Hepatitis Delta Research Articles

Prevalence of Hepatitis B, C and D Infections in Preoperative Patients at a Tertiary Hospital in Southern Nigeria

Patients going for surgical operations are required to be screened for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among other transmissible infections. This is necessary for better assessment of the patient's condition alongside the need for extra precautions during surgery. Hepatitis D virus (HDV) infection is not commonly reported but occurs in association with commonly reported but occurs in association with that of hepatitis B virus. The epidemiology of this co-infection is worth investigating, as it constitutes a more aggressive form of hepatitis Following due ethical considerations, this cross-sectional descriptive study enrolled 180 pre-operative patients for viral hepatitis screening. Immunochromatographic methods were used for detection of HBV and HCV infections, while detection of HDV was based on enzyme-linked immunosorbent assay method. Data processing was carried out using SPSS version 22.0. Results are presented as numbers and frequencies as percentage. The prevalence of HBV, HCV and HDV as recorded among pre-operative patients was 7.8%, 1.7% and 1.1% respectively. Hepatitis B virus alone accounted for 68.8% of all hepatitis cases, while its co-infection with HDV and HCV were observed to be 12.5% and 6.2% respectively Single infection of HCV was seen to be 12.5% of all infected cases. Hepatitis B virus was observed to be the most prevalent viral hepatitis agent within the studied population, while hepatitis D virus was detected at a rate of 1.1%

Metabolomics in viral hepatitis: advances and review.

Viral hepatitis is a major worldwide public health issue, affecting hundreds of millions of people and causing substantial morbidity and mortality. The majority of the worldwide burden of viral hepatitis is caused by five biologically unrelated hepatotropic viruses: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). Metabolomics is an emerging technology that uses qualitative and quantitative analysis of easily accessible samples to provide information of the metabolic levels of biological systems and changes in metabolic and related regulatory pathways. Alterations in glucose, lipid, and amino acid levels are involved in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway, and amino acid metabolism. These changes in metabolites and metabolic pathways are associated with the pathogenesis and medication mechanism of viral hepatitis and related diseases. Additionally, differential metabolites can be utilized as biomarkers for diagnosis, prognosis, and therapeutic responses. In this review, we present a thorough overview of developments in metabolomics for viral hepatitis.

HDV RNA Levels and Progression of Hepatitis Delta Infection: A 14 Year Follow Up Experience in Italy

Background: Identification of outcome predictors is one of the unmet needs in chronic HDV infection. Until recently, no reliable quantitative assays for HDV RNA were available. Aims: To evaluate the impact of baseline viremia on natural history of HDV infection in a cohort of patients whose serum samples were stored at their first visit 15 years ago. Methods: Quantitative HBsAg, HBeAg, HBeAb, HBV DNA, HDV RNA, genotypes, and liver disease severity were assessed at baseline. Patients who were no longer on active follow-up were recalled and re-evaluated in August 2022. Results: The majority of patients were male (64.9%); the median age was 50.1 years; and all patients were Italian, with only three born in Romania. All were HBeAg negative with HBV genotype D infection. Patients were subdivided three groups: 23 were in active follow-up (Group 1), 21 were recalled due to no longer being in follow-up (Group 2), and 11 died (Group 3). Liver cirrhosis was diagnosed in 28 subjects at the first visit; 39.3% of diagnosed patients were in Group 3, 32.1% were in Group 1 and 28.6% were in Group 2 (p = 0.001). Baseline HBV DNA IU/mL Log10 were 1.6 (1.0–5.9) in Group 1, 1.3 (1.0–4.5) in Group 2, and 4.1 (1.5–4.5) in Group 3; median baseline HDV RNA Log10 levels were 4.1 (0.7–6.7) in Group 1, 3.2 (0.7–6.2) in Group 2, and 5.2 (0.7–6.7) in Group 3, resulting significantly higher rates among patients in Group 3 compared to the other groups (p = 0.038). Eighteen patients in Group 2, as compared to 7 in Group 1, had undetectable HDV RNA at the follow-up evaluation (p = 0.001). Conclusions: HDV chronic infection is a heterogeneous disease. It may not only progress but also improve over time in patients, who eventually become HDV RNA-undetectable. HDV RNA levels may help identify the subgroup of patients with less progressive liver disease.

Systemic Inflammatory Molecules Are Associated with Advanced Fibrosis in Patients from Brazil Infected with Hepatitis Delta Virus Genotype 3 (HDV-3).

Hepatitis Delta virus (HDV) genotype 3 is responsible for outbreaks of fulminant hepatitis in Northeastern South America. This study investigates if systemic inflammatory molecules are differentially expressed in patients with advanced fibrosis chronically infected with Hepatitis Delta virusgenotype 3(HDV-3). Sixty-one patients from the north of Brazil coinfected with hepatitis B virus (HBV)/HDV-3 were analyzed. HDV quantification and genotyping were performed by semi-nested real-time polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP) methodologies. Ninety-two systemic inflammatory molecules (SIMs) were measured by Proximity Extension Assay (PEA) technology. The Shapiro-Wilk, Student's t-test, Mann-Whitney tests, and logistic regression analysis were used when appropriate. The median age was 41 years, and all patients were HBeAg negative. Advanced fibrosis or cirrhosis was diagnosed by histological staging in 17 patients, while 44 presented with minimal or no fibrosis. Advanced necroinflammatory activity correlated positively with serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Established non-invasive fibrosis scores (APRI, FIB-4, and AST/ALT ratio) revealed low sensitivities and positive predictive values (PPVs) with an AUROC maximum of 0.586. Among the 92 SIMs analyzed, MCP.4, CCL19, EN.RAGE, SCF, and IL18 showed a positive correlation with fibrosis stage. A combined score including CCL19 and MCP.4 revealed a sensitivity of 81% and an odds ratio of 2.202 for advanced fibrosis. Standard non-invasive fibrosis scores showed poor performance in HDV-3 infection. We here suggest that the determination of CCL19 and MCP.4 may be used to identify patients with advanced fibrosis. Moreover, this study gives novel insights into the immunopathogenesis of HDV-3 infection.

Characterization of RBD-specific cross-neutralizing antibodies responses against SARS-CoV-2 variants from COVID-19 convalescents.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been posing a severe threat to global public health. Although broadly neutralizing antibodies have been used to prevent or treat corona virus disease 2019 (COVID-19), new emerging variants have been proven resistant to these antibodies. In this study, we isolated receptor binding domain (RBD)-specific memory B cells using single-cell sorting method from two COVID-19 convalescents and expressed the antibody to test their neutralizing activity against diverse SARS-CoV-2 variants. Then, we resolved antibody-RBD complex structures of potent RBD-specific neutralizing antibodies by X-ray diffraction method. Finally, we analyzed the whole antibody repertoires of the two donors and studied the evolutionary pathway of potent neutralizing antibodies. We identified three potent RBD-specific neutralizing antibodies (1D7, 3G10 and 3C11) from two COVID-19 convalescents that neutralized authentic SARS-CoV-2 WH-1 and Delta variant, and one of them, 1D7, presented broadly neutralizing activity against WH-1, Beta, Gamma, Delta and Omicron authentic viruses. The resolved antibody-RBD complex structures of two antibodies, 3G10 and 3C11, indicate that both of them interact with the external subdomain of the RBD and that they belong to the RBD-1 and RBD-4 communities, respectively. From the antibody repertoire analysis, we found that the CDR3 frequencies of the light chain, which shared high degrees of amino acid identity with these three antibodies, were higher than those of the heavy chain. This research will contribute to the development of RBD-specific antibody-based drugs and immunogens against multiple variants.

Persistent hepatic IFN system activation in HBV-HDV infection determines viral replication dynamics and therapeutic response.

Hepatitis delta virus (HDV), a satellite virus of HBV, is regarded as the most severe type of hepatitis virus because of the substantial morbidity and mortality. The IFN system is the first line of defense against viral infections and an essential element of antiviral immunity; however, the role of the hepatic IFN system in controlling HBV-HDV infection remains poorly understood. Herein, we showed that HDV infection of human hepatocytes induced a potent and persistent activation of the IFN system whereas HBV was inert in triggering hepatic antiviral response. Moreover, we demonstrated that HDV-induced constitutive activation of the hepatic IFN system resulted in a potent suppression of HBV while modestly inhibiting HDV. Thus, these pathogens are equipped with distinctive immunogenicity and varying sensitivity to the antiviral effectors of IFN, leading to the establishment of a paradoxical mode of viral interference wherein HDV, the superinfectant, outcompetes HBV, the primary pathogen. Furthermore, our study revealed that HDV-induced constitutive IFN system activation led to a state of IFN refractoriness, rendering therapeutic IFNs ineffective. The present study provides potentially novel insights into the role of the hepatic IFN system in regulating HBV-HDV infection dynamics and its therapeutic implications through elucidating the molecular basis underlying the inefficacy of IFN-based antiviral strategies against HBV-HDV infection.

Epidemiology Pattern, Prevalent Genotype Distribution, Fighting Stigma and Control Options for Hepatitis D in Bulgaria and Other European Countries.

Hepatitis D virus (HDV) is a satellite virus that causes the most aggressive form of all viral hepatitis in individuals already infected with HBV (hepatitis B virus). In recent years, there has been a negative trend towards an increase in the prevalence of chronic hepatitis D in Europe, especially among immigrant populations coming from regions endemic for the virus. The aim of this review is to analyse the current epidemiology of chronic HDV, routes of transmission, prevalent genotype, its management, prevention, fighting stigma and options for viral control in European countries, such as Bulgaria.

No virologic resistance to bulevirtide monotherapy detected in patients through 24 weeks treatment in phase II and III clinical trials for chronic hepatitis delta

Bulevirtide (BLV) is a hepatitis D virus (HDV)/hepatitis B virus (HBV) entry inhibitor that has shown virologic response (responder, HDV-RNA undetectable or ≥2 log10 IU/mL decrease from baseline) in >50% of patients after 24-week treatment. However, some patients achieve <1 log10 IU/mL decline in HDV-RNA through 24-week treatment (non-responder). Here we report viral resistance analyses for BLV monotreated participants who were non-responders or experienced virologic breakthrough (VB, 2 consecutive increases in HDV-RNA of ≥1 log10 IU/mL from nadir or 2 consecutive HDV-RNA detectable if previously undetectable) in phase II study MYR202 and phase III study MYR301. Deep-sequencing of BLV-corresponding region in HBV PreS1 and HDV HDAg gene and in vitro phenotypic testing were performed for the participant with VB (n=1) and non-responders (n=20) at baseline (BL) and Week 24 (WK24). No amino acid exchanges within the BLV-corresponding region and HDAg associated with reduced susceptibility to BLV were identified in isolates from any of the 21 participants at BL and WK24. Although variants (HBV n=1; HDV n=13) were detected at BL in some non-responders or the participant with VB, none were associated with reduced sensitivity to BLV in vitro. Furthermore, the same variant was found in virologic responders. A comprehensive phenotypic analysis demonstrated that the BLV EC50 values from 116 BL samples were similar across non-responders, partial responders (HDV RNA decline ≥1 but <2 log10 IU/mL), and responders regardless of the presence of HBV and/or HDV polymorphisms. No amino acid substitutions associated with reduced sensitivity to BLV monotherapy were detected at BL or WK24 in non-responders or the participant with VB after 24-week BLV treatment.

The Influence of Different SARS-CoV-2 Strains on Changes in Maximal Oxygen Consumption, Ventilatory Efficiency and Oxygen Pulse of Elite Athletes.

The aim of this study was to evaluate the influence of different SARS-CoV-2 strains on the functional capacity of athletes. In total, 220 athletes underwent cardiopulmonary exercise testing (CPET) after coronavirus infection and before returning to sports activities. Eighty-eight athletes were infected by the Wuhan virus, and 66 were infected during the Delta and Omicron strain periods of the pandemic. The CPET results showed significantly decreased maximal oxygen consumption, ventilatory efficiency, and oxygen pulse in athletes who were infected with Wuhan and Delta strains compared to athletes who suffered from Omicron virus infection. An early transition from aerobic to anaerobic metabolic pathways for energy production was observed in the Wuhan and Delta groups but not in athletes who were infected with the Omicron strain. There were no differences in the obtained results when Wuhan and Delta virus variants were compared. These results suggest that the Wuhan and Delta virus strains had a significantly greater negative impact on the functional abilities of athletes compared to the Omicron virus variant, especially in terms of aerobic capacity and cardiorespiratory function.

A changing landscape: Tracking and analysis of the international HDV epidemiology 1999-2020.

The international epidemiology of Hepatitis Delta Virus (HDV) is challenging to accurately estimate due to limited active surveillance for this rare infectious disease. Prior HDV epidemiological studies have relied on meta-analysis of aggregated and static datasets. These limitations restrict the capacity to actively detect low-level and/or geographically dispersed changes in the incidence of HDV diagnoses. This study was designed to provide a resource to track and analyze the international HDV epidemiology. Datasets analyzed collectively consisted of >700,000 HBV and >9,000 HDV reported cases ranging between 1999-2020. Datasets mined from government publications were identified for Argentina, Australia, Austria, Brazil, Bulgaria, Canada, Finland, Germany, Macao, Netherlands, New Zealand, Norway, Sweden, Taiwan, Thailand, United Kingdom, and United States. Time series analyses, including Mann-Kendall (MK) trend test, Bayesian Information Criterion (BIC), and hierarchal clustering, were performed to characterize trends in the HDV timelines. An aggregated prevalence of 2,560 HDV/HBV100,000 cases (95% CI 180-4940) or 2.56% HDV/HBV cases was identified, ranging from 0.26% in Canada to 20% in the United States. Structural breaks in the timeline of HDV incidence were identified in 2002, 2012, and 2017, with a significant increase occurring between 2013-2017. Significant increasing trends in reported HDV and HBV cases were observed in 47% and 24% of datasets, respectively. Analyses of the HDV incidence timeline identified four distinct temporal clusters, including Cluster I (Macao, Taiwan), Cluster II (Argentina, Brazil, Germany, Thailand), Cluster III (Bulgaria, Netherlands, New Zealand, United Kingdom, United States) and Cluster IV (Australia, Austria, Canada, Finland, Norway, Sweden). Tracking of HDV and HBV cases on an international scale is essential in defining the global impact of viral hepatitis. Significant disruptions of HDV and HBV epidemiology have been identified. Increased surveillance of HDV is warranted to further define the etiology of the recent breakpoints in the international HDV incidence.

The Role of Antiviral Prophylaxis in Preventing HBV and HDV Recurrence in the Setting of Liver Transplantation.

Hepatitis B virus (HBV) is a prevalent underlying disease, leading to liver transplantation (LT) for both decompensated cirrhosis and hepatocellular carcinoma (HCC). The hepatitis delta virus (HDV) affects approximately 5-10% of HBsAg carriers, accelerating the progression of liver injury and HCC. The initial introduction of HBV immunoglobulins (HBIG), and then of nucleos(t)ide analogues (NUCs), considerably improved the survival of HBV/HDV patients post-transplantation, as they helped prevent re-infection of the graft and recurrence of liver disease. Combination therapy with HBIG and NUCs is the primary post-transplant prophylaxis strategy in patients transplanted for HBV- and HDV-related liver disease. However, monotherapy with high-barrier NUCs, such as entecavir and tenofovir, is safe and also effective in some individuals who are at low risk of HBV reactivation. To address the problems of organ shortage, last-generation NUCs have facilitated the use of anti-HBc and HBsAg-positive grafts to meet the ever-increasing demand for grafts.

Elimination of HDV: Epidemiologic implications and public health perspectives.

Hepatitis delta virus (HDV) infection causes the severest form of viral hepatitis in humans. Discovered in 1977, it was considered an infection prevalent in the eastern Mediterranean region. Today it is recognized as a global infection of public health importance, however accurate prevalence remains uncertain because of lack of good epidemiological studies. Under-screening for HDV is the single most important factor in under-estimating the true burden of infection. Urgent efforts are therefore needed to apply reliable screening tools and robust surveillance methodologies to study HDV. There is now a move by major hepatology societies to recommend HDV antibody testing in all persons with HBV infection. Important differences also need to be recognized between countries considered endemic or non-endemic countries. While the endemic infections likely spread horizontally in the general population, and is quite often nosocomial, in non-endemic countries special populations may carry the greater burden, such as persons with injection drug use and various sexual exposures. Even in endemic countries, HDV often exists in significant pockets of the general population. HDV has been categorized as an orphan infection due to lack of approved therapies. Recently there have significant advances in therapy and further clinical trials continue. However, as new therapies are approved, equitable access to the medications will become a major public health issue, particularly because most HDV patients live in low or low middle income countries.

Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response.

Hepatitis delta virus (HDV) is a viroid-like satellite that may co-infect individuals together with hepatitis B virus (HBV), as well as cause superinfection by infecting patients with chronic hepatitis B (CHB). Being a defective virus, HDV requires HBV structural proteins for virion production. Although the virus encodes just two forms of its single antigen, it enhances the progression of liver disease to cirrhosis in CHB patients and increases the incidence of hepatocellular carcinoma. HDV pathogenesis so far has been attributed to virus-induced humoral and cellular immune responses, while other factors have been neglected. Here, we evaluated the impact of the virus on the redox status of hepatocytes, as oxidative stress is believed to contribute to the pathogenesis of various viruses, including HBV and hepatitis C virus (HCV). We show that the overexpression of large HDV antigen (L-HDAg) or autonomous replication of the viral genome in cells leads to increased production of reactive oxygen species (ROS). It also leads to the upregulated expression of NADPH oxidases 1 and 4, cytochrome P450 2E1, and ER oxidoreductin 1α, which have previously been shown to mediate oxidative stress induced by HCV. Both HDV antigens also activated the Nrf2/ARE pathway, which controls the expression of a spectrum of antioxidant enzymes. Finally, HDV and its large antigen also induced endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR). In conclusion, HDV may enhance oxidative and ER stress induced by HBV, thus aggravating HBV-associated pathologies, including inflammation, liver fibrosis, and the development of cirrhosis and hepatocellular carcinoma.

Circulation of HDV Genotypes in Brazil: Identification of a Putative Novel HDV-8 Subgenotype.

Hepatitis D virus (HDV) is classified into 8 genotypes (1 to 8) and several subgenotypes. In Brazil, HDV-3 and HDV-1 predominate; however, most of the diagnosis efforts and molecular studies are directed to the area of endemicity of the Amazon Basin. Here, we determined the molecular epidemiological profile of circulating HDV in Brazilian HBsAg-positive patients between 2013 and 2015 in areas of endemicity and non-areas of endemicity. From 38 anti-HDV-positive individuals, 13 (34.2%) had detectable HDV-RNA and 11 (28.9%) were successfully sequenced. Partial HDAg (~320 nt) sequencing followed by phylogenetic analysis with reference sequences resulted in the identification of HDV-3 (9/11; 81.8%), HDV-5 (1/11; 9.1%), and HDV-8 (1/11; 9.1%). Most HDV-3 samples (8/9; 88.9%) were found in the endemic North region, while one was found in Central-West Brazil, a non-area of endemicity. HDV-5 and 8, genotypes native from African countries, were found in São Paulo, a cosmopolitan city from Southeast Brazil with a high circulation of immigrants. Phylogenetic analysis of HDV-8 strains indicated that the sample determined in our study, along with previously reported sequences from Brazil, formed a highly supported monophyletic clade, likely representing a putative novel HDV-8 subgenotype. IMPORTANCE Considered a neglected pathogen until the last 2 decades, an increase in the availability of genetic data of hepatitis D virus (HDV) strains around the world has been noticed recently, resulting in the proposition of different classifications. Our study aimed to determine the molecular epidemiological profile of HDV isolates circulating in areas of endemicity and non-areas of endemicity in Brazil. Based on the analyzed fragment, HDV-8 sequences clustered out of the clades formed by subgenotypes 8a and 8b might suggest the identification of a novel subgenotype, putatively designated subgenotype 8c. Our findings demonstrate the importance of continuous epidemiological surveillance to map HDV spread pathways and the introduction of imported variants. It also reinforces that as the amount of HDV genomes generated and reported increases, we will have changes in viral classification and, consequently, in our understanding of the dynamics of variability of this viral agent.

In SARS-CoV-2 delta variants, Spike-P681R and D950N promote membrane fusion, Spike-P681R enhances spike cleavage, but neither substitution affects pathogenicity in hamsters

The SARS-CoV-2 delta (B.1.617.2 lineage) variant was first identified at the end of 2020 and possessed two unique amino acid substitutions in its spike protein: S-P681R, at the S1/S2 cleavage site, and S-D950N, in the HR1 of the S2 subunit. However, the roles of these substitutions in virus phenotypes have not been fully characterized. We used reverse genetics to generate Wuhan-D614G viruses with these substitutions and delta viruses lacking these substitutions and explored how these changes affected their viral characteristics invitro and invivo. S-P681R enhanced spike cleavage and membrane fusion, whereas S-D950N slightly promoted membrane fusion. Although S-681R reduced the virus replicative ability especially in VeroE6 cells, neither substitution affected virus replication in Calu-3cells and hamsters. The pathogenicity of all recombinant viruses tested in hamsters was slightly but not significantly affected. Our observations suggest that the S-P681R and S-D950N substitutions alone do not increase virus pathogenicity, despite of their enhancement of spike cleavage or fusogenicity. A full list of funding bodies that contributed to this study can be found under Acknowledgments.

Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually.

Distinct histological patterns in chronic hepatitis D with nucleos(t)ide analogue therapy.

Chronic hepatitis delta virus (HDV) infection leads to a more severe hepatitis than hepatitis B virus (HBV) infection alone. Specific histological staining patterns have been described in HBV mono-infection, however this has not been extensively investigated in HDV co-infection. This study evaluated whether the use of nucleos(t)ide analogs (NAs) for concurrent HBV infection has an impact on the histological appearance of chronic HDV. Liver biopsies of all patients referred for management of HDV infection were reviewed and hepatitis-specific stains for HBV antigens were evaluated. Clinical and histological characteristics were compared between patients on and off-NA therapy. 50 patients were included in our analysis, of which 26 (52%) were on NA therapy at the time of the biopsy. Overall, 8% stained for HBV core antigen and 86% stained for HBV surface antigen. On and off-NA groups had similar degrees of fibrosis and inflammation, however NA patients had an odds ratio of 7.15 for membranous staining and 0.13 for scattered granular staining (p = 0.001). No association was found with markers of disease severity or viral activity, with nonetheless a lower score of total inflammation noted in biopsies with a positive membranous stain (8.5 vs. 10.3 p = 0.04). In chronic HDV infection, patients treated with nucleos(t)ide analogs demonstrate a unique membranous staining pattern for hepatitis B surface antigen, which is not associated with HBV or HDV replicative activity. These findings may help improve the understanding of the role of HBV directed therapy in HDV pathophysiology. Histological staining is associated with viral activity in chronic HBV, however this has been infrequently explored in HDV. In HDV, staining patterns differ based on HBV treatment status and do not appear to be associated with markers of viral activity.

In vitro cell culture models to study hepatitis B and D virus infection.

Chronic infection with the hepatitis B virus (HBV) and hepatitis D virus (HDV) can cause a major global health burden. Current medication regimens can repress viral replication and help to control disease progression, but a complete cure is hardly achieved due to the difficulties to eradicate viral templates (cccDNA and integrates). To develop novel curative antiviral therapies for HBV/HDV infection, it is vital to precisely understand the details of the molecular biology of both viruses and the virus-host interactions. One important prerequisite for gaining this aim is the availability of suitable in vitro models that support HBV/HDV infection, replicate both viruses via their authentic template and allow to adequately study host cell responses. The discovery of sodium taurocholate cotransporting polypeptide (NTCP) receptor as the most crucial host factor promoted HBV/HDV research to a new era. Recently, the structure of human NTCP was solved, gaining a deeper understanding of HBV recognition as the bona fide receptor. After decades of continuous efforts, new progress has been achieved in the development of cell culture models supporting HBV/HDV study. This review summarizes the cell culture models currently available, discusses the advantages and disadvantages of each model, and highlights their future applications in HBV and HDV research.

Hepatitis D virus infection: Progress on the path toward disease control and cure.

This article discusses the impact of Hepatitis D virus (HDV) infection as a major cause of liver-related morbidity and mortality in people with Hepatitis B virus (HBV) infection. The article reviews the current knowledge and unanswered questions about the epidemiology, pathogenesis, and natural history of HDV infection. Although effective treatments for HDV infection have been elusive, interferon alfa is recommended for at least 48 weeks. However, response rates with standard-of-care peginterferon alfa are suboptimal, leading to few patients with a sustained virologic response. The article proposes novel approaches to treating HDV and HBV, including targeting reduction or loss of hepatitis B surface antigen (HBsAg) reduction, and discusses potential strategies for achieving HBsAg loss in patients with chronic HBV infection. Finally, the article discusses the landmark decision of accepting viral and biochemical surrogates by regulatory authorities, opening the door for the clinical development of drugs for patients with HDV infection.

Molecular and Clinical Features of Hepatocellular Carcinoma in Patients with HBV-HDV Infection.

Hepatitis D virus (HDV) infection affects more than 10 million people worldwide, with an estimated prevalence of nearly 4.5% among HBsAg-positive individuals. Epidemiological studies have shown a significant increase in the prevalence of hepatocellular carcinoma (HCC) in patients with chronic HDV infection compared to those with chronic hepatitis B virus (HBV) mono-infection. Despite the clinical findings, data on molecular oncogenic mechanisms are limited and fragmentary. Moreover, the role of HDV in promoting the development of HCC has so far been controversial, because it is difficult to weigh the respective contributions of the two viruses. In this review, we focused on the direct oncogenic action of HDV, its role in modifying the tumor microenvironment, and the genetic signature of HDV-related HCC, comparing these features with HBV-related HCC.