逆转录酶区A181T/V和A181T/V＋N236T变异的乙型肝炎病毒感染者临床特征分析

目的：比较逆转录酶区A181T/V变异与A181T/V＋N236T变异的乙型肝炎病毒感染者临床特征的异同。方法对55例发生rtA181T/V单独变异和34例发生rtA181T/V＋rtN236T联合变异的乙型肝炎病毒感染者既往核苷（酸）类似物治疗情况进行回顾,对耐药时谷丙转氨酶、谷草转氨酶、HBV M、HBV DNA等指标进行检测,并根据耐药测序结果确定病毒的基因型。结果阿德福韦单药治疗患者发生A181T/V＋N236T变异较A181T/V变异的比例高（57.6%对42.4%,P〈0.05）,而拉米夫定换用（或加用）阿德福韦治疗患者发生 A181T/V 变异较A181T/V＋N236T变异的比例高（75.5%对24.5%,P〈0.05）;在89例患者中B基因型和C基因型分别是14例和75例,不同变异在B或C基因型中的分布无统计学差异;A181T/V变异与A181T/V＋N236T变异相比,两组患者的年龄、性别构成、谷丙转氨酶、谷草转氨酶、HBV DNA、HBsAg定量、HBeAg状态等指标均无统计学差异。结论不同的核苷（酸）类似物治疗可导致A181T/V变异和A181T/V＋N236T变异模式的差异,但这两种变异感染者临床指标无明显差异。     

340例慢性乙型肝炎患者乙型肝炎病毒多位点耐药相关突变分析

目的 分析慢性乙型肝炎患者HBV逆转录酶基因与核苷(酸)类似物耐药相关的12个位点上的突变情况及其临床意义.方法 提取血清HBV DNA,扩增HBV逆转录酶基因,对PCR产物进行DNA双向测序,对测序成功的样本进行基因型分析.检测逆转录酶基因12个位点上的碱基突变情况,分析不同核苷(酸).类似物使用情况、患者的耐药相关突变情况及不同核苛(酸)类似物耐药的突变形式. 结果 检出拉米夫定耐药突变63例,阿德福韦耐药突变10例,恩替卡韦耐药突变8例,替比夫定耐药突变1例.拉米夫定耐药突变中以M204V和M204I最常见,前者通常伴随L180M突变,后者常单独出现,阿德福韦耐药中以N236T±A181位碱基替换为主;恩替卡韦耐药突变发生在拉米夫定耐药基础上,以T184位碱基替换为主;替比夫定的耐药突变为M204I.少数未接受过核苷(酸)类似物治疗的患者也可检出耐药相关突变.结论 检测HBV逆转录酶基因多位点耐药相关突变,有助于临床及时发现和确认乙型肝炎患者是否存在HBV耐药,合理进行抗病毒治疗.     

658例乙型肝炎患者HBV多位点耐药基因检测结果分析

目的分析乙型肝炎患者HBV核苷(酸)类似物耐药相关的10个位点的突变情况及其临床意义。方法采用焦磷酸测序法对658例各型乙型肝炎患者行核苷类似物抗乙肝病毒多位点耐药基因检测并分析不同核苷(酸)类似物耐药的突变形式,对常见突变模式者ALT和HBV-DNA水平进行比较。结果 300例发生不同位点变异,变异率为45.59%,其中有明确用药史者202例。拉米夫定耐药突变中以M204V和M204I最常见,前者通常伴随L180M突变,后者常单独出现;阿德福韦酯耐药中以N236T和A181位碱基替换为主;恩替卡韦耐药均伴随拉米夫定和阿德福韦酯耐药变异,以T184位点的碱基替换最为常见;主要变异模式间ALT及HBV-DNA水平均无明显差异。90例未接受过核苷(酸)类似物治疗者亦检出耐药相关突变。结论检测HBV多位点耐药基因相关突变有助于临床及时发现和确认乙型肝炎患者HBV耐药并指导抗病毒治疗。     

慢性乙型肝炎患者HBV基因型分布及其耐药基因突变分析*

目的 探讨慢性乙型肝炎（CHB）患者HBV基因型及其耐药突变发生情况。方法 纳入240例接受核苷（酸）类似物单药或联合或序贯治疗的CHB患者,采用PCR扩增HBV逆转录（RT）区和序列测定鉴定耐药基因突变,采用HBV S基因测序法鉴定基因型。结果 在35例单用拉米夫定治疗的CHB患者中,发生耐药突变14例（40.0%）,突变位点为rtL80I/V、rtVl73L、rtLl80M、rtM204V/I和rtV207I,23例单用阿德福韦治疗者发生耐药突变11例（47.8%）,突变位点为rtAl81T/V、rtS213T/N、rtV214A、rtQ215S/H/P、rtl233V、rtN236T、rtP237H和rtN/H238A/K/D/S,70例单用恩替卡韦治疗者发生耐药突变10例（14.3%）,突变位点为rtM204I,12例单用替比夫定治疗者发生耐药突变5例（41.7%）,突变位点为rtI169T、rtL180M、rtT184G/S/A/I/L/F、rtS202I/G、rtM204V和rtM250V/I/L,100例接受联合或序贯治疗者发生耐药突变51例（51.0%）,突变位点为rtA194T,恩替卡韦治疗患者耐药突变发生率最低（P<0.05）;240例CHB患者中,HBV基因B型21例（8.8%）、C型216例（90.0）和D型3例（1.2%）;在发生耐药突变的91例患者中,B型6例（6.6%）、C型83例（91.2%）和D型2例（2.2%,x²=1.22,P>0.05）;在发生耐药突变的6例B型感染者中有2例（33.3%）和83例C型感染者中有15例（18.1%）发生了多重耐药突变。结论 检测CHB患者感染HBV基因型并及时获得耐药突变基因分布,将有助于指导临床治疗。     

耐核苷(酸)类药物慢性乙型肝炎和肝硬化患者血清HBV基因型和P区耐药突变位点分析

目的了解慢性乙型肝炎和肝硬化患者HBV基因型分布和P区耐药突变位点的变异模式。方法选择39例经核苷(酸)类似物(NAs)治疗后存在耐药或疑似耐药的慢性乙型肝炎和肝硬化患者为研究对象,采用实时荧光定量PCR法测定血清HBV DNA,将PCR产物经琼脂糖凝胶电泳,鉴定和回收纯化后,交由上海生工生物工程(北京)有限公司进行测序,与HBVseq数据库比对,观察HBV基因型分布和耐药位点变化情况。结果 34例(87.2%)患者能检出HBV基因型,其中C基因型有32例(82.1%),B基因型有2例(5.1%);27例(69.2%)患者存在RT区序列突变,其中点变异12例(30.8%),rt M204I/V/S、rt A181V/T、rt I169T突变分别占15.4%、5.1%、10.3%,组合变异15例(38.4%);23例患者存在对NAs耐药,其中8例患者对阿德福韦酯耐药(1例为B基因型,7例为C基因型),耐药位点为rt A181V/T/S、rt V214A/E和rt N236T;11例患者对拉米夫定和替比夫定同时耐药,均为C基因型,其共同耐药位点为rt M204I/V/S和rt L180M;3例患者存在对LAM、LDT和恩替卡韦同时耐药,均为C基因型;1例C基因型患者对LAM、LDT和ADV同时耐药,其变异模式为rt M204I/V/S+rt A181V/T/S+rt L180M。结论多数对NAs耐药患者可在HBV P区检出基因突变,且突变形式多样,其中以rt M204I/V/S突变为主,不同核苷(酸)类似物中存在共同耐药位点。     

江苏部分地区慢性乙型肝炎病毒感染者天然耐药的调查

目的 通过连续监测江苏部分地区乙型肝炎病毒（HBV）感染者发生天然耐药基因变异的频度及耐药位点的分布特点,为合理选择抗病毒治疗的药物提供依据.方法 回顾性分析2004～2010年未服用核苷类似物抗病毒药物的352例慢性乙型肝炎（CHB）患者临床资料.应用焦磷酸测序技术及双脱氧链终止法基因测序的方法进行耐药基因的检测.结果 352例CHB患者中,345例基因测序成功,7例测序失败.8例有耐药基因突变,天然耐药突变检出率为2.32％.主要耐药位点为rtV173L、rtL180M、rtA181T、rtM204V、rtV207L、rtS213T、rtV214I、rtN236T.2004～2006年间145例CHB患者均未检测出耐药突变,2007、2008、2009及2010年耐药突变的检出率分别为2.63％、3.92％、4.69％和4％.多因素Logistic回归分析显示耐药突变的发生与感染者年龄相关.结论 江苏部分地区CHB患者有天然耐药基因突变,耐药突变检出率为2.32％.2004～2010年耐药突变检出率呈上升趋势.年龄超过30岁是耐药突变发生的相关因素.     

HBV反转录酶A181位点变异与临床耐药的关系

目的分析核苷（酸）类似物（NA）疗程中HBV反转录酶（rt）A181位点的变异与临床耐药的关系。方法对5例rtA181位点变异的慢性HBV感染患者做回顾性调查与随访,对比核苷类似物治疗前后的病毒学及肝功能生化应答情况。结果在85例HBV反转录酶测序中发现5例rtA181位点变异,5例中2例发生rtA181V变异,2例发生rtA181T变异,1例发生rtA181S变异,均未出现rtN236T及YMDD（rtM204）变异,其中4例与临床耐药相关。结论rtA181V／T／S变异与NA治疗中的耐药有关。     

慢性乙型肝炎患者HBV基因型分布及其耐药基因突变分析

目的探讨慢性乙型肝炎(CHB)患者HBV基因型及其耐药突变发生情况。方法纳入240例接受核苷(酸)类似物单药或联合或序贯治疗的CHB患者,采用PCR扩增HBV逆转录(RT)区和序列测定鉴定耐药基因突变,采用HBV S基因测序法鉴定基因型。结果在35例单用拉米夫定治疗的CHB患者中,发生耐药突变14例(40.0%),突变位点为rt L80I/V、rt Vl73L、rt Ll80M、rt M204V/I和rt V207I,23例单用阿德福韦治疗者发生耐药突变11例(47.8%),突变位点为rt Al81T/V、rt S213T/N、rt V214A、rt Q215S/H/P、rtl233V、rt N236T、rt P237H和rt N/H238A/K/D/S,70例单用恩替卡韦治疗者发生耐药突变10例(14.3%),突变位点为rt M204I,12例单用替比夫定治疗者发生耐药突变5例(41.7%),突变位点为rt I169T、rt L180M、rt T184G/S/A/I/L/F、rt S202I/G、rt M204V和rt M250V/I/L,100例接受联合或序贯治疗者发生耐药突变51例(51.0%),突变位点为rt A194T,恩替卡韦治疗患者耐药突变发生率最低(P0.05);240例CHB患者中,HBV基因B型21例(8.8%)、C型216例(90.0)和D型3例(1.2%);在发生耐药突变的91例患者中,B型6例(6.6%)、C型83例(91.2%)和D型2例(2.2%,x2=1.22,P0.05);在发生耐药突变的6例B型感染者中有2例(33.3%)和83例C型感染者中有15例(18.1%)发生了多重耐药突变。结论检测CHB患者感染HBV基因型并及时获得耐药突变基因分布,将有助于指导临床治疗。     

慢性乙型肝炎阿德福韦酯治疗应答不佳者外周血单个核细胞HBV-P区基因突变分析

目的研究阿德福韦酯（ADV）治疗基因C型慢性乙型肝炎（cHB）患者外周血单个核细胞（PBMcs）乙肝病毒聚合酶区（HBV—P区）序列的基因突变。方法14例基因c型CHB患者分为初治组（ADV初始治疗）7例,经治组（拉米夫定100mg口服每日1次,治疗24～56个月出现YMDD变异后换用ADV治疗）7例,ADV用药时间2～59个月,剂量10mg口服每日1次,血清HBVDNA≥1000copies／ml（应答不佳）者应用直接测序法检测血清及PBMCs内的HBV-P区基因突变,比较两者的异同。结果所有患者的血清和PBMCs内HBV均成功测序,大部分患者血清和PBMCs内的HBV序列一致。1例经治者和3例初治者感染的HBV为野生株,分别有11691＋＋＋V＋、Q215H＋＋＋Q＋、P237T＋＋＋突变。另10例（71．4％）检测到HBV有1个或多个耐药位点变异,主要变异位点为A181V／T／I、N236T。有1例血清HBV基因突变（A181T＋＋＋、N236T＋＋＋）与PBMCs内的HBV基因突变（A181T＋＋＋、N236T＋＋＋、11691＋＋＋V＋）不完全一致。结论ADV治疗cHB应答不佳者大部分血清与PBMCs内的HBV-P区基因突变一致,耐药模式不同,可有一个或多个位点突变,主要变异位点为A181V／T／I、N236T。     

拉米夫定耐药后联合阿德福韦酯治疗发生再耐药的慢性乙型肝炎患者的基因型及耐药位点分析

目的研究拉米夫定(LAM)耐药后联合阿德福韦酯(ADV)抗病毒治疗中发生病毒学突破的慢性乙型肝炎(CHB)患者的耐药位点和基因分型。方法收集2010年6月-2013年6月河南省人民医院收治的89例单用LAM耐药后,联合ADV抗病毒治疗的CHB患者的血清,应用实时定量PCR进行HBV拷贝检测,通过测序进行基因分型,并对rt N236T、rt A181V、rt M204V、rt L180M耐药位点进行检测。计量资料组间比较采用t检验,计数资料组间比较采用χ2检验。结果 89例患者单用LAM治疗后均发生LAM rt M204V位点突变,联合ADV治疗后,9例发生ADV rt N236T单位点突变,5例发生ADV rt A181V单位点突变,8例发生rt A181V+rt N236T双位点联合突变,累计ADV耐药率为24.7%(22/89)。89例患者的HBV基因分型中,C基因型82例,其中8例发生rt A181V+rt N236T双位点联合突变;B基因型7例。结论与B基因型相比,C基因型CHB患者单用LAM耐药后,联合ADV治疗中更易发生rt A181V+rt N236T双位点联合突变。     

No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg− patients with chronic hepatitis B after 8 years of treatment

A major hurdle in the long‐term treatment of chronic hepatitis B (CHB) patients is to maintain viral suppression in the absence of drug resistance. To date, no evidence of resistance to tenofovir disoproxil fumarate (TDF) has been observed. A cumulative evaluation of CHB patients who qualified for resistance surveillance over 8 years of TDF treatment was conducted. Patients in studies GS‐US‐174‐0102 (HBeAg?) and GS‐US‐174‐0103 (HBeAg+) were randomized 2:1 to receive TDF or adefovir dipivoxil (ADV) for 48 weeks followed by open‐label TDF through year 8. Population sequencing of HBV pol/RT was attempted for all TDF‐treated patients at baseline and, annually if viremic, at discontinuation, or with addition of emtricitabine. Overall, 88/641 (13.7%) patients qualified for sequence analysis at one or more time points. The percentage of patients qualifying for sequence analysis declined over time, from 9 to 11% in years 1‐2 to <4% over years 3‐8. Forty‐one episodes of virologic breakthrough (VB) occurred throughout the study, with most (n=29, 70%) associated with nonadherence to study medication. Fifty‐nine per cent of VB patients with an opportunity to resuppress HBV achieved HBV DNA resuppression. A minority of patients who qualified for sequencing had polymorphic (41/165, 24.8%) or conserved (17/165, 10.3%) site changes in pol/RT, with six patients developing lamivudine and/or ADV resistance‐associated mutations. No accumulation of conserved site changes was detected. The long‐term treatment of CHB with TDF monotherapy maintains effective suppression of HBV DNA through 8 years, with no evidence of TDF resistance or accumulation of conserved site changes.     

替诺福韦酯和恩替卡韦对慢性乙型肝炎初治患者疗效的荟萃分析

目的评价替诺福韦酯(TDF)和恩替卡韦(ETV)对慢性乙型肝炎(CHB)初治患者抗病毒的疗效及安全性。方法对2006年1月至2016年10月在国际生物医学期刊有关TDF和ETV治疗CHB的临床研究进行质量评价,并对相关文献进行荟萃分析。结果共纳入6篇文献。荟萃分析结果显示ETV和TDF抗病毒治疗的HBV DNA转阴率差异无统计学意义[48周时的RR=1.19,95%CI=1.09~1.30;96周时的RR=1.08,95%CI=1.02~1.14];两种药物的ALT复常率及HBeAg血清学转换率同样差异无统计学意义;且两种药物长期使用安全性良好,未观察到严重不良反应。结论 ETV和TDF对CHB核苷(酸)类药物初治患者抗病毒疗效相似,但仍需进一步观察远期治疗的安全性。     

Similar efficacy and safety of tenofovir in Asians and non-Asians with chronic hepatitis B

AIM:To compare the efficacy and safety of tenofovir disoproxil fumarate(TDF)in Asian and non-Asian chronic hepatitis B(CHB)patients.METHODS:The efficacy and safety of the initial 48wk of treatment with TDF was compared in a posthoc analysis of combined data from 217 Asians and299 non-Asians included in Studies 102 and 103and a post-approval,open-label trial(Study 123).Patient groups were compared according to baseline hepatitis B e antigen(HBe Ag)status and viral load.The main outcome measures included the proportion of patients who achieved a hepatitis B virus(HBV)DNA level400 copies/m L at Week 48 of treatment.Secondary measures included:HBV DNA and alanine aminotransaminase(ALT)levels over time;proportion of patients with normal ALT levels;proportion of patients with HBe Ag loss/seroconversion and proportion of patients with hepatitis B surface antigen loss/seroconversion;changes in liver histology.Safety and tolerability were evaluated by the occurrence of adverse events(AEs),serious AEs,laboratory abnormalities,discontinuation of the study drug due to AEs,or death.The primary efficacy and safety analysis set included all patients who were randomly assigned to treatment and received at least one dose of study drug.RESULTS:At week 48,similar proportions of Asians and non-Asians reached HBV DNA400 copies/m L(96%of Asian and 97%of non-Asian patients with HBe Ag-negative CHB and 83%of Asian and 79%of non-Asian patients with HBe Ag-positive CHB had HBV DNA)and normal ALT(78%of Asian and 81%of nonAsian patients with HBe Ag-negative CHB and 71%of Asian and 74%of non-Asian patients with HBe Agpositive CHB had normal ALT).On-treatment HBV DNA decline rates were similar between Asians and nonAsians regardless of baseline HBe Ag status and viralload.HBV DNA decline during the first four weeks was2.9 log10 copies/m L in HBe Ag-negative Asians and nonAsians,and in HBe Ag-positive non-Asians,and 3.1log10 copies/m L in HBe Ag-positive Asians.HBe Ag loss and seroconversion was achieved in 14%of Asians vs 26%and 24%,respectively,in non-Asians.Liver histology improved in 77.2%of Asians and 71.5%of non-Asians.No resistance to TDF developed.No renal safety signals were observed.CONCLUSION:TDF demonstrated similar viral suppression,normalization of ALT,improvements in liver fibrosis,and no detectable resistance in Asian and non-Asian patients regardless of baseline HBe Ag status.     

核苷和核苷酸类药物治疗慢性乙型肝炎产生多重耐药的挽救治疗观察

目的探索核苷和核苷酸类药物治疗慢性乙型肝炎产生多重耐药（MDR）的挽救治疗方法。方法 2011年2月-2012年5月在本院住院及门诊产生MDR的慢性乙型肝炎患者27例,分成替诺福韦（TDF）加恩替卡韦（ETV）组、TDF单用组及阿德福韦（ADV）加ETV组。按4、12和24周时间段观察肝肾生化指标,病毒基因及HBV标志物检测值。率的比较采用卡方检验。结果TDF＋ETV联合组,4周时血清肝生化检测值正常、HBV DNA检测值低于检测下限9/9例。TDF单用组,4周时血清肝生化指标复常9/9例,HBV DNA检测值低于检测下限6/9例。12周时HBV DNA检测值低于检测下限9/9例。沿用耐药时的ADV＋ETV治疗组,24周未见应答。与前两组对照,χ2=5.35～6.40,P〈0.01。结论 TDF可有效用于慢性乙型肝炎核苷和核苷酸类药物MDR的挽救治疗,效果优于ADV＋ETV治疗。     

Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease

Data are limited on the safety and effectiveness of oral antivirals other than lamivudine and adefovir dipivoxil for treatment of chronic hepatitis B (CHB) in patients with decompensated liver disease. This Phase 2, double-blind study randomized 112 patients with CHB and decompensated liver disease to receive either tenofovir disoproxil fumarate (TDF; n = 45), emtricitabine (FTC)/TDF (fixed-dose combination; n = 45), or entecavir (ETV; n = 22). The primary endpoint was safety; more specifically, tolerability failure (adverse events resulting in permanent treatment discontinuation) and confirmed serum creatinine increase ≥ 0.5 mg/dL from baseline or confirmed serum phosphorus <2 mg/dL. Patients with insufficient viral suppression (e.g., confirmed HBV DNA ≥ 400 copies/mL at week 8 or 24) could begin open-label FTC/TDF but were considered failures in this interim week 48 analysis for efficacy endpoints. Tolerability failure was infrequent across arms: 6.7% TDF, 4.4% FTC/TDF, and 9.1% ETV (P = 0.622) as were confirmed renal parameters meeting threshold 8.9%, 6.7%, and 4.5% (P = 1.000), respectively. Six patients died (none considered related to study drug) and six received liver transplants (none had HBV recurrence). The adverse event and laboratory profiles were consistent with advanced liver disease and complications, with no unexpected safety signals. At week 48, HBV DNA was <400 copies/mL (69 IU/mL) in 70.5% (TDF), 87.8% (FTC/TDF), and 72.7% (ETV) of patients. Proportions with normal alanine aminotransferase were: 57% (TDF), 76% (FTC/TDF), and 55% (ETV). Hepatitis B e antigen (HBeAg) loss/seroconversion occurred in 21%/21% (TDF), 27%/13% (FTC/TDF), and 0%/0% (ETV). Child-Turcotte-Pugh and Modification for End-stage Liver Disease scores improved in all groups. CONCLUSION: All treatments were well tolerated in patients with decompensated liver disease due to CHB with improvement in virologic, biochemical, and clinical parameters.     

乙型肝炎病毒感染不同状态下血清病毒反转录酶区准种特点及其临床意义

目的 研究HBV感染不同状态下血清病毒反转录酶(RT)区准种特点和临床意义.方法 50例未接受抗病毒治疗的HBV感染者分为慢性HBV携带者(ASC)组10例、慢性乙型肝炎(CHB)组30例和乙型肝炎肝硬化(LC)组10例.收集患者外周血血清,抽提HBV DNA,PCR扩增RT区基因组后克隆、测序.每例患者获得15～30个序列,进行HBV RT区的准种异质性分析及相关基因突变统计等生物信息学分析.多均数比较采用方差分析,中位数比较采用非参数检验分析,非计量资料比较采用x2检验.结果 总共测序1221个克隆,其中ASC组152个,CHB组780个,LC组289个.3组间基因型构成差异无统计学意义.准种复杂度为LC组＞CHB组＞ASC组,3组间差异有统计学意义(F=33.400,P＜0.05).准种离散度为LC组＞CHB组＞ASC组,LC组与CHB组及ASC组均差异有统计学意义(F=18.070,P＜0.05),CHB组与ASC组间差异无统计学意义.结论 慢性HBV感染过程中,免疫清除期比免疫耐受期具有更宽的HBV变异谱系,随着病程的延长和病情加重,HBV的准种趋向复杂.     

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.     

Tenofovir versus tenofovir plus entecavir for chronic hepatitis B with lamivudine resistance and entecavir resistance

We compared the viral suppressive efficacy of tenofovir disoproxil fumarate (TDF) mono‐rescue therapy (TDF group) and TDF plus entecavir (ETV) combination‐rescue therapy (TDF + ETV group) in chronic hepatitis B (CHB) patients with lamivudine resistance and entecavir resistance. One hundred and thirty‐three CHB patients with lamivudine and entecavir resistance were investigated. Ninety‐six patients were treated with TDF and 37 with TDF + ETV for at least 6 months. We compared the virologic response rate (HBV DNA level <20 IU/mL) between the two groups and identified the predictive factors of treatment outcome. There were no significant differences between the two groups in demographic characteristics. Up to 24 months [median: 18 (range 6‐24) months], 85.4% and 89.2% of the TDF group and TDF + ETV group, respectively, achieved a virologic response (P=.068). Only the HBV DNA level at baseline was significantly associated with a virologic response in the multivariate analysis. In a subanalysis of patients with HBV DNA levels ≥4 log (IU/mL) at baseline, a higher proportion of patients in the TDF + ETV group than the TDF group achieved a virologic response (92.9% vs 68.3%; P<.001), while 90% of patients with HBV DNA (IU/mL) levels <4 log in all both TDF and TDF + ETV groups achieved a virologic response. TDF mono‐rescue therapy is a reasonable option in patients with lamivudine resistance and entecavir resistance. However, the combination strategy should be considered in patients with high baseline HBV DNA levels.     

Tenofovir rescue therapy for chronic hepatitis B patients after multiple treatment failures

AIM: To evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB) patients after multiple failures.METHODS: A total of 29 CHB patients who had a suboptimal response or developed resistance to two or more previous nucleoside/nucleotide analogue (NA) treatments were included. Study subjects were treated with TDF alone (n = 13) or in combination with lamivudine (LAM, n = 12) or entecavir (ETV, n = 4) for ≥ 6 mo. Complete virologic response (CVR) was defined as an achievement of serum hepatitis B virus (HBV) DNA level ≤ 60 IU/mL by real-time polymerase chain reaction method during treatment. Safety assessment was based on serum creatinine and phosphorus level. Eleven patients had histories of LAM and adefovir dipivoxil (ADV) treatment and 18 patients were exposed to LAM, ADV, and ETV. Twenty-seven patients (93.1%) were hepatitis B e antigen (HBeAg) positive and the mean value of the baseline serum HBV DNA level was 5.5 log IU/mL ± 1.7 log IU/mL. The median treatment duration was 16 mo (range 7 to 29 mo).RESULTS: All the patients had been treated with LAM and developed genotypic and phenotypic resistance to it. Resistance to ADV was present in 7 patients and 10 subjects had a resistance to ETV. One patient had a resistance to both ADV and ETV. The cumulative probabilities of CVR at 12 and 24 mo of TDF containing treatment regimen calculated by the Kaplan Meier method were 86.2% and 96.6%, respectively. Although one patient failed to achieve CVR, serum HBV DNA level decreased by 3.9 log IU/mL from the baseline and the last serum HBV DNA level during treatment was 85 IU/mL, achieving near CVR. No patients in this study showed viral breakthrough or primary non-response during the follow-up period. The cumulative probability of HBeAg clearance in the 27 HBeAg positive patients was 7.4%, 12%, and 27% at 6, 12, and 18 mo of treatment, respectively. Treatment efficacy of TDF containing regimen was not statistically different according to the presence of specific HBV mutations. History of prior exposure to specific antiviral agents did not make a difference to treatment outcome. Treatment efficacy of TDF was not affected by combination therapy with LAM or ETV. No patient developed renal toxicity and no cases of hypophosphatemia associated with TDF therapy were observed. There were no other adverse events related to TDF therapy observed in the study subjects.CONCLUSION: TDF can be an effective and safe rescue therapy in CHB patients after multiple NA therapy failures.