Assessment of the level of vaccine-induced anti-HBs antibodies in children with inflammatory systemic connective tissue diseases treated with immunosuppression

Objectives

Protective vaccinations are the most effective method of prevention of type B virus hepatitis. The aim of the study was to determine whether in children receiving immunosuppressive therapy due to inflammatory systemic connective tissue diseases the protective concentration of the anti-HBs antibodies produced after vaccination against type B virus hepatitis in infancy is maintained.

Material and methods

The concentration of anti-HBs antibodies was assessed in the sera of 50 children with inflammatory connective tissue diseases – 37 girls (74%) and 13 boys (26%), aged 1.5–17.5 years – during the immunosuppressive treatment, which lasted at least 6 months. The control group consisted of 50 healthy children – 28 girls (56%) and 22 boys (44%) aged 2–17 years. All children were vaccinated in infancy with Engerix B vaccine according to the 0–1–6 months schedule. The antibody concentration of ≥ 10 mIU/ml in patients is regarded as protective.

Results

No protective antibody concentrations were found in 25 cases (50%) in the group of diseased children and only in 2 children in the control group (4%).

Conclusions

The concentration of vaccine-induced antibodies should be assessed in children with inflammatory systemic connective tissue diseases and, in case of the absence of a protective concentration, revaccination should be started. The use of glucocorticosteroids, synthetic and biological disease-modifying antirheumatic drugs is no contraindication to vaccination against hepatitis B.     

High frequency of hepatitis B virus infection in patients with beta-thalassemia receiving multiple transfusions

BACKGROUND AND OBJECTIVES: Hepatitis B virus (HBV) may occasionally be transmitted through transfusion of blood units that are hepatitis B surface antigen (HBsAg) negative but HBV DNA positive. Children with beta-thalassemia are particularly susceptible to HBV because they receive multiple blood transfusions. These children have high infection rates despite vaccination against HBV. Post-vaccination infections may be a result of viruses harbouring surface (S)-gene mutations (e.g. G587A) in a region critical for reactivity to antibody to hepatitis B surface antigen (anti-HBs). The true prevalence of HBV in individuals with beta-thalassemia has not been studied previously. PATIENTS AND METHODS: Seventy patients with beta-thalassemia (median age 6 years; range 8 months to 22 years; 49 male), who had received seven to 623 (median 61) units of blood each and three doses (10/20 micro g) of HBV vaccine (Engerix B) before presentation to us, were included in the study; 50 of the 70 patients had received transfusions prior to vaccination. Enzyme-linked immunoassay for serological markers [HBsAg, antibody to hepatitis B core antigen (anti-HBc) and quantitative anti-HBs] and polymerase chain reaction (PCR) followed by Southern hybridization for molecular detection of hepatitis B, was performed on all samples. The PCR-amplified product was cloned, sequenced and the nucleotide and deduced amino acid sequences for the HBV S and polymerase (P) genes were analysed for mutations. RESULTS: Four of 70 (5.7%) individuals with beta-thalassemia were HBsAg positive and 14 (20%) were anti-HBc positive. The prevalence of serological markers increased with number of transfusions (P < 0.01). Of 70 patients, 53 (75.7%) had an anti-HBs titre of > 10 IU/l following vaccination and 17 (24.3%) were non-responders (< 10 IU/l); 22 (31.4%) of the 70 were DNA positive. The frequency of HBV infection in beta-thalassemia was similar in vaccine responders and non-responders. The virus was of subtype ayw (genotype D) in the five DNA-positive samples in which a 388-nucleotide region of the S gene was sequenced. Mutations occurred at 13 positions in the S gene and at 10 positions in the P gene. Hydrophobicity plots revealed differences in amino acid regions 117-165 and 195-211. Some of these amino acid substitutions coincided with the putative cytotoxic T-lymphocyte epitopes of both S and P proteins. CONCLUSIONS: A high frequency of HBV infection was seen using molecular methods in thalassemic patients. The frequency of infection was similar in vaccine responders and non-responders. A number of mutations were observed in the S gene, which could have implications for viral replication as well as virus-host cell interaction.     

Long-term safety of lamivudine treatment in patients with chronic hepatitis B

BACKGROUND & AIMS: Data on the long-term safety of lamivudine are limited. The aim of this analysis was to determine the incidence of hepatitis flares, hepatic decompensation, and liver-disease-related (LDR) serious adverse events (SAE) during long-term lamivudine treatment. METHODS: We reviewed data on 998 patients with HBeAg-positive compensated chronic hepatitis B who received lamivudine for up to 6 years (median, 4 years) and 200 patients who received placebo for 1 year. RESULTS: Hepatitis flares occurred in 10% of the lamivudine-treated patients in year 1 and in 18%-21% in years 2-5. A temporal association between hepatitis flares and lamivudine-resistant mutations increased from 43% in year 1 to >80% in year 3. Ten hepatic decompensation events occurred in 8 (<1%) lamivudine-treated patients. Fifty-three (5%) lamivudine-treated patients experienced a total of 60 LDR SAEs. Four patients died, 2 from liver-related causes. The proportion of patients with a documented lamivudine-resistant mutation increased from 23% in year 1 to 65% in year 5. During each year of the study, patients with lamivudine-resistant mutations experienced significantly more hepatitis flares than patients without lamivudine-resistant mutations (P < 0.005). The occurrence of hepatic decompensation (0%-2%) and LDR SAEs (1%-10%) among patients with lamivudine resistance remained stable during the first 4 years with mutations and increased afterward to 6% (P = 0.03) and 20% (P = 0.009), respectively. CONCLUSIONS: This study demonstrated that lamivudine treatment for up to 6 years has an excellent safety profile in patients with HBeAg-positive compensated liver disease, but patients with long-standing lamivudine-resistant mutations may experience worsening liver disease.     

抗-HBs阳性HBV感染者5年前瞻性随访观察

目的观察乙肝表面抗体(抗-HBs)阳性HBV感染者5年疾病演变。方法对62例抗-HBs阳性者检测5年前后血清乙肝病毒标志物(HBVM)、HBVDNA水平及观察临床演变。结果5年后肝硬化、肝癌发生率分别11.3%、4.8%,死亡5例见于123、12阳性模式组,123、12、245阳性模式5年后仍有48.1%、66.7%、61.1%保持原模式不变,临床类型构成比有显著性差异,5年后抗-HBs和HBVDNA水平总趋势下降,123模式HBVDNA定量显著下降,12模式抗—HBs水平显著下降。结论HBVDNA和血清抗-HBs水平高低是预示疾病转归的重要指标。     

Identification of a hepatitis B virus S gene mutant in lamivudine-treated patients experiencing HBsAg seroclearance

BACKGROUND & AIMS: Seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is a rare event in chronic hepatitis B patients receiving lamivudine therapy. It is generally believed to be a benevolent sign, implicating clearance of viremia. The aim of this study is to examine the authenticity of this dogma. METHODS: In a 5-year period, 11 patients treated with lamivudine experienced seroclearance of HBsAg. The clinical data were examined. The HBV S gene sequences derived from the patient's serum samples before and after seroclearance of HBsAg were analyzed. RESULTS: Serum HBV-DNA could be detected by nested polymerase chain reaction (PCR) in all 11 patients, by 1-step PCR in 8, and by Cobas Amplicor HBV-DNA test (>200 copies/mL) in 5. A mutation hot spot, P120A in the S gene, was identified in 6 of the 11 patients. Site-directed mutagenesis experiments indicated that the Ausria-II RIA test failed to detect this mutant. Decreased sensitivity of detection was also observed when other monoclonal antibodies were applied. CONCLUSIONS: Seroclearance of HBsAg during lamivudine therapy may not indicate viral clearance. Specifically, it may be caused by a point mutation in the S gene, which results in detection failure. In such patients, further verification and follow-up using a sensitive HBV-DNA test are advised.     

Randomised controlled trial: effect of metformin add-on therapy on functional cure in entecavir-treated patients with chronic hepatitis B

Introduction and ObjectivesHepatitis B surface antigen (HBsAg) clearance, indicating functional cure or resolved chronic hepatitis B (CHB), remains difficult to achieve via nucleos(t)ide analogue monotherapy. We investigated whether metformin add-on therapy could help achieve this goal in entecavir-treated patients with hepatitis B e antigen (HBeAg)-negative CHB.Patients and MethodsPatients with HBeAg-negative CHB who met eligibility criteria (entecavir treatment for > 12 months, HBsAg < 1000 IU/mL) were randomly assigned (1:1) to receive 24 weeks of either metformin (1000 mg, oral, once a day) or placebo (oral, once a day) add-on therapy. The group allocation was blinded for both patients and investigators. Efficacy and safety analyses were based on the intention-to-treat set. The primary outcome, serum HBsAg level (IU/mL) at weeks 24 and 36, was analysed using mixed models.ResultsSixty eligible patients were randomly assigned to the metformin (n = 29) and placebo (n = 31) groups. There was no substantial between-group difference in the HBsAg level at week 24 (adjusted mean difference 0.05, 95% confidence interval -0.04 to 0.13, p = 0.278) or week 36 (0.06, -0.03 to 0.15, p = 0.187), and no significant effect of group-by-time interaction on the HBsAg level throughout the trial (p = 0.814). The occurrence of total adverse events between the two groups was comparable (9 [31.0%] of 29 vs. 5 [16.1%] of 31, p = 0.227) and no patient experienced serious adverse events during the study.ConclusionAlthough it was safe, metformin add-on therapy did not accelerate HBsAg clearance in entecavir-treated patients with HBeAg-negative CHB.     

A pilot model of vaccination against hepatitis B virus suitable for mass vaccination campaigns in hyperendemic areas.

A hepatitis B vaccination campaign was carried out in a town of 60,000 inhabitants, Afragola, Campania, Italy, a hyperendemic area for hepatitis B where HBsAg prevalence was 13.4% and anti-HBc prevalence was 64.7%. This experimental pilot project aimed to reduce the incidence of both acute and asymptomatic viral hepatitis B and of related chronic liver complications. From 1983-1989, 8,400 subjects were vaccinated: 6,900 children up to 10 years of age and 1,500 subjects from 11-60 years of age. High seroconversion rates were observed: 99.0% in all children under one year of age, 96.0% in the older children, and 86.7% in adults. The rate of infection in Afragola has diminished from 63/100,000 in 1983 to 10/100,000 in 1989. Carriers of HBsAg decreased in the general population (7.3% compared to 13.4%), especially in children up to 10 years of age (1.0% compared to 9.0%). In babies who received hepatitis B vaccine at the same time as compulsory vaccinations compliance was 98% while it was 80% in babies who were vaccinated separately. In June 1991 the Italian Parliament promulgated a decree which imposes hepatitis B vaccination for all newborn babies at 3, 5, and 11 months of age, at the same times as the mandatory childhood vaccinations (diphtheria, tetanus, and polio) according to a new protocol (Piazza scheme) which has been in use since January 1987 in our pilot vaccination campaign in Afragola.     

2006年山西省太谷县学龄前集居儿童乙型肝炎病毒表面抗体检测结果分析

了解山西省太谷县乙型病毒性肝炎（乙肝）疫苗在学龄前集居儿童中的免疫情况。 对所有监测儿童采静脉血，采用酶联免疫吸附试验法检测乙肝病毒表面抗原，乙肝病毒表面抗体（抗-HBs）。 3153名儿童中，抗-HBs阳性的1614人，阳性率51.19%；各年龄组间差异无统计学意义；乙肝疫苗初次全程免疫后再次加强过乙肝疫苗的儿童，抗-HBs阳性率明显高于未加强乙肝疫苗的儿童。监测抗-HBs乙肝表面抗体，适时加强乙肝疫苗接种，可以提高儿童对乙肝病毒的免疫水平，减少乙肝病毒的感染的机会。     

用单克隆抗-HBs免疫同系小鼠制备抗独特型抗体

单克隆抗-HBs在同系BALB/c 小鼠体内所诱生的抗独特型抗体,能模拟HBsAg的作用,该抗独特型抗体既能与抗-HBs发生特异性结合,又能在同系动物中添生出抗HBs的独特型抗体,从而为生产乙肝疫苗开辟了一条新的可能的途径。由于单克隆抗-HBs在同系动物体内只诱生抗独特型抗体,故无同种型和同种异型的干扰,且纯化程序简单,避免了许多干扰因素,有利于研究机体免疫网络中各细胞间的相互作用。