Australian vaccine preventable disease epidemiological review series: Hepatitis B, 2000-2019.

Introduction: Hepatitis B vaccination was nationally funded for adolescents in 1996, with inclusion of universal infant immunisation under the National Immunisation Program (NIP) in May 2000. This study describes hepatitis B epidemiology in Australia in the two decades since 2000. Methods: This article analyses newly-acquired (within the prior 24 months) and unspecified (all other) hepatitis B notifications (2000-2019) from the National Notifiable Diseases Surveillance System; acute hepatitis B hospitalisations (2001-2019) from the National Hospital Morbidity Database; and acute (2000-2019) and chronic (2006-2019) hepatitis B deaths from the Australian Bureau of Statistics and Australian Coordinating Registry. Rates over the reporting period were described overall, and by age group, sex, and Aboriginal and Torres Strait Islander status (Aboriginal and/or Torres Strait Islander versus other [neither Aboriginal nor Torres Strait Islander, unknown or not stated]). Trend analyses were performed using Poisson or negative binomial regression. Additional analyses were performed for the cohort born after May 2000. Results and discussion: The annual all-age notification rate per 100,000 per year declined (p < 0.001) from 2.13 in 2000 to 0.65 in 2019 for newly-acquired hepatitis B and from 38.3 to 22.3 for unspecified hepatitis B (likely to predominantly represent chronic hepatitis B). Newly-acquired and unspecified hepatitis B notification rates were lowest among children aged < 15 years. The most substantial reductions in notification rates of newly-acquired hepatitis B were among adolescents aged 15-19 years and young adults aged 20-24 and 25-29 years (respectively 17-, 11-, and 7-fold); these age groups also recorded the most substantial reductions in unspecified hepatitis B notifications (respectively 5-, 3.5-, and 2-fold). Newly-acquired hepatitis B notification and acute hepatitis B mortality rates were two- to threefold higher in males than females. The all-age newly-acquired hepatitis B notification rate in Aboriginal and Torres Strait Islander people decreased twofold between 2000 and 2019, but remained threefold higher than in other people. Acute hepatitis B hospitalisations also declined over the study period (p < 0.001) and followed similar patterns. There were no acute or chronic hepatitis B deaths among people born after May 2000; this cohort featured 52 newly-acquired and 887 unspecified hepatitis B notifications. Due to lack of data on country of birth (and hence eligibility for infant vaccination under the NIP or overseas programs), vaccination status and likely transmission routes, we were unable to assess factors contributing to these potentially preventable infections. Conclusion: Adolescent and infant immunisation under the NIP has led to significant reductions in notification rates of newly-acquired hepatitis B, and in acute hepatitis B hospitalisation rates, both overall and in Aboriginal and Torres Strait Islander people. Unspecified hepatitis B notification rates have also greatly decreased in children and young adults, likely largely due to the impact of overseas infant immunisation programs on prevalence in child and adolescent migrants. Work to improve completeness of variables within national datasets is crucial, along with enhanced surveillance of both newly-acquired and unspecified hepatitis B cases to investigate transmission routes, vaccination status and factors contributing to acquisition of hepatitis B, in order to optimise the impact of immunisation programs and ensure linkage with care.

Juveniles, young adults, and infants with hepatitis B virus infection: A genomic study.

Integration of hepatitis B virus (HBV) DNA into the human genome is recognized as an oncogenic factor and a barrier to hepatitis B cure. In the study, biopsy liver tissues were collected from adolescents and young adults with acute HBV infection younger than or equal to 35 years of age and from HBV-infected infant patients younger than or equal to 6 months of age. A high-throughput sequencing method was used to detect HBV DNA integration. Totally, 12 adolescents, young adults, and 6 infants were included. Among the 12 patients with acute HBV infection, immunohistochemical staining of intrahepatic hepatitis B surface antigen for all displayed negative results, and no HBV DNA integrants in the hepatocyte DNA were confirmed. All infant patients had elevated levels of alanine aminotransferase and high levels of serum HBV DNA. Numerous gene sites of hepatocyte DNA were integrated by HBV DNA for each infant patient, ranging from 120 to 430 integration sites. The fragile histidine triad gene was the high-frequency integrated site in the intragenic region for infant patients. In conclusion, hepatocyte DNA is integrated by HBV DNA in babies with active hepatitis B but seems seldom affected among adolescents and young adults with acute HBV infection. Infantile hepatitis B should be taken seriously considering abundant HBV DNA integration events.

Temporal trend analysis of acute hepatitis B virus infection in China, 1990-2019.

China faces challenges in meeting the World Health Organization (WHO)'s target of reducing hepatitis B virus (HBV) infections by 95% using 2015 as the baseline. Using Global Burden of Disease (GBD) 2019 data, joinpoint regression models were used to analyse the temporal trends in the crude incidence rates (CIRs) and age-standardized incidence rates (ASIRs) of acute HBV (AHBV) infections in China from 1990 to 2019. The age-period-cohort model was used to estimate the effects of age, period, and birth cohort on AHBV infection risk, while the Bayesian age-period-cohort (BAPC) model was applied to predict the annual number and ASIRs of AHBV infections in China through 2030. The joinpoint regression model revealed that CIRs and ASIRs decreased from 1990 to 2019, with a faster decline occurring among males and females younger than 20 years. According to the age-period-cohort model, age effects showed a steep increase followed by a gradual decline, whereas period effects showed a linear decline, and cohort effects showed a gradual rise followed by a rapid decline. The number of cases of AHBV infections in China was predicted to decline until 2030, but it is unlikely to meet the WHO's target. These findings provide scientific support and guidance for hepatitis B prevention and control.

Lamivudine and Entecavir for Acute Hepatitis B: A Systematic Review and Meta-Analysis.

BACKGROUND: Acute hepatitis B infection is associated with severe liver disease and chronic sequelae in some cases. The purpose of this review was to determine the efficacy of nucleoside analogues (NA) (lamivudine versus entecavir) compared to placebo or no intervention for treating acute primary HBV infection. METHODS: A meta-analysis for drug intervention was performed, following a fixed-effect model. Randomized controlled trials (RCTs) and quasi-randomized studies that evaluated the outcomes of NA in acute hepatitis B infection were included. The following outcomes were considered: virological cure (PCR negative), elimination of acute infection (seroconversion of HBsAg), mortality, and serious adverse events. RESULTS: Five trials with 627 adult participants with severe acute hepatitis B defined by biochemical and serologic parameters were included. Virological cure did not favor any intervention: OR 0.96, 95% CI 0.54 to 1.7 (p = 0.90), I2 = 58%. Seroconversion of HBsAg to negative favored placebo/standard-of-care compared to lamivudine: OR 0.54, 95% CI 0.33 to 0.9 (p = 0.02), I2 = 31%. The only trial that compared entecavir and lamivudine favored entecavir over lamivudine (OR: 3.64, 95% CI 1.31-10.13; 90 participants). Adverse events were mild. CONCLUSION: There is insufficient evidence that NA obtain superior efficacy compared with placebo/standard-of-care in patients with acute viral hepatitis, based on low quality evidence.

Efficacy of hemoperfusion with Seraph-100 in series with single pass albumin dialysis in acute hepatitis B infection: A case report.

Acute and acute-on-chronic liver failure is a cause of death in patients suffering from viral hepatitis, and many cases need liver transplantation. Infection from hepatitis B virus may range from asymptomatic to severe acute and fulminant hepatitis. In this setting, treatment is mainly supportive as there is no consensus on antiviral therapy based on non-nucleoside reverse transcriptase inhibitors. Single-pass albumin dialysis is a liver-support technique for patients suffering from liver failure, that has shown effectiveness in the removal of both water-soluble and albumin-bound toxins, which accumulate due to impairment of the liver's cleansing function. We report here the case of a 62-year-old male who presented with a severe acute hepatitis B infection, liver failure, and marked hyperbilirubinemia. Treatment with single-pass albumin dialysis combined with a hemoperfusion device was successful in improving clinical, physiological, and laboratory parameters.

Trend and prediction of the disease burden of acute hepatitis B in China / 临床肝胆病杂志

ObjectiveTo investigate the situation and development trend of the disease burden of acute hepatitis B in China in 1990 — 2019. MethodsThe Global Burden of Disease 2019 was used to analyze the incidence rate， mortality rate， and disability-adjusted life year （DALY） rate of acute hepatitis B in different sex and age groups and predict the trend of the incidence rate of acute hepatitis B. ResultsIn 2019， the incidence rate， mortality rate， and DALY rate of acute hepatitis B in China were 1 623.71/100 000， 0.20/100 000， and 10.04/100 000 respectively， which were reduced by 42.03%， 79.38%， and 80.21%， respectively， compared with the data in 1990， and women showed lower incidence rate， mortality rate， and DALY rate of acute hepatitis B than men. In 2019， the 20～<54 years group had the highest incidence rate （2 285.85/100 000） and DALY rate （10.53/100 000）， and the ≥55 years group had the highest mortality rate of 0.52/100 000. The Joinpoint regression model analysis showed that the incidence rate， mortality rate， and DALY rate of acute hepatitis B in China tended to decrease from 1990 to 2019， with an average annual percent change of -1.9%， -5.2%， and -5.5%， respectively （P<0.05）. The grey prediction model GM （1，1） showed that the incidence rate of acute hepatitis B will decrease from 2020 to 2030 in China. ConclusionThe disease burden of acute hepatitis B tended to decrease from 1990 to 2019 in China， indicating that the prevention and treatment measures for acute hepatitis B have achieved a marked effect in China； however， due to the large population base of China， active preventive measures should be further adopted to reduce the disease burden of acute hepatitis B.

Cytokine profiles and CD8+ T cells in the occurrence of acute and chronic hepatitis B.

Objective: We explore the expression of functional molecules on CD8+ T lymphocytes, cytokines concentration, and their correlation to occurrence of hepatitis B and hepatitis B virus (HBV) desoxyribose nucleic acid (DNA), hepatitis B surface antigen (HBsAg), hepatitis B envelope antigen (HBeAg), and alanine aminotransferase (ALT) in patients infected with HBV. Methods: This is a single center study. 32 patients with acute hepatitis B (AHB), 30 patients with immune tolerant (IT) phase chronic HBV infected, and 50 patients with chronic hepatitis B (CHB) were enrolled. The activation molecules (CD69) and the apoptosis-inducing molecules (CD178) on surface of CD8+ T lymphocytes were tested by the flow cytometry. Fms-like tyrosine kinase 3 ligand (Flt-3L), interleukin 17A (IL-17A), interferon γ (IFN-γ), and Interferon α2 (IFN-α2) were quantitated by Luminex assay. We use linear regression analysis to analyze their correlations to ALT, HBV DNA, HBsAg, and HBeAg. Results: The frequency of CD69+CD8+ T lymphocytes in CHB and AHB groups were increased significantly compared with IT group (4.19[3.01, 6.18]% and 4.45[2.93, 6.71]% vs. 3.02[2.17, 3.44]%; H=26.207, P=0.001; H=28.585, P=0.002), and the mean fluorescence intensity (MFI) of CD69 in AHB group was significantly higher than IT and CHB groups (27.35[24.88, 32.25] vs. 20.45[19.05, 27.75] and 23.40[16.78, 28.13]; H=25.832, P=0.005 and H=22.056, P=0.008). In IT group, HBsAg levels and HBV DNA loads were negatively correlated with CD69MFI (ß=-0.025, t=-2.613, P=0.014; ß=-0.021, t=-2.286, P=0.030), meanwhile, HBeAg was negatively related to the frequency of CD69+CD8+ T lymphocytes (ß=-61.306, t=-2.116, P=0.043). In AHB group, IFN-α2 was positively related to the frequency of CD8+ T lymphocytes (ß=6.798, t=2.629, P=0.016); however, in CHB group, IFN-α2 was negatively associated with frequency of CD8+ T lymphocytes (ß=-14.534, t=-2.085, P=0.043). In CHB group, HBeAg was positively associated with frequency of CD69+CD8+ T lymphocytes (ß=43.912, t=2.027, P=0.048). In AHB group, ALT was positively related to CD69MFI (ß=35.042, t=2.896, P=0.007), but HBsAg was negatively related to CD178MFI (ß=-0.137, t=-3.273, P=0.003). Conclusions: The activation of CD8+ T lymphocytes was associated with the occurrence of AHB and CHB. However, due to the insufficient expression of functional molecules of CD8+ T lymphocytes and the depletion of CD8+ T lymphocytes, CHB patients were difficult to recover from HBV infection.

Epidemiological and clinical aspects of hepatitis B virus infection in Italy over the last 50 years.

A relevant gradual reduction of both the incidence rate of acute hepatitis B (AHB) and prevalence of chronic hepatitis B has occurred in Italy in the last 50 years, due to substantial epidemiological changes: Improvement in socioeconomic and hygienic conditions, reduction of the family unit, accurate screening of blood donations, abolition of re-usable glass syringes, hepatitis B virus (HBV)-universal vaccination started in 1991, use of effective well tolerated nucleo(t)side analogues able to suppress HBV replication available from 1998, and educational mediatic campaigns against human immunodeficiency virus infection focusing on the prevention of sexual and parenteral transmission of infections. As an example, AHB incidence has gradually decreased from 10/100000 inhabitants in 1985 to 0.21 in 2020. Unfortunately, the coronavirus disease 2019 (COVID-19) pandemic has interrupted the trend towards HBV eradication. In fact, several HBV chronic carriers living in the countryside have become unable to access healthcare facilities for screening, diagnosis, clinical management, and nucleo(t)side analogue therapy in the COVID-19 pandemic, mainly for anxiety of becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), movement restrictions, and reduced gains from job loss. In addition, one-third of healthcare facilities and personnel for HBV patients have been devolved to the COVID-19 assistance.

Acute hepatitis B among HIV positive persons: A two-decade review of cases from a Spanish cohort.

PURPOSE: To review the incidence and characteristics of acute hepatitis B (AHB) in a large cohort of HIV infected persons from a low prevalence region during the last two decades. METHODS: Retrospective review of an HIV Cohort from a single reference centre in Madrid, Spain, between 2000 and 2018. AHB was diagnosed in persons with newly acquired HBAgS and acute hepatitis with positive IgM anti-HBc. RESULTS: Out of 5443 HIV+ patients in our cohort (3098 anti-HBc negative), 18 developed AHB from 2000 to 2018. The global incidence was 0.02 (0.01-0.04) per 100 patient-year in the entire population and 0.06 (0.01-0.1) per 100 patient-year in the anti-HBc negative population. A statistically significant decrease in AHB incidence was observed during these years (ß=-0.006; p=0.047). All 18 patients diagnosed with AHB were men, the majority (16) occurred in men who have sex with men. AHB was observed in 4 persons previously unresponsive to vaccination. Regarding antiretroviral treatment (ART), 15 were not receiving ART, two persons were on ART with any HBV active drugs and one person had lamivudine in the regimen. Two persons (11%) developed chronic hepatitis B. There were no cases of fulminant hepatitis. CONCLUSION: The incidence of AHB in HIV positive persons in our cohort was low and shows a progressive decline in the last 20 years. Cases occurred in persons not protected against VHB: not vaccinated or non-responders to vaccine that were not receiving tenofovir.

Acute hepatitis B among HIV positive persons: A two-decade review of cases from a Spanish cohort / Hepatitis B aguda en pacientes infectados por VIH en las dos últimas décadas en una cohorte española

ObjetivoRevisar la incidencia y las características de la hepatitis B aguda (HAB), en pacientes infectados por VIH en seguimiento durante las dos últimas décadas.MétodosRevisión retrospectiva de los casos de HAB en la cohorte de pacientes infectados por VIH y seguimiento en el Hospital Universitario La Paz, entre los años 2000 y 2018. La HAB se definió como la reciente aparición del AgS frente al virus de la hepatitis B (VHB) y anticuerpos anti-HBc+ de tipo IGM.ResultadosSe siguieron 5.443 pacientes VIH+, de ellos, 3.098 sin contacto previo con el VHB (anti-HBc negativo). Diagnosticamos 18 casos de HAB, lo que supone una incidencia de 0,02 (0,01-0,04) por 100 pacientes-año en toda la población y 0,06 (0,01-0,1) por 100 pacientes-año en aquellos anti-HBc negativo. Observamos una disminución significativa en la incidencia a lo largo de los años (β = -0,006; p = 0,047).Los 18 pacientes eran hombres y la mayoría (16) tenían sexo con hombres. En cuatro casos, la HAB se produjo en pacientes vacunados sin respuesta. Quince pacientes estaban sin tratamiento frente al VIH (TAR), dos recibían TAR sin drogas frente al VHB y uno tenía TAR con lamivudina, pero no tenofovir. No observamos ninguna hepatitis B grave, pero dos pacientes (11%) desarrollaron una hepatitis crónica B.ConclusiónLa incidencia de la HAB en pacientes VIH+ en nuestro hospital es baja y ha disminuido en los últimos 20 años. Aun así, seguimos viendo casos en pacientes sin protección para el VHB: sin vacunar o vacunados sin respuesta, que no reciben tenofovir.

PurposeTo review the incidence and characteristics of acute hepatitis B (AHB) in a large cohort of HIV infected persons from a low prevalence region during the last two decades.MethodsRetrospective review of an HIV Cohort from a single reference centre in Madrid, Spain, between 2000 and 2018. AHB was diagnosed in persons with newly acquired HBAgS and acute hepatitis with positive IgM anti-HBc.ResultsOut of 5443 HIV+ patients in our cohort (3098 anti-HBc negative), 18 developed AHB from 2000 to 2018. The global incidence was 0.02 (0.01–0.04) per 100 patient-year in the entire population and 0.06 (0.01–0.1) per 100 patient-year in the anti-HBc negative population. A statistically significant decrease in AHB incidence was observed during these years (β=−0.006; p=0.047).All 18 patients diagnosed with AHB were men, the majority (16) occurred in men who have sex with men. AHB was observed in 4 persons previously unresponsive to vaccination. Regarding antiretroviral treatment (ART), 15 were not receiving ART, two persons were on ART with any HBV active drugs and one person had lamivudine in the regimen. Two persons (11%) developed chronic hepatitis B. There were no cases of fulminant hepatitis.ConclusionThe incidence of AHB in HIV positive persons in our cohort was low and shows a progressive decline in the last 20 years. Cases occurred in persons not protected against VHB: not vaccinated or non-responders to vaccine that were not receiving tenofovir.

Enduring Challenges despite Progress in Preventing Mother-to-Child Transmission of Hepatitis B Virus in Angola.

Sub-Saharan Africa has one of the highest rates of hepatitis B virus (HBV) infection globally, with an incidence of 1.5 million and 0.8 million yearly deaths, which drives synergistic efforts towards its elimination. To assess the risk of mother-to-child transmission of HBV infection, a cross-sectional study was conducted on 1012 pregnant women in Angola to investigate HBV serological and molecular profiles. The prevalence of HBV was 8.7% (n = 88), with hepatitis B core IgM antibody (anti-HBc IgM) positivity identified in 12.8%, hepatitis B "e" antigen (HBeAg) positivity in 30%, and HBV DNA ≥ 200,000 IU/mL in 28.2%. Family tracking studied 44 children, of which 11 (25%) received at least two doses of the hepatitis B vaccine. HBV was detected in 10/44 (22.7%) children, with vaccination reported in one infected child. Further testing identified anti-HBc IgM positivity in 3/10 (30%), HBeAg positivity in 55%, and both seromarkers in 20%. The results revealed the importance of antenatal HBV screening, antiviral prophylaxis for mothers with high viral loads or HBeAg positivity, and timely first-dose hepatitis B vaccines in newborns. Anti-HBc IgM positivity among pregnant women and children highlights prophylactic measures worth considering, including antenatal hepatitis B vaccination and catch-up vaccination to young children.

Asian Pacific association for the study of liver (APASL) guidelines: hepatitis B virus in pregnancy.

Hepatitis B virus (HBV) infection still remains a major public health issue in the Asia-Pacific region. Most of the burden of HBV-related disease results from infections acquired in infancy through perinatal or early childhood exposure to HBV in Asia-Pacific. Hepatitis B during pregnancy presents unique management issues for both the mother and fetus. These APASL guidelines provide a comprehensive review and recommendations based on available evidence in the literature, for the management of females with HBV infection through every stage of pregnancy and postpartum. These also address the concerns, management challenges, and required follow-up of children born to hepatitis B-positive mothers.

Treatment and Prevention of Acute Hepatitis B Virus.

This article reviews the incidence of acute hepatitis B virus (HBV) infection, its clinical course, strategies to prevent acute HBV infection in susceptible individuals, and the management of patients with acute HBV.

A quantitative systems pharmacology model for acute viral hepatitis B.

Hepatitis B liver infection is caused by hepatitis B virus (HBV) and represents a major global disease problem when it becomes chronic, as is the case for 80-90% of vertical or early life infections. However, in the vast majority (>95%) of adult exposures, the infected individuals are capable of mounting an effective immune response leading to infection resolution. A good understanding of HBV dynamics and the interaction between the virus and immune system during acute infection represents an essential step to characterize and understand the key biological processes involved in disease resolution, which may help to identify potential interventions to prevent chronic hepatitis B. In this work, a quantitative systems pharmacology model for acute hepatitis B characterizing viral dynamics and the main components of the innate, adaptive, and tolerant immune response has been successfully developed. To do so, information from multiple sources and across different organization levels has been integrated in a common mechanistic framework. The final model adequately describes the chronology and plausibility of an HBV-triggered immune response, as well as clinical data from acute patients reported in the literature. Given the holistic nature of the framework, the model can be used to illustrate the relevance of the different immune pathways and biological processes to ultimate response, observing the negligible contribution of the innate response and the key contribution of the cellular response on viral clearance. More specifically, moderate reductions of the proliferation of activated cytotoxic CD8+ lymphocytes or increased immunoregulatory effects can drive the system towards chronicity.

Involvement of Innate Immune Receptors in the Resolution of Acute Hepatitis B in Woodchucks.

The antiviral property of small agonist compounds activating pattern recognition receptors (PRRs), including toll-like and RIG-I receptors, have been preclinically evaluated and are currently tested in clinical trials against chronic hepatitis B (CHB). The involvement of other PRRs in modulating hepatitis B virus infection is less known. Thus, woodchucks with resolving acute hepatitis B (AHB) after infection with woodchuck hepatitis virus (WHV) were characterized as animals with normal or delayed resolution based on their kinetics of viremia and antigenemia, and the presence and expression of various PRRs were determined in both outcomes. While PRR expression was unchanged immediately after infection, most receptors were strongly upregulated during resolution in liver but not in blood. Besides well-known PRRs, including TLR7/8/9 and RIG-I, other less-characterized receptors, such as IFI16, ZBP1/DAI, AIM2, and NLRP3, displayed comparable or even higher expression. Compared to normal resolution, a 3-4-week lag in peak receptor expression and WHV-specific B- and T-cell responses were noted during delayed resolution. This suggested that PRR upregulation in woodchuck liver occurs when the mounting WHV replication reaches a certain level, and that multiple receptors are involved in the subsequent induction of antiviral immune responses. Liver enzyme elevations occurred early during normal resolution, indicating a faster induction of cytolytic mechanisms than in delayed resolution, and correlated with an increased expression of NK-cell and CD8 markers and cytolytic effector molecules. The peak liver enzyme level, however, was lower during delayed resolution, but hepatic inflammation was more pronounced and associated with a higher expression of cytolytic markers. Further comparison of PRR expression revealed that most receptors were significantly reduced in woodchucks with established and progressing CHB, and several RNA sensors more so than DNA sensors. This correlated with a lower expression of receptor adaptor and effector molecules, suggesting that persistent, high-level WHV replication interferes with PRR activation and is associated with a diminished antiviral immunity based on the reduced expression of immune cell markers, and absent WHV-specific B- and T-cell responses. Overall, the differential expression of PRRs during resolution and persistence of WHV infection emphasizes their importance in the ultimate viral control during AHB that is impaired during CHB.

Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability.

The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients' responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.

Everolimus Related Fulminant Hepatitis in Pancreatic Neuroendocrine Tumor With Liver Metastases: A Case Report and Literature Review.

Background: Everolimus, an immunosuppressant, is approved for the treatment of advanced renal cell carcinoma, metastatic hormone receptor-positive breast cancer, and pancreatic neuroendocrine tumors (P-NETs) but has been reported to be related to hepatitis B reactivation. Here, we present the first case of fatal fulminant hepatitis B reactivation in a man with P-NET accompanied by multiple liver metastases who received everolimus and octreotide long-acting repeatable (LAR). Case Presentation: A 45-year-old male had a history of chronic hepatitis B infection. He was found to have a complicated liver cyst incidentally, and then he underwent biopsy, which disclosed a grade 2 neuroendocrine tumor (NET). Subsequent MRI of the abdomen and PET revealed a solid mass at the pancreatic tail with numerous liver tumors favoring metastases and peripancreatic lymph node metastases. Transarterial chemoembolization (TACE) of the right lobe of the liver was performed, and he started to take 5 mg everolimus twice a day and 20 mg octreotide LAR every month 8 days after the 1st TACE. No hepatitis B virus (HBV) prophylaxis treatment was administered. He then underwent laparoscopic distal pancreatectomy and splenectomy three and half months after the initial treatment of everolimus. He continued everolimus 5 mg twice a day and octreotide 20 mg every month after the operation. Three months later, hepatic failure occurred due to acute hepatitis B flare-up-related fulminant hepatic failure since other possible causes of hepatic failure were excluded. Five days after hepatic failure presented, hepatic failure was apparent, and pulseless ventricular tachycardia occurred. The patient expired after failed resuscitation. Conclusion: A literature review of everolimus-related hepatitis B reactivation was conducted. In P-NET patients with chronic hepatitis B who will undergo everolimus treatment, HBV prophylaxis should be considered since fatal hepatitis B reactivation might occur under rare conditions.

Restricted TcR ß chain CDR3 clonotype is associated with resolved acute hepatitis B subjects.

BACKGROUND: T cells play an important role in the prognosis of hepatitis B virus (HBV) infection, and are involved in the seroconversion of a patient from HBsAb negative to positive. To compare the T-cell receptor ß-chain variable region (TcRBV) complementarity-determining region 3 (CDR3) in subjects with or without hepatitis B surface antigen (HBsAg) convert to hepatitis B surface antibody (HBsAb), the TcRBV was determined using high throughput sequencing (HTS). METHODS: The clonotype and diversity of CDR3 in peripheral blood mononuclear cells of subjects with resolved acute hepatitis B (AHB, HBsAb+, HBsAg-) (n = 5), chronic hepatitis B (CHB, HBsAb-, HBsAg+) (n = 5), and healthy controls (HC, HBsAb-, HBsAg-) (n = 3) were determined and analyzed using HTS (MiSeq). RESULTS: The overlapping rate of CDR3 clones of any two samples in AHB group was 2.00% (1.74% ~ 2.30%), CHB group was 1.77% (1.43% ~ 2.61%), and HC group was 1.82% (1.62% ~ 2.12%), and there was no significant difference among the three groups by Kruskal-Wallis H test. However, among the top 10 cumulative frequencies of clonotypes, only the frequency of clonotype (TcRBV20-1/BD1/BJ1-2) in AHB group was lower than that of HC group (P < 0.001). Moreover, exclude the 10 top clonotypes, there are 57 markedly different frequency of clones between AHB and CHB groups (18 clones up, 39 clones down), 179 (180-1) different clones between AHB and HC groups, and 134 different clones between CHB and HC groups. With regard to BV and BJ genotypes, there was no significant different frequency among the groups. Furthermore, there was no significant difference in the diversity of TcRBV CDR3 among the three groups (P > 0.05). CONCLUSIONS: Thus, there are 57 TcRBV clonotypes that may be related to HBsAg seroconversion of AHB subjects, but the diversity of TcRBV CDR3 is not significantly related to the HBsAb positive status.

Abatacept treatment for patients with severe acute hepatitis caused by hepatitis B virus infection-Pilot study.

Although glucocorticoids have been used for immunosuppression of patients with primary hepatitis B virus (HBV) infection-induced severe hepatitis, the treatment is associated with a high frequency of adverse events. We conducted a pilot study for evaluating the efficacy and safety of abatacept, a cytotoxic T lymphocyte antigen-4 immunoglobulin (CTLA4), for acute hepatitis B. Five patients with severe acute hepatitis B (prothrombin activity ≤ 60%) were treated for immunosuppression by abatacept. Four patients received abatacept concurrently with methylprednisolone, and another patient was treated with abatacept alone. Rapid decrease in serum alanine aminotransferase levels, increase in prothrombin activity and improvement of general condition were obtained in four out of five patients. The patient with the most severe hepatitis underwent liver transplantation due to exacerbation of hepatitis in spite of treatment with both abatacept and methylprednisolone. None of the patients developed significant adverse events associated with the use of abatacept. Hepatitis B surface antigen (HBsAg) became negative in all five patients. The effect of abatacept and methylprednisolone for severe hepatitis B was compared using a mouse model. Rapid reduction in mouse serum HBV DNA and human albumin levels and elevation of serum interferon-gamma and granzyme A levels were observed in HBV-infected human hepatocyte-transplanted immunodeficient mice that were administered human peripheral blood mononuclear cells. These hepatocyte injuries were inhibited to a greater extent by abatacept compared to methylprednisolone. Abatacept might be an effective therapy alternative to methylprednisolone to reduce acute massive liver damage for patients with severe acute hepatitis caused by HBV infection.

Acute hepatitis B among HIV positive persons: A two-decade review of cases from a Spanish cohort.

PURPOSE: To review the incidence and characteristics of acute hepatitis B (AHB) in a large cohort of HIV infected persons from a low prevalence region during the last two decades. METHODS: Retrospective review of an HIV Cohort from a single reference centre in Madrid, Spain, between 2000 and 2018. AHB was diagnosed in persons with newly acquired HBAgS and acute hepatitis with positive IgM anti-HBc. RESULTS: Out of 5443 HIV+ patients in our cohort (3098 anti-HBc negative), 18 developed AHB from 2000 to 2018. The global incidence was 0.02 (0.01-0.04) per 100 patient-year in the entire population and 0.06 (0.01-0.1) per 100 patient-year in the anti-HBc negative population. A statistically significant decrease in AHB incidence was observed during these years (ß=-0.006; p=0.047). All 18 patients diagnosed with AHB were men, the majority (16) occurred in men who have sex with men. AHB was observed in 4 persons previously unresponsive to vaccination. Regarding antiretroviral treatment (ART), 15 were not receiving ART, two persons were on ART with any HBV active drugs and one person had lamivudine in the regimen. Two persons (11%) developed chronic hepatitis B. There were no cases of fulminant hepatitis. CONCLUSION: The incidence of AHB in HIV positive persons in our cohort was low and shows a progressive decline in the last 20 years. Cases occurred in persons not protected against VHB: not vaccinated or non-responders to vaccine that were not receiving tenofovir.