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Background: Hepatitis D virus research has advanced in recent decades. In this study, we aim to quantitatively analyze the scientific data in the field of "hepatitis D virus" by using bibliometric analysis. Methods: Research documents published in the Web of Science database between 1984 and 2022 were included in the study. The search keywords were "hepatitis D" or "hepatitis-D" or "HDV" or "hepatitis virus D." The full record and cited references of documents extracted were converted to a "bibtex" file as well. The R-Studio software's Bibliometrix package and Biblioshinny application are used to perform the bibliometric analysis. Results: A total of 1530 publications written by 6042 authors were identified. Most of the publications were articles (62.81%). The number of published articles increased gradually, especially after 2008. The articles of the authors were mostly published in the United States, Germany, and China. The affiliation where the most studies were conducted was Hannover Medical School (8.82%). Also, the United States and Germany were found to be the main countries in the collaboration network. Mario Rizzetto was the author of the most published articles on HDV. The most frequently used words in the articles were "infection," "prevalence," and "b-virus." Conclusion: Clinical and epidemiological studies on HDV were given more focus, while studies on treatment were less numerous. It can also be predicted that potent treatment options will increase more in the coming years, and the frequency of studies on this will increase.

The article commemorates the centenary of Dr. Gilberta Bensabath, a prominent researcher in hepatology in Latin America, known for her work on hepatitis B and Delta viruses in the Amazon region. Dr. Bensabath's research led to the discovery of hepatitis delta virus (HDV) and its prevalence in the western Amazon, particularly in indigenous and quilombola groups. Her team's studies highlighted the significant public health impact of hepatitis B and Delta infections in the Amazon region, emphasizing the need for further research and intervention to address these infections effectively. [Extracted from the article]

Pegylated interferon alpha 2a continues to be used for the treatment of chronic hepatitis D. The reported on-treatment virologic response varies between 17 and 47%, with relapses in more than 50% of these patients. No stopping rules have been defined, and the duration of the treatment is not clearly established, but it should be between 48 and 96 weeks. In total, 76 patients with compensated liver disease treated with peg-interferon according to the Romanian National protocol for the treatment of hepatitis D were retrospectively included. The duration of treatment was up to 96 weeks, with the following stopping rules: less than a 2 log HDV RNA decrease by week 24 and less than a 1 log decrease every 6 months afterwards. Six months after stopping the treatment, it can be restarted for unlimited cycles. The inclusion criteria were aged above 18, HBs Ag-positive, HDV RNA detectable, ALT above ULN and/or liver fibrosis at least F1 at liver biopsy, or Fibrotest and/or Fibroscan higher than 7 KPa and/or inflammation at least A1 at liver biopsy or Fibrotest. We monitored our patients for a total period of 4 years (including those that repeated the cycle). After the first 6 months of treatment, 27 patients (35.5%) had a greater than 2 log HDV RNA decrease, 19 of them achieving undetectable HDV RNA. Seventeen patients (22.3%) had undetectable HDV RNA 24 weeks after stopping 96 weeks of treatment, and none relapsed in the following 2 years. Of these 17 patients, 6 were cirrhotic, and 4 had F3. Undetectable HDV RNA at 24 weeks was the only parameter that predicted a long-term suppression of HDV RNA. In 49 patients, the treatment was stopped after 6 months according to protocol, but it was restarted 6 months later. Five of these patients finished a 48-week course of treatment; none achieved undetectable HDV RNA. During the first course of therapy, 45 patients had at least one moderate adverse reaction to treatment. In one patient, the treatment was stopped due to a serious adverse event (osteomyelitis). Treatment doses had to be reduced in 29 patients. The virologic response at week 24 can select the patients who will benefit from continuing the treatment from those who should be changed to another type of medication when available.

Background & Aims: HBsAg proteins are useful to identify HBV inactive carriers (ICs), but data on chronic hepatitis D (CHD) are scarce. This study aimed to describe HBsAg composition in CHD, its changes during the evolution, and the potential association with clinical outcomes. In addition, we assess the composition of HBsAg across different HBV genotypes and validate previous results on HBsAg proteins in an independent HBV cohort. Methods: Quantitative HBsAg, medium HBsAg proteins (MHBs), and large HBsAg proteins (LHBs) were measured in two cohorts. The first cohort consisted of patients with CHD. A cross-sectional study of samples from two European institutions (N = 46) was conducted. Outcomes were assessed in a retrospective–prospective study of those patients with a follow-up of >1 year (n = 36), and the longitudinal evolution of HBsAg proteins in those with samples >5 years apart (n = 12) was analysed. The second cohort consisted of patients with HBeAg-negative HBV, and a cross-sectional study was performed (N = 141). Results: Forty-one (89%) patients with CHD had detectable HDV-RNA, and the presence of HDV-RNA was associated with higher LHBs proportion (p = 0.010). Baseline MHBs (p = 0.051) and MHBs proportion (p = 0.086) tended to be higher in those developing clinical outcomes (9/36, 25%) after a median follow-up of 5.9 years. Patients in which HDV-RNA became spontaneously undetectable during follow-up (5/31, 16.1%) tended to present lower MHBs proportion (p = 0.085). In the longitudinal study, changes in LHBs proportion were observed (p = 0.041), whereas MHBs proportion remained stable (p = 0.209). Regarding HBV, ICs showed lower LHBs proportion (p = 0.027). LHBs and MHBs differed significantly according to HBV genotype, regardless of the HBV phase. Conclusions: Patients with CHD with detectable HDV-RNA presented higher LHBs proportion than those with undetectable HDV-RNA. A trend toward having higher baseline MHBs proportion was observed in patients who developed clinical outcomes or remained with detectable HDV-RNA. This study validates the different HBsAg composition in HBV ICs and reveals the HBV-genotype influence in HBsAg composition. Impact and implications: The composition of HBsAg in chronic hepatitis D differs in patients with detectable and undetectable HDV viral load and may help predict the likelihood of achieving undetectable HDV viraemia and the development of clinical events such as decompensation. The composition of the surface antigen is also useful to distinguish inactive carriers of HBV, and it varies according to HBV genotype.

While the observed disease progression was lower as compared with the early studies, these longitudinal studies convincingly supported the assumed role of hepatitis Delta as the most aggressive form of viral hepatitis.[[13], [16]] A particular poor prognosis is evident for HBV/HDV patients who suffer from coinfection with the human immunodeficiency virus (HIV). Residual low HDV viraemia is associated HDV RNA relapse after PEG-IFNa-based antiviral treatment of hepatitis Delta: results from the HIDIT-II study. Hepatitis Delta virus infection prevalence, diagnosis and treatment in the Middle East: a scoping review. In their dedicated review article of this special issue, Tharwani and Hamid discuss the requirements on a global scale and nicely describe more specific needs depending on the HDV prevalence and affected population.[44] Another important task will be the further improvement of HDV therapy. [Extracted from the article]

Chronic hepatitis delta (CHD) affects approximately 10–20 million people worldwide and represents the most severe form of chronic viral hepatitis, as it is characterized by high rates of progression to cirrhosis and its complications (end‐stage liver disease, hepatocellular carcinoma). In the last 30 years, the only treatment option for CHD has been represented by the off‐label administration of Interferon (or Pegylated Interferon)‐alpha: antiviral treatment, however, resulted in suboptimal (20–30%) virological response and was burdened by several side effects, de facto contraindicating Interferon (IFN) administration in patients with more advanced liver disease. Recently, Bulevirtide (BLV), a first‐in‐class HBV‐HDV entry inhibitor blocking Na+‐taurocholate co‐transporting polypeptide (NTCP), has provided very promising efficacy data in Phase II and Phase III (interim analysis) trials as well as in preliminary real‐life reports. In July 2020, BLV has granted conditional approval by EMA for treatment of compensated CHD, at the dose of 2 mg/day by self‐administered subcutaneous injections. In Phase II and Phase III trials, BLV was evaluated at different doses (2 vs. 10 mg/day) for 24 or 48 weeks, either in monotherapy or in combination with PegIFN. Administration of BLV monotherapy for 24 or 48 weeks resulted in 50%–83% virological response (HDV RNA ≥ 2 Log decline) rates and 45%–78% ALT normalization. Combination therapy with PegIFN provided synergistic effects. These results were replicated in real‐life studies and confirmed also in patients with advanced cirrhosis and clinically significant portal hypertension. BLV treatment was optimally tolerated, resulting only in an asymptomatic increase of bile acids. [ABSTRACT FROM AUTHOR]

Management of chronic hepatitis D (CHD) has entered a new era. In this new era, the virus entry inhibitor bulevirtide has received conditional approval as a treatment for compensated CHD. Three phase 3 studies with two new compounds are ongoing for the treatment of CHD. In this context, surrogate markers of treatment efficacy have been well defined for chronic hepatitis B (CHB) (7) and chronic hepatitis C (8) but not for CHD. The aim of this review is to give a perspective on treatment endpoints in CHD. For this, we took guidance from CHB studies and tried to make suggestions which differed according to finite versus prolonged treatment durations and also took into account the different characteristics of the new compounds. [ABSTRACT FROM AUTHOR]

The introduction of Hepatitis B Immunoglobulins (HBIg) prophylaxis at and after liver transplantation (LT) facilitated excellent long‐term survival of transplant patients with chronic hepatitis B virus (HBV) infection. Several studies suggested that only short‐term (i.e. 4–8 weeks) HBIg prophylaxis after LT followed by the long‐term administration of HBV polymerase inhibitors prevents HBV recurrence. In hepatitis D virus (HDV)/HBV co‐infected patients, the need for long‐term HBIg prophylaxis on top of HBV polymerase inhibitors is unknown. HDV requires HBV surface antigen (HBsAg) for uptake into hepatocytes to subsequently establish HDV replication. Data on HDV recurrence and its impact on outcomes after LT are limited. In this review, we evaluated the available data on post‐LT recurrence of HBV and/or HDV. Overall, HBIg prophylaxis was effective, but 10–13% of patients became HBsAg positive after LT. Only a single study from Turkey reported HDV recurrence, which was not observed in other LT centres. Since all studies administered continuous HBIg prophylaxis, the post‐LT recurrence rates without HBIg prophylaxis remain unknown. In a German study, the clinical course and histopathological aspects of liver injury (inflammation, fibrosis and steatosis) were similar in post‐LT patients on continuous HBIg and those who stopped HBIg after a median of 72 months. Discontinuation of HBIg in stable patients after LT for HBV/HDV co‐infection did not lead to impaired overall survival or a higher recurrence rate in this long‐term follow‐up. In summary, discontinuation of HBIg after liver transplantation for HBV/HDV liver disease seems safe, but randomized controlled studies are needed before it can be generally recommended. [ABSTRACT FROM AUTHOR]

Hepatitis D viral infection in humans is a disease that requires the establishment of hepatitis B, relying on hepatitis B surface Ag and host cellular machinery to replicate and propagate the infection. Since its discovery in 1977, substantial progress has been made to better understand the hepatitis D viral life cycle, pathogenesis and modes of transmission along with expanding on clinical knowledge related to prevention, diagnosis, monitoring and treatment. The availability of serologic diagnostic assays for hepatitis D infection has evolved over time with current widespread availability, improved detection and standardized reporting. With human migration, the epidemiology of hepatitis D infection has changed over time. Thus, the ability to use diagnostic assays remains essential to monitor the global impact of hepatitis D infection. Separately, while liver biopsy remains the gold standard for the staging of this rapidly progressive and severe form of chronic viral hepatitis, there is an unmet need for clinical monitoring of chronic hepatitis D infection for management of progressive disease. Thus, exploration of the utility of non‐invasive fibrosis markers in hepatitis D is ongoing. In this review, we discuss the virology, the evolution of diagnostics and the development of non‐invasive markers for the detection and monitoring of fibrosis in patients with hepatitis D infection. [ABSTRACT FROM AUTHOR]

A severe course has been described in early studies on chronic hepatitis D (CHD), with faster pace towards liver cirrhosis with subsequent high liver‐related morbidity and mortality in the majority of patients. Earlier studies have included risk groups as people using intravenous drugs (PWID) or those with multiple co‐morbidities. During the last decade, the epidemiological landscape of CHD has changed with domestic cases decreasing while increasing cases of CHD consisting of younger persons immigrating from endemic regions to low‐endemic regions. Recently, further insights into the spectrum of the disease with an indolent disease course in a substantial proportion of persons with CHD have been gained. At diagnosis, ≥30%–50% had already established liver cirrhosis. Older age, liver cirrhosis, co‐infection with HIV and lack of interferon (IFN) therapy are the main predictors of worse clinical outcome. The newly introduced and upcoming antivirals against CHD are highly anticipated, considering the historically low virological response rates to antiviral therapy. Further knowledge is needed to fully comprehend the natural course and the spectrum of this severe form of viral hepatitis. This is also to be able to evaluate the long‐term effects of the new antivirals on disease progression. [ABSTRACT FROM AUTHOR]

Infection with the hepatitis D virus induces the most severe form of chronic viral hepatitis, affecting over 12 million people worldwide. Chronic HDV infection leads to rapid development of liver cirrhosis and hepatocellular carcinoma in ~70% of patients within 15 years of infection. Recent evidence suggests that an interplay of different components of the immune system are contributing to viral control and may even be implicated in liver disease pathogenesis. This review will describe general concepts of antiviral immune response and elicit the present evidence concerning the interplay of the hepatitis D virus with the immune system. [ABSTRACT FROM AUTHOR]

Treatment of hepatitis D virus (HDV) infection has been based on the administration of interferon‐alfa for more than three decades. First studies to treat HDV‐infected patients with type 1 interferons were already performed in the 1980s. Several smaller trials and case series were reported thereafter. During the mid 2000s the use of pegylated interferons for hepatitis D was established. Since then, additional trials were performed in different countries exploring strategies to personalize treatment including extended treatment durations. The overall findings were that about one‐quarter to one‐third of patients benefit from interferon treatment with persistent suppression of HDV replication. However, only few patients achieve also functional cure of hepatitis B with HBsAg loss. Importantly, several studies indicate that successful interferon treatment is associated with improved clinical long‐term outcomes. Still, only a proportion of patients with hepatitis D can be treated with interferons. Even though alternative treatments are currently developed, it is likely that pegylated interferon‐alfa will still have an important role in the management of hepatitis D – either alone or in combination. Therefore, better biomarkers are needed to select patients with a high likelihood to benefit from interferon‐based treatments. In this review we are discussing basic principles of mode of action of interferon alpha against HDV, summarize previous data on interferon treatment of hepatitis D and give an outlook on potential combinations with novel drugs currently in development. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) represents a major public health problem being one of the most common causes of cancer‐related deaths worldwide. Hepatitis B (HBV) and C viruses have been classified as oncoviruses and are responsible for the majority of HCC cases, while the role of hepatitis D virus (HDV) in liver carcinogenesis has not been elucidated. HDV/HBV coinfection is related to more severe liver damage than HBV mono‐infection and recent studies suggest that HDV/HBV patients are at increased risk of developing HCC compared to HBV mono‐infected patients. HBV is known to promote hepatocarcinogenesis via DNA integration into host DNA, disruption of molecular pathways by regulatory HBV x (HBx) protein and excessive oxidative stress. Recently, several molecular mechanisms have been proposed to clarify the pathogenesis of HDV‐related HCC including activation of signalling pathways by specific HDV antigens, epigenetic dysregulation and altered gene expression. Alongside, ongoing chronic inflammation and impaired immune responses have also been suggested to facilitate carcinogenesis. Finally, cellular senescence seems to play an important role in chronic viral infection and inflammation leading to hepatocarcinogenesis. In this review, we summarize the current literature on the impact of HDV in HCC development and discuss the potential interplay between HBV, HDV and neighbouring liver tissue in liver carcinogenesis. [ABSTRACT FROM AUTHOR]

Keywords: HDV; hepatitis; HBV; bulevirtide; delta EN HDV hepatitis HBV bulevirtide delta 293 304 12 11/03/23 20230801 NES 230801 Lay Summary First discovered over 40 years ago, the hepatitis delta virus (HDV) is unique, requiring the presence of the hepatitis B virus (HBV). In more than 90% of cases, HBV/HDV coinfection ends in complete viral clearance and is self-limiting; as HDV is dependent on HBV, the rate of HDV chronicity cannot be any higher than the rate of HBV chronicity from that acute infection of HBV. Ag, antigen; DAg, HDV antigen; ds, double stranded; HBsAg, HBV surface antigen; HBV, hepatitis B virus; HDV, hepatitis delta virus. Lancet Gastroenterol Hepatol 2017; 2 (12): 877-889 94 Bazinet M, Pântea V, Cebotarescu V. Persistent control of hepatitis B virus and hepatitis delta virus infection following REP 2139-Ca and pegylated interferon therapy in chronic hepatitis B virus/hepatitis delta virus coinfection. [Extracted from the article]

Background: It is assumed that the prevalence of hepatitis D in HBsAg-positive individuals reaches 4.5–13% in the world and on average about 3% in Europe. Data from several European countries, including Slovakia, are missing or are from an older period. Methods: We analyzed all available data on hepatitis D from Slovakia, including reports from the Slovak Public Health Authority and the results of one prospective study, and three smaller surveys. The determination of anti-HDV IgG and IgM antibodies and/or HDV RNA was used to detect hepatitis D. Results: In the years 2005–2022, no confirmed case of acute or chronic HDV infection was reported in Slovakia. The presented survey includes a total of 343 patients, of which 126 were asymptomatic HBsAg carriers, 33 acute hepatitis B, and 184 chronic hepatitis B cases. In a recent prospective study of 206 HBsAg-positive patients who were completely serologically and virologically examined for hepatitis B and D, only 1 anti-HDV IgG-positive and no anti-HDV IgM or HDV RNA-positive cases were detected. In other smaller surveys, two anti-HDV IgG-positive patients were found without the possibility of HDV RNA confirmation. In total, only 3 of 329 HBsAg-positive patients (0.91%) tested positive for anti-HDV IgG antibodies, and none of 220 tested positive for HDV RNA. Conclusion: The available data show that Slovakia is one of the countries with a very low prevalence of HDV infection, reaching less than 1% in HBsAg-positive patients. Routine testing for hepatitis D is lacking in Slovakia, and therefore it is necessary to implement testing of all HBsAg-positive individuals according to international recommendations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background & Aims: Infection with the hepatitis D virus (HDV) causes the most severe form of viral hepatitis with a high risk to develop clinical complications of liver disease. In addition, hepatitis delta has been shown to be associated with worse patient‐reported outcomes. Until recently, only pegylated interferon alfa could be used to treat hepatitis delta. Methods: Here, we investigated quality of life (QOL) as assessed by the Short Form 36 Health Survey (SF‐36) in patients undergoing antiviral therapy with pegylated interferon alfa (PEG‐IFNa‐2a)‐based treatment in the HIDIT‐II trial. HIDIT‐II was a randomized prospective trial exploring PEG‐IFNa‐2a with tenofovir disoproxil (TDF) or placebo for 96 weeks in patients with compensated hepatitis delta. Surveys completed by 83 study participants before, during, and after treatments were available. Results: Overall, we observed a reduced QOL of HDV patients compared with a reference population, both in physical as well as mental scores. Interestingly, PEG‐IFNa‐2a treatment showed only minor impairment of the QOL during therapy. Moreover, HDV‐RNA clearance was not associated with relevant changes in physical or social SF‐36 scores, whereas an improvement of fibrosis during treatment was associated with increased QOL. Overall, slight improvements of the QOL scores were observed 24 weeks after the end of treatment as compared with baseline. TDF co‐treatment had no influence on QOL. Conclusions: Overall, our findings suggest that PEG‐IFNa‐2a was reasonably tolerated even over a period of 96 weeks by hepatitis D patients reporting SF‐36 questionnaires. Of note, several patients may benefit from PEG‐IFNa‐2a‐based therapies with off‐treatment improvements in quality of life. [ABSTRACT FROM AUTHOR]

Historically, viral hepatitis has been a considerable public health problem in Central Asian countries, which may have worsened after the dissolution of the Soviet Union. However, up-to-date seroepidemiological studies are lacking. The aim of the present study was, therefore, to provide current estimates of the seroprevalence of viral hepatitis in Kyrgyzstan, one of the economically least developed countries in the region. We conducted a population-based cross-sectional study in 2018 in the capital of Kyrgyzstan, Bishkek (n = 1075). Participants, children and adults, were recruited from an outpatient clinic. The data were collected during face-to-face interviews. A blood sample (6 mL) was collected from each participant and tested with ELISA for the presence of serological markers for five viral hepatitides (A, B, C, D, and E). Post-stratification weighing was performed to obtain nationally representative findings. The overwhelming majority of the study participants were positive for anti-HAV (estimated seroprevalence, 75.3%; 95% confidence interval, 72.5–77.9%). The weighted seroprevalence estimates of HBsAg, anti-HCV, and anti-HDV were 2.2% (1.5–3.3%), 3.8% (2.8–5.1%), and 0.40% (0.15–1.01%), respectively. Anti-HEV seropositivity was 3.3% (2.4–4.5%). Of the 33 HBsAg-positive participants, five (15%) were anti-HDV-positive. Our study confirms that Kyrgyzstan remains a highly endemic country for hepatitis virus A and C infections. However, seroprevalences of HBV and HDV were lower than previously reported, and based on these data, the country could potentially be reclassified from high to (lower) intermediate endemicity. The observed anti-HEV seroprevalence resembles the low endemicity pattern characteristic of high-income countries. [ABSTRACT FROM AUTHOR]

Hepatitis Delta is a disease caused by exposure to hepatitis B (HBV) and hepatitis D (HDV) viruses, usually with a more severe clinical outcome when compared to an HBV monoinfection. To date, the real prevalence of HDV infection is underestimated and detection methods are poorly available, especially in more endemic regions. Therefore, a one-step RT-qPCR method for quantification of HDV-RNA was developed. Biological samples were selected between 2017 and 2023 from patients at the Ambulatório Especializado em Hepatites Virais of the Centro de Pesquisa em Medicina Tropical de Rondônia and Serviço de Assistência Especializada and underwent the test developed by this study and a second quantitative RT-qPCR assay. The slope of the initial quantitative assay was − 3.321 with an efficiency of 100.04% and amplification factor equal to 2. Analysis of the repeatability data revealed a Limit of Quantification of 5 copies/reaction and Limit of Detection (95%) of 2.83 copies per reaction. In the diagnostic sensitivity tests, there was an accuracy of 97.37% when compared to the reference test. This assay proved to be highly efficient and reproducible, making it a valuable tool to monitor hepatitis Delta patients and assess the risk of disease progression, as well as the effectiveness of treatment. [ABSTRACT FROM AUTHOR]

The hepatitis D virus (HDV) or delta hepatitis is the most difficult form of viral hepatitis to treat. It is also the most aggressive, with the most rapid evolution to cirrhosis, hepatocellular carcinoma, and death. HDV is found globally with areas of greater prevalence, known as hotspots. Due to the dependence of HDV on the hepatitis B virus (HBV), it is likely that as HBV vaccination rates increase the population vulnerable to HDV will decrease. There is currently no HDV vaccine, leaving those infected with HBV vulnerable to HDV. HDV utilizes the host for almost all its replicative cycle, leading to a paucity of true antiviral targets. Diagnosis depends on accurate testing for HDV, and as testing has improved and expanded, the full extent of HDV has increasingly been appreciated. Although not satisfactory, the mainstay of therapy thus far has been interferon alpha and liver transplant where indicated. However, as the molecular virology of HDV has been unlocked, there has been a corresponding development of multiple therapeutic options. It is these therapeutic options that hold the promise of cure. Unmet needs include identifying patients infected with HDV, accurate noninvasive staging of their liver disease, and easy to administer curative therapies. It is hoped that the next decade will bring us substantively closer to meeting all unmet needs and closer towards the eradication of HDV. [ABSTRACT FROM AUTHOR]

The article presents the discussion on valid therapies to cure hepatitis D infection. Topics include HDV, the smallest viral pathogen infecting humans having biologic features similar to those of the viroids of plants; and RNA replicates without assistance from HBV where HDV relies on HBV for all other functions of its life cycle including viral packaging, infectivity, and transmission.

BACKGROUND: Coinfection with hepatitis D virus (HDV) accelerates the progression of liver disease associated with chronic hepatitis B. Bulevirtide inhibits the entry of HDV into hepatocytes. METHODS: In this ongoing phase 3 trial, patients with chronic hepatitis D, with or without compensated cirrhosis, were randomly assigned, in a 1:1:1 ratio, to receive bulevirtide subcutaneously at 2 mg per day (2-mg group) or 10 mg per day (10-mg group) for 144 weeks or to receive no treatment for 48 weeks followed by bulevirtide subcutaneously at 10 mg per day for 96 weeks (control group). Patients will complete 96 weeks of additional follow-up after the end of treatment. The primary end point was a combined response at week 48 of an undetectable HDV RNA level, or a level that decreased by at least 2 log10 IU per milliliter from baseline, and normalization of the alanine aminotransferase (ALT) level. The key secondary end point was an undetectable HDV RNA level at week 48, in a comparison between the 2-mg group and the 10-mg group. RESULTS: A total of 49 patients were assigned to the 2-mg group, 50 to the 10-mg group, and 51 to the control group. A primary end-point response occurred in 45°/o of patients in the 2-mg group, 48% in the 10-mg group, and 2% in the control group (P<0.001 for the comparison of each dose group with the control group). The HDV RNA level at week 48 was undetectable in 12% of patients in the 2-mg group and in 20% in the 10-mg group (P=0.41). The ALT level normalized in 12% of patients in the control group, 51% in the 2-mg group (difference from control, 39 percentage points [95% confidence interval {CI}, 20 to 56]), and 56% in the 10-mg group (difference from control, 44 percentage points [95% CI, 26 to 60]). Loss of hepatitis B virus surface antigen (HBsAg) or an HBsAg level that decreased by at least 1 log10 IU per milliliter did not occur in the bulevirtide groups by week 48. Headache, pruritus, fatigue, eosinophilia, injection-site reactions, upper abdominal pain, arthralgia, and asthenia were more common in the 2-mg and 10-mg groups combined than in the control group. No treatment-related serious adverse events occurred. Dose-dependent increases in bile acid levels were noted in the 2-mg and 10-mg groups. CONCLUSIONS: After 48 weeks of bulevirtide treatment, HDV RNA and ALT levels were reduced in patients with chronic hepatitis D. (Funded by Gilead Sciences; MYR 301 ClinicalTrials .gov number, NCT03852719). [ABSTRACT FROM AUTHOR]

Hepatitis D virus (HDV), also referred to as hepatitis delta virus, is the smallest virus capable of causing human disease. It is unable to replicate on its own and can only propagate in the presence of hepatitis B virus (HBV). Infection with both HBV and HDV frequently results in more severe disease than HBV alone, with higher instances of cirrhosis, liver failure and hepatocellular carcinoma (HCC). Thus, there is a need for effective treatment for HDV; however, currently approved treatment options are very limited both in terms of their efficacy and availability. This makes the management of HDV a challenge for physicians. In this review, we look at the background, diagnosis and treatment of HDV, informed by our hospital data, to set out the optimal management of HDV; we also explore novel treatment options for this disease. [ABSTRACT FROM AUTHOR]

Hepatitis D virus (HDV) infection represents the most serious form of chronic hepatitis. Turkey is among the countries with high HDV and intermediate hepatitis B virus prevalence. In Turkey, hepatitis B virus (HBV) vaccine series was included in the routine vaccination program in 1998. There have been regional differences in prevalence of HBV and HDV. Although a decline in HDV prevalence is estimated, there are uncertainties about the epidemic patterns of it. HDV prevalence was studied in varying groups and geographic regions. In this study, we aimed to analyse hepatitis D epidemiology in all groups and geographic regions in recent 35 years. During the study period of 35 years, 111 publications were noted. The analysis was done on the basis of three periods: 1999 and before (Period 1), 2000–2009 (Period 2), and 2010 and after (Period 3). The groups studied included inactive carrier state, chronic hepatitis B, all HBsAg‐positive individuals and special groups. Among inactive HBV carriers, HDV prevalence did not change significantly over three decades. Among patients with chronic hepatitis, studies reported decreasing (from Period 1 to Period 2) and then increasing (from Period 2 to period 3) HDV prevalence. The studies including all HBsAg‐positive patients reported decreasing (from Period 1 to Period 2) and then increasing (from Period 2 to period 3) HDV prevalence. Cumulative data of these 3 groups were taken to reveal HDV prevalence in HBV‐infected patients, and it showed decreasing (from Period 1 to Period 2) and then increasing (from Period 2 to period 3) HDV prevalence. Cumulative data of these 3 groups analysed according to the geographic regions of the country showed that Eastern and Southeastern Anatolia regions still have a high burden of HDV. The study showed that although HDV prevalence decreased from 8.3% in Period 1 to 4.8% in Period 2, it tended to increase 5.5% in Period 3. HDV infection is still a healthcare problem in Turkey. [ABSTRACT FROM AUTHOR]

Bulevirtide (BLV) is an entry inhibitor blocking entry of HBsAg into hepatocytes by interfering with the bile acid transporter Na+‐taurocholate co‐transporting polypeptide. We here investigated if bile acid levels before or during BLV treatment would correlate with HDV RNA declines. We studied 20 patients with compensated HDV infection receiving a daily dose of 2 mg bulevirtide subcutaneously qd for at least 24 weeks. ALT levels improved in all patients including 13/20 patients showing normal ALT values at treatment Week 24. An HDV RNA drop of at least 50% was evident in 20/20 patients at Week 24 including 10 patients showing a ≥ 2 log HDV RNA decline. Elevated bile acid levels were detected already before treatment in 10 patients and further increased during BLV administration with different kinetics. Baseline bile acids were associated with higher transient elastography values (p =.0029) and evidence of portal hypertension (p =.0004). Bile acid levels before treatment were associated with HDV RNA declines throughout therapy, but not at Week 24 (rho = −0.577; p =.0078; rho = −0.635, p =.0026; rho = −0.577, p =.0077; rho = −0.519, p =.0191; rho = −0.564, p =.0119 and rho = −0.393, p =.087 at treatment Weeks 2, 8, 12, 16, 20 and 24, respectively). However, bile acid increases during treatment were not associated with HDV RNA or ALT declines at any of the time points. BLV‐induced increases in bile salts do not correlate with HDV RNA declines suggesting that the inhibitory effects of BLV on NTCP differ between blocking bile acid transport and hindering HBsAg entry. If baseline bile salt levels could be useful to predict virological response remains to be confirmed. [ABSTRACT FROM AUTHOR]

Na+/taurocholate cotransporting polypeptide (NTCP) is a member of the solute carrier (SLC) family 10 transporters (gene symbol SLC10A1) and is responsible for the sodium-dependent uptake of bile salts across the basolateral membrane of hepatocytes. In addition to its primary transporter function, NTCP is the high-affinity hepatic receptor for hepatitis B (HBV) and hepatitis D (HDV) viruses and, therefore, is a prerequisite for HBV/HDV virus entry into hepatocytes. The inhibition of HBV/HDV binding to NTCP and internalization of the virus/NTCP receptor complex has become a major concept in the development of new antiviral drugs called HBV/HDV entry inhibitors. Hence, NTCP has emerged as a promising target for therapeutic interventions against HBV/HDV infections in the last decade. In this review, recent findings on protein–protein interactions (PPIs) between NTCP and cofactors relevant for entry of the virus/NTCP receptor complex are summarized. In addition, strategies aiming to block PPIs with NTCP to dampen virus tropism and HBV/HDV infection rates are discussed. Finally, this article suggests novel directions for future investigations evaluating the functional contribution of NTCP-mediated PPIs in the development and progression of HBV/HDV infection and subsequent chronic liver disorders. [ABSTRACT FROM AUTHOR]

Objective To investigate the status and molecular epidemiology of hepatitis D virus（HDV） infection in the gathering area of Mongolian population in Inner Mongolia Autonomous Region of China. Methods A total of 230 patients with positive hepatitis B surface antigen（HBsAg） who attended Inner Mongolia International Mongolian Hospital from April 2019 to October 2020 were enrolled, and according to related information, they were divided into hepatitis B+liver cirrhosis group（n=18） and hepatitis B group（n=212）. According to HBsAg quantification with a cut-off value of 250 IU/mL, the patients were divided into HBsAg ＜250 IU/mL group（n=104） and HBsAg ≥250 IU/mL group（n=126）. ELISA was used to detect HDV antibody, and quantitative real-time PCR was used to measure HDV RNA in patients with positive HDV antibody. Genotyping was performed for HDV RNA-positive samples. The chi-square test was used for comparison of categorical data between two groups. Results The positive rate of HDV antibody was 16.09%, and among the patients with positive HDV antibody, the positive rate of HDV RNA was 91.89%. Among the 18 patients with hepatitis B and liver cirrhosis, the positive rate of HDV antibody was 44.44%, and among the patients with positive HDV antibody, the positive rate of HDV RNA was 100%. There were 104 patients with HBsAg ＜250 IU/mL, among whom only 3 patients（2.88%） were positive for hepatitis D antibody, and there were 126 patients with HBsAg ≥250 IU/mL, with a positive rate of HDV antibody of 26.98%. Genotype 1 was observed in all the samples that could be genotyped. Conclusion There is a relatively high infection rate of HDV in Inner Mongolia Autonomous Region, especially in patients with HBsAg ≥250 IU/mL or those with liver cirrhosis. It is necessary to strengthen the detection of hepatitis D in HBsAg-positive patients and perform early diagnosis and treatment to prevent the further progression of hepatitis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Aims: 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). Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Hepatitis D is a global public health issue, and the infection rate and genotype of HDV infection vary greatly across different regions. The overlapping infection of hepatitis D virus (HDV) in patients with chronic hepatitis B virus (HBV) infection can accelerate disease progression, but hepatitis D has not been taken seriously to a large extent. Xinjiang in China is an area with a high incidence rate of hepatitis B, but there is a lack of research on hepatitis D. This article discusses the prevalence of HDV infection in Xinjiang and briefly reviews the prevalence rate of HDV infection in Xinjiang, the molecular epidemiology of HDV among different ethnic groups, and the current status of HDV infection in neighboring countries, so as to provide a reference for the conduct of molecular epidemiological research on HDV and disease prevention and control in Xinjiang. [ABSTRACT FROM AUTHOR]

Hepatitis D is a severe form of viral hepatitis caused by co-infection with hepatitis D virus (HDV) and hepatitis B virus (HBV) or superinfection of HDV in HBV carriers. There is still a huge gap in the diagnosis of hepatitis D due to insufficient emphasis on this disease for a long time. With the advances in related studies in recent years, the academia and the medical industry have gradually realized the harm of hepatitis D, and meanwhile, breakthroughs in drug development have also brought new opportunities for the treatment or even cure of hepatitis D. These advances greatly increase the demand for the diagnosis of hepatitis D. HDV antibodies are the key markers for the diagnosis of hepatitis D. This article summarizes and compares the detection methods for HDV antibodies including total HDV antibodies, IgG, and IgM and discusses related important issues, so as to understand the current status of the detection of HDV antibodies and provide a reference for developing better diagnostic tools for hepatitis D. [ABSTRACT FROM AUTHOR]

Since the discovery of hepatitis D virus (HDV) in the 1970s, Chinese scholars have started to conduct extensive studies on HDV and hepatitis D (HD). By searching for related articles published on the platforms of Chinese scientific and technological journals and the journals in PubMed database by Chinese scholars, this article comprehensively analyzes and summarizes the advances and scientific findings in HDV and HD by Chinese scholars from basic to clinical research from the perspective of historical development. Over the past years, Chinese scholars have conducted extensive research on the establishment of detection techniques and methods, the construction of infected animal models, the function and application of ribozymes, and clinical diagnosis and manifestation. The research findings in the past 40 years have laid a foundation for further research on the virological characteristics, infection mechanism, and immune response and injury of HDV, the clinicopathological changes of HD, and related antiviral treatment. [ABSTRACT FROM AUTHOR]

Hepatitis D virus (HDV) infection is an important health problem around the world. The epidemiology of HDV infection has been changed significantly over the past 10 years due to widespread hepatitis B vaccination and human migration. HDV infection can manifest as co-infection or superinfection. Patients with HBV/HDV co-infection have a significantly higher risk of liver cirrhosis and hepatocellular carcinoma than those with HBV infection alone. Research and development are being conducted for new therapeutic drugs for hepatitis D, some of which have entered phase Ⅲ clinical trials. These drugs will replace the current therapies with lower efficacy. [ABSTRACT FROM AUTHOR]

Bulevirtide recently received conditional approval from the EMA for the treatment of chronic hepatitis delta, but the ideal duration of therapy is unknown. Herein, we describe the first case of hepatitis delta cure following 3 years of bulevirtide monotherapy in a patient with compensated cirrhosis and esophageal varices. During the 72-week off-bulevirtide follow-up, virological and biochemical responses were maintained. In the off-therapy liver biopsy, intrahepatic HDV RNA and hepatitis D antigen were undetectable, <1% of hepatocytes were hepatitis B surface antigen positive and all were negative for hepatitis B core antigen. Ishak grading and staging were improved following treatment. [ABSTRACT FROM AUTHOR]

Hepatitis delta virus (HDV) is a small RNA virus which needs Hepatitis B Surface Antigen for its envelope, for entry into hepatocytes and secretion. HDV chronic infection affects around 12 million people worldwide. HDV infection is believed to be the most severe form of viral hepatitis, with a high risk of developing cirrhosis and hepatocellular carcinoma. Pegylated interferons has been used and recommended by guidelines, although not approved, with low efficacy and poor tolerability. Bulevirtide (entry inhibitor) has been recently conditionally approved by the European Medicines Agency. These treatments have many advantages, but they have also limitations since there are non‐responders to these previous therapies. There is an urgent need to develop new drugs. In this article, we review antiviral treatments under development for HDV chronic infection (except bulevirtide reviewed in a specific article), including those in the HBV cure programme, outlining their respective mechanisms‐of‐action. [ABSTRACT FROM AUTHOR]

Chronic hepatitis Delta (CHD) is a rare and severe form of chronic viral hepatitis. Until recently, the only therapeutic approach has been the off‐label use of a 48 weeks course of PegInterferon alpha (PegIFNα), that was characterized by suboptimal efficacy and burdened by significant side effects that limited treatment applicability in patients with advanced liver disease. In July 2020, European Medicines Agency (EMA) conditionally approved the entry inhibitor Bulevirtde (BLV) at the dose of 2 mg/day for the treatment of adult patients with compensated CHD. Efficacy and safety of BLV in CHD have been evaluated in clinical trials either as monotherapy or in combination with PegIFNα. These results were confirmed by real‐life studies, which also evaluated long‐term BLV monotherapy in patients with advanced compensated cirrhosis. Notwithstanding these promising results there are still several issues to be addressed, such as the optimal duration of the treatment, the rates of off‐therapy responses, as well as the long‐term clinical benefits. This review summarizes updated and current literature data about clinical trials and real‐life studies with BLV monotherapy and/or in combination with PegIFNα. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Delta Hepatitis is considered the most severe form of hepatitis, with varied prevalence, genotype distribution and risk factors worldwide. Current knowledge of global epidemiology is limited due to variable screening practices for HDV. Here, we summarize what is currently known about the prevalence of testing and prevalence of HDV positivity globally. [ABSTRACT FROM AUTHOR]

Hepatitis D virus (HDV) causes one of the most severe forms of hepatitis in people with chronic hepatitis B (CHB) infection. Timely and accurate assessment of hepatitis delta virus (HDV) and disease stratification is mandatory for thorough pre‐therapeutic evaluation for prioritizing treatment and outcome prediction. Viral biomarkers associated with HDV and hepatitis B virus (HBV) are crucial to aid in diagnosis, and monitoring of serum viral nucleic acids for both viruses is recommended. Liver biopsy remains the gold standard for staging of liver fibrosis and grading of histological activity and should remain central for diagnostic purposes, but is also of importance for research to enhance our understanding of HDV. The emergence of novel non‐invasive tests for the assessment of liver fibrosis in HDV patients coupled with the well‐recognized potential complications of liver biopsy has resulted in reduced utility of liver biopsy in clinical practice. Preliminary data suggest that these emerging non‐invasive modalities appear to be reliable, and their use is supported, similar to other viral hepatitis. Nevertheless, further validation is required before their widespread adoption into clinical practice. [ABSTRACT FROM AUTHOR]

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Infection with both Hepatitis B (HBV) and D (HDV) virus causes more severe liver damage than HBV alone. Superinfections among chronic HBV infected cohorts often lead to HDV persistence with rapid progression to cirrhosis, necessitating continuous surveillance to determine their prevalence and relative contribution to liver pathology. A cross-sectional study among hospital outpatients in Ekiti and Osunstates was conducted using random sampling technique. Blood samples were collected from 410 participants and tested for HBV serological markers. All samples positive for HBsAg samples were tested for Hepatitis D virus antigen (HDAg), serum anti-HDV IgM, and serum anti-HDV IgG using enzyme-linked immunosorbent assay kits. The prevalence of HBV infection among the 410 samples was 12.4% (CI 9.5–15.9). Past HBV exposure was detected in 120 (29.2%), while 147(35.8%) were susceptible to HBV infection. Among the HBsAg positive individuals, 9.8% were hepatitis D antigen (HDAg) positive, while 3.9% and 1.9% were positive for IgG anti-HDV and IgM anti-HDV, respectively. Risk factors associated with HBV infections in this study were multiple sexual partners and sharing of sharp objects. Our investigation has verified the endemicity of HBV in Nigeria and revealed that HBV- HDV co-infection is highly prevalent in south-west Nigeria. [ABSTRACT FROM AUTHOR]

Hepatitis D virus (HDV) infection is highly prevalent in patients with chronic hepatitis B (CHB). AASLD guidelines recommend a risk‐based screening approach. Our aim was to ascertain if the risk‐based approach leads to appropriate HDV screening, identify targets to improve screening rates, and study HDV clinical burden. CHB patients screened for HDV from 01/2016 to 12/2021 were identified. Level of training and specialty of providers ordering HDV screening tests were determined. HDV seropositive (HDV+) patient charts were reviewed for the presence of individual risk factors per the AASLD guidelines to determine if they met screening criteria. The severity of liver disease at the time of HDV screening was compared between the HDV+ group and a matched (based on age, hepatitis B e antigen status, BMI and sex) HDV seronegative (HDV−) group. During the study period, 1444/11,190 CHB patients were screened for HDV. Most screening tests were ordered by gastroenterology (90.2%) specialists and attending physicians (80.5%). HDV+ rate was 88/1444 (6%), and 72 HDV+ patients had complete information for analysis. 18% of HDV+ patients would be missed by a risk‐based screening approach due to unreported or negative risk factors (see Table). A significantly higher number of HDV+ patients had developed significant fibrosis (p = 0.001) and cirrhosis (p < 0.01) by the time of screening than HDV− (n = 67) patients. In conclusion, targeted interventions are needed towards trainees and primary care clinics to improve screening rates. Current risk‐based criteria do not appropriately screen for HDV. It is time for universal screening of HDV in CHB patients. [ABSTRACT FROM AUTHOR]

We have set up a new session intended for students and fellows targeting the management of viral hepatitis in consultation. This session was co-animated by Professor Marc Bourlière and Doctor Isabelle Rosa. During two hours, clinical cases of patients with chronic viral hepatitis were presented. Several key messages emerged. With regard to hepatitis C, the screening procedures for at-risk populations were recalled. The simplified management pathway is intended for patients who are treatment-naive, without comorbidities, and with compensated disease. Treatment is based on 8 to 12 weeks of a pangenotypic antiviral treatment. A negative viral load measured by PCR performed 12 weeks after the end of the treatment indicates the cure of the viral hepatitis. The management of chronic hepatitis B is complex, the use of liver biopsy is low, and non-invasive testing should be performed annually. Treatment is started according to the criteria of viral load > 2000 IU/ml and elevated transaminases. Screening for hepatocellular carcinoma is based on the PAGE B score. In case of high risk, screening is based on a biannual liver ultrasound. Finally, do not forget to perform a Delta serology in any patient with a positive HBsAg. [ABSTRACT FROM AUTHOR]