitis flare is also common particularly among patients developing virological relapse after discontinuation of lamivudine.     

苦参素联合拉米夫定对慢性乙型肝炎血清HBsAg影响的Meta分析

目的:评价苦参素联合拉米夫定对慢性乙型肝炎血清HBsAg的影响。方法:按照系统评价的原则制定检索策略,收集符合纳入标准的研究并采集相关信息进行Meta分析。结果:14篇研究符合纳入标准。疗程为3个月时相对危险度(RR)为2.03,95%可信区间(CI)为(0.85,4.84)。6个月时RR为1.89,95%CI为(1.00,3.56),联合组与对照组差异均无统计学意义。疗程为12个月时RR为2.16,95%CI为(1.30,3.59),两组差异有统计学意义。结论:随着疗程的延长,拉米夫定联合苦参素治疗慢性乙型肝炎血清HBsAg转阴率的疗效有优于单用拉米夫定的趋势。