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.     

A case of hepatitis B reactivation in an anti-HBs positive, anti-HBc positive non-Hodgkin’s lymphoma patient

Dear Editor, We report a case of HBV reactivation in an anti-HBs positive,anti-HBc positive non-Hodgkin's lymphoma patient.Hepatitis B virus (HBV) reactivation is a well-recognized complication of patients undergoing chemotherapy or immunosuppressive therapy for lymphomas.The presence of antibodies to the hepatitis B surface antigen (anti-HBs) has been identified to be a factor preventing HBV reactivation in patients with occult HBV infection receiving chemotherapy.In this paper,we present a non-Hodgkin Lymphoma patient who,before immunosuppressive therapy,displayed positive anti-HBs and positive antibodies to hepatitis B core antigens (anti-HBc),as markers of resolved HBV infection,and developed hepatitis B surface antigen (HBsAg) and high viraemia with an HBV escape mutant after rituximabbased administration.The sequencing data revealed HBV genotype D with two known escape mutations,P120S.     

Occult hepatitis B virus infection among injecting drug users in the Central-West Region of Brazil

The prevalence of occult hepatitis B virus (HBV) infection was investigated in 149 hepatitis B surface antigen (HBsAg) negative injecting drug users (IDUs) in the Central-West Region of Brazil. Of these individuals, 19 were positive for HBV DNA, resulting in an occult HBV infection prevalence of 12.7% (19/149); six of these 19 individuals had anti-HBV core and/or anti-HBV surface antibodies and 13 were negative for HBV markers. All IDUs with occult hepatitis B reported sexual and/or parenteral risk behaviours. All HBV DNA-positive samples were successfully genotyped. Genotype D was the most common (17/19), followed by genotype A (2/19). These findings reveal a high prevalence of occult HBV infection and the predominance of genotype D among IDUs in Brazil''s Central-West Region.     

Anti-tumor necrosis factor treatment in occult hepatitis B virus infection: a retrospective analysis of 62 patients with psoriatic disease

One of the problems possibly related to the use of biological agents targeting tumor necrosis factor (TNF)-alpha is the increased risk of infections, including the activation of hepatitis B virus (HBV). HBV activation can occur in carriers of hepatitis B surface antigen (HBsAg), but the risk may also involve the HBsAg-negative (anti-HBc ± anti-HBs) occult carriers. Precise data on the safety of anti-TNF and/or other immunosuppressive drugs in HBV occult carriers are not available. We performed a retrospective analysis of 62 psoriatic patients with occult HBV infection treated with anti-TNF biological agents over a period of approximately 4 years: 44 subjects were treated with etanercept, 8 with infliximab and 10 with adalimumab. During the observational treatment period, no signs of HBV activation were observed. Only in one patient the reappearance of HBsAg, without detectable HBV-DNA, was noted before retreatment with etanercept and after 10 months from discontinuation of the previous course. In this patient etanercept was re-administered in association with lamivudine without any adverse event. Our results suggest the overall safety of treatment with anti-TNF drugs in HBV occult carriers, although a careful and constant monitoring of virological markers is required in such patients during treatment with anti-TNF drugs in order to have an early recognition of viral reactivation.     

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.     

慢性乙型肝炎病毒感染对妊娠期糖尿病及妊娠结局的影响

目的:探讨慢性乙型肝炎病毒(HBV)感染对妊娠期糖尿病(GDM)及妊娠结局的影响,为妊娠期产妇慢性HBV感染预防提供参考。方法:回顾性分析2015年2月-2017年2月在我院住院分娩的2615例慢性HBV感染产妇的临床病历资料,根据《慢性乙型肝炎防治指南》(2015年版)诊断标准,将所有产妇分为4组:慢性HBV携带者(A组)1128例、乙型肝炎e抗原(HBe Ag)阳性慢性乙型肝炎(B组)406例、HBe Ag阴性慢性乙型肝炎(C组)307例、非活动性乙型肝炎表面抗原(HBs Ag)携带者(D组)774例,并收集同期入院的823例HBV阴性产妇为对照组(E组)。比较各组的GDM发生率及不良妊娠结局发生率。结果:2615例慢性HBV感染产妇中,共发生GDM 866例,发生率为33.12%。B组与C组GDM发生率分别为38.92%、37.46%,均大于E组的30.74%(P0.05)。A组、B组、C组的妊娠期高血压疾病(PIH)发生率分别为7.98%、8.87%、9.77%,均高于E组的3.52%(P0.05);A组、B组、C组及早产发生率分别为3.10%、3.94%、4.56%,均高于E组的0.49%(P0.05)。C组的新生儿窒息发生率为1.63%,高于E组的0.36%(P0.05)。结论:产妇慢性HBV感染若合并肝功能受损或肝组织学病变,可能增加GDM的发生率,若HBV病毒复制活跃,可能导致PIH及早产发生风险增加。     

Genotype and subtype analyses of hepatitis B virus (HBV) and possible co-infection of HBV and hepatitis C virus (HCV) or hepatitis D virus (HDV) in blood donors, patients with chronic liver disease and patients on hemodialysis in Surabaya, Indonesia

Four subtypes (adw, adr, ayw, and ayr ) and eight genotypes (A to H) of the hepatitis B virus (HBV) have been identified. They appear to be associated with particular geographic distribution, ethnicity, and possibly clinical outcomes. In this study, hepatitis B surface antigen (HBsAg) subtyping and HBV genotyping were carried out on sera obtained from HBsAg-positive HBV carriers, including healthy blood donors; patients with acute hepatitis, chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma; and patients on hemodialysis all located in Surabaya, Indonesia. We report here that all HBV isolates tested in Surabaya belonged to genotype B, with more than 90% of them being classified into subtype adw. Our results also revealed that prevalence of hepatitis C virus (HCV) co-infection among HBV carriers in Surabaya was approximately 10% for healthy blood donors and patients with chronic liver disease, and approximately 60% for patients on maintenance hemodialysis. Interestingly, HBsAg titers were lower in HBV carriers with HCV co-infection than in those without HCV co-infection. We also found that prevalence of hepatitis D virus (HDV) co-infection was < 0.5% among HBV carriers in Surabaya.     

Vaccine- and hepatitis B immune globulin-induced escape mutations of hepatitis B virus surface antigen

Hepatitis B virus surface antigen (HBsAg) vaccination has been shown to be effective in preventing hepatitis B virus (HBV) infection. The protection is based on the induction of anti-HBs antibodies against a major cluster of antigenic epitopes of HBsAg, defined as the 'a' determinant region of small HBsAg. Prophylaxis of recurrent HBV infection in patients who have undergone liver transplantation for hepatitis B-related end-stage liver disease is achieved by the administration of hepatitis B immune globulins (HBIg) derived from HBsAg-vaccinated subjects. The anti-HBs-mediated immune pressure on HBV, however, seems to go along with the emergence and/or selection of immune escape HBV mutants that enable viral persistence in spite of adequate antibody titers. These HBsAg escape mutants harbor single or double point mutations that may significantly alter the immunological characteristics of HBsAg. Most escape mutations that influence HBsAg recognition by anti-HBs antibodies are located in the second 'a' determinant loop. Notably, HBsAg with an arginine replacement for glycine at amino acid 145 is considered the quintessential immune escape mutant because it has been isolated consistently in clinical samples of HBIg-treated individuals and vaccinated infants of chronically infected mothers. Direct binding studies with monoclonal antibodies demonstrated a more dramatic impact of this mutation on anti-HBs antibody recognition, compared with other point mutations in this antigenic domain. The clinical and epidemiological significance of these emerging HBsAg mutants will be a matter of research for years to come, especially as data available so far document that these mutants are viable and infectious strains. Strategies for vaccination programs and posttransplantation prophylaxis of recurrent hepatitis need to be developed that may prevent immune escape mutant HBV from spreading and to prevent these strains from becoming dominant during the next decennia.     

Hepatitis B viral factors and clinical outcomes of chronic hepatitis B

Hepatitis B virus (HBV) infection is an important health problem and the major cause of chronic hepatitis, cirrhosis as well as hepatocellular carcinoma (HCC) worldwide. The natural history of chronic HBV infection can be divided into 4 dynamic phases in HBV carriers who acquire the virus early in life. In general, the frequency and severity of hepatitis flares in the immune clearance or reactivation phase predict disease progression in HBV carriers, and early HBeAg seroconversion typically confers a favorable outcome. In contrast, late or absent HBeAg seroconversion after multiple hepatitis flares accelerates the progression of chronic hepatitis to cirrhosis. Recently, several hepatitis B viral factors predictive of clinical outcomes have been identified. For example, serum HBV DNA level at enrollment is the best predictor of adverse outcomes (cirrhosis, HCC and death from liver disease) in adults with chronic HBV infection. In addition, HBV genotype C, basal core promoter (BCP) mutant and pre-S deletion mutant are associated with increased risk of HCC development. In conclusion, hepatitis B viral factors such as serum HBV DNA level, genotype and mutants have already been clarified to influence disease progression of chronic hepatitis B. Further studies are needed to investigate the pathogenic mechanism of each viral factor.     

Hepatitis B infection among patients attending a sexually transmitted diseases clinic in Rio de Janeiro, Brazil

Hepatitis B virus (HBV) has a low endemicity in Rio de Janeiro, Brazil. Sexual transmission must play an important role in this virus, but the prevalence and risk factors have never been properly investigated. The aim of this paper is to determine the prevalence and risk factors for HBV infection in patients attending a Sexually Transmitted Diseases Clinic of the Universidade Federal Fluminense, from the State of Rio de Janeiro, Brazil. In a retrospective study, HBV seroprevalence was investigated in 440 patients. Serum of each patient was assayed for antibodies against hepatitis B core antigen (anti-HBc), hepatitis B surface antigen (HBsAg) and antibodies against hepatitis B surface antigen (anti-HBs). Demographic and risk factor data were extracted from clinic notes. The overall seroprevalence of exposure markers for HBV (anti-HBc, HBsAg and anti-HBs) were 13%, 3.4% and 8.5% respectively. Homo/bisexual behaviour, anal intercourse, HIV infection, positive serology for syphilis and blood transfusion were predictors of the HBV exposure. Among demographic data, age and place of birth were associated with the anti-HBc seropositivity.     

Prevalence of hepatitis B virus in chronic hepatitis B patients

The aim of the current study was to detect HBV by Real time - PCR in chronic hepatitis B patients. Fifty-eight sera of chronic hepatitis B patients were subjected during the period March 2009 to April 2010 in Ilam cities in West of Iran. Sera assayed by real-time PCR and ELISA methods. Twenty serum samples from healthy volunteers and non-hepatitis B patients and negative for hepatitis B seromarkers served as negative controls for the study. Among fifty-eight sera, ELISA showed fifty-five (94.8%) of the samples were positive for HBsAg and three (5.2%) negative results obtained while real-time PCR specified fifty-eight (100%) positive results in chronic hepatitis B patients. HBsAg status did not necessarily reflect HBV DNA level in the serum, as 5.2% of chronic Hepatitis B patients were positive for HBV DNA but negative for HBsAg. HBV DNA was not found to be positive amongst any of the negative controls. Real time - PCR is a sensitive and reproducible assay for HBV DNA quantization.     

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     

Hepatocellular Carcinoma in The Gambia and the role of Hepatitis B and Hepatitis C

Objectives

Hepatocellular Carcinoma is the commonest form of cancer in The Gambia, and although Hepatitis B and Hepatitis C are known risk factors, accurate baseline data on Hepatitis B and Hepatitis C distribution in the region are limited. Similarly data including information on the involvement of the viruses in HCC remains unknown. The current study was undertaken to estimate the risk of HCC in relation to HCV and HBV in The Gambia.

Methods

Thirteen patients with histological proven history of HCC and 39 healthy controls were enrolled in the study. Each subject blood was screened individually for anti-HCV using ORTHO HCV 3.0 ELISA test system (Ortho-Clinical Diagnostics, Inc, U.S.A) and for HBsAg using QUADRATECH CHECK 4-HBs one step generation hepatitis B surface antigen test kit (VEDALAB, France) following the manufacturers instructions.

Results

HBsAg and anti-HCV was detected in 38.5 %(5/13) and 7.7% (1/39) of the persons with a history of HCC respectively. HBsAg but not anti-HCV was detected in 12.8% (5/39 of the case control subjects. HBsAg and HCV rates among the HCC patients were higher in men than women. Rates were highest in patients 48 years and above (37.5%; 3/8). No patient was found with anti-HCV and anti-HBV.

Conclusion

These results indicate that the involvement of HBV and HCV in HCC in the country is in a ratio of 5:1 and that these two viruses might be independently involved in the pathogenesis of the disease. The study revealed a statistically significant association (p = 0.04) between HBsAg and HCC patients.The results also indicate that up to 50% of HCC cases in the country may be due to non viral factors and calls for further studies in this regard. These findings call for provision of diagnostic facilities for these viruses in hospitals and for their routine screening in blood banks while intervention programmes should be put in place.

     

Large fragment pre-S deletion and high viral load independently predict hepatitis B relapse after liver transplantation

Hepatitis B virus (HBV) associated end-stage liver diseases are the leading causes of liver transplantation (LT) in Taiwan. Relapse of hepatitis B occurs after LT, raising the risk of graft failure and reducing patient survival. Although several oral antiviral agents have been approved for anti-HBV treatment, lamivudine (LAM) remained to be the most widely used preventive regimen in Taiwan. While several clinical predictors have been identified for hepatitis B relapse, the predictive roles of the histopathological characteristics in liver explants as well as the genotypic features of the viruses in pre-LT serum samples have not been assessed. Between September 2002 and August 2009, 150 consecutive hepatitis B surface antigen (HBsAg) positive patients undergoing LT were included for outcome analysis following assessment of the clinicopathological and virological factors prior to LT. Kaplan-Meier analyses discovered that pre-operative LAM treatment ≤3 months; membranous distribution and higher expression of tissue HBsAg in liver explants; preoperative viral load ≧10⁶ copies/ml; and presence of large fragment (>100 base pairs) pre-S deletion (LFpreSDel) correlated significantly with hepatitis B relapse. Multivariate Cox regression analysis showed that the presence of LFpreSDel (P = 0.001) and viral load ≧10⁶ copies/mL (P = 0.023) were independent predictors for hepatitis B relapse. In conclusion, besides high viral load, LFpreSDel mutation is an important independent predictor for hepatitis B relapse after LT. More aggressive preventive strategies should be applied for patients carrying these risk factors.     

Hepatitis B in a hospital for the mentally subnormal in southern England.

The prevalence of hepatitis B viral (HBV) infection was assessed in 340 patients and 268 staff in a hospital for the mentally subnormal in Wessex. Hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen, antibody to HBsAg, e antigen (eAg), and antibody to eAg were used as markers of such infection. Forty patients and 10 staff had evidence of recent or current infection, while 149 patients and 50 staff had evidence of past infection. HBV markers were more common in mongols, epileptics, patients with cerebral palsy, and those of lower mental grades and reached a peak after 5-15 years of hospitalisation. eAg was detected in 12 out of 26 patients with HBsAg but in none of the four staff with HBsAg. Abnormal liver function values were found in 24 (60%) of the patients with recent or current HBV infection but in only 30 (19%) of those without HBV markers. Among the staff the prevalence of HBV markers correlated with the duration of employment and degree of contact with patients. Of those with recent or current infection, 4 (40%) had abnormal liver function values compared with 25 (12%) of those without HBV markers. Despite the high prevalence of markers clinically overt hepatitis B was rare.     

Doxorubicin Activates Hepatitis B Virus Replication by Elevation of p21 (Waf1/Cip1) and C/EBPα Expression

Hepatitis B virus reactivation is an important medical issue in cancer patients who undergo systemic chemotherapy. Up to half of CHB carriers receiving chemotherapy develop hepatitis and among these cases a notable proportion are associated with HBV reactivation. However, the molecular mechanism(s) through which various chemotherapeutic agents induce HBV reactivation is not yet fully understood. In this study, we investigated the role of the cell cycle regulator p21 (Waf1/Cip1) in the modulation of HBV replication when a common chemotherapeutic agent, doxorubicin, is present. We showed that p21 expression was increased by doxorubicin treatment. This elevation in p21 expression enhanced the expression of CCAAT/enhancer-binding protein α (C/EBPα); such an increase is likely to promote the binding of C/EBPα to the HBV promoter, which will contribute to the activation of HBV replication. Our current study thus reveals the mechanism underlying doxorubicin modulation of HBV replication and provides an increased understanding of HBV reactivation in CHB patients who are receiving systemic chemotherapy.     

慢性乙型肝炎病毒感染自然史中HBsAg和HBsAb共存血清学模式分析

目的分析慢性乙肝病毒感染者HBsAg和HBsAb共存模式中血清学指标、HBV-DNA和肝酶等指标与自然病程的关系,探讨其临床意义。方法回顾性分析2016年重庆医科大学附属第一医院HBsAg和HBsAb双阳性患者的血清学指标、HBV-DNA和ALT、GGT检测结果,并对其感染的自然病程进行分析。结果 2016年该院HBsAg和HBsAb双阳性患者共520例,占全部HBV感染者的2.80%,占总送检标本数的0.42%。可分期的184例双阳性患者中,免疫耐受期47例(25.54%),免疫清除期17例(9.24%),低复制期108例(58.70%),再活动期12例(6.52%),HBsAg、HBsAg/HBsAb比值、HBV-DNA、ALT和GGT水平差异均有统计学意义(P<0.05),低复制期患者HBsAg/HBsAb比值均低于其他患者(P<0.05)。不同分期患者HBsAb、年龄和性别比较差异无统计学意义(P>0.05),且HBsAb水平均较低。284例资料完整HBsAg和HBsAb共存病例中HBV-DNA阳性136例,占47.89%。HBsAg浓度与HBV-DNA载量成正相关(r=0.295,P<0.05),HBsAb浓度与HBV-DNA载量之间没有显著相关性(r=0.04,P>0.05)。结论 HBsAg和HBsAb共存患者并不少见,与性别无关,可发生在各个年龄阶段,以低复制期患者为最多。HBsAg和HBsAb共存患者中HBsAb多以低浓度形式存在,且浓度与自然病程无关。HBsAb的出现并非代表患者体内病毒复制停止,在诊断及治疗HBsAg和HBsAb共存模式的乙肝病毒感染者时仍需结合HBV-DNA载量来判断感染状态。     

从干扰素诱导蛋白MxA筛选抗乙肝病毒活性肽

黏病毒抗性蛋白A（myxovirus resistance protein A,MxA）是由干扰素诱导的具有重要抗乙肝病毒（hepatitis B virus,HBV）功能的蛋白质,我们前期工作发现,MxA主要依赖其中心互作结构域（central interactive domain,CID）与病毒直接相互作用发挥功能,但其具体的抗病毒功能区以及功能区是否具有独立的抗病毒活性仍不清楚。本研究拟鉴定MxA蛋白上的抗乙肝病毒活性肽。首先从全长MxA构建缺失突变体ΔCID和截短体CID,以HepG2-2-15细胞为病毒模型,分别转染空载质粒、MxA、ΔCID和CID,免疫荧光法检测转染效率,Western印迹法检测质粒表达,酶联免疫法测定细胞培养液中HBsAg、HBeAg的量及荧光定量PCR法测定乙肝病毒 DNA的量,评估CID段的抗乙肝病毒活性。根据CID段的晶体结构,缩短肽段长度,构建α1、α2、α3等9段肽段质粒,鉴定各段的抗乙肝病毒活性和细胞毒性（MTT法）。运用计算生物学手段--分子对接法预测MxA蛋白与病毒相互作用的模式和位点。结果显示,ΔCID、CID和9段肽段质粒的序列及表达正确,9段肽段的表达量未见显著性差异,无显著的细胞毒性。CID组和黏病毒抗性蛋白A组较对照组乙肝病毒的复制水平显著降低,CID组细胞上清中HBsAg、HBeAg及乙肝病毒 DNA的量分别减少了55.57%±8.48%、68.37%±6.24%、66.67%±6.40%,P＜0.01;MxA组的3个指标分别减少了61.63%±3.11%、70.77%±7.25%、73.73%±6.18%,P＜0.01;ΔCID组较对照组无明显变化。9段肽段中α1组较对照组HBsAg、HBeAg及乙肝病毒 DNA的量有显著下降,分别减少了48.33%±1.70%、70.67%±3.30%、68.95%±2.55%,P＜0.001,表明α1对乙肝病毒具有强抑制活性。分子对接的结果显示,384 ～ 408位氨基酸是MxA蛋白与病毒互作的关键位点,该区域落在α1肽段上,验证了α1是MxA蛋白抗乙肝病毒及与乙肝病毒相互作用中的关键区段。本研究筛选并鉴定出人干扰素诱导蛋白MxA上最有效的抗乙肝病毒活性肽α1,研究结果为抗乙肝病毒多肽类新药的研发奠定了基础。     

Infantile Hepatitis B in Immunized Children: Risk for Fulminant Hepatitis and Long-Term Outcomes

Background

Infantile hepatitis B after neonatal immunoprophylaxis is a rare yet distinct disease. This study aimed to analyze the long-term outcomes and risk factors in immunized infants with hepatitis B.

Methods

The clinical parameters and outcomes of 41 infants born after universal immunization, and admitted for HBV-positive hepatitis were studied. All patients were followed for at least 6 months (median  = 4.4 years, range 0.6–18.1 years). Patient survival, changes of HBsAg and HBeAg status, and complications were analyzed.

Results

Among the 41 cases (32 males, 9 females), 21 presented with fulminant hepatitis (FH), and 20 with non-fulminant hepatitis (NFH). Ninety-five percent (36/38) of the mothers were positive for hepatitis B surface antigen (HBsAg). Multivariate analyses revealed younger age of onset (age <7 months) and negative maternal hepatitis B e antigen (HBeAg) were associated with FH (p = 0.03 and p = 0.01, respectively). An infantile fulminant hepatitis B risk score using maternal/infant HBeAg positivity and onset age was proposed. Among the FH cases, the rate of mortality, HBsAg clearance, and chronic HBV infection were 47.6%, 38.1%, and 14.3%, respectively. Among the NFH cases, 35% developed chronic infection. Of the 9 chronically infected children received long-term follow-up, 8 had HBeAg seroconversion before 4 years of age. One case of FH developed hepatocellular carcinoma 14 years later.

Conclusions

Maternal HBsAg + /HBeAg- and early onset age were risk factors for FH in immunized infants. A significant portion of patients with FH or NFH evolve to chronic HBV infection, with HBeAg seroconversion in young childhood. Close surveillance for hepatocellular carcinoma is warranted in patients surviving infantile hepatitis B.     

Inhibition of the replication of hepatitis B virus in vitro by a novel 2,6-diaminopurine analog, beta-LPA

Antiviral therapy of chronic hepatitis B remains a major clinical problem worldwide. Like lamivudine, nucleoside analogs have become the focus of investigation of anti-hepatitis B virus (anti-HBV) drugs. Here, β-LPA is a novel 2,6-diaminopurine analog found to possess potent anti-HBV activity. In HepG2.2.15 cell line, β-LPA had a 50% effective concentration (EC₅₀) of 0.01 μM against HBV, as determined by analysis of secreted and intracellular episomal HBV DNA. Levels of HBV surface antigen (HBsAg) and e antigen (HBeAg) in drug-treated cultures revealed that β-LPA had no significant inhibitory effects on HBsAg and HBeAg. β-LPA didn’t show any cytotoxicity up to 0.4 μM with a 50% cytotoxic concentration (CC₅₀) of 50 μM. Furthermore, treatment with β-LPA resulted in no apparent inhibitory effects on mitochondrial DNA content. Considering the potent inhibition of HBV DNA synthesis and no obvious toxicity of β-LPA, this compound should be further explored for development as an anti-HBV drug.