欧洲例慢性乙型肝炎常见的耐药性

StephenW

                                                              Drug resistance common among European patients with chronic hepatitis B                                                            
                                                                                                                                                                                                                    Mon, 07/13/15 - 09:19                                                            By Anne Harding
NEW YORK (Reuters Health) - Rates of lamivudine resistance are high among patients with chronic hepatitis B (CHB) infection across Europe, with many patients developing cross-resistance to entecavir, according to a new report.
Among 1,568 patients under treatment who had detectable serum hepatitis B virus (HBV) DNA, nearly three-quarters had received lamivudine monotherapy, and just over half had drug resistant strains of HBV, Dr. Annemarie M. J. Wensing of University Medical Center Utrecht in the Netherlands and her colleagues found.
"The burden of historical and continuous lamivudine use in Europe is very large," Dr. Wensing told Reuters Health by email. "This has resulted in many patients with lamivudine resistance and cross-resistance to entecavir. This may not seem to be an issue since no cross-resistance to tenofovir or interferon is induced. However a considerable group has renal toxicity and those patients should be treated with entecavir. For these patients pretreatment fully compromises HBV treatment options."
Currently, European guidelines recommend patients with CHB be treated with entecavir or tenofovir, and discourage monotherapy with lamivudine, adefovir, and telbivudine. But many patients are still being treated with older drugs, which carry a greater risk of treatment failure and drug resistance, Dr. Wensing and her team note in the Journal of Infectious Diseases, online July 1.
To investigate the prevalence and characteristics of nucleoside analog resistance among CHB patients, the researchers looked at genotypic resistance testing results from patients with CHB who were undergoing routine monitoring, gathering data from 18 countries across Europe.
Sample draw dates were divided into four time periods based on when different nucleoside analogs became available in Europe: 1998-2002 for lamivudine; 2003-2005 for adefovir; 2006-2008 for entecavir; and 2009-2012 for tenofovir.
The researchers identified at least one drug-resistance mutation in 52.7% of patients. The most common mutation identified was rtM204V/I, found in 48.7% of all patients studied, which is associated with lamivudine and telbivudine use. Most of these patients had additional mutations. About 6% of patients carried one of two mutations that conferred adefovir resistance. Among the 1,175 patients who had been exposed to lamivudine, 56.6% had drug resistance, while 22.3% of adefovir-exposed patients and 35.3% of entecavir-exposed patients had drug resistance.
Multivariate analysis identified age, HBV-DNA levels and lamivudine use as independent risk factors for resistance, while patients with viral genotype A were also at increased risk of resistance. Samples collected in 2003-2005 and 2006-2008 were more likely to be drug-resistant than samples collected later. Samples from northern and western Europe were less likely to be drug-resistant.
Although European guidelines recommend against lamivudine use for HBV, the drug is still being used, especially in countries with limited resources, due to its lower cost, Dr. Wensing told Reuters Health.
"We would indeed recommend not to use lamivudine. Lamivudine is obsolete, and risky," she said. "For treatment as well as for prophylaxis lamivudine should not be used. Each country should take clinical decisions on the base of the cost and efficacy, but the rate of damage often driven by lamivudine in terms of failures and resistance does not justify an 'in full' approach with this drug only because it is inexpensive."
"For HIV it has been shown that it is possible to supply patients in very resource-limited settings with tenofovir," Dr. Wensing added. "We cannot accept that this treatment option will not be made available for patients with HBV."
HBV infection is much more common than infection with hepatitis C virus (HCV) or HIV, the researcher noted. While patients with HCV or HIV are often treated by doctors who specialize in these infections, she added, non-specialist clinicians often treat patients with HBV.
"However, HBV infection is a far larger threat than what is commonly thought, even in patients who have seroconverted since the virus is not eliminated from the body," Dr. Wensing said. "With the rise of patients with iatrogenic immunosuppression we will experience more HBV reactivation and clinical risks. Proper use of drugs is important in this vulnerable population."
SOURCE: http://bit.ly/1furVof
J Infect Dis 2015.
(c) Copyright Thomson Reuters 2015. Click For Restrictions - http://about.reuters.com/fulllegal.asp

      

         
  


  
                                                            

StephenW

其中欧洲例慢性乙型肝炎常见的耐药性
周一，15年7月13日 - 09:19

由安妮·哈丁

纽约（路透社健康） - 拉米夫定耐药的税率也有患者在欧洲慢性乙型肝炎（CHB）感染，许多患者发展两岸关系，耐恩替​​卡韦高，根据一项新的报告。

在接受治疗的患者1568谁了检测血清乙肝病毒（HBV）DNA，近四分之三接受了拉米夫定单药治疗，而一半以上的HBV，大学医疗中心乌得勒支在荷兰安娜玛丽MJ Wensing博士耐药菌株并发现她的同事。

“历史和连续使用拉米夫定在欧洲的负担是非常大的，”Wensing告诉路透社记者通过电子邮件。 “这导致了许多患者拉米夫定耐药和交叉耐药性恩替卡韦，这可能似乎不是因为没有交叉耐药性替诺福韦或干扰素诱导的问题。但是相当组具有肾毒性和那些患者应该被视为恩替卡韦。对于这些患者治疗前的完全妥协乙肝的治疗方案。“

目前，欧洲指南建议慢性乙肝患者使用恩替卡韦或替诺福韦治疗，并阻止单用拉米夫定，阿德福韦，替比夫定和。但是，许多患者仍在治疗老药，携带治疗失败和耐药性，Wensing博士和她的团队注意到在传染病杂志，在线7月1日的风险更大。

调查患病率和中慢性乙型肝炎患者核苷类似物耐药的特点，研究人员观察从慢性乙肝患者的基因型耐药性检测结果谁正在接受常规监测，来自18个国家在欧洲收集的数据。

样本彩日期分为基于不同的时候核苷类似物在欧洲变得可利用四个时间段：1998-2002拉米夫定; 2003-2005阿德福韦; 2006-2008恩替卡韦;和2009-2012替诺福韦。

研究人员识别的至少一个药物抗性突变的患者52.7％。确定最常见的突变是rtM204V / I，发现在所有患者中48.7％的研究，这是与拉米夫定和替比夫定的使用有关。大多数这些患者有额外的突变。约6％的患者携带两个突变赋予阿德福韦耐药之一。其中1175例谁已经暴露于拉米夫定，56.6％有耐药性，而阿德福韦暴露患者的22.3％和恩替卡韦，暴露患者的35.3％有抗药性。

多变量分析确定年龄，HBV-DNA水平和拉米夫定作为独立危险因素性，而患者病毒A基因型也以抵抗风险增加。在收集和2003 - 2005年2006 - 2008年的样本更可能是药物性比后收集的样本。来自北欧和西欧样品不太可能耐药。

虽然欧洲指南建议对拉米夫定用于乙肝，药物仍在使用，特别是在资源有限的国家，由于其成本低，Wensing告诉路透社记者。

“我们的确会建议不要使用拉米夫定。拉米夫定是过时了，有风险的，”她说。 “对于治疗以及用于预防拉米夫定不应使用。每个国家应当采取的成本和有效性的基础上的临床决定，但损害常由拉米夫定在故障和电阻方面驱动的速率不一个'中证明全“的方法用此药不仅因为它价格便宜。”

“为HIV已经表明，有可能提供患者与替诺福韦非常资源有限的环境，”Wensing博士补充。 “我们不能接受这种治疗选项将不会进行供患者乙肝病毒。”

HBV感染比感染了丙型肝炎病毒（HCV）或HIV普遍得多，研究者指出。虽然HCV患者或HIV往往被通过谁专门在这些感染的医生，她补充说，非专业医生通常将患者的乙肝病毒。

“然而，乙肝病毒感染是一个更大的威胁比普遍认为，即使是在谁已经血清转换，因为病毒没有排出体外的患者，”Wensing博士说。 “随着患者的医源性免疫抑制的兴起，我们会遇到更多的HBV再和临床风险。正确使用药物是在这一脆弱人群很重要。”

来源：http://bit.ly/1furVof

Ĵ传染病杂志2015年。

StephenW

Combined Analysis of the Prevalence of drug Resistant HBV in antiviral therapy Experienced patients in Europe (CAPRE)

    L.E. Hermans1,2,*, V. Svicher3,*, S.D. Pas2, R. Salpini3, M. Alvarez4, Z. Ben Ari20, G. Boland1, B. Bruzzone5, N. Coppola6, C. Seguin-Devaux7, T. Dyda8, F. Garcia4, R. Kaiser9, S. Köse10, H. Krarup11, I. Lazarevic12, M.M. Lunar13, S. Maylin14, V. Micheli15, O. Mor16, S. Paraschiv17, D. Paraskevis18, M. Poljak13, E. Puchhammer-Stöckl19, F. Simon14, M. Stanojevic12, K. Stene-Johansen21, N. Tihic22, P. Trimoulet23, J. Verheyen24, A. Vince25, N. Weis26, T. Yalcinkaya27, S. Zidovec Lepej26, C. Perno3, C.A.B. Boucher2 and A.M.J. Wensing1 on behalf of the HEPVIR working group of the European Society for translational antiviral research (ESAR)

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Author Affiliations

    1Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands
    2Department of Virology, Erasmus Medical Centre, Rotterdam, The Netherlands
    3Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Rome, Italy
    4Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada, Granada, Spain
    5Hygiene Unit, IRCCS AOU San Martino - IST, Genoa, Italy
    6Malattie Infettive, Seconda Università degli studi di Napoli, Naples, Italy
    7Laboratory of Retrovirology, CRP-Santé, Luxembourg, Luxembourg
    8Molecular Diagnostics Laboratory, Hospital of Infectious Diseases, Warsaw, Poland
    9Institute of Virology, University of Cologne, Cologne, Germany
    10Izmir Tepecik Education and Research Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Izmir, Turkey
    11Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
    12Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
    13Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
    14Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, Paris, France
    15“L. Sacco” Hospital, Milan, Italy
    16National HIV Reference Laboratory, Central Virology Laboratory, Ministry of Health, Tel Hashomer, Ramat Gan, Israel
    17Molecular Diagnostics Laboratory, National Institute for Infectious Diseases “Matei Bals”, Bucharest, Romania
    18National Retrovirus Reference Centre, Department of Hygiene, Epidemiology and Medical Statistics, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece
    19Department for Virology, Medical University of Vienna, Vienna, Austria
    20Liver Disease Centre, Sheba Medical Centre, Ramat Gan, Israel
    21Department of Virology, Norwegian Institute of Public Health, Oslo, Norway
    22Institute of Microbiology, Polyclinic for Laboratory Diagnostics, University Clinical Centre Tuzla, Tuzla, Bosnia and Herzegovina
    23Virology Laboratory, Centre Hospitalier Régional et Université "Victor Segalen", Bordeaux, France
    24Institute of Virology, University-Hospital, University Duisburg-Essen, Essen, Germany
    25University of Zagreb School of Medicine and University Hospital for Infectious Diseases “Dr. Fran Mihaljevic”, Zagreb, Croatia
    26Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark
    27Refik Saydam National Public Health Agency, Ankara, Turkey

    Corresponding author: Annemarie M.J. Wensing, MD PhD, University Medical Centre Utrecht – Virology, Dept of Medical Microbiology G04.614, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands, Phone: +31 88 7556526, Fax: +31 88 7555426, [email protected]

    ↵* These authors contributed equally to the paper.

Abstract

Introduction. European guidelines recommend treatment of chronic Hepatitis B virus infection (CHB) with the nucleos(t)ide analogs (NAs) entecavir or tenofovir. However, many European CHB patients have been exposed to other NAs, which are associated with therapy failure and resistance. The CAPRE study was performed to gain insight in prevalence and characteristics of NA resistance in Europe.

Methods. A survey was performed on genotypic resistance testing results acquired during routine monitoring of CHB patients with detectable serum HBV-DNA in European tertiary referral centres.

Results. Data of 1568 patients was included. The majority (73.8%) was exposed to lamivudine monotherapy. Drug resistant strains were detected in 52.7%. The most frequently encountered primary mutation was M204V/I (48.7%), followed by A181T/V (3.8%) and N236T (2.6%). In patients exposed to entecavir (n=102), full resistance was present in 35.3%. Independent risk factors for resistance were age, viral load and lamivudine exposure (p<0.001).

Conclusion. These findings support resistance testing in cases of apparent NA therapy failure. This survey highlights the impact of exposure to lamivudine and adefovir on development of drug resistance and cross-resistance. Continued use of these NAs needs to be reconsidered at a pan-European level.

    © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].

StephenW

在抗病毒治疗经验的患者在欧洲药耐药的乙肝患病率的联合分析（卡普雷）

    L.E. Hermans1,2，*，V Svicher3，*，S.D。 PAS2，R. Salpini3，M Alvarez4，Z.本Ari20，G Boland1，B. Bruzzone5，N. Coppola6，塞甘C. - Devaux7，T. Dyda8，F Garcia4，R. Kaiser9，S.Köse10，H 。Krarup11，一Lazarevic12，MM Lunar13，S. Maylin14，五Micheli15，澳Mor16，S. Paraschiv17，D Paraskevis18，M. Poljak13，E Puchhammer-Stöckl19，F Simon14，M. Stanojevic12，K. Stene-Johansen21，N. Tihic22， P. Trimoulet23，J. Verheyen24，A Vince25，N. Weis26，T Yalcinkaya27，S Zidovec Lepej26，C Perno3，CAB Boucher2和A.M.J. Wensing1代表欧洲学会平移抗病毒药研究HEPVIR工作组（东南非）

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作者机构

    医学微生物学，大学医​​疗中心乌得勒支，乌得勒支，荷兰教研室
    病毒学，Erasmus医学中心，鹿特丹，荷兰教研室
    3Department实验医学和外科手术，罗马“在Tor Vergata”大学，罗马，意大利
    4Servicio德Microbiología，医院圣塞西，研究所德InvestigaciónBiosanitaria ibs.GRANADA，Hospitales Universitarios格拉纳达，格拉纳达，西班牙
    5Hygiene单位，IRCCS AOU圣马蒂诺 - IST，意大利热那亚
    6Malattie Infettive，Seconda UNIVERSITA德利阿布鲁Studi住宅迪那不勒斯，那不勒斯，意大利
    反转录病毒学，CRP - 桑特，卢森堡，卢森堡7Laboratory
    8Molecular诊断实验室，传染病医院，华沙，波兰
    病毒学，科隆大学，科隆，德国9Institute
    10Izmir Tepecik教育和研究医院，传染病门诊和临床微生物学，伊兹密尔，土耳其
    分子诊断11Section，临床生化，奥尔堡大学医院，奥尔堡，丹麦
    微生物学与免疫学，医学系，贝尔格莱德大学，贝尔格莱德，塞尔维亚12Institute
    微生物学与免疫学，医学系，卢布尔雅那大学，斯洛文尼亚卢布尔雅那的13Institute
    14Service德Microbiologie，巴黎大学狄德罗，HOPITAL圣路易斯，法国巴黎
    15“L。萨科“医院，米兰，意大利
    16National艾滋病参比实验室，中央病毒学实验室，卫生部，电话Hashomer，拉马特甘，以色列
    17Molecular诊断实验室，国立传染病“马太巴尔斯”，布加勒斯特，罗马尼亚
    18National逆转录病毒参考中心，卫生学，流行病学和医学统计学，医学，国家和雅典Kapodistrian大学法律系，雅典，希腊科
    19Department病毒学，维也纳医科大学，维也纳，奥地利
    20Liver病中心，Sheba医疗中心，拉马特甘，以色列
    病毒学，公共卫生研究所挪威奥斯陆，挪威21Department
    微生物学22Institute，分科实验室诊断，大学临床中心图兹拉，图兹拉，波斯尼亚和黑塞哥维那
    23Virology实验室，中心医院等区域UNIVERSITE“谢阁兰”，法国波尔多
    病毒学，大学，医院，杜伊斯堡 - 埃森大学，德国埃森的24Institute
    医药大学附属医院萨格勒布学校传染病“博士25University弗兰Mihaljevic“，萨格勒布，克罗地亚
    26Department传染病，哥本哈根大学医院，哈维德夫，丹麦哥本哈根
    27Refik Saydam国家公共卫生局，安卡拉，土耳其

    通讯作者：安娜玛丽MJ Wensing，医学博士大学医学中心的乌得勒支， - 病毒学医学微生物学G04.614，Heidelberglaan 100，3584 CX荷兰乌得勒支，电话，部：+31 88 7556526，传真：+31 88 7555426，AMJ [email protected]

    ↵*这些作者同等贡献的文件。

抽象

简介。欧洲指南推荐的治疗慢性乙肝病毒感染（CHB）与核苷（酸）类似物（NAS），恩替卡韦或替诺福韦。然而，许多欧洲CHB患者已经暴露给其他NAS，​​这是与治疗失败和阻力有关。进行该研究卡普雷获得的患病率在欧洲北美阻力特性的见解。

方法。一项调查，在使用过程中可检测到血清HBV-DNA在欧洲三级转诊中心日常监测CHB患者获得基因型耐药性检测结果进行。

结果。 1568例患者的数据被列入。大部分（73.8％）暴露于拉米夫定单药治疗。在52.7％的检出耐药菌株的产生。最常遇到的主要突变M204V / I（48.7％），其次是A181T / V（3.8％）和N236T（2.6％）。在患者暴露于恩替卡韦（N = 102），全抗性是目前在35.3％。独立危险因素抵抗年龄，病毒载量和拉米夫定曝光（P <0.001）。

结论。这些发现支持性测试中明显的NA治疗失败的病例。这项调查突出暴露于拉米夫定和阿德福韦耐药性和交叉耐药性的发展的影响。继续使用这些新来港定居的需要，在一个泛欧层面重新考虑。