慢性乙型肝炎的研究进展

乙型肝炎病毒(HBV)感染已呈世界性流行,全世界共约3.5亿人为慢性HBV感染者(HBsAg阳性＞6个月),每年死于HBV感染所致的终末期肝病和肝细胞癌的人数超过100万.我国HBV感染率较高,1～59岁人群HBsAg携带率为7.18%,1～4岁人群HBsAg携带率为0.96%,与以前流行病学调查结果相比,HBsAg携带率已大幅下降.尽管如此,由于我国人口众多,大量HBV感染者携带病毒,乙型肝炎的防治工作形势依然严峻[1].     

慢性乙型肝炎抗病毒治疗的新规范

随着新的抗乙型肝炎病毒药物陆续上市．抗乙型肝炎病毒治疗经验也不断丰富。有关慢性乙型肝炎的抗病毒治疗的策略亟待更新和完善。为此．美国肝病学会（AASLD）对2004年版《慢性乙型肝炎的临床实践指南》（以下简称《指南》2004）再次进行了更新。使其更具灵活性和实用性。现通过对指南2007与指南2004进行比较．     

慢性乙型肝炎患者抗病毒治疗药物进展

核苷类似物主要的药物有拉米夫定（Lamivudine，LAM）、阿德福韦酯（adefovir，ADV）、恩替卡韦（entecavir,ETV）、替比夫定和尚未上市的替诺福韦。其他的核苷类似物还有克拉夫定（Clevudine．LFMAU）、恩曲他滨（Emtricitabine，FTC）等。干扰素目前主要指长效干扰素（聚乙二醇化干扰素，Peg-Interferonα-2a，PEG—IFN）。现就这些药物的最新进展作一综述。     

慢性乙型肝炎的研究进展

乙型肝炎病毒(HBV)感染已呈世界性流行,全世界共约3.5亿人为慢性HBV感染者(HBsAg阳性＞6个月),每年死于HBV感染所致的终末期肝病和肝细胞癌的人数超过100万.我国HBV感染率较高,1～59岁人群HBsAg携带率为7.18%,1～4岁人群HBsAg携带率为0.96%,与以前流行病学调查结果相比,HBsAg携带率已大幅下降.尽管如此,由于我国人口众多,大量HBV感染者携带病毒,乙型肝炎的防治工作形势依然严峻[1].     

慢性乙型肝炎需要长期、有效地抗病毒治疗

目前研究证明．持续高HBV载量是慢性乙型肝炎（CHB）病情进展的主要病因．通过对26个前瞻性研究荟萃分析显示．血清HBVDNA水平与肝组织病变严重程度及活动性呈正相关。经抗病毒治疗后．随着HBVDNA水平下降．肝病活动指数（HAt）也明显下降，因此，在CHB时，病毒载量可以衡量组织病变的严重和活动程度。台湾学者证明持续高载量HBVDNA，     

慢性乙型肝炎的研究进展

乙型肝炎病毒(HBV)感染已呈世界性流行,全世界共约3.5亿人为慢性HBV感染者(HBsAg阳性＞6个月),每年死于HBV感染所致的终末期肝病和肝细胞癌的人数超过100万.我国HBV感染率较高,1～59岁人群HBsAg携带率为7.18%,1～4岁人群HBsAg携带率为0.96%,与以前流行病学调查结果相比,HBsAg携带率已大幅下降.尽管如此,由于我国人口众多,大量HBV感染者携带病毒,乙型肝炎的防治工作形势依然严峻[1].     

慢性乙型肝炎抗病毒治疗的药物选择策略

持续HBV感染是慢性乙型肝炎（CHB）患者病情反复加重甚至发展成肝硬化、肝癌的重要因素，抗HBV是治疗慢性乙型肝炎的关键。临床医生必须严格把握抗HBV治疗的适应症、了解药物特点、选择合理的治疗方案才能有效地控制疾病进展。     

拉米夫定治疗慢性乙型肝炎28例

目的:观察拉米夫定治疗慢性乙型肝炎的疗效.方法:53例慢性乙型肝炎患者随机分为两组,治疗组28例,口服拉米夫定100 mg,qd;对照组25例,口服肝复康4片,tid.疗程均为9～12个月.结果:治疗组在乙型肝炎病毒学指标HBeAg、HBV DNA阴转,抗 HBe阳转方面均明显优于对照组,且停药后治疗组复发率亦低于对照组(P＜0.05).结论:拉米夫定服用方便,能有效抑制乙型肝炎病毒复制,改善肝功能,治疗慢性乙型肝炎疗效确切,无明显副作用.     

拉米夫定治疗慢性乙型肝炎40例

目的;观察拉米夫定治疗慢性乙型肝炎的疗效.方法;84例慢性乙型肝炎患者随机分为治疗组40例,服拉米夫定100 mg,qd;对照组44例,口服水飞蓟宾、肌苷等.两组疗程均为52周.结果;治疗2个月后临床症状、体征均得以缓解,疗程结束6个月后,治疗组复发率5.0%,对照组复发率22.7%;两组患者HBeAg,HBV DNA转阴情况治疗组优于对照组(P＜0.05);副作用两组差异无显著性(P＞0.05).结论;拉米夫定具有显著抑制乙型肝炎病毒复制,改善肝功能的作用.     

DSG-Ⅰ型电脑肝病治疗仪治疗慢性乙型肝炎和肝炎肝硬化

目的 观察DSG-Ⅰ型电脑肝病治疗仪治疗慢性乙型肝炎和肝炎肝硬化的疗效.方法 129例慢性乙型病毒性肝炎和肝炎肝硬化患者随机分为两组,对照组给予常规药物治疗,治疗组在常规治疗的基础上加用DSGⅠ型(生物信息)电脑肝病治疗仪照射肝区.观察治疗前、后患者临床症状、肝功能、肝纤维化指标及外周血T细胞亚群、白细胞介素(IL)-2、IL-6、IL-8水平的变化.结果 治疗后治疗组患者血清丙氨酸氨基转移酶、总胆红素、肝纤维化指标显著降低,白蛋白、A/G和T4/T8比值显著升高,而治疗前增高的血清IL-2、IL-6、IL-8,随病情恢复而下降,同时失眠、肝区不适症状明显好转.结论 DSGⅠ型电脑肝病治疗仪治疗能改善慢性乙型病毒性肝炎和肝炎肝硬化患者的临床症状,恢复肝功能,降低肝纤维化指标,且能激活人体的免疫系统,促进肝病康复.     

拉米夫定治疗儿童慢性乙型肝炎的临床研究

目的　观察拉米夫定治疗儿童慢性乙型肝炎的临床疗效及对乙肝病毒标志物的影响。方法　选择慢性乙型肝炎患儿 6 3例 ,随机分为拉米夫定治疗组和对照组 ,治疗组给予拉米夫定每天 3mg/kg服用 ,同时给予西利宾胺片和甘草甜素片护肝治疗 ,疗程 2年 ,追踪观察 1年。对照组仅给予西利宾胺片及甘草甜素片 ,剂量疗程与治疗组相同。观察两组患儿外周血白细胞数、血小板数、血肌酐、肝功能及乙肝病毒标志物的变化。结果　两组患儿的外周血白细胞数、血小板数及血肌酐差异无显著意义 (P >0 0 5 )。两组患儿的ALT复常率分别是 94 3%和 5 3 6 % (P <0 0 1) ;HBVDNA阴转率分别是 88 6 %和 3 6 % (P <0 0 1) ;HBeAg的阴转率分别是 5 4 3%和 3 6 % (P <0 0 1) ;抗HBe阳转率分别是 4 8 6 %和 3 6 % (P <0 0 1) ,停药 1年时 ,两组患儿的ALT复常率分别是 74 3%和 4 2 9% (P <0 0 5 ) ,HBVDNA阴转率分别是 4 5 7%和 3 6 % (P <0 0 1) ,HBeAg/抗HBe血清转换率分别是 4 5 7%和 3 6 % (P <0 0 1)。结论　拉米夫定治疗儿童慢性乙型肝炎是安全有效的药物之一。     

抗慢性乙肝临床常用核苷类药物联合用药研究进展

乙型肝炎是一种严重危害人类健康的疾病。本文主要介绍目前临床使用较多的几种核苷类抗病毒药物联合用药,并介绍近2年来能够在体内外有效抑制乙肝病毒复制的候选药物,为研发新型抗乙肝病毒药物提供参考。     

Treatment of chronic hepatitis B: from research to clinical practice via the consensus conferences

The aim of antiviral therapy of chronic hepatitis B is to control Hepatitis B Virus (HBV) replication and to cure liver disease avoiding the progression of chronic hepatitis to cirrhosis and the end stage complications of cirrhosis. HBeAg/anti-HBe seroconversion is the hallmark of response in hepatitis B "e" antigen (HBeAg) positive patients. In the patients with antibody against HBeAg (anti-HBe positive) the combination of HBV DNA and anti-HBc IgM tests provides adequate diagnostic accuracy. Patients with biochemical and/or histological disease activity are eligible to therapy. The drug choice is based on age, disease severity, risk of complications, side effects and compliance, particularly in anti-HBe positive patients where prolonged treatment is needed. Interferon (5-6 MU daily or 9-10 MU thrice weekly for 4-6 months) is the first line therapy for HBeAg positive patients and (5-6 MU thrice weekly for 12-24 months) for anti-HBe positive patients. When IFN is contraindicated or ineffective, Lamivudine (100 mg) or Adefovir Dipivoxil (10 mg) are given as long as 4-6 months after HBeAg/anti-HBe seroconversion or for long-term treatments in HBeAg positive non-responders and anti-HBe positive patients. Patients with more advanced forms of cirrhosis and portal hypertension are to be treated within liver transplantation programs. Fifteen to 30% of treated patients achieve sustained response and more than 60% of them experience long-term disease remission during therapy. In perspectives, currently available molecular and immunologic tools and modelling of viral dynamics will help to address the therapy issue with more complex, efficacious and individually tailored treatment schedules.     

Telbivudine for the treatment of chronic hepatitis B

The hepatitis B virus (HBV) has a complex natural history and causes a wide spectrum of disease. Choices of therapy depend on a number of factors predictive of treatment response, clinical circumstances and stage of disease, and the likelihood and consequences of resistance to treatment. Telbivudine (beta-L-2'deoxythymidine) is a thymidine analogue that belongs to a new class of beta-L-configuration nucleoside analogues with specific activity against hepadnavirus. Phase III studies of telbivudine versus lamivudine in hepatitis B e antigen (HBeAg) and anti-HBe have been completed. In HBeAg-positive patients, HBV DNA was not detectable by polymerase chain reaction (PCR) assay in 56% of the HBeAg-positive patients receiving telbivudine after two years of treatment. In HBeAg-negative patients, at two years, HBV DNA was undetectable by PCR in 82% of HBeAg-negative patients (versus 52% of lamivudine recipients). Patients who were PCR-negative after 24 weeks were less likely to develop resistance. HBeAg seroconversion rates were also greatest in patients whose HBV DNA was undetectable at 24 weeks. These results are promising and could be used to devise a strategy to utilize combination therapy or to adjust therapy if an inadequate early viral response is observed. However, resistance is a potential shortcoming of the use of single agents for the treatment of HBV.     

Lamivudine for the treatment of chronic hepatitis B

Lamivudine (Zeffix, Epivir, GlaxoSmithKline) is the most important recent advance in the treatment of chronic hepatitis B in both adults and children. It is the only available oral treatment and has an excellent safety profile, which makes it even more attractive. It increases the rate of hepatitis B e antigen (HBeAg) loss and seroconversion in compensated chronic HBeAg-positive carriers, with subsequent improvement of histology at a similar rate as IFN-alpha. Lamivudine is mostly active in patients with elevated transaminases and is not effective in compensated patients with quiescent disease. Long-term follow-up studies are still required to evaluate long-term benefits, including those on hepatitis B surface antigen (HBsAg) seroconversion rate and disease evolution control. In decompensated patients, the drug can stabilise and improve liver function, allowing the patient to wait safely for transplantation. Patients may improve to such an extent that transplantation can be postponed. Combined with hepatitis B immunoglobulin (HBIG), lamivudine considerably decreases the risk of graft re-infection after transplantation. It is also active in chronic HBeAg-negative hepatitis patients, for whom IFN is less efficient. The major drawback is the emergence of the tyrosine-methionine-aspartate-aspartate (YMDD) mutation, which prevents further efficacy of the drug and may lead to flares of hepatitis. Due to the questions the YMDD mutation raises and because hepatitis B is a complex disease, indications for treatment must be established with care and only by physicians with expert knowledge of the disease, the drug and YMDD mutation-related issues.     

Lamivudine for the treatment of chronic hepatitis B

Lamivudine (Zeffix^®, Epivir^®, GlaxoSmithKline) is the most important recent advance in the treatment of chronic hepatitis B in both adults and children. It is the only available oral treatment and has an excellent safety profile, which makes it even more attractive. It increases the rate of hepatitis B e antigen (HBeAg) loss and seroconversion in compensated chronic HBeAg-positive carriers, with subsequent improvement of histology at a similar rate as IFN-α. Lamivudine is mostly active in patients with elevated transaminases and is not effective in compensated patients with quiescent disease. Long-term follow-up studies are still required to evaluate long-term benefits, including those on hepatitis B surface antigen (HBsAg) seroconversion rate and disease evolution control. In decompensated patients, the drug can stabilise and improve liver function, allowing the patient to wait safely for transplantation. Patients may improve to such an extent that transplantation can be postponed. Combined with hepatitis B immunoglobulin (HBIG), lamivudine considerably decreases the risk of graft re-infection after transplantation. It is also active in chronic HBeAg-negative hepatitis patients, for whom IFN is less efficient. The major drawback is the emergence of the tyrosine-methionine-aspartate-aspartate (YMDD) mutation, which prevents further efficacy of the drug and may lead to flares of hepatitis. Due to the questions the YMDD mutation raises and because hepatitis B is a complex disease, indications for treatment must be established with care and only by physicians with expert knowledge of the disease, the drug and YMDD mutation-related issues.     

Pegylated interferons for chronic hepatitis B

Conventional interferon therapy has been used for the treatment of chronic hepatitis B (CHB) for many decades. However, the use of interferon has been limited by its short half-life and high incidence of dose-related side effects. A meta-analysis investigating the short- and long-term consequences of interferon therapy showed that, whilst interferon therapy was beneficial in the short term, resulting in normalization of alanine aminotransferase (ALT) levels, loss of HBeAg, 'e' seroconversion and suppression of hepatitis B virus (HBV) DNA, the long-term benefits were less substantial. Pegylation of interferon (peginterferon alpha-2a [40 kDa]) led to improved pharmacokinetic and pharmacodynamic profiles, which translated to superior efficacy compared with conventional, nonpegylated interferon, in the treatment of chronic hepatitis C. A phase II study investigated the safety and efficacy of peginterferon alpha-2a (40 kDa) in the treatment of chronic hepatitis B. The results demonstrated a rapid and dramatic reduction in HBV DNA levels, HBeAg clearance and normalization of ALT with peginterferon alpha-2a (40 kDa) compared with conventional interferon. Furthermore, peginterferon alpha-2a (40 kDa) conferred a notably improved treatment response in patients with 'difficult-to-treat' hepatitis B infection. In conclusion, peginterferon alpha-2a (40 kDa) is a promising emerging therapy for CHB.     

Prevalence of hepatitis B and C infection in a methadone clinic population: implications for hepatitis B vaccination

AIMS: To examine the HBV and HCV markers of injecting drug users on methadone maintenance, and the feasibility of vaccination at the drug clinic. METHODS: Systematic serological testing of patients for hepatitis B and C was undertaken, and free hepatitis B vaccination was offered via arranged clinic appointments. RESULTS: Hepatitis B serology was obtained in 163 of the 220 clinic patients. 85 (52.1%) patients had evidence of hepatitis B exposure, and 3 (1.8%), of previous vaccination. Positive hepatitis B markers were associated with increasing age (p=0.004), and the duration of injecting prior to treatment (p=0.008). Hepatitis B and C serology was obtained for 153 patients, with 76 (49.7%) having evidence of dual exposure. 164 (84.1%) of 195 patients were positive for antibody to hepatitis C. Completion of the vaccine course was lower than anticipated (36.5% of HBV negative patients). CONCLUSIONS: The high rates of hepatitis B exposure in injecting drug users on methadone treatment confirm the need for hepatitis B vaccination, particularly in view of their endemic hepatitis C infection. Monitoring of this group for the development of chronic liver disease and hepatocellular carcinoma is recommended. Routine cost-free vaccination of patients on entering drug treatment, using a rapid vaccination schedule, may improve compliance.     

Current pharmacotherapy for the treatment of chronic hepatitis B

The virological profile of infection with the hepatitis B virus (HBV) is changing in many parts of the world from the classical hepatitis B e antigen (HBeAg)-positive serological pattern to a HBeAg-negative pattern, linked to the replacement of wild-type HBV by HBV variants with mutations in the core-promoter and in the precore region that prevent the secretion of HBeAg. The wild-type HBV disease is characterised by steady levels of alanine aminotransferase (ALT) and high HBV-DNA levels, responding relatively well to IFN treatment (3 – 5 MU/day or 10 MU every other day for 16 weeks), which induces anti-HBe seroconversion and normalises ALT levels in ～ 30% of the adults, with a minimal risk of relapse. Pegylated-IFN appears to have superior efficacy over conventional IFN-α. Mutant-type disease (anti-HBe-positive/HBeAg-negative) is less responsive to IFN given for 6 – 12 months. This has led to the use of novel nucleoside analogues, of which the prototype is lamivudine. The response to lamivudine therapy shares with IFN a rapid decline in ALT accompanied by an improvement in histology; at variance with IFN, in HBeAg-positive chronic hepatitis B (CHB) there is delayed seroconversion to anti-HBe which accumulates over time, the switch to anti-HBs is more rare and in the long-term, the activity of the drug is abolished by the emergence of viral mutations (YMDD-motif mutants) that may rekindle the disease. The combination of IFN plus lamivudine may be more efficacious than IFN or lamivudine monotherapy. Lamivudine therapy needs to be prolonged in HBeAg-negative CHB. Short-term lamivudine-therapy is highly efficacious in preventing HBV reinfection in liver transplants. Recent data suggest that long-term IFN therapy (24 months) may achieve a response in 30% of HBeAg-negative patients. The advent of adefovir, an analogue of adenosine monophosphate, may provide a safer alternative to lamivudine in the control of HBV disease; the drug is well-tolerated and treatment raises drug-resistant mutants in < 2% of the patients over 2 years of therapy. Adefovir provides rescue therapy against YMDD mutants raised by lamivudine therapy.