经动脉化疗栓塞术对肝癌乙肝病毒再激活的影响及抗病毒药物的治疗作用

经动脉化疗栓塞(transarterial chemoembolization,TA C E)是治疗不能切除肝细胞癌(hepatocellular carcinoma,HCC)的首选治疗方法,被证实能延长不能切除HCC患者的存活时间.然而,近期研究发现:TACE可能诱发HCC的乙肝病毒(hepatitis B virus,HBV)再激活,HBV-DNA大量复制,从而诱发HBV相关肝炎,甚至肝衰竭,导致HCC病人死亡,而术前应用抗病毒药物则可能降低术后HBV的再激活,改善病人的存活.本文将TACE对HCC-HBV再激活的影响及抗病毒药物对HBV再激活的抑制作用以及术后存活的影响进行综述.     

慢性乙型肝炎治疗的最新进展

我国约有3000万慢性乙型病毒性肝炎(慢乙肝)患者,如未经积极、正确治疗,每年有2.1%的慢乙肝患者发展为肝硬化,约4.4%的患者经9年发展为肝细胞癌(HCC)[1];而经垂直传播而感染乙型肝炎病毒(乙肝病毒,HBV)的婴儿中,90%以上成为慢性感染者。因此,有效治疗慢性乙型肝炎,降低乙肝病毒感染率是我们的当务之急。     

乙型肝炎相关性肝癌术后抗病毒治疗的临床意义

目的探讨抗病毒治疗对HBV相关性肝癌术后的影响。方法回顾性分析113例HBV相关性肝癌并行根治性切除患者的病例资料,术后接受抗病毒治疗的为治疗组44例,单纯手术切除的为对照组69例。比较两组1、3、5年无瘤生存率及肝癌复发时肝功能的差异。结果治疗组和对照组的1、3、5年无瘤生存率分别为81.8%、38.6%、26.7%和73.9%、26.5%、13.6%,两组比较差异有统计学意义(P=0.038)。至随访终点,共有88例肝癌复发,治疗组(n=32)相对于对照组(n=56)的ALT、Child-Pugh评分、HBV DNA在肝癌复发时明显降低,分别为[(38.2±20.9)U/L比(48.0±20.3)U/L,P=0.046]、[(5.41±0.76)lg拷贝/mL比(6.14±1.55)lg拷贝/mL,P=0.014]、[2.70 lg拷贝/mL比(5.23±1.49)lg拷贝/mL,P0.01]。结论抗病毒治疗能够改善HBV相关性肝癌切除术后的无瘤生存率,并有助于肝癌患者术后残肝功能的恢复,为肝癌复发的综合治疗创造条件。     

抗病毒治疗对乙型肝炎相关原发性肝癌患者生活质量及预后的影响

目的 探讨抗病毒治疗对乙型肝炎相关原发性肝癌患者生活质量的影响.方法 选择95例诊断为乙型肝炎相关性原发性肝癌且无手术治疗指征的患者,分为抗病毒联合介入治疗组22例、介入治疗组26例、抗病毒治疗组23例、常规治疗组24例.随访监测治疗后4、12、24及48周肝功能、腹部彩色超声或肝脏CT,每4周对患者生活质量包括食欲、体质量(排除腹水影响因素)及乏力情况进行现场或电话随访,所有患者随访4周至48周.统计学处理采用t检验和x2检验.结果 抗病毒联合介入治疗组、介入治疗组、抗病毒治疗组与常规治疗组患者24周生存率分别为86.4％(19例)、73.1％(19例)、73.9％(17例)、54.2％(13例),48周生存率分别为68.2％(15例)、46.2％(8例)、47.8％(11例)、16.7％(4例).抗病毒联合介入治疗组、介入治疗组及抗病毒治疗组患者1年生存率明显高于常规治疗组(P＜0.05).抗病毒联合介入治疗组、介入治疗组及抗病毒治疗组患者12周内生活质量较常规治疗组明显改善,其中抗病毒联合介入治疗组改善最明显,其次为介入治疗组与抗病毒治疗组,常规治疗组在生活质量方面无明显改善.治疗24周后抗病毒联合介入治疗组及介入治疗组的肿瘤大小未明显增大,而常规治疗组患者的肿瘤较抗病毒治疗组增大明显.结论 在介入治疗及常规治疗的基础上联合抗病毒治疗可提高乙型肝炎相关原发性肝癌患者1年生存率、改善生活质量、延缓肿瘤生长.     

恩替卡韦抗病毒对TACE治疗的HBV DNA阴性乙型肝炎相关性肝癌的影响

目的 探讨应用恩替卡韦预防治疗接受肝动脉化疗栓塞术（TACE）的乙型肝炎病毒（HBV）DNA阴性的乙型肝炎相关性肝细胞癌（HCC）患者对病毒激活的影响。方法 将45例HBV DNA阴性乙型肝炎相关性HCC患者随机分为观察组23例和对照组22例。两组患者均在常规护肝治疗基础上接受TACE治疗,观察组于TACE治疗前1周开始应用恩替卡韦分散片抗病毒治疗,对照组未行抗病毒治疗。采用荧光定量PCR法检测血清HBV DNA,采用微粒发光法检测血清HBV标志物,使用全自动生化分析仪检测血生化指标。观察并比较两组TACE后血清HBV DNA转阳和肝衰竭发生率及生存率情况。结果 在治疗24 w,观察组血清HBV DNA水平仍为<2 lg IU/mL,明显低于对照组的（4.10±2.86） lg IU/mL（P<0.01）,观察组HBV DNA转阳率为8.7%,明显低于对照组的36.4%（P<0.05）;观察组肝衰竭发生率为0.0%,对照组为22.7%,但两组差异无统计学意义（P>0.05）;在治疗12 w,观察组血清ALT为（56.75±20.74） IU/L,明显低于对照组的（125.78±42.75） IU/L,PTA为（48.65±8.26）%,明显高于对照组的（42.74±7.42）%（P<0.05）;在24 w,观察组血清ALT水平和Child-Pugh评分分别为（50.73±18.45）IU/L和（6.26±1.46）分,明显低于对照组的（97.48±30.56） IU/L和（7.84±1.65） 分,PTA为（52.45±9.10）%,明显高于对照组的（39.56±6.78）%（均P<0.01）;两组近期临床疗效差异无统计学意义(P>0.05);观察组2 a生存率为69.6%,明显高于对照组的36.4%（P<0.05）。结论 对接受TACE治疗的HBV DNA阴性的乙型肝炎相关性HCC患者,给予恩替卡韦抗病毒预防性治疗可以抑制HBV再激活,改善肝功能。     

肝动脉化疗栓塞联合射频消融治疗大肝癌的疗效评价

目的探讨经导管肝动脉化疗栓塞（transcatheter arterial chemoembolization,TACE）联合射频消融（radiofrequency ablation,RFA）治疗大肝癌的临床应用价值。方法回顾性分析我院2006年4月至2008年7月收治的66例肝细胞癌患者的治疗结果,根据治疗方法分为TACE＋RFA组、TACE组及RFA组,其中19例行RFA联合TACE治疗（TACE＋RFA组）,24例单纯TACE治疗（TACE组）,23例单纯RFA治疗（RFA组）。结果 TACE＋RFA组的肿瘤坏死率达73.68%,明显高于单纯TACE组及单纯RFA组（分别为50.00%,52.17%,P〈0.01,P〈0.05）。局部复发率分别为26.32%、37.50%和30.43%,三组间无显著统计学差异（P〉0.05）。TACE＋RFA组的平均生存期为28.3个月,显著高于TACE组的13.6个月（P〈0.01）和单纯RFA组的21.7个月（P〈0.05）。结论 TACE联合RFA治疗大肝癌与单纯TACE和单纯RFA治疗效果相比,可提高肿瘤坏死率,延长患者生存期。     

保肝细胞生长素治疗重型肝炎及慢性重度肝炎的临床研究

促肝细胞生长素是一种多肽物质 ,是临床治疗重型肝炎的有效新药 ,动物试验证实对实验性小鼠的肝损伤有保护肝细胞功能的作用[1] 。亦可用于治疗慢性病毒性肝炎[2 ,3 ] ,为进一步观察促肝细胞生长素的有效性及安全性 ,1999年 11月至 2 0 0 0年 12月全国 42家医院进行了多中心的临床验证 ,现总结如下。对象与方法一、病例选择　　按 1995年 5月北京第 5次全国传染病与寄生虫病学术会议修订的《病毒性肝炎防治方案》的诊断和分期标准[4 ] ,选择 6 91例各型重型肝炎和慢性重度肝炎患者作为临床实验对象。年龄 16～ 75岁 ,平均 (41.35± 12 .36 )…     

乙型肝炎相关原发性肝癌术后抗病毒治疗的临床研究

目的:观察乙型病毒性肝炎相关原发性肝癌术后抗病毒治疗的临床疗效。方法:选择2009年7月至2012年7月我科收治的75例乙型病毒性肝炎相关原发性肝癌术后患者,随机分为两组,治疗组39例,患者术后口服核苷类似物抗病毒药品(拉米夫定100mg/d),对照组36例,患者单纯手术切除。观察术后患者肝功能、AFP、HBV DNA定量、Child-Pugh分级、无瘤生存率等。结果:随访所有患者,这期间64例肿瘤复发转移,50例死亡。术后6个月治疗组患者HBV DNA定量较前明显降低(P0.01),谷丙转氨酶(ALT)、谷草转氨酶(AST)、总胆红素(TBil)均明显降低(P0.01),血白蛋白(Alb)明显升高,Child-Pugh分级明显降低(P0.01);对照组HBV DNA水平无明显变化(P0.05),ALT、AST、TBil、AIb、Child-Pu曲分级等指标虽有改善,但与术前相比差异无统计学意义(P0.05)。随访3年,治疗组与对照组的无瘤生存率1~,2~,3~年分别为89.74%、74.36%、61.54%和77.78%、50.00%、33.33%,两组之间差异有统计学意义(P0.01)。结论:肝癌根治术后予以积极抗HBV治疗能有效降低肿瘤复发率.延长无瘤生存期,因此对术前HBV DNA高水平复制肝癌患者,应尽早联合抗病毒治疗。     

抗病毒联合经导管肝动脉化疗栓塞治疗乙型肝炎后肝硬化合并肝细胞癌患者的临床观察

目的探讨抗病毒联合经导管肝动脉化疗栓塞(TACE)治疗在乙型肝炎后肝硬化合并肝细胞癌(HCC)患者中的临床疗效。方法回顾性分析抗病毒联合TACE治疗78例乙型肝炎后肝硬化合并HCC患者的临床疗效,并与同期单独行TACE患者81例对比,观察比较两组患者1、2年生存率、肝功能Child-Pugh积分及HBV DNA定量的变化。两组基线临床资料(如性别、年龄、肿瘤的大小、实验室检查及Child-Pugh评分)比较差异无统计学意义(P均>0.05)。结果治疗1、2年后,治疗组HBV DNA阴转率均显著高于对照组(P均<0.0001),肝功能Child-Pugh积分治疗组明显低于对照组(P均<0.001),差异均有统计学意义。治疗组和对照组1、2年生存率分别为83.33%、66.67%和59.2%、36.67%(P均<0.001),差异均有统计学意义。结论应用核苷酸类似物联合TACE治疗乙型肝炎后肝硬化合并HCC的患者,可抑制HBV复制,保护患者肝功能,提高患者生存率。     

丙型肝炎直接抗病毒治疗与肝癌发生及复发的关系

HCV感染后引起的慢性肝炎,是导致肝硬化和肝细胞癌的主要原因之一。近年来,直接抗病毒药物(DAA)逐渐成为治疗丙型肝炎的主流药物。研究表明DAA可能会增加HCV相关肝硬化患者发生肝癌或者导致肝癌复发的风险,给DAA的临床应用带来了巨大的争议。综述了DAA对肝癌发生和复发的影响,以期为DAA的临床应用提供更好的依据。     

Preemptive therapy for hepatitis B patients undergoing chemotherapy

Abstract   In areas where hepatitis B virus (HBV) is endemic, the increased use of cytotoxic or immunosuppressive therapy has resulted in an increased incidence of liver-related morbidity and mortality due to HBV reactivation in patients infected with the virus. As the hepatitis is preceded by HBV virological reactivation, administration of effective antiviral therapy to HBV (anti-HBV) such as lamivudine preemptively before or at the initiation of cytotoxic therapy and to cover the entire period of immunsuppression, has greatly reduced the risk of liver-related morbidity and mortality due to HBV reactivation. However, such an early 'preemptive' approach runs the risk of over-treating patients who might not be suffering from HBV reactivation with nucleoside analog. In addition, the duration of therapy with nucleoside analog, such as lamivudine, would be longer with this approach. Taken together, such an indiscriminant preemptive approach could result in an increased risk of developing HBV viral resistance. Indeed, severe liver damage due to the development of mutations in the polymerase gene related to lamivudine, namely at M204V and at L180M, has been reported in hepatitis B surface antigen (HBsAg) positive recipients of allogeneic bone marrow transplantation and who were treated with preemptive lamivudine. In order to further optimize the management of postchemotherapy HBV reactivation, more studies aiming to identify risk factors for HBV reactivation after chemotherapy should be undertaken.     

Perioperative reactivation of hepatitis B virus replication in patients undergoing partial hepatectomy for hepatocellular carcinoma

Background and Aim: Reactivation of hepatitis B virus (HBV) replication happens in patients who receive transarterial chemoembolization or systemic chemotherapy for hepatocellular carcinoma (HCC). The incidence and risk factors of HBV reactivation during the perioperative period in HCC patients receiving hepatic resection is unknown. Methods: Between May 2009 and November 2010, 164 consecutive patients with HBV‐related HCC who underwent hepatic resection were prospectively enrolled in the study. Among these, 126 patients received antiviral treatment before the operation (the antiviral group) and 38 patients did not receive any antiviral treatment (the non‐antiviral group). Results: Ten patients (6.1%) developed HBV reactivation perioperatively (within 1 month after hepatectomy). The incidence of HBV reactivation in the antiviral group and non‐antiviral group were 1.6% (2/126) and 21.1% (8/38), respectively (P < 0.001). On univariate analysis, preoperative HBV DNA < 1.0 × 10³ copies/mL and non‐antiviral therapy were significantly correlated with the occurrence of HBV reactivation (P = 0.044 and P < 0.001, respectively). Only non‐antiviral therapy remained as a predictive factor on multivariate analysis (odds ratio, 15.46; 95% confidence interval, 2.80–85.46, P = 0.002). The recovery of liver function (defined as a decrease of alanine aminotransferase back to normal) was achieved in 86.8% (132/152) patients without HBV reactivation and in 37.5% (3/8) patients with HBV reactivation when evaluated on day 30 after hepatectomy (P < 0.001). Conclusion: Hepatectomy could reactivate HBV replication during the perioperative period, especially in patients who did not receive any antiviral therapy. A close monitoring of HBV DNA during the perioperative period was necessary irrespective of the preoperative HBV DNA level. Once HBV was reactivated, antiviral therapy should be given.     

Long-term follow-up of cumulative incidence of hepatocellular carcinoma in hepatitis B virus patients without antiviral therapy

BACKGROUNDChina has a high prevalence of hepatitis B virus (HBV), but most chronic hepatitis B (CHB) patients do not receive standardized antiviral therapy. There are few relevant reports addressing the outcomes of the large number of CHB patients who do not receive antiviral therapy.AIMTo observe the outcomes of long-term follow-up of patients with CHB without antiviral treatment.METHODSThis study included 362 patients with CHB and 96 with hepatitis B cirrhosis without antiviral treatment and with only liver protection and anti-inflammatory treatment from 1993 to 1998. The median follow-up times were 10 and 7 years, respectively. A total of 203 CHB and 129 hepatitis B cirrhosis patients receiving antiviral therapy were selected as the control groups. The median follow-up times were 8 and 7 years, respectively. Kaplan-Meier curves were used to analyze the cumulative incidence of hepatocellular carcinoma (HCC), and the Cox regression model was used to analyze the risk factors for HCC.RESULTSAmong the patients in the non-antiviral group, 16.9% had spontaneous decreases in HBV DNA to undetectable levels, and 32.8% showed hepatitis B e antigen (HBeAg) seroconversion. In the antiviral group, 87.2% of patients had undetectable HBV DNA, and 52% showed HBeAg seroconversion. Among CHB and hepatitis B cirrhosis patients, the cumulative incidence rates of HCC were 14.9% and 53.1%, respectively, in the non-antiviral group and were 10.7% and 31.9%, respectively, in the antiviral group. There was no difference between the two groups regarding the CHB patients (P = 0.842), but there was a difference between the groups regarding the hepatitis B cirrhosis patients (P = 0.026). The cumulative incidence rates of HCC were 1.6% and 22.3% (P = 0.022) in the groups with and without spontaneous HBeAg seroconversion, respectively. The incidence rates of HCC among patients with and without spontaneous declines in HBV DNA to undetectable levels were 1.6% and 19.1%, respectively (P = 0.051). There was no difference in the cumulative incidence of HCC between the two groups regarding the patients with drug-resistant CHB (P = 0.119), but there was a significant difference between the two groups regarding the patients with cirrhosis (P = 0.004). The Cox regression model was used for regression of the corrected REACH-B score, which showed that alanine aminotransferase > 400 U/L, history of diabetes, and family history of liver cancer were risk factors for HCC among men aged > 40 years (P < 0.05). Multifactorial analysis showed that a family history of HCC among men was a risk factor for HCC.CONCLUSIONAntiviral therapy and non-antiviral therapy with liver protection and anti-inflammatory therapy can reduce the risk of HCC. Antiviral therapy may mask the spontaneous serological response of some patients during CHB. Therefore, the effect of early antiviral therapy on reducing the incidence of HCC cannot be overestimated.     

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.     

Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy

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Hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy

Patients with chronic hepatitis B are at increased risk of hepatocellular carcinoma(HCC),while the inhibition of viral replication can represent a reasonable target for HCC prevention.Interferon-αtherapy results in decreased HCC risk,which is more evident in patients with high baseline HCC risk.The majority of chronic hepatitis B patients are treated with a nucleos(t)ide analogue(NA)for several reasons including the nonsustained response after interferon-α.The effect of the first licensed and low genetic barrier NA,lamivudine,on HCC incidence,has been repeatedly evaluated.Lamivudine,compared to no treatment,reduces the HCC incidence,which may increase again in cases with lamivudine resistance.Emerging data with the currently first-line NAs,entecavir and tenofovir,suggest that they also reduce the HCC incidence.The treatment benefit in reduction of the HCC incidence is always greater in patients with high baseline HCC risk,particularly cirrhotics,and without virological remission under entecavir/tenofovir.However,the HCC risk is not eliminated even in the vast majority of patients who remain in virological remission under entecavir/tenofovir.Therefore,patients at increased baseline HCC risk should continue to undergo HCC surveillance even if they have achieved complete long-term inhibition of viral replication and improvements in liver histology.     

Effect of antiviral treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis B

Chronic hepatitis B (CHB) is a major risk factor for hepatocellular carcinoma (HCC). The prevention of HCC is of paramount importance in patients with CHB, particularly in those with cirrhosis. Antiviral treatment can potentially reduce the risk for HCC since it suppresses viral replication, induces HBeAg seroconversion and improves liver histology. However, most evidence supporting a protective effect of antiviral treatment originates from non-randomized or retrospective studies and is limited to conventional interferon and lamivudine. There is a paucity of data on the effects of pegylated interferon and "newer" oral agents (telbivudine, tenofovir, entecavir) on HCC risk. However, it should be emphasized that the existing randomized control studies in patients with CHB were relatively short-term and not designed to assess the effects of antiviral treatment on HCC risk. Since viral load directly correlates with HCC risk, it is reasonable to hypothesize that the reduction in viral load with antiviral treatment will also lower the risk of HCC. This benefit might become more readily apparent with the newer agents used in the management of CHB which are more effective and have a more favorable resistance profile.     

Prediction models of hepatocellular carcinoma development in chronic hepatitis B patients

Chronic hepatitis B virus(HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma(HCC). Applying the same strategies for antiviral therapy and HCC surveillance to all chronic hepatitis B(CHB) patients would be a burden worldwide. To properly manage CHB patients, it is necessary to identify and classify the risk for HCC development in such patients. Several HCC risk scores based on risk factors such as cirrhosis, age, male gender, and high viral load have been used, and have negative predictive values of ≥ 95%. Most of these have been derived from, and internally validated in, treatment-na?ve Asian CHB patients. Herein, we summarized various HCC prediction models, including IPM(Individual Prediction Model), CU-HCC(Chinese University-HCC), GAG-HCC(Guide with Age, Gender, HBV DNA, Core Promoter Mutations and Cirrhosis-HCC), NGM-HCC(NomogramHCC), REACH-B(Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B), and Page-B score. To develop a noninvasive test of liver fibrosis, we also introduced a new scoring system that uses liver stiffness values from transient elastography, including an LSM(Liver Stiffness Measurement)-based model, LSM-HCC, and mR EACH-B(modified REACH-B).