Reactivation of Hepatitis B Virus in HBsAg-Negative Patients with Hepatocellular Carcinoma

Background & Aims

Despite increasing attention to hepatitis B virus (HBV) reactivation in hematologic settings, information on reactivation in hepatitis B surface (HBsAg)-negative patients with hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine the incidence and risk factors of HBV reactivation in HBsAg-negative patients undergoing transarterial chemoembolization (TACE).

Methods

A total of 109 HBsAg-negative patients with HCC were consecutively recruited for this study and treated with either mono- (n = 75), combination-drug TACE (n = 20), or combination-drug TACE plus radiotherapy (n = 14). With serial monitoring of virological markers every 2–3 months, patients were observed for HBV reactivation (defined as the reappearance of HBV DNA or sero-reversion of HBsAg) in comparison with control subjects with HBsAg-negative cirrhosis (n = 16) or HBsAg loss (n = 46).

Results

During the study period, HBV reactivation occurred in 12 (11.0%) and 1 (1.6%) patients in the TACE and control groups, respectively. The median level of HBV DNA at reactivation was 5,174 copies/ml (range: 216–116,058). Of the 12 patients with HBV reactivation, four (33.3%) developed clinical hepatitis, including one patient who suffered from decompensation. All antiviral-treated patients achieved undetectable HBV DNA or HBsAg loss after commencement of antiviral drugs. TACE was significantly correlated with a high incidence of HBV reactivation, with increasing risk of reactivation with intensive treatment. On multivariate analysis, treatment intensity and a prior history of chronic hepatitis B remained independently predictive of reactivation.

Conclusions

TACE can reactivate HBV replication in HBsAg-negative patients, with a dose-risk relationship between treatment intensity and reactivation. Patients with prior chronic HBV infection who are to undergo intensive TACE should be closely monitored, with an alternative approach of antiviral prophylaxis against HBV reactivation.     

Effects of Entecavir on Hepatitis B Virus Covalently Closed Circular DNA in Hepatitis B e Antigen-Positive Patients with Hepatitis B

The aim of this study was to assess the effect of 48-week entecavir therapy on serum and intrahepatic hepatitis B virus, covalently closed circular DNA (HBV cccDNA) levels in hepatitis B e antigen (HBeAg)-positive patients. A total of 120 patients with HBeAg-positive chronic hepatitis were treated with entecavir for 48 weeks. Serum HBV markers, total HBV DNA, and HBV cccDNA levels were measured at baseline and week 48. Biopsies from 20 patients were available for both intrahepatic total HBV DNA and cccDNA testing at these timepoints. HBV cccDNA levels were decreased from a median level of 5.1×10⁶ copies/mL at baseline to a median level of 2.4×10³ copies/mL at week 48. Reduction magnitudes of HBV cccDNA in patients with normalized alanine aminotransferase levels and those undergoing HBeAg seroconversion were significantly greater than those in alanine aminotransferase-abnormal and HBeAg positive patients. Intrahepatic HBV cccDNA was decreased significantly after 48 weeks of treatment, but could not be eradicated. In conclusion, treatment of HBeAg-positive hepatitis B patients with entecavir for 48 weeks decreased serum and intrahepatic HBV cccDNA significantly, and the magnitude of HBV cccDNA reduction was related to total HBV DNA decrease, alanine aminotransferase normalization, and HBeAg seroconversion.     

Prophylactic Effect of Lamivudine for Chemotherapy-Induced Hepatitis B Reactivation in Breast Cancer: A Meta-Analysis

Background

Three strategies using lamivudine have been proposed to prevent chemotherapy-induced HBV (hepatitis B virus) reactivation in the clinical setting. The purpose of this meta-analysis is to evaluate the efficacy of the early preemptive strategy, deferred preemptive strategy and therapeutic strategy in patients with HBsAg-positive breast cancer during chemotherapy.

Methods

Clinical studies published from database inception until Nov 1, 2014, were included for analysis. The primary outcomes were overall survival, rate of chemotherapy disruption and virological and clinical reactivation. The secondary outcomes were the rates of HBV-related chemotherapy disruption, HBV-related mortality, YMDD mutations and withdrawal hepatitis.

Results

Four hundred and thirty patients in four studies that compared the early preemptive strategy with a therapeutic strategy were included. Application of early preemptive lamivudine was superior in reducing HBV recurrence (pooled OR: 0.12, 95% CI, 0.04 to 0.31, P< 0.0001), the incidence of HBV-related hepatitis (pooled OR: 0.13, 95% CI, 0.04 to 0.37, P< 0.0001) and the rate of chemotherapy disruption (pooled OR: 0.37, 95% CI, 0.23 to 0.60, P< 0.0001). In these two groups, no significant difference was found in overall mortality (P = 0.32), YMDD mutant rate (P = 0.13) or incidence of withdrawal hepatitis (P = 0.38). Of the two studies that compared the efficacy of an early and a deferred preemptive strategy, one showed that an early preemptive strategy significantly reduced the incidence of hepatitis (P = 0.046), whereas the other showed no significant difference (P = 0.7).

Conclusions

An early preemptive strategy is superior to a therapeutic strategy in decreasing the incidence of HBV reactivation, incidence of HBV-related hepatitis and rate of chemotherapy disruption in patients with breast cancer. A deferred preemptive strategy might be an alternative approach to controlling viral replication.     

The Compliance of Doctors with Viral Hepatitis B Screening and Antiviral Prophylaxis in Cancer Patients Receiving Cytotoxic Chemotherapy Using a Hospital-Based Screening Reminder System

MethodsUsing a computer-assisted reminder system, doctors were alerted of both HBsAg screening and antiviral prophylaxis prior to prescribing chemotherapy. The compliance between different doctors and outcomes of patients were investigated during the period of execution of this system. The rates of compliance with both recommendations were compared among various cancer types.ResultsA total of 1053 patients were enrolled, of which only 88 had previous data pertaining to HBsAg status. Using this reminder system, an overall screening rate of 85.5% (825/965) was achieved and did not significantly differ according to cancer type. However, the overall antiviral prophylactic rate was only 45.5% (61/134). The rates of antiviral prophylaxis were lower for doctors treating lung, breast and colorectal cancers than for those treating hematological malignancies (all p<0.05). Consequently, the rate of HBV reactivation was lower in patients who received antiviral prophylaxis than in those who did not (1.6% vs. 15.1%; p<0.01). Multivariate analysis revealed that male gender and antiviral prophylaxis were both related to reactivation of hepatitis B (p<0.05).ConclusionsBy using this reminder system, the overall screening rate for HBsAg was satisfactory, whereas the antiviral prophylaxis was inadequate in patients with solid tumors due to the varying compliance of the attending doctors. Further strategies to improve both screening and prophylaxis are needed to minimize HBV-related events during cytotoxic chemotherapy.     

乳腺癌患者化疗后乙肝病毒再激活及拉米夫定预防性应用的临床研究

目的:探讨化疗引起的乳腺癌患者肝功能损害与乙肝病毒(HBV)感染的相关性及抗病毒治疗在预防化疗引起的HBV再激活中的作用。方法:2006年3月-2010年10月在武汉市第三医院接受化疗的病理确诊为乳腺癌患者(包括术后辅助化疗)为研究对象,比较HBs Ag阴性138例和HBs Ag阳性50例患者化疗后肝功能损害的发生情况,并分析在HBs Ag阳性患者中,预防性使用(21例)与未预防性使用(27例)抗病毒药物拉米夫定后乙肝病毒再激活率的差异。结果:化疗后出现肝功能损害的乳腺癌患者中,HBs Ag阳性患者(31.25%)与HBs Ag阴性患者(16.67%)所占比例的差异有统计学意义(P<0.001)。化疗前预防性使用拉米夫定(4.62%)与未预防性使用(25.93%)拉米夫定,患者出现HBV再激活率的差异亦有统计学意义(P<0.01)。结论:乳腺癌患者化疗后,HBs Ag阳性患者较HBs Ag阴性患者更易出现肝功能损害,预防性使用核苷类似物抗病毒药物拉米夫定,可明显降低乳腺癌合并乙肝患者化疗后HBV再激活肝炎的发生。     

Comparison of the Efficacy of Entecavir and Tenofovir in Nucleos(T)ide Analogue-Experienced Chronic Hepatitis B Patients

The efficacy of entecavir (ETV) and tenofovir (TDF) for the treatment of nucleos(t)ide analogue (NA)-experienced chronic hepatitis B (CHB) patients has been little studied. Here, we compare the efficacy of both ETV and TDF in NA-experienced CHB patients without detectable genotypic resistance. This retrospective cohort study included consecutive NA-experienced patients who had neither current nor previous genotypic resistance and had received ETV or TDF for at least 6 months. Overall, 202 patients (146 patients in the ETV group and 56 in the TDF group) were analyzed. The cumulative probabilities of complete virologic suppression (CVS) at month 12 were 76.1% in the ETV group and 95.0% in the TDF group (P<0.001), respectively. The TDF-treated group achieved CVS more rapidly than the ETV group for both Hepatitis B e antigen (HBeAg)-negative and -positive patients (P = 0.006 and < 0.001, respectively), and for those with both low (< 2,000 IU/mL) and high (≥ 2,000 IU/mL) HBV DNA levels (P = 0.01 and 0.002, respectively). TDF group had an increased probability of achieving CVS (hazard ratio, 2.242; 95% confidence interval, 1.587–3.165; P = 0.001), after adjustment for HBV DNA level, the presence of HBeAg, and a history of CVS during prior treatment. During the treatment period, 23 patients (15.8%) in the ETV group developed virologic breakthrough, compared to none in the TDF group. The cumulative probabilities of developing virologic breakthrough and ETV-resistance at month 24 were 9.7% and 5.3%, respectively. In conclusion, TDF is preferable to ETV for achieving CVS in NA-experienced CHB patients without genotypic resistance.     

Comparison of the Efficacies and Safety of Combined Therapy between Telbivudine Plus Adefovir and Lamivudine Plus Adefovir in Patients with Hepatitis B Virus Infection in Real-World Practice

MethodsThis study enrolled a total of 171 patients (110 patients received LAM+ADV and 60 patients received LdT+ADV). We analyzed the changes in renal function using the estimated glomerular filtration rate (eGFR). The DNA undetectable rate, hepatitis B e antigen (HBeAg) seroconversion rate, and alanine aminotransferase (ALT) normalization rate were analyzed. We checked the serum uric acid, phosphate and creatine kinase, and lactic acid levels to analyze safety. We observed these patients for 48 to 240 weeks and checked their serum profile every 6 months.ResultsThere was no statistically significant difference between the two groups in anti-hepatitis B virus (HBV) efficacy in terms of DNA undetectable rate, ALT normalization rate, and HBeAg seroconversion rate. Both the LAM+ADV and LdT+ADV groups had stable or improved renal function. However, a higher eGFR was found in the LdT+ADV group with continuous serum fluctuation during 3 years of combined therapy as well as a higher serum creatine kinase level.ConclusionsLong-term LdT+ADV combined therapy and LAM+ADV combined therapy were both associated with stable or improved renal function. The clinical efficacy was similar between the two groups, but the LdT group had a higher serum creatine kinase level. We need to monitor the data regularly in clinical practice.     

阿德福韦酯与拉米夫定治疗慢性乙肝的疗效对比

目的:比较阿德福韦酯与拉米夫定治疗慢性乙肝的远期疗效。方法:回顾性分析2012年5月至2014年5月我院收治的80例慢性乙肝患者的临床资料,随机分为研究组和对照组,每组各40例。研究组患者给予阿德福韦酯治疗,对照组患者给予拉米夫定治疗。观察两组患者不同时段肝功能指标复常率、病毒量转阴率、乙肝E抗原(HBe Ag)转阴率、粒细胞降低率及乙肝病毒脱氧核糖核酸(HBV-DNA)抑制率,并比较两组患者不良反应发生率。结果:研究组患者肝功能指标复常率、血病毒量转阴率、Hbe Ag转阴率均显著高于对照组同期对应值,差异具有统计学意义(P0.05),但两组患者血粒细胞降低率无显著差异(P0.05);研究组患者HBV-DNA水平总抑制率高于对照组,差异有统计学意义(P0.05);两组患者均无严重不良反应发生(P0.05)。结论:阿德福韦酯治疗慢性乙肝的疗效更显著,能有效抑制HBV-DNA复制且安全性较高。     

两株乙型肝炎病毒基因组结构分析及其复制和抗原表达特性的比较

为从全基因组水平研究乙型肝炎病毒（ＨＢＶ）的核苷酸结构及复制和抗原表达特性,分别从２例ＨＢｓＡｇ和ＨＢｅＡｇ阳性、ＨＢＶ ＤＮＡ滴度为１０＾１４和１０＾１３拷贝／ｍｌ的慢性乙型肝炎患者（编号为５６和２－１８）血清中扩增、克隆了ＨＢＶ全基因组,并测定了核苷酸序列。两株病毒基因组转染ＨｅｐＧ２细胞的培养上清中ＨＢｓＡｇ水平基本相同,但＃５６毒株表达的ＨＢｅＡｇ约为＃２－１８株的３倍,Ｓｏｕｔｈｅｒｍ印     

恩替卡韦治疗HBeAg 阳性乙型肝炎临床观察

目的:探讨恩替卡韦治疗HBeAg阳性乙型肝炎的疗效与安全性。方法:140例慢性乙肝患者随机分为2组:观察组予恩替卡韦0.5 mg/d,对照组予拉米夫定100 mg/d,疗程均为48周。观察两组HBV DNA阴转率、ALT复常率、HbeAg血清转换率以及不良反应发生情况。结果:在治疗12周后,观察组与对照组HBV DNA阴转率分别为47.1%、22.9%(P<0.01),ALT复常率分别为51.4%、31.4%(P<0.05),在治疗48周后,观察组与对照组HBV DNA阴转率分别为88.6%、48.6%(P<0.01),ALT复常率分别为90.0%、72.9%(P<0.01)。HbeAg血清转换率无统计学差异,两组患者未见严重不良反应。结论:恩替卡韦治疗HBeAg阳性乙肝患者,较拉米夫定起效快、作用强,且安全性好。     

乙型肝炎病人重叠感染丙型肝炎的评价

应用ＥＬＩＳＡ和ＰＣＲ法检测５０２例乙肝病人血清,４０１例ＨＢｓＡｇ阳性血清中,有１１４例（２８．４％）抗－ＨＣＶ和ＨＣＶＲＮＡ双项阳性,２５例（６．２％）ＨＣＶＲＮＡ单项阳性;２１例（５．２％）抗－ＨＣＶ单项阳性。将ＨＢｓＡｇ乙肝病人分成ＨＢＶＤＮＡ,ＨＢｅＡｇ阳性组和ＨＢＶＤＮＡ,ＨＢｅＡｇ阴性组。前者抗－ＨＣＶ阳性率为１１．６％～２０．５％,ＨＣＶＲＮＡ阳性率为１６．２％～２０．５％。后者抗－ＨＣＶ阳性率为２０．２％～５５．６％,ＨＣＶＲＮＡ阳性率为２３％～６０．３％。结果说明长期携带ＨＢＶ者和慢性乙肝病人均可重叠ＨＣＶ感染。ＨＢＶＤＮＡ阳性组抗－ＨＣＶ和ＨＣＶＲＮＡ阳性率明显高于ＨＢＶＤＮＡ阳性组     

恩替卡韦治疗HBeAg阳性乙型肝炎临床观察

目的：探讨恩替卡韦治疗HBeAg阳性乙型肝炎的疗效与安全性。方法：140例慢性乙肝患者随机分为2组：观察组予恩替卡韦0．5mg／d,对照组予拉米夫定100mg／d,疗程均为48周。观察两组HBVDNA阴转率、ALT复常率、HbeAg血清转换率以及不良反应发生情况。结果：在治疗12周后,观察组与对照组HBVDNA阴转率分别为47．1％、22．9％（P〈0．01）,ALT复常率分别为51．4％、31．4％（P〈0．05）,在治疗48周后,观察组与对照组HBVDNA阴转率分别为88．6％、48．6％（P〈0．01）,ALT复常率分别为90．0％、72．9％（P〈0．01）。HbeAg血清转换率无统计学差异,两组患者未见严重不良反应。结论：恩替卡韦治疗HBeAg阳性乙肝患者,较拉米夫定起效快、作用强,且安全性好。     

Replication Inhibition of Hepatitis B Virus and Hepatitis C Virus in Co-Infected Patients in Chinese Population

Background

Hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infections contributes to a substantial proportion of liver disease worldwide. The aim of this study was to assess the clinical and virological features of HBV-HCV co-infection.

Methods

Demographic data were collected for 3238 high-risk people from an HCV-endemic region in China. Laboratory tests included HCV antibody and HBV serological markers, liver function tests, and routine blood analysis. Anti-HCV positive samples were analyzed for HCV RNA levels and subgenotypes. HBsAg-positive samples were tested for HBV DNA.

Results

A total of 1468 patients had chronic HCV and/or HBV infections. Among them, 1200 individuals were classified as HCV mono-infected, 161 were classified as HBV mono-infected, and 107 were classified as co-infected. The HBV-HCV co-infected patients not only had a lower HBV DNA positive rate compared to HBV mono-infected patients (84.1% versus 94.4%, respectively; P<0.001). The median HCV RNA levels in HBV-HCV co-infected patients were significantly lower than those in the HCV mono-infected patients (1.18[Interquartile range (IQR) 0–5.57] versus 5.87[IQR, 3.54–6.71] Log₁₀ IU/mL, respectively; P<0.001). Furthermore, co-infected patients were less likely to have detectable HCV RNA levels than HCV mono-infected patients (23.4% versus 56.5%, respectively; P<0.001). Those HBV-HCV co-infected patients had significantly lower median HBV DNA levels than those mono-infected with HBV (1.97[IQR, 1.3–3.43] versus 3.06[IQR, 2–4.28] Log₁₀ IU/mL, respectively; P<0.001). The HBV-HCV co-infection group had higher ALT, AST, ALP, GGT, APRI and FIB-4 levels, but lower ALB and total platelet compared to the HBV mono-infection group, and similar to that of the HCV mono-infected group.

Conclusion

These results suggest that co-infection with HCV and HBV inhibits the replication of both viruses. The serologic results of HBV-HCV co-infection in patients suggests more liver injury compared to HBV mono-infected patients, but is similar to HCV mono-infection.     

肝癌乙型肝炎病毒感染患者术后恩替卡韦抗病毒治疗的临床疗效及安全性评价

目的:探讨肝癌乙型肝炎病毒(HBV)感染患者根治性切除术后采用恩替卡韦抗病毒治疗的临床疗效及安全性。方法:收集2015年1月-2017年8月在我院行根治性切除术的肝癌HBV感染患者279例为研究对象,以血清HBV-DNA载量10~5 copies/ml为界限,分为高病毒复制组128例,低病毒复制组151例,按照随机数字表法将高病毒复制组分为高-治疗组64例、高-对照组64例,将低病毒复制组分为低-治疗组76例、低-对照组75例。高-治疗组和低-治疗组术后给予恩替卡韦0.5 mg/d,高-对照组和低-对照组未行抗病毒治疗。比较手术前、术后7 d各组的血清HBV-DNA水平,血清白蛋白(ALB)、谷丙转氨酶(ALT)、前白蛋白(PA),以及术后并发症的发生情况。结果:高-治疗组、高-对照组、低-治疗组、低-对照组术后血清ALB、PA均较治疗前降低,血清ALT均较治疗前升高,且高-治疗组或低-治疗组术后血清ALB、PA均高于高-对照组或低-对照组,血清ALT水平均低于高-对照组或低-对照组,差异均有统计学意义(P0.05);高-治疗组或低-治疗组术后血清HBV-DNA水平均低于治疗前,且均低于同期高-对照组或低-对照组,差异均有统计学意义(P0.05)。高-治疗组与高-对照组、低-治疗组与低-对照组患者术后并发症发生率均无统计学差异(P0.05)。结论:恩替卡韦能显著改善肝癌HBV感染患者术后的血清HBV-DNA载量水平和肝功能,安全性高,值得临床推广。     

苦参碱联合恩替卡韦抗乙型肝炎病毒感染的作用及其机制

目的:探讨苦参碱联合恩替卡韦治疗乙型肝炎病毒(HBV)感染的疗效并初步探讨其作用机制。方法:选择2014年9月-2016年8月我院收治的HBeAg阳性乙肝患者98例,按治疗方法分为对照组和观察组,每组49例。对照组患者给予恩替卡韦治疗,观察组患者在对照组基础上应用苦参碱联合治疗。分别在治疗后12、24、48周观察和比较两组患者的HBeAg转阴率、ALT复常率、HBV DNA转阴率、血清球蛋白水平。结果:观察组在治疗后24、48周的HBeAg转阴率、ALT复常率、HBV DNA转阴率均显著高于对照组,差异均具有统计学意义(P0.05)。观察组血清球蛋白水平明显高于对照组,差异有统计学意义(P0.05)。两组间不良反应发生情况比较差异无统计学意义(P0.05)。结论:苦参碱联合恩替卡韦对于HBV具有较好的协同治疗作用,且安全性较好,可能与苦参碱降低血清转氨酶水平,增强患者免疫功能有关。     

Tumor Necrosis Factor-Alpha Induced by Hepatitis B Virus Core Mediating the Immune Response for Hepatitis B Viral Clearance in Mice Model

Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). An efficient control of virus infections requires the coordinated actions of both innate and adaptive immune responses. In order to define the role of innate immunity effectors against HBV, viral clearance was studied in a panel of immunodeficient mouse strains by the hydrodynamic injection approach. Our results demonstrate that HBV viral clearance is not changed in IFN-α/β receptor (IFNAR), RIG-I, MDA5, MYD88, NLRP3, ASC, and IL-1R knock-out mice, indicating that these innate immunity effectors are not required for HBV clearance. In contrast, HBV persists in the absence of tumor necrosis factor-alpha (TNF-α) or in mice treated with the soluble TNF receptor blocker, Etanercept. In these mice, there was an increase in PD-1-expressing CD8⁺ T-cells and an increase of serum HBV DNA, HBV core, and surface antigen expression as well as viral replication within the liver. Furthermore, the induction of TNF-α in clearing HBV is dependent on the HBV core, and TNF blockage eliminated HBV core-induced viral clearance effects. Finally, the intra-hepatic leukocytes (IHLs), but not the hepatocytes, are the cell source responsible for TNF-α production induced by HBcAg. These results provide evidences for TNF-α mediated innate immune mechanisms in HBV clearance and explain the mechanism of HBV reactivation during therapy with TNF blockage agents.     

拉米夫定联合胸腺肽A1 治疗慢性乙型肝炎的疗效观察

目的:探讨拉米夫定(LAM)联合胸腺肽α1(Tα1)治疗慢性乙型肝炎的长期疗效和安全性。方法:72例慢性乙肝患者(HBV-DNA和HBeAg均阳性),按1:1随机分配进入联合治疗组(LAM+Tα1组)和单用拉米夫定组(LAM组)。结果:治疗1年时LAM+Tα1组HBeAg血清转换率(44.4%,16/36例)明显高于LAM组(5.6%,2/36例),P<0.01。停药1年后,持续的HBeAg血清转换率分别为36.1%(13/36例)和8.3%(3/36例),P<0.01。治疗过程中及停药后,两组HBV-DNA水平均明显下降,但两组的HBV-DNA转阴率相仿。治疗后1年ALT复常率联合治疗组与拉米夫定组相似,分别为75%(27/36例)和66.7%(24/36例)、随访1年时ALT复常率联合治疗组明显高于拉米夫定组,分别为58.3%(21/36例)和16.7%(6/36例)。在治疗过程中,未发现严重的不良反应。结论:LAM联合Tα1治疗慢性乙肝,不良反应少,疗效优于单一LAM用药组。     

乙型肝炎病毒持续感染患者细胞内病毒复制的研究

用Southern blot技术对乙肝病毒感染肝脏和外周血白细胞的情况进行了对比研究,发现白细胞的阳性率为44％,肝组织的阳性率为46％,两者无统计学差异。根据琼脂糖凝胶电泳速度可将病毒DNA分子分为游离型、整合型和混合型,配对检查两者亦无明确相关性,说明外周血白细胞是乙肝病毒攻击的靶细胞,亦是病毒复制的场所。白细胞中病毒DNA游离型与血清学指标HBeAg( ),HBV DNA斑点杂交( )关系密切,而整合型除与上述指标有关外,还和抗-HBe( )有关,表明病毒在乙肝发病过程中复制和部分静止的差异。