核苷（酸）类似物抗乙型肝炎病毒的安全性回顾

核苷（酸）类似物是一类口服抗乙型肝炎病毒的药物,多数患者从其治疗中获益,其安全性亦不可忽视。此文就此类药物不良反应的临床表现、发生机制和影响因素作一综述。     

核苷（酸）类似物单药和联合治疗慢性乙型肝炎疗效分析

慢性乙型肝炎是我国最常见的慢性传染病之一,目前慢性乙型肝炎的治疗有两种不同方法,其中一种是口服抗HBV的核苷（酸）类似物长期有效地抑制乙肝病毒复制。本文将对近年核苷（酸）类似物的单药治疗和联合治疗的疗效及优劣进行综述。     

不同核苷（酸）类似物治疗慢性乙型肝炎患者对eGFR的影响

目的 本研究旨在研究在接受核苷（酸）类似物（NAs）治疗的慢性乙型肝炎（CHB）患者对估算的肾小球滤过率（eGFR）的影响。方法 40例替诺福韦（TDF）、56例替比夫定（LDT）和68例恩替卡韦（ETV）初治的CHB患者,采用慢性肾脏病流行病学合作研究公式 （CKD-EPI）方程对基线和治疗24个月 eGFR进行评估。结果 在治疗24个月时,ETV组和TDF组eGFR分别为（89.5±13.2） ml·min^-1·1.73 m^-2和（93.8±13.2） ml·min^-1·1.73 m^-2,均明显较基线下降【分别为（93.4±9.8） ml·min^-1·1.73 m^-2,P=0.041和（98.6±11.2） ml·min^-1·1.73 m^-2,P=0.016】,而LDT组eGFR为（108.5±10.9） ml·min^-1·1.73 m^-2,明显较基线升高【（96.6±10.3） ml·min^-1·1.73 m^-2,P=0.002】;基线时3组患者eGFR构成比无统计学差异（P=0.870）,而在治疗24个月时3组患者eGFR构成比有统计学差异（P=0.028）,LDT组肾功能正常者的比例明显高于ETV和TDF组（P=0.001）,TDF组和ETV组eGFR构成比无统计学差异（P=0.861）;24个月时,ETV和TDF组分别有16.7%（3/18）和44.4%（4/9）基线肾功能正常者进展成eGFR<90 ml·min^-1·1.73 m^-2,而69.2%（9/13）LDT组基线肾功能损伤患者eGFR水平恢复至正常（≥90 ml·min^-1·1.73 m^-2）。结论 应用LDT长期治疗CHB患者能改善eGFR水平,而应用TDF和ETV有可能导致eGFR降低。     

核苷（酸）类似物治疗慢性乙型肝炎停药患者随访观察

目的观察在停止核苷类药物（NUCs）治疗后,CHB患者的病情复发情况。方法收集接受NUCs治疗达到停药标准的CHB患者79例,其中HBeAg阳性患者47例,HBeAg阴性患者32例。接受拉米夫定（LAM）治疗者33例、阿德福韦酯（ADV）治疗者27例、恩替卡韦（ETV）治疗者19例。观察停药48 w患者生物化学和病毒学指标的反弹情况。结果在79例接受NUCs治疗达到停药标准的CHB患者,在停药48 w时HBV DNA转阳43例（54.4%）。在HBeAg阳性患者,HBV DNA转阳26例（55.3%）,在HBeAg阴性患者,HBV DNA转阳17例（53.1%）,两组间差异无统计学意义（P〉0.05）;接受LAM、ADV和ETV治疗患者在停药后血清HBV DNA转阳发生率无统计学差异（P〉0.05）;在48 w时ALT再次升高36例（45.6%）。在HBeAg阳性患者,ALT再次升高20例（42.6%）,在HBeAg阴性患者,ALT再次升高16例（50.0%）,两组间差异无统计学意义（P〉0.05）。接受LAM、ADV和ETV治疗的患者血清ALT再次升高发生率的差异无统计学意义（P〉0.05）。结论接受NUCs治疗达到停药标准的CHB患者,不管应用现有的何种药物,在停药后仍有较高的复发率,对这些患者的再治疗问题值得研究。     

核苷（酸）类似物抗病毒治疗慢性乙型肝炎的优化策略

目前我国有4种核苷（酸）类似物可用于慢性乙型肝炎的抗病毒治疗,即拉米夫定、阿德福韦酯、恩替卡韦和替比夫定。但由于患者的性别、年龄、遗传背景、感染乙型肝炎病毒（HBV）的途径、病毒基因型、病程长短、肝脏病变程度和对治疗药物敏感性等不同,即使有同样治疗适应证的患者按同样的规范方案治疗后,仍有     

核苷（酸）类似物初始治疗慢性乙型肝炎患者疗效和安全性的网络Meta分析

目的 比较核苷（酸）类似物单药初始治疗慢性乙型肝炎患者的疗效和安全性。方法 计算机检索阿德福韦酯（ADV）、恩替卡韦（ETV）、拉米夫定（LAM）、替比夫定（LdT）和富马酸替诺福韦酯（TDF）初始治疗慢性乙型肝炎患者的随机对照试验。应用Stata13进行网络Meta分析。采用固定效应模型和效应指标相对危险度（RR)及其95%可信区间（CI）进行分析。结果 纳入14篇RCTs,总计5720例患者,其中ETV 治疗1396例,LdT 治疗982例,LAM 治疗2015例,TDF 治疗783例,ADV 治疗544例。经1年治疗,在HBV DNA低于检测下限方面, TDF为88.5%,ETV为79.9%,LdT为55.4%,LAM为19.9%,ADV为6.2%;在ALT复常方面, ETV为95.9%,TDF为56.6%,LdT为44.6%,ADV为34.1%,LAM为18.8%;在HBeAg消失方面, LdT为80.2%,TDF为76.2%,ETV为42.5%,LAM为27.4%,ADV为23.7%;在HBeAg血清学转换方面,LdT为79.9%,TDF为66.5%,ETV为39.1%,LAM为35.5%,ADV为29.0%。结论 TDF在HBV DNA低于检测下限方面疗效最好,ETV在ALT复常方面疗效最好,LdT在HBeAg消失/HBeAg血清学转换方面疗效最好。     

核苷(酸)类似物治疗慢性乙型肝炎存在的问题与对策

目前用于慢性乙型肝炎抗病毒治疗的药物主要有干扰素或聚乙二醇化干扰紊及核苷（酸）类似物两类，其中核苷（酸）类似物具有高效、低毒、使用方便等优点，在临床应用范围广泛。已批准用于乙型肝炎抗病毒治疗的核苷（酸）类似物有拉米夫定、阿德福韦酯和恩替卡韦；此外正在进行临床试验和开发的还有特比夫定、依曲他滨和克拉夫定等。随着新的核苷（酸）类似物不断问世及治疗方案的优化，其疗效已得到肯定。但核苷（酸）类似物抗乙型肝炎病毒（HBV）治疗开始容易，治疗过程中医师会面临众多难题：如疗程难以确定；停药难，可能出现停药反弹，不停药也难，继续治疗部分患者有出现耐药的可能；一旦出现耐药（基因型耐药或者表型耐药），在什么时机加用或改用其它药物治疗等。这些是任何现有核苷类药物都无法回避的问题。作为有责任和合格的肝病专科医师，在确定使用核苷（酸）类似物治疗后，需与患者进行充分和必要的沟通，将这些有关核苷（酸）类似物的重要信息告知患者。本文对核苷（酸）类似物治疗慢性乙型肝炎中常见的几个主要问题进行讨论。     

辨证施治联合核苷（酸）类似物治疗慢性乙型肝炎疗效的初步评价

目的：观察辨证施治联合核苷（酸）类似物治疗慢性乙型肝炎的疗效。方法：收集100例符合抗病毒治疗指征的慢性乙型肝炎患者,分为观察组与对照组,观察组患者采用中医中药联合核苷（酸）类似物治疗,对照组患者仅用核苷（酸）类似物治疗,定期观察其临床症状及肝功能、HBV DNA、肝纤维化等指标,疗程均为52周。结果：观察组与对照组相比,在改善临床症状、缩短肝功能复常时间、改善血清肝纤维化指标等方面差异均有显著性意义（P〈0.05）;在HBV DNA转阴率、HBeAg血清转换率、病毒反跳率等方面,两组比较差异无显著性意义（P〉0.05）。结论：联合用药能提高治疗慢性乙型肝炎的疗效。     

核苷（酸）类似物治疗慢性重型乙型肝炎的研究进展

乙型肝炎病毒（HepatitisBvirus,HBV）感染是我国重型肝炎发生的主要病因,在我国由于慢性HBV感染患者较多,因此慢性重型乙型肝炎（chronicseverehepatitisB,CSHB）远多于急性和亚急性重型肝炎。CSHB是肝衰竭（慢加急性及慢性肝衰竭）的一组病变,具有病情危重、病死率高且目前缺乏特效治疗。此病不仅是肝脏本身的严重病变,也可引起肝性脑病、微循环障碍、内毒素血症、凝血功能障碍、肾功能衰竭等多方面的病理生理改变。     

核苷（酸）类似物抗病毒治疗慢性乙型肝炎的优化策略

目前我国有4种核苷（酸）类似物可用于慢性乙型肝炎的抗病毒治疗,即拉米夫定、阿德福韦酯、恩替卡韦和替比夫定。但由于患者的性别、年龄、遗传背景、感染乙型肝炎病毒（hepatits B virus,HBV）     

核苷(酸)类似物抗病毒治疗慢性乙型肝炎的优化策略

目前,我国有4种核苷(酸)类似物可用于慢性乙型肝炎(CHB)患者的抗病毒治疗,即拉米夫定、阿德福韦酯、恩替卡韦和替比夫定.但由于患者的性别、年龄、遗传背景、HBV感染途径、病毒基因型、病程长短、肝脏病变程度和对治疗药物敏感性等不同,即使有同样治疗适应证的患者按同样的规范方案治疗后,仍有相当一部分患者早期应答欠佳,从而影响了抗病毒治疗的长期疗效.如何进一步优化现有的治疗方案以提高远期疗效已成为国内外专家关注的热点问题.     

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。     

一线核苷(酸)类药物对慢性乙型肝炎患者脂质代谢的影响

慢性乙型肝炎(chronic hepatitis B,CHB)是我国重要的公共卫生问题.目前,核苷(酸)类似物[nucleos(t)ide analogs,NAs]是抗病毒治疗的一线用药,其长期服用的安全性问题也引起了临床医师的广泛关注.有研究表明,NAs抗病毒治疗可能影响脂质代谢,不同药物对脂质代谢的影响不同,脂质代...     

Exploration of nucleos(t)ide analogs cessation in chronic hepatitis B patients with hepatitis B e antigen loss

BACKGROUNDNucleos(t)ide analogs (NAs) cessation in chronic hepatitis B (CHB) patients remains a matter of debate in clinical practice. Current guidelines recommend that patients with hepatitis B e antigen (HBeAg) seroconversion discontinue NAs after relatively long-term consolidation therapy. However, many patients fail to achieve HBeAg seroconversion after the long-term loss of HBeAg, even if hepatitis B surface antigen (HBsAg) loss occurs. It remains unclear whether NAs can be discontinued in this subset of patients.AIMTo investigate the outcomes and factors associated with HBeAg-positive CHB patients with HBeAg loss (without hepatitis B e antibody) after cessation of NAs.METHODSWe studied patients who discontinued NAs after achieving HBeAg loss. The Cox proportional hazards model was used to identify predictors for virological relapse after cessation of NAs. The cut-off value of the consolidation period was confirmed using receiver operating characteristic curves; we confirmed the cut-off value of HBsAg according to a previous study. The log-rank test was used to compare cumulative relapse rates among groups. We also studied patients with CHB who achieved HBeAg seroconversion and compared their cumulative relapse rates. Propensity score matching analysis (PSM) was used to balance baseline characteristics between the groups.RESULTSWe included 83 patients with HBeAg loss. The mean age of these patients was 32.1 ± 9.5 years, and the majority was male (67.5%). Thirty-eight patients relapsed, and the cumulative relapse rate at months 3, 6, 12, 24, 36, 60, 120, and 180 were 22.9%, 36.1%, 41.0%, 43.5%, 45.0%, 45.0%, 45.0%, and 52.8%, respectively. Twenty-six (68.4%) patients relapsed in the first 3 mo after NAs cessation, and 35 patients (92.1%) relapsed in the first year after NAs cessation. Consolidation period (≥ 24 mo vs < 24 mo) (HR 0.506, P = 0.043) and HBsAg at cessation (≥ 100 IU/mL vs < 100 IU/mL) (HR 14.869, P = 0.008) were significant predictors in multivariate Cox regression. In the PSM cohort, which included 144 patients, there were lower cumulative relapse rates in patients with HBeAg seroconversion (P = 0.036).CONCLUSIONHBeAg-positive CHB patients with HBeAg loss may be able to discontinue NAs therapy after long-term consolidation, especially in patients with HBsAg at cessation < 100 IU/mL. Careful monitoring, especially in the early stages after cessation, may ensure a favorable outcome.     

替诺福韦挽救治疗耐药复发的慢性乙型肝炎患者48周疗效初探

目的观察替诺福韦（TDF）单药或联合恩替卡韦（ETV）挽救治疗耐药复发的慢性乙型肝炎患者的疗效及安全性。方法回顾性分析11例耐药复发的慢性乙型肝炎患者的挽救治疗,其中6例患者单用TDF,5例患者采用TDF联合ETV。采用时间分辨免疫荧光法检测血清乙型肝炎病毒标志物,采用脱氧核糖核酸测序法检测与耐药相关的HBV P区169、173、180、181、184、202、204、233、236、250位耐药变异,采用PCR-荧光探针法检测血清HBV DNA载量,采用苦味酸法检测血清肌酐（Cr）水平。应用Kaplan-Meier分析血清HBV DNA累积不可检出率。结果挽救治疗前,1例患者检测到ADV基因型耐药,7例患者检测到LAM/ETV基因型耐药,3例患者检测到LAM/ETV/ADA基因型耐药;HBV DNA基线水平为（4.82±1.29） lg IU/ml,挽救治疗第4周降至（3.57±0.55） lg IU/ml,第12周降至（2.91±0.37） lg IU/ml,随访至第48周,仅1例患者可检测出HBV DNA。挽救治疗4、12、24和36周,血清HBV DNA累积不可检出率分别为36.4%（4/11）、63.6%（7/11）、81.8%（9/11）和90.9%（10/11）;随访结束时,血清ALT水平由（64.36±34.55） U/L降至（37.7±24.49） U/L;治疗期间未发生肾功能异常或其他不良事件。结论TDF单药或联合ETV挽救治疗耐药复发的慢性乙型肝炎患者仍能较快速地抑制病毒复制,具有良好的疗效和安全性。     

Benefits of nucleos(t)ide analog treatments for hepatitis B virus-related cirrhosis

Chronic hepatitis B infection induces progressive liver disease. Before nucleos(t)ide analogs(NUCs) became established as a safe and effective treatment for hepatitis B,it was difficult to suppress the activity of the hepatitis B virus(HBV). Currently,many patients withhepatitis or cirrhosis associated with HBV are treated with NUCs for an extended period of time,and the effects,benefits,and limitations of these treatments have been apparent. This article reviews HBV-related cirrhosis,its natural course and survival,histological improvement after NUC treatments,treatment effects for decompensated cirrhosis,the incidence of hepatocellular carcinoma(HCC) after NUC treatments,and the efficacy of NUC treatments before and after the treatment of patients for HBV-related HCC. Of particular interest are the histological improvements,including regression of fibrosis,that have been achieved with NUC treatments. Liver function of patients with decompensated cirrhosis has significantly improved regardless of the type of NUC applied,and treatment with NUCs has reduced the incidence of HCC in cirrhotic patients. However,cirrhosis remains the strongest risk factor for HCC occurrence following NUC treatments,and the long-term cumulative incidence of HCC after NUC treatments remains high. When recurrence does occur,it is important to reconsider the treatment modality according to the degree of improved liver function that was achieved.     

Serum hepatitis B surface antigen levels predict treatment response to nucleos(t)ide analogues

Quantification of hepatitis B surface antigen(HBsAg)has been suggested to be helpful in the management of chronic hepatitis B(CHB)patients.Nucleos(t)ide analogs(NAs)are the therapy of choice for CHB and are used in the majority of CHB patients.NAs are able to induce hepatitis B virus(HBV)viral suppression,normalization of alanine aminotransferase(ALT)levels,and improvement in liver histology.Automated quantitative assays for serum HBsAg have recently become available,facilitating standardized quantification of serum HBsAg.This has led to increased interest in the clinical application of quantitative serum HBsAg for predicting therapeutic response to NAs.Recent studies have shown that a decline in serum HBsAg levels in patients receiving peginterferon may signal successful induction of immune control over HBV,and can therefore be used to predict therapeutic response.NA treatment typically induces a less rapid decline in HBsAg than interferon treatment;it has been estimated that full HBsAg clearance can require decades of NA treatment.However,a rapid HBsAg decline during NA therapy may identify patients who will show clearance of HBsAg.Currently,there is no consensus on the clinical utility of serum HBsAg monitoring for evaluating patient responses to NA therapy.This review focuses on recent findings regarding the potential application of HBsAg quantification in the management of CHB patients receiving NA therapy.     

Recent data on treatment of chronic hepatitis B with nucleos(t)ide analogues

Forty years ago in 1967, Professor Blumberg discovered the Australian Antigen, later known as the hepatitis B surface antigen, and was awarded the Nobel Prize. This discovery enables the diagnosis of hepatitis B virus (HBV) infection and defines its epidemiology. Viral hepatitis B infection affects global health situation, and chronic hepatitis B (CHB) is particularly serious in the Asia-Pacific region. HBV vaccines created the first breakthrough in HBV prevention. Through universal HBV vaccination program for the newborns, promoted since the mid-1980s, the main route that perpetuates chronic infection from mother to child is curbed. Most children and young adults now have immunity against HBV infection. The next breakthrough comes with therapy for CHB. This prevents progression to cirrhosis and hepatocellular carcinoma. Standard interferon therapy with modest efficacy has been largely replaced by therapy with nuclos(t)ide analogues or pegylated interferons alfa-2a and -2b. Lamivudine was approved by the FDA USA in 1998, followed by adefovir dipivoxil in 2002, entecavir in 2005, and telbivudine in 2006. Clevudine, tenofovir, and many promising candidates are in different stages of development and clinical trial. This paper critically reviews recent data published or presented since the APASL Consensus and Guideline Update of 2005. Clinical efficacy mostly in patients with raised serum alanine aminotransferase will be analyzed.     

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.