Editorial

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Open AccessEditorial

Special Issue “Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease”

by Thomas Tu and Mark W. Douglas

Viruses 2023, 15(11), 2173; https://doi.org/10.3390/v15112173 - 30 Oct 2023

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Chronic hepatitis B affects >300 million people worldwide and is a major cause of liver disease, causing ~800,000 deaths each year [...] Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

Research

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18 pages, 874 KiB

Open AccessArticle

Possible Association between Genetic Diversity of Hepatitis B Virus and Its Effect on the Detection Rate of Hepatitis B Virus DNA in the Placenta and Fetus

by Sirinart Sirilert, Pattara Khamrin, Kattareeya Kumthip, Rungnapa Malasao, Niwat Maneekarn and Theera Tongsong

Viruses 2023, 15(8), 1729; https://doi.org/10.3390/v15081729 - 12 Aug 2023

Cited by 1 | Viewed by 1207

Abstract

Background: The prevalence of HBV infection and HBV genotypes varies from country to country, and the role of HBV genotypes in the presence of HBV in the placenta and fetus has never been explored. This study was conducted to (1) identify HBV [...] Read more.

Background: The prevalence of HBV infection and HBV genotypes varies from country to country, and the role of HBV genotypes in the presence of HBV in the placenta and fetus has never been explored. This study was conducted to (1) identify HBV genotypes, and their frequencies, that infected Northern Thai pregnant women; (2) evaluate the association between HBV genotypes and the detection rate of HBV DNA in the placenta and fetus; (3) evaluate the association between specific mutations of the HBV genome and HBV DNA detection in placental tissue; and (4) identify the mutation of the HBV genome that might occur between maternal blood, placenta, and cord blood. Methods: Stored samples of the maternal blood, placental tissue, and cord blood that were collected from 145 HBsAg-positive pregnant Thai women were analyzed to identify HBV DNA. Results: Approximately 25% of infected mothers had fetal HBV DNA detection, including cases with concomitant HBV DNA detection in the placenta (77.3%). A total of 11.7% of cases with placental detection had no HBV DNA detection in the maternal blood, indicating that the placenta could be a site of HBV accumulation. Of the 31 HBV-positive blood samples detected by nested PCR, the detected strains were subgenotype C1 (77.4%), subgenotype B9 (9.7%), and subgenotype C2, B2, B4, and recombinant B4/C2 (3.2% for each). Genotype B had a trend in increased risk of placental HBV DNA detection compared to genotype C, with a relative risk of 1.40 (95% CI: 1.07–1.84). No specific point mutation had a significant effect on HBV DNA detection in placental tissue. Mutation of C454T tended to enhance HBV DNA detection in placental tissue, whereas T400A tended to have a lower detection rate. No mutation was detected in different sample types collected from the same cases. Conclusions: HBV DNA detection in the fetus was identified in approximately 25% of HBV-positive mothers, associated with the presence of HBV in the placenta in most cases. The placenta could possibly be a site of HBV accumulation. Subgenotype C1 was the most common subgenotype, followed by subgenotype B9. HBV genotype B possibly had a higher trend in intrauterine detection than HBV genotype C. Mutation is unlikely to occur during intrauterine exposure. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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16 pages, 10750 KiB

Open AccessArticle

Hepatitis B Virus X Protein Modulates p90 Ribosomal S6 Kinase 2 by ERK to Promote Growth of Hepatoma Cells

by Ning Han, Qingbo Zhang, Xiaoqiong Tang, Lang Bai, Libo Yan and Hong Tang

Viruses 2023, 15(5), 1182; https://doi.org/10.3390/v15051182 - 17 May 2023

Cited by 1 | Viewed by 1477

Abstract

Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), one of the most prevalent malignant tumors worldwide that poses a significant threat to human health. The multifunctional regulator known as Hepatitis B virus X-protein (HBx) interacts with host factors, [...] Read more.

Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), one of the most prevalent malignant tumors worldwide that poses a significant threat to human health. The multifunctional regulator known as Hepatitis B virus X-protein (HBx) interacts with host factors, modulating gene transcription and signaling pathways and contributing to hepatocellular carcinogenesis. The p90 ribosomal S6 kinase 2 (RSK2) is a member of the 90 kDa ribosomal S6 kinase family involved in various intracellular processes and cancer pathogenesis. At present, the role and mechanism of RSK2 in the development of HBx-induced HCC are not yet clear. In this study, we found that HBx upregulates the expression of RSK2 in HBV-HCC tissues, HepG2, and SMMC-7721 cells. We further observed that reducing the expression of RSK2 inhibited HCC cell proliferation. In HCC cell lines with stable HBx expression, RSK2 knockdown impaired the ability of HBx to promote cell proliferation. The extracellularly regulated protein kinases (ERK) 1/2 signaling pathway, rather than the p38 signaling pathway, mediated HBx-induced upregulation of RSK2 expression. Additionally, RSK2 and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) were highly expressed and positively correlated in HBV-HCC tissues and associated with tumor size. This study showed that HBx upregulates the expression of RSK2 and CREB by activating the ERK1/2 signaling pathway, promoting the proliferation of HCC cells. Furthermore, we identified RSK2 and CREB as potential prognostic markers for HCC patients. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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16 pages, 4339 KiB

Open AccessArticle

Super-Resolution Microscopy Analysis of Hepatitis B Viral cccDNA and Host Factors

by Phuong Thi Bich Doan, Kouki Nio, Tetsuro Shimakami, Kazuyuki Kuroki, Ying-Yi Li, Saiho Sugimoto, Hideo Takayama, Hikari Okada, Shuichi Kaneko, Masao Honda and Taro Yamashita

Viruses 2023, 15(5), 1178; https://doi.org/10.3390/v15051178 - 16 May 2023

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Abstract

Infection with hepatitis B virus (HBV) cannot be cured completely because of the persistence of covalently closed circular DNA (cccDNA). We previously found that the host gene dedicator of cytokinesis 11 (DOCK11) was required for HBV persistence. In this study, we further investigated [...] Read more.

Infection with hepatitis B virus (HBV) cannot be cured completely because of the persistence of covalently closed circular DNA (cccDNA). We previously found that the host gene dedicator of cytokinesis 11 (DOCK11) was required for HBV persistence. In this study, we further investigated the mechanism that links DOCK11 to other host genes in the regulation of cccDNA transcription. cccDNA levels were determined by quantitative real-time polymerase chain reaction (qPCR) and fluorescence in situ hybridization (FISH) in stable HBV-producing cell lines and HBV-infected PXB-cells®. Interactions between DOCK11 and other host genes were identified by super-resolution microscopy, immunoblotting, and chromatin immunoprecipitation. FISH facilitated the subcellular localization of key HBV nucleic acids. Interestingly, although DOCK11 partially colocalized with histone proteins, such as H3K4me3 and H3K27me3, and nonhistone proteins, such as RNA Pol II, it played limited roles in histone modification and RNA transcription. DOCK11 was functionally involved in regulating the subnuclear distribution of host factors and/or cccDNA, resulting in an increase in cccDNA closely located to H3K4me3 and RNA Pol II for activating cccDNA transcription. Thus, it was suggested that the association of cccDNA-bound Pol II and H3K4me3 required the assistance of DOCK11. DOCK11 facilitated the association of cccDNA with H3K4me3 and RNA Pol II. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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12 pages, 411 KiB

Open AccessArticle

Factors Associated with Disagreement of Fibrosis Stages between 2D-Shear Wave Elastography and Transient Elastography in Chronic Hepatitis B

by Fernanda Gdalevici Miodownik, Ana Carolina Cardoso, Leticia Cancella Nabuco, Cibele Franz, Renata Perez and Cristiane Alves Villela-Nogueira

Viruses 2023, 15(4), 846; https://doi.org/10.3390/v15040846 - 26 Mar 2023

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Abstract

Introduction and objectives: The agreement of elastography techniques in chronic Hepatitis B (CHB) needs evaluation. We aimed to evaluate, in CHB, the agreement between transient elastography (TE) and two-dimensional shear wave elastography (2D-SWE), analyzing the factors related to the disagreement of measures. Materials [...] Read more.

Introduction and objectives: The agreement of elastography techniques in chronic Hepatitis B (CHB) needs evaluation. We aimed to evaluate, in CHB, the agreement between transient elastography (TE) and two-dimensional shear wave elastography (2D-SWE), analyzing the factors related to the disagreement of measures. Materials and methods: CHB patients underwent liver stiffness measures with both TE and 2D-SWE on the same day. For concordance analysis, we defined liver fibrosis as F0/1 vs. F ≥ 2, F0/1-F2 vs. F ≥ 3 and F0/1-F2-F3 vs. F4 for both methods. Logistic regression analysis was used to identify the variables independently associated with the disagreement between methods. RESULTS: A total of 150 patients were enrolled. Liver fibrosis categorization according to TE was: F0-F1 = 73 (50.4%), F ≥ 2 = 40 (27.6%), F ≥ 3 = 21 (14.5%) and F4 = 11 (7.6%), and according to 2D-SWE was: F0/F1 = 113 (77.9%), F ≥ 2 = 32 (22.1%), F≥ 3 = 25 (17.2%) and F4 = 11 (7.6%). It was observed that 20.0% of the sample had steatosis (CAP≥ 275 dB/m). TE and SD-SWE estimated equal fibrosis stages in 79.3% of cases. Spearman's correlation coefficient was 0.71 (p < 0.01). Kappa values for F ≥ 2, F ≥ 3 and F = 4 were: 0.78, p < 0.001; 0.73, p < 0.001; and 0.64, p < 0.001, respectively. Diabetes mellitus (DM) (OR 5.04; 95%CI: 1.89–13.3; p < 0.001) and antiviral treatment (OR 6.79; 95%CI: 2.33–19.83; p < 0.001) were independently associated with discordance between both methods. Conclusions: In CHB, there is strong correlation and good agreement between TE and 2D-SWE in identifying fibrosis stages. Diabetes mellitus and antiviral therapy may impact the agreement of stiffness measures obtained with these elastographic methods. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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12 pages, 1802 KiB

Open AccessArticle

A Novel and Simplified Score for Determining Treatment Eligibility for Patients with Chronic Hepatitis B

by Tanawat Geeratragool, Pisit Tangkijvanich, Supot Nimanong, Siwaporn Chainuvati, Phunchai Charatcharoenwitthaya, Tawesak Tanwandee and Watcharasak Chotiyaputta

Viruses 2023, 15(3), 724; https://doi.org/10.3390/v15030724 - 10 Mar 2023

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Abstract

Background: International guidelines for hepatitis B infection (HBV) recommend initiating antiviral treatment based on viral replication with inflammation or fibrosis. HBV viral loads and liver fibrosis measurements are not widely available in resource-limited countries. Aim: To develop a novel scoring system for the [...] Read more.

Background: International guidelines for hepatitis B infection (HBV) recommend initiating antiviral treatment based on viral replication with inflammation or fibrosis. HBV viral loads and liver fibrosis measurements are not widely available in resource-limited countries. Aim: To develop a novel scoring system for the initiation of antiviral treatment in HBV-infected patients. Methods: We examined 602 and 420 treatment-naïve, HBV mono-infected patients for derivation and validation cohorts. We performed regression analysis to identify parameters associated with the initiation of antiviral treatment based on the European Association for the Study of the Liver (EASL) guidelines. The novel score was developed based on these parameters. Results: The novel score (HePAA) was based on HBeAg (hepatitis B e-antigen), the platelet count, alanine transaminase, and albumin. The HePAA score showed excellent performance, with AUROC values of 0.926 (95% CI, 0.901–0.950) for the derivation cohort and 0.872 (95% CI, 0.833–0.910) for the validation cohort. The optimal cutoff was ≥3 points (sensitivity, 84.9%; specificity, 92.6%). The HePAA score performed better than the World Health Organization (WHO) criteria and the Risk Estimation for HCC in Chronic Hepatitis B (REACH-B) score, and it performed similarly to the Treatment Eligibility in Africa for HBV (TREAT-B) score. Conclusions: The HePAA scoring system is simple and accurate for chronic hepatitis B treatment eligibility in resource-limited countries. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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12 pages, 554 KiB

Open AccessArticle

Clinical Outcomes and Quantitative HBV Surface Antigen Levels in Diverse Chronic Hepatitis B Patients in Canada: A Retrospective Real-World Study of CHB in Canada (REVEAL-CANADA)

by Carla S. Coffin, Sarah Haylock-Jacobs, Karen Doucette, Alnoor Ramji, Hin Hin Ko, David K. Wong, Magdy Elkhashab, Robert Bailey, Julia Uhanova, Gerald Minuk, Keith Tsoi, Alexander Wong, Mang M. Ma, Edward Tam, Mayur Brahmania, Carmine Nudo, Julie Zhu, Christopher F. Lowe, Carla Osiowy, B. Cord Lethebe, Stephen E. Congly, Eric K. H. Chan, Angelina Villasis-Keever, Urbano Sbarigia, Curtis L. Cooper and Scott Fung Show full author list Hide full author list

Viruses 2022, 14(12), 2668; https://doi.org/10.3390/v14122668 - 29 Nov 2022

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Abstract

Background: Hepatitis B surface antigen (HBsAg) loss is associated with improved clinical outcomes for individuals with chronic hepatitis B (CHB); however, the effects of varying HBsAg levels on clinical outcomes in diverse cohorts are understudied. Methods: In this cross-sectional, multicentre, retrospective study, the [...] Read more.

Background: Hepatitis B surface antigen (HBsAg) loss is associated with improved clinical outcomes for individuals with chronic hepatitis B (CHB); however, the effects of varying HBsAg levels on clinical outcomes in diverse cohorts are understudied. Methods: In this cross-sectional, multicentre, retrospective study, the data on adult subjects enrolled in the Canadian HBV Network with CHB seen from 1 January 2012 to 30 January 2021 with the treatment and virologic data within 1 year of HBsAg testing were analyzed. Patients were tested for HBsAg using qualitative (for HBsAg-negative samples) and/or commercial quantitative assays. Fibrosis or hepatic necroinflammation was determined by the liver stiffness measurement (LSM). The baseline data were summarized using descriptive statistics and compared by using univariable/multivariable analyses. Results: This study included 844 CHB patients, with a median age of 49.6 years (IQR 40.1–60.5), and 37% were female. In total, 751 patients (78.6%) had known ethnicity data, and 76.7% self-reported as Asian, 11.4% as Black, 6.8% as White, and 4.8% as other. Among the 844 patients, 237 (28.0%) were HBsAg (−) (<LLOQ), 190 (22.5%) had qHBsAg 1–100, 91 (10.8%) had qHBsAg 100–500, 54 (6.4%) had qHBsAg 500–1000, and 272 (32.2%) had qHBsAg >1000 IU/mL. Overall, 80% (682) had known HBeAg status at the last follow-up, and the majority (87.0%) were HBeAg-negative. In addition, 54% (461/844) had prior antiviral therapy, 19.7% of which (16.3, 23.7, n = 91) were HBsAg (−). The treated patients had a lower risk of cirrhosis (16.46, 95% CI 1.89–143.39, p = 0.01) or HCC (8.23, 95% CI 1.01–67.39, p = 0.05) than the untreated patients. A lower proportion of the HBsAg-loss group had cirrhosis (5.7% vs. 10.9%, p = 0.021) and HCC (0.9% vs. 6.2%, p = 0.001). Conclusion: In this retrospective, ethnically diverse cohort study, CHB patients who received antiviral therapy and/or had HBsAg loss were less likely to develop cirrhosis and HCC, confirming the results of the studies in less diverse cohorts. No association was found between the qHBsAg level and fibrosis determined with LSM. Individuals who achieved HBsAg loss had low-level qHBsAg within 1 year of seroclearance. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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13 pages, 1477 KiB

Open AccessArticle

Impact of Hepatitis B Virus Infection, Non-alcoholic Fatty Liver Disease, and Hepatitis C Virus Co-infection on Liver-Related Death among People Tested for Hepatitis B Virus in British Columbia: Results from a Large Longitudinal Population-Based Cohort Study

by Jean Damascene Makuza, Dahn Jeong, Mawuena Binka, Prince Asumadu Adu, Georgine Cua, Amanda Yu, Héctor Alexander Velásquez García, Maria Alvarez, Stanley Wong, Sofia Bartlett, Mohammad Ehsanul Karim, Eric M. Yoshida, Alnoor Ramji, Mel Krajden and Naveed Zafar Janjua

Viruses 2022, 14(11), 2579; https://doi.org/10.3390/v14112579 - 21 Nov 2022

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Abstract

Data on the contribution of hepatitis B virus (HBV) infection and related comorbidities to liver-related mortality in Canada are limited. We assessed the concurrent impact of HBV infection, non-alcoholic fatty liver disease (NAFLD), and hepatitis C virus (HCV) coinfection on liver-related deaths in [...] Read more.

Data on the contribution of hepatitis B virus (HBV) infection and related comorbidities to liver-related mortality in Canada are limited. We assessed the concurrent impact of HBV infection, non-alcoholic fatty liver disease (NAFLD), and hepatitis C virus (HCV) coinfection on liver-related deaths in British Columbia (BC), Canada. We used data from the BC Hepatitis Testers Cohort (BC-HTC). We used Fine–Gray multivariable sub-distributional hazards models to assess the effect of HBV, NAFLD, and HCV coinfection on liver-related mortality, while adjusting for confounders and competing mortality risks. The liver-related mortality rate was higher among people with HBV infection than those without (2.57 per 1000 PYs (95%CI: 2.46, 2.69) vs. 0.62 per 1000 PYs (95%CI: 0.61, 0.64), respectively). Compared with the HBV negative groups, HBV infection was associated with increased liver-related mortality risk in almost all of the subgroups: HBV mono-infection (adjusted subdistribution hazards ratio (asHR) of 3.35, 95% CI 3.16, 3.55), NAFLD with HBV infection, (asHR 12.5, 95% CI 7.08, 22.07), and HBV/HCV coinfection (asHR 8.4, 95% CI 7.62, 9.26). HBV infection is associated with a higher risk of liver-related mortality, and has a greater relative impact on people with NAFLD and those with HCV coinfection. The diagnosis and treatment of viral and fatty liver disease are required to mitigate liver-related morbidity and mortality. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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14 pages, 299 KiB

Open AccessArticle

Exploring the Public Health and Social Implications of Future Curative Hepatitis B Interventions

by Jack Wallace, Jacqueline Richmond, Jessica Howell, Behzad Hajarizadeh, Jennifer Power, Carla Treloar, Peter A. Revill, Benjamin Cowie, Su Wang, Mark Stoové, Alisa Pedrana and Margaret Hellard

Viruses 2022, 14(11), 2542; https://doi.org/10.3390/v14112542 - 17 Nov 2022

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Abstract

Hepatitis B is a significant global health issue where the 296 million people estimated to live with the infection risk liver disease or cancer without clinical intervention. The World Health Organization has committed to eliminating viral hepatitis as a public health threat by [...] Read more.

Hepatitis B is a significant global health issue where the 296 million people estimated to live with the infection risk liver disease or cancer without clinical intervention. The World Health Organization has committed to eliminating viral hepatitis as a public health threat by 2030, with future curative hepatitis B interventions potentially revolutionizing public health responses to hepatitis B, and being essential for viral hepatitis elimination. Understanding the social and public health implications of any cure is imperative for its successful implementation. This exploratory research, using semi-structured qualitative interviews with a broad range of professional stakeholders identifies the public health elements needed to ensure that a hepatitis B cure can be accessed by all people with hepatitis B. Issues highlighted by the experience of hepatitis C cure access include preparatory work to reorientate policy settings, develop resourcing options, and the appropriateness of health service delivery models. While the form and complexity of curative hepatitis B interventions are to be determined, addressing current disparities in cascade of care figures is imperative with implementation models needing to respond to the cultural contexts, social implications, and health needs of people with hepatitis B, with cure endpoints and discourse being contested. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

18 pages, 2567 KiB

Open AccessArticle

Ivermectin Inhibits HBV Entry into the Nucleus by Suppressing KPNA2

by Anna Nakanishi, Hiroki Okumura, Tadahiro Hashita, Aya Yamashita, Yuka Nishimura, Chihiro Watanabe, Sakina Kamimura, Sanae Hayashi, Shuko Murakami, Kyoko Ito, Takahiro Iwao, Akari Ikeda, Tomoyasu Hirose, Toshiaki Sunazuka, Yasuhito Tanaka and Tamihide Matsunaga

Viruses 2022, 14(11), 2468; https://doi.org/10.3390/v14112468 - 08 Nov 2022

Cited by 2 | Viewed by 6360

Abstract

Hepatitis B virus (HBV) specifically infects human hepatocytes and increases the risks of cirrhosis and liver cancer. Currently, nucleic acid analogs are the main therapeutics for chronic hepatitis caused by HBV infection. Although nucleic acid analogs can eliminate HBV DNA by inhibiting HBV [...] Read more.

Hepatitis B virus (HBV) specifically infects human hepatocytes and increases the risks of cirrhosis and liver cancer. Currently, nucleic acid analogs are the main therapeutics for chronic hepatitis caused by HBV infection. Although nucleic acid analogs can eliminate HBV DNA by inhibiting HBV reverse transcriptase, they cannot lead to negative conversion of covalently closed circular DNA (cccDNA) and hepatitis B surface antigen (HBsAg). In this study, we revealed that the antifilarial drug ivermectin suppresses HBV production by a different mechanism from the nucleic acid analog entecavir or Na⁺ taurocholate co-transporting polypeptide-mediated entry inhibitor cyclosporin A. Ivermectin reduced the levels of several HBV markers, including HBsAg, in HBV-infected human hepatocellular carcinoma cells (HepG2-hNTCP-C4 cells) and humanized mouse hepatocytes (PXB hepatocytes). In addition, ivermectin significantly decreased the expression of HBV core protein and the nuclear transporter karyopherin α2 (KPNA2) in the nuclei of HepG2-hNTCP-C4 cells. Furthermore, depletion of KPNA1–6 suppressed the production of cccDNA. These results suggest that KPNA1–6 is involved in the nuclear import of HBV and that ivermectin suppresses the nuclear import of HBV by inhibiting KPNA2. This study demonstrates the potential of ivermectin as a novel treatment for hepatitis B. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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12 pages, 2978 KiB

Open AccessArticle

Prevalence and Genomic Sequence Analysis of Domestic Cat Hepadnavirus in the United States

by Cassidy Stone, Raegan Petch, Roderick B. Gagne, Mary Nehring, Thomas Tu, Julia A. Beatty and Sue VandeWoude

Viruses 2022, 14(10), 2091; https://doi.org/10.3390/v14102091 - 21 Sep 2022

Cited by 12 | Viewed by 2357

Abstract

Hepadnaviruses are partially double-stranded DNA viruses that infect a variety of species. The prototypical virus in this family is the human hepatitis B virus, which chronically infects approximately 400 million people worldwide and is a risk factor for progressive liver disease and liver [...] Read more.

Hepadnaviruses are partially double-stranded DNA viruses that infect a variety of species. The prototypical virus in this family is the human hepatitis B virus, which chronically infects approximately 400 million people worldwide and is a risk factor for progressive liver disease and liver cancer. The first hepadnavirus isolated from carnivores was a domestic cat hepadnavirus (DCH), initially identified in Australia and subsequently detected in cats in Europe and Asia. As with all characterized hepadnaviruses so far, DCH infection has been associated with hepatic disease in its host. Prevalence of this infection in the United States has not been explored broadly. Thus, we utilized conventional and quantitative PCR to screen several populations of domestic cats to estimate DCH prevalence in the United States. We detected DCH DNA in 1 out of 496 animals (0.2%) in the U.S. cohort. In contrast, we detected circulating DCH DNA in 7 positive animals from a cohort of 67 domestic cats from Australia (10.4%), consistent with previous studies. The complete consensus genome of the U.S. DCH isolate was sequenced by Sanger sequencing with overlapping PCR products. An in-frame deletion of 157 bp was identified in the N-terminus of the core open reading frame. The deletion begins at the direct repeat 1 sequence (i.e., the 5′ end of the expected double-stranded linear DNA form), consistent with covalently closed circular DNA resultant from illegitimate recombination described in other hepadnaviruses. Comparative genome sequence analysis indicated that the closest described relatives of the U.S. DCH isolate are those previously isolated in Italy. Motif analysis supports DCH using NTCP as an entry receptor, similar to human HBV. Our work indicates that chronic DCH prevalence in the U.S. is likely low compared to other countries. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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16 pages, 619 KiB

Open AccessArticle

Hepatitis B among University Population: Prevalence, Associated Risk Factors, Knowledge Assessment, and Treatment Management

by Syed Ayaz Kazmi, Abdul Rauf, Mohammed Merae Alshahrani, Ahmed Abdullah Al Awadh, Zahoor Iqbal, Raya Soltane, ElSayed Tag-Eldin, Altaf Ahmad, Zulqarnain Ansari and Zia-ur-Rehman

Viruses 2022, 14(9), 1936; https://doi.org/10.3390/v14091936 - 31 Aug 2022

Cited by 2 | Viewed by 2358

Abstract

Background: Very few studies have been reported on hepatitis B in the State of Azad Jammu and Kashmir, Pakistan, and none of them are specific to the prevalence and causes of hepatitis B spread among educational institutes. This study aimed to estimate the [...] Read more.

Background: Very few studies have been reported on hepatitis B in the State of Azad Jammu and Kashmir, Pakistan, and none of them are specific to the prevalence and causes of hepatitis B spread among educational institutes. This study aimed to estimate the prevalence of hepatitis B infection and its associated risk factors among the University of AJ and K population. Methods: An observational, cross-sectional, and analytical study was conducted with 7015 students and employees. Hepatitis B was detected by rapid immunochromatographic tests (ICTs), enzyme-linked immunosorbent assay (ELISA), and real-time quantitative PCR. A questionnaire and interview method was used to assess the disease knowledge and associated risk factors with hepatitis B through Chi-square, Fisher’s exact test, and paired t-test. Results: Of the participants, 150 (2.13%) were found positive for the hepatitis B surface antigen (57.3% male and 42.7% female). Only 0.3% participants were found fully vaccinated against the hepatitis B virus. Among ethnic groups, the Syed tribe was found more prevalent for hepatitis B infection (40.6%), while use of contaminated mourning blades (95% CI: p = 0.0001) was found as an overlooked risk factor. Hepatitis preventive awareness sessions were found to be very significant (p = 0.0001). Conclusions: The study showed that an overlooked risk factor is playing a key role in the spread of HBV in a tribe living worldwide, which must be addressed globally to eradicate hepatitis B. In Pakistan, a country-wide annual HBV vaccination program should be launched to control hepatitis B. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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16 pages, 1807 KiB

Open AccessArticle

HBx 128–133 Deletion Affecting HBV Mother-to-Child Transmission Weakens HBV Replication via Reducing HBx Level and CP/ENII Transcriptional Activity

by Yarong Song, Ying Lu, Yi Li, Minmin Liu, Hui Zhuang, Jie Li and Jie Wang

Viruses 2022, 14(9), 1887; https://doi.org/10.3390/v14091887 - 26 Aug 2022

Cited by 6 | Viewed by 1526

Abstract

Some infants born to hepatitis B surface antigen (HBsAg)-positive mothers, especially born to hepatitis B e antigen (HBeAg)-positive mothers, can still be infected with hepatitis B virus (HBV) through mother-to-child transmission (MTCT) of HBV and develop chronic HBV infection. At present, the virological [...] Read more.

Some infants born to hepatitis B surface antigen (HBsAg)-positive mothers, especially born to hepatitis B e antigen (HBeAg)-positive mothers, can still be infected with hepatitis B virus (HBV) through mother-to-child transmission (MTCT) of HBV and develop chronic HBV infection. At present, the virological factors affecting HBV MTCT are still unclear. In this study, we found that the mutation rates of amino acids in the HBV X region were high, and there were obvious differences between the immunoprophylaxis success group and the immunoprophylaxis failure group of HBeAg-positive mothers. Specifically, the mutation rate of HBx 128–133 deletion (x128–133del) or corresponding nucleotide 1755–1772 deletion (nt1755–1772del) in the immunoprophylaxis success group was significantly higher than that in the immunoprophylaxis failure group. Furthermore, we found that x128–133del could weaken HBV replication by reducing the level of the HBx protein due to the increased proteasome-dependent degradation of HBx protein, and the transcriptional activity of HBV core promoter (CP)/enhancer II (ENII) due to the attenuated binding capacity of hepatocyte nuclear factor 4α (HNF4α) to HBV CP/ENII. This study suggests that x128–133del may contribute to immunoprophylaxis success, which may be helpful in clarifying the virological mechanism affecting HBV MTCT and formulating an optimal immunization strategy for children born to HBeAg-positive mothers. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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Review

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20 pages, 2230 KiB

Open AccessReview

The Complex Role of HBeAg and Its Precursors in the Pathway to Hepatocellular Carcinoma

by Kiyasha Padarath, Aurélie Deroubaix and Anna Kramvis

Viruses 2023, 15(4), 857; https://doi.org/10.3390/v15040857 - 27 Mar 2023

Cited by 1 | Viewed by 2535

Abstract

Hepatitis B virus (HBV) is one of the seven known human oncogenic viruses and has adapted to coexist with a single host for prolonged periods, requiring continuous manipulation of immunity and cell fate decisions. The persistence of HBV infection is associated with the [...] Read more.

Hepatitis B virus (HBV) is one of the seven known human oncogenic viruses and has adapted to coexist with a single host for prolonged periods, requiring continuous manipulation of immunity and cell fate decisions. The persistence of HBV infection is associated with the pathogenesis of hepatocellular carcinoma, and various HBV proteins have been implicated in promoting this persistence. The precursor of hepatitis e antigen (HBeAg), is translated from the precore/core region and is post-translationally modified to yield HBeAg, which is secreted in the serum. HBeAg is a non-particulate protein of HBV and can act as both a tolerogen and an immunogen. HBeAg can protect hepatocytes from apoptosis by interfering with host signalling pathways and acting as a decoy to the immune response. By evading the immune response and interfering with apoptosis, HBeAg has the potential to contribute to the hepatocarcinogenic potential of HBV. In particular, this review summarises the various signalling pathways through which HBeAg and its precursors can promote hepatocarcinogenesis via the various hallmarks of cancer. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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19 pages, 1808 KiB

Open AccessReview

Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects

by Andrew Vaillant

Viruses 2022, 14(9), 2052; https://doi.org/10.3390/v14092052 - 16 Sep 2022

Cited by 9 | Viewed by 2796

Abstract

Three types of oligonucleotide-based medicines are under clinical development for the treatment of chronic HBV infection. Antisense oligonucleotides (ASOs) and synthetic interfering RNA (siRNA) are designed to degrade HBV mRNA, and nucleic acid polymers (NAPs) stop the assembly and secretion of HBV subviral [...] Read more.

Three types of oligonucleotide-based medicines are under clinical development for the treatment of chronic HBV infection. Antisense oligonucleotides (ASOs) and synthetic interfering RNA (siRNA) are designed to degrade HBV mRNA, and nucleic acid polymers (NAPs) stop the assembly and secretion of HBV subviral particles. Extensive clinical development of ASOs and siRNA for a variety of liver diseases has established a solid understanding of their pharmacodynamics, accumulation in different tissue types in the liver, pharmacological effects, off-target effects and how chemical modifications and delivery approaches affect these parameters. These effects are highly conserved for all ASO and siRNA used in human studies to date. The clinical assessment of several ASO and siRNA compounds in chronic HBV infection in recent years is complicated by the different delivery approaches used. Moreover, these assessments have not considered the large clinical database of ASO/siRNA function in other liver diseases and known off target effects in other viral infections. The goal of this review is to summarize the current understanding of ASO/siRNA/NAP pharmacology and integrate these concepts into current clinical results for these compounds in the treatment of chronic HBV infection. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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13 pages, 4132 KiB

Open AccessSystematic Review

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

by Cesar Henriquez-Camacho, Ana Isabel Hijas-Gomez, Carlos Risco Risco, Maria Angeles Ruiz Lapuente, Rosa Escudero-Sanchez and Victor Moreno Cuerda

Viruses 2023, 15(11), 2241; https://doi.org/10.3390/v15112241 - 10 Nov 2023

Cited by 2 | Viewed by 994

Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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9 pages, 591 KiB

Open AccessHypothesis

The Origin of Capsid-Derived Immune Complexes and Their Impact on HBV-Induced Liver Diseases

by Xiaonan Zhang, Yijie Tang, Min Wu, Cong Wang, Lyuyin Hu and Zhanqing Zhang

Viruses 2022, 14(12), 2766; https://doi.org/10.3390/v14122766 - 12 Dec 2022

Cited by 1 | Viewed by 1615

Abstract

Over 240 million people worldwide are chronically infected with Hepatitis B Virus (HBV), a hepatotropic DNA virus with an evolutionary root of over 400 million years. Persistent HBV infection exhibits distinct and diverse phases of disease, from minimal liver pathology to fulminant Hepatitis, [...] Read more.

Over 240 million people worldwide are chronically infected with Hepatitis B Virus (HBV), a hepatotropic DNA virus with an evolutionary root of over 400 million years. Persistent HBV infection exhibits distinct and diverse phases of disease, from minimal liver pathology to fulminant Hepatitis, that vary in duration and severity among individuals. Although huge progress has been made in HBV research which has yielded an effective prophylactic vaccine and potent antiviral therapy, our understanding of its virology and immunobiology is still far from complete. For example, the recent re-discovery of serum HBV RNA in chronic Hepatitis B (CHB) patients has led to the proposal of noncanonical viral particles such as RNA virion and capsid-derived immune complex (Capsid-Antibody-Complexes, CACs) that contradict long-established basic theory. Furthermore, the existence of capsid-derived immune complex may hint at novel mechanism of HBV-induced liver disease. Here, we summarize the past and recent literature on HBV-induced immune complex. We propose that the release of capsid-derived particles by HBV has its deep evolutionary origin, and the associated complement activation serves as an indispensable trigger for intrahepatic damage and a catalyst for further cell-mediated immunopathology. Full article

(This article belongs to the Special Issue Hepatitis B Virus: New Breakthroughs to Conquer an Ancient Disease)

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