拉米夫定与恩替卡韦治疗HBeAg阴性的慢性B型病毒性肝炎

目的探讨恩替卡韦治疗HBeAg阴性慢性B型病毒性肝炎的效果和安全性。方法 652例HBeAg阴性慢性B型病毒性肝炎(CHB)患者分别给予恩替卡韦0.5mg或拉米夫定100mg,每日一次持续治疗52周。主要终点是组织学改善(Knodell坏死炎症记分降低≥2分,纤维化无恶化)。结果治疗结束后组织学改善恩替卡韦组211/300例(70.3%),拉米夫定组为150/252例(59.5%)(P=0.02);血清肝炎病毒B(HBV)DNA水平检测转阴患者恩替卡韦组90.0%,拉米夫定组71.5%(P<0.001);丙氨酸转氨酶正常患者分别为79%和70%(P=0.045)。血清HBV-DNA水平平均下降5.0、4.5log10/ml,P<0.001)。恩替卡韦组无耐药现象。两组安全性和不良事件相似。结论 HBeAg阴性CHB病人应用恩替卡韦能够改善组织学和病毒学反应,血清丙氨酸转氨酶水平正常化显著增加,恩替卡韦和拉米夫定治疗的完全性和不良事件相似。

两种聚乙二醇干扰素联合利巴韦林治疗1b及6a亚型慢性丙型肝炎的疗效

目的观察两种聚乙二醇干扰素(PEG-INF)联合利巴韦林治疗慢性丙型肝炎的临床疗效。方法回顾分析澳门仁伯爵综合医院171例慢性丙型肝炎患者的临床资料,其中基因1b型145例,基因6a型26例。140例患者采用聚乙二醇干扰素α-2b注射剂(PEG-IFN-2b)与利巴韦林联合治疗,31例采用聚乙二醇干扰素α-2a注射液(PEG-IFN-2a)与利巴韦林联合治疗,总疗程48周,分别于治疗12、24、48周及治疗结束后24周评价病毒学疗效。结果所有患者均完成治疗,总早期病毒应答率(EVR)为78.95%,持续病毒学应答率(SVR)为69.59%。两组患者在EVR(P=0.091)、治疗结束时病毒学应答率(ETVR)(P=0.542)、SVR(P=0.079)和复发率(P=0.497)方面差异均无统计学意义。两种基因型患者的EVR(P=0.268)、ETVR(P=0.276)、SVR(P=0.479)和复发率(P=1.000)间差异也均无统计学意义。结论两种PEG-INF联合利巴韦林治疗慢性丙型肝炎均有较高应答率且疗效相当,对两种HCV基因型患者的疗效也无明显差异。

社区医学之新挑战——物质滥用者艾滋病、B型肝炎及C型肝炎的高发病率

目的 至2004年全球有2亿物质滥用者及13．2万静脉毒瘾者，据估计台湾有6万静脉毒瘾者，占成人人口的0．4％。在过去两年台湾被HIV感染的人数急剧增加，年新增感染人数倍增，其中60．0％为静脉毒瘾者，以至于在社区中诊治被感染病患的几率大大增加；另外两种血液传染疾病——B型及C型肝炎，在台湾亦是相当常见。本研究主要研究这些经血液传染疾病在静脉毒瘾者中的发病率。方法收集2005年2～9月在桃园某疗养院戒毒的患者。所有人皆接受HIV、B型肝炎病毒（HBV）、C型肝炎病毒（HCV）及梅毒血清检查。所有人皆取得其签署之同意书。结果 总共收案801人，其中36．0％（289人）为一级毒品（海洛因，古柯碱）滥用者，其余64．0％（512人）为二级毒品（安非他命，快乐丸）滥用者；34．2％（274人）有HCV感染，16．8％（135人）有HBV感染，7．6％（61人）有HIV感染。在289位静脉毒瘾者中，71．6％（207人）有HCV感染，

直接作用抗病毒药物的抗丙型肝炎病毒作用及对患者血清血管内皮生长因子水平的影响

目的评估直接作用抗病毒药物(DAAs)治疗慢性基因1b型HCV感染患者的疗效和安全性,并分析其对患者血清VEGF水平的影响,评估DAAs治疗诱导肿瘤复发的风险因素。方法选取2012年12月至2016年1月至本院接受治疗的58例基因1b型慢性HCV患者,根据治疗方式的不同,将所有患者分为索菲布韦(SOF)+达卡他韦(DCV)组和SOF+雷迪帕韦(LDV)组。两组患者均接受DAAs无干扰素方案,药物为患者自购,疗程均为24周,随访24周。使用荧光定量PCR法检测定量HCV RNA,比较两组DAAs无干扰素方案的抗病毒作用,并统计两组患者治疗期间不良反应发生率。分别在治疗前、治疗后4周、结束治疗当天、持续病毒学应答(SVR)4和SVR12,采集研究组患者血清,使用Randox仪器精确分析治疗前后患者血清血管内皮生长因子(vascular endothelial growth factor,VEGF)水平变化。结果 SOF+DCV组SVR24率为96.7%,SOF+LDV组SVR24率96.4%,且无患者出现严重不良反应。治疗开始后4周时,两组患者血清VEGF水平较治疗前明显增加(P<0.05),且一直维持至治疗结束时;治疗结束后4周时降低至治疗前水平,而后较治疗前再次升高(P<0.05)。结论两组DAAs无干扰素方案治疗基因1b型慢性HCV感染均取得良好疗效,安全性较高。DAAs给药诱导患者血清VEGF水平显著增加,可能是DAAs治疗风险因素之一。

中国大陆1b型丙型肝炎病毒3’非编码区序列变异研究

丙型肝炎病毒(HCV)是一类有包膜的单股正链RNA病毒,其基因组全长约9 600bp,5'端和3'端各有一非编码区,3'非编码区(3'UTR)长约220～272 bp[1].

核苷用于HBV的治疗并无明显效果

据美国BIOCOMPARE科技新闻网（2006／6／20）报道，治疗慢性B型肝炎病毒（chronich epatitis Bvirus）使用复合式疗法，即Emtricitabine（一种病毒核苷反转录酶抑制物）加Clevudine（一种核苷相似物）合并治疗与Emtricitabine加安慰剂治疗的结果并没有显著差异。Gilead Sciences生化制药公司的Rousseau博士指出：这项试验可能证明核苷用于HBV的治疗并无明显的帮助。试验结果发表于5月的Antimicrobial Agents and Chemotherapy。

科学家发表宿主抵抗HBV感染机制的最近研究成果

乙型肝炎是中国人群中高发的一类传染型疾病,乙肝会导致肝功能障碍,肝硬化以及肝癌的发生。引起乙肝的是一种B型肝炎病毒（HBV）。最近,日本北海道大学遗传医学研究所的Akinori Takaoka课题组在《immunity》杂志发表了他们对于宿主抵抗HBV感染机制的最近研究成果。

Interplay between hepatitis B virus and the innate immune responses:implications for new therapeutic strategies

Hepatitis B virus(HBV) infection is still a worldwide health problem;however,the current antiviral therapies for chronic hepatitis B are limited in efficacy.The outcome of HBV infection is thought to be the result of complex interactions between the HBV and the host immune system.While the role of the adaptive immune responses in the resolution of HBV infection has been well characterized,the contribution of innate immune mechanisms remains elusive until recent evidence implicates that HBV appears to activate the innate immune response and this response is important for controlling HBV infection.Here,we review our current understanding of innate immune responses to HBV infection and the multifaceted evasion by the virus and discuss the potential strategies to combat chronic HBV infection via induction and restoration of host innate antiviral responses.

Epidemiology of Hepatitis B and Associated Liver Diseases in China

Hepatitis B virus (HBV) infection has long been a critical public health challenge in China. National surveys revealed a prevalence of approximate 10% for chronic HBV infection in general population. HBV has been the leading cause of chronic hepatitis, cirrhosis, and liver cancers in Chinese population and a common pathogen of acute viral hepatitis. Meanwhile, the epidemic provided important opportunities to research the natural history, public health impact, and therapeutic and preventive interventions for HBV in China. In this review, we summarized the selected key epidemiological studies since 1970s regarding HBV infection and its associated liver diseases in China, and provided considerations for future research, prevention and treatment of HBV.

A Case of Hepatitis B Reactivation due to the Hepatitis B Virus Escape Mutant in a Patient undergoing Chemotherapy

A 62-year-old man had chronic hepatitis B virus （HBV） infection and was diagnosed with liver cirrhosis. At the time of diagnosis the patient＇s virologic markers were positive for hepatitis B surface antigen （HBsAg）, antibody to hepatitis B e antigen （anti-HBe） and antibody to hepatitis B core antigen （anti-HBc）, while antibody to hepatitis B surface antigen （anti-HBs） and HBV DNA were negative. Later the patient received chemotherapy for malignancy. However, this was interrupted due to elevated liver enzymes. At the same time HBV DNA became positive. Lamivudine （LMV） therapy was administered immediately. However, the levels of serum aminotransferase and total bilirubin （TB） were still rising. Finally the patient died of fulminant hepatic failure. A sequence revealed HBV genotype C （HBsAg subtype adw） with immune escape mutations, F8L, $34L, F41S, G44V, F93C, V96G, Lll0I, C149Y and F161Y. The high morbidity and mortality of this complication is one of the major obstacles to completing the standard treatment for malignancy in HBV carriers. Therefore, the relative risk of antiviral prophylactic failure should be further assessed and the optimal strategy for antiviral prophylaxis in HBsAg-positive patients with oncologic and hematologic malignancies undergoing chemotherapy should be revised.

B-cell clonality in the liver of hepatitis C virus-infected patients

AIM:The association of hepatitis C virus(HCV) infection with typeⅡmixed cryoglobulinemia is well established,but the role of HCV in B-cell lymphoma remains controversial.In patients with HCV infection,B-cell clonal expansions have been detected in peripheral blood and bone marrow,and a high prevalence of B-cell non-Hodgkin's lymphomas has been documented.Liver biopsies in chronic HCV infection frequently show portal lymphoid infiltrates with features of B follicles,whose clonality has not yet been investigated.The object of this study was to determine the frequency of liver-infiltrating monoclonal B-cells in 40 patients with HCV infection.METHODS:Eight hundred and forty-eight patients were studied prospectively,including 40 HCV-positive patients and 808 patients with chronic hepatitis B virus(HBV)infection.Immunohistochemical study for B-and T-cell markers was performed on the paraffin-embedded liver tissue sections.The clonality of lymphoid B-cells was tested using a polymerase chain reaction(PCR)approach designed to identify immunoglobulin heavy chain gene(IgH) rearrangements.RESULTS:Liver-infiltrating monoclonal B-cells were detected in the liver for 4(10%)of 40 HCV-positive patients but were present in only 3(0.37%)of 808 liver biopsy specimens with chronic HBV infection.Chi-square testing showed that the monoclonal B-cells infiltration in the liver was more frequent in the HCV-infected patients(P=0.000).A clonal IgH rearrangement was detected in 5(71.4%)of 7 liver biopsy specimens with monoclonal B-cells infiltration.In 2 of 5 patients with both a clonal B-cell expansion and monoclonal B-cells infiltration in the liver,a definite B-cell malignancy was finally diagnosed.CONCLUSION:Liver-infiltrating monoclonal B-cells are detected in the liver of patients with chronic HCV and HBV infection.A high percentage of patients with monoclonal B-cells infiltration and B-cell clonality in the liver were finally diagnosed as having a definite B-cell malignancy.

Association between polymorphisms of the APOBEC3G gene and chronic hepatitis B viral infection and hepatitis B virusrelated hepatocellular carcinoma

AIM to determine the relationship between five A3 G gene single nucleotide polymorphisms and the incidence of hepatitis B virus(HBV) infection and hepatocellular carcinoma(HCC). METHODS this association study was designed as a retrospective study, including 657 patients with chronic HBV infection(CHB) and 299 healthy controls. All subjects were ethnic Han Chinese. Chronic HBV-infected patients recruited between 2012 and 2015 at the First Hospital of Jilin University(Changchun) were further classified into HBV-related HCC patients(n = 287) and non-HCC patients(n = 370). Frequency matching by age and sex was performed for each group. Human genomic DNAwas extracted from whole blood. Gene polymorphisms were identified using a mass spectroscopic method.RESULTS there were no significant differences between the genotype and allele frequencies of the rs7291971, rs5757465 and rs5757463 A3 G gene polymorphisms, and risk of CHB and HBV-related HCC. the AG genotype and G allele for rs8177832 were significantly related to a decreased risk of CHB(OR = 0.67, 95%CI: 0.47-0.96; OR = 0.69, 95%CI: 0.50-0.95, respectively) and HCC(OR = 0.53, 95%CI: 0.34-0.84; OR = 0.58, 95%CI: 0.39-0.87, respectively). A significant relationship was found between rs2011861 computed tomography, tt genotypes and increased risk of HCC(OR = 1.69, 95%CI: 1.02-2.80; OR = 1.82, 95%CI: 1.08-3.06, respectively). Haplotype analyses showed three protective and four risk haplotypes for HCC. Also, one protective haplotype was found against CHB.CONCLUSION this study indicates that the A3 G rs8177832 polymorphism is associated with a decreased risk of CHB infection and HCC, while the rs2011861 polymorphism is associated with an increased risk of HCC.

Survival and prognostic factors in hepatitis B virus-related acute-on-chronic liver failure

AIM:To investigate the survival rates and prognostic factors in patients with hepatitis B virus-related acuteon-chronic liver failure(HBV-ACLF).METHODS:Clinical data in hospitalized patients with HBV-ACLF admitted from 2006 to 2009 were retrospectively analyzed.Their general conditions and survival were analyzed by survival analysis and Cox regression analysis.RESULTS:A total of 190 patients were included in this study.The overall 1-year survival rate was 57.6%.Patients not treated with antiviral drugs had a significantly higher mortality[relative risk(RR)=0.609,P=0.014].The highest risk of death in patients with ACLF was associated with hepatorenal syndrome(HRS)(RR=2.084,P=0.026),while other significant factors were electrolyte disturbances(RR=2.062,P=0.010),and hepatic encephalopathy(HE)(RR=1.879,P<0.001).CONCLUSION:Antiviral therapy has a strong effect on the prognosis of the patients with HBV-ACLF by improving their 1-year survival rate.HRS,electrolyte disturbances,and HE also affect patient survival.

Biological impacts of "hot-spot" mutations of hepatitis B virus X proteins are genotype B and C differentiated

AIM: To investigate the biological impacts of 'hot-spot'mutations on genotype B and C HBV X proteins (HBx).METHODS: Five types of'hot-spot' mutations of genotype B or C HBV X genes, which sequentially lead to the amino acid substitutions of HBx as I127T, F132Y, K130M+V131I,I127T+K130M+V131I, or K130M+V131I+F132Y, respectively,were generated by means of site-directed mutagenesis.To evaluate the anti-proliferative effects, HBx or related mutants' expression vectors were transfected separately to the Chang cells by lipofectamine, and the cells were cultured in hygromycin selective medium for 14 d, drug-resistant colonies were fixed with cold methanol, stained with Giemsa dyes and scored (increase of the colonies indicated the reduction of the anti-proliferation activity,and vice versa). Different types of HBx expression vectors were co-transfected separately with the reporter plasmid pCMVβ to Chang cells, which were lysed 48 h post-transfection and the intra-cellular β-galactosidase activities were monitored (increase of the β-galactosidase activities indicated the reduction of the transactivation activity, and vice versa). All data obtained were calculated by paired-samples t-test.RESULTS: As compared to standard genotype B HBx,mutants of I127T and I127T+K130M+V131I showed higher transactivation and anti-proliferative activities, while the mutants of F132Y, K130M+V131I, and K130M+V131I+F132Y showed lower activities. As compared to standard genotype C HBx, I127T mutant showed higher transactivation activity, while the other four types of mutants showed no differences. With regard to anti-proliferative activity,compared to standard genotype C HBx, F132Y and K130M+V131I mutants showed lower activities, and K130M+V131I +F132Y mutant, on the other hand, showed higher activity,while the mutants of I127T and I127T+K130M+V131I showed no differences.CONCLUSION: 'Hot-spot' mutations affect the antiproliferation and transactivation activities of genotype B and/or C HBx, and the biological impacts of most 'hot-spot' mutations on HBx are genotype B and C differentiated.

Clonal evolution of hepatitis B virus polymerase gene mutations during lamivudine-adefovir combination treatment

AIM:To identify hepatitis B virus polymerase gene mutations during antiviral therapy using lamivudineadefovir sequential monotherapy followed by lamivudine-adefovir combination therapy.METHODS:The patient cohort included four adult chronic hepatitis B patients who had undergone sequential monotherapy,first with lamivudine(LMV) and then,after developing viral breakthrough,with adefovir(ADV) therapy.All of the patients had non-response or viral breakthrough after LMV-ADV sequential monotherapy,which resulted in the switching of their antiviral regimen to LMV-ADV combination therapy.Eleven serum samples from the four patients who showed non-response to rescue LMV-ADV combination therapy were collected sequentially at a time before the antiviral treatment and then during the LMV monotherapy,ADV monotherapy,and LMV-ADV combination therapy.For the genotypic analysis,the whole 1310-bp polymerase gene region was amplified,cloned and sequenced.RESULTS:All patients had been previously treated with 100 mg of LMV once daily for a 15-to 26-mo period.The emergence of resistance mutations to LMV,such as rtM204V/I and/or rtL180M,were found in all patients.Their antiviral regimens were switched to ADV monotherapy as the second line treatment.All patients had viral breakthrough or non-response after the LMV-ADV sequential monotherapy.ADV-resistant mutations were detected after 13 to 19 mo of LMV-ADV sequential monotherapy.The rtA181V/T mutations were predominantly identified during the ADV treatment in the LMV-resistant patients.Twenty-seven of 38 clones were combined with an amino acid change at rt181;three clones had mutations in rt236 and one clone had a combined mutation.The rtA181V/T mutations were not suppressed by the LMV-ADV combination therapy.Thirty-nine of 64 clones showed an rtA181V/T mutation and six clones showed combined mutations in rt181 and rt236.Mutations in rt204 re-emerged during the combination treatment.The rt181 and rt204 mutations did not co-exist in one clone.CONCLUSION:Add-on lamivudine therapy with adefovir for adefovir resistance may not suppress the pre-existing adefovir-resistant mutation that develops during lamivudine-adefovir sequential monotherapy.

慢性乙型肝炎的抗病毒药物及靶点的研究进展

慢性乙型病毒性肝炎及其相关并发症给人类的健康造成了严重的危害,已经成为世界性的公共问题。由于还没有药物能够彻底消除共价闭合环状DNA(ccc DNA),所以现在还没有根治慢性乙型肝炎的办法。但是近些年随着病毒分子生物学研究的进展和临床抗病毒药物的经验积累,使得人们在寻求新靶点和新药物以实现治愈愿望的道路上又迈进了坚实的一步。本文从病毒的生命周期、临床药物使用经验和靶点药物研究这三个方面做了汇总和简介。

Clinical significance of connective tissue growth factor in hepatitis B virus-induced hepatic fibrosis

AIM:To determine the utility of connective tissue growth factor(CCN2/CTGF) for assessing hepatic fibrosis in hepatitis B virus(HBV)-induced chronic liver diseases(CLD-B).METHODS:Enzyme-linked immunosorbent assay was used to measure CCN2 in sera from 107 patients with chronic hepatitis B(CHB) and 39 patients with HBVinduced active liver cirrhosis and 30 healthy individuals.Liver samples from 31 patients with CHB,8 patients with HBV-induced liver cirrhosis and 8 HBV carriers with normal liver histology were examined for transforming growth factor β-1(TGF-β1) or CCN2 mRNA levels by in situ hybridization,and computer image analysis was performed to measure integrated optimal density(IOD) of CCN2 mRNA-positive cells in liver tissues.Histological inflammation grading and fibrosis staging were evaluated by H and E staining and Van Gieson's method.RESULTS:Serum CCN2 concentrations were,respectively,4.0-or 4.9-fold higher in patients with CHB or active liver cirrhosis as compared to healthy individuals(P < 0.01).There was good consistency between the levels of CCN2 in sera and CCN2 mRNA expression in liver tissues(r = 0.87,P < 0.01).The levels of CCN2 in sera were increased with the enhancement of histological fibrosis staging in patients with CLD-B(r = 0.85,P < 0.01).Serum CCN2 was a reliable marker for the assessment of liver fibrosis,with areas under the receiver operating characteristic(ROC) curves(AUC) of 0.94 or 0.85 for,respectively,distinguishing normal liver controls from patients with F1 stage liver fibrosis or discriminating between mild and significant fibrosis.CONCLUSION:Detection of serum CCN2 in patients with CLD-B may have clinical significance for assessment of severity of hepatic fibrosis.

Retrospective analysis of hepatitis B virus reactivation after rituximab combination chemotherapy in patients with B-cell lymphoma

Objective： The aim of the study was to investigate the reactivations of hepatitis B virus （HBV） after rituximab- containing chemotherapy in patients with B-cell lymphoma with surface antigen of hepatitis B virus （HBsAg）-positive, or hepatitis B core antibody （HBcAb）-positive. Methods： A retrospective study of HBV-related markers was performed before and after dtuximab-containing treatment in 189 consecutive patients with CD20-positive B-cell lymphoma. Results： Among the 189 non-Hodgkin＇s lymphoma （NHL） patients who received rituximab combination chemotherapy, 31 （16.6%） were HBsAg positive and 82 （43.9%） HBsAg negative/HBcAb positive, and 76 were HBsAg and HBcAb negative. Of the 31 HBsAg positive patients, 3 （9.7%） experienced reactivation of HBV. The prevalence of HBV reactivation was 4.0% （1/25） in patients who received prophylactic antiviral treatment and 33.3% （2/6） in those who did not receive prophylactic antiviral treatment （P = 0.032）. Prophylactic antiviral treatment decreased the rate of HBV reactivation. Among the 82 HBsAg negative/HBcAb positive patients, 1 （1.2%） experienced HBV reactivation leading to serious hepatitis. Conclusion： Our experience indicates that rituximab-based therapy may cause serious HBV-related complications and even death in HBsAg-positive patients. Preemp- tive use of antiviral treatment enabled successful management of HBV reactivation. In HBsAg-negative and HBcAb-positive lymphoma patients the prevalence of HBV reactivation is low （1.2%）. Close monitoring HBV until at least 6 months after anticancer therapy is required, prophylactic antiviral therapy needs to be evaluated further.