慢性乙型肝炎的抗病毒治疗

目的 根据慢性乙型肝炎患者的自身情况选择抗病毒药物.方法 查阅国内外相关资料,进行总结分析.结果 干扰素及核苷类似物在临床应用方面日趋成熟.结论抗病毒治疗是慢性乙型肝炎最根本的治疗方法.     

慢性乙型肝炎抗病毒治疗进展

慢性乙型肝炎的抗病毒治疗仍是国内外所面临的一大难题,近年来虽已取得显著成果,但目前临床的抗病毒治疗只能抑制病毒的复制,尚不能彻底清除体内乙型肝炎病毒。病毒的耐药变异仍然是影响CHB抗病毒疗效的重要原因之一,现国际国内仍在探讨新的抗病毒治疗方法,特别是新的免疫治疗策略以期获得持久的病毒学和血清学应答,达到CHB的永久性治愈。本文就慢性乙型肝炎的抗病毒治疗最新进展进行综述。     

乙型肝炎药物治疗的新进展

乙型肝炎(乙肝)由乙肝病毒(HBV)引起的传染病，全球HBV感染者达3．5亿，我国为1．3亿，在各类肝炎中，危害最严重的是乙肝。HBV属嗜肝病素病毒科，在宿主细胞核内形成共价闭合环状DNA(cccDNA)进行复制。目前抗HBV药物主要有免疫调节剂(如α-干扰素)，核苷类(如拉米夫定)和中草药(如苦参素)。对乙肝采用综合治疗的方法，即抗病毒，免疫调节和抗纤维化，而抗病毒是关键，HBV具有高度变异性而易产生耐药，因此需要长期治疗和多种药物联用，才能提高疗效，降低毒副反应，抑制病毒复制，使细胞内cccDNA库得不到补充而逐渐耗竭。     

慢性乙型肝炎抗病毒治疗的共识与浅见

慢性乙型肝炎(慢乙肝,CHB)的发病机制复杂,仍未完全阐明。但病毒持续复制和机体免疫清除反应,是发病的两个基本因素。慢性乙型肝炎是当前最严重的健康问题之一,全球目前有3.5亿慢性乙型肝炎病毒(HBV)感染者,每年约有100万人死于乙型肝炎病毒感染的相关疾病,占疾病死因的第9位,其中75％分布在亚太地区。长期以来,许多基础学者和临床学者对治疗慢性乙型肝炎的研究进行了不懈地努力。对有效的治疗药物和方法也已形成共识,但均未取得突破性进展。因此进一步研究仍是当务之急。     

康宁胶囊联合谷胱甘肽治疗慢性乙型肝炎的疗效观察

目的观察康宁胶囊联合谷胱甘肽治疗慢性乙型肝炎的临床疗效.方法对照组79例用谷胱甘肽治疗,治疗组93例用谷胱甘肽加用康宁胶囊治疗,通过肝功能指标及纤维化指标评价疗效.结果经4～8周治疗后,治疗组及对照组肝功能指标及纤维化指标均有明显改善,但在部分指标上,治疗组优于对照组.结论康宁胶囊联合谷胱甘肽治疗慢性乙型肝炎有较好作用.     

抗病毒药物对慢性乙型肝炎患者染色体脆性的影响

本文应用HuIFN—α．ARA—AMP、QLN三种不同抗乙型肝炎病毒药物，以单独和联合用药的方式，离体和体内分别处理慢性乙型肝是患者外周血淋巴细胞，分别观察TRCA、CAR、fra3 p14ER、MI平均值和HBVM等多项实验指标。研究结果表明，6个体内处理组、9个体外处理组均能降低和显著地降低患者外周血淋巴细胞TRCA、CAR、fra3 p14ER、MI平均值，具有显著的HBeAg、HBV—DNA的阴转率和ALT的复常率，说明上述三种抗病毒药物及其组成的6种治疗方案均具有诱导慢乙肝患者遗传物质损伤的修复作用；慢乙肝患者TRCA、CAR、fra3 p14ER平均值下降，ALT复常率、HBV-DNA和HBeAg阴转率的增加均与药物体内和离体处理(治疗)相关。     

加强慢性乙型肝炎的抗病毒治疗

我国“慢性乙型肝炎防治指南”指出:“慢性乙型肝炎治疗主要包括抗病毒、免疫调节、抗炎保肝、抗纤维化和对症治疗,其中抗病毒治疗是关键,只要有适应证,且条件允许,就应进行规范的抗病毒治疗[1]。”但据调查,我国仅有19%慢性乙型肝炎患者接受抗病毒治疗;45%医务人员不知道慢性乙型肝炎规范化抗病毒治疗;73%医师仅用中成药和保肝降酶药治疗慢性乙型肝炎患者;38%慢性乙型肝炎患者轻信虚假广告。因此,多数慢性乙型肝炎患者未能得到及时、规范的抗病毒治疗,从而延误了病情,甚至发展成为肝硬化和肝细胞癌(HCC)。值得指出的是:我国一方面是大多…     

抗病毒序贯疗法联合胸腺肽治疗慢性乙型肝炎的疗效

1999年8月至2003年8月本研究应用抗病毒序贯疗法联合胸腺肽对33例应用拉米夫定停药后慢性乙型肝炎（CHB）进行观察，现报道如下。     

慢性乙型肝炎抗病毒治疗的研究进展

抗病毒治疗是慢性病毒性乙型肝炎治疗的核心问题之一。本文就慢性病毒性乙型肝炎抗病毒药物的研究进展、联合治疗的现状以及目前抗病毒治疗存在的问题和可能的对策作一综述。     

慢性乙型肝炎抗病毒治疗的研究进展

抗病毒治疗是慢性病毒性乙型肝炎治疗的核心问题之一。本文就慢性病毒性乙型肝炎抗病毒药物的研究进展、联合治疗的现状以及目前抗病毒治疗存在的问题和可能的对策作一综述。     

抗病毒治疗对慢性乙型肝炎肝衰竭1年的疗效

目的探讨抗病毒治疗对慢性乙型肝炎肝衰竭的1年疗效。方法收集慢性乙型肝炎肝衰竭病例,选取54例为抗病毒治疗组,选取历史病例67例为对照组。抗病毒治疗组在常规内科治疗的基础上加用抗病毒药物治疗（拉米夫定、恩替卡韦、替比夫定）,对照组仅使用内科常规治疗。分析两组患者在不同时间点病死率、HBVDNA水平、INR、MELD评分及肝功能结果。结果治疗1个月后,两组死亡率差异无统计学意义（P〉0．05）。治疗3个月后,抗病毒治疗组死亡15例（27．8％）,显著低于对照组（32例,47．8％）,差异有统计学意义（P〈0．05）。治疗1年后抗病毒治疗组死亡15例（27．8％）,显著低于对照组（37例,61．7％）,差异有统计学意义（P〈0．05）。治疗1个月后,两组患者ALT、AST、TBIL、INR水平及MELD评分差异无统计学意义（P〉0．05）;抗病毒治疗组HBVDNA水平显著低于对照组．差异有统计学意义（P〈0．05）。治疗3个月及1年后抗病毒治疗组AⅡ、AST、TBIL、INR、HBVDNA水平及MELD评分显著低于对照组,差异有统计学意义（P〈0．05）。结论抗病毒治疗可降低慢性乙型肝炎肝衰竭患者的死亡率,加快肝功能好转,抑制病毒复制,具有肯定的治疗作用。病情好转后维持抗病毒治疗,可以明显改善慢性乙型肝炎肝衰竭患者的长期预后。     

Foscarnet therapy in chronic hepatitis B virus E antigen carriers

Foscarnet (trisodium phosphonoformate) is a novel antiviral agent that inhibits viral-specific DNA polymerase. In the present study, eight males with chronic HBV carriage (HBeAg and HBV-DNA seropositivity greater than 12 months) showing chronic persistent hepatitis (CPH) or chronic active hepatitis (CAH) on liver biopsy received either a continuous infusion of foscarnet at 0.15 mg/kg/min for 7 days or 180 mg/kg/day divided into three daily boluses for 2 weeks. In all eight, HBV-DNA levels fell during therapy (median, 401 pg/40 microliters serum; range, 4-3, 100) vs. pretreatment levels (median, 533 pg/40 microliters; range, 30-4, 175), but in none was HBV-DNA undetectable at any stage. Within 1 month, the HBV-DNA had risen to pretreatment levels in all but one patient (with the lowest pretreatment level), who cleared HBeAg and developed anti-HBe within 3 months. Two further patients were anti-HBe positive at 6 months, but their pretreatment serum HBV-DNA levels were already low, suggesting a high probability of spontaneous seroconversion. Toxicity was not evident with the continuous infusion, but for those receiving IV bolus therapy, serum creatinine and phosphate levels rose in three of four patients, necessitating a 25% dose reduction. There was no difference in the effect on serum HBV-DNA between the two regimes. We conclude that foscarnet has only modest antiviral activity in chronic HBV carriers.     

Serum HBeAg quantitation during antiviral therapy for chronic hepatitis B

Hepatitis Be antigen (HBeAg) seroconversion is considered the principal short-term goal of antiviral therapy in chronic hepatitis B. To test whether the pre- and per-treatment HBeAg quantitation has a higher predictive value than that of hepatitis B virus DNA (HBV-DNA) quantitation for the outcome of antiviral therapy in chronic hepatitis B. A quantitative measurement of HBV-DNA and HBeAg (AxSYM HBe 2.0 Quantitative, Abbott Laboratories) was undertaken in serial serum samples from 30 patients with 16-week interferon-α (IFN-α) treatment (follow-up 36 weeks; 14 responders) and from 15 patients with 24-week lamivudine treatment (follow-up 24 weeks; 2 responders). In the group of interferon-treated patients, the median pretreatment HBV-DNA level was significantly lower in responders compared to nonresponders (P = 0.02); the difference in median HBeAg level was not significant. However, the percentage of response was significantly related (P = 0.003) to the magnitude of decline in HBeAg level between the start of therapy and week 4. This phenomenon was not observed for HBV-DNA. Using multivariate analysis, it was found that the fall of HBeAg levels between weeks 0 and 4 was the most important independent predictor of response. In the group of lamivudine treated patients, the rapid decline in HBV-DNA (>90%) in 12 patients at week 4 had no relation to HBeAg seroconversion. In contrast, the fall in HBeAg-level (one patient with >50% reduction at week 4 seroconverted) appears to be predictive. Quantitation of HBeAg at start and early during therapy may have clinically important predictive value for long-term response to antiviral therapy. J. Med. Virol. 53:282–287, 1997. © 1997 Wiley-Liss, Inc.     

长效干扰素治疗慢性乙型肝炎e抗原阴性患者疗效研究

目的 观察长效干扰素对慢性乙型肝炎HBeAg阴性患者的临床疗效.方法 将46例HBeAg阴性慢性乙肝患者随机分为两组,其中长效干扰素组：派罗欣180μg,一周一次,皮下注射,疗程48周;普通干扰素组：赛诺金500MU,肌肉注射,隔日一次,疗程48周.治疗结束后随访24周.结果 长效干扰素组和普通干扰素组的ALT水平复常率在治疗结束和随访结束比较,差异有统计学意义（x2 =9.106,P＜0.05;x2=9.832,P＜0.05）.长效干扰素组和普通干扰素组的HBV-DNA阴转率在治疗结束和随访结束比较,差异有统计学意义（x2 =4.312,P＜0.05;x2=6.158,P＜0.05）.但两组在HBV-DNA下降程度上无明显差别（P＞0.05）.结论 长效干扰素治疗慢性乙型肝炎e抗原阴性患者可以明显提高疗效.     

自体树突状细胞联合抗病毒药治疗HBeAg阳性慢性乙型肝炎临床效果研究

目的探讨体外诱导自体树突状细胞（DC）对 HBeAg阳性慢性乙型肝炎的治疗效果。方法选择 HBeAg阳性的慢性乙型肝炎病例126例,随机分成治疗组（75例）和对照组（51例）,治疗组采用自体 DC联合恩替卡韦治疗,对照组仅采用恩替卡韦治疗。抽取患者静脉血50 ml,密度梯度离心法获得单个核细胞,加入含 GM-CSF和 rhIL-4的培养基,隔日换液,培养至第6天加入 HBsAg,4 h后加入 TNF,继续培养1 d收获 DC。取 DC 2 ml,皮下注射和静脉输注各1 ml,连续3个月。两组患者于治疗前和治疗后6个月检测肝功、HBV-DNA 定量及血清乙型肝炎标志物,并将两组各项检测指标进行对比。结果治疗6个月后检测患者 HBeAg/抗-HBe血清转换率,治疗组和对照组分别为30.62%（23/75）和21.4%（11/51）,自体 DC联合恩替卡韦治疗 HBeAg阳性的慢性乙型肝炎的效果优于单纯恩替卡韦的治疗。HBV-DNA 滴度检测治疗组为500拷贝/ml,对照组为1400拷贝/ml。两组差异有统计学意义。结论自体 DC联合恩替卡韦治疗 HBeAg阳性的慢性乙型肝炎的效果优于单纯恩替卡韦的治疗。     

Intrahepatic CD8 T-lymphocytes and HBV core expression in relation to response to antiviral therapy for chronic hepatitis B patients

Recognition of HBV-infected hepatocytes by CD8 T-lymphocytes is important for viral clearance. Expression of hepatitis B core antigen (HBcAg) in HBV-infected hepatocytes can trigger this antiviral T-cell response. The intrahepatic CD8 T-lymphocytes and HBcAg expression were investigated in relation to response to antiviral therapy. Forty chronic HBeAg-positive patients treated with either lamivudine (n = 20) or interferon-alpha (n = 20) were investigated. Ten patients from each treatment group exhibited a response. Liver biopsies were carried out before and after therapy. CD8 T-lymphocytes and HBcAg expression were detected by immunohistochemistry. The number of pretreatment intrahepatic CD8 T-lymphocytes was significantly higher in responders (P = 0.008). In responders baseline nuclear HBcAg expression tended to be lower (P = 0.09). Cytoplasmic expression was not significantly different between responders and non-responders (P = 0.46). The number of CD8 T-lymphocytes correlated with cytoplasmic HBcAg (r(s) = 0.31; P = 0.04); CD8 T-lymphocytes were situated in clusters of hepatocytes with cytoplasmic HBcAg. Longitudinal analysis showed a significant reduction of CD8 T-lymphocytes after treatment in responders (P < 0.001). Multivariate analysis revealed pretreatment CD8 T-lymphocytes and age as independent prognostic factors for response (n = 40). The number of pretreatment CD8 T-lymphocytes was the only independent prognostic indicator for response to interferon-alpha (P = 0.03); it was of borderline significance for lamivudine therapy (P = 0.06). It is concluded that the number of pretreatment intrahepatic CD8 T-lymphocytes is an important predictor of response to HBV therapy with either interferon-alpha or lamivudine. Response to therapy led to a significant reduction of intrahepatic CD8 T-lymphocytes. Co-localisation of CD8 T-lymphocytes and HBcAg-positive hepatocytes suggests antiviral activity predominantly at the site of maximum HBV replication.     

Effect of antiviral therapy on the immunohistochemical expression of bcl-xL and bax protein in patients with HBeAg-negative chronic hepatitis B

The effect of antiviral treatment on apoptosis in chronic hepatitis B (CHB) has not been clarified. We evaluated the hepatic immunohistochemical expression of the pro-apoptotic bax and the antiapoptotic bcl-xL protein in HBeAg-negative CHB patients before and after treatment. In our study we included 72 paired biopsies from 36 HBeAg-negative CHB patients: 29 treated (interferon-alfa: 17, adefovir: 12) and 7 untreated. Changes in expression of apoptotic proteins (D-bax, D-bcl-xL), necroinflammation and fibrosis (D-grade/D-stage) (Ishak classification) were evaluated. We found that Bax-positive compared to bax-negative biopsies had worse necroinflammation (8.2 vs. 6.7, P = 0.05) and fibrosis score (3.9 vs. 3, P = 0.036). bcl-xL-positive compared to bcl-xL-negative biopsies had lower intralobular inflammation (1.6 vs. 2.2, P = 0.03). Decreased compared to stable/increased D-bax was associated with greater improvement in necroinflammation only in treated patients (D-grade: -4.6 vs. -1.6, P = 0.05) and greater fibrosis improvement in interferon treated patients (D-stage: -0.4 vs. 0.55, P = 0.05). Increased compared to stable/decreased total apoptotic trend [D-apoptosis: (D-bax)-(D-bcl-xL)], was associated with worsening fibrosis, particularly in adefovir treated patients (D-stage: 2.3 vs. 0, P = 0.004). In the 11 patients without significant changes from 1st to 2nd biopsy, increased apoptosis was more frequent in treated than untreated cases (P = 0.046). In multivariate analysis, bax change was independently associated with change of grade (P = 0.038) and antiviral therapy (P = 0.015). In conclusions, in HBeAg-negative CHB, histological improvement after treatment is associated with decreased hepatocyte apoptosis. In patients without substantial histological changes, treatment seems to increase the apoptosis of hepatocytes, thus having a possible protective effect on hepatocarcinogenesis.     

Association of lamivudine‐resistant mutational patterns with the antiviral effect of adefovir in patients with chronic hepatitis B

Adefovir has a potent antiviral activity as a rescue treatment against lamivudine‐resistant strains. The aim of this study was to assess the patterns of lamivudine‐resistant mutations and their influence on the virologic response to adefovir rescue therapy in patients with lamivudine‐resistant chronic hepatitis B. Sixty‐seven patients with lamivudine‐resistant chronic hepatitis B were treated with adefovir monotherapy. Baseline blood samples were analyzed for lamivudine‐resistant mutations via restriction fragment mass polymorphism. Virologic responses, ALT normalization and loss of HBeAg were assessed. Serum HBV DNA levels were measured using real‐time PCR at baseline and 24 weeks of adefovir therapy. Of the 67 patients with chronic hepatitis B, 65 patients (97%) had lamivudine‐resistant mutations in the YMDD motif [27 (41%) rtM204I, 22 (34%) rtM204V, and 16 (25%) rtM204I/V]. In addition to the YMDD mutations, the rtL180M, rtL80I, and rtV173L mutations were also present in 78%, 43%, and 11% of patients, respectively. The rtM204V mutation always accompanied rtL180M, and rtL80I was always observed in conjunction with rtM204I. Decrease in mean serum HBV did not differ between patients carrying the rtM204I versus rtM204V mutant at week 24 (?3.3 vs. ?3.3 log₁₀ copies/ml, respectively; P = 0.303). The presence of the rtL180M, rtL80I, and rtV173L did not significantly affect viral load reduction during adefovir administration. These results demonstrate that the rtL80I mutant is co‐selected with rtM204I as a compensatory mutation in the same manner as rtL180M with rtM204V, and that adefovir shows similar antiviral efficacy against all of the evaluated patterns of lamivudine‐resistant HBV mutations. J. Med. Virol. 81:417–424, 2009. © 2009 Wiley‐Liss, Inc.     

Characterization of viral kinetics in patients with hepatitis B e antigen-positive chronic hepatitis B

A study was conducted during a 1 year follow-up to characterize the viral kinetics in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B and to develop a model of predicting the probability of spontaneous HBeAg seroconversion. Fifty-seven patients with HBeAg-positive chronic hepatitis B were enrolled with monthly follow-ups from three Phase III clinical trial placebo groups. According to serial viral loads, 30 patients (52.6%) with the stationary pattern maintained stable HBV DNA levels with fluctuations of less than 1.5 log copies/ml. Twenty patients (35.1%) with the declining pattern exhibited a spontaneous decline of more than 1.5 log copies/ml without a following rebound of at least 1.5 log copies/ml. The remaining seven patients (12.3%) had the wavering pattern. Both declining and wavering patterns, when compared with the stationary pattern, had significantly higher hepatic necroinflammation in terms of ALT and Knodell scores at the baseline and peak ALT levels during the follow-up period. The declining pattern had a significantly better clinical outcome in terms of the lowest final HBV DNA and a reduction in the necroinflammatory score after 1 year. Furthermore, the declining pattern had a favorable HBeAg seroconversion rate (40%) compared with the wavering (14.3%) and stationary patterns (0%). A regression equation, incorporating simultaneous serum bilirubin, ALT, and HBV DNA levels, predicted the probability of HBeAg seroconversion with a sensitivity of 76.8% and a specificity of 74.7%. In conclusion, different viral kinetic patterns in patients with chronic hepatitis B implicate distinct clinical significance and immunologic perspective.