阿德福韦酯与恩替卡韦治疗HBeAg阳性慢性乙型肝炎患者临床疗效观察

目的：观察阿德福韦酯和恩替卡韦治疗初治的 HBeAg 阳性慢性乙型肝炎患者96 w 的临床疗效及不良反应。方法在初治的 HBeAg 阳性慢性乙型肝炎患者中,接受阿德福韦酯治疗的患者38例,接受恩替卡韦治疗的患者30例,比较两组患者治疗前基线 ALT、HBV DNA、HBsAg、HBeAg、肌酐及治疗96 w 时的疗效。结果阿德福韦酯治疗患者基线 ALT 水平为（186.6±124.5） U/L,HBV DNA 水平为（7.3±1.1） log10拷贝/毫升,恩替卡韦治疗患者基线 ALT 水平为（190.8±116.8） U/L,HBV DNA水平为（7.5±1.5） log10拷贝/毫升 ml,两组具有可比性（P＜0.05）;在治疗96 w 时,恩替卡韦治疗患者 HBV DNA 阴转率为98.2%,显著高于阿德福韦酯治疗患者的60.2%（P＜0.05）;恩替卡韦组 ALT 复常率为97.1%,与阿德福韦酯组的92.7%相比,无显著性相差（P＞0.05）;恩替卡韦组 HBeAg 阴转率28.8%,与阿德福韦酯组的26.2%相比,无显著性相差（P＞0.05）。结论恩替卡韦在降低患者血清 HBV DNA 载量方面优于阿德福韦酯,但在血清 HBeAg 转阴率、ALT 复常率方面两者相似。     

恩替卡韦分散片对HBeAg阴性慢性乙型肝炎患者T细胞亚群的影响

目的探讨HBeAg阴性慢性乙型肝炎(CHB)患者接受恩替卡韦抗病毒治疗前后细胞免疫功能的变化。方法纳入HBeAg阴性CHB患者62例,接受恩替卡韦抗病毒治疗24周。通过流式细胞术检测患者治疗前后外周血T淋巴细胞亚群的变化。结果在治疗24周结束时,患者肝功能ALT、HBV DNA水平较治疗前明显下降,差异有统计学意义(P0.05);患者外周血CD3~+、CD4~+和CD8~+细胞计数较治疗前升高,CD4~+/CD8~+比值也显著高于治疗前,差异有统计学意义(P0.05)。结论恩替卡韦可能通过抑制HBV复制、降低CHB患者体内病毒载量,间接引起机体细胞免疫功能的改善。     

恩替卡韦治疗拉米夫定失效的慢性乙型肝炎患者3年临床研究

目的评价恩替卡韦对重庆地区拉米夫定治疗失效的CHB患者3年的疗效和安全性。方法选取拉米夫定治疗失效的CHB患者32例,其中恩替卡韦组28例(剂量1.0 mg/d),安慰剂组4例。完成12周的双盲冶疗后,所有患者均接受开放的恩替卡韦1.0mg/d,持续治疗至168周。定期检测血清HBV DNA水平、HBeAg、抗-HBe和肝功能的变化情况。结果在接受恩替卡韦治疗后,患者血清HBV DNA水平对数值的均数在2周内由9.14log10拷贝/ml迅速下降至6.72log10拷贝/ml,其后持续平稳下降,4、8、12、24、48周分别下降至6.28 log10、5.46 log10、5.10 log10、4.49 log10、4.41 log10拷贝/ml,至96周时下降至3.91 log10拷贝/ml,其后下降速度减慢,至144周和168周时分别为4.05 log10、4.21 log10拷贝/ml。HBV DNA>10~5拷贝/ml的百分比治疗前为100%,随着服药时间的延长逐渐下降,在12周时下降至46.43%,其后仍逐渐下降,到96周时仅为17.86%。与其相反,HBV DNA<10~3拷贝/ml的百分比在治疗前为0,从第8周开始逐渐上升(7.14%),12周时为10.71%,尤其在96周明显上升至46.43%,到168周时为57.14%。168周末HBeAg阴转率为10.07%。服用恩替卡韦后ALT下降较迅速,12周后均数达正常水平,且3年内持续低于40 U/L。3年治疗期间,患者不良事件发生率为21%,有1例发生严重不良事件。结论恩替卡韦治疗拉米夫定失效的CHB患者,可明显抑制HBV DNA复制,HBV DNA水平降低迅速且持久;能促进ALT复常;使用安全,耐受性良好。     

慢性乙型肝炎优化治疗疗效评价

目的根据基线ALT及HBV DNA水平评价乙型肝炎e抗原（HBeAg）阳性慢性乙型肝炎（CHB）患者优化治疗疗效。方法观察不同基线ALT水平患者,行拉米夫定抗病毒治疗12周、24周及52周时的HBeAg阴转率,不同基线HBV DNA患者抗病毒治疗24周后HBV DNA阴转率。结果基线ALT〈2 ULN组患者12周和52周HBeAg阴转率分别为2.1%和29.27%;基线ALT〉5 ULN组12周和52周HBeAg阴转率分别为22.5%和63.89%。24周治疗结束,单纯ALT≥2 ULN组和ALT≥2 ULN组且HBV DNA〈8log10拷贝/mL组病毒学应答分别为56.88%和73.22%。结论基线ALT水平较高患者抗病毒治疗HBeAg阴转率更高。较低病毒载量时病毒学应答更优。     

恩替卡韦治疗慢性乙型肝炎患者血清IL-4和IL-10水平变化

目的：探讨恩替卡韦（ETV）对慢性乙型肝炎（CHB）患者血清白细胞介素4（IL-4）和白细胞介素-10 （IL-10）水平的影响及其临床意义.方法：检测健康对照人群及CHB患者恩替卡韦抗病毒治疗24周前后血清ALT、HBV DNA、IL-4及IL-10的浓度,分析治疗前后4种指标的变化情况.结果：CHB患者血清中IL-4和IL-10水平高于健康对照组,差异有统计学意义（P均＜0.05）;CHB患者血清中ALT、HBV DNA、IL-4及IL-10水平在恩替卡韦抗病毒治疗后较治疗前均下降,差异有统计学意义（P均＜0.05）.结论：恩替卡韦能有效抑制HBV复制,降低CHB患者血清IL-4和IL-10的水平,并减轻肝脏炎症,改善CHB患者的免疫功能.     

恩替卡韦对 HBeAg 阴性慢性乙型肝炎患者血清脂联素浓度的影响

目的：观察 HBeAg 阴性慢性乙型肝炎患者恩替卡韦治疗前后血清脂联素水平的变化,探讨脂联素和HBeAg 阴性慢性乙型肝炎之间的关系。方法60例 HBeAg 阴性 CHB 患者接受恩替卡韦治疗24周,治疗前后采用ELISA 法检测血清脂联素水平,同时检测肝功能、血脂、空腹血糖、HBV DNA 载量,测量人体身高,体质量,计算体质指数（BMI）。结果CHB 患者使用恩替卡韦治疗24周后,ALT、AST、TBil、HBV DNA 和脂联素水平较治疗前相比明显下降,差异有统计学意义（P ＜0．05）,但 TC、TO、BMI 和 FBG 水平较治疗前相比差异无统计学意义（P ＞0．05）。结论HBeAg 阴性慢性乙型肝炎患者血清脂联素水平与肝脏炎症活动相关,对于 HBeAg 阴性慢性乙型肝炎患者的抗病毒治疗效果以及预后的判断具有一定参考意义。     

恩替卡韦与替诺福韦酯治疗高病毒载量慢性乙型肝炎患者的效果分析

目的 探讨恩替卡韦（ETV）与替诺福韦酯（TDF）对于高病毒载量初治患者的疗效及应答不佳的处理方案。方法 选取2016年6月—2021年7月广西医科大学第一附属医院感染性疾病科慢性乙型肝炎（CHB）患者抗病毒治疗队列中符合入组条件的患者165例。入组患者为基线HBV DNA>6 lg拷贝/mL,使用ETV或TDF满48周的CHB初治患者,并采用荧光定量PCR法检测HBV DNA。统计48周治疗的病毒学应答率;Logistic回归分析影响48周HBV DNA<500拷贝/mL和<100拷贝/mL应答的因素;分层分析比较48周后不同年龄、性别、基线HBV DNA、ALT、一线用药种类、HBeAg状态情况下HBV DNA<500拷贝/mL和<100拷贝/mL的应答率。非正态分布的计量资料2组间比较采用Mann-Whitney U检验,计数资料组间比较采用χ²检验或Fisher确切概率法,多因素分析采用二分类logistic回归模型分析。结果 48周治疗后85.5%（141/165）的患者HBV DNA<500拷贝/mL,66.1%（1...     

替比夫定与恩替卡韦治疗e抗原阳性慢性乙型肝炎的近期疗效比较

目的 观察替比夫定与恩替卡韦治疗HBeAg阳性慢性乙型肝炎患者近期疗效及安全性. 方法 80例患者随机分为替比夫定治疗组和恩替卡韦治疗组,分别在治疗前,治疗第12周和24周检测患者血清HBV DNA水平、ALT复常率、HBeAg阴转率和HBeAg/抗-HBe转换率,并比较不同基线血清HBV DNA水平患者治疗12周和24周时的血清HBV DNA下降值,HBV DNA低于检测值率,HBV DNA＜104拷贝/ml患者的比例.观察治疗过程中药物使用的安全性.结果 替比夫定和恩替卡韦组患者的基础人口学、临床和病毒学特征均具有可比性.治疗12周时,替比夫定组和恩替卡韦组患者HBV DNA低于检测值率均为50.0%,ALT复常率分别为52.5%和60.0%(P＞0.05),HBeAg阴转率分别为30.0%和5.0%(P＜0.01),HBeAg血清学转换率分别为20.0%和5.0%(P＜0.05);在治疗24周时,两组HBV DNA低于检测值率分别为80%和70%,(P＞0.05),ALT复常率分别为77.5%和75.0%(P＞0.05),HBeAg阴转率分别为45.0%和32.5%(P＞0.05),HBeAg血清学转换率分别为27.5%和17.5%(P＞0.05),两组均未发现明显不良反应.结论 替比夫定与恩替卡韦治疗HBeAg阳性的慢性乙型肝炎的近期HBV DNA水平低于检测值率,ALT复常率无明显差异;12周时替比夫定HBeAg血清学转换率高于思替卡韦组,但24周时两组间差异无统计学意义.     

替比夫定和恩替卡韦治疗HBeAg阳性慢性乙型肝炎患者早期疗效分析

目的比较替比夫定与恩替卡韦治疗HBeAg阳性慢性乙型肝炎患者24周疗效及安全性。方法将60例HBeAg阳性慢性乙型肝炎患者随机分为替比夫定组和恩替卡韦组,比较两组治疗第12周和24周的疗效。结果在治疗12周时,两组患者HBV DNA低于检测水平和ALT复常率相比较,差异无统计学意义（P〉0.05）,替比夫定治疗组HBeAg阴转率和HBeAg血清学转换率高于恩替卡韦组（36.7%对14.3%,26.7%对6.7%,P〈0.05）;在治疗24周时,两组HBV DNA低于检测水平、ALT复常率、HBeAg血清学转换率相比较,差异均无统计学意义（P〉0.05）,而替比夫定组HBeAg阴转率高于恩替卡韦组（P〈0.05）;多因素Logistic回归分析发现仅基线ALT水平高的患者更易出现HBeAg血清学转换。结论替比夫定和恩替卡韦治疗CHB患者疗效相当,但替比夫定治疗患者HBeAg阴转率稍高于恩替卡韦治疗。     

恩替卡韦长期治疗核苷（酸）类药物初治H BeAg阳性慢性乙型肝炎患者的疗效和安全性

目的：了解恩替卡韦单药治疗至少5年对核苷（酸）类药物初治的 HBeAg 阳性慢性乙型肝炎患者的疗效和安全性。方法选择BMS463-012和BMS463-023研究项目在瑞金医院感染科入组的20例 HBeAg 阳性慢性乙型肝炎核苷初治患者。所有患者在第一阶段（第1～2年）口服恩替卡韦0．5 mg/d,第二阶段（第3～5年）口服恩替卡韦1．0 mg/d。检测并记录基线以及治疗48、96、144、192和240周时患者的ALT、HBV DNA、HBeAg和 HBsAg水平。如治疗240周时HBV DNA ≥300拷贝/mL,则进行基因序列测定以明确是否发生耐药。结果恩替卡韦治疗第48、96、144、192和240周,HBV DNA ＜300拷贝/mL的比例分别为60％、40％、50％、85％和85％,HBeAg消失率分别为15％、15％、20％、30％和65％。有3例患者在第192周发生 HBeAg 血清学转换。恩替卡韦治疗48周时血清 HBV DNA＜300拷贝/mL 与＞300拷贝/mL患者相比,240周病毒学应答率分别为100％和66．7％;240周 HBeAg 血清学转换率分别为27．3％和0。入组患者中基线ALT＞2倍和＜2倍患者相比,前者240周病毒学应答率为100％,后者为75％;前者240周 HBeAg 血清学转换率为37．5％,而后者为0。入组患者基线高病毒载量（＞10^8拷贝/mL）和低病毒载量（＜10^8拷贝/mL）比较,前者240周病毒学应答率为83．3％,后者为100％;前者240周 HBeAg血清学转换率为11．1％,而后者为50％。以上二者相比,均差异有统计学意义（P＜0．05）。基线、治疗48、96、144、192和240周血清 HBsAg 水平分别为（4．04±0．40）、（3．64±0．44）、（3．73±0．41）、（3．53±0．55）、（3．55±0．55）和（3．55±0．63）lg IU/mL。相对于基线,在第48周、144周、192周、240周 HBsAg效价有明显下降（P值分别为0．005、0．005、0．009、0．018）。治疗240周时 HBeAg消失和未消失的患者,其基线 HBsAg效价（3．95±0．54）lg IU/mL比（4．20?     

Prediction of response to entecavir therapy in patients with HBeAg-positive chronic hepatitis B based on on-treatment HBsAg, HBeAg and HBV DNA levels

Summary. Quantitative hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) assays are emerging as effective tools of on‐treatment predictors of response to antiviral agents, in addition to monitoring serum HBV DNA levels. However, the dynamic relationship between quantitative HBsAg, as well as HBeAg and HBV DNA, and the predictability of subsequent clinical outcomes during entecavir (ETV) therapy remain unclear. Eighty‐two patients with HBeAg‐positive chronic hepatitis B (CHB) received ETV therapy for ≥3 years. Virologic response (VR) after 3 years of ETV therapy was achieved in 73 (89.0%) patients. Among baseline and on‐treatment factors, on‐treatment HBV DNA levels performed better with respect to the prediction of response than HBsAg and HBeAg levels. Especially, the performance of absolute values of HBV DNA with respect to response was superior to HBV DNA decline from the baseline. The best predictive value was an absolute HBV DNA level of 2.3 log₁₀ IU/mL at month 6 (areas under the curve [AUROC], 0.977; 95% CI, 0.940–1.000; P < 0.001). HBeAg seroconversion after 3 years of therapy was achieved in 26 (31.7%) patients. On‐treatment HBeAg levels performed better with respect to the prediction of seroconversion than HBsAg and HBV DNA levels. The best cut‐off value for the HBeAg level at month 12 for the prediction of seroconversion was 0.62 log₁₀ PEIU/mL. Although the HBsAg level at baseline is often used to predict the antiviral potency of entecavir, on‐treatment HBV DNA and HBeAg levels are more helpful for prediction of subsequent clinical outcomes in HBeAg‐positive CHB patients with entecavir treatment.     

阿德福韦酯单药挽救治疗对拉米夫定耐药的慢性乙型肝炎患者3年疗效观察

目的总结阿德福韦酯(ADV)单药挽救治疗拉米夫定(LAM)耐药慢性乙型肝炎患者效果,分析疗效影响因素,探讨单药挽救LAM耐药的可行性。方法 60例慢性乙型肝炎应用LAM耐药后入组挽救治疗。收集患者的基本特征:如年龄、性别、肝生化指标、HBV DNA及HBV M。纪录治疗持续时间及应答,并进行分组对照。结果 60例中,HBV DNA定量反弹≥1log10拷贝/ml 20例,HBV DNA测序rtM204I/V、rtL180M位点变异40例。生化学突破的LAM耐药患者,给予ADV单药治疗。完成156周治疗者42例。HBV DNA低复制组(基线水平HBV DNA 103～105拷贝/ml)治疗后第12至156周HBV DNA转阴率均为80.0%,高复制组(基线水平HBV DNA≥106拷贝/ml)转阴率为40.7%～44.7%,两组相比差异有统计学意义(P<0.01)。HBV DNA转阴率随治疗时间延长渐增加。治疗156周时,HBeAg阳性血清学转换率24.1%。4例因检测出rtA181V/I/S位点变异改用恩替卡韦(ETV)。结论 ADV单药挽救治疗LAM耐药慢性乙型肝炎,具有一定的疗效,且更适合于低病毒载量患者。     

拉米夫定和阿德福韦酯初始联合与恩替卡韦单药治疗慢性乙型肝炎的疗效和安全性比较

目的 观察拉米夫定(LAM)和阿德福韦酯(ADV)初始联合与恩替卡韦(ETV)单药治疗慢性乙型肝炎的疗效,并比较两者的安全性.方法 选择我院2007年6月-2008年1月符合抗病毒治疗的未曾使用核苷(酸)类似物的初治慢性乙型肝炎患者120例,分为联合组60例和单药组60例,联合组应用LAM 100 mg,ADV 10 mg,每日1次;单药组应用ETV 0.5 mg,每日1次.分别在基线、12、24、48、96周时留取血清,采用全自动分析生物化学仪检测肝功能、肾功能、血生物化学指标;采用化学发光法定量检测HBsAg和HBeAg;采用实时荧光定量PCR检测HBV DNA水平;采用PCR产物直接测序法检测病毒耐药基因.组间比较采用配对t检验,率的比较采用χ2检验.结果 (1)联合组54例,单药组50例完成了48周随访,联合组51例,单药组48例完成了96周随访.两组治疗前性别、年龄、血清ALT、血肌酐、HBV DNA、HBsAg水平及HBeAg阳性率,差异无统计学意义,具有可比性.(2)两组在治疗12周和24周时,HBV DNA＜300拷贝/ml和HBV DNA＜1000拷贝/ml的比率,差异无统计学意义.治疗12周时,单药组和联合组HBV DNA下降＜1 log10拷贝/ml的分别为3.7%(2/54)和18.0%(9/50),两组比较,χ2=5.556,P＜0.05,差异有统计学意义.(3)治疗48周时,单药组和联合组的ALT复常率、HBVDNA＜1000拷贝/ml的比率、HBeAg血清转换率以及与基线比较HBV DNA下降绝对值,差异均无统计学意义.联合组与单药组HBV DNA＜300拷贝/ml的患者分别为90.7%(49/54)和76.0%(38/50),两组比较,χ2=4.125,P＜0.05,差异有统计学意义.(4)治疗96周时,HBV DNA＜300拷贝/ml、HBV DNA＜1000拷贝/ml患者比率和HBeAg血清转换率,联合组分别为96.1%(49/51)、98.0%(50/51)、41.7%(15/36),单药组分别为79.2%(38/48)、87.5%(42/48)、16.7%(6/36),两组比较,χ2值分别为6.639、4.180、5.445,P值均＜0.05,差异有统计学意义;但两组患者与基线比较HBV DNA和HBsAg下降绝对值以及ALT复常率差异无统计学意义.(5)治疗96周时,联合组未见病毒学突破和耐药发生,而单药组累计发生病毒学突破4例,其中3例(6.3%,3/48)检测到ETV相关耐药基因变异位点,2例患者在基线时存在LAM相关耐药基因变异位点(rtL180M+M204V).(6)治疗48、96周时,联合组与单药组患者血肌酐水平及治疗前后血肌酐升高水平差异无统计学意义.在治疗期间,两组均无血清肌酐水平超过正常上限或由于肌酐升高0.5 mg/dl而调整剂量的患者.结论 LAM和ADV初始联合治疗,在减少病毒学突破和耐药发生,以及提高HBeAg血清转换率方面优于ETV单药治疗.

Abstract：

Objective To compare the efficacy and safety of Lamivudine (LAM) plus Adefovir dipivoxil (ADV) combination therapy and Entecavir(ETV) monotherapy for chronic hepatitis B patients.Methods 120 patients with chronic hepatitis B managed in a single-centre clinical practice (median 96 weeks)were split into 2 cohorts,one was treated with de-novo combination Lamivudine (100 mg/day) plus Adefovir (10 mg/day) (LAM+ADV),thc other with Entecavir (0.5 mg/day) monotherapy.Serum levels of ALT,creatinine,HBsAg,HBeAg and HBV viral load,together with genotypic resistence were analyzed at 0,12,24,48,96 weeks,respectively.HBV DNA was determined by real-time PCR.HBsAg and HBeAg were assessed by chemiluminescence.Serum levels of ALT and creatinine were detected by automatic biochemical analyzer.HBV genotypic resistence was tested by direct sequencing.Results (1) At the time point of 96 weeks,a total of 99 patients(51 cases in combination therapy cohort and 48 case in monotherapy cohort) were compared.The baseline characteristics as for HBV viral load,median age,serum levels of ALT and creatinine were compatible between combination therapy cohort and monotherapy cohort.(2) The rates of HBV DNA ＜300 copies/ml and HBV DNA ＜ 1000 copies/ml had no significant difference between LAM + ADV and ETV cohorts by the 12 and 24 weeks (P ＞ 0.05).(3) At the time point of 48 weeks,the rates of HBV DNA＜1000copies/ml,HBeAg seroconversion,and ALT normalization were similar in both cohorts,though the rate of HBV DNA ＜ 300 copies/ml was obviously higher in combination therapy cohort than that of monotherapy cohort (90.7% vs 76%,P ＜ 0.05).(4) At the time point of 96 weeks,the rates of HBV DNA ＜ 300 copies/ml (96.1% vs 79.2%),HBV DNA ＜ 1000 copies/ml (98% vs 87.5%) and the HBeAg seroconversion (41.7% vs 16.7%) were markedly higher in combination therapy cohort than those of monotherapy cohort statistically (P ＜ 0.05 for all).The mean values of decreases for HBV viral loads and HBsAg levels were smilar in both cohorts at 48 and 96 weeks.(5) Elevated serum creatinine not be found in both cohorts at the end of treatment.(6) No virological breakthrough occurred in combination therapy cohort at the end of treatment.Four patients in monotherapy cohort were found with virological breakthrough at 96 weeks and three cases among were confirmed to be of variants associated with ETV resistance (rtLl80M + T184L + M204V).Conclusions Present study suggests that Lamivudine plus Adefovir dipivoxil de-novo combination therapy was more efficacious than Entecavir monotherapy for CHB patients and the tolerance is compatible.     

Poor durability of lamivudine effectiveness despite stringent cessation criteria: a prospective clinical study in hepatitis B e antigen-negative chronic hepatitis B patients

Background and Aims: Lamivudine, a nucleoside analog, is commonly used for treatment of chronic hepatitis B (CHB) but its durability of effectiveness after withdrawal is still uncertain. This study was designed to assess the durability of lamivudine treatment with stringent cessation criteria in hepatitis B e antigen (HBeAg)‐negative patients and to explore potential predictive factors. Methods: Sixty one HBeAg‐negative CHB patients who had received lamivudine for at least 24 months and had maintained undetectable serum hepatitis B virus (HBV) DNA plus normal alanine aminotransferase for ≥ 18 months before withdrawal were included. They were followed up monthly during the first 4 months and at 3‐month or 6‐month intervals thereafter. Relapse was defined as serum HBV DNA ≥ 10⁴ copies/mL. Results: Thirty one of 61 patients relapsed during follow‐up, over 90% occurred within 18 months after lamivudine withdrawal. Cumulative relapse rates at months 6, 12, 24, 36, 48 and 60 were 26.2%, 43.6%, 49.7%, 52.1%, 56.1% and 56.1%, respectively. Cox regression revealed that age was the only predictive factor for relapse, with lower relapse rates found in younger patients. Hepatitis B surface antigen (HBsAg) turned negative in eight patients, and none of them relapsed during follow‐up. Conclusion: Effectiveness of lamivudine treatment is not durable in HBeAg‐negative CHB patients even when stringent cessation criteria are adopted, with the exception of patients aged ≤ 20 years. The ideal end point of lamivudine treatment is clearance of serum HBsAg.     

Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir

Quantitative hepatitis B surface antigen (qHBsAg) and quantitative hepatitis B e antigen (qHBeAg) titers are emerging as useful tools for measuring viral loads and for predicting the virological response (VR) and serological response (SR) to pegylated interferon therapy. However, the clinical utility of these assays in patients taking entecavir (ETV) is largely unknown. Treatment-naive patients with chronic hepatitis B (CHB) who were taking ETV for 2 years were enrolled. The qHBsAg and qHBeAg levels were serially measured with the Architect assay. From 95 patients, 60.0% of whom were hepatitis B e antigen-positive [HBeAg(+)], 475 samples were analyzed. The median baseline log hepatitis B virus (HBV) DNA, log qHBsAg, and log qHBeAg values were 6.73 copies/mL (4.04-9.11 copies/mL), 3.58 IU/mL (1.17-5.10 IU/mL), and 1.71 Paul Ehrlich (PE) IU/mL (-0.64 to 2.63 PE IU/mL), respectively. For the prediction of VR (HBV DNA < 60 copies/mL at 24 months) in HBeAg(+) patients, baseline alanine aminotransferase (P = 0.013), HBV DNA (P = 0.040), and qHBsAg levels (P = 0.033) were significant. For the prediction of VR, the area under the curve for the baseline log qHBsAg level was 0.823 (P < 0.001); a cutoff level of 3.98 IU/mL (9550 IU/mL on a nonlogarithmic scale) yielded the highest predictive value with a sensitivity of 86.8% and a specificity of 78.9%. As for SR (HBeAg loss at 24 months), the reduction of qHBeAg was significantly greater in the SR(+) group versus the SR(-) group. The sensitivity and specificity were 75.0% and 89.8%, respectively, with a decline of 1.00 PE IU/mL at 6 months. With ETV therapy, the correlation between HBV DNA and qHBsAg peaked at 6 months in HBeAg(+) patients. CONCLUSION: Both qHBsAg and qHBeAg decreased significantly with ETV therapy. The baseline qHBsAg levels and the on-treatment decline of qHBeAg in HBeAg(+) patients were proven to be highly useful in predicting VR and SR, respectively. The determination of qHBsAg and qHBeAg can help us to select the appropriate strategy for the management of patients with CHB. However, the dynamic interplay between qHBsAg, qHBeAg, and HBV DNA during antiviral therapy remains to be elucidated.     

核苷(酸)类似物抗乙型肝炎病毒达到治疗终点标准停药后复发的相关因素分析

目的 探讨影响核苷(酸)类似物(NA)治疗慢性乙型肝炎(CHB)患者达到治疗终点标准(达标)停药后复发的相关因素.方法 CHB患者81例,接受NA抗病毒治疗.拉米夫定(LAM)治疗38例,阿德福韦酯(ADV)25例,恩替卡韦(ETV)12例,LAM+ADV 6例.HBeAg阳性40例,NA初治患者67例,耐药复治14例.达标停药或延长疗程后停药,分别于基线、病毒学应答前每个月、病毒学应答后每3个月、停药后半年内每个月、半年后每2个月检测HBV DNA、HBV血清学标志物和ALT.将性别、年龄、乙型肝炎家族史、基线HBV DNA、基线HBeAg、基线ALT、病毒学应答时间、总疗程(月)、延长疗程(月)、初治或耐药复治、停药时HBsAg水平、药物种类共12个可能影响复发的因素进行单因素、多因素Cox比例风险模型和分层分析,累计复发率采用Kaplan-Meier法计算.结果 81例患者达标停药后,36例患者在1年内复发,占44.4%.初治或耐药复治、乙型肝炎家族史、病毒学应答时间、停药时HBsAg水平分别是影响停药后复发的独立危险因素.耐药复治者复发率高于初治患者(78.6%比37.3%,χ2=7.983,P=0.005),有乙型肝炎家族史的患者复发率高于无乙型肝炎家族史者(64.5%比15.0%,χ2=12.096,P=0.002),病毒学应答发生在3个月内的患者复发率低于发生在3个月后的患者(34.0%比64.3%,χ2=6.823,P=0.009),停药时HBsAg≤150μg/L的患者复发率低于>150μg/L者(27.6%比53.8%,χ2=5.199,P=0.023).结论 耐药复治、有乙型肝炎家族史、病毒学应答时间晚、停药时高水平HBsAg是导致NA治疗停药后复发的主要因素.对此类患者治疗达标后应适当延长疗程,巩固疗效.

Abstract：

Objective To explore the influence factors on hepatitis B virus (HBV) relapse after nucleos(t)ide analogues (NA) withdrawal in the chronic hepatitis B (CHB) patients who met NA cessation criteria. Methods Eighty-one consecutive CHB patients were treated with NA, 38 with lamivudine (LAM), 25 with adefovir dipivoxil (ADV), 12 with entecavir (ETV), 6 with LAM +ADV. Among recruited patients, 40 were hepatitis B virus e antigen (HBeAg) positive, 41 were HBeAg negative, 67 of them were initial treatment, 14 were retreatment due to resistance to NA at baseline. The treatment was discontinued after meeting China therapeutic end-point criteria. HBV DNA, HBV serological markers, alanine aminotransferase (ALT) were measured respectively at baseline, every month before virological response, every 3 months after virological response, every month within first 6 months and every 2 months over 6 months after drugs withdrawal. Twelve probable influence factors on relapse which were sex, age, HBV family history, baseline HBV DNA,baseline HBeAg status, baseline ALT, virological response time, total duration of treatment, duration of additional treatment, the level of hepatitis B virus surface antigen (HBsAg) at cessation therapy,initial treatment or retreatment, drug category were analyzed with univariate, multivariate Cox regression modle and stratified analysis. The cumulative relapse was calculated by the Kaplan-Meier method. Results A total of 36 patients (44. 4%) relapsed within 1 year. Initial treatment or retreatment, HBV family history, virological response time, the level of HBsAg at cessation therapy were independent risk factors. The relapse rate of retreatment was higher than that of initial treatment (78.6% vs 37. 3% , χ2 = 7. 983, P = 0. 005) , those of patients with HBV family history higher than without family history (64. 5% vs 15.0%, χ2 =12. 096,P = 0.002), those of patients obtained virological response within 3 months lower than after 3 months(34. 0% vs 64. 3% , χ2 =6. 823,P=0. 009) , those of patients with HBsAg≤150 μg/L at cessation therapy lower than >150 μg/L(27. 6% vs 53. 8%, χ2=5. 199,P=0. 023). Conclusions Retreatment, HBV family history, later virological response and higher HBsAg level at cessation therapy are risk factors of relapse after NA withdrawal. Such patients should be treated with prolonged duration after meeting end-point criteria to strengthen the efficacy.     

恩替卡韦或其联合阿德福韦酯补救治疗拉米夫定联合阿德福韦酯应答不佳的慢性乙型肝炎

目的 对拉米夫定(LAM)初治耐药后,LAM联合阿德福韦酯(ADV)应答不佳的慢性乙型肝炎患者,分别采用恩替卡韦(ETV)单药或ETV联合ADV进行补救治疗,比较两种补救方案的疗效.方法 对LAM初治耐药后应用LAM联合ADV应答不佳的40例患者,分别应用ETV 1.0 mg/d(14例)及ETV 0.5 mg/d联合ADV 10mg/d (26例)两种方案进行补救治疗,至少观察48周,定期监测HBV DNA、肝肾功能、HBV标志物等指标.根据资料不同分别采用t检验Wilcoxon检验或x2检验.结果 两组患者采用补救治疗前的基线情况差异无统计学意义.分别采用两种补救方案治疗后,两组患者HBV DNA水平均有下降,但ETV联合ADV组下降幅度较大.补救治疗24周时,ETV 1,0mg组有28.6％％(4例)达到HBV DNA转阴,ETV联合ADV组则有80.8％ (21例)达到HBV DNA转阴,x2=8.469,P=0.004,差异具有统计学意义;48周时,ETV1.0mg组仍仅有4例患者HBV DNA转阴,而ETV联合ADV组全部26例患者均达到HBV DNA转阴.补救治疗24周时,ETV 1.0mg组有42.9％(6例)患者ALT复常,ETV联合ADV组有92.3％ (24例)患者ALT复常,x 2=9.337,P=0.002,差异具有统计学意义;48周时,ETV 1.0mg组有57.1％(8例)患者ALT复常,而ETV联合ADV组所有患者均达到ALT复常.补救治疗48周时,ETV 1.0mg组有1例患者发生HBeAg血清学转换,ETV联合ADV组有4例患者发生HBeAg血清学转换.结论 对于LAM耐药后LAM联合ADV应答不佳的慢性乙型肝炎患者,采用ETV联合ADV的补救方案较ETV单药1.0mg的方案更为有效,可以实现更好的病毒学及生物化学应答.     

恩替卡韦与拉米夫定治疗慢性乙型肝炎随机、双盲、双模拟对照研究

目的以拉米夫定（LVD）为对照,评估恩替卡韦（ETV）治疗中国成人慢性乙型肝炎（CHB）的抗病毒疗效和安全性。方法多中心（26个中心）、随机、双盲、双模拟的对照研究。519例核苷类初治的CHB患者,随机分为ETV组（0．5mg／d）258例和LVD组（100mg／d）261例,用药时间至少52周。应用两种HBV定量法（bDNA和PCR）于12、24、36和48周检测血清病毒载量,每隔4周随访患者,记录不良事件和实验室异常的数据,以监测研究药物的安全性。结果ETV和LVD两组患者的基础人口学、临床和病毒学特征相似。经过48周的治疗,到达主要疗效终点者,ETV组为90％,LVD组仅69％（P〈0．0001）。HBV DNA的载量（PCR定量）,ETV组平均下降5．9lg拷贝／ml,LVD组平均下降4．3lg拷贝／ml,二者相差超过1．5lg拷贝／ml（P〈0．0001）。用PCR法,ETV组中有76％的患者测不到病毒（〈300拷贝／ml）,而LVD组中仅为43％。ALT的复常,ETV组也优于LVD组,分别为90％和78％（P=0．0003）。两组患者HBeAg的血清学转换率分别为15％和18％,差异无统计学意义（P=0．39）。两组患者不良事件的发生率基本相似,分别为60％和56％,严重不良事件的发生率分别为3％和5％。在治疗期间,没有死亡病例。结论ETV治疗核苷类初治CHB患者,抑制病毒和改善肝脏生化功能方面均优于LVD,安全性与LVD相当。     

Effect of nucleoside analog‐interferon sequential therapy on patients with acute exacerbation of chronic hepatitis B

Aim: Nucleoside analog (NA)‐interferon (IFN) sequential therapy may enable the long‐term control of chronic hepatitis B (CHB) and the withdrawal of the nucleoside analog. We evaluated the efficacy of NA‐IFN sequential therapy for acute exacerbation of CHB. Methods: A total of 12 patients with acute exacerbation of CHB, nine of whom were positive for hepatitis B e antigen (HBeAg), were enrolled in this study. All the patients were treated with lamivudine 100 mg/day alone for 20 weeks, then with both IFN‐α 6 megaunits three times per week and lamivudine for 4 weeks, and lastly, with IFN‐α alone for 20 weeks. Patients whose serum alanine aminotransferase (ALT) level was normalized, whose serum hepatitis B virus (HBV) DNA level decreased to less than 5 log copies/mL, and HBeAg level was absent 24 weeks after the end of treatment were defined as having sustained virological response (SVR). The other patients were defined as having no response (NR). Results: Four out of nine (44.4%) HBeAg‐positive and all three HBeAg‐negative patients achieved SVR. The levels of serum alanine aminotransferase (ALT), HBV DNA and HBV core‐related antigen were similar between SVR and NR patients at baseline. Three of four patients (75.0%) whose serum HBeAg became negative at the end of treatment achieved SVR, while one of five (20.0%) whose serum HBeAg remained positive achieved SVR. Conclusion: NA‐IFN sequential therapy for patients with acute exacerbation of CHB enables the withdrawal of treatment and is particularly effective for patients whose serum HBeAg has become undetectable by the end of the IFN treatment.