慢性乙型肝炎的抗病毒治疗

慢性乙型病毒性肝炎(CHB)一直是一个全球性健康问题，全球大约3．5亿人感染乙肝病毒(HBV)。在慢性HBV感染的病程中，约15％～40％将产生并发症，如重症肝炎、肝硬化、肝功能衰竭及肝细胞肝癌(HCC)。目前，CHB的治疗目的仅在于抑制乙型肝炎病毒(HBV)的复制，缓解肝脏病变，本综述总结α-干扰素和拉米夫定在治疗慢性乙肝有效性和安全性的资料，不同临床状态下的治疗策略和未来的治病方向。     

慢性乙型肝炎的抗病毒及免疫治疗

慢性乙型病毒性肝炎 (ＣＨＢ)是一种严重危害人类健康的常见病。目前我国有现症ＣＨＢ患者约 2千万人 ,每年有 2 3 7万人死于乙型肝炎相关的疾病 ,其中有 15 6万人死于肝癌。因此 ,加强慢性乙型肝炎的治疗 ,寻求有效的治疗方法 ,是当前亟待解决的重大课题。目前 ,抗病毒治疗是治疗慢性乙型肝炎、阻止病程进展最为有效的方法 ,抗病毒治疗药物主要是α干扰素和核苷类似物。其中 ,核苷类似物中已广泛用于临床治疗的是拉米夫定 ,即将应用于临床并有较好前景的是阿德福韦。免疫治疗是慢性乙型肝炎的另一种清除病毒的治疗方法 ,临床应用的主要是…     

拉米夫定耐药后慢性乙型肝炎的后续抗病毒治疗研究

目的采用干扰素和阿德福韦酯治疗慢性乙型肝炎患者经拉米夫定治疗后出现YMDD变异,比较两种治疗策略的临床疗效。方法选择2002年2月2008年12月经100mg拉米夫定治疗后出现YMDD变异的慢性乙型肝炎患者76例。其中,男52例,女24例;年龄18～55岁,平均年龄33岁。服用100mg拉米夫定52～156周发生YMDD变异,HBVDNA低于治疗前水平,丙氨酸转移酶（alanine aminotransferase,ALT）〈2×ULN/L患者分为A组（26例）,继续用100mg拉米夫定治疗48周;服用100mg拉米夫定52～156周发生YMDD变异,HBVDNA定量检测高于或等于治疗前水平,ALT〉2×ULN/L,根据患者自愿分为B组（27例）和C组（23例）。B组用100mg拉米夫定联合10mg阿德福韦酯治疗48周;C组用干扰素治疗48周。分别观察3组ALT复常率及HBVDNA转阴率、HBeAg阳性患者血清学转换率。结果治疗48周时,B、C组患者ALT复常率分别是74.1%和78.3%,明显高于A组的34.6%,差异有统计学意义（P〈0.05）;B、C组患者HBVDNA转阴率分别是77.7%和73.9%,明显高于A组的11.5%,差异有统计学意义（P〈0.05）;3组HBeAg阳性患者血清学转换率比较,差异均无统计学意义（P〉0.05）。结论慢性乙型肝炎患者经拉米夫定治疗后出现YMDD变异,继续用拉米夫定治疗疗效不理想,改用干扰素或联合阿德福韦酯治疗更安全有效。     

拉米夫定联合干扰素α治疗慢性乙型肝炎的临床观察

我国是HBV感染的高发区，据：1992～1995年全国病毒性肝炎血清流行病学调查，人群HbsAg携带率达9．75％，约1．2亿人，其中慢性乙型肝炎患者3000万人^[1]。有效的抗HBV治疗是慢性乙型肝炎能否治愈及能否阻止部分患者肝硬化和肝癌的关键。α-干扰素是目前公认的抗乙肝病毒首选药物，但其有效应答率仅为25％～40％^[2]，拉米夫定是新一代核苷类药     

拉米夫定在慢性乙型肝炎抗病毒治疗中的进展

文献总结了10余年拉米夫定在慢性乙型肝炎抗病毒治疗的效果分析,包括临床疗效、经济-成本、生存质量等相关指标的分析以及耐药管理等问题.     

慢性乙型肝炎的抗病毒治疗和耐药株监测

慢性乙型肝炎是由乙型肝炎病毒 (ＨＢＶ)感染引起的全球性疾病 ,严重危害人类健康和生活质量。目前慢性乙型肝炎的治疗主要有α干扰素和拉米夫定 (Ｌａｍｉｖｕｄｉｎｅ) ,α干扰素为非特异性抗病毒药物 ,且有免疫调节作用 ;拉米夫定为抗病毒药物 ,是一种双脱氧核苷类似物 ,吸收后在体内代谢成为拉米夫定三磷酸化物 ( 3ＴＣ ＴＰ)。ＨＢＶ在复制过程中存在前基因组ＲＮＡ的逆转录过程 ,3ＴＣ ＴＰ在逆转录过程中可掺入到新合成的ＤＮＡ链中 ,由于其戊糖环为双脱氧硫代呋喃糖环 ,不具有 3′羟基 ,不能形成磷酸二酯键 ,所以可以阻止下一个核苷…     

胸腺肽联合甘利欣治疗慢性乙型肝炎36例

慢性乙肝的治疗以抗病毒（应用干扰素或拉米夫定）为主,但费用较高。我院自2005年1月～2006年7月,采用胸腺肽联合甘利欣治疗慢性乙肝36例,取得一定疗效,现报道如下：[第一段]     

胸腺肽α1联合拉米夫定治疗慢性乙型肝炎疗效观察

拉米夫定是一种新的脱氧核苷类药物,可抑制HBV-DNA复制,但HBeAg阴转率低,治疗时间长易产生耐药[1],胸腺肽a1是由人工合成的28个氨基酸组成的多肽,纯度高,活性强,但有细胞免疫滞后作用,不良反应极少,起效时间慢[2],作者探讨两者联合治疗慢性乙型肝炎的疗效.     

1704例慢性乙型肝炎患者拉米夫定耐药相关基因突变分析

目的对慢性乙型肝炎(CHB)患者进行拉米夫定(LAM)多位点耐药突变检测。方法提取病毒核酸,对聚合酶链反应扩增产物进行测序,采用DNA STAR(Lasergene)软件分析测序结果。结果共对1 704例CHB患者进行耐药突变检测,检出的主要突变类型为rtM204V/I,约占60.1%,约36.1%的患者合并rtL180M突变,1.3%的患者合并rtV173L突变。结论rtM204V/I是LAM耐药突变的主要类型,可合并rtL180M或rtV173L突变;准确检测各类型耐药突变对临床用药具有重要的指导意义。     

阿德福韦酯与拉米夫定联合胸腺肽α1治疗拉米夫定耐药患者疗效观察

目的观察阿德福韦酯与拉米夫定联合胸腺肽α1治疗拉米夫定耐药慢性乙型肝炎患者的疗效。方法90例拉米夫定耐药HBeAg阳性CHB患者随机分为阿德福韦酯组和联合治疗组,阿德福韦酯组在继续给予拉米夫定的基础上加用阿德福韦酯10mg／d,连续应用12个月以上;联合治疗组在拉米夫定加用阿德福韦酯组治疗的基础上联合胸腺肽α1针1．6mg,皮下注射,每周2次,连用12个月以上。观察两组患者的生化应答率,病毒应答率,HBeAg阴转率及HbeAg转换率。结果治疗12个月时联合治疗组ALT复常率75％、HBVDNA转阴率66．7％,与单加用阿德福韦酯组比较有显著性意义。结论拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者在加用阿德福韦酯的基础上联合胸腺肽α1治疗效果显著,与单加用阿德福韦酯比较有显著性意义。     

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.     

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.     

Hepatitis B genotypes in chronic hepatitis B and lamivudine therapy

The influence of hepatitis B virus (HBV) genotypes on the natural history and the response to treatment of patients with chronic hepatitis B are of potential interest. Compared to the patients with HBV genotype C, those with genotype B were of a younger age and had a higher cumulative rate of hepatitis B e antigen (HBeAg) seroconversion during the initial 6 years of follow-up. The earlier HBeAg seroconversion in the patients with genotype B, however, did not provide them with a benefit in terms of a reduced risk of developing long-term complications. The response to lamivudine therapy was evaluated in 21 patients infected with HBV genotype B (all of subtype Ba) and 61 with genotype C. There were no differences in the virological response to lamivudine therapy, based on the reduction in median logarithmic HBV DNA titer as well as alanine aminotransferase (ALT) levels, normalization of ALT and the rate of HBeAg seroconversion between the patients with genotypes B and C. No differences were noted either, in the frequency of YMDD mutants at week 52 or the cumulative risk of HBV DNA breakthroughs with YMDD mutations during long-term lamivudine therapy (median 37.5 months). In conclusion, there is no influence of HBV genotypes on the development of long-term complications and lamivudine therapy in Hong Kong.     

Viral breakthrough during lamivudine therapy for chronic hepatitis B

The mainstay of therapy for patients with chronic hepatitis B is inhibition of the replicative cycle of hepatitis B virus (HBV) in hepatocytes. Antiviral agents have different potencies. The measurement of HBV DNA in serum can monitor the potency of these therapeutic agents. Viral breakthrough may occur during therapy, which is defined as an abrupt increase in serum HBV DNA levels after a period of persistent suppression. The accuracy of HBV DNA detection depends on the sensitivity of assays. The third-generation quantitative assays have a lower limit of detection in ranges similar to those of quantitative PCR reaching 2 log10 copies/ml. The sensitive assays also give insight into the pathophysiology of chronic hepatitis B. Monotherapy usually suppresses the viral replication inadequately. It only brings about a reduction of serum HBV DNA levels from 8 to 4 log10 copies/ml. In other words, HBV is not completely eliminated. Viral breakthrough occurs with noncompliance to therapy and, also, when drug-resistant mutants emerge. Mutations in the YMDD motif of HBV polymerase lead to resistance to antivirals, such as lamivudine and famciclovir. In clinical practice, the diagnosis and management of viral breakthroughs are problematic and controversial. Due to advances in therapy, more potent agents are available such as adefovir dipivoxil that seldom induce viral breakthroughs for up to 134 weeks of therapy. Potent antiviral agents also lead to the decline of cccDNA in hepatocytes. Combination therapies may further improve efficacy and avoid viral breakthroughs.     

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.     

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.     

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.     

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。