替诺福韦酯治疗恩替卡韦耐药和应答不佳慢性乙型肝炎的临床观察

目的 探讨对恩替卡韦应答不佳和耐药的慢性乙型肝炎采用替诺福韦酯治疗的效果.方法 选取2016年3月至2019年4月在联勤保障部队906医院温州医疗区就诊的慢性乙型肝炎对恩替卡韦治疗应答不佳患者(A组)36例,对恩替卡韦耐药(B组)44例,均换用富马酸替诺福韦酯单独抗病毒治疗,观察治疗12、24、48周的HBV DNA转...     

一线核苷（酸）类似物经治的慢性乙型肝炎患者低病毒血症的发生及治疗策略

强效低耐药口服抗病毒治疗可使HBV复制受到强力抑制,但部分患者接受恩替卡韦、替诺福韦酯、丙酚替诺福韦、艾米替诺福韦治疗48周及以上仍存在低病毒血症（LLV）。国内外多项研究结果提示,抗病毒治疗后LLV与慢性乙型肝炎肝纤维化进展、失代偿期肝硬化和肝细胞癌发生风险以及长期生存率降低密切相关。因此,本文聚焦有关一线核苷（酸）类似物治疗后LLV的发生及其危险因素和临床危害以及不同的治疗方案,以期为今后慢性乙型肝炎患者LLV的治疗提供参考。     

《慢性乙型肝炎防治指南(2019年版)》新亮点

为进一步规范我国慢性乙肝的预防诊断和治疗,中华医学会感染学分会和肝病学分会发表了《慢性乙型肝炎防治指南》(2019年版)。本文介绍了本版指南在流行病学、自然史、预防、诊断和治疗方面的十大亮点。其最突出的变化是放宽了慢性乙型肝炎及肝硬化的抗病毒治疗适应证;进一步明确推荐高效低耐药的恩替卡韦、替诺福韦酯或丙酚替诺福韦;推荐高病毒载量的孕妇于妊娠中晚期开始服用替诺福韦酯或替比夫定以进一步提供母婴阻断率。     

替诺福韦酯与恩替卡韦对慢性乙型肝炎初治疗患者的疗效

目的评估替诺福韦酯与恩替卡韦在治疗慢性乙型肝炎的疗效。 方法纳入2010年6月至2015年6月入住济南军区总医院的慢性乙型肝炎的初治患者100例,采用随机数字表法分为观察组(替诺福韦酯)50例、对照组(恩替卡韦)50例,随访时间12、24个月,比较二者在HBV-DNA转阴率、HBeAg血清学转换率、丙氨酸转氨酶复常率、耐药率、安全性方面是否存在差异。 结果与治疗前比较,观察组与对照组在随访观察12、24个月后各项指标较前明显改善,但二者在HBV-DNA转阴率(32/50 vs.28/50、46/50 vs.42/50)、HBeAg血清学转换率(4/28 vs.6/30、8/28 vs.12/30)、丙氨酸转氨酶复常率(42/50 vs.40/50、49/50 vs.46/50)、耐药率方面未见明显差异;但长期口服恩替卡韦对肾脏影响高于替诺福韦酯组,差异有统计学意义(P<0.05)。 结论替诺福韦酯与恩替卡韦比较,二者在治疗慢性乙型肝炎效果相当,但长期口服药物安全性方面有优势,因此建议长期治疗慢性乙型肝炎临床运用替诺福韦酯作为首选方案。     

恩替卡韦与替诺福韦治疗的慢性乙型肝炎患者发生肝细胞癌的风险:一项韩国全国性队列研究

正【据《JAMA Oncol》2018年9月报道】题:恩替卡韦与替诺福韦治疗的慢性乙型肝炎患者发生肝细胞癌的风险:一项韩国全国性队列研究恩替卡韦和替诺福韦是治疗慢性HBV感染的一线抗病毒药物,但在长期治疗中肝细胞癌的发生风险是否相似尚未可知。一项来自于韩国全国性队列研究发现,在24 156例初治慢性HBV成人感染者中,与恩替卡韦治疗组相比,替诺福韦治疗组肝细胞癌发生风险和病死率降低更为明显。这一结论在一组包含2701慢性乙型肝炎初治成人患者的医院队列研究中得到验证。     

对阿德福韦酯不完全应答的慢性乙型肝炎患者在接受替诺福韦联合恩曲他滨治疗与单独替诺福韦治疗具有类似的病毒准种演变

<正>【据《J Hepatol》2013年10月报道】题:对阿德福韦酯不完全应答的慢性乙型肝炎患者在接受替诺福韦联合恩曲他滨治疗与单独替诺福韦治疗具有类似的病毒准种演变(作者Lavocat F等)体外试验表明,阿德福韦酯耐药后诱导替诺福韦交叉耐药率较低。比较对阿德福韦酯不完全应答患者,其单独应用替诺福韦以及应用替诺福韦联合恩曲他滨,两者之间的病毒动力学、核苷类似物耐药突变位点及准种演变。里昂肿瘤学研究中心Lavocat F等人通过随机双盲对阿德福韦酯不完全应答的慢性乙型肝炎患者分为2组,1组替诺福韦治     

本期导读

梁尘格等通过观察合并非酒精性脂肪性肝病的慢性乙型肝炎患者服用富马酸替诺福韦酯的疗效, 目的是为此类特殊人群的抗病毒治疗提供循证依据, 结果显示, 在慢性乙型肝炎的抗病毒治疗中, 非酒精性脂肪性肝病可影响富马酸替诺福韦酯的病毒学应答及生物化学应答(梁尘格等, 第113～117页)。刘丽萍等通过观察恩替卡韦经治后低病毒血症的慢性乙型肝炎患者序贯或联合富马酸丙酚替诺福韦的疗效及其影响因素, 发现序贯或联合富马酸丙酚替诺福韦抗病毒治疗可以更有效地提高恩替卡韦经治后发生低病毒血症的慢性乙型肝炎患者96周完全病毒学应答率, 且可以改善患者肝肾功能和减轻纤维化程度。48周后续用恩替卡韦和48周时乙型肝炎病毒(HBV)DNA载量是低病毒血症患者96周HBV DNA未转阴的预测因素(刘丽萍等, 第118～125页)。尚梦月等分析了慢性乙型肝炎合并代谢相关脂肪性肝病患者的临床及病理组织学特征。并认为慢性乙型肝炎患者合并代谢紊乱易发生代谢相关脂肪性肝病, HBV病毒因素、肝脏纤维化程度与肝脏组织脂肪变性之间有一定的相关性(尚梦月等, 第126～132页)。柯若曼等研究结果显示, 慢性乙型肝炎患者的血清可溶性...     

2011年肝病领域的重要进展

过去的2011年国内外肝病领域取得诸多进展,现将有关病毒性和非病毒性肝病方面的几个重要进展介绍如下. 一、病毒性肝炎 1.慢性乙型肝炎(CHB):在2009年的美国肝病学会(American Association for the Study of Livr Diseases,AASLD)指南中,聚乙二醇干扰素、恩替卡韦及替诺福韦酯被列为一线药物推荐[1].Liaw等[2]的一项2期临床双盲的研究中,将112位慢性乙型肝炎肝硬化失代偿期患者随机分为3组,分别给予替诺福韦酯、替诺福韦酯/依曲西他滨及恩替卡韦治疗,3组患者均良好耐受,并且在病毒学,生物化学指标及临床表现方面均有所好转.Snow-Lampart等[3]研究表明,无论是经过核苷酸类药物治疗抑或是未经治疗过的患者,经144周的替诺福韦酯单药治疗后,均未出现HBV pol/RT突变导致的耐药.     

替诺福韦酯治疗慢性乙型肝炎的最新进展

核苷(酸)类似物抗病毒药物已广泛应用于慢性乙型肝炎的治疗,其中替诺福韦酯作为一种新型药物,以其良好的抗病毒作用及低耐药性成为目前研究的热点.本文概述了近年来替诺福韦酯的体内外研究进展及其在临床应用的前景.     

替诺福韦治疗核苷(酸)类耐药的慢性乙型肝炎患者的疗效研究

目的探讨对阿德福韦酯耐药的慢性乙型肝炎患者应用替诺福韦治疗的临床效果。方法将本院收集的61例对阿德福韦酯耐药的慢性乙型肝炎患者采用随机数字表法分为替诺福韦组30例(替诺福韦+拉米夫定)和阿德福韦组31例(阿德福韦酯+拉米夫定),两组患者的预计疗程为48~96周,比较两组患者的疗效差异。结果治疗前替诺福韦组和阿德福韦组的HBV DNA检出值比较差异不具有统计学意义(P0.05),治疗后第24、48、96周两组患者的HBV DNA检出值均较治疗前呈显著下降趋势(P0.05),组间比较差异不具有统计学意义(P0.05)。治疗后96周时,替诺福韦组的HBV DNA累积转阴率达到93.33%显著高于阿德福韦组73.33%(P0.05),替诺福韦组的HBeAg累积转阴率达到43.33%显著高于阿德福韦组13.33%(P0.05)。治疗前后两组患者的肝功能指标ALT、AST、TBil组间比较差异均不具有统计学意义(P0.05);治疗后两组患者的ALT、AST、TBil较治疗前均显著降低(P0.05)。结论对阿德福韦酯耐药的慢性乙型肝炎患者,应用替诺福韦+拉米夫定治疗能够更有效地提高HBV DNA及HBeAg转阴率。     

核苷(酸)类似物序贯干扰素治疗乙型肝炎病毒e抗原阳性慢性乙型肝炎患者的临床观察

目的 观察HBeAg阳性慢性乙型肝炎(CHB)患者在核苷(酸)类似物抗病毒治疗基础上序贯聚乙二醇干扰素α-2a(PEG IFNα-2a)治疗48周血清HBsAg的变化.方法 6例HBeAg阳性CHB患者中,3例采用核苷(酸)类似物序贯PEG IFNα-2a治疗48周,3例维持原核苷(酸)类似物治疗方案,每12周采用实时PCR定量检测HBV DNA,采用时间分辨免疫荧光分析法检测HBsAg、抗-HBs、HBeAg、抗-HBe及抗-HBc.结果 核苷(酸)类似物序贯PEG lFNα-2a治疗48周后,3例序贯治疗患者血清HBsAg均消失,而维持原核苷(酸)类似物治疗患者血清HBsAg效价为100～320 IU/mL.结论 对核苷(酸)类似物治疗产生较好应答反应且伴有血清HBsAg效价明显下降的HBeAg阳性CHB患者,在核苷(酸)类似物抗病毒治疗基础上序贯PEG IFNα-2a治疗48周能有效促进血清HBsAg下降,并出现血清HBsAg消失的现象.     

血清乙型肝炎病毒前基因组RNA水平对核苷(酸)类似物初治的慢性乙型肝炎患者疗效预测价值*

目的 探讨应用血清乙型肝炎病毒前基因组RNA(HBV pgRNA)水平预测核苷(酸)类似物初治的慢性乙型肝炎(CHB)患者疗效的价值。方法 2015年8月～2019年12月我院诊治的初始治疗的CHB患者107例,接受恩替卡韦、替诺福韦或替比夫定治疗观察48 w。采用实时荧光定量PCR法检测血清HBV pgRNA,采用ELISA法检测血清HBsAg和HBeAg。应用Logistic回归分析影响疗效的因素,应用MedCalc1 5.1统计学软件绘制ROC,计算曲线下面积(AUC)评价血清HBV pgRNA水平预测核苷(酸)类似物治疗的疗效。结果 在治疗48周末,27例(25.2%)患者不应答,另80例(74.8%)患者获得完全应答或部分应答;(完全或部分)应答组血清HBV DNA载量为(6.1±1.0)lg copies/mL,显著低于不应答组【(7.2±1.2) lg copies/mL,P<0.05】,外周血CD4^＋/CD8^＋比值为(0.7±0.2),显著高于不应答组【(0.6±0.1),P<0.05】,血清HBeAg阳性率为41.3%,显著低于不应答组(70.4%,P<0.05),血清HBV pgRNA水平为(5.3±0.8)lg copies/mL,显著低于不应答组【(6.5±1.1)lg copies/mL,P<0.05】;Logistic回归分析显示,基线HBV DNA载量、HBeAg状态和血清HBV pgRNA水平均为影响核苷(酸)类似物治疗的CHB患者疗效的因素(OR=2.793、OR=3.827、OR=4.035,P均<0.05);经ROC分析显示,血清HBV pgRNA水平预测核苷(酸)类似物治疗CHB患者不应答的最佳截断点为5.89 lgcopies/mL,AUC值为0.865(95%CI:0.816～0.905),其预测的灵敏度为74.1%(20/27),特异度为88.8%(71/80)。结论 监测血清HBV pgRNA水平预测核苷(酸)类似物初治的CHB患者的疗效有一定的临床应用价值,如果检测结果稳定,不失为一种临床决策的参考依据。     

Effects of antiviral therapy in patients with chronic hepatitis B and cirrhosis

Introduction: Hepatitis B virus (HBV) infection is the major cause of cirrhosis worldwide. The ultimate goal of current antiviral treatments for chronic hepatitis B (nucleos(t)ide analogs and interferon-α) is to prevent the development of end-stage liver diseases.

Areas covered: We present a review of the current literature on antiviral therapy in patients with chronic hepatitis B and cirrhosis. Medline search was performed to identify relevant literature from 1993 through January of 2017.

Expert commentary: One randomized controlled trial and a number of observational studies have shown that nucleos(t)ide analogs can decrease the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B patients with advanced fibrosis. Data from clinical trials of entecavir and tenofovir have shown that histological improvement and regression of fibrosis can be achieved in the majority of patients with chronic hepatitis B by successful viral suppression. Entecavir and tenofovir are the preferred antiviral agents for treatment of chronic hepatitis B in patients with cirrhosis due to their high antiviral potency and high genetic barrier to resistance. Pegylated interferon-α is another therapeutic option for chronic hepatitis B patients with well-compensated cirrhosis. However, interferon therapy is contraindicated in patients with decompensated cirrhosis, and evidence for reduced HCC is currently insufficient.     

核苷(酸)类似物抗乙型肝炎病毒应用进展及耐药新认识

核苷(酸)类似物是目前临床上治疗乙型肝炎的重要药物,但应用过程中可出现乙型肝炎病毒的变异,从而发生耐药。本文就核苷(酸)类似物在乙型肝炎治疗方面的进展以及病毒耐药的新认识作一综述。     

Considerations for the long-term treatment of chronic hepatitis B with nucleos(t)ide analogs

Treatment of chronic hepatitis B (CHB) with nucleos(t)ide analogs is often required over a prolonged period to achieve durable virologic suppression. One barrier to the success of long-term therapy is the emergence of drug-resistant mutants. Current guidelines therefore recommend the most potent drugs with optimal resistance profiles, that is, entecavir and tenofovir are used as first-line monotherapies in CHB. Characteristics of the hepatitis B virus, the disease, the patient and the drug can influence the response to antiviral treatment and risk of relapse. This review discusses factors to consider maximizing the chances of successful long-term treatment of CHB, and provides an overview of the long-term efficacy and safety data that have become available over the 4–5 years since entecavir and tenofovir were first approved for the treatment of CHB. Recent findings on whether and under what circumstances long-term therapy of CHB might be stopped are also discussed.     

Management of hepatitis B in liver transplant recipients

Summary.  Advances in hepatitis B virus (HBV) antiviral prophylaxis have dramatically improved graft and patient survival for patients undergoing liver transplantation for hepatitis B related end-stage liver disease. In particular, the availability of hepatitis B immune globulin (HBIg) in combination with nucleos(t)ide analogues such as lamivudine and adefovir, have transformed outcomes. The availability of newer antivirals such as adefovir, tenofovir and entecavir either as monotherapy or in combination offer an increasing number of antiviral options. Despite these advances, significant challenges remain. Factors that affect the efficacy of anti-viral therapy include detectable HBV viraemia at the time of transplant and emergence of HBV mutants (especially in patients with prior exposure to lamivudine). HBV prophylaxis protocols are expensive especially with use of high-dose HBIg and newer nucleos(t)ide analogues. This review summarizes current HBV prophylaxis protocols and management of recurrent disease post-transplantation. There is an increasing need for individualization of therapy based on prior drug exposures, level of HBV DNA at time of transplantation and type of prophylaxis used.     

Management of patients with hepatitis B in special populations

The development of effective nucleos(t)ide analogs(NAs)against hepatitis B virus(HBV)has improved the outcome of patients with chronic hepatitis B(CHB).This review updates issues related to the management of CHB patients included in special populations.Entecavir(ETV)and tenofovir(TDF)represent the currently recommended first-line NAs in patients with HBV decompensated cirrhosis.The combination of HBV immunoglobulin(usually for a finite duration)and NA is considered the standard of care for prophylaxis against HBV recurrence after liver transplantation.TDF is the best choice for hemodialysis patients and in patients with chronic kidney disease with nucleoside resistance.ETV and telbivudine are the preferred options in na?ve renal transplant recipients and with low viremia levels,respectively.All hepatitis B surface antigen(HBs Ag)-positive candidates should be treated with NAs before renal transplantation to achieve undetectable HBV DNA at the time of transplantation.Conventional interferon or NAs can also be used in children,on the basis of well-established therapeutic indication.Pregnant women at high risk of perinatal transmission could be treated with lamivudine,telbivudine or TDF in the last trimester of pregnancy.HBs Ag-positive patients under immunosuppression should receive NA preemptively(regardless of HBV DNA levels)up to 12 mo after its cessation.In HBs Ag negative,anti-HBc positive patients under immunosuppression,further studies are needed to form a final conclusion;however,it seems that anti-HBV prophylaxis is justified in such patients with hematological diseases and/or for those receiving rituximab-containing regimens,regardless of their antiHBs or serum HBV DNA status.     

Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues

Hepatocellular carcinoma(HCC) is a major health problem worldwide, representing one of the leading causes of death. Chronic hepatitis B virus(HBV) infection(CHB) is the most important etiologic factor of this tumor, accounting for the development of more than50% of the cases in the world. Primary prevention ofHCC is possible by hepatitis B vaccination conferring protection from HBV infection. However, according to the World Health Organization Hepatitis B Fact sheet N° 204(update of July 2014) globally there exists a large pool of 240 million people chronically infected with HBV who are at risk for development of HCC. These individuals represent a target population for secondary prevention both of cirrhosis and of HCC. Since ongoing HBV replication in CHB is linked with the progression of the underlying liver disease to cirrhosis as well as with the development of HCC, effective antiviral treatment in CHB has also been evaluated in terms of secondary prevention of HCC. Currently, most patients with active CHB are subjected to long term treatment with the first line nucleos(t)ide analogues entecavir and tenofovir. These compounds are of high antiviral potency and have a high barrier to HBV resistance compared to lamivudine, adefovir dipivoxil and even telbivudine. Many studies have shown that patients under antiviral treatment, especially those in virological remission, develop less frequently HCC compared to the untreated ones. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC of patients with chronic hepatitis B must be lifelong or until a time in the future when new treatments will be able to completely eradicate HBV from the liver particularly in the early stages of CHB infection. In this context, the aim of this review is to outline the magnitude of the risk for development of HCC among patients with CHB, in the various phases of the infection and in relation to virus, host and environmental factors as evaluated in the world literature. Moreover, the benefits of antiviral treatment of CHB with nucleos/tide analogs, which have changed the natural history of the disease and have reduced but not eliminated the risk of HCC are also reviewed.