Hepatitis-B-Virus-Infektionen und impfinduzierte Immunität: die Rolle von soziodemografischen Determinanten

Zusammenfassung Hintergrund und Ziel Trotz niedriger Prävalenz der Hepatitis-B-Virus-(HBV-)Infektion in Deutschland ist es wichtig, vulnerable Gruppen und Ansatzpunkte für die Prävention zu identifizieren. In ersten Analysen der „Studie zur Gesundheit Erwachsener in Deutschland“ (DEGS1, 2008–2011) waren HBV-Infektion und -Impfung mit sozidemografischen Determinanten assoziiert. In dieser Arbeit werden die Ergebnisse im Detail untersucht. Material und Methoden In DEGS1 lag für 7046 Teilnehmende (Alter: 18–79 Jahre) eine HBV-Serologie vor. Die stattgehabte HBV-Infektion war durch Antikörper gegen das Hepatitis-B-Core-Antigen (Anti-HBc) definiert, die impfinduzierte Immunität durch alleinigen Nachweis von Antikörpern gegen das Hepatitis-B-Surface-Antigen (Anti-HBs). Seroprävalenzen von HBV-Infektions- und -Impfstatus wurden geschlechtsstratifiziert geschätzt und Assoziationen mit Alter, Gemeindegröße, Einkommen, formaler Bildung, Krankenversicherung und Migrationsgeneration in logistischen Regressionen analysiert. Ergebnisse Die HBV-Infektion war bei Männern und Frauen unabhängig mit den Altersgruppen 34–64 und ≥ 65 Jahre, erster Migrationsgeneration und Leben in größeren Gemeinden assoziiert, zudem bei Männern mit niedrigem Einkommen und bei Frauen mit niedriger Bildung. Die impfinduzierte Immunität war bei Männern und Frauen unabhängig mit den Altersgruppen 18–33 und 34–64 Jahre, mittlerer und hoher Bildung und hohem Einkommen assoziiert, darüber hinaus bei Männern mit mittlerem Einkommen und privater Krankenversicherung und bei Frauen mit fehlendem Migrationshintergrund. Diskussion Die Berücksichtigung von Migrationsstatus, Einkommen und Bildung könnte zur zielgenauen Ausrichtung der HBV-Prävention beitragen.

Analyses of blood donor samples from eight provinces in Lao PDR suggest considerable variation concerning HBV exposure and carriage

Introduction Hepatitis B is endemic in Lao PDR and about 9% of the adult population is chronically infected. In this study, we investigated regional, occupational, age and sex-related differences in hepatitis B epidemiology in Lao blood donors. Methods 5017 voluntary blood donors from 8 different provinces were tested for hepatitis B markers by ELISA. Predictors for the prevalence of hepatitis B surface antigen (HBsAg) and antibodies against the core antigen (anti-HBc) were assessed by bivariate and multivariable analyses. Results In total, 41% of the participants were positive for anti-HBc; the HBsAg prevalence was estimated at 6.9% among all participants (9.2% among first-time donors and 3.9% among repeat donors). Among first-time donors, HBsAg positivity was associated independently with being male (p<0.001), being from the North (p<0.001) and being soldier (p<0.001). Participants were more likely to be anti-HBc positive when they were male (p<0.001), from the Northern provinces (p<0.001) and older than 20 years (p<0.01). Conclusion In conclusion, our study confirmed an overall high HBsAg and anti-HBc prevalence in Lao PDR, albeit with considerable regional variation. The identification of a sizeable number of HBsAg positives among repeat donors warrants a thorough investigation of current blood screening, record keeping, donor identification and counselling practises.

Hepatitis B Virus Reactivation upon Immunosuppression: Is There a Role for Hepatitis B Core-Related Antigen in Patients with Immune-Escape Mutants? A Case Report

The reactivation of hepatitis B virus (HBVr) in patients undergoing pharmacological immunosuppression is a potentially fatal clinical event that may occur in patients with overt or occult HBV infection. The risk of HBVr is mainly determined by the type of immunosuppressive therapy and the HBV serologic profile, with a higher risk in patients positive for the hepatitis B surface antigen (HBsAg), and a lower risk in HBsAg-negative/antibodies to core antigen-positive subjects. Notably, a considerable proportion of patients experiencing HBVr showed a high degree of variability of the HBV S gene, possibly leading to immune escape mutants. These mutations, usually in the “a-determinant” of the HBsAg, can cause diagnostic problems and consequently hamper the appropriate management strategy of patients at risk of HBVr. Here, we describe a case of HBVr in a patient with a diagnosis of chronic myeloid leukemia and a previous history of kidney transplant, providing evidence of the potential usefulness of hepatitis B core-related antigen measurement in patients with HBV immune-escape mutants at risk of viral reactivation.

Virus-like particles displaying conserved toxin epitopes stimulate broadly reactive, polyspecific, murine antibody responses capable of snake venom recognition

Antivenom is currently the first-choice treatment for snakebite envenoming. However, only a low proportion of antivenom immunoglobulins are specific to venom toxins, resulting in poor dose efficacy and potency. We sought to investigate whether linear venom epitopes displayed on virus like particles can stimulate a robust and focused antibody response capable of recognising venom toxins from diverse medically important species. Bioinformatically-designed epitopes, corresponding to predicted conserved regions of group I phospholipase A2 and three finger toxins, were engineered for display on the surface of hepatitis B core antigen virus like particles and used to immunise female CD1 mice over a 14-weeks. Antibody responses to all venom epitope virus like particles were detectable by ELISA by the end of the immunisation period, although total antibody and epitope specific antibody titres were variable against the different epitope immunogens. Immunoblots using pooled sera demonstrated recognition of various venom components in a diverse panel of six elapid venoms, representing three continents and four genera. Finally, pooled terminal sera was compared to conventional antivenom via quantitative immunoblot, and demonstrated superior recognition of lower-molecular weight elapid venom toxins. This study demonstrates proof-of-principle that virus like particles engineered to display conserved toxin linear epitopes can elicit specific antibody responses in mice which are able to recognise a geographically broad range of elapid venoms.

A baseline model including quantitative anti-HBc to predict response of peginterferon in HBeAg-positive chronic hepatitis B patients

Background Few models to predict antiviral response of peginterferon were used in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients and the prediction efficacy was unsatisfied. Quantitative antibody to hepatitis B core antigen (anti-HBc) is a new predictor of treatment response. We aimed to develop a new model to identify HBeAg-positive Chinese patients who were more likely to respond to peginterferon. Methods Data from 140 peginterferon recipients with HBeAg-positive were applied with generalized additive models and multiple logistic regression analysis to develop a baseline scoring system to predict serological response (SR: HBeAg loss and HBeAg seroconversion 24 weeks post-treatment) and combined response (CR: SR plus serum HBV DNA levels <2000 IU/mL 24 weeks post-treatment). Results Anti-HBc levels, alanine aminotransferase ratio, and HBeAg were retained in the final model. The new model scored from 0 to 3. Among patients with scores of 0, 1, or ≥2, SR was achieved in 6.45% (2/31), 13.21% (7/51), and 55.36% (31/56), respectively, and CR in 3.23% (1/31), 9.43% (5/53), and 25.00% (14/56), respectively. Our model has a higher AUROC for SR comparing to Chan’s (Z = 2.77 > 1.96, p < 0.05) and Lampertico’s (Z = 2.06 > 1.96, p < 0.05) model. The negative predictive value for SR and CR were both 100% in patients with score 0 and hepatitis B surface antigen ≥20,000 IU/mL at week 12. Conclusions Patients with higher scores at baseline were more likely to respond to peginterferon. This new model may predict the treatment response.

Hepatitis C Virus Core Antigen as an Alternative to RNA in the Assessment of Response to Treatment with Direct-acting Oral Antivirals

Background: Affordable and effective diagnostic and treatment monitoring algorithms are urgently needed to achieve the global elimination of hepatitis C virus (HCV) infection. Methods: A total of 274 patients were treated with direct-acting antivirals (DAAs) in the Spanish Hospital of Albacete between 2004 and 2020. This study compared the enzyme-immunoassay technique for HCV core antigen (HCVcAg) with the determination of RNA of HCV (HCV RNA) by polymerase chain reaction (PCR) in monitoring treatment with DAA, setting the lower limit of detection of HCVcAg < 3 fmol/L and RNA < 10 IU/mL. In all cases, the P value of differences associated with the contrast test was less than or equal to 0.05. Results: We evaluated the viral loads of our patients before treatment, during their treatment, and after its completion. The HCV RNA quantification at diagnosis was 2309327 IU/mL. The mean HCVcAg load was 5972 fmol/L. There was a strong correlation between HCVcAg levels and RNA levels with a Spearman rho of 0.832 (P < 0.01). The HCVcAg sensitivity at diagnosis was 99%, but the specificity could not be calculated because there were no true negatives or false positives at this point. Twelve weeks after treatment, in patients with treatment failure, we obtained a mean of 19084 IU/mL for RNA, while for HCVcAg, the mean was 103 fmol/L. At this time point, we also found a strong correlation between HCVcAg levels and HCV RNA levels with a Spearman rho of 0.775 (P < 0.01). Finally, the virological cure was achieved in 99% of our patients. The results for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 100%, 99.87%, 86.33%, and 100%, respectively. Conclusions: HCVcAg determination is an excellent alternative to HCV RNA in the assessment of treatment response. This is particularly relevant in lower- and middle-income countries and resource-limited settings where the high cost of labor, equipment, and reagents can prohibit molecular testing.

In Vivo Modelling of Hepatitis B Virus Subgenotype A1 Replication Using Adeno-Associated Viral Vectors

The paucity of animal models that simulate the replication of the hepatitis B virus (HBV) is an impediment to advancing new anti-viral treatments. The work reported here employed recombinant adeno-associated viruses (AAVs) to model HBV subgenotype A1 and subgenotype D3 replication in vitro and in vivo. Infection with subgenotype A1 is endemic to parts of sub-Saharan Africa, and it is associated with a high risk of hepatocellular carcinoma. Recombinant AAV serotype 2 (AAV2) and 8 (AAV8) vectors bearing greater-than-genome-length sequences of HBV DNA from subgenotype A1 and D3, were produced. Transduced liver-derived cultured cells produced HBV surface antigen and core antigen. Administration of AAV8 carrying HBV subgenotype A1 genome (AAV8-A1) to mice resulted in the sustained production of HBV replication markers over a six-month period, without elevated inflammatory cytokines, expression of interferon response genes or alanine transaminase activity. Markers of replication were generally higher in animals treated with subgenotype D3 genome-bearing AAVs than in those receiving the subgenotype A1-genome-bearing vectors. To validate the use of the AAV8-A1 murine model for anti-HBV drug development, the efficacy of anti-HBV artificial primary-microRNAs was assessed. Significant silencing of HBV markers was observed over a 6-month period after administering AAVs. These data indicate that AAVs conveniently and safely recapitulate the replication of different HBV subgenotypes, and the vectors may be used to assess antivirals’ potency.

Molecular and Serological Characterization of Hepatitis B Virus (HBV)-Positive Samples with Very Low or Undetectable Levels of HBV Surface Antigen

Background: Gaps remain in the detection of nucleic acid test (NAT) yield and occult hepatitis B virus (HBV) infection (OBI) by current HBV surface antigen (HBsAg) assays. The lack of detection may be due to HBsAg levels below current assay detection limits, mutations affecting HBsAg assays or HBsAg levels, or the masking of HBsAg by antibody to HBsAg (anti-HBs). In this study, we evaluate the incremental detection of NAT yield and OBI from five diverse geographic areas by an improved sensitivity HBsAg assay and characterize the samples relative to the viral load, anti-HBs status, and PreS1–S2–S mutations. Included is a comparison population with HBV DNA levels comparable to OBI, but with readily detectable HBsAg (High Surface–Low DNA, HSLD). Methods: A total of 347 samples collected from the USA, South Africa, Spain, Cameroon, Vietnam, and Cote D’Ivoire representing NAT yield (HBsAg(−), antibody to HBV core antigen (anti-HBc)(−), HBV DNA(+), N = 131), OBI (HBsAg(−), anti-HBc(+), HBV DNA(+), N = 188), and HSLD (HBsAg(+), anti-HBc(+), HBV DNA(+), N = 28) were tested with ARCHITECT HBsAg NEXT (HBsAgNx) (sensitivity 0.005 IU/mL). The sequencing of the PreS1–S2–S genes from a subset of 177 samples was performed to determine the genotype and assess amino acid variability, particularly in anti-HBs(+) samples. Results: HBsAgNx detected 44/131 (33.6%) NAT yield and 42/188 (22.3%) OBI samples. Mean HBV DNA levels for NAT yield and OBI samples were lower in HBsAgNx(−) (50.3 and 25.9 IU/mL) than in HBsAgNx(+) samples (384.1 and 139.5 IU/mL). Anti-HBs ≥ 10 mIU/mL was present in 28.6% HBsAgNx(+) and 45.2% HBsAgNx(−) OBI, and in 3.6% HSLD samples. The genotypes were A1, A2, B, C, D, E, F, and H. There was no significant difference between HBsAgNx(−) and HBsAgNx(+) in the proportion of samples harboring substitutions or in the mean number of substitutions per sample in PreS1, PreS2, or S for the NAT yield or OBI (p range: 0.1231 to >0.9999). A total of 21/27 (77.8%) of HBsAgNx(+) OBI carried S escape mutations, insertions, or stop codons. HSLD had more PreS1 and fewer S substitutions compared to both HBsAgNx(−) and HBsAgNx(+) OBI. Mutations/deletions associated with impaired HBsAg secretion were observed in the OBI group. Conclusions: HBsAgNx provides the improved detection of NAT yield and OBI samples. Samples that remain undetected by HBsAgNx have exceptionally low HBsAg levels below the assay detection limit, likely due to low viremia or the suppression of HBsAg expression by host and viral factors.