核苷类药物在乙型肝炎后肝硬化治疗中的疗效分析

目的观察核苷类抗病毒药物拉米夫定(LAM)、阿德福韦酯(ADV)、恩替卡韦(ETV)在失代偿期乙型肝炎肝硬化患者中的疗效。方法失代偿期乙肝后肝硬化患者120名随机分为A、B、C三组,在内科综合治疗的基础上,A组单用LAM(100 mg/d),B组单用ADV(10 mg/d),C组单用ETV(O.5 mg/d)治疗,观察患者3,6,9及12个月时血清生化指标及病毒载量变化。结果经过核苷类似物抗病毒治疗后,各组HBV DNA载量在3,6,9和12个月后均有大幅度下降,ETV组患者HBV DNA载量下降及HBeAg阴转率显著高于LAM组和ADV组。结论 ETV更适合于失代偿期乙肝后肝硬化患者中的抗病毒治疗。     

核酸类似物PNA在HepG2．2．15细胞中对乙型肝炎病毒复制的抑制作用

目的评价核酸类似物PNA在HepG2．2．15细胞中对乙型肝炎病毒复制的抑制作用。方法以HepG2．2．15细胞作为细胞模型,拉米夫定作为阳性对照药物。HepG2．2．15细胞于药物处理14d后,收集上清液及细胞。采用ELISA检测上清液中HBsAg和HBeAg含量,HBV荧光定量检测上清液和细胞内HBV DNA水平,CCK-8试剂盒检测药物对细胞的毒性作用。结果核酸类似物PNA与拉米夫定在浓度1．6-1000μmol·L^-1内对HepG2．2．15细胞的毒性均较小。与药物未处理组比较,PNA和拉米夫定均可有效抑制细胞上清HBV DNA,半数抑制浓度（IC50）分别为0．05-0．10μmol·L^-1和0．09-0．18μmol·L^-1,两者之间差异无统计学意义。结论在体外细胞实验中,PNA对细胞的毒性小,与拉米夫定的安全指数相当;PNA对乙型肝炎病毒复制有较强的抑制作用,且具有一定时效量效关系,与拉米夫定的抑制强度相当。     

Treatment paradigms on hepatitis B e antigen-negative chronic hepatitis B patients

The primary goal of treatment in hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB) is potent and durable suppression of hepatitis B virus (HBV) replication. It results in biochemical and histological remission of CHB and is the prerequisite for the prevention of cirrhosis, its life-threatening complications and hepatocellular carcinoma. Responses that are durable after the cessation of treatment are referred to as sustained virological responses, whereas those persisting under therapy are referred to as treatment-maintained virological responses. Treatment paradigms of sustained virological response in HBeAg-negative CHB are practically restricted to conventional IFN-α and pegylated interferons (peg-IFNs), and are limited only to patients with compensated liver disease. Long-lasting maintained virological responses without HBV resistance in HBeAg-negative CHB are achievable by all approved nucleos(t)ide analogues (lamivudine, adefovir and entecavir) in highly variable rates, depending on their potency, rapidity of virological response and genetic barrier to resistance. The maintenance of response under 5 years of adefovir treatment represents the most effective treatment paradigm for HBeAg-negative CHB, whereas such long-term data with entecavir and tenofovir monotherapy may become available in the near future. In patients with lamivudine-resistant HBV mutants, the recommended treatment strategy is to add adefovir at the same time as continuing treatment with lamivudine. There are no treatment paradigms as yet of combination therapy from the very outset with two nucleoside analogues for use in treatment-naive patients.     

Adefovir dipivoxil in chronic hepatitis B: history and current uses

Introduction: Sodium oxybate (SMO) has been shown to be safe and effective in the treatment of patients with alcohol use disorders (AUDs); it was approved in Italy and Austria for the treatment of alcohol withdrawal syndrome and for relapse prevention. The focus of this review is to discuss the clinical evidence on the therapeutic potential of SMO for AUDs.

Areas covered: This review covers the studies in patients with alcohol withdrawal syndrome who received SMO for the treatment of withdrawal symptoms and the studies in patients with AUDs who received SMO to achieve total alcohol abstinence, reduction of alcohol intake, and relapse prevention. Relevant medical literature on SMO was identified by searching databases including MEDLINE and EMBASE (searches last updated 20 September 2013), bibliographies from published literature, clinical trial registries/databases, and websites.

Expert opinion: SMO has proved safe and effective in the treatment of alcohol withdrawal syndrome and in the prevention of relapses. Craving for and abuse of SMO have been reported, in particular in some subtypes of alcoholic patients, e.g., those affected by co-addiction and/or psychiatric comorbidity. Future multicenter, multinational, randomized clinical trials should be useful to optimize the treatments in relation with patients' characteristics, for example, pharmacogenetic, neurobiological, and psychological.     

Complications in treating chronic hepatitis B in patients with HIV

The management of chronic hepatitis B virus (HBV) poses specific problems in the presence of HIV infection, as therapeutic approaches have to consider both HBV and HIV. There are currently four drugs approved for the treatment of chronic HBV: IFN-α, lamivudine, adefovir and entecavir. Furthermore, the dual antiviral activity against HIV and HBV of antiretrovirals such as tenofovir and emtricitabine broadens the armamentarium against HBV in the HIV-coinfected population. Nucleotide analogues adefovir and tenofovir have the advantage of a higher genetic barrier for resistance when compared with the nucleoside analogues lamivudine and emtricitabine. Fortunately, the two families do not share resistance mutations, allowing salvage therapy and the consideration of combination therapy for drug-naive individuals. Although response to IFN-α is poorer in HBV/HIV-coinfected patients compared with HBV-monoinfected individuals, the more potent pegylated forms of IFN-α have brought new hopes.     

恩替卡韦与拉米夫定对慢性乙型肝炎抗病毒作用与安全性的对照研究

目的:比较恩替卡韦和拉米夫定治疗慢性乙型肝炎的抗病毒作用与安全性。方法:33例未经抗病毒治疗的慢性乙型肝炎患者随机分为2组:恩替卡韦组(16例)、拉米夫定组(17例)。恩替卡韦组与拉米夫定组的剂量分别为0.5mg/d和100mg/d。疗程为48～96周。观察两药对HBV DNA、ALT、e抗原/e抗体血清转换的影响及其所致不良反应。结果:在治疗24周和48周时,恩替卡韦组和拉米夫定组未检测到HBV DNA的病例分别为56.25%,29.41%;87.50%,29.41%。e抗原阴转率与e抗原/e抗体血清学转换率以及不良反应2组无明显差异。结论:恩替卡韦与拉米夫定比较能更有效的抑制HBV复制,不良反应与拉米夫定相似。因此,可以用于慢性乙型肝炎的长期治疗。     

恩替卡韦治疗慢性乙型肝炎临床评价

目的：回顾恩替卡韦治疗慢性乙型肝炎临床疗效。方法：选取慢性乙型肝炎病人56例,其中28例使用恩替卡韦（治疗组）,28例使用拉米夫定（对照组）进行比较。治疗组与对照组的治疗剂量分别为0．5mg／d和100mg／d,观察两药在第4、8、12和24周共4个治疗阶段的ALT（丙氨酸氨基转移酶）、HBVDNA（乙肝病毒脱氧核糖核酸）及e抗原血清转换情况。结果：治疗组与对照组在治疗4周时AIJT复常率、HBVDNA转阴率及e抗原血清学转换率分别为25％和21％（P〉0．05）,50％和25％（P〉0．05）,0％和5％（P〉0．05）;8周时分别为36％和29％（P〉0．05）,71％和32％（P〈0．05）,19％和21％（P〉0．05）;12周时分别为54％和39％（P〉0．05）,75％和71％（P〉0．05）,31％和32％（P〉0．05）;24周时分别为75％和61％（P〉0．05）,89％和75％（P〉0．05）,44％和42％（P〉0．05）。结论：恩替卡韦相对于拉米夫定能更早、更有效的抑制乙肝病毒复制,伴随着HBVDNA的下降,两组间Au、复常率及e抗原血清转换率差异无显著性。     

替比夫定联合阿德福韦酯治疗青年高病毒载量HBeAg阳性慢性乙型肝炎的临床观察

目的 对比观察替比夫定（LdT）联合阿德福韦酯（ADV）治疗青年高病毒载量乙型肝炎e抗原（HBeAg）阳性慢性乙型病毒性肝炎（CHB）的疗效。方法 106例HBeAg阳性、HBV DNA≥10⁷ 拷贝/mL的青年CHB初治患者分为替比夫定（LdT）联合阿德福韦酯（ADV）联合治疗组（54例）和恩替卡韦（ETV）对照组（52例）。联合治疗组口服LdT 600 mg/d+ADV 10 mg/d,1次/d;对照组口服ETV 0.5 mg/d,1次/d。总疗程48周,观察两组患者治疗12、24、36、48周时乙型病毒性（HBV）DNA阴转率、HBeAg血清学转换率及丙氨酸氨基转移酶（ALT）的复常率。结果 治疗后,两组患者均取得较好的疗效,获得较高的HBV DNA转阴率和ALT复常率。在治疗第12、24、36、48周时两组的HBV DNA阴转率及ALT复常率比较,差异均无统计学意义;但联合治疗组HBeAg血清学转换率24周后明显高于ETV对照组（33.3% vs 13.5%,χ²=5.804、P=0.016）,差异有统计学意义,且36周和48周统计学差异更加显著（42.6% vs 15.4%,χ²=9.477、P=0.002;48.1% vs 19.2%,χ²=9.877、P=0.002）。结论 替比夫定联合阿德福韦酯治疗青年高病毒载量的初治HBeAg阳性CHB患者,不仅获得较高的病毒学应答率和肝功能复常率,与恩替卡韦相比还能获得更高的HBeAg血清转换率。     

拉米夫定防治肾病综合征患者乙肝病毒复制或再感染初探

目的：观察拉米夫定防治服用激素的肾病综合征患者乙肝病毒复制或再感染的可行性。方法：给予5例乙肝病毒标志物阳性的肾病综合征患者口服强的松或酶酚酸酯的同时，口服拉米夫定治疗，观察患者乙肝病毒标志物、肝功能的变化。结果：治疗3个月，1例HBeAg阴转，肝功能轻度异常的1例ALT，AST恢复正常；治疗6个月后，1例HBeAg阴转，无1例肝功能、乙肝病毒标志物恶化。结论：拉米夫定可以防治服用激素治疗的肾病综合征患者的乙肝病毒复制或再感染。     

HBV-前C区基因变异与乙肝病毒复制的相关性

目的 研究乙型肝炎病毒(HBV)前C区G1896A变异与乙肝病毒复制的相关性.方法 选取38例慢性轻度,57例慢性中度,29例慢性重度的乙型肝炎患者为研究对象.采用突变特异PCR技术检测HBV前C基因nt1896位点突变情况,并对血清中HBVDNA进行测序.同时检测乙型肝炎病毒HBeAg/抗-Hbe、HBVDNA定量、肝纤维化指标.结果 (1)抗Hbe阳性者在单纯变异株感染的慢性乙型肝炎患者中所占的比例(84.61%)高于单纯野生株感染者(24.32%).(2)随着变异株感染率的增加,HBVDNA的含量增高.(3)随着变异株感染率增加,肝脏纤维化分期的逐渐加重.结论 前C区G1896A变异与乙肝病毒的复制程度相关.     

HBV病毒复制机制及慢性乙型肝炎药物靶点

乙型肝炎病毒(HBV)感染是一种严重影响公共卫生与人体健康的全球性流行性疾病,尽管乙肝防治已有很大提高,但仍缺乏高效的药物与手段。研究表明,肝损伤、肝衰竭程度与HBV及宿主免疫系统相互作用存在复杂关系。因而详细地探明HBV生命周期和感染过程,为研究HBV药物靶点和制定新的抗病毒策略提供前期坚实的基础,意义重大。该文详细介绍HBV病毒复制机制,并系统地阐述近年来新发现的和潜在的药物靶点,为制备新型的抗HBV药物提供参考。     

Evaluation of hepatitis B virus replication and proteomic analysis of HepG2.2.15 cell line after cyclosporine A treatment

Aim： The effect of cyclosporine A （CsA） on hepatitis B virus （HBV） replication was investigated, and proteomics expression differentiation after CsA treatment was studied in order to provide clues to explore the effect of CsA on HBV replication. Methods： Methyl thiazolyl tetrazolium （MTT） assay was used to evaluate the cytotoxicity of CsA. The HBV replication level in the HBV genomic DNA transfected HepG2.2.15 cell line was determined by an ELISA analysis of hepatitis B surface antigens （HBsAg） and Hepatitis B e antigens （HBeAg） in culture supernatant, while the intracellular HBV DNA replication level was analyzed by slot blot hybridization. Two-dimensional electrophoresis was used to investigate the alteration of protein expression in HepG2.2.15 after CsA treatment in vitro. The differentially-expressed proteins were identified by Matrix-assisted laser desorption/ionization-time of flight mass spectrometry combined with an online database search. Results： CsA was able to inhibit the expression of HBsAg, HBeAg, and HBV DNA replication in vitro in a dose-dependent manner. A proteomics analysis indicated that the expression of 17 proteins changed significantly in the CsA treatment group compared to the control group. Eleven of the 17 proteins were identified, including the overexpression of eukaryotic translation initiation factors （eIF） 3k, otubain 1, 14.3.3 protein, eIF2-1α, eIF5A, and the tyrosine 3/tryptophan 5-mono-oxygenase activation protein in CsA-treated HepG2.2.15 cells. The downregulation of the ferritin light subunit, erythrocyte cytosolic protein of 51 kDa （ECP-51）, stathmin 1/oncoprotein, adenine phosphoribosyl-transferase, and the position of a tumor protein, translationally- controlled 1, was shifted, suggesting it had undergone posttranslational modifications. Conclusion： Our study identified the inhibitory effect of CsA on HBV replication, and found that a group of proteins may be responsible for this inhibitory effect.     

Preclinical pharmacokinetics and metabolism of a potent non-nucleoside inhibitor of the hepatitis C virus NS5B polymerase

The disposition of compound A, a potent inhibitor of the hepatitis C virus (HCV) NS5B polymerase, was characterized in animals in support of its selection for further development. Compound A exhibited marked species differences in pharmacokinetics. Plasma clearance was 44?ml?min^?1?kg^?1 in rats, 9?ml?min^?1?kg^?1 in dogs and 16?ml?min^?1?kg^?1 in rhesus monkeys. Oral bioavailability was low in rats (10%) but significantly higher in dogs (52%) and monkeys (26%). Compound A was eliminated primarily by metabolism in rats, with biliary excretion accounting for 30% of its clearance. Metabolism was mainly mediated by cyclohexyl hydroxylation, with N-deethylation and acyl glucuronide formation constituting minor metabolic pathways. Qualitatively, the same metabolites were identified using in vitro systems from all species studied, including humans. The low oral bioavailability of compound A in rats was mostly due to poor intestinal absorption. This conclusion was borne out by the findings that hepatic extraction in the rat was only 30%, intraperitoneal bioavailability was good, and compound A was poorly absorbed from the rat isolated intestinal loop, with no detectable intestinal metabolism. Compound A was not an inhibitor of major human cytochrome P450 enzymes, indicating minimal potential for clinical drug–drug interactions. The metabolic clearance of compound A in rat, dog and monkey hepatocytes correlated with the systemic clearance observed in these species. Since compound A was very stable in human hepatocytes, the results suggest that it will be a low clearance drug in humans.     

拉米夫定和替比夫定阻断乙型病毒性肝炎病毒母婴传播的疗效分析

目的：评价拉米夫定（LAM）和替比夫定（LDT）阻断乙型病毒性肝炎病毒（ HBV）母婴传播的疗效及安全性。方法乙型病毒性肝炎病毒表面抗原（ HBsAg）和乙型病毒性肝炎病毒e抗原（ HBeAg）双阳性孕妇36例,按患者意愿分为LAM组16例及LDT组20例,同期未接受抗病毒治疗的HBsAg和HBeAg双阳性孕妇22例作为对照组。治疗组自孕28周至分娩后3月口服LAM 或LDT,观察各组在孕28周、分娩时和分娩后3个月血清HBV DNA水平及婴儿出生、8月龄血清HBsAg及HBV DNA的阳性率。结果 LAM及LDT组孕妇分娩及分娩后3个月HBV DNA显著低于对照组（ P＜0.05）;但LAM和LDT组HBV DNA下降差异无统计学意义（分娩时P＞0.05;产后3月：P＞0.05）。出生及8个月龄LAM、LDT组婴儿HBsAg和HBV DNA阳性率均显著低于对照组（均P＜0.05）。结论 HBsAg和HBeAg双阳性孕妇在妊娠晚期服用LAM或LDT均可有效阻断乙肝病毒母婴传播,2种药物疗效差异无统计学意义。     

非霍奇金淋巴瘤患者乙型肝炎病毒感染状况与预后的关系

目的:探讨非霍奇金淋巴瘤(NHL)患者乙型肝炎病毒(HBV)感染状况及预后的关系。方法:回顾性分析67例非霍奇金淋巴瘤患者HBV病毒表面抗原(HB sA g)的表达、肝功能变化及拉米夫定的作用,同时与67例非原发性肝癌实体瘤患者及67例普通人群做对比。结果:67例NHL患者HB sA g阳性率为23.9%,明显高于本地区普通人群(9.0%)及非原发性肝癌实体瘤患者(10.4%);HB sA g阳性的NHL组中,化疗后肝损害发生率(68.8%)与HB sA g阴性患者发生率(29.4%)之间差异有显著性(P<0.05);拉米夫定在预防病毒复活时起到重要作用。结论:NHL患者HB sA g阳性率高于本地非原发性肝癌实体瘤患者(其他肿瘤组)及普通人群组,拉米夫定可在一定程度上预防HBV的再激活;HBV感染者在化疗时应加强保肝并密切监测肝功能的变化。     

核苷(酸)类抗肝炎药物对慢性乙型肝炎住院患者肝肾功能的影响

目的：分析核苷（酸）类抗肝炎药物（NAs）对慢性乙型肝炎患者肝肾功能的影响,为临床合理用药提供参考。方法：综合应用某院临床药学管理系统（PASS PharmAssist）、病案质控监测系统和中国医院药物警戒系统检索病历,回顾性分析某院2017年1月至2018年6月因患慢性乙型肝炎而采用NAs药物治疗的患者病例。利用SPSS 23.0软件,采用正态分布、t检验、卡方检验进行单因素分析,把符合单因素分析（P<0.05）的协变量纳入二元logistic分析,以考察多种协变量对NAs药物诱导患者肝肾功能变化的影响。结果：收集到因患慢性乙型肝炎而服用抗肝炎药物的患者病例116份,其中包括男性79例（68.1%）,女性37例（31.9%）,肝功能正常者65例,慢性肝功能不全者51例。在肝功能不全组,NAs药物性肝损加重发生率为17.65%（9/51）,时间为用药后4~13 d;在肝功能正常组,NAs药物性肝损伤发生率为4.61%（3/65）,时间为用药后15~19 d。此外,研究表明NAs药物对肝脏的安全性为恩替卡韦 > 拉米夫定 > 阿德福韦酯 > 替比夫定 > NAs药物联用。在116例患者中肾功能正常者74例,慢性肾功能不全者42例,在肾功能不全组发现患者因服用NAs药物导致血清肌酐升高发生率为14.29%（6/42）,时间为用药后2~10 d,在肾功能正常组未发现NAs药物性肾损伤者。此外,研究表明NAs药物对肾脏的安全性为：NAs药物联用,拉米夫定,阿德福韦酯 > 恩替卡韦 > 替比夫定,相关因素分析表明NAs药物性肝损伤的发生与患者的肝功能不全（OR=5.344,95% CI：1.349-21.167）（P=0.017）有关。结论：NAs药物对患者肝功能和肾功能确实有影响,主要发生在肝功能不全患者身上,但对肝功能正常的患者影响较小。此外,核苷（酸）类抗肝炎药物中拉米夫定对肝脏和肾脏的安全性相对较高。研究结果提示临床在治疗肝功能不全的患者时,应注意调整NAs药物品种或给药剂量并监测患者肝功能指标变化,以确保用药安全。     

Agents in clinical development for the treatment of chronic hepatitis B

Chronic hepatitis B remains a public health problem of global importance despite the availability of an effective vaccine. Between 350 and 400 million people, approximately 6% of the world’s population, suffer from chronic hepatitis B and face a 30% likelihood of developing cirrhotic liver disease or hepatocellular carcinoma. Current treatment options include three monotherapies of subcutaneous interferon, oral nucleoside lamivudine and oral nucleotide adefovir dipivoxil. Unfortunately, these agents have not effectively and frequently been able to attain a ‘cure’ or complete eradication of the virus. Consequently, the expectation of current therapies is confined to the achievement of clinically beneficial and durable responses defined by lasting suppression of virus replication, histological improvement and increased survival for patients with decompensated liver diseases. Other disadvantages include the undesirable tolerability of interferon, the rapid resistance to lamivudine and the compromise between efficacy and toxicity that led to the development of the 10 mg dose of adefovir dipivoxil. Clearly, better therapeutics and treatment strategies are needed. Increased potency, activity against current treatment-refractory viruses, as well as efficacy in difficult-to-treat populations will be critical to meeting the therapeutic challenge of chronic hepatitis B.     

广东地区HBV基因型对拉米夫定应答的影响

目的研究广东地区乙型肝炎病毒慢性感染者不同基因型与其对拉米夫定治疗应答的关系。方法采用限制性片段长度多态性(RFLP)及序列测定法检测广东地区经拉米夫定(100mg/d,口服12月)治疗的87例慢性乙型肝炎患者的HBV基因型。结果87例患者中检测到HBV基因型B型44例(50.6%),C型43例(49.4%),未发现其他基因型。C型基因型在慢性乙型肝炎、重型肝炎及肝硬化的比例依次增高,C型与严重肝损害有关。拉米夫定治疗12m时有效应答B型31.8%(14/44)高于C型14%(6/43),有显著性差异,P<0.05。HBVDNA转阴者在B型36例(81.8%),C型27例(62.8%),B型与C型间有显著差异,P<0.05。B型和C型间HBeAg转换、ALT复常及YMDD变异率无显著差异,P>0.05。发生YMDD变异的患者HBVDNA含量B基因型(4.4±1.9 logcopies/ml)较C基因型(5.8±2.6 log copies/ml)水平低,有显著性差异,P<0.05。结论广东地区C基因型与严重肝损害有关。B型慢性乙型肝炎患者对拉米夫定应答率高于C型。B型和C型发生YMDD变异率无差异,但是变异后C型较易复发。     

Reactivation of hepatitis B virus with rituximab

Rituximab has become a useful drug for the treatment of non-Hodgkin’s lymphoma (NHL) and such autoimmune diseases as idiopathic thrombocytopenic purpura and rheumatoid arthritis. When combined with cytotoxic agents, rituximab showed synergistic effects for the treatment of NHL. In such treatment, hepatitis B virus (HBV) reactivation is a crucial complication when patients are treated with immunosuppressive or chemotherapeutic agents. Despite its treatment efficacy, several studies have pointed out unusual viral infections after its administration that resulted in fatal hepatitis due to HBV reactivation. In the cases at the authors’ institute, the authors analysed the kinetics of HBV antibodies, HBV-reactivation timing, and the prophylactic efficacy of lamivudine. The authors reviewed their cases and the previous literature to clarify the characteristics of HBV-reactivated patients who were administered rituximab.     

拉米夫定联合干扰素治疗乙型肝炎病毒感染疗效及对免疫功能的影响

目的 探讨拉米夫定（LAM）联合干扰素（IFN）治疗乙肝病毒（HBV）感染疗效及对免疫功能的影响.方法 将72例HBV感染者随机分为两组,A组35例行常规治疗,B组37例给予LAM＋IFN治疗,观察两组机体免疫功能改善情况.结果 B组HBeAg、HBV-DNA转阴率高于A组（P〈0.05）;7个月后B组HBV-DNA反跳率低于A组（P〈0.01）;治疗后B组CD4＋、CD8＋水平高于A组（P〈0.05）,CD4＋/CD8＋比值高于A组（P〈0.05）.结论 LAM＋IFN治疗HBV感染疗效显著,可提高患者机体免疫功能.