Search Results (28)

Background/Objectives: The baseline determinants of functional cure in chronic hepatitis B (CHB) are largely unknown. By applying propensity score matching (PSM) to real-world data, we aimed to identify traits associated with functional cure. Methods: We included CHB cases which achieved a functional cure and randomly selected non-achievers from patients followed from 2000 to 2020. Initial screening of baseline candidate traits was conducted using PSM-balanced cases and controls. Subsequently, through multiple rounds of leave-one-covariate-out on the balanced cohorts, we validated the impact of these traits using survival analysis. Results: In total, 85 cases (mean age: 35.78; female/male: 23/62) were compared with 247 controls (mean age: 37.08; female/male: 80/167, out of 3666), with a median follow-up of 69.56 months. Steatosis and interferon (IFN) treatment were significantly more frequent in the cases, as confirmed by forest plots showing significant hazard ratios. During validation, whether through balancing all covariates or leave-one-covariate-out matching, both steatosis and exposure to IFN resulted in a higher number of functional cures and HBsAg seroconversions. Further comparisons revealed that add-on or monotherapy outperformed switching (from IFN to NUC), while the de novo (IFN + NUC, followed by NUC) approach was not observed. Conclusions: We confirmed that individuals with steatosis at baseline or those who received IFN were more likely to achieve HBsAg immune control, with monotherapy/add-on therapy being emphasized. Full article

Background/Objectives: In chronic hepatitis B infection (CHB), the hepatitis B surface antigen (HBsAg) continuously exhausts the hepatitis B surface antibody (HBsAb), which leads to the formation of immune tolerance. Accordingly, the hepatitis B virus (HBV) infection can be blocked by inhibiting the binding of the hepatitis B surface pre-S1/pre-S2 antigen to the hepatocyte receptor NTCP, but the clinical cure rate of pre-S-based vaccines for CHB is limited. Methods: In this study, we designed and prepared multivalent hepatitis B therapeutic mRNA vaccines encoding three hepatitis B surface antigen proteins (L, M, and S) at the cell membrane, verified via in vitro transfection and expression experiments. An in vivo immunization experiment in HBV transgenic (Tg) mice was first completed. Subsequently, an adeno-associated virus plasmid vector carrying the HBV1.2-fold genome (pAAV HBV1.2) model and the adeno-associated virus vector carrying HBV1.3-fold genome (rAAV HBV1.3) model were constructed and immunized with mRNA vaccines. The HBV antigen, antibodies, and HBV DNA in serum were detected. Indirect (enzyme-linked immunosorbent assay) ELISA were made to analyze the activated antigen-specific IgG in HBV Tg mice. Antigen-dependent T-cell activation experiments were carried out, as well as the acute toxicity tests in mice. Results: The L protein/pre-S antigens could be stably presented at the cell membrane with the support of the S protein (and M protein). After vaccinations, the vaccines effectively reactivated the production of high levels of HBsAb, disrupted immune tolerance, and activated the production of high-affinity antibodies against structural pre-S antigen in HBV Tg mice. The HBsAg seroconversion and serum HBV DNA clearance were achieved in two HBV mice models. Furthermore, pre-S antigen-dependent T-cell response against HBV infection was confirmed. The therapeutic vaccine also showed safety in mice. Conclusions: A novel therapeutic mRNA vaccine was developed to break through HBsAg-mediated immune tolerance and treat CHB by stably presenting the pre-S antigen at the membrane, and the vaccine has great potential for the functional cure of CHB. Full article

Background and Aims: Chronic hepatitis B virus (HBV) infection is a global public health challenge since more than 250 million individuals are affected worldwide. Since different treatment modalities are available and not all patients are candidates for antiviral treatment, biomarkers that potentially predict the possibility of HBsAg clearance and seroconversion may be useful in clinical practice. Patients and methods: In this retrospective study, we aimed to identify factors positively correlated with HBsAg seroconversion in a large cohort of 371 chronic hepatitis B patients treated at a German tertial center between 2005 and 2020. Results: Seroconversion occurred in 25/371 (6.7%) and HBsAg loss in 29/371 patients (7.8%) with chronic HBV infection. Antiviral therapy was associated with a lower chance of seroconversion (seroconversion antiviral therapy 14/260 (5.4%) vs. therapy-naïve patients 11/111 (9.9%), p = 0.027). Seroconversion rates were higher in patients with (very) low titers of HBV DNA (best cut-off value 357 IU/mL) and quantitative HBsAg. The best cut-off value with regard to seroconversion was 357 IU/mL for HBV DNA (AUC 0.693 (95%-CI 0.063–0.422), sensitivity 0.714, specificity 0.729; p < 0.0005) and 33,55 IU/mL for HBsAg (AUC 0.794 (95%-CI 0.651–0.937), sensitivity 0.714, specificity 0.949; p < 0.0005). However, male gender was positively associated with seroconversion (seroconversion: males 7.6% vs. females 2.7%, p = 0.036). Conclusions: Treatment-naïve male chronic HBV patients with low viral load and inflammatory activity have the best chance to achieve seroconversion. In the absence of cirrhosis, antiviral therapy should therefore not be performed in this patient collective. Full article

Infection with the hepatitis B virus (HBV) is highly prevalent globally. Over 250 million people suffer from chronic hepatitis B, and more than 800,000 patients die each year due to hepatitis B complications, including liver cancer. Although protective HBV vaccines are recommended for all newborns, global coverage is suboptimal. In adults, sexual transmission is by far the most frequent route of contagion. The WHO estimates that 1.5 million new HBV infections occur annually. Oral nucleos(t)ide analogues entecavir and tenofovir are the most frequent antivirals prescribed as HBV therapy. Almost all patients adherent to the medication achieve undetectable plasma viremia beyond 6 months of monotherapy. However, less than 5% achieve anti-HBs seroconversion, and viral rebound occurs following drug discontinuation. Therefore, nucleos(t)ide analogues need to be lifelong. New long-acting formulations of tenofovir and entecavir are being developed that will maximize treatment benefit and overcome adherence barriers. Furthermore, new antiviral agents are in development, including entry inhibitors, capside assembly modulators, and RNA interference molecules. The use of combination therapy pursues a functional HBV cure, meaning it is negative for both circulating HBV-DNA and HBsAg. Even when this goal is achieved, the cccDNA reservoir within infected hepatocytes remains a signal of past infection, and HBV can reactivate under immune suppression. Therefore, new gene therapies, including gene editing, are eagerly being pursued to silence or definitively disrupt HBV genomes within infected hepatocytes and, in this way, ultimately cure hepatitis B. At this time, three actions can be taken to push HBV eradication globally: (1) expand universal newborn HBV vaccination; (2) perform once-in-life testing of all adults to identify susceptible HBV persons that could be vaccinated (or re-vaccinated) and unveil asymptomatic carriers that could benefit from treatment; and (3) provide earlier antiviral therapy to chronic HBV carriers, as being aviremic reduces the risk of both clinical progression and transmission. Full article

Several antiviral treatment regimens for chronic hepatitis B (CHB) virus infection have been shown to be effective in suppressing viral load and reducing the risk of hepatocellular injury and its complications. It has been hypothesized that high levels of circulating HBV surface antigen(s) may lead to immune tolerance against HBV and contribute to chronic carriership. Conversely, low-level HBsAg may create a window for the reconstitution of an HBV-specific immune response through vaccination and control of infection. Previous studies in non-responders to yeast-derived HBV vaccines, using a third-generation pre-S/S vaccine, have led to up to 95% anti-HBs seroconversion. This report evaluates the long-term outcome after experimental vaccination with a pre-S/S HBV vaccine intended as a therapeutic intervention in chronic HBV carriers. Four low-level HBsAg carriers (<500 IU/mL) were vaccinated three to seven times with 20 μg PreHevbrio^R. Three out of four carriers eliminated HBsAg completely and seroconverted to anti-HBs. One patient seroconverted to anti-HBs but remained with a borderline HBsAg titer (10 IU/mL). Serum anti-HBs levels following repeated vaccination varied between 27 and >1000 IU/L, respectively. Long-term observation (>6 years) showed that after discontinuing NUC treatment for at least two years, HBsAg and HBV DNA remained negative with anti-HBs positive titers ranging between 80 and >1000 IU/L. Based on our preliminary observations, there is a rationale to further evaluate the role of this vaccine as a therapeutic agent. Full article

Background/Objectives: Currently, there are insufficient data to recommend the treatment of patients with hepatitis B e antigen (HBeAg)-negative chronic infection who have normal ALT and low HBV DNA, since the prognosis is generally regarded as favorable. The aim of this pilot study was to determine whether the use of tenofovir disoproxil fumarate (TDF) 300 mg/day for 3 years was able to achieve functional cure (HBsAg loss) and HBsAg seroconversion in HBeAb-positive individuals. Methods: Fifty patients not on antiviral therapy (40% men, mean age 48.9 ± 10.9 years, 84% Asians) with minimal fibrosis were enrolled. Results: TDF reduced HBV DNA significantly to undetectable levels after 6 months. Overall, 48.3% of inactive carriers (baseline HBV DNA < 2000 IU/mL) remained HBV DNA negative 6 months after treatment withdrawal, which was significantly higher than the 5.6% in those who were not inactive carriers (baseline HBV DNA ≥ 2000 IU/mL) (p = 0.003). The HBsAg levels did not drop throughout the study period with no difference between inactive carriers versus those who were not. Five inactive carriers achieved functional cure, but none of these were amongst those who were not inactive carriers. No renal dysfunction or ALT flare on treatment withdrawal was observed. Conclusions: TDF could potentially be used to induce functional cure in patients who are inactive carriers with normal ALT, low HBV DNA and without advanced fibrosis. Full article

Background: The hepatitis B core-related antigen (HBcrAg) correlates with HBV DNA in patients with chronic HBV infection without antiviral treatment. Its utility in monitoring patients during and after the cessation of nucleos(t)ide analog (NA) treatment is unknown. Methods: The levels of HBcrAg were longitudinally determined in two cohorts of chronic HBV-infected patients with (A) newly started NA treatment or (B) after NA cessation during a median follow up (FU) of 60 months or 48 weeks, respectively. The correlation of HBcrAg and HBV DNA and the predictive value for HBeAg seroconversion and HBsAg loss were evaluated. Results: Fifty-six patients with newly-started NA treatment and 22 patients with NA cessation were identified. HBcrAg and HBV DNA strongly correlated before NA treatment (r = 0.77, p < 0.0001) and at virological relapse (0.66, p = 0.0063). At the individual level, the discrepant kinetics of HBcrAg and HBV DNA became evident. During NA treatment, 33% (6/18) and 9% (5/56) of patients showed HBeAg seroconversion or HBsAg loss/HBsAg < 100 IU/mL, respectively. Low levels of HBcrAg were associated with these endpoints. Conclusion: HBcrAg levels before antiviral treatment help to identify patients with chances of HBsAg loss or HBeAg seroconversion. However, its utility in replacing quantitative HBV DNA to evaluate treatment efficacy or virological relapse off-treatment is limited. Full article

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. Full article

The immune system in humans is regulated by the circadian rhythm. Published studies have reported that the time of vaccination is associated with the immune response to vaccine for some pathogens. Our study aimed to evaluate the association between time of dose administration of challenge HBV vaccine and seroconversion for anti-HBs in medical students vaccinated at birth who were found to be unprotected at pre-training screening. Humoral protection for HBV was assessed in 885 medical students vaccinated during childhood. In total, 359 (41.0%) of them showed anti-HBs titer < 10 UI/mL and received a challenge dose of HBV vaccine followed by post-vaccination screening 30–60 days later. The challenge dose elicited a protective immune response (anti-HBs IgG titer > 10 UI/mL) in 295 (83.8%) individuals. Seroconversion was significantly associated with female gender and time of vaccination after controlling for age group and nationality at logistic regression analysis. Students who received the booster dose in the morning had a higher response rate than those who received the vaccine in the afternoon (OR 1.93; 95% C.I. 1.047–3.56: p < 0.05). This finding suggests that morning administration of the HBV booster may result in a better immune response in susceptible individuals. Full article

The immune system acts as an intricate apparatus that is dedicated to mounting a defense and ensures host survival from microbial threats. To engage this faceted immune response and provide protection against infectious diseases, vaccinations are a critical tool to be developed. However, vaccine responses are governed by levels that, when interrogated, separately only explain a fraction of the immune reaction. To address this knowledge gap, we conducted a feasibility study to determine if multi-view modeling could aid in gaining actionable insights on response markers shared across populations, capture the immune system’s diversity, and disentangle confounders. We thus sought to assess this multi-view modeling capacity on the responsiveness to the Hepatitis B virus (HBV) vaccination. Seroconversion to vaccine-induced antibodies against the HBV surface antigen (anti-HBs) in early converters (n = 21; <2 months) and late converters (n = 9; <6 months) and was defined based on the anti-HBs titers (>10IU/L). The multi-view data encompassed bulk RNA-seq, CD4+ T-cell parameters (including T-cell receptor data), flow cytometry data, and clinical metadata (including age and gender). The modeling included testing single-view and multi-view joint dimensionality reductions. Multi-view joint dimensionality reduction outperformed single-view methods in terms of the area under the curve and balanced accuracy, confirming the increase in predictive power to be gained. The interpretation of these findings showed that age, gender, inflammation-related gene sets, and pre-existing vaccine-specific T-cells could be associated with vaccination responsiveness. This multi-view dimensionality reduction approach complements clinical seroconversion and all single modalities. Importantly, this modeling could identify what features could predict HBV vaccine response. This methodology could be extended to other vaccination trials to identify the key features regulating responsiveness. Full article

Hepatitis B (HB) vaccination is recommended for people with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). We aimed to assess the immune response to the HB vaccine and associated factors using the standard vaccination schedule among people with HIV (PWH) in China. A prospective study was carried out from 2016 to 2020 in Beijing, China. PWH were given three 20 μg doses of recombinant HB vaccine at 0, 1, and 6 months. Blood samples were taken within 4–6 weeks after each dose to evaluate the anti-HBs levels. A total of 312 participants completed vaccination and serologic testing. The seroconversion (anti-HBs ≥ 10 IU/L) rates following the first, second, and third doses of the vaccine were 35.6% (95% CI: 30.3–40.9%), 55.1% (95% CI: 49.6–60.7%), and 86.5% (95% CI: 82.8–90.3%), respectively, and the geometric means of the anti-HBs titers were 0.8 IU/L (95% CI: 0.5–1.6 IU/L), 15.7 IU/L (95% CI: 9.4–26.3 IU/L), and 241.0 IU/L (95% CI: 170.3–341.1 IU/L), respectively. In multivariate analysis, after three doses of vaccination, age, CD4 cell count, and HIV-RNA viral load were significantly associated with strong, moderate, and weak response, respectively. These findings confirm that these personal health conditions are related to the HB response. HB vaccination in PWH using the standard schedule was still highly effective in the context of early treatment initiation, especially among participants aged 30 years and younger. Full article

Background: Children with chronic kidney disease (CKD), particularly those who require hemodialysis (HD), are at high risk of hepatitis B virus (HBV) infection. The HBV vaccine non-/hypo-response rate among HD children remains high, and it is critical to investigate the influencing factors and their linkages. The aim of this study was to identify the pattern of HB vaccination response in HD children and to analyze the interference of various clinical and biomedical factors with the immunological response to HB vaccination. Methods: This cross-sectional study included 74 children on maintenance hemodialysis, aged between 3 and 18 years. These children were subjected to complete clinical examination and laboratory investigations. Results: Out of a total of 74 children with HD, 25 (33.8%) were positive for the HCV antibody. Regarding the immunological response to hepatitis B vaccine, 70% were non-/hypo-responders (≤100 IU/mL) and only 30% mounted a high-level response (more than 100 IU/mL). There was a significant relation between non-/hypo-response and sex, dialysis duration, and HCV infection. Being on dialysis for more than 5 years and being HCV Ab-positive were independent variables for non-/hypo-response to HB vaccine. Conclusions: Children with CKD on regular HD have poor seroconversion rates in response to the HBV vaccine, which were influenced by dialysis duration and HCV infection. Full article

Little is known about the treatment of patients with hepatitis B surface antigen (HBsAg) recurrence after being clinically cured by peginterferon alpha(peg-IFN-α)-based regimens. This study aimed to investigate the efficacy and safety of peg-IFNα-2b in re-treating patients with HBsAg recurrence after stopping peg-IFN α-based regimens. In this two-center, prospective observational study, 33 patients with HBsAg recurrence after stopping peg-IFN α-based regimens were enrolled and re-treated with an individualized course of peg-IFN α-2b. The hepatitis B virus (HBV) vaccine could be injected immediately after HBsAg clearance, according to patients’ willingness. All patients were monitored and followed-up for 48 weeks after peg-IFN α-2b re-treatment stop. The primary endpoint was HBsAg clearance at the end of follow-up. At baseline, all patients had HBsAg levels of <10 IU/mL and undetectable HBV DNA, with the median HBsAg level of 1.66 (0.56–2.87) IU/mL. After a median of 24 (24–30) weeks of peg-IFN α-2b re-treatment, 87.9% (29/33) of the patients achieved HBsAg clearance again and 66.7% (22/33) of the patients achieved HBsAg seroconversion. At the end of follow-up, the HBsAg clearance and HBsAg seroconversion rates decreased to 78.8% (26/33) and 51.5% (17/33), respectively. Furthermore, 88.9% (16/18) of the patients with HBsAg clearance benefited from receiving the HBV vaccine therapy. Generally, both peg-IFN α-2b and HBV vaccine therapy were well tolerated. A high functional cure rate can be achieved by a short-course of peg-IFN α-2b re-treatment in patients with HBsAg recurrence after stopping peg-IFN α-based regimens. Furthermore, injecting HBV vaccine is beneficial after HBsAg clearance. Full article

Chronic infection with hepatitis B virus (HBV) represents one of the main causes of the development of cirrhosis and its complications. Treatment with potent third-generation nucleos(t)ide analogues (NUCs) results in >99% HBV DNA undetectability, and prevents fibrosis progression and liver-related complications. However, NUCs are not able to induce the so-called functional cure, which is hepatitis B surface antigen (HBsAg) loss and anti-HBs seroconversion. Consequently, NUC treatment is currently intended as being long-term or lifelong, resulting in the need for clinical monitoring and potentially suffering from compliance issues. Consequently, drug development in HBV has the goal of developing new agents in order to achieve a functional cure for HBV. Currently, the three main strategies include the following: inhibition of viral replication, inhibition of viral antigens, and immune modulation. This review summarizes the most recent updates concerning HBV compounds among these three main classes. Full article

The Common Specifications/EU 2017/746 regulation for market approval of class D in vitro diagnostic devices (IVDs) intended for detection of blood borne viruses requires testing of the International Standard and 10–30 seroconversion panels to demonstrate ‘state of the art’ assay performance. We examined whether these requirements for performance evaluation are reasonable for HBV-DNA and HBsAg assays. For this purpose, we quantified HBsAg and HBV-DNA (genotype A) in the ramp-up phase of five seroconversion panels and demonstrated a remarkably parallel increase in the Log concentration of both analytes over time. Testing of seroconversion panels by three nucleic acid amplification technology (NAT) methods in multiple replicates and probit analysis with sufficient critical samples from all five panels taken together showed detection limits in copies/mL that were comparable to those on a HBV-DNA genotype A standard dilution panel. This indicates that the viral doubling time in the ramp-up phase is equal above and below the quantification limit of the viral load assay. The geometric mean HBsAg (PRISM) cutoff crossing point was 20 days later than the 50% NAT (Ultrio Plus) conversion point equivalent to 1500 (range: 1100–2200) and 4.8 (CI: 3.7–6.4) HBV-DNA copies/mL, respectively. Analytical sensitivity data of different NAT assay versions obtained over a decade demonstrated that the detection limit on the International Standard is not representative of all genotyped reference samples. From our detailed mathematical analysis, we conclude that HBV-DNA and HBsAg standard dilution series are functionally equivalent to seroconversion panels. A general requirement of a 95% detection limit ≤100 HBV-DNA copies/mL for different viral genotypes would be a better-defined regulation for EU market approval of NAT blood screening assays than the testing of multiple seroconversion panels to claim ‘state of the art’ performance. Full article