【作者】 袁雯霞；

【导师】 黄建荣；

【作者基本信息】 浙江大学 ， 内科学， 2010， 硕士

【摘要】 背景：慢性乙型肝炎是一个全球性的健康问题,预计约影响4亿人群。我国是乙肝病毒感染的高流行区,发病率列世界第一位。慢性乙肝占中国50%的慢性病毒性肝病病例,估计在中国有9千万乙肝携带者,其中80-85%处在慢性无症状阶段,大约有2千8百万处于有临床症状的慢性乙型肝炎阶段。每10万人中的患病率约为2770人,每年的新发病率约为每10万人中230人。在中国,绝大部分的肝硬化都是从慢性乙肝发展而来的；慢性乙肝的发病率分布与肝癌也存在密切相关性,在80%的肝癌患者中都能检测到乙肝病毒。至今为止,有效的抗病毒治疗乙肝的药物只有核苷类似物和干扰素(IFN)。而核苷类似物是近年来抗HBV药物研究的热点,进展很快。治疗慢性乙肝的核苷类似物主要有下面几种：拉米夫定(Lamivudine)、阿德福韦(Adefovir)、恩替卡韦(Entecavir)、左旋脱氧胸腺嘧啶(LdT)、替诺福韦(Viread tenofovir)、恩曲他滨(Emtritabine)。核苷类似物同其他抗病毒药一样,只能抑制HBV病毒复制而难以彻底清除病毒,且HBV易发生变异,变异病毒对抗病毒药易发生耐药,如拉米夫定治疗后的YMDD变异株可发生耐药等,治疗过程中出现的耐药性已成为影响其长期抗病毒治疗最大临床问题之一。如何提高核苷类药物的疗效,降低耐药的发生是目前临床治疗中最为关注的问题。阿德福韦单用或拉米夫定联合阿德福韦是目前最常用的拉米夫定耐药的乙肝患者的挽救性治疗方案。大量临床研究表明,拉米夫定耐药后换用阿德福韦酯或两者联合均可取得较好的临床疗效,且有研究认为拉米夫定耐药后联合治疗的效果优于阿德福韦酯单用。拉米夫定和阿德福韦没有交叉耐药,有研究指出肝硬化患者初治时联合应用拉米夫定和阿德福韦抗病毒疗效优于拉米夫定耐药后换用阿德福韦酯或联合。目前初治联合抗病毒治疗已广泛应用于肝硬化、肝移植以及合并HIV等其他病毒感染的病人,而对慢性乙型肝炎初治患者使用拉米夫定联合阿德福韦酯的联合抗病毒的报道较少。目的：通过拉米夫定联合阿德福韦治疗慢性乙型肝炎初治患者,观察两者联合抗病毒在慢性乙型肝炎患者的HBV-DNA抑制情况,同时观察两者联合对慢性乙型肝炎患者近期疗效的影响,以及两者联合抗病毒的耐药率及安全性,进一步探索核苷类药物的治疗方法,为慢乙肝的治疗提供更加合理的治疗策略及试验依据。方法：选择2009年1月至2010年1月期间符合入组条件的e抗原阳性或e抗原阴性的慢性乙型肝炎初治患者给予拉米夫定联合阿德福韦抗病毒治疗(下称观察组),同时回顾性统计分析了30例拉米夫定单药抗病毒治疗的e抗原阳性或e抗原阴性的慢性乙型肝炎初治患者的相关资料(下称对照组)。观察的指标包括症状体征的变化,肝肾功能,DNA水平,乙肝的血清学标记物等,分别在治疗的0、2、4、8、12、24、36、48周测定,同时观察记录相关不良反应。入组病例严格按照入组标准和排除标准选择。结果：观察组一共入组116例病例,其中完成了12周疗程有116例,DNA阴转率为50%,ALT复常率为44.7%,e抗原血清学转换率为0.86%；完成24周疗程的有79例,DNA阴转率为83.5%,ALT复常率为67.1%,e抗原血清学转换率为3.80%；完成48周疗程的有24,DNA阴转率为95.83%,ALT复常率为87.5%,e抗原血清学转换率为16.70%；所有病例均未发现病毒学突破,未发现严重不良反应。对照组一共30例,48周时DNA阴转率为43.3%,ALT复常率为76.7%,e抗原血清学转换率为19.0%,病毒学突破率为13.3%,未发现严重不良反应。48周时,观察组较对照组具有更高的DNA阴转率(P<0.05)。结论：拉米夫定联合阿德福韦治疗慢性乙型肝炎初治患者可快速持久地抑制病毒复制,可降低病毒耐药的发生,而且具有良好的安全性。更多还原

【Abstract】 Background:Hepatitis B (HBV) viral infection is a serious public health problem worldwide,there are almost 400 million people infected with HBV.China is the area where hepatitis B virus infection is in high prevalence,and the incidence has the first place in the world.Chronic hepatitis B accounted for 50% of chronic viral liver disease,it is estimated there are 90 million HBV carriers in China,of which 80-85% is in chronic asymptomatic stage,and about 28 million people is chronic hepatitis B patients who have clinical symptoms.The prevalence rate is about 2,770 pre 10 thousand,the annual new incidence rate is about 230 pre 10 thousand.In China,the vast majority of liver cirrhosis is developed from chronic hepatitis B,and primary hepatocellar carcinoma is related to Hepatitis B virus infection,of which 80% can be found hepatitis B virus in their blood.To date, the nucleoside analogues and interferon (IFN) are the effective anti-viral drug can be treated in hepatitis B infection.The nucleoside analogues is the research focus.Now the Nucleoside analogues for chronic hepatitis B has the following main categories:lamivudine, Adefovir, entecavir, L-deoxy-thymidine (LdT), Viread tenofovir and Emtritabine.Like other anti-viral drugs，the nucleoside analogues only can inhibit the HBV viral replication and can’t completely remove the virus,and HBV is easy to variant, variant viruses resistant to the antiviral drugs such as ymdd variation after lamivudine can occur such drug resistance.drug resistance arising in the treatment has been the biggest clinical problems which effects the long-term anti-viral treatment. How to improve the efficacy of nucleoside drugs and reduce the incidence of resistance is the most concern in clinical treatment.Lamivudine combined with adefovir or adefovir alone is the most commonly choice in hepatitis B patients with lamivudine resistant as salvage therapy. Many clinical studies have shown that both Lamivudine combined with adefovir and adefovir alone can achieve well clinical efficacy in hepatitis B patients with lamivudine resistant,and some studies show that in these cases Lamivudine combined with adefovir has better clinical efficacy than adefovir alone.These is no cross-resistance between lamivudine and adefovir,and some studies show that choosing Lamivudine combined with adefovir at the beginning has better clinical than choosing it after it is arealy resist to lamivudine.Now Combined antiretroviral therapy is widely used in cirrhosis, liver transplantation and patients wo has combined HIV or other virus-infected.But there is little reports about combined antiretroviral therapy using in chronic hepatitis B patients.Objectives:We observe the HBV-DNA inhibition,the therapeutic effect,drug resistance and security of Lamivudine combined with adefovir treatment in the patients who haven’t receive nucleoside analogues treatment before. And we want to further explore the treatment of nucleoside drugs and to offers a more rational and experimental basis for treatment strategies of chronic hepatitis B patients through our reasch.Methods:We choose the untreated e-antigen positive or e antigen negative chronic hepatitis B patients who met the inclusion criteria to accepted antiviral therapy with Lamivudine combined adefovir from January 2009 to January 2010 (the experimental group),and retrospectively analyzed 30 untreated e-antigen positive or e-antigen negative chronic hepatitis B patients who accepted antiviral therapy with lamivudine monotherapy (the control group).Observed indicators including DNA levels, hepatitis B serological markers and transaminase,which were measured in the treatment of 0,2,4,8,12,24,36,48 week,and safety assessments were also conducted. We choose the enrolled patients into groups strictly according to selection criteria and exclusion criteria.Results:Experimental group, a total of 116 cases of patients enrolled, of which completed 12-week of treatment were 116 cases, which DNA negative conversion rate was 50%, ALT normalization rate was 44.7% and e antigen seroconversion rates is 0.86%; completed 24 weeks of treatment were 79 cases, which DNA negative conversion rate was 83.5%,ALT normalization rate was 67.1% and e antigen seroconversion rates is 3.80%; completed 48 weeks of treatment were 24, which DNA negative conversion rate was 95.83%,ALT normalization rate was 87.5%,and e antigen seroconversion rates is 16.70%.Virological breakthrough weren’t found in all cases, and no serious adverse reactions found. A total of 30 cases were enrolled in control group, after 48 weeks treatment, the DNA negative conversion rate was 43.3%, ALT normalization rate was 76.7%, e antigen seroconversion rates is 19.0%,virological breakthrough rate is 13.3%, no serious adverse reactions was found.After 48 weeks treatment, the experimental group compared with the control group had higher DNA negative conversion rate (P<0.05).Conclusion:Lamivudine combined with adefovir treatment of chronic hepatitis B patients who is untreated with nucleoside analogues before can inhibit virus replication rapid and sustained, can significantly reduce the occurrence of drug resistance, and also has good security.更多还原