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Perinatal hepatitis B virus (HBV) infection carries a significant risk of chronicity and complications while making infected people reservoirs for further transmission. Hepatitis B immunization in infants, with or without hepatitis B immune globulin (HBIG), has proven effective in preventing mother-to-child transmission. Nevertheless, some newborns of mothers with high viremia testing positive for hepatitis B e antigen (HBeAg) may not benefit from HBV immunoprophylaxis. Nineteen (10.2 %) of 186 infants born to HBV-infected mothers were HBV DNA-positive. HBV genotypes, serotypes, and hepatitis B surface antigen (HBsAg) sequences were comparable in most mother-cord blood-infant sample pairings, indicating that the infants' HBV strains originated from their mothers. Three (15.3 %) infants had overt HBV infection, whereas 16 (84.2 %) had occult HBV infection (OBI). The HBV isolates from infants exhibited 26 mutations: 38.5 % in the ‘a’ determinant and 61.5 % in the rest of HBsAg. Mutations were identified in B-cell and T-cell epitopes, impairing humoral and cellular responses to detect or neutralize the virus. This rendered immunoprophylaxis and diagnostics ineffective while inducing tolerance to the infection. HBV strains with these mutations can persist and cause complications, but they can be transmitted undetected by HBsAg tests commonly used in community healthcare. This study reveals the risk of HBV transmission from HBsAg mutant-infected mothers to newborns despite having received the birth dose with HBIG and complete hepatitis B vaccination. •HBV S protein mutation can impair detection and immune neutralization of the virus•HBV mutants can persist in fully vaccinated infants and spread unnoticed•Babies born to mothers infected with HBV mutants may not be prevented by vaccination and HBIG•Vaccine escape and diagnosis failure are challenges to the efficacy of vaccination

In a phase 2 trial, bepirovirsen, an antisense oligonucleotide that targets all hepatitis B virus mRNAs, resulted in sustained loss of hepatitis B surface antigen and HBV DNA in 9 to 10% of participants with chronic HBV infection.

Non invasive immunologic markers of virus-induced liver disease are unmet needs. We tested the clinical significance of quantitative total and IgM-anti-HBc in well characterized chronic-HBsAg-carriers. Sera (212) were obtained from 111 HBsAg-carriers followed-up for 52 months (28-216) during different phases of chronic-HBV-genotype-D-infection: 10 HBeAg-positive, 25 inactive-carriers (HBV-DNA≤2000IU/ml, ALT<30U/L), 66 HBeAg-negative-CHB-patients and 10 with HDV-super-infection. In 35 patients treated with Peg-IFN±nucleos(t)ide-analogues (NUCs) sera were obtained at baseline, end-of-therapy and week-24-off-therapy and in 22 treated with NUCs (for 60 months, 42-134m) at baseline and end-of-follow-up. HBsAg and IgM-anti-HBc were measured by Architect-assays (Abbott, USA); total-anti-HBc by double-antigen-sandwich-immune-assay (Wantai, China); HBV-DNA by COBAS-TaqMan (Roche, Germany). Total-anti-HBc were detectable in all sera with lower levels in HBsAg-carriers without CHB (immune-tolerant, inactive and HDV-superinfected, median 3.26, range 2.26-4.49 Log10 IU/ml) versus untreated-CHB (median 4.68, range 2.76-5.54 Log10 IU/ml), p<0.0001. IgM-anti-HBc positive using the chronic-hepatitis-cut-off\" (0.130-S/CO) were positive in 102 of 212 sera (48.1%). Overall total-anti-HBc and IgM-anti-HBc correlated significantly (p<0.001, r=0.417). Total-anti-HBc declined significantly in CHB patients with response to Peg-IFN (p<0.001) and in NUC-treated patients (p<0.001); the lowest levels (median 2.68, range 2.12-3.08 Log10 IU/ml) were found in long-term responders who cleared HBsAg subsequently. During spontaneous and therapy-induced fluctuations of CHB (remissions and reactivations) total- and IgM-anti-HBc correlated with ALT (p<0.001, r=0.351 and p=0.008, r=0.185 respectively). Total-anti-HBc qualifies as a useful marker of HBV-induced-liver-disease that might help to discriminate major phases of chronic HBV infection and to predict sustained response to antivirals.

Hepatitis B virus (HBV) infection is a major public health problem, with an estimated 296 million people chronically infected and 820 000 deaths worldwide in 2019. Diagnosis of HBV infection requires serological testing for HBsAg and for acute infection additional testing for IgM hepatitis B core antibody (IgM anti-HBc, for the window period when neither HBsAg nor anti-HBs is detected). Assessment of HBV replication status to guide treatment decisions involves testing for HBV DNA, whereas assessment of liver disease activity and staging is mainly based on aminotransferases, platelet count, and elastography. Universal infant immunisation, including birth dose vaccination is the most effective means to prevent chronic HBV infection. Two vaccines with improved immunogenicity have recently been approved for adults in the USA and EU, with availability expected to expand. Current therapies, pegylated interferon, and nucleos(t)ide analogues can prevent development of cirrhosis and hepatocellular carcinoma, but do not eradicate the virus and rarely clear HBsAg. Treatment is recommended for patients with cirrhosis or with high HBV DNA levels and active or advanced liver disease. New antiviral and immunomodulatory therapies aiming to achieve functional cure (ie, clearance of HBsAg) are in clinical development. Improved vaccination coverage, increased screening, diagnosis and linkage to care, development of curative therapies, and removal of stigma are important in achieving WHO's goal of eliminating HBV infection by 2030.

People without effective immunization are vulnerable to infection with hepatitis B virus (HBV). At present, there is no appropriate hepatitis B vaccination strategy for HBV-susceptible adults. We aim to assess the long-term effect of neonatal hepatitis B immunization and HBV markers among college students, so as to explore hepatitis B vaccination strategies suitable for high-risk group. The enrolled freshmen from four universities were initially tested for hepatitis B screening using colloidal gold test strips. Subjects with positive hepatitis B surface antigen (HBsAg) or negative hepatitis B surface antibody (anti-HBs) were further confirmed using Abbott reagents. HBsAg and anti-HBs double negative individuals were administered hepatitis B vaccination. Using Abbott reagents, we confirmed that among 3242 enrolled freshmen, 1604 (49.5 %) were negative for both HBsAg and anti-HBs, and 27 (0.8 %) were HBsAg-positive. Among the double negative freshmen, 1263 received hepatitis B vaccination. After the first and second dose of hepatitis B vaccine, the protective anti-HBs seroconversion rates reached 91.4 % and 98.5 %, respectively. Only one (0.1 %) freshman was still negative for anti-HBs after the third dose of hepatitis B vaccine. In addition, 96.3 % (104/108) of the fresmen who failed to achieve protective anti-HBs seroconversion after the first dose of hepatitis B vaccine had a baseline anti-HBs level < 2 mIU/mL. The HBsAg prevalence among college students has been significantly reduced after the integration of hepatitis B vaccine into Expanded Program on Immunization, but the rate of seroprotective anti-HBs among these students remains low. Hepatitis B vaccination or booster dose is advised for a high-risk group who have negative anti-HBs, and two doses of hepatitis B vaccine are advised for those with anti-HBs < 2 mIU/mL.

Infection with hepatitis B virus (HBV) may lead to acute or chronic hepatitis. HBV infections were previously much more frequent but there are still 240 million chronic HBV carriers today and ca. 620,000 die per year from the late sequelae liver cirrhosis or hepatocellular carcinoma. Hepatitis B was recognized as a disease in ancient times, but its etiologic agent was only recently identified. The first clue in unraveling this mystery was the discovery of an enigmatic serum protein named Australia antigen 50 years ago by Baruch Blumberg. Some years later this was recognized to be the HBV surface antigen (HBsAg). Detection of HBsAg allowed for the first time screening of inapparently infected blood donors for a dangerous pathogen. The need to diagnose clinically silent HBV infections was a strong driving force in the development of modern virus diagnostics. HBsAg was the first infection marker to be assayed with a highly sensitive radio immune assay. HBV itself was among the first viruses to be detected by assay of its DNA genome and IgM antibodies against the HBV core antigen were the first to be selectively detected by the anti-μ capture assay. The cloning and sequencing of the HBV genome in 1978 paved the way to understand the viral life cycle, and allowed development of efficient vaccines and drugs. Today’s hepatitis B vaccine was the first vaccine produced by gene technology. Among the problems that still remain today are the inability to achieve a complete cure of chronic HBV infections, the recognition of occult HBV infections, their potential reactivation and the incomplete protection against escape mutants and heterologous HBV genotypes by HBV vaccines.

Despite the high global prevalence of chronic hepatitis B (CHB) infection, datasets covering the whole hepatitis B viral genome from large patient cohorts are lacking, greatly limiting our understanding of the viral genetic factors involved in this deadly disease. We performed deep sequencing of viral samples from patients chronically infected with HBV to investigate the association between viral genome variation and patients’ clinical characteristics. We discovered novel viral variants strongly associated with viral load and HBeAg status. Patients with viral variants C1817T and A1838G had viral loads nearly three orders of magnitude lower than patients without those variants. These patients consequently experienced earlier viral suppression while on treatment. Furthermore, we identified novel variants that either independently or in combination with precore mutation G1896A were associated with the transition from HBeAg positive to the negative phase of infection. These observations are consistent with the hypothesis that mutation of the HBeAg open reading frame is an important factor driving CHB patient’s HBeAg status. This analysis provides a detailed picture of HBV genetic variation in the largest patient cohort to date and highlights the diversity of plausible molecular mechanisms through which viral variation affects clinical phenotype.

•In 2015, the prevalence of chronic hepatitis B prevalence was 1.1% in the South-East Asia Region.•16 million chronic hepatitis B virus infections were averted through vaccination from 1992 to 2015.•The three dose coverage of hepatitis B vaccine increased by 31% from 2011 to 2015.•Significant progress has been made in the region towards control of hepatitis B virus infection.•Targeted strategies in each country are needed to achieve hepatitis B control and elimination. In 2016, the Immunization Technical Advisory Group of the South-East Asia Region (SEAR) endorsed a regional goal to achieve ≤1% prevalence of hepatitis B surface antigen (HBsAg) among 5-year-old children by 2020. Chronic hepatitis B virus (HBV) infection is largely preventable with a birth dose of hepatitis B vaccine (HepB-BD) followed by two to three additional doses. We reviewed the progress towards hepatitis B control through vaccination in SEAR during 1992–2015. We summarized hepatitis B vaccination data and reviewed the literature to determine the prevalence of chronic HBV infection pre- and post-vaccine introduction. We used a mathematical model to determine post-vaccine prevalence of HBsAg among 5 year olds in countries lacking national serosurvey data and estimated the impact of vaccination on disease burden. Regional coverage with three doses of hepatitis B vaccine (HepB3) increased from 56% in 2011 to 87% in 2015. By 2016, 7 of 11 countries had introduced universal HepB-BD. Regional HepB-BD coverage increased from 9% in 2011 to 34% in 2015. In 2015, estimated HBsAg among 5 year olds was 1.1% with variability among countries. Myanmar (3.8%), Timor-Leste (2.7%), Indonesia (1.8%), and India (1%) had the highest prevalence of HBsAg. During 1992–2015, vaccination prevented approximately 16 million chronic HBV infections and 2.6 million related deaths. In 2015, around 197,640 perinatal HBV infections occurred in SEAR with majority occurring in India (62%), Bangladesh (24%), and Myanmar (8%). Myanmar had the highest rate of perinatal chronic HBV infections at 16 per 1000 live births. Despite significant progress in the control of HBV, SEAR needs to secure political commitment for elimination and consider additional strategies, such as promoting health facility births, universal birth dose administration, developing strong coordination between health sectors, and using alternative vaccine delivery methods, to improve HepB-BD coverage and subsequently achieve HBV control and elimination.

Belarus conducted a representative, national hepatitis B serosurvey to evaluate the impact of hepatitis B vaccination programme. We used a multi-stage cluster design to select 3783 children born between 2009 and 2015. We collected demographic and immunization data, as well as venous blood samples, which were analysed for HBsAg by ELISA. Out of 2870 participants with valid test results, one tested positive for HBsAg, resulting in a weighted seroprevalence of 0.02% (one-sided 95% upper bound = 0.09%). Of the 3731/3783 (99%) participants with immunization records, 86.8% (95% CI: 84.8; 88.6) had received a timely birth dose of hepatitis B vaccine and 85.6% (95% CI: 83.5; 87.4) had received a birth dose and at least two subsequent doses of the vaccine. This study findings demonstrated the achievement of the regional hepatitis B control targets and significant progress toward the elimination of hepatitis B as a public health threat in Belarus. •Representative hepatitis B serosurvey evaluated impact of vaccination in Belarus.•Vaccination programme reduced hepatitis B prevalence in children to 0.02%.•Post-vaccination hepatitis B prevalence in a country of the WHO European Region.

Hepatitis B virus (HBV) cannot be completely eliminated from infected hepatocytes due to the existence of intrahepatic covalently closed circular DNA (cccDNA). Serological biomarkers reflect intrahepatic viral replicative activity as non-invasive alternatives to liver biopsy. Hepatitis B core-related antigen (HBcrAg) is a novel biomarker that has an important role in chronic hepatitis B (CHB), because it correlates with serum HBV DNA and intrahepatic cccDNA. In clinical cases with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with promising outcomes for CHB patients. HBcrAg can predict spontaneous or treatment-induced hepatitis B envelope antigen (HBeAg) seroconversion, persistent responses before and after cessation of nucleos(t)ide analogues, potential HBV reactivation, HBV reinfection after liver transplantation, and risk of hepatocellular carcinoma progression or recurrence. In this review, the clinical applications of HBcrAg in CHB patients based on its virological features are described. Furthermore, new potential therapeutic anti-HBV agents that affect intrahepatic cccDNA are under development, and the monitoring of HBcrAg might be useful to judge therapeutic effects. In conclusion, HBcrAg might be a suitable surrogate marker beyond other HBV markers to predict the disease progression and treatment responses of CHB patients.