乙型肝炎表面抗原阳性供肝在肝移植中的应用

目的 探讨HBsAg阳性供肝在成人肝移植中应用的安全性及其对患者预后的影响.方法 回顾性分析本中心2007年1月至2010年2月23例接受HBsAg阳性供肝的成人肝移植患者临床资料,患者全部为男性,中位年龄42.5岁(29 ～ 61岁),原发病均为乙型肝炎相关终末期肝病,其中13例术前HBsAg、HBeAg和抗-HBc为阳性,10例术前HBsAg、抗-HBe和抗-HBc为阳性.供体HBsAg均为阳性,术后口服恩替卡韦0.5mg,1次/d,静脉滴注乙型肝炎免疫球蛋白(HBIG),术后1周每天滴注2000 IU.术中及术后采用无激素的免疫抑制方案,术后第1、7、14、21、30天检测患者血清HBsAg、抗-HBs、HBeAg、抗-HBe、抗-HBc、HBV DNA水平,并行肝脏彩色多普勒超声检查.1个月后每月检测及检查1次,并记录患者术后肝功能、肾功能、急性排斥反应、感染、血管并发症、胆道并发症、乙型肝炎复发、肿瘤复发及患者生存等数据.结果 围手术期2例患者死于严重肺部感染,其余21例患者随访至2010年12月(10 ～ 38个月),所有患者术后乙型肝炎未转阴,其中1例患者于术后5个月因胆道缺血再次行肝移植,3例肿瘤患者分别于术后9、14、18个月死于肿瘤复发,18例患者生存,肝功能良好,彩色多普勒超声监测显示肝脏形态、质地良好,HBV DNA监测显示其均为阴性.随访期内,23例患者的生存率为78.3％(18/23),移植肝生存率为73.9％(17/23),未出现乙型肝炎复发所致的肝功能异常、移植肝丢失和病死患者.结论 HBsAg阳性供肝可以安全地应用于乙型肝炎相关终末期肝病的患者.     

Successful living donor liver transplantation using a graft from a hepatitis B surface antigen-positive donor.

BACKGROUND/AIMS: Liver transplantation using a graft from a donor with a positive hepatitis B surface antigen (HBsAg) has been contraindicated owing to the extremely high risk for recurrent disease leading to graft loss. However, the severe shortage of donors often forces the transplant community to utilize suboptimal donors, especially in the setting of living donor liver transplantation (LDLT). METHOD: Here, we report a case of successful LDLT for a patient with hepatitis B-related cirrhosis utilizing a graft from an HBsAg-positive 'healthy carrier' donor using a combination prophylaxis of lamivudine and adefovir dipivoxil. RESULTS: To date, the patient has been doing well with normal liver function tests and liver histological findings at 4 years after the transplantation and the donor has also been doing well. CONCLUSIONS: Although virological recurrence appears to be universal despite prophylaxis, re-evaluation of the use of a graft from a healthy HBsAg-positive donor is warranted in this era of combination prophylaxis.     

Four-year follow-up of two chronic hepatitis B recipients of hepatitis B surface antigen-positive cadaveric liver grafts from asymptomatic carriers

Aim: Only seven cases of liver transplantation (OLT) with positive serum hepatitis B surface antigen (HBsAg) grafts have been reported in the world till now. Here we report the 4‐year follow‐up results and clinical pathologic characteristics of two recipients of chronic hepatitis B transplanted with HBsAg‐positive cadaveric liver grafts from asymptomatic carriers. Methods: Lamivudine combined with hepatitis B immune globulin were used for the control of hepatitis B virus (HBV) infection in both of the recipients post‐OLT. The liver functions, virus status and pathologic characteristics of two recipients were followed up according to the rounte protocol of Liver Transplantation Center of West China Hospital. Results: The serum HBV deoxyribonucleic acid (DNA) turned negative within 30 days post‐OLT, but HBsAg remained positive for both of the recipients during follow up. HBV breakthrough occurred in one recipient at the month 12 post‐OLT, with detectable serum HBV‐DNA (740 copies/mL) and tyrosine‐methionine‐aspartate‐aspartate motif mutation (rtM204I and rtM204V). After the replacement of lamivudine by adefovir dipivoxil 10 mg daily for 2 months, serum HBV‐DNA of this recipient became undetectable again and maintained undetectable during follow up. Both of the recipients have survived for more than 4 years post‐OLT, with stable liver function and mild hepatitis. Conclusion: Due to extreme scarcity of liver graft, we think that HBsAg‐positive liver graft without active HBV‐DNA replication and severe pathological manifestation from asymptomatic carriers may deserve consideration when no other graft is available in a bearable waiting time.     

High-dose hepatitis B immunoglobulin therapy in hepatocellular carcinoma with hepatitis B virus-DNA/hepatitis B e antigen-positive patients after living donor liver transplantation

AIM: To investigate the impact of high-dose hepatitis B immunoglobulin(HBIG) on hepatocellular carcinoma(HCC) and hepatitis B virus(HBV) recurrence and overall survival after living donor liver transplantation(LDLT).METHODS: We investigated 168 patients who underwent LDLT due to HCC, and who were HBV-DNA/hepatitis B e antigen(HBe Ag)-positive, from January 2008 to December 2013. After assessing whether the patients met the Milan criteria, they were assigned to the low-dose HBIG group and high-dose HBIG group. Using the propensity score 1:1 matching method, 38 and 18 pairs were defined as adhering to and not adhering to the Milan criteria. For each pair, HCC recurrence, HBV recurrence and overall survival were analyzed by the Kaplan-Meier method and the log rank test according to the HBIG dose. RESULTS: Among those who met the Milan criteria, the 6-mo, 1-year, and 3-year HCC recurrence-free survival rates were 88.9%, 83.2%, and 83.2% in the low-dose HBIG group and 97.2%, 97.2%, and 97.2% in the high-dose HBIG group, respectively(P = 0.042).In contrast, among those who did not meet the Milan criteria, HCC recurrence did not differ according to the HBIG dose(P = 0.937). Moreover, HBV recurrence and overall survival did not differ according to the HBIG dose among those who met(P = 0.317 and 0.190, respectively) and did not meet(P = 0.350 and 0.987, respectively) the Milan criteria. CONCLUSION: High-dose HBIG therapy can reduce HCC recurrence in HBV-DNA/HBe Ag-positive patients after LDLT.     

A prophylactic approach for bone marrow transplantation from a hepatitis B surface antigen-positive donor

It has been accepted that bone marrow transplantation (BMT)is the only curative therapeutic option for certain hematologic malignancies.The southeast Asia region is an endemic area of hepatitis B virus(HBV)infection;thus,BMT using a hepatitis B surface antigen(HBsAg)-positive donor is occasionally unavoidable.Organ transplantation using a HBsAg-positive donor can lead to post-transplantation de novo HBV infection and severe HBV-related hepatitis if no effective prophylactic measures are taken prior to and after transplantation.In this report,a four-level approach was designed for a patient with chronic myeloid leukemia,beginning with a booster HBV vaccination before performing BMT with a HBsAg-positive donor.Prior to BMT,the HBV viral load of the donor was reduced to an undetectable level by antiviral therapy.After BMT,hepatitis B immunoglobulin was administered intramuscularly for 1 wk together with a long-term antiviral drug,lamivudine.One year after discontinuation of lamivudine,the patient is still free of HBV infection.     

Prediction of occult hepatitis B virus infection in liver transplant donors through hepatitis B virus blood markers

Background

Occult hepatitis B virus infection is defined as detectable HBV-DNA in liver of HBsAg-negative individuals, with or without detectable serum HBV-DNA. In deceased liver donors, results of tissue analysis cannot be obtained prior to allocation for liver transplantation.

Aims

we investigated prevalence and predictability of occult hepatitis B using blood markers of viral exposure/infection in deceased liver donors.

Methods

In 50 consecutive HBsAg-negative/anti-HBc-positive and 20 age-matched HBsAg-negative/anti-HBc-negative donors, a nested-PCR assay was employed in liver biopsies for diagnosis of occult hepatitis B according to Taormina criteria. All donors were characterized for plasma HBV-DNA and serum anti-HBs/anti-HBe.

Results

In liver tissue, occult hepatitis B was present in 30/50 anti-HBc-positive (60%) and in 0/20 anti-HBc-negative donors (p < 0.0001). All anti-HBc-positive donors with detectable HBV-DNA in plasma (n = 5) or anti-HBs > 1,000 mIU/mL (n = 5) eventually showed occult infection, i.e, 10/30 occult hepatitis B-positive donors which could have been identified prior to transplantation. In the remaining 40 anti-HBc-positive donors, probability of occult infection was 62% for anti-HBe-positive and/or anti-HBs ≥ 58 mIU/mL; 29% for anti-HBe-negative and anti-HBs < 58 mIU/mL.

Conclusions

In deceased donors, combining anti-HBc with other blood markers of hepatitis B exposure/infection allows to predict occult hepatitis B with certainty and speed in one third of cases. These findings might help refine the allocation of livers from anti-HBc-positive donors.     

阿德福韦酯治疗HBeAg阳性慢性乙型肝炎101例临床观察

目的观察阿德福韦酯治疗HBeAg阳性慢性乙型肝炎和拉米夫定治疗无效的慢性乙型肝炎患者,单药连续144周治疗,停药后监测96周疗效和药物安全性。方法初始治疗69例,拉米夫定治疗无效再治疗32例共101例,采用单药阿德福韦酯(ADV)10mg,每日1次口服,连续治疗144周,疗程结束继续监测到240周。结果阿德福韦酯初治组和复治组经144周连续治疗和停药后监测至240周血清ALT累积复常率分别为91.3%和90.6%,血清HBV DNA转阴率分别为88.4%和84.3%,HBeAg转阴率分别为34.7%和28.1%,HBeAg/HB-eAb血清转换率分别为55.0%和53.1%,HBsAg/HBsAb血清学转换均在停药后不同时间段发生,初治组为7.2%,复治组为6.3%。经144周连续治疗和停药后随访期间血、尿常规和肾功能,均无与治疗相关的异常发现。结论阿德福韦酯单药10mg每日1次口服治疗HBeAg阳性慢性乙型肝炎患者,有显著抑制HBV DNA复制,对拉米夫定治疗无效患者,可获得同样疗效,长期服药无明显耐药性,安全性好。     

阿德福韦酯片治疗乙型肝炎病毒e抗原阳性的慢性乙型肝炎临床观察

目的评价国产阿德福韦酯片治疗HBeAg阳性慢性乙型肝炎患者的安全性与效果。方法采用多中心、双盲、随机对照的方法，观察238例HBeAg阳性慢性乙型肝炎患者经口服阿德福韦酯片10mg／d，48圃治疗期间和治疗后，血清HBVDNA阴转率、ALT复常率、HBeAg阴转率、抗-HBe阳转率以及不良反应。结果在前12周的双盲对照试验中，试验组血清HBVDNA阴转率、ALT复常率、HBeAg阴转率和抗-HBe阳转率均高于安慰剂对照组，分别为50．0％比5．1％；35．0％比8．5％；12．5％比2．5％；5．8％比0（X^2值分别为59．89，24．52，P〈0．05；四格表确切概率法检验，P〈0．05）。在试验组和安慰剂对照组均口服阿德福韦酯片的后36周开放试验期结束后，则分别为87．5％比78．0％；78．3％比72．7％；29．6％比24．5％；15．6％比10．9％（X。值分别为3．78，0．83，0．72，1．09，P〉0．05）。结论国产阿德福韦酯片治疗HBeAg阳性慢性乙型肝炎的安全性与有效性与国外同类批准上市使用的药物相似。     

慢性乙型肝炎肝组织内HBsAg、HBcAg的表达及临床研究进展

一直以来临床将血清乙型肝炎e抗原(HBeAg)、乙肝病毒DNA(HBV DNA)阳性作为乙肝病毒复制的标志,随着肝穿活检及抗病毒治疗的研究进展,肝活检组织中乙肝表面抗原(HBsAg)和乙肝核心抗原(HBcAg)的表达模式与血清乙型肝炎病毒(HBV)DNA定量、肝组织炎症活动度分级及纤维化分期之间关系的临床研究日益增多,本文就HBsAg和HBcAg在肝组织的表达模式及临床研究进展综述如下.     

Occult hepatitis B in blood donors in Indonesia: altered antigenicity of the hepatitis B virus surface protein

Background and aims  

Occult hepatitis B virus infection (OBI) poses a challenge to the safety of blood donation. The prevalence of OBI is not well documented in Indonesia, although this information in such an endemic country is needed. This study was aimed to evaluate the prevalence of occult hepatitis B in blood donors from two cities of Indonesia, and to study the genetic variation and its effect on the predicted antigenicity of HBsAg.     

Efficacy of a Chinese herbal formula on hepatitis B e antigen-positive chronic hepatitis B patients

BACKGROUND No guideline recommends antiviral therapy for hepatitis B e antigen(HBe Ag)-positive chronic hepatitis B patients with persistently normal alanine aminotransferase levels and a high hepatitis B virus(HBV) DNA viral load.AIM To evaluate the feasibility and safety of a Chinese herbal formula as a therapeutic option for chronic HBV infection.METHODS In total,395 patients(30–65 years old) with confirmed HBe Ag-positive chronic hepatitis B infection and persistently normal alanine aminotransferase were randomized to receive either Chinese herbal formula or placebo for 96 wk.Endpoints to evaluate therapeutic efficacy included:(1) HBV DNA levels decreased to less than 4 log10 IU/m L at weeks 48 and 96;and(2) HBe Ag clearance and seroconversion rates at weeks 48 and 96.RESULTS HBV DNA levels ≤ 4 log10 IU/m L were 10.05% at week 48 and 18.59% at week 96 in the treatment group.The HBe Ag clearance and conversion rates were 8.54% and 8.04% at week 48 and 16.08% and 14.57% at week 96,respectively.However,HBV DNA levels ≤ 4 log10 IU/m L were 2.55% and 2.55% at weeks 48 and 96,respectively,and the HBe Ag clearance rates were 3.06% and 5.61% at weeks 48 and 96,respectively,in the control group.The quantitative hepatitis B surface antigen and HBe Ag levels at baseline and changes during the treatment period as well as the alanine aminotransferase elevation at weeks 12 and 24 were strong predictors of HBe Ag clearance.CONCLUSION High rates of HBV DNA reduction,HBe Ag clearance and seroconversion could be achieved with Chinese herbal formula treatments,and the treatments were relatively safe for HBe Ag-positive chronic hepatitis B-infected patients with persistently normal alanine aminotransferase.The ability of the compound to modulate host immune function probably contributed to this effect.     

聚乙二醇化干扰素治疗乙型肝炎病毒e抗原阳性慢性乙型肝炎患者乙型肝炎病毒表面抗原消失的相关因素

目的 探讨聚乙二醇化干扰素（PEG-IFN α-2a）治疗HBeAg阳性慢性乙型肝炎(CHB)患者过程中预测HBsAg消失的相关因素。方法 对72例HBeAg阳性CHB患者,应用PEG-IFN α-2a 180 μg,每周1次,共48周。每3个月检测ALT、AST及HBV DNA、HBeAg和H BsAg定量,对48周治疗结束时HBsAg消失与基线、12周、24周的HBV DNA、HBeAg和HBsAg定量的相关关系进行分析。计数资料行Fisher精确检验及受试者工作特征(ROC)曲线分析。结果65例HBeAg阳性CHB患者完成本研究,其中7例HBsAg消失。48周时HBsAg的消失与治疗12周时H BeAg水平有关（Fisher确切概率法,P=0.023）,与治疗24周时HBeAg水平高度相关 （Fisher确切概率法,P=0.004）,与12周或24周时HBsAg＜250 IU/mL相关(Fisher确切概率法,P=0.001,P=0.002)。与12周时HBV DNA阴转相关（Fisher确切概率法,P=0.039）,而与24周时HBV DNA是否阴转无关（Fisher确切概率法,P= 0.130）。经ROC曲线分析显示,12周、24周HBsAg及24周HBeAg曲线下面积(AUC)分别为0.8584(P=0.0021)、0.9606(P=0.001)及0.8350(P=0.040)。结论 联合应用24周HBeAg和HBsAg定量水平可能是预测48周疗程结束时是否发生HBsAg消失的有效指标。     

Global prevalence of hepatitis B virus serological markers among healthcare workers: A systematic review and meta-analysis

BACKGROUNDThe hepatitis B virus (HBV) infection is a global public health concern that affects about 2 billion people and causes 1 million people deaths yearly. HBV is a blood-borne disease and healthcare workers (HCWs) are a high-risk group because of occupational hazard to patients’ blood. Different regions of the world show a highly variable proportion of HCWs infected and/or immunized against HBV. Global data on serologic markers of HBV infection and immunization in HCWs are very important to improve strategies for HBV control.AIMTo determine the worldwide prevalence of HBV serological markers among HCWs.METHODSIn this systematic review and meta–analyses, we searched PubMed and Excerpta Medica Database (Embase) to identify studies published between 1970 and 2019 on the prevalence of HBV serological markers in HCWs worldwide. We also manually searched for references of relevant articles. Four independent investigators selected studies and included those on the prevalence of each of the HBV serological markers including hepatitis B surface antigen (HBsAg), hepatitis e antigen (HBeAg), immunoglobulin M anti-HBc, and anti-HBs. Methodological quality of eligible studies was assessed and random-effect model meta-analysis resulted in the pooled prevalence of HBV serological markers HBV infection in HCWs. Heterogeneity (I²) was assessed using the χ² test on Cochran’s Q statistic and H parameters. Heterogeneity’ sources were explored through subgroup and metaregression analyses. This study is registered with PROSPERO, number CRD42019137144.RESULTSWe reviewed 14059 references, out of which 227 studies corresponding to 448 prevalence data among HCWs (224936 HCWs recruited from 1964 to 2019 in 71 countries) were included in this meta-analysis. The pooled seroprevalences of current HBsAg, current HBeAg, and acute HBV infection among HCWs were 2.3% [95% confidence interval (CI): 1.9-2.7], 0.2% (95%CI: 0.0-1.7), and 5.3% (95%CI: 1.4-11.2), respectively. The pooled seroprevalences of total immunity against HBV and immunity acquired by natural HBV infection in HCWs were 56.6% (95%CI: 48.7-63.4) and 9.2% (95%CI: 6.8-11.8), respectively. HBV infection was more prevalent in HCWs in low-income countries, particularly in Africa. The highest immunization rates against HBV in HCWs were recorded in urban areas and in high-income countries including Europe, the Eastern Mediterranean and the Western Pacific.CONCLUSIONNew strategies are needed to improve awareness, training, screening, vaccination, post-exposure management and treatment of HBV infection in HCWs, and particularly in low-income regions.     

拉米夫定治疗期间患者血清乙型肝炎表面抗原定量的变化

我们在应用拉米夫定过程中发现，随着患者血清乙型肝炎病毒（HBV）DNA的抑制，血清乙型肝炎表面抗原（HBsAg）定量有一定的变化，现报道如下。     

Transformation of hepatitis B serologic markers in babies born to hepatitis B surface antigen positive mothers

AIM: To better understand the clinical significance of hepatitis B seroiogic markers in babies born to hepatitis B surface antigen (HBsAg) positive mothers, the incidence of maternal seroiogic markers of hepatitis B via placenta and its transformation in these babies were investigated. METHODS: Mothers with positive HBsAg were selected in the third trimester of pregnancy. Their babies received immunoprophylaxis with hepatitis B immunoglobulin and hepatitis B vaccine after birth, and were consecutively followed up for hepatitis B seroiogic markers and HBV DNA at birth, mo 1, 4, 7, 12, and 24. RESULTS: Forty-two babies entered the study, including 16 born to hepatitis B e antigen (HBeAg)-positive HBsAg carrier mothers and 26 to HBeAg-negative HBsAg carrier mothers. Apart from four babies born to HBeAg-positive carrier mothers and demonstrated persistent positive HBeAg eventually became HBV carriers, all other babies developed anti-HBs before 12 mo of age. Among the other 12 babies born to HBeAg-positive carrier mothers, HBeAg was detected in 7 at birth, in 4 at mo 1, and in none of them thereafter. No antibody response to the transplacental HBeAg was detected. Among the babies born to HBeAg-negative carrier mothers, anti-HBe was detected 100% at birth and mo 1, in 88.5% at mo 4, in 46.2% at mo 7, in 4.2% at mo 12 and none in mo 24. Among all the immunoprophylaxis-protected babies born to either HBeAg-positive or HBeAg-negative carrier mothers, anti-HBc was detected in 100% at birth, mo 1 and mo 4, in 78.9% at mo 7, in 36.1% at mo 12 and in none at mo 24. CONCLUSION: HBeAg can pass through human placenta from mother to fetus and become undetectable before 4 mo of age, but no antibodies response to the transplacental HBeAg can be detected till mo 24 in the immunoprophylaxis-protected babies. The sole existence of anti-HBe before 1 year of age or anti-HBc before 2 years of age in babies born to HBsAg carrier mothers may simply represent the transplacental maternal antibodies, instead of indicators of HBV infection status.