People infected with both hepatitis B virus (HBV) and hepatitis Delta virus (HDV) face a higher mortality risk than those mono-infected with HBV. As unhealthy behaviours can influence liver disease progression, we compared the effects of various behavioural factors on all-cause mortality among people with chronic hepatitis B (CHB), with or without chronic hepatitis Delta (CHD). We used 5-year follow-up data from people with CHB participating in the French ANRS CO22 HEPATHER cohort. A Cox proportional hazards model helped determine whether the pattern of risk factors for all-cause mortality differed according to CHD status. Of the 3884 people included, 183 had CHD and 154 died during follow-up. After multivariable adjustment, daily soft drink consumption significantly increased mortality risk in people with CHD and almost reached significance in those without CHD (adjusted hazard ratio (aHR) [95% CI]: 6.09 [2.40-15.48], p < 0.001, and 1.58 [0.97-2.56], p = 0.066 respectively). Moreover, past or current unhealthy alcohol use and tobacco smoking were both associated with a higher risk of mortality in all people with CHB (1.74 [1.09-2.79], p = 0.020, and 1.61 [1.13-2.31], p = 0.009 respectively). Daily soft drink consumption significantly increased all-cause mortality in people with CHD. Unhealthy alcohol use and tobacco smoking were associated with a higher mortality risk in all people with CHB. Education about healthy eating and support for smoking cessation and alcohol reduction could greatly improve health and survival of people with CHB, with and without CHD.

Background: Worldwide, an estimated 296 million individuals are chronic carriers of hepatitis B virus (HBV), with approximately 5% also coinfected with hepatitis delta virus (HDV). In Brazil, HBV and HDV are endemic in the states of the Western Amazon. This study is aimed at characterizing a cohort of patients coinfected with HBV and HDV and comparing their clinical and epidemiological profiles with those of HBV monoinfected individuals. Methods: The study involved a retrospective clinical analysis of individuals monoinfected with HBV and coinfected with HDV, conducted between 2017 and 2018 in Rondônia, Brazil. Results: A total of 324 patients were enrolled in the study, comprising 302 individuals with HBV monoinfection and 22 with HBV-HDV coinfection. Patients with HDV exhibited significantly more clinical signs of advanced liver disease. Using APRI and FIB-4 scores with cut-off values established for HBV, over 40% of HDV-infected patients had values indicative of advanced liver fibrosis, compared to 5%-10% in the HBV monoinfected group. Across all evaluated parameters of liver disease, HDV patients displayed more severe characteristics, with 45.5% already showing signs of advanced liver disease at the time of enrollment. Conclusion: Our study underscores the importance of the clinical analysis of hepatitis delta as a more aggressive disease model compared to hepatitis B in the population of the Western Brazilian Amazon, highlighting its significance as a public health concern in the region.

HDV infection is the most severe form of chronic hepatitis. However, studies on outcomes and causes of death in a US-born population, with primarily horizontal transmission of HDV, are lacking. The aim of this study was to conduct a national study of patients with hepatitis D to understand the natural history and outcomes compared to patients with HBV infection.

In a national cohort of 4817 veterans infected with HBV tested for HDV (99.6% US-born, 3.3% HDV-positive) over a 23-year period, we used multivariable models to identify the factors associated with a composite outcome of HCC, decompensation, and liver-related mortality, and all-cause mortality of patients with HDV compared to HBV mono-infection. HDV coinfection (vs. HBV mono-infection) was associated with a significantly higher incidence of composite liver-related outcomes at both 5 (23.84 vs. 7.98, p < 0.001) and 10 years (19.14 vs. 10.18, p < 0.001), respectively. The most common cause of death was liver-related (33.8% for HDV vs. 24.7% for HBV), followed by nonhepatic malignancies (15.6% vs. 14.8%), cardiac (11.7% vs. 15.2%), and lung disease (5.2% vs. 3.7%). In multivariable models, HDV was associated with an increased risk of composite liver outcomes (adjusted hazard ratio: 2.57, 95% CI: 1.87-3.52, p < 0.001) and all-cause mortality (adjusted hazard ratio: 1.52, 95% CI: 1.20-1.93, p < 0.001).

In a predominantly US-born cohort of veterans, HDV coinfection was associated with an increased risk of liver-related outcomes and all-cause mortality. Our findings support widespread testing for early identification of HDV.

Hepatitis D virus (HDV) affects nearly 5% of people globally who are chronically infected with hepatitis B virus, according to the World Health Organisation. The prevalence of HDV in the United States is considered lower than in other countries. However, HDV seroprevalence studies of the US population are limited, and reported seroprevalences vary. To improve diagnoses, universal HDV testing of hepatitis B surface antigen (HBsAg)-positive specimens has been proposed. The objective of this study was to estimate the prevalence of HDV infection within the United States in HBsAg-positive specimens. Unique deidentified remnant HBsAg-positive specimens submitted for routine clinical testing to Quest Diagnostics, representing all 10 Health and Human Services (HHS) regions, were included. Reflex testing of HBsAg-positive specimens for HDV antibody testing, and further testing of positive specimens for HDV RNA, was conducted from July 2023 to June 2024 for 5251 HBsAg-positive specimens. The cohort was 45% female, with mean ages of 50.8 (M) and 49.4 (F) years. The seroprevalence of anti-HDV was 2.2% [95% CI: 1.8%-2.6%; range: 2.5%-4.1%]. Of 107 anti-HDV-positive specimens, 28% were positive for HDV RNA (viral load range: 94-7,480,000 IU/mL: n = 23; Detected < 40 IU/mL: n = 7). This is the first nationwide seroprevalence study examining HBsAg-positive samples collected from 10 HHS regions across the United States, which offers an overview of the prevalence of HDV in the United States through the use of HbsAg-positive remnant specimens in proportion to regional population sizes. Expanded screening for HDV would help identify patients who may benefit from HDV-related interventions.

The updated EASL Clinical Practice Guidelines on the management of hepatitis B virus (HBV) infection provide comprehensive, evidence-based recommendations for its management. Spanning ten thematic sections, the guidelines address diagnostics, treatment goals, treatment indications, therapeutic options, hepatocellular carcinoma surveillance, management of special populations, HBV reactivation prophylaxis, post-transplant care, HBV prevention strategies, and finally address open questions and future research directions. Chronic HBV remains a global health challenge, with over 250 million individuals affected and significant mortality due to cirrhosis and hepatocellular carcinoma. These guidelines emphasise the importance of early diagnosis, risk stratification based on viral and host factors, and tailored antiviral therapy. Attention is given to simplified algorithms, vaccination, and screening to support global HBV elimination targets. The guidelines also discuss emerging biomarkers and evolving definitions of functional and partial cure. Developed through literature review, expert consensus, and a Delphi process, the guidelines aim to equip healthcare providers across disciplines with practical tools to optimise HBV care and outcomes worldwide.

This study aims to evaluate the prevalence of undiagnosed hepatitis delta in southern Spain (Andalusia) and assess the effectiveness and cost-efficiency of implementing reflex testing for hepatitis D detection in HBsAg-positive patients. A multicenter ambispective study was conducted in 17 Andalusian hospitals. The retrospective phase (January 2018-June 2022) analyzed diagnostic processes for hepatitis delta in HBsAg-positive patients. The prospective phase (October 2022-March 2023) implemented reflex testing, performing anti-HDV serology on all HBsAg-positive patients without prior testing. HDV RNA testing followed for those who tested anti-HDV-positive. In the retrospective phase, out of 18,583 HBsAg-positive patients, anti-HDV tests were performed on 3,436 (18%), identifying 205 (6%) positive cases. HDV RNA was tested in 158 (77%) anti-HDV-positive patients, with 69 (44%) testing positive. In the prospective phase, out of 2,384 HBsAg-positive patients without prior anti-HDV testing, 2,293 (96%) were tested, identifying 109 (4.7%) positive cases. HDV RNA was analyzed in 97 (89%) anti-HDV-positive patients, with 30 (31%) testing positive. Reflex testing increased anti-HDV detection by 77%, resulting in a fourfold increase in detecting anti-HDV-positive patients and a threefold increase in detecting HDV RNA-positive patients, reducing undiagnosed HDV RNA-positive cases to 4% compared to 45% with clinical practice. Cost analysis indicated a saving of €265,954 with reflex testing. Reflex testing improves HDV detection, reduces costs, and simplifies diagnosis, making it an efficient strategy for managing chronic hepatitis D patients.

Hepatitis Delta virus (HDV) requires co-infection with hepatitis B virus (HBV) and increases the risk of hepatitis-related morbidity and mortality compared to HBV mono-infection. HBV/HDV co-infected patients will likely benefit from new HDV antiviral drugs, but reliable estimates of co-infection rates are lacking due to limited HDV testing of HBV-infected patients.

First-time blood and bone tissue donors in the Netherlands (2006-2023) with a newly diagnosed chronic HBV infection were retrospectively tested for HDV antibodies, and for HDV RNA if HDV antibodies were detected. HBV genotyping using phylogenetic analysis was performed to determine the most likely origin of HBV infection.

HBV-DNA was detected in 254/758.081 (0.034%) first-time donors in the Netherlands. HBsAg-positive first-time donors had a median age of 43 years (IQR: 33-52), were predominantly male (67%), mostly first- or second-generation migrants (76%) and HBV (sub)genotype strongly correlated with the country of birth. HDV testing was performed for 200 first-time donors with chronic (HBsAg-positive) HBV infection: 5 donors (2.5%) had HDV antibodies, and 1 donor (0.5%) also had detectable HDV RNA. None of the 17 donors with occult (HBsAg-negative) HBV infection had experienced HDV infection.

Chronic HBV/HDV co-infection in first-time donors in the Netherlands is extremely rare, affecting 0.00013% of all first-time donors, and only 0.5% of HBsAg-positive first-time donors consisting predominantly of migrants from high(er) HDV-endemic countries. Despite low HBV/HDV co-infection rates, a one-time HDV reflex testing strategy for HBsAg-positive patients remains essential to identify patients and to initiate antiviral treatment if needed to reduce the risk of serious liver disease.

Circular RNAs (circRNAs) are emerging as important regulatory molecules in both host and viral systems, acting as microRNA sponges, protein decoys or scaffolds, and templates for protein translation. Host-derived circRNAs are increasingly recognized for their roles in immune responses, while virus-encoded circRNAs, especially those from DNA viruses, have been shown to modulate host cellular machinery to favor viral replication and immune evasion. Recently, RNA virus-encoded circRNAs were also discovered, but evidence suggests that they might be generated using a different mechanism compared to the circRNAs produced from the host and DNA viruses. This review highlights recent advances in our understanding of both host and virus-derived circRNAs, with a focus on their biological roles and contributions to pathogenesis. Furthermore, we discuss the potential of circRNAs as biomarkers and their application as therapeutic targets or scaffolds for RNA-based therapies. Understanding the roles of circRNAs in host-virus interactions offers novel insights into RNA biology and opens new avenues for therapeutic strategies against viral diseases and associated cancers.

Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, carrying a greater risk of developing cirrhosis and its complications. For decades, pegylated interferon alpha (PegIFN-α) has represented the only therapeutic option, with limited virological response rates and poor tolerability. In 2020, the European Medicines Agency approved bulevirtide (BLV) at 2 mg/day, an entry inhibitor of hepatitis B virus (HBV)/hepatitis delta virus (HDV), which proved to be safe and effective as a monotherapy for up to 144 weeks in clinical trials and real-life studies, including patients with cirrhosis. Long-term BLV monotherapy may reduce decompensating events in patients with cirrhosis. The combination of BLV 2 mg with PegIFN-α increased the HDV RNA undetectability rates on-therapy but not off-therapy, compared with PegIFN monotherapy. However, combination therapy, but not BLV monotherapy, may induce hepatitis B surface antigen (HBsAg) loss in some patients. The PegIFN lambda study has been discontinued due to liver toxicity issues, while lonafarnib boosted with ritonavir showed limited off-therapy efficacy in a phase 3 study. Nucleic acid polymer-based therapy is promising but large studies are still lacking. New controlled trial data come from molecules, such as monoclonal antibodies and/or small interfering RNA, that target HBsAg or HBV RNAs, which demonstrated not only profound HDV suppression, but also HBsAg decline.While waiting for new compounds to be approved as monotherapy or in combination, BLV monotherapy 2 mg/day remains the only approved therapy for CHD, at least in the European Union region.

The impact of bulevirtide in patients awaiting liver transplantation (LT) for decompensated liver disease and/or hepatocellular carcinoma (HCC) is unclear. We assessed clinical, virological, and biochemical responses to bulevirtide in patients with chronic hepatitis delta virus (HDV) awaiting LT and compared outcomes with a cohort of similar untreated patients.

Consecutive HDV-infected patients waiting for LT since bulevirtide approval were included. Patients receiving 2 mg of bulevirtide daily had clinical, biological, and virological data collected at baseline, Week 24, Week 48, at LT, and post-LT. Patients not receiving bulevirtide had data collected at baseline, LT, and post-LT for comparison.

Forty-one patients from nine LT centers were included. In the bulevirtide group (20 patients; mean age 52.8 ± 9.98 years; 75% male), 65%, 10% and 25% were Child-Pugh A, B and C, respectively. Fifteen completed 48 weeks of therapy. At 48 weeks, median HDV RNA decreased by 2.56 log IU/mL (p = 0.004). Virological and biochemical responses were obtained in 73.3% and 66.6% of patients. Twelve patients (60%) underwent LT. No serious adverse events occurred. Bulevirtide improved liver function, enabling one (7.1%) HCC patient to undergo chemoembolization while on the WL and leading to delisting of three (15%) other patients. In untreated patients (mean age 42.9 ± 7.9 years; 76.2% Child-Pugh C), none were delisted. Three-month transplant-free survival was 76.9% in the bulevirtide group versus 36.7% (p = 0.007) in the control group.

Bulevirtide demonstrates safety and efficacy in HDV-infected patients listed on the LT waiting list and may potentially improve pre-transplant outcomes.

In the last few years there have been innovations in HDV therapy which have brought new excitement in the scientific community also considering the few therapeutic opportunities. Recently, new molecular targets have been identified, both in monotherapy and in combination with peginterferon alpha (PegIFNα). Evaluating this review of the literature of the last ten years, HDV-related chronic hepatitis seems to have become a potentially curable disease, a statement that was unthinkable a few years ago. There are old and new weapons at our disposal. The old weapons are PegIFNα and recently PegIFN-lambda (PegIFNλ). PegIFNα, for which there are more data, appears to be an excellent combination regimen, if not contraindicated, both for Bulevirtide (BLV), data supported by important clinical trials and real-world studies, and probably for lonarfanib, although in the latter case the results are not yet definitive as the studies are fewer. However, data on long-term follow-up are needed.

Chronic hepatitis D (CHD) is a severe form of chronic viral hepatitis. The estimated hepatitis delta prevalence in Spain is around 5% of patients with hepatitis B. Reimbursement of new antiviral therapies (Bulevirtide, BLV) was delayed in our country until February 2024. We aimed to characterize the clinical profile of patients with HDV/HBV infection in Spain and current barriers in their management at the time of BLV approval.

Multicenter registry including patients with positive anti-HDV serology actively monitored in 30 Spanish centers. Epidemiological, clinical and virological variables were recorded at the start of follow-up and at the last visit.

We identified 329 anti-HDV patients, 41% were female with median age 51 years. The most common geographical origin was Spain (53%) and East Europe (24%). Patients from Spain were older and had HCV and HIV coinfection probably associated to past drug injection (p<0.01). HDV-RNA was positive in 138 of 221 assessed (62%). Liver cirrhosis was present at diagnosis in 33% and it was more frequent among viremic patients (58% vs 25%, p<0.01). After a median follow-up of 6 (3-12) years, 44 (16%) resolved infection (18 spontaneously and 26 after Peg-INF). An additional 10% of patients developed cirrhosis (n=137) during follow-up (45% had portal hypertension and 14% liver decompensation). Liver disease progression was associated to persisting viremia.

One-third of the patients with CHD already have cirrhosis at diagnosis. Persistence of positive viremia is associated to rapid liver disease progression. Importantly, barriers to locally determine/quantify HDV-RNA were present.

Despite European guidelines recommending anti-hepatitis D virus (HDV) screening for all hepatitis B surface antigen (HBsAg)-positive cases, screening rates remain insufficient.

We analysed anti-HDV screening rates in primary care and implemented prospective HDV screening in HBsAg-positive cases identified in the preventive medical examination from the age of 35 ("Check-Up 35+").

From 2012 to 2021, we reviewed anti-HDV and HDV RNA test rates in HBsAg-positive patients at 11 sites of a large German laboratory group. From 2022 to 2023, we prospectively screened HBsAg-positive samples from the "Check-Up 35+" for anti-HDV. Anti-HDV positive patients were then contacted again for HDV RNA testing.

Retrospectively, 2792/13,905 (20%) HBsAg-positive cases were tested for anti-HDV, with 142/2792 (5.1%) being positive. HDV RNA was tested in 57/142 (40%) anti-HDV-positive cases, with 26/57 (46%) being positive. In the prospective screening, 1159/225,901 (0.51%) individuals were HBsAg-positive. Of these, 700 (60%) were tested for anti-HDV, with 18/700 (2.6%) positive test results. 4/18 (22%) were successfully contacted again for HDV RNA analysis, with one case testing positive. Neither the HBsAg nor the anti-HDV positive result was known prior to screening in these cases. Anti-HDV testing could not be performed in 459/1159 (40%) HBsAg-positive cases, primarily due to insufficient blood sample volume (310/459 cases, 68%), with others missed due to logistical errors.

Retrospective data show insufficient anti-HDV screening in clinical routine. The prospective anti-HDV screening provides a blueprint for using existing hepatitis B virus screening programms for population-based HDV double reflex testing, provided that adequate logistical prerequisites are established.

German Clinical Trial Register: DRKS00029180.

Hepatitis delta virus (HDV) infection has an aggressive disease course and is the most difficult to treat of the human hepatitis viruses. In Denmark, as in many countries, the national prevalence of HDV has not been established. Based on diagnoses and laboratory test results in national healthcare registries, we estimated that the prevalence of current HDV infection amongst patients with chronic hepatitis B was 3.1% and the general population prevalence approximately 4 in 100,000.

Background: Viral hepatitis, particularly hepatitis B (HBV) and hepatitis C (HCV), is highly prevalent in Mongolia. Moreover, Mongolia has the highest prevalence of hepatitis delta virus (HDV) globally, with over 60% of HBV-infected individuals also co-infected with HDV. Since HBV/HDV infections accelerate liver disease progression more compared to HBV infection alone, urgent national health measures are required. Method: This study presents a clinicopathological analysis of 49 hepatocellular carcinoma cases surgically resected at the Mongolia-Japan Hospital of the Mongolian National University of Medical Sciences. Results: HBV infection was found in 27 (55.1%) cases of all HCC cases. Immunohistochemical staining of the liver revealed that 14 (28.6%) cases were HDV antigen-positive in the HCC cases. HDV-positive cases exhibited significantly higher inflammatory activity compared to HDV-negative cases, with lymphocytic infiltrates predominantly composed of CD4-positive cells. Furthermore, HDV-positive cells were spatially distinct from HBs antigen-positive cells, suggesting that HDV-infected cells may interfere with HBV replication. No significant differences in fibrosis or in tumor characteristics were observed between the HDV-positive and negative cases. Early diagnosis of HBV/HDV infections is essential for appropriate treatment and to prevent further domestic transmission of the virus. However, routine testing for HDV infection is rarely conducted in Mongolia. Since HDV-positive cells are morphologically indistinguishable from surrounding HDV-negative cells, routine histopathological analysis may not be sufficient enough to detect HDV infection. Conclusions: Based on this clinicopathological study, CD4 and CD8 immunostaining can be considered an adjunctive diagnostic tool in cases with significant lymphocytic infiltration and hepatocellular damage. Additionally, HDV screening using blood and tissue samples may be recommended to ensure accurate diagnosis.

Hepatitis D virus (HDV) prevalence data and country-specific HDV guidelines are not widely available in the Gulf Cooperation Council (GCC) states. We developed consensus recommendations to guide healthcare professionals, policymakers, and researchers in improving HDV management and patient health outcomes in three GCC states: Kuwait, Saudi Arabia, and the United Arab Emirates. A consensus panel comprising hepatology experts (n = 6) from the three GCC societies was formed. The panel identified two broader areas related to clinical practice (screening and diagnosis, and treatment and management), addressed critical questions, and developed draft recommendations in February 2024. The strength of the final set of recommendations was subjected to consensus voting in March 2024. A majority was defined apriori with a two-thirds vote (67%). The paper outlines those recommendations alongside showcasing the current epidemiology of HDV in the GCC states, emphasizing the variability in prevalence, demographic patterns, and region-specific risk factors. It also highlights the current state of screening and diagnosis practices, identifying key obstacles, such as access to advanced screening protocols and diagnostic tools. Furthermore, HDV treatment landscape and preventative strategies are outlined, focusing on vaccination, public health initiatives, and the crucial role of public awareness and education. Ethical and sociocultural considerations are discussed, underscoring the importance of culturally sensitive healthcare practices. These recommendations present a comprehensive overview of the challenges and strategies for managing HDV in these states. Policy recommendations are provided to support HDV management, including standardizing care protocols and promoting public health measures.

Hepatocellular carcinoma (HCC) accounts for >90% of primary liver cancer cases, and chronic infections with hepatitis B virus (HBV) and hepatitis D virus (HDV) are major contributors.

A comprehensive literature review was conducted using the MEDLINE (PubMed) database, focusing on studies related to HBV, HDV, and HCC.

HBV contributes to HCC through mechanisms like viral integration into the host genome, chronic inflammation, and immune modulation, leading to genomic instability and altered cell signaling. HDV exacerbates HBV-induced liver damage, accelerating fibrosis and cirrhosis, and significantly increasing HCC risk. Antiviral therapies and vaccinations have majorly reduced the burden of HBV-related HCC, but HDV remains challenging to treat due to limited therapeutic options. Emerging treatments like Bulevirtide showed promising results.

This review highlights the critical impact of HBV and HDV co-infections on HCC development, emphasizing the need for more effective therapeutic strategies. While advances in antiviral therapies have reduced the incidence of HBV-related HCC, the high burden of HDV-related complications persists. Future research should focus on improving treatments for HDV and understanding its unique contribution to HCC pathogenesis.

Chronic hepatitis D virus (HDV) is associated with rapid progression to severe liver disease. Co-infection with HDV and hepatitis B virus is likely underdiagnosed due to challenges in diagnostic test availability and standardization. With new HDV antiviral options, HDV RNA quantification is essential for understanding the patient response to treatment. To this end, a quantitative real-time reverse transcription PCR (qRT-PCR) assay utilizing synthetic RNA calibrators and a conversion factor to quantify HDV RNA in WHO international standard units (IU/mL) was developed and validated.

qRT-PCR primers and probes were selected within the ribozyme region. Thermocycling conditions and reactions were optimized. Synthetic RNA transcripts were prepared as quantification standards and calibrators. Transcript dilutions (log10 8 to log10 1 copies/μL) were calibrated against the WHO standard and a conversion factor calculated to convert copies/μL to IU/mL. Assay validation and evaluation was conducted, including use of specimens from 8 HDV genotypes and comparison to a commercial assay.

The assay lower limit of detection was determined by probit analysis to be 11 IU/mL (8.63-15.78 95% CI). Inter- and intra-assay coefficient of variation analysis showed 96.6% precision and 90.6% accuracy. A conversion factor of 16.5 was used to convert copies/μL to IU/mL. All 8 HDV genotypes were quantified by the assay and commercial assay comparison showed good agreement.

The developed assay has clinical utility for the sensitive and specific quantitative monitoring of HDV RNA, appropriate for medium to high throughput laboratories.

Genetic polymorphisms in the sodium taurocholate cotransporting peptide (NTCP encoded by SLC10A1) have been described, but their role in untreated and treated patients with chronic hepatitis delta (CHD) remains unknown. Virological response (VR) to the NTCP inhibitor bulevirtide (BLV) was achieved at week 48 by >70% of patients with CHD, but nearly 15% experienced virological non-response (VNR) or partial response (PR). This study aimed to evaluate whether NTCP genetic polymorphisms affect baseline HDV RNA load and response to BLV in patients with CHD.

BLV-untreated and -treated patients were enrolled in a retrospective cross-sectional and longitudinal study. Clinical and virological characteristics were collected at baseline and up to 96 weeks in the BLV-treated patients. NTCP genetic polymorphisms were identified by Sanger sequencing.

Of the six NTCP polymorphisms studied in 209 untreated patients with CHD, carriers of the rs17556915 TT/CC (n = 142) compared to CT (n = 67) genotype presented with higher median HDV RNA levels (5.39 vs. 4.75 log10 IU/ml, p = 0.004). Of 209 patients receiving BLV monotherapy at 2 mg/day, 76 were evaluated at week 24 and 40 up to week 96. Higher mean baseline HDV RNA levels were confirmed in TT/CC (n = 43) compared to CT (n = 33) carriers (5.38 vs. 4.72 log10 IU/ml, p = 0.010). Although 24-week VR was comparable between TT/CC and CT carriers (25/43 vs. 17/33, p = 0.565), the former group presented VNR more often than PR (9/11 vs. 9/23, p = 0.02) at week 24. 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment.

The NTCP rs17556915 C>T genetic polymorphisms may influence baseline HDV RNA load both in BLV-untreated and -treated patients with CHD and may contribute to identifying patients with different early virological responses to BLV.

Although several sodium taurocholate cotransporting polypeptide (NTCP) genetic polymorphisms have been described, no data are available on their potential role in modifying HDV RNA load or treatment response to bulevirtide (BLV) in patients with chronic hepatitis delta (CHD). In this study, we demonstrated that patients with CHD, either treated or untreated, carrying NTCP rs17556915 TT/CC, presented higher baseline HDV RNA levels compared to those with the CT genotype. Higher HDV RNA levels in TT/CC carriers compared to CT carriers were also confirmed in patients with CHD treated with BLV monotherapy up to 96 weeks. Furthermore, carriers of TT/CC, compared to CT genotype, more frequently showed viral non-response (VNR) than partial response (PR) at week 24 of BLV treatment, and 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment. This is the first study demonstrating a potential role of NTCP genetic polymorphisms in influencing HDV viral load and early virological response to BLV monotherapy. Since no direct HDV resistance to BLV has been described so far, if confirmed in larger studies, the genetic polymorphisms in NTCP may help identify patients with different patterns of early virological response to BLV.

Current US guidelines recommend risk-based testing for hepatitis delta virus (HDV) in persons with chronic hepatitis B (CHB). While there is debate as to whether a risk-based or universal testing approach is most effective, limited data exist on universal HDV testing programs in the United States. We performed a 1-year pilot study evaluating the outcomes of a universal HDV testing approach among US veterans with CHB. All consecutive adults with CHB receiving care at hepatology clinics at a single-centre Veterans Affairs Health System from 1 October 2022 to 30 September 2023 were prospectively tested for anti-HDV antibody (anti-HDV). Patients who were anti-HDV Ab-positive were subsequently tested for HDV RNA. Comparison of HDV testing between groups utilised chi-square testing. A total of 91 consecutive CHB patients (90.0% male, mean age 60.9 ± 14.1 years, 73.9% Asian, 26.1% non-Asia, 16.5% cirrhosis and 17.1% with active or past history of drug use) had anti-HDV ordered. Overall, 76.9% (n = 70) completed anti-HDV testing; 4.3% (n = 3) were positive. HDV RNA testing was ordered in all three patients; two patients completed HDV RNA testing and one had detectable HDV RNA. No significant differences in completion of anti-HDV testing was observed by age, sex, race/ethnicity, cirrhosis status or drug use history. Among a single-centre prospective cohort study piloting a universal HDV testing approach, one patient with viremic HDV was identified. Implementing true reflex testing of all CHB patients with anti-HDV, followed by automated HDV RNA testing for anti-HDV-positive patients would improve the HDV testing cascade and timely diagnosis of HDV.

Data on the economic burden of chronic hepatitis B infection in Japan are lacking. This study investigated healthcare resource utilization and costs of chronic hepatitis B infection and liver complications in Japan.

This non-interventional study used the Medical Data Vision database. For the first analysis, a population with prevalent chronic hepatitis B infection and absence of liver complications was identified and further stratified by nucleos(t)ide analog treatment history. In the second analysis, patients with prevalent chronic hepatitis B infection and incident liver complications were identified. Patients were followed for 1 year in the first analysis and 2 years in the second analysis. Numbers of all-cause outpatient, inpatient, emergency hospitalizations, medication use, and associated costs per person-year were described across patients without/with nucleos(t)ide analog treatment and in those without/with liver complications.

For patients with chronic hepatitis B infection, 75,967 had no liver complications while 17,678 patients had liver complications. All-cause outpatient visits were the largest contributor to healthcare resource utilization and costs, for patients without and with liver complications, and were numerically higher for patients on nucleos(t)ide analog than not. Patients with liver complications had numerically higher all-cause healthcare resource utilization and total costs than patients without complications.

Japan has a high economic burden of chronic hepatitis B infection, particularly in patients with liver complications. Optimizing treatment to prevent complications may reduce this burden.

Data on the economic burden of chronic hepatitis B infection in Japan are lacking. This study investigated healthcare resource utilization and costs of chronic hepatitis B infection and liver complications in Japan.

This non-interventional study used the Medical Data Vision database. For the first analysis, a population with prevalent chronic hepatitis B infection and absence of liver complications was identified and further stratified by nucleos(t)ide analog treatment history. In the second analysis, patients with prevalent chronic hepatitis B infection and incident liver complications were identified. Patients were followed for 1 year in the first analysis and 2 years in the second analysis. Numbers of all-cause outpatient, inpatient, emergency hospitalizations, medication use, and associated costs per person-year were described across patients without/with nucleos(t)ide analog treatment and in those without/with liver complications.

For patients with chronic hepatitis B infection, 75,967 had no liver complications while 17,678 patients had liver complications. All-cause outpatient visits were the largest contributor to healthcare resource utilization and costs, for patients without and with liver complications, and were numerically higher for patients on nucleos(t)ide analog than not. Patients with liver complications had numerically higher all-cause healthcare resource utilization and total costs than patients without complications.

Japan has a high economic burden of chronic hepatitis B infection, particularly in patients with liver complications. Optimizing treatment to prevent complications may reduce this burden.

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.

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.

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.

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.

The present study highlights the need for increased screening and monitoring of HDV infection. Reflex testing helps to identify HDV-infected individuals.

Chronic hepatitis B virus (HBV) infection is a significant global public health concern, and the clearance of HBV is closely linked to the activity of HBV-specific T cells, which is regulated by various co-suppressor molecules. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is among these co-suppressor molecules which induces T cell exhaustion by competitively inhibiting CD28 and dampening the function of HBV-specific T cells. CTLA-4 also plays a role in the regulation of T helper (Th) cell differentiation and influences cytokine release. In addition, CTLA-4 can impact glucose metabolism in hepatocellular carcinoma through its interaction with T regulatory (Treg) cells. This review aims to provide a comprehensive overview of the existing literature related to the role of CTLA-4 in HBV patients across different subsets of T cells. Additionally, we propose a discussion on the possible mechanisms through which CTLA-4 may contribute to HBV infection, as well as the development of HBV-induced cirrhosis and hepatocellular carcinoma.

Hepatitis delta virus (HDV) is a defective virus needing the envelope provided by hepatitis B virus (HBV) in order to enter liver cells and propagate. Chronic HDV infection is considered the most severe viral hepatitis, resulting in accelerated fibrosis progression until cirrhosis and its complications (hepatocellular carcinoma, liver decompensation) compared with HBV mono-infected patients. Off-label treatment with interferon has represented the only treatment option in the last 40 years, resulting in suboptimal virological response rates and being limited by safety issues especially in patients with advanced cirrhosis. Recently, the first HBV-HDV entry inhibitor Bulevirtide (BLV) has been approved by the European Medicines Agency (EMA) for treatment of chronic compensated HDV.

This review summarises most recent updates on HDV epidemiology, diagnosis and treatment, with a special focus both on clinical trials and real-life studies about BLV. An overview on new HDV compounds under development is also provided.

BLV, the HBV-HDV entry inhibitor, has shown promising safety and efficacy data in clinical trials and in real-life studies, also in patients with advanced cirrhosis and portal hypertension. However, according to EMA label treatment is currently intended long-term until clinical benefit and predictors of responses are still undefined. The potential combination with PegIFNα seems to increase virological and clinical responses. New compounds are under development or in pipeline for treatment of HDV.

After more than 40 years since HDV discovery, new treatment options are currently available to provide efficient strategies for chronic hepatitis Delta.

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.

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 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.

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% (64 938 [95% CI 33055-97 392] 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 75 005 (95% CI: 42187-108 393) persons with HDV in the U.S.

Including both FB and U.S.-born persons, we estimated that 1.971 M and 75 005 persons were living with CHB and HDV, respectively, in the U.S. in 2022.

The aim of this study was to describe the demographic and clinical characteristics of hepatitis B virus (HBV) associated hepatocellular carcinoma (HCC), analyse the risk factors associated with HBV-associated HCC, and to provide some references to the diagnosis and treatment of HCC.

This study retrospectively enrolled 730 patients, including 390 patients with chronic hepatitis B (CHB) as controls, and 340 patients with CHB complicated with HCC as patients. Relevant information and medical records of these participants were collected, including age, sex, cigarette smoking, alcoholism, diabetes mellitus (DM), hypertension, coronary heart disease (CHD), cirrhosis, occupation, ascites, HBV-DNA load, the qualitative analysis of HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb serological markers, and levels of alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), gamma-glutamyltransferase (GGT), TNM stage, tumor size and tumor number. The T test, Chi-square test, non-parametric rank-sum test, logistic regression analyses were used to explore the influencing factors and their degree of association with HCC in patients with HBV.

The proportion of smoking, alcoholism, married status, DM, hypertension, and the rate of HBV-DNA with a viral load of ≥500 copies/mL were significantly higher in the HCC group than in the controls (all p<0.05). Cirrhosis was more common among patients with CHB+HCC than in controls (p=0.013). The proportion of patients with HBsAg, HBeAb, and HBcAb positive was greater in CHB+HCC group than that in CHB group. Logistic regression analysis indicated that age ≥60 years (OR: 1.835, 95% CI: 1.020-3.302, p=0.043), HBeAb positive (OR: 9.105, 95% CI: 4.796-17.288, p<0.001), antiviral treatment with entecavir (OR: 2.209, 95% CI: 1.106-4.409, p=0.025), and GGT (OR: 1.004, 95% CI: 1.001-1.007, p=0.002) were risk factors for HCC in patients with CHB.

Advanced age, HBeAb positive, antiviral treatment with entecavir, and GGT were independent risk factors for HCC in HBV patients.

Chronic liver disease presents a significant global health burden, characterized by several etiologies, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), chronic hepatitis B virus infection, and chronic hepatitis C virus infection. This review explored current epidemiological trends and projections for each etiology, looking into their respective burdens and challenges. MASLD, formerly known as nonalcoholic fatty liver disease, is the most prevalent cause of chronic liver disease, and its global incidence and prevalence are steadily rising. ALD, fueled by increased alcohol consumption, is also on the rise, with concerning implications for future mortality rates. Chronic hepatitis B and C infections remain major public health concerns, particularly in specific regions of the world, necessitating concerted efforts for screening and treatment. The coronavirus disease 2019 (COVID-19) pandemic has impacted the epidemiology of chronic liver disease, exacerbating mortality rates and disrupting healthcare services. Mental health issues arising from the pandemic further complicate the treatment of chronic liver disease, making comprehensive healthcare strategies essential. Despite advancements in treatment, chronic liver disease continues to impose a substantial economic burden, emphasizing the importance of preventive measures and early intervention. In conclusion, ongoing surveillance and research efforts are crucial for understanding and addressing the evolving landscape of chronic liver disease. Comprehensive strategies that encompass prevention, screening, and treatment of its different etiologies are essential for mitigating its impact and improving patient outcomes.

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.

The prevalence of Hepatitis Delta Virus (HDV) is underestimated and the assessment of fibrosis is recommended for this infection. We tested the diagnostic impact of an annual screening for HDV serology in Hepatitis B Surface Antigen (HBs Ag) chronic carriers and followed the progression of fibrosis in these patients.

Between January 2014 and October 2021, we annually tested all chronic HBs Ag-positive patients for HDV antibody (HDV Ab). Each HDV Ab positive patient underwent annually repeated elastometry. Patients with detectable HDV RNA levels (group 1) were compared to those with undetectable HDV RNA (group 2).

We identified 610 chronic HBs Ag-positive patients, and repeated screening for HDV Ab was performed in 534 patients. Sixty (11%) patients were HDV Ab positive at baseline and were considered as "coinfected". Seven cases of HDV superinfection were diagnosed through repeated screening. In co-infected patients, cirrhosis was initially diagnosed in 12/60 patients and developed in six patients during follow-up. HDV RNA PCR was performed in 57/67 patients and 27 had detectable levels (group 1). Cumulative incidence of cirrhosis at 7 years was 13.8% (95% CI 0-30) in group 1 and 0 (95% CI 0-0) in group 2 (p = 0.026).

A systematic screening for HDV in chronic HB Ag carriers revealed a high prevalence of HDV Ab. Repeated serological screening enables the diagnosis of superinfections in asymptomatic patients. Regular assessment of fibrosis using elastometry leads to the identification of incidental cirrhosis in patients with detectable HDV RNA.

The hepatitis D virus (HDV) is a compact, enveloped, circular RNA virus that relies on hepatitis B virus (HBV) envelope proteins to initiate a primary infection in hepatocytes, assemble, and secrete new virions. Globally, HDV infection affects an estimated 12 million to 72 million people, carrying a significantly elevated risk of developing cirrhosis, liver failure, and hepatocellular carcinoma (HCC) compared to an HBV mono-infection. Furthermore, HDV-associated HCC often manifests at a younger age and exhibits more aggressive characteristics. The intricate mechanisms driving the synergistic carcinogenicity of the HDV and HBV are not fully elucidated but are believed to involve chronic inflammation, immune dysregulation, and the direct oncogenic effects of the HDV. Indeed, recent data highlight that the molecular profile of HCC associated with HDV is unique and distinct from that of HBV-induced HCC. However, the question of whether the HDV is an oncogenic virus remains unanswered. In this review, we comprehensively examined several crucial aspects of the HDV, encompassing its epidemiology, molecular biology, immunology, and the associated risks of liver disease progression and HCC development.