Nucleos(t)ide analogs in the prevention of hepatitis B virus related hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is among the most common cancer types and causes of cancer related mortality worldwide.Almost 50% of all HCC cases globally are attributable to chronic hepatitis B virus(HBV) infection.The incidence rates of HCC in untreated Asian subjects with HBV infection was estimated to be 0.2% in inactive carriers,0.6% for those with chronic hepatitis without cirrhosis,and 3.7% for those with compensated cirrhosis.In Western populations,HCC incidences are reported to be 0.02% in inactive carriers,0.3% in subjects with chronic hepatitis without cirrhosis,and 2.2% in subjects with compensated cirrhosis.Despite effective antiviral treatment options which are able to transform chronic hepatitis into an inactive carrier state,the risk of HCC cannot be fully ruled out to exclude those patients from surveillance.Newer nucleos(t)ide analogues(NAs) as entecavir and tenofovir are very potent in terms of sustained virological suppression which leads to improved liver histology.However,they do not have any influence on the ccc DNA or integrated DNA of HBV in the liver.Nonetheless,viral replication is the only modifiable component among the established risk factors for HBV-related HCC with the current treatment options.In this review,it was aimed to summarize cumulative evidence behind the concept of prevention of HBV related HCC by NAs,and to discuss remaining obstacles to eliminate the risk of HCC.     

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。     

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC.     

核苷(酸)类耐药患者中乙型肝炎病毒逆转录酶区基因变异类型及其特点

目的 了解核苷(酸)类药物治疗慢性乙型肝炎过程中HBV耐药变异模式特点以及是否有新的变异位点产生. 方法对2005年9月-2007年6月送检的227份慢性乙型肝炎患者血清标本,应用Trugene试剂盒抽提、扩增HBV基因组聚合酶逆转录酶区,PCR产物经过CLIP反应后加到MicroCel 500电泳胶板中电泳,应用GeneObjects软件获得样本的序列,分析其突变,并应用SPSS15.0软件进行统计分析.结果 在227份标本中有111份(48.9%)发现已知耐药位点(M204V/I,L180M,V173L,V207I,N236T,A18lV/T等)变异,其中有明确用药史的共75例.在拉米夫定和阿德福韦序贯治疗的患者中出现多重耐药变异的概率较高,为25.0%(4/16),而在先用拉米夫定后联合阿德福韦治疗的16例患者中未发现后续阿德福韦耐药变异.在其他位点的变异中,以A222T、L229V和S256C频率较高.数据采用SPSS15.0软件分析,组间比较用Kruskal-Wallis和SNK方法检验. 结论在核苷(酸)类药物治疗慢性乙型肝炎过程中,出现的变异模式复杂,对拉米夫定耐药的患者,换用阿德福韦可导致多重耐药变异.     

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.     

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...     

Nucleos(t)ide analogues to treat hepatitis B virus-related hepatocellular carcinoma after radical resection

Significant advances have been made in nucleos(t)ideanalogue(NA) therapy to treat chronic hepatitis B,and this therapy reduces the risk of hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC) in somepatients.However,whether NAs can also prevent recurrence after radical resection of HBV-related HCC remains controversial and is an important question,giventhat most patients will experience recurrence within afew years of curative surgery.Here we systematicallyreviewed the literature since 2004 on outcomes afteradministering NAs to patients with HBV-related HCCfollowing radical resection.We focused on treatmentindications,duration,effects on recurrence-free survivaland overall survival,and the management of NA resistance.We find that patients with HCC should stronglyconsider NA therapy if they are positive for HBV-DNA,and that the available evidence suggests that postoperative NA therapy can increase both recurrence-free andoverall survival.To minimize drug resistance,cliniciansshould opt for potent analogues with higher resistancebarriers,and they should monitor the patient carefully for emergence of NA-resistant HBV.     

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.     

Role of antiviral therapy in the natural history of hepatitis B virus-related chronic liver disease

Hepatitis B virus(HBV) infection is a dynamic state ofinteractions among HBV, hepatocytes, and the host immune system. Natural history studies of chronic hepatitis B(CHB) infection have shown an association between active viral replication and adverse clinical outcomes such as cirrhosis and hepatocellular carcinoma. The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, hepatocellular carcinoma(HCC) and death. This goal can be achieved if HBV replication is suppressed in a sustained manner. The accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and of HCC, particularly in non-cirrhotic patients. However, CHB infection cannot be completely eradicated, due to the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the integration of the HBV genome into the host genome may favour oncogenesis, development of HCC and may also contribute to HBV reactivation.     

核苷(酸)类似物抗病毒治疗对慢性乙肝患者血脂异常的潜在影响及其临床意义

慢性乙型肝炎病毒感染及相关肝病仍是我国重要的公共卫生问题.目前,核苷(酸)类似物是抗病毒治疗的一线用药,但其长期服用的安全性问题也引起了临床医师的广泛关注.近期亚太肝病学会(APASL)会议报道长期富马酸丙酚替诺福韦治疗中伴发的低密度脂蛋白胆固醇水平升高,谨慎评价这种抗病毒治疗过程中的血脂异常,探讨其对终末期肝病发生风...     

核苷(酸)类似物治疗慢性乙型肝炎10例临床分析

本研究对10例用核苷(酸)类似物(NUCs)治疗出现HBsAg阴转或血清学转换的病例资料进行了回顾性分析,现报道如下.一、资料与方法1.病例资料:收集2005年2月至2010年8月于沈阳市第六人民医院入院的10例慢性乙型肝炎(CHB)患者应用NUCs治疗出现HBsAg阴转或血清学转换的患者资料.临床诊断符合2005年慢性乙型肝炎防治指南[11标准.     

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.     

Antiviral drug resistance increases hepatocellular carcinoma: A prospective decompensated cirrhosis cohort study

AIM:To study the clinical outcome of antiviral therapy in hepatitis B-related decompensated cirrhotic patients.METHODS:Three hundred and twelve patients with decompensated hepatitis B cirrhosis were evaluated in a prospective cohort.With two years of follow-up,198patients in the group receiving antiviral therapy with nucleos(t)ide analogues and 39 patients in the control group without antiviral treatment were analysed.RESULTS:Among the antiviral treatment patients,162had a complete virological response(CVR),and 36 were drug-resistant(DR).The two-year cumulative incidence of hepatocellular carcinoma(HCC)in the DR patients(30.6%)was significantly higher than that in both the CVR patients(4.3%)and the control group(10.3%)(P<0.001).Among the DR patients in particular,the incidence of HCC was 55.6%(5/9)in those who failed rescue therapy,which was extremely high.The rtA181T mutation was closely associated with rescue therapy failure(P=0.006).The Child-Pugh scores of the CVR group were significantly decreased compared with the baseline(8.9±2.3 vs 6.0±1.3,P=0.043).CONCLUSION:This study showed that antiviral drug resistance increased the risk of HCC in decompensated hepatitis B-related cirrhotic patients,especially in those who failed rescue therapy.     

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。     

Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy

Hepatocellular carcinoma(HCC)is a grave primary liver cancer that has a limited therapeutic option because it is generally diagnosed later in an advanced stage due to its aggressive biologic behavior.The early detection of HCC has a great impact on the treatment efficacy and survival of patients at high risk for cancer.Potential host,environmental,and virus-related risk factors have been introduced.Hepatitis B virus(HBV)is a major cause of end-stage liver diseases such as liver cirrhosis or HCC in endemic areas,and its serologic or virologic status is considered an important risk factor.HCC risk prediction derived from the identification of major risk factors is necessary for providing adequate screening/surveillance strategies to high-risk individuals.Several risk prediction models for HBV-related HCC have been presented recently with simple,efficient,and readily available to use parameters applicable to average-or unknown-risk populations as well as high-risk individuals.Predictive scoring systems of risk estimation to assess HCC development can provide the way to an evidence-based clinical approach for cost-and effort-effective outcomes,capable of inducing a personalized surveillance program according to risk stratification.In this review,the concepts and perspectives of the risk prediction of HCC are discussed through the analysis of several risk prediction models of HBV-related HCC.     

核苷(酸)类似物及干扰素治疗对慢性HBV感染者远期肝癌和死亡风险的影响

目的观察核苷(酸)类似物(NAs)和α干扰素(IFN-α)抗病毒治疗对慢性乙型肝炎(CHB)和代偿期肝硬化(LC)患者远期发生肝细胞癌(HCC)及死亡风险的影响。方法采用回顾性-前瞻性双向队列研究设计,自2008年1月起,对1998年8月至2007年12月间住院的慢性HBV感染者通过回顾性调查建立研究队列,并随访至2013年5月。共2 035例患者纳入队列研究,其中NAs治疗组380例,IFN-α治疗组153例,未治疗(对照)组1 502例。结果 IFN-α治疗组中位随访时间10.08(IQR:7.96~11.67)年,HCC发生率为2.70/1 000人年;NAs治疗组中位随访时间7.58(IQR:6.08~9.67)年,HCC发生率为6.76/1 000人年;对照组中位随访时间9.2(IQR:7.0~11.33)年,HCC发生率为13.02/1 000人年。在CHB患者中,IFN-α治疗组的HCC累积发生率显著低于对照组(P=0.008)和NAs治疗5年的患者(P=0.039),其累积肝病相关病死率亦显著低于对照组(P=0.001)和NAs治疗5年(P=0.007)的患者;NAs治疗≥5年患者的累积肝病相关病死率显著低于对照组(P=0.019)和NAs治疗5年的患者(P=0.034)。在基线代偿期LC患者中,NAs治疗≥5年的患者HCC累积发生率显著低于对照组(P=0.028)及NAs治疗5年患者(P=0.031);同时其累积肝病死亡率亦显著低于对照组(P=0.001)及NAs治疗5年患者(P=0.017)。结论 IFN-α治疗能显著降低CHB患者远期发生HCC和死亡的风险,而NAs长期治疗可以减少CHB患者的死亡风险,并显著降低代偿性肝硬化患者HCC的发生风险及死亡率。     

抗病毒治疗乙型肝炎肝硬化的过去、现在和将来

<正>乙型肝炎病毒(Hepatitis B virus,HBV)感染是肝硬化、原发性肝癌发生的重要原因。慢性HBV感染进展为肝硬化的5 a累积发生率约为8%~20%,代偿期肝硬化5 a生存率为85%~90%。一旦进展为失代偿期,患者常因门静脉高压导致的食管胃静脉曲张出血、腹水、肝性脑病、肝肾综合征等并发症,使死亡风险显著增加,其5 a生存率仅为14%~35%[1]。研究显     

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.     

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.