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Micro‐RNAs (miRNAs) are involved in the modulation of viral replication and host immune antiviral response. Using next‐generation sequencing, we investigated the miRNome profile of circulating extracellular vesicles in 20 patients with chronic hepatitis D virus (HDV) infection undergoing pegylated interferon alpha (Peg‐IFNα) treatment. Circulating miRNAs' expression was analysed according to virologic response (i.e., HDV RNA clearance maintained at least 6 months after the end of therapy). Overall, 8 patients (40%) achieved a virologic response to Peg‐IFNα treatment. At baseline, 14 miRNAs were differentially expressed between responders and non‐responders; after 6 months of Peg‐IFNα treatment, 7 miRNAs (miR‐155‐5p, miR‐1246, miR‐423‐3p, miR‐760, miR‐744‐5p, miR‐1307‐3p and miR‐146a‐5p) were consistently de‐regulated. Among de‐regulated miRNAs, miR‐155‐5p showed an inverse correlation with HDV RNA (at baseline: rs = −0.39, p = 0.092; at 6 months: rs = −0.53, p = 0.016) and hepatitis B surface antigen (HBsAg) (at baseline: rs = −0.49, p = 0.028; at 6 months: rs−0.71, p < 0.001). At logistic regression analysis, both miR‐155‐5p (at baseline: OR = 4.52, p = 0.022; at 6 months: OR = 5.30, p = 0.029) and HDV RNA (at baseline: OR = 0.19, p = 0.022; at 6 months: OR = 0.38, p = 0.018) resulted significantly associated to virologic response. Considering that Peg‐IFNα still has a relevant role in the treatment of patients with chronic hepatitis D infection, the assessment of EV miR‐155‐5p may represent an additional valuable tool for the management of HDV patients undergoing Peg‐IFNα treatment. [ABSTRACT FROM AUTHOR]

ABSTRACT Screening for hepatitis D virus (HDV) is recommended for all individuals with hepatitis B virus (HBV) infection. Coinfected individuals experience more severe liver‐related outcomes. We determined the HDV testing and coinfection rates and all‐cause mortality among those infected with HBV. We used the US Department of Veterans Affairs (VA) healthcare system's national databases to identify individuals with HBV infection. We determined the proportion of individuals referred to gastroenterologists/hepatologists, or infectious diseases providers, and the proportion screened and tested positive for HDV. We calculated the HBV treatment rates, defined as ≥ 3 months of continuous prescription with an approved drug. Finally, we calculated all‐cause mortality stratified by HDV coinfection and HBV treatment status. Among 44,951 individuals with at least one positive HBsAg, HBeAg or HBV DNA test, 5964 (13.3%) were screened for HDV (180 [3.0%] tested positive), and 28,291 (62.9%) were referred to gastroenterology/hepatology or infectious diseases. Treatment for HBV was prescribed for 73 (40.5%) of HDV‐coinfected and 2425 (41.9%) HDV‐uninfected individuals. All‐cause mortality rate per 100 person‐years was lower among those without HDV coinfection (2.98 for untreated HBV, 2.53 for treated HBV; p < 0.001) compared with those with HDV coinfection (5.14 for untreated HBV, 3.0 for treated HBV; p = 0.02). Kaplan–Meier curves demonstrated a significantly higher mortality among HDV‐coinfected individuals who were not treated for HBV (log‐rank p < 0.0001). Screening rates for HDV among HBV‐infected individuals are suboptimal. While HDV coinfection is associated with higher all‐cause mortality, HBV treatment may confer a survival benefit. [ABSTRACT FROM AUTHOR]

Recent advances in studies exploring the roles of extracellular vesicles (EVs) in viral transmission and replication have illuminated hepatotropic viruses, such as hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), and hepatitis E (HEV). While previous investigations have uncovered these viruses' ability to exploit cellular EV pathways for replication and transmission, most have focused on the impacts of exosomal pathways. With an improved understanding of EVs, four main subtypes, including exosomes, microvesicles, large oncosomes, and apoptotic bodies, have been categorized based on size and biogenic pathways. However, there remains a noticeable gap in comprehensive reviews summarizing recent findings and outlining future perspectives for EV studies related to hepatotropic viruses. This review aims to consolidate insights into EV pathways utilized by hepatotropic viruses, offering guidance for the future research direction in this field. By comprehending the diverse range of hepatotropic virus-associated EVs and their role in cellular communication during productive viral infections, this review may offer valuable insights for targeting therapeutics and devising strategies to combat virulent hepatotropic virus infections and the associated incidence of liver cancer. [ABSTRACT FROM AUTHOR]

Background and Aims: Chronic hepatitis D infection is the most severe form of viral hepatitis and can rapidly progress to cirrhosis or hepatocellular carcinoma. Despite recommendations for systematic screening of hepatitis B surface antigen (HBsAg)‐positive individuals, data from real‐world studies have reported a low frequency of hepatitis D (or delta) virus (HDV) screening. Our cross‐sectional analysis evaluated the diagnostic cascade for hepatitis D infection in tertiary centres and described the characteristics of HDV‐positive patients. Methods: A total of 6772 individuals who tested HBsAg positive for the first time between 2018 and 2022 were retrospectively included. Demographic, clinical and laboratory data were analysed. Results: A total of 5748 HBsAg‐positive individuals (84.9%) were screened for HDV infection. The screening rate varied from 63% to 97% according to the screening strategy used in the centres including or not HDV reflex testing. The prevalence of HDV infection was 6.3%. HDV RNA levels were determined in 285 of the 364 (78.3%) HDV antibody screening‐positive patients, and 167 (58.6%) had active HDV infection. 66.8% were males, with a mean age of 44.9 years. A total of 97.5% were born abroad, and 92.9% were HBeAg negative. At the time of diagnosis, HDV RNA levels were 6.0 Log UI/mL; 60.1% had alanine aminotransferase >40 U/L, and 56.3% had significant fibrosis (≥F2), including 41.6% with cirrhosis. The most common genotype was HDV‐1 (75.4%). Coinfections were not uncommon: 7.4% were HIV positive, and 15.0% were HCV antibody positive. Conclusions: The present study highlights the need for increased screening and monitoring of HDV infection. Reflex testing helps to identify HDV‐infected individuals. [ABSTRACT FROM AUTHOR]

Viral hepatitis (A–E) presents a major global health challenge. In 2015, the World Health Organization (WHO) launched an initiative to eliminate viral hepatitis, with the aim of reducing new infections by 90% and deaths by 65% by 2030. Mexico is one of 38 focus countries identified by the WHO, collectively accounting for 80% of global infections and deaths. While hepatitis B and C are commonly diagnosed in Mexico, routine diagnosis for hepatitis D and E is lacking, with no specific epidemiological data available. In 2020, Mexico implemented the National Hepatitis C Elimination Program, focusing on preventing new infections, reducing complications like cirrhosis and hepatocellular carcinoma, ensuring access to treatment, and improving patient care. However, this program has not been extended to hepatitis B and E. Addressing the challenges of viral hepatitis control in Mexico requires increased resource allocation, expanded diagnosis, vaccination for hepatitis A and B, and treatment coverage for hepatitis B and C, along with multisectoral engagement. This work provides an overview of Mexico's response to the global initiative, highlighting its progress, challenges, and areas of opportunity. [ABSTRACT FROM AUTHOR]

ABSTRACT Hepatitis D virus leads to a severe form of viral hepatitis and affects nearly 5% of people living with chronic hepatitis B. Chronic infection with hepatitis D virus leads to more rapid progression to cirrhosis, hepatocellular carcinoma and ultimately liver disease‐related death compared with hepatitis B monoinfection. Health outcomes and treatment adherence can be affected by patient perception of, engagement in, and satisfaction with care. Our objective was to better understand the experiences of people with chronic hepatitis D, identify their preferred sources of information, and recognise unmet needs from their perspectives. Sixty‐seven participants from the United States and the European Union took part in monthly, online, self‐guided surveys for a minimum of 3 months with an optional extension. Participants reported feeling anxious and scared at the time of diagnosis but over time came to accept living with chronic hepatitis D. They voiced a need for access to information from trusted sources, fewer barriers to care, and shorter wait times for provider visits and test results after diagnosis. Participants experienced both physical and psychological strain living with chronic hepatitis D. Although most participants reported the ability to continue their regular activities and employment, some stated such activities were done at a reduced pace. Self‐reported overall health appeared to be closely linked with emotional support. Understanding patient perspectives, with concurrent clinician perspectives, is crucial when working toward developing solutions to fulfil unmet patient needs associated with chronic hepatitis D management and advancing health equity. [ABSTRACT FROM AUTHOR]

Background and Aims: Chronic hepatitis delta represents a major global health burden. Clinical features of hepatitis D virus (HDV) infection vary largely between different regions worldwide. Treatment approaches are dependent on the approval status of distinct drugs and financial resources. Methods: The Hepatitis Delta International Network (HDIN) registry involves researchers from all continents (Wranke, Liver International 2018). We here report long‐term follow‐up data of 648 hepatitis D patients recruited by 14 centres in 11 countries. Liver‐related clinical endpoints were defined as hepatic decompensation (ascites, encephalopathy and variceal bleeding), liver transplantation, hepatocellular carcinoma or liver‐related death. Results: Patient data were available from all continents but Africa: 22% from Eastern Mediterranean, 32% from Eastern Europe and Central Asia, 13% from Central and Southern Europe, 14% from South Asia (mainly Pakistan) and 19% from South America (mainly Brazil). The mean follow‐up was 6.4 (.6–28) years. During follow‐up, 195 patients (32%) developed a liver‐related clinical event after 3.5 (±3.3) years. Liver cirrhosis at baseline and a detectable HDV RNA test during follow‐up were associated with a worse clinical outcome in multivariate regression analysis while patients receiving interferon alfa‐based therapies developed clinical endpoints less frequently. Patients from South Asia developed endpoints earlier and had the highest mortality. Conclusions: The HDIN registry confirms the severity of hepatitis D and provides further evidence for HDV viraemia as a main risk factor for disease progression. Hepatitis D seems to take a particularly severe course in patients born in Pakistan. There is an urgent need to extend access to antiviral therapies and to provide appropriate education about HDV infection. [ABSTRACT FROM AUTHOR]

The hepatitis D virus (HDV) superinfection of individuals with chronic hepatitis B virus (HBV) infection causes severe liver damage and the poorest long-term prognosis among viral hepatitis. This is attributed to the unique pathogenic mechanisms of HDV characterized by a direct cytopathic effect on hepatocytes and a significant impairment of the host immune response. The HDV genotype largely influences the extent of the pathogenic mechanisms with consequences on disease progression towards cirrhosis, liver decompensation, or hepatocellular carcinoma. In this context, identifying the circulating HDV genotypes in European regions with high prevalence, such as Romania, is crucial for effectively managing the long-term liver health. Here, we report the first comprehensive HDV study in Romania that clinically characterizes 82 patients and performs HDV genotyping by combining the nested-PCR reaction with sequencing analysis in 49 samples with an HDV-RNA load higher than 5000 IU/mL. While all isolates in our study belong to the HDV-1 genotype, the phylogenetic analysis based on sequence data from GenBank reveals the presence of the following potential three groups: (i) Italy and France; (ii) Spain; and (iii) Turkey, Iran, Pakistan, and Germany. This broad clustering highlights the recent surge in migration to and from Western Europe and the Middle East. Equally important, no differences in viral markers, clinical and paraclinical parameters, or treatment options were observed between these identified clusters. Nevertheless, this study considerably advances the understanding of hepatitis D epidemiology and clinical aspects in Romania. [ABSTRACT FROM AUTHOR]

Viral hepatitis D (HDV infection) worsens the prognosis of HBV infection course in 80-90% of cases, accelerating fibrosis and leading to liver cirrhosis or hepatocellular carcinoma. Hepatitis D affects at least 125 000 people in Russia, and in the world, according to rough estimates, there are 15–20 million patients. The main measures to combat hepatitis D can be attributed to widespread scheduled vaccination against hepatitis B and the appointment of effective etiotropic therapy. A detailed study of the hepatitis D virus genome structure and its replication cycle allows the development of a number of drugs that target and block key mechanisms of the virus life cycle. This review provides a brief characterization of hepatitis D virus, its genome structure, key processes of its life cycle and mechanisms of genetic information realization. The review considers the main potential targets for targeted antiviral therapy of HDV infection and describes specific drugs (bulevirtide, lonafarnib, nucleic acid polymers). The review describes the mechanism of action of bulevirtide, which according to the current national clinical guidelines is a key element of antiviral therapy as monotherapy or in combination with pegylated interferons. Promising drugs affecting the processes of synthesis and post-translational modification of HDAg or reducing the production of surface proteins of hepatitis B virus are also considered. Further efforts are needed to develop safe, effective and cost-effective drugs against hepatitis D to ensure that treatment is widely available to those who desperately need it. Therefore, it is important that the life cycle of the hepatitis D virus be studied further, in greater detail, in order to develop highly effective antiviral drugs.

This study assesses the prevalence of hepatitis D virus (HDV) in people living with HIV (PLWHIV) in Greece. Given the compounding effects of HDV and hepatitis B (HBV) on liver disease progression, as well as the emergence of new therapeutic options such as bulevirtide, understanding regional disparities and the epidemiological impact of such co-infections is vital. A cross-sectional analysis was conducted utilizing 696 serum samples from PLWHIV attending five major university hospitals. The methodology included HDV antibody detection by ELISA and HDV RNA confirmation. Of the 30 HBsAg-positive samples analyzed, the study population was primarily male (93%), with a median age of 54 years. Participants had been on antiretroviral therapy for a median of 10 years, and the median CD4 count was 738 (539–1006) copies/mL. Additional serological findings revealed a 7% prevalence of hepatitis C virus (HCV) IgG antibodies and a 55% prevalence of hepatitis A virus (HAV) IgG antibodies. Seroreactivity for syphilis (RPR/VDRL/TPHA positive) was identified in 33% of the participants. The results indicated a low HDV prevalence, with only one individual (3%) testing positive for anti-HDV IgG antibodies and none for HDV RNA. This indicates a lower prevalence of HDV among PLWHIV with chronic HBV in Greece compared to global data. [ABSTRACT FROM AUTHOR]

Background and Aims: Suboptimal awareness and low rates of hepatitis delta virus (HDV) testing contribute to underdiagnosis and gaps in accurate estimates of U.S. HDV prevalence. We aim to provide an updated assessment of HDV prevalence in the U.S. using a comprehensive literature review and meta-analysis approach. Methods: A comprehensive literature review of articles reporting HBsAg seropreva-lence and anti-HDV prevalence was conducted to calculate country-specific rates and pooled prevalence of CHB and HDV using meta-analyses. Country-specific CHB and HDV rate estimates were combined with number of foreign-born (FB) persons in the U.S. in 2022 from U.S. Census Bureau to estimate total numbers of FB with CHB and HDV, respectively. These estimates were further combined with updated estimates of U.S.-born persons with CHB and HDV to yield the total number of persons with CHB and HDV. Results: In 2022, we estimated 1.971 million (M) (95% CI 1.547-2.508) persons with CHB; 1.547 M (95% CI 1.264-1.831) were FB and 0.424 M (95% CI: 0.282-0.678) were U.S.-born. The weighted average HDV prevalence among FB persons in the U.S. was 4.20% (64938 [95% CI 33055-97392] persons), among whom 45% emigrated from Asia, 25% from Africa, and 14% from Europe. When combined with updated estimates of U.S.-born persons with HDV, we estimate 75005 (95% CI: 42187-108393) persons with HDV in the U.S. Conclusions: Including both FB and U.S.-born persons, we estimated that 1.971M and 75005 persons were living with CHB and HDV, respectively, in the U.S. in 2022. [ABSTRACT FROM AUTHOR]

Bulevirtide (BLV) is a first-in-class entry inhibitor and the only approved treatment for patients chronically infected with HDV in Europe. We aimed to investigate the efficacy of BLV treatment in paired liver biopsies obtained at baseline and after 24 or 48 weeks of treatment. We performed a combined analysis of 126 paired liver biopsies derived from three clinical trials. In the phase II clinical trial MYR202, patients with chronic hepatitis D were randomised to receive 24 weeks of BLV at 2 mg, 5 mg or 10 mg/day. Patients in MYR203 (phase II) and MYR301 (phase III) received 48 weeks of BLV at 2 mg or 10 mg/day. Tenofovir disoproxil fumarate monotherapy or delayed treatment served as comparators. Virological parameters and infection-related host genes were assessed by qPCR and immunohistochemistry. At week 24, median intrahepatic HDV RNA decline from baseline was 0.9Log 10 with 2 mg (n = 7), 1.1Log 10 with 5 mg (n = 5) and 1.4 Log 10 with 10 mg (n = 7) of BLV. At week 48, median reductions were 2.2Log 10 with 2 mg (n = 27) and 2.7Log 10 with 10 mg (n = 37) of BLV, while HDV RNA levels did not change in the comparator arms. Notably, a drastic decline in the number of hepatitis delta antigen-positive hepatocytes and a concomitant decrease in transcriptional levels of inflammatory chemokines and interferon-stimulated genes was determined in all BLV-treatment arms. Despite the abundance of HBsAg-positive hepatocytes, replication and covalently closed circular DNA levels of the helper virus HBV were low and remained unaffected by BLV treatment. Blocking viral entry diminishes signs of liver inflammation and promotes a strong reduction of HDV infection within the liver, thus suggesting that some patients may achieve HDV cure with long-term treatment. Chronic infection with HDV causes the most severe form of viral hepatitis, affecting approximately 12 million people worldwide. The entry inhibitor bulevirtide (BLV) is the only recently approved anti-HDV drug, which has proven efficacious and safe in clinical trials and real-word data. Here, we investigated paired liver biopsies at baseline and after 24 or 48 weeks of treatment from three clinical trials to understand the effect of the drug on viral and host parameters in the liver, the site of viral replication. We found that BLV treatment strongly reduces the number of HDV-infected cells and signs of liver inflammation. This data implies that blocking viral entry ameliorates liver inflammation and that prolonged treatment regimens might lead to HDV cure in some patients. This concept will guide the further development of therapeutic strategies and combination treatments for patients with CHD. NCT03546621, NCT02888106, NCT03852719 [Display omitted] • Combined analysis of paired liver biopsies from three clinical trials investigating the entry inhibitor bulevirtide. • Bulevirtide strongly reduces intrahepatic HDV RNA levels and HDV-infected hepatocytes. • The reduction of infected cells reflects changes in viral loads in the serum. • Inflammatory gene expression is also decreased by bulevirtide treatment. • Intrahepatic levels of the helper virus HBV are not affected by the treatment. [ABSTRACT FROM AUTHOR]

Foreign‐born (FB) persons represent a large proportion of adults with chronic hepatitis B (CHB) in Canada due to higher prevalence rates in countries of birth for FB persons. Suboptimal awareness and low rates of hepatitis delta virus (HDV) testing contribute to underdiagnosis and gaps in accurate estimates of Canada HDV prevalence. We aim to provide an assessment of CHB and HDV prevalence in Canada using a comprehensive literature review and meta‐analysis. A comprehensive literature review of articles reporting HBsAg seroprevalence and anti‐HDV prevalence was conducted to calculate country‐specific rates and pooled prevalence of CHB and HDV using meta‐analyses. Country‐specific CHB and HDV rate estimates were combined with number of FB persons in Canada in 2021 from Statistics Canada to estimate total numbers of FB with CHB and HDV, respectively. These estimates were combined with estimates of Canada‐born persons with CHB and HDV to yield the total number of persons with CHB and HDV. In 2021, we estimated 0.550 million (M) (95% CI 0.488–0.615) persons with CHB; 0.344 M (95% CI 0.288–0.401) were FB and 0.206 M (95% CI: 0.200–0.214) were Canada‐born. The weighted average HDV prevalence among FB persons in Canada was 5.19% (17,848 [95% CI 9611–26,052] persons), among whom 50% emigrated from Asia and 31% from Africa. When combined with estimates of Canada‐born persons with HDV, we estimate 35,059 (95% CI: 18,744–52,083) persons with HDV in Canada. In conclusion, we estimate 0.550 M and 35,059 persons living with CHB and HDV, respectively, in Canada in 2021. [ABSTRACT FROM AUTHOR]

Hepatitis D virus (HDV) depends on hepatitis B virus (HBV) to enter and exit hepatocytes and to replicate. Despite this dependency, HDV can cause severe liver disease. HDV accelerates liver fibrosis, increases the risk of hepatocellular carcinoma, and hastens hepatic decompensation compared to chronic HBV monoinfection. The Chronic Liver Disease Foundation (CLDF) formed an expert panel to publish updated guidelines on the testing, diagnosis, and management of hepatitis delta virus. The panel group performed network data review on the transmission, epidemiology, natural history, and disease sequelae of acute and chronic HDV infection. Based on current available evidence, we provide recommendations for screening, testing, diagnosis, and treatment of hepatitis D infection and review upcoming novel agents that may expand treatment options. The CLDF recommends universal HDV screening for all patients who are Hepatitis B surface antigen-positive. Initial screening should be with an assay to detect antibodies generated against HDV (anti-HDV). Patients who are positive for anti-HDV IgG antibodies should then undergo quantitative HDV RNA testing. We also provide an algorithm that describes CLDF recommendations on the screening, diagnosis, testing, and initial management of Hepatitis D infection.

Introduction: Hepatitis D (Delta) Virus (HDV) infection is present worldwide, with an estimated 18 million people being infected. HDV can infect individuals who are already infected with the Hepatitis B virus (HBV), leading to severe liver disease. The global prevalence of HDV varies by geographical region. In India, there is a lack of data on HDV infection among individuals exposed to HBV. Detecting HDV infection in Hepatitis B surface Antigen (HBsAg)-positive patients can improve patient outcomes. Aim: To determine the seroprevalence of HDV in HBsAg-positive patients. Materials and Methods: This cross-sectional study was conducted in the Department of Microbiology, Shri M.P. Shah Government Medical College and Guru Gobind Singh Government Hospital in Jamnagar, Gujarat, India, over a period of one year from September 2022 to August 2023. A total of 350 HBsAg Enzyme-Linked Immunosorbent Assay (ELISA)-positive cases were included in the study. Serum samples from patients in various inpatient and outpatient departments of the hospital were tested for HBsAg infection using ELISA. After confirming positive results for HBsAg, all samples were tested for anti-HDV IgM antibodies by ELISA. Demographic and clinical findings were recorded for all patients. Statistical analysis was performed using means and percentages, and p-values were calculated using the Chi-square test to determine the seroprevalence of HDV. Results: Among the 350 HBsAg-positive cases, a higher prevalence was observed in middle-aged and older females. Ten (2.9%) cases were positive for anti-HDV antibodies. Of the 10 anti-HDV antibody-positive patients, 5 (50%) reported a history of blood transfusion. Conclusion: The seroprevalence of HDV was found to be 2.9% in HBsAg-positive patients in this study, with a predominance in middle-aged and older females. Additionally, the most common route of transmission identified was blood transfusion. [ABSTRACT FROM AUTHOR]