BACKGROUND & AIMS: BACKGROUND:Recent data about hepatitis A virus (HAV) seroprevalence in industrialized countries and the impact of travels to endemic areas are sparse or absent, particularly for children. OBJECTIVE:To determine the impact of travel to endemic areas on HAV seroprevalence and estimate the overall HAV seroprevalence in children in France. To identify risk factors for positive HAV serologic results. STUDY DESIGN:This prospective multicentre cross-sectional seroprevalence study took place in eight paediatric emergency units throughout France. Children 1-16 years of age following all inclusion and exclusion criteria were included. Demographic, socioeconomic, and travel data were prospectively collected with a standardized questionnaire before measurement of specific HAV antibodies. HAV seroprevalence was determined and its association with diverse variables assessed by univariate and multivariate analyses. RESULTS:430 children were included, of whom 116 had travelled to endemic areas. The HAV seroprevalence in the overall population was 5% (95%CI, 3-7) and was higher among the travellers (12% [95%CI, 6-18]) than among the others (2% [95%CI, 0-3]), OR=7.0 [95%CI, 2.6-18.8]. Risk factors identified for positive serologic results for HAV were travel to an endemic area >7 days (adjusted OR [aOR]=4.3 [95%CI, 1.5-12]), age of 14-16 years (aOR=7.7 [95%CI, 1.6-38.3]) and mother's birth in an endemic area (aOR=5.2 [95%CI, 1.8-14.8]). CONCLUSION:Statistical evidence showed that travel to endemic areas and parents' place of birth both play a role in HAV serologic results in children with a significant difference of HAV seroprevalence between traveller and non-traveller children in France.

背景与目标： 背景：关于工业化国家中甲型肝炎病毒（HAV）血清流行率的最新数据以及前往流行地区的影响稀少或缺乏，特别是对儿童而言。
目的：确定前往流行地区的旅行对HAV血清阳性率的影响，并估算法国儿童的总体HAV血清阳性率。确定阳性HAV血清学结果的危险因素。
研究设计：这项前瞻性多中心横断面血清阳性率研究是在法国的八个儿科急诊室进行的。遵循所有纳入和排除标准的1-16岁儿童被纳入。在测量特定的HAV抗体之前，将使用标准化的调查表前瞻性地收集人口，社会经济和旅行数据。确定了HAV血清阳性率，并通过单因素和多因素分析评估了其与各种变量的相关性。
结果：包括430名儿童，其中116名曾前往流行地区。总人口中的HAV血清阳性率为5％（95％CI，3-7），旅行者中的HAV血清阳性率（12％[95％CI，6-18]）高于其他人群（2％[95％CI， 0-3]），或= 7.0 [95％CI，2.6-18.8]。确诊为HAV阳性血清学结果的危险因素是前往> 7天的流行区（校正OR [aOR] = 4.3 [95％CI，1.5-12]），年龄14-16岁（aOR = 7.7 [95％] CI，1.6-38.3]）和母亲在地方病地区的出生（aOR = 5.2 [95％CI，1.8-14.8]）。
结论：统计证据表明，在法国，旅行者和非旅行者儿童的HAV血清阳性率存在显着差异，前往流行地区和父母的出生地均对HAV血清学结果有影响。

BACKGROUND & AIMS: BACKGROUND & AIMS:Some patients with chronic hepatitis B virus (HBV) infection progress to hepatocellular carcinoma (HCC). However, the long-term effect of nucleos(t)ide analogue (NA) therapy on progression to HCC is unclear. METHODS:Therefore, we compared chronic hepatitis B patients who received NA therapy to those who did not, using a propensity analysis. RESULTS:Of 785 consecutive HBV carriers between 1998 and 2008, 117 patients who received NA therapy and 117 patients who did not, were selected by eligibility criteria and propensity score matching. Factors associated with the development of HCC were analyzed. In the follow-up period, HCC developed in 57 of 234 patients (24.4%). Factors significantly associated with the incidence of HCC, as determined by Cox proportional hazards models, include higher age (hazard ratio, 4.36 [95% confidence interval, 1.33-14.29], p=0.015), NA treatment (0.28 [0.13-0.62], p=0.002), basal core promoter (BCP) mutations (12.74 [1.74-93.11], p=0.012), high HBV core-related antigen (HBcrAg) (2.77 [1.07-7.17], p=0.036), and high gamma glutamyl transpeptidase levels (2.76 [1.49-5.12], p=0.001). CONCLUSIONS:NA therapy reduced the risk of HCC compared with untreated controls. Higher serum levels of HBcrAg and BCP mutations are associated with progression to HCC, independent of NA therapy.

背景与目标： 背景与目的：某些慢性乙型肝炎病毒（HBV）感染患者会发展为肝细胞癌（HCC）。然而，尚不清楚核苷酸（t）ide类似物（NA）治疗对肝癌进展的长期影响。
方法：因此，我们使用倾向分析将接受NA治疗的慢性乙型肝炎患者与未接受NA治疗的慢性乙型肝炎患者进行比较。
结果：在1998年至2008年之间的785例连续HBV携带者中，通过资格标准和倾向评分匹配选择了接受NA治疗的117例患者和未接受NA治疗的117例患者。分析了与肝癌发展相关的因素。在随访期间，234例患者中有57例发生了HCC（24.4％）。由Cox比例风险模型确定的与HCC发生率显着相关的因素包括较高的年龄（风险比，4.36 [95％置信区间，1.33-14.29]，p = 0.015），NA治疗（0.28 [0.13-0.62]） ，p = 0.002），基础核心启动子（BCP）突变（12.74 [1.74-93.11]，p = 0.012），高HBV核心相关抗原（HBcrAg）（2.77 [1.07-7.17]，p = 0.036）和高γ-谷氨酰转肽酶水平（2.76 [1.49-5.12]，p = 0.001）。
结论：与未治疗的对照组相比，NA治疗降低了HCC的风险。血清HBcrAg和BCP突变水平升高与肝癌进展有关，而与NA治疗无关。

BACKGROUND & AIMS: :Hepatitis C virus (HCV) infection is a serious health problem leading to cirrhosis, liver failure and hepatocellular carcinoma. The recent introduction of telaprevir, which was approved in November 2011, in combination with peg-interferon and ribavirin is expected to markedly improve the eradication rate of the virus. However, side effects of triple therapy may be severe. In a phase three III clinical trial, 2250 mg of telaprevir, which is the same dosage used in clinical trials in Western countries, was given to Japanese patients. As this dosage is considered to be relatively high for Japanese patients, who typically have lower weight than patients in Western countries, reduction of telaprevir is recommended in the 2012 revision of the guidelines established by the Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis published by the Ministry of Health, Labour and Welfare of Japan. Other protease inhibitors with fewer side effects are now in clinical trials in Japan. Alternatively, treatment of patients with combination of direct acting antivirals without interferon has been reported. In this review we summarize current treatment options in Japan and discuss how we treat patients with chronic HCV infection.

背景与目标： 丙型肝炎病毒（HCV）感染是导致肝硬化，肝衰竭和肝细胞癌的严重健康问题。近期在2011年11月批准了telaprevir的引入，与聚乙二醇干扰素和利巴韦林联用，有望显着提高该病毒的根除率。但是，三联疗法的副作用可能很严重。在一项三期III期临床试验中，向日本患者提供了2250毫克的telaprevir，与西方国家的临床试验中使用的剂量相同。由于对于日本患者来说此剂量相对较高，通常体重要比西方国家的患者低，因此在2012年修订由病毒性肝炎标准化治疗研究组制定的指南中，建议减少telaprevir的使用，其中包括日本厚生劳动省出版的《肝硬化》。目前，其他副作用较小的蛋白酶抑制剂正在日本进行临床试验。或者，已经报道了将直接作用的抗病毒药物与无干扰素联合治疗的患者。在这篇综述中，我们总结了日本目前的治疗方案，并讨论了我们如何治疗慢性HCV感染患者。

BACKGROUND & AIMS: :Hepatitis B is one of the most common infectious diseases in the world, and 350 million people have been estimated to be chronic hepatitis B virus carriers world-wide. Hepatitis B virus (HBV) has been classified into 8 genotypes (A-H) based on an intergroup divergence of 8% or more in the complete nucleotide sequence. Different genotypes of the hepatitis B virus may influence the clinical outcome of the disease. HBV genotyping method using restriction fragment length polymorphism (RFLP) can reliably identify genotypes. HBV genotyping with S gene sequence is consistent with genetic analysis using the full genomic sequences. The aim of this study was to determine the genotypes of HBV by using restriction fragment length polymorphism (RFLP) method in the region of Elazig. A total of 127 HBV-DNA positive patients (74 male, 53 female) were included in the study. Semi-nested polymerase chain reaction (PCR) was performed to amplify the specific parts of HBV S gene. In the first step, 685 base paired (bp) region was amplified by sense primer HBMF1 and anti-sense primer HBMR2, while in the second step 485 bp region was amplified by using inner-sense primer HBMF2 and anti-sense primer HBMR2. PCR products were then digested by the restriction enzymes, Alwl, Earl, Hphl, Ncil and NlalV. The RFLP assay indicated that genotype D was the only detected type in our samples. In conclusion, genotype D is the predominant type among hepatitis B patients in our region. RFLP is considered to be an easy and useful method for genotyping HBV strains.

背景与目标： ：乙型肝炎是世界上最常见的传染病之一，据估计全世界有3.5亿人是慢性乙型肝炎病毒携带者。乙型肝炎病毒（HBV）已根据完整核苷酸序列中8％或更高的组间差异分为8个基因型（A-H）。乙型肝炎病毒的不同基因型可能会影响该疾病的临床结果。使用限制性片段长度多态性（RFLP）的HBV基因分型方法可以可靠地鉴定基因型。具有S基因序列的HBV基因分型与使用完整基因组序列进行的遗传分析一致。这项研究的目的是通过使用限制性片段长度多态性（RFLP）方法在Elazig地区确定HBV的基因型。研究共纳入127例HBV-DNA阳性患者（男74例，女53例）。进行了半巢式聚合酶链反应（PCR），以扩增HBV S基因的特定部分。第一步，通过有义引物HBMF1和反义引物HBMR2扩增685个碱基对（bp）区域，而在第二步中，通过使用内感引物HBMF2和反义引物HBMR2扩增485 bp对区域。然后用限制酶Alwl，Ear1，Hph1，Ncil和NalV消化消化PCR产物。 RFLP分析表明，基因型D是我们样本中唯一检测到的类型。总之，在我们地区的乙型肝炎患者中，基因型D是主要类型。 RFLP被认为是对HBV毒株进行基因分型的简便方法。

BACKGROUND & AIMS: :Polychromatic flow-cytometric assays were used to analyze paired intrahepatic and peripheral lymphocyte samples from 37 patients with chronic hepatitis C. Compared with peripheral cells, intrahepatic T cells were selectively enriched with CD45RO+ memory T cells but had a lower percentage of CD4+ T cells expressing the differentiation markers CD27 and CD28. The percentage of intrahepatic CD45RO+ and CD28+ T cells correlated with the degree of liver inflammation, which suggests that memory T cells at relatively early stages of differentiation are directly involved in liver inflammation. Despite their memory phenotype, intrahepatic T cells were defective in proliferation capability, produced less interferon- gamma in response to stimulation by T cell receptor, and contained less perforin but expressed higher levels of Fas and Fas ligand, compared with their counterparts in peripheral blood. The distinct characteristics of intrahepatic T cells suggest that they play an important role in the immunopathogenesis of chronic hepatitis C.

背景与目标： ：采用多色流式细胞术分析了37例慢性丙型肝炎患者的肝内和外周血淋巴细胞配对样本。与外周血细胞相比，肝内T细胞选择性富集了CD45RO记忆T细胞，但表达CD4 T细胞的百分比较低分化标记CD27和CD28。肝内CD45RO和CD28 T细胞的百分比与肝脏炎症程度相关，这表明处于分化早期的记忆T细胞直接参与肝脏炎症。尽管具有记忆表型，但与外周血中的肝细胞相比，肝内T细胞在T细胞受体的刺激下应答能力较弱，产生的干扰素γ较少，穿孔素含量较低，但表达的Fas和Fas配体水平较高。肝内T细胞的独特特征表明它们在慢性丙型肝炎的免疫发病机制中起着重要作用。

BACKGROUND & AIMS: :The hepatitis C virus (HCV) infects 3% of the world's population, or approximately 170 million people. Most of those acutely infected progress to chronic infection and are unresponsive to existing antiviral treatment. Over a 20-year period, chronic HCV infection leads to cirrhosis and the sequelae of end-stage liver disease, including hepatic encephalopathy, ascites, variceal haemorrhage and hepatocellular carcinoma. Orthotopic liver transplantation (OLT) is the optimal treatment for decompensated HCV cirrhosis, but is limited by organ availability and universal graft reinfection. This review discusses the results with OLT for HCV from the Dumont-UCLA Liver Transplant Center and discusses future directions in the management of HCV.

背景与目标： ：丙型肝炎病毒（HCV）感染了全球3％的人口，约有1.7亿人。大多数急性感染者会发展为慢性感染，并且对现有的抗病毒治疗无反应。在20年的时间里，慢性HCV感染会导致肝硬化和终末期肝病的后遗症，包括肝性脑病，腹水，静脉曲张出血和肝细胞癌。原位肝移植（OLT）是失代偿性HCV肝硬化的最佳治疗方法，但受到器官可用性和通用移植物再感染的限制。这篇综述讨论了Dumont-UCLA肝移植中心使用OLT进行HCV的结果，并讨论了HCV管理的未来方向。

BACKGROUND & AIMS: :Hepatitis C virus (HCV) infection is a global health problem, common worldwide, leading to acute and chronic hepatitis and its consequences of hepatocirrhosis and hepatocellular carcinoma. Patients on hemodialysis belong to the high-risk group of HCV infection. The prevalence of HCV infection in dialysis patients ranges from 4% to more than 70% in some countries. The main reasons for such a high incidence of infections are a high prevalence of HCV infection in the general population, lack of standard infection precautions and effective vaccination, inadequate disinfection procedures of dialysis machines and other medical equipment, as well as spread of infection from patient to patient, especially in dialytic centers with a high percentage of infected patients. The diagnostic procedures useful in the evaluation of HCV infection are detection of anti-HCV antibodies, identification of HCV RNA, counts of virus copies, and identification of its genome. From the 6 major genotypes and multiple subtypes of the HCV, genotypes 1a and 1b are the most common in Europe and Japan, and 1b is responsible for more severe liver disease and aggressive course leading to liver fibrosis. Antiviral therapy of HCV+ dialysis patients with interferon-alpha (INF-alpha) gives slightly better results than in the general population, but is poorly tolerated and associated with side effects. Although ribavirin in not recommended for dialysis patients, the addition of small doses of this compound to pegylated INF is discussed, especially for patients in whom previous infection treatment failed.

背景与目标： 丙型肝炎病毒（HCV）感染是全球性的健康问题，在全球范围内普遍存在，导致急性和慢性肝炎及其对肝硬化和肝细胞癌的后果。接受血液透析的患者属于HCV感染的高危人群。在某些国家，透析患者的HCV感染率从4％到70％以上不等。如此高的感染率的主要原因是普通人群中HCV感染率高，缺乏标准的感染预防措施和有效的疫苗接种，透析机和其他医疗设备的消毒程序不足以及患者感染的传播对患者，尤其是在感染中心患者感染率很高的透析中心。评估HCV感染有用的诊断程序是抗HCV抗体的检测，HCV RNA的鉴定，病毒拷贝数以及其基因组的鉴定。在HCV的6种主要基因型和多种亚型中，基因型1a和1b在欧洲和日本最为常见，而基因1b导致更严重的肝病和导致肝纤维化的侵袭性病程。与一般人群相比，干扰素-α（INF-alpha）的HCV透析患者的抗病毒治疗效果稍好，但耐受性差且具有副作用。尽管不建议将利巴韦林用于透析患者，但仍讨论了在聚乙二醇化INF中添加小剂量这种化合物，特别是对于先前感染治疗失败的患者。

BACKGROUND & AIMS: AIM:Biomarkers predicting sustained virological response (SVR) to pegylated interferon-α plus ribavirin (PEG IFN-α/RBV) were investigated. METHODS:Peptides in pretreatment sera from 107 patients with hepatitis C virus (HCV) genotype 1 were comprehensively analyzed by mass spectrometry. Ion intensity of the peptides was used to generate discriminant models between the responders who achieved SVR (R) and the non-responders (NR) to PEG IFN-α/RBV. RESULTS:In total, 107 peptides were detected in a training set (n = 23). A discriminant model using a peptide, complement 3f des-arginine (C3f-dR), showed sensitivity of 35% and specificity of 94% for SVR prediction in a testing set (n = 68). In all the R and NR (n = 96), an area under the receiver-operator curve (AUROC) of 0.64 in the C3f-dR model was increased to 0.78 by addition of platelet (PLT) counts (C3f-dR/PLT model). Another model using the 107 peptides (AUROC, 0.77) also showed higher AUROC (0.79) by addition of hemoglobin (Hb), body mass index (BMI) and age (107P/Hb/BMI/Age model). The sensitivity and specificity of the C3f-dR/PLT model were 59% and 88%, and those of the 107P/Hb/BMI/Age model were 70% and 92%, respectively. The C3f-dR/PLT model showed high AUROC (0.82), similar to that of interleukin-28B rs8099917 genotype analysis (0.86) in the 45 tested patients. Prediction by the combination of the C3f-dR/PLT model, the 107P/Hb/BMI/Age model and the rs8099917 genotype analysis was accurate in 44 out of the 45 patients (AUROC, 0.95). CONCLUSION:Serum peptides, especially C3f-dR, would be useful predictors for SVR to PEG IFN-α/RBV. The complements may be involved in the HCV elimination.

背景与目标： 目的：研究了预测对聚乙二醇化干扰素-α和利巴韦林（PEGIFN-α/ RBV）持续病毒学应答（SVR）的生物标志物。
方法：采用质谱法对107例丙型肝炎病毒（HCV）基因1型患者血清中的多肽进行了综合分析。肽的离子强度用于在获得SVR（R）的应答者和对PEGIFN-α/ RBV的非应答者（NR）之间生成判别模型。
结果：在一个训练集中总共检测到107个肽（n = 23）。使用肽补体3f des-精氨酸（C3f-dR）的判别模型在测试集中对SVR的预测显示35％的敏感性和94％的特异性（n = 68）。在所有R和NR（n = 96）中，通过添加血小板（PLT）计数（C3f-dR / PLT模型），C3f-dR模型中的接收者-操作者曲线（AUROC）下的面积为0.64 ）。另一种使用107种肽的模型（AUROC，0.77）通过添加血红蛋白（Hb），体重指数（BMI）和年龄（107P / Hb / BMI / Age模型）也显示出较高的AUROC（0.79）。 C3f-dR / PLT模型的敏感性和特异性分别为59％和88％，而107P / Hb / BMI / Age模型的敏感性和特异性分别为70％和92％。 C3f-dR / PLT模型在45位接受测试的患者中显示出较高的AUROC（0.82），与白细胞介素28B rs8099917基因型分析（0.86）相似。通过对C3f-dR / PLT模型，107P / Hb / BMI / Age模型和rs8099917基因型分析的组合进行的预测在45例患者中有44例是准确的（AUROC，0.95）。
结论：血清肽，特别是C3f-dR，将成为SVR转化为PEGIFN-α/ RBV的有用预测因子。补体可能参与HCV的消除。

BACKGROUND & AIMS: :Chronic hepatitis C virus (HCV) infection causes substantial morbidity and mortality in the United States. Testing and treatment of asymptomatic persons might avert progression to more advanced disease. In 1998, CDC published guidelines for HCV testing based on risk factors for infection; however, recent studies indicate that at least one half of all persons living with HCV infection in the United States are unaware of their infection status. To increase testing rates, in 2012 CDC recommended one-time testing of all persons born during 1945-1965. To better understand where and why persons with chronic HCV infection sought their initial testing, 2006-2010 data were analyzed from a survey conducted as part of the ongoing Chronic Hepatitis Cohort Study. Of 4,689 patients with HCV infection who responded to the survey, 60.4% reported that their initial HCV test occurred in a physician's office. CDC's risk-based indications (e.g., injection drug use and hemodialysis) were cited by 1,045 (22.3%) of the patients as reasons for testing, whereas clinical indications (e.g., abnormal liver function tests or liver-related symptoms such as jaundice) were cited by 2,121 (45.2%), suggesting that many HCV infections were identified only after the patient had become symptomatic. Promoting U. S. Preventive Services Task Force and CDC recommendations for testing and identifying strategies that help physicians implement HCV testing in their offices might help facilitate timely identification of HCV infection and reduce morbidity and mortality.

背景与目标： ：慢性丙型肝炎病毒（HCV）感染在美国引起大量发病和死亡。无症状者的测试和治疗可能会避免病情恶化。 1998年，疾病预防控制中心发布了基于感染危险因素的HCV检测指南；但是，最近的研究表明，在美国，所有感染HCV的人中至少有一半不知道其感染状况。为了提高检测率，CDC于2012年建议对1945-1965年间出生的所有人进行一次性检测。为了更好地了解慢性HCV感染者在何处以及为什么要进行初次检查，我们从一项正在进行的慢性肝炎队列研究中进行的调查中分析了2006-2010年的数据。在接受调查的4689例HCV感染患者中，有60.4％的人报告说他们最初的HCV测试发生在医生的办公室。 1,045（22.3％）的患者将CDC基于风险的指征（例如，注射药物的使用和血液透析）作为测试的原因，而临床指征（例如，异常的肝功能测试或与肝有关的症状，例如黄疸）被引用为CDC。被2,121（45.2％）引用，表明只有在患者出现症状后才发现许多HCV感染。促进美国预防服务工作队和CDC关于检测和确定有助于医师在其办公室进行HCV检测的策略的建议，可能有助于促进及时识别HCV感染并降低发病率和死亡率。

BACKGROUND & AIMS: BACKGROUND AND AIMS:Infection with the hepatitis C virus (HVC) is one of the most common viral infections worldwide. Approximately 170 million individuals are infected worldwide. HCV is an important cause of morbidity and mortality. In Mexico, according to the National Health Survey 2000, it is estimated that 70,000 cases exist. We undertook this study to estimate the prevalence of anti-HCV antibodies in patients with association to the risk factors for HCV infection in the lowland (bajio) region. METHODS:There were 2803 individuals 15 years of age or older who were treated at the General Hospital Zone #4 who were included in this study. Following informed consent, the participants were given a questionnaire listing the major risk factors for hepatitis C. If they answered positive to any of these identified factors, a blood sample was taken to determine anti-HCV antibodies via ELISA analysis. RESULTS:Average age in this study was 38.4 ± 13.5 years, and 75.5% were female (n = 2116). Anti-HCV antibodies were isolated in 1.3% of the patients (n = 36). The most commonly identified risk factor among all the participants was a history of previous transfusions (28.8 % of all patients, n = 813 and 41.7%, n = 15 of those with positive HCV antibodies). This was the only statistically significant risk factor identified in this study (p = 0.066). CONCLUSIONS:Mexico is currently considered to have a lower prevalence for HCV in relation to developed countries and other endemic areas. The figures reported are lower than those observed in this study, suggesting that the strategies for detecting HCV in Mexico may be inadequate.

背景与目标： 背景与目的：丙型肝炎病毒（HVC）感染是全世界最常见的病毒感染之一。全世界大约有1.7亿人被感染。 HCV是发病率和死亡率的重要原因。在墨西哥，根据2000年国家健康调查，估计有70,000例病例。我们进行了这项研究，以估计与低地（bajio）地区HCV感染危险因素相关的患者中抗HCV抗体的患病率。
方法：本研究纳入了在4号综合医院接受治疗的15岁以上的2803个人。知情同意后，将为参与者提供一份调查表，列出丙型肝炎的主要危险因素。如果他们对这些已识别因素中的任何一个回答为肯定，则将采取血液样本通过ELISA分析来确定抗HCV抗体。
结果：本研究的平均年龄为38.4±13.5岁，女性为75.5％（n = 2116）。在1.3％的患者中分离出了抗HCV抗体（n = 36）。在所有参与者中，最常见的危险因素是既往有输血史（占所有患者的28.8％，n = 813和41.7％，n = 15的HCV抗体阳性的患者）。这是在这项研究中确定的唯一具有统计学意义的危险因素（p = 0.066）。
结论：相对于发达国家和其他流行地区，墨西哥目前被认为丙型肝炎的患病率较低。报告的数字低于本研究中观察到的数字，这表明在墨西哥检测HCV的策略可能不够充分。

BACKGROUND & AIMS: :Many viruses take advantage of cellular trafficking machineries to assemble and release new infectious particles. Using RNA interference (RNAi), we demonstrate that the Golgi/autophagosome-associated Rab33B is required for hepatitis B virus (HBV) propagation in hepatoma cell lines. While Rab33B is dispensable for the secretion of HBV subviral envelope particles, its knockdown reduced the virus yield to 20% and inhibited nucleocapsid (NC) formation and/or NC trafficking. The overexpression of a GDP-restricted Rab33B mutant phenocopied the effect of deficit Rab33B, indicating that Rab33B-specific effector proteins may be involved. Moreover, we found that HBV replication enhanced Rab33B expression. By analyzing HBV infection cycle steps, we identified a hitherto unknown membrane targeting module in the highly basic C-terminal domain of the NC-forming core protein. Rab33B inactivation reduced core membrane association, suggesting that membrane platforms participate in HBV assembly reactions. Biochemical and immunofluorescence analyses provided further hints that the viral core, rather than the envelope, is the main target for Rab33B intervention. Rab33B-deficiency reduced core protein levels without affecting viral transcription and hampered core/NC sorting to envelope-positive, intracellular compartments. Together, these results indicate that Rab33B is an important player in intracellular HBV trafficking events, guiding core transport to NC assembly sites and/or NC transport to budding sites.

背景与目标： ：许多病毒利用细胞运输设备来组装和释放新的传染性颗粒。使用RNA干扰（RNAi），我们证明了高尔基体/自噬体相关的Rab33B是乙型肝炎病毒（HBV）在肝癌细胞系中繁殖所必需的。尽管Rab33B对于HBV亚病毒包膜颗粒的分泌是必不可少的，但其敲除将病毒的产量降低到20％，并抑制了核衣壳（NC）的形成和/或NC的运输。 GDP受限的Rab33B突变体的过表达表型化了缺乏的Rab33B的作用，表明可能参与了Rab33B特异的效应蛋白。此外，我们发现HBV复制增强了Rab33B的表达。通过分析HBV感染的循环步骤，我们在形成NC的核心蛋白的高碱性C末端结构域中确定了迄今未知的膜靶向模块。 Rab33B失活减少了核心膜的缔合，表明膜平台参与了HBV组装反应。生化和免疫荧光分析提供了进一步的提示，即病毒核心而不是包膜是Rab33B干预的主要目标。 Rab33B缺乏症降低了核心蛋白水平，而没有影响病毒的转录，也没有阻碍核心/ NC对包膜阳性细胞内区室的分选。总之，这些结果表明，Rab33B是细胞内HBV转运事件的重要参与者，指导核心转运至NC装配位和/或NC转运至萌芽位。

BACKGROUND & AIMS: BACKGROUND/AIMS:Sequential antiviral therapy for chronic hepatitis B may lead to the selection of multidrug-resistant mutation. This study was carried out to assess the efficacy of entecavir in patients that have experienced adefovir monotherapy failure after the development of lamivudine resistance. METHODOLOGY:Fifty-three patients with confirmed genotypic lamivudine-resistant chronic hepatitis B were treated with entecavir. Thirty patients were switched to entecavir directly (LAM-ETV group), whereas the remaining 23 were adefovir-refractory patients who were switched to entecavir (LAM-ADV-ETV group). These 23 patients included 9 patients with inadequate response (ADV-I subgroup) and 14 that exhibited adefovir resistance (ADV-R subgroup). RESULTS:Significantly greater reductions in HBV DNA levels were observed after 24, 48 and 72 weeks of entecavir therapy in the LAM-ETV group than in the LAM-ADV-ETV group, respectively. However, between these two groups at 48 and 72 weeks, no significant differences were observed in cumulative proportions of virological response or breakthrough, respectively. Furthermore, efficacy of entecavir was not significantly different in the ADV-I and ADV-R subgroups. Four patients in the LAM-ETV group and six patients in the LAM-ADV-ETV group developed genotypic resistance to entecavir. CONCLUSIONS:Entecavir therapy is less effective in adefovir-refractory patients with prior lamivudine resistance than in lamivudine-resistant patients.

背景与目标： 背景/目的：慢性乙型肝炎的顺序抗病毒治疗可能会导致选择多药耐药性突变。这项研究旨在评估恩替卡韦在拉米夫定耐药性发生后经历阿德福韦单药治疗失败的患者中的疗效。
方法：对53例确诊具有基因型拉米夫定耐药的慢性乙型肝炎患者进行恩替卡韦治疗。 30例患者直接改用恩替卡韦（LAM-ETV组），其余23例是阿德福韦难治性患者改用恩替卡韦（LAM-ADV-ETV组）。这23名患者包括9名反应不足的患者（ADV-1亚组）和14名表现出阿德福韦耐药的患者（ADV-R亚组）。
结果：恩特卡韦治疗24、48和72周后，与LAM-ADV-ETV组相比，恩替卡韦治疗后HBV DNA水平明显降低。但是，两组在第48周和第72周时，病毒学应答或突破的累积比例均未观察到显着差异。此外，恩替卡韦的功效在ADV-1和ADV-R亚组中无显着差异。 LAM-ETV组的4例患者和LAM-ADV-ETV组的6例患者对恩替卡韦产生了基因型耐药性。
结论：恩替卡韦治疗对难治性拉米夫定的阿德福韦耐药患者的疗效不如对拉米夫定耐药的患者。

BACKGROUND & AIMS: OBJECTIVE:To explore the relationship between hepatitis C virus (HCV)/HIV coinfection and responses to initial antiretroviral treatment (ART). METHODS:Four AIDS Clinical Trials Group HIV treatment studies' data were combined to compare initial ART responses between HCV/HIV-coinfected and HIV-monoinfected patients as evaluated by virologic failure, CD4 cell measures, occurrence of AIDS/death and grade 3/4 safety events, using Kaplan-Meier estimates and proportional hazard, regression and mixed effects models, adjusting for baseline covariates. RESULTS:Of the 3041 included participants, 81% were men, 19% had prior history of AIDS, the median (25th, 75th percentile) baseline HIV RNA was 4.72 (4.38-5.18) log10 copies/ml, and the median (25th, 75th percentile) baseline CD4 cell count was 216.0 (76.5-327.0) cells/μl. The 279 HCV/HIV-coinfected individuals were older (44 vs. 37 years), more likely to be black non-Hispanic (47 vs. 36%), and previous/current intravenous drug user (52 vs. 5%) than the 2762 HIV-monoinfected patients (all P values <0.001). HCV/HIV coinfection was associated with earlier virologic failure, hazard ratio (95% confidence interval): 1.43 (1.07-1.91); smaller mean CD4 cell increase and CD4% increase [-33.8 (-52.2 to -15.4) cells/μl and -1.16% (-1.43 to -0.89%), respectively] over a median of 132 weeks of follow-up; earlier occurrence of grade 3/4 safety event, hazard ratio 1.51 (1.26-1.81); and increased AIDS/mortality, hazard ratio 2.10 (1.31-3.37). Treatment effects comparing antiretroviral regimens were not significantly different by HCV/HIV coinfection status. CONCLUSION:HCV/HIV coinfection is associated with attenuated response to ART. Results support earlier initiation of HIV therapy and increased monitoring of those initiating ART with HCV/HIV coinfection.

背景与目标： 目的：探讨丙型肝炎病毒（HCV）/ HIV合并感染与初始抗逆转录病毒治疗（ART）反应之间的关系。
方法：将四个艾滋病临床试验组的HIV治疗研究数据进行比较，以比较HCV / HIV合并感染和HIV单感染的患者的最初ART反应，并通过病毒学衰竭，CD4细胞测量，AIDS /死亡的发生和3/4级进行评估安全事件，使用Kaplan-Meier估计值和比例风险，回归和混合效应模型，针对基线协变量进行调整。
结果：3041名参与者中，男性占81％，曾有艾滋病史；中位数（第25、75个百分位数）基线HIV RNA为4.72（4.38-5.18）×log10×拷贝/ ml，中位数（第25， 75％的基线CD4细胞计数为216.0（76.5-327.0）细胞/μl。与HCV / HIV合并感染的279名个体相比，年龄更大（44岁对比37岁），更可能是非西班牙裔黑人（47岁对比36％），以及以前/现在的静脉吸毒者（52岁对比5％）。 2762名HIV单一感染患者（所有P值<0.001）。 HCV / HIV合并感染与早期病毒学衰竭，危险比（95％置信区间）：1.43（1.07-1.91）相关；在132周的中位数随访中，平均CD4细胞增加和CD4％增加较小[-33.8（-52.2至-15.4）细胞/μl和-1.16％（-1.43至-0.89％）]；较早发生3/4级安全事件，危险比1.51（1.26-1.81）;艾滋病/死亡率增加，危险比为2.10（1.31-3.37）。比较抗逆转录病毒疗法的治疗效果在HCV / HIV合并感染状态方面无显着差异。
结论：HCV / HIV合并感染与对ART的反应减弱有关。结果支持更早地启动HIV治疗，并加强对以HCV / HIV合并感染启动ART的人群的监测。

BACKGROUND & AIMS: :The aim of this study was to assess the frequencies and patterns of naturally occurring genotypic resistance to nucleos(t)ide analogues (NUCs) and typical hepatitis B surface antigen (HBsAg) amino acid substitutions in naive hemodialysis (HD) patients with chronic hepatitis B. In order to achieve this, the genotypic resistance to NUCs and HBsAg amino acid substitutions were classified into primary/compensatory resistance mutation and antiviral drug-associated potential vaccine-escape mutation (ADAPVEM)/typical HBsAg amino acid substitution, respectively. Direct sequencing of polymerase (pol) gene of hepatitis B virus (HBV) was performed on DNA samples obtained from 248 HBsAg-positive Turkish patients. Overall, 38% (n = 94) of HBsAg-positive HD patients had detectable HBV DNA in their serum. Naturally occurring primary and compensatory resistance mutations to NUCs were detected in 30% (n = 28) and 52% (n = 49) of HD patients, respectively. However, 6 types of ADAPVEMs and 48 types of typical HBsAg amino acid substitutions were found in 10.6% (n = 10) and 46% (n = 43) of the HD patients, respectively. Our study suggests that every HD patient diagnosed with chronic hepatitis B, who is a potential candidate for NUCs treatment, should also be monitored for the baseline pol gene sequence changes before the initial treatment, for a more effective management of future treatment options. Further, a relatively higher frequency of ADAPVEMs variants needs to be addressed as a public health problem.

背景与目标： ：这项研究的目的是评估天真的血液透析（HD）慢性肝炎患者对核苷酸（t）核苷酸类似物（NUCs）和典型的乙型肝炎表面抗原（HBsAg）氨基酸替代的天然基因型耐药的频率和模式B.为了实现这一点，分别将对NUCs和HBsAg氨基酸替代的基因型抗性分为原发性/代偿性抗性突变和抗病毒药物相关的潜在疫苗逃逸突变（ADAPVEM）/典型的HBsAg氨基酸替代。乙型肝炎病毒（HBV）的聚合酶（pol）基因的直接测序是从248例HBsAg阳性土耳其患者获得的DNA样品上进行的。总体上，有38％（n = 94）的HBsAg阳性HD患者血清中可检测到HBV DNA。分别在30％（n = 28）和52％（n = 49）的HD患者中检测到对NUC的自然发生的原发性和代偿性耐药突变。然而，在HD患者中分别发现了6种类型的ADAPVEM和48种典型的HBsAg氨基酸取代，分别为10.6％（n = 10）和46％（n = 43）。我们的研究表明，每位被诊断患有慢性乙型肝炎的HD患者（可能是NUCs治疗的候选人）也应在初次治疗前接受基线pol基因序列变化的监测，以更有效地管理未来的治疗方案。此外，作为公共卫生问题，需要解决相对较高频率的ADAPVEM变体的问题。

BACKGROUND & AIMS: BACKGROUND:During the years preceding this study, we noticed a relatively unusual high number of individuals with elevated alanine aminotransferase (ALT) levels in O'Brien, a small rural town in Argentina. Moreover, four individuals from this town underwent liver transplantation owing to hepatitis C virus (HCV)-induced liver cirrhosis. These findings prompted us to conduct a large population-based survey to evaluate the prevalence of HCV in this community. METHODS AND RESULTS:A total of 1637 individuals were studied. The overall HCV-seroprevalence was 5.7% (93/1637), being slightly higher in men (45/769; 5.9%) than in women (48/868; 5.5%). HCV seroprevalence increased with age, reaching a peak rate of 23.9% among individuals between 61 and 70 years of age. HCV RNA was present in 82.7% of all HCV seropositive individuals identified and 100% of them were infected with genotype 1b. ALT elevations were detected in 44% of HCV+ patients and were only observed among viremic individuals. Hepatitis B virus infection was also prevalent (52%) among HCV-seropositive patients. The most common risk factor associated with HCV transmission identified was the apparent use of inadequately sterilized glass syringes by a health care provider serving the community; however, other risk factors may have also played a role in the dissemination of HCV. CONCLUSIONS:Our findings provide an explanation for the relative high number of individuals with elevated ALT levels observed in this community and form the basis of future prospective studies on the natural history of genotype 1b infection.

背景与目标： 背景：在这项研究之前的几年中，我们注意到在阿根廷的一个小乡镇O'Brien中，丙氨酸氨基转移酶（ALT）水平升高的人群相对罕见。此外，由于丙型肝炎病毒（HCV）引起的肝硬化，该镇的四名患者接受了肝移植。这些发现促使我们进行了一项基于人群的大规模调查，以评估该社区中HCV的患病率。
方法与结果：共研究1637人。总体HCV血清阳性率为5.7％（93/1637），男性（45/769; 5.9％）略高于女性（48/868; 5.5％）。 HCV血清阳性率随年龄增长而增加，在61至70岁之间的人群中达到23.9％的峰值率。在所有已鉴定的HCV血清反应阳性个体中，HCV RNA存在于82.7％，其中100％感染了基因型1b。在44％的HCV患者中检测到ALT升高，并且仅在病毒血症患者中观察到。在HCV血清反应阳性患者中，乙型肝炎病毒感染也很普遍（52％）。确定的与HCV传播有关的最常见风险因素是为社区服务的医疗服务提供者明显使用了未充分消毒的玻璃注射器。但是，其他危险因素也可能在HCV传播中发挥了作用。
结论：我们的发现为在该社区观察到的ALT水平升高的相对较高的人数提供了解释，并为将来对基因型1b感染自然史的前瞻性研究奠定了基础。