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Background and Aims: Chronic hepatitis D (CHD) is the most severe form of chronic viral hepatitis, with a high risk of developing hepatocellular carcinoma (HCC) and liver-related mortality. Risk stratification is needed to guide HCC surveillance strategies and to prioritize treatment with antiviral agents., Methods: We conducted a multicenter retrospective cohort of anti-HDV positive individuals managed at sites in the Netherlands and the United Kingdom. We studied the 5-year cumulative incidences of HCC and liver-related events (first of HCC, liver transplantation and liver-related mortality), in the overall cohort and among relevant subgroups., Results: We analyzed 269 anti-HDV positive individuals with a median follow-up of 4.3 years in which 47 first events occurred. The 5-year cumulative incidences of HCC and liver-related events were 3.8% and 15.6% in the overall cohort. The 5-year cumulative incidence of HCC and liver-related events for individuals without cirrhosis was 0% and 0.9% compared to 12% and 41.3% for individuals with cirrhosis (p<0.001). The 5-year cumulative incidence of HCC and liver-related events was 0% and 2.1% among individuals with low PAGE-B scores, compared to 3.2% and 21.1% with intermediate and 25.4% and 45.5% with high risk scores (p<0.001). We found comparable results for the FIB-4 score. Findings were consistent regardless of cirrhosis or detectable HDV RNA (p<0.001)., Conclusion: Anti-HDV positive individuals are at high risk of adverse liver-related outcomes. The incidences of HCC was negligible among individuals without cirrhosis and among individuals with low baseline PAGE-B and/or FIB-4 scores. Therefore, these score can be used to guide HCC surveillance strategies and potentially also for treatment prioritization., (Copyright © 2024. Published by Elsevier Inc.)

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., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Hepatitis Delta Virus (HDV), a satellite virus of Hepatitis B virus, exacerbates liver damage in affected individuals. Screening for HDV antibodies in HBsAg positive patients is recommended, but the diagnostic accuracy of serological tests remains uncertain. This review aimed to assess the diagnostic accuracy of serological tests for HDV. We searched PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Scopus etc. for relevant studies. Studies measuring the sensitivity and specificity of serological HDV tests against PCR as a reference standard were included. Pooled sensitivity and specificity for each test method and sero-marker were calculated. The review included six studies with 11 study arms, evaluating ARCHITECT immunoassay, EIA, ELISA, QMAC, RIA, and Western Blot test methods targeting Anti-HDV IgG, Total anti-HDV and Anti-HDV IgM. Sensitivities for Anti-HDV IgG, Total Anti-HDV and Anti-HDV IgM, tests were 97.4%, 51.9%, and 62.0%, respectively, with specificities of 95.3%, 80.0%, and 85.0%. Our findings, with its limited number of studies, suggest that HDV serological tests, particularly those identifying Anti IgG exhibit high accuracy and can serve as effective screening tools for HDV., (© 2024. The Author(s).)

Hepatitis D virus (HDV), which occurs as a co-infection with the hepatitis B virus (HBV), is a significant public health burden. Currently, there is a scarcity of data regarding this co-infection in the developing countries. This study aims to address the clinical prevalence of HDV among HBV-infected patients in Sulaymaniyah Governorate, Iraq. This prospective cross-sectional study, conducted from May to November 2022, screened HBV DNA-positive patients visiting Sulaimani Teaching Hospital in Sulaymaniyah governorate, Iraq, for anti-HDV antibodies and HDV RNA. The study included 150 confirmed HBV DNA-positive patients. Of these, 54.7% were male. The mean age of the patients was 49.1 ± 10.1 (18-68). Serological assessment found that 23 (15.3%) of the patients had anti-HDV IgG antibodies, suggesting past or chronic HDV infection, while 16 (10.7%) tested positive for anti-HDV IgM, indicating recent/acute infection. Further molecular analysis confirmed HDV RNA in 15 (10%) of HBV patients, indicating real HDV prevalence. The prevalence of anti-HDV and HDV RNA did not significantly differ by age, gender, marital status, residency, medical, family or medical history (p > 0.05). In conclusion, this study demonstrated a relatively high HDV prevalence among HBV patients in Sulaymaniyah Governorate, Iraq, at 10%, which stresses the need for better screening, health strategies and focused research to combat its impact., (© 2024 John Wiley & Sons Ltd.)

Chikungunya virus is an emerging pathogen with widespread distribution in regions of Africa, India, and Asia that threatens to spread into temperate climates following the introduction of its major vector, Aedes albopictus . Recent cases have been documented in Europe, the Caribbean, and the Americas. Chikungunya virus causes a disease frequently misdiagnosed as Dengue fever, with potentially life-threatening symptoms that can result in long term debilitating arthritis. There have been ongoing investigations of possible therapeutic interventions for both acute and chronic symptoms, but to date none have proven effective in reducing the severity or lasting effects of this disease. Recently, a promising vaccine candidate has received accelerated approval, indicating the importance of remedies to this emerging worldwide health threat. Nonetheless, therapeutic interventions for Chikungunya and other mosquito borne virus diseases are urgently needed yet remain elusive. The increasing risk of spread from endemic regions via human travel and commerce, coupled with the absence of a vaccine or approved therapeutic, puts a significant proportion of the world population at risk for this disease. In this report we explore the possibility of using Specific On/oFf Adapter Hepatitis Delta Virus Ribozymes as antivirals in cells infected with Chikungunya virus. The results we obtained suggest there could be some role in using these ribozyme molecules as antiviral therapies for not only Chikungunya virus, but potentially other viruses as well.

Background and Aims: 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., Method: 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., Results: 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., Conclusion: 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., (Copyright © 2024. Publicado por Elsevier España, S.L.U.)

Background & Aims: 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., Methods: 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., Results: 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 log 10  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 log 10  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., Conclusions: 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., Impact and Implications: 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., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

With the increasing momentum and success of monoclonal antibody therapy in conventional medical practices, there is a revived emphasis on the development of monoclonal antibodies targeting the hepatitis B surface antigen (anti-HBs) for the treatment of chronic hepatitis B (HBV) and hepatitis D (HDV). Combination therapies of anti-HBs monoclonal antibodies, and novel anti-HBV compounds and immunomodulatory drugs presenting a promising avenue to enhanced therapeutic outcomes in HBV/HDV cure regimens. In this review, we will cover the role of antibodies in the protection and clearance of HBV infection, the association of anti-HBV surface antigen antibodies (anti-HBs) in protection against HBV and how antibody effector functions, beyond neutralization, are likely necessary. Lastly, we will review clinical data from previous and ongoing clinical trials of passive antibody therapy to provide a state-of-the-are perspective on passive antibody therapies in combinations with additional novel agents., Competing Interests: Declaration of competing interest Adam J. Gehring provides scientific consulting/advisory services for Aligos Therapeutics, Arbutus Biopharma, Assembly Biosciences, Bluejay Therapeutics, Gilead Sciences, GSK, Janssen Pharmaceuticals, Roche, Vir Biotechnology, Virion Therapeutics, VBI and receives research funding from Aligos Therapeutics, Bluejay Therapeutics, GSK, Roche, Vir Biotechnology., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Hepatitis Delta represents a greater risk in the progression of advanced liver disease and HCC compared with HBV. The exact mechanism that determines the spontaneous clearance of delta virus or its progression to cirrhosis remains unknown. Therefore, this study aimed to analyze the clinical profile of HBV and HBV/HDV individuals in the Western Amazon., Methods: The study was carried out at the Specialized Outpatient Clinic for Viral Hepatitis belonging to the Centro de Pesquisa em Medicina Tropical de Rondônia/CEPEM. 100 individuals were included, stratified into two groups: 50 with hepatitis B virus and 50 with hepatitis Delta virus., Results: The overall mean age was 48 years. For the HBV and HDV groups, 66 % (33/50) and 54 % (27/50) were men and 56 % (28/50) and 58 % (29/50) were on antiviral treatment, respectively. Patients with detectable HDV-RNA demonstrated high levels of ALT and AST compared to individuals with undetectable HDV-RNA. Comparative analysis between HBV carriers and infected with HDV shows significant differences in terms of age, HBV-DNA levels, albumin, hepatomegaly and splenomegaly., Conclusion: Several markers were important for differentiating HBV and HDV infections. HDV-RNA detectable showed significant changes in biomarkers compared to undetectable patients, suggesting a possible worse prognostic effect in this group., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Objective: Infection with the hepatitis delta virus (HDV), a unique RNA virus that requires hepatitis B virus (HBV) antigens for its assembly, replication, and transmission, causes severe viral hepatitis. Compared to HBV monoinfection, HDV infection increases the risk of severe liver disease, necessity for liver transplant, and mortality. Global HDV prevalence estimates vary from 5% to 15% among persons with HBV, but screening guidelines for HDV are inconsistent; some recommend risk-based screening, while others recommend universal screening for all people with HBV. Among primary care providers (PCPs) in the US, there is a lack of awareness and/or insufficient adherence to current recommendations for the screening of HDV infection and management of chronic HDV., Methods: Publications were obtained by conducting literature searches between July and August 2022 using the PubMed database and by manual searches of the retrieved literature for additional references. Information was synthesized to highlight HDV screening and management strategies for PCPs. Best practices for PCPs based on current guidelines and comanagement strategies for patients with HBV and HDV infection were summarized., Results: We recommend universal screening for HDV in patients positive for hepatitis B surface antigen. Confirmed HDV infection should prompt evaluation by a liver specialist, if available, with whom the PCP can comanage the patient. PCPs should counsel patients on the expected course of the disease, lifestyle factors that may influence liver health, need for consistent disease monitoring and follow-up, and risk of disease transmission. Screening is suggested for sexual partners, household contacts, and family members, with HBV immunization recommended for those found to be susceptible. There are currently no US Food and Drug Administration-approved therapies for HDV infection; thus, management is limited to treatments for chronic HBV infection plus long-term monitoring of liver health., Conclusions: PCPs can be a valuable point of care for patients to access HDV/HBV screening, HBV immunization, and education, and can comanage patients with HBV and/or HDV infection.

The prevalence of hepatitis B and delta viruses (HBV/HDV) among people who use drugs (PWUD) remains largely unknown. In the context of one Philadelphia-based harm reduction organization (HRO), this study aimed to assess HBV/HDV prevalence and facilitate linkage to care. Participants completed a demographic HBV/HDV risk factor survey and were screened for HBV and reflexively for HDV if positive for HBV surface antigen or isolated core antibody. Fisher's exact tests and regression were used to understand relationships between risks and HBV blood markers. Of the 498 participants, 126 (25.3%) did not have hepatitis B immunity, 52.6% had been vaccinated against HBV, and 17.9% had recovered from a past infection. Eleven (2.2%) participants tested positive for isolated HBV core antibody, 10 (2.0%) for HBV surface antigen, and one (0.2%) for HDV antibody. History of incarceration was associated with current HBV infection, while transactional sex and experience of homelessness were predictive of previous exposure. This study found high rates of current and past HBV infection, and a 10% HBV/HDV co-infection rate. Despite availability of vaccine, one quarter of participants remained vulnerable to infection. Findings demonstrate the need to improve low-threshold HBV/HDV screening, vaccination, and linkage to care among PWUD. The study also identified gaps in the HBV/HDV care cascade, including lack of point-of-care diagnostics and lack of support for HROs to provide HBV services.

Infection with the hepatitis B virus (HBV) is highly prevalent globally. Over 250 million people suffer from chronic hepatitis B, and more than 800,000 patients die each year due to hepatitis B complications, including liver cancer. Although protective HBV vaccines are recommended for all newborns, global coverage is suboptimal. In adults, sexual transmission is by far the most frequent route of contagion. The WHO estimates that 1.5 million new HBV infections occur annually. Oral nucleos(t)ide analogues entecavir and tenofovir are the most frequent antivirals prescribed as HBV therapy. Almost all patients adherent to the medication achieve undetectable plasma viremia beyond 6 months of monotherapy. However, less than 5% achieve anti-HBs seroconversion, and viral rebound occurs following drug discontinuation. Therefore, nucleos(t)ide analogues need to be lifelong. New long-acting formulations of tenofovir and entecavir are being developed that will maximize treatment benefit and overcome adherence barriers. Furthermore, new antiviral agents are in development, including entry inhibitors, capside assembly modulators, and RNA interference molecules. The use of combination therapy pursues a functional HBV cure, meaning it is negative for both circulating HBV-DNA and HBsAg. Even when this goal is achieved, the cccDNA reservoir within infected hepatocytes remains a signal of past infection, and HBV can reactivate under immune suppression. Therefore, new gene therapies, including gene editing, are eagerly being pursued to silence or definitively disrupt HBV genomes within infected hepatocytes and, in this way, ultimately cure hepatitis B. At this time, three actions can be taken to push HBV eradication globally: (1) expand universal newborn HBV vaccination; (2) perform once-in-life testing of all adults to identify susceptible HBV persons that could be vaccinated (or re-vaccinated) and unveil asymptomatic carriers that could benefit from treatment; and (3) provide earlier antiviral therapy to chronic HBV carriers, as being aviremic reduces the risk of both clinical progression and transmission.

Background: In French Polynesia, hepatitis B virus (HBV) infection appears as a major risk factor for hepatocellular carcinoma (HCC), which detection rate in the Austral archipelago is among the highest in the world. Through a nationally representative cross-sectional survey of the adult population, this study aimed at assessing the prevalence of HBV, but also hepatitis C virus (HCV), and hepatitis delta virus (HDV)., Methods: A total of 1942 blood samples from participants aged 18-69 years were tested for anti-HBc, anti-HBs, HBsAg, anti-HCV IgG, and HDV RNA. Complete genome sequencing of detected HBV strains was performed., Findings: Among participants, 315/1834, 582/1834, 33/1834, 0/1857, and 0/33 tested positive for anti-HBc, anti-HBs, HBsAg, anti-HCV IgG, and HDV RNA, respectively. The population prevalence of HBsAg was estimated at 1.0% (95% CI: 0.6-1.7). All HBsAg carriers were born in French Polynesia before vaccination at birth became mandatory. In multivariate analyses, identified factors associated with HBsAg carriage included: the archipelago of residence ( p  < 0.0001), age ( p  < 0.0001), and education level ( p  = 0.0077). HBV genotypes B, C, and F were detected., Interpretation: French Polynesia has a low endemicity level of HBV and its population may be considered at low risk for HCV and HDV infection. However, prevalence of HBsAg was found concerning in Austral (3.8%; 95% CI: 1.9-7.5) and Marquesas (6.5%; 95% CI: 3.8-11) archipelagoes. In the Austral archipelago, the presence of genotype C may account for the elevated rate of HCC. Our findings warrant more efforts to improve access to detection, prevention and care to people born before the systematic vaccination policy application, and residing in higher-risk areas, to achieve HBV elimination in French Polynesia., Funding: Research Delegation of French Polynesia., Competing Interests: We declare that we have no conflicts of interest., (© 2024 The Authors.)

Recommended post-liver transplant (LT) prophylaxis in patients with hepatitis delta includes a nucleos(t)ide analogue (NA) and anti-hepatitis B immunoglobulin (HBIG) indefinitely. We analysed the use of HBIG in real-life clinical practice and its impact on HBV/HDV recurrence in 174 HDV-related LT patients from 10 Spanish liver transplant centres (1988-2018). Median post-LT follow-up was 7.8 (2.3-15.1) years and patient survival at 5 years was 90%. Most patients (97%) received HBIG in the immediate post-LT, but only 42% were on HBIG at the last control. Among those discontinuing HBIG, the median time on treatment was 18 (7-52) months. Post-LT HBsAg+ was detected in 16 (9%) patients and HBV-DNA in 12 (7%). Despite HBsAg positivity, HDV recurrence was reported only in three patients (1.7%), all of whom were not receiving NA and had discontinued HBIG. Our data suggest that a finite HBIG prophylaxis in HDV-LT is feasible, especially if high-barrier NAs are used., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden., Methods: HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti-HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti-HDV testing was analysed in relation to liver-related outcomes with logistic regression., Results: Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti-HDV screening; within a median of 1.8 months (range 0.0-57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti-HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty-five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow-up. The predictive factors for anti-HDV screening were Asian origin, diagnosis after the year 2012, HIV co-infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co-infection was the only remaining factor in multivariable analysis. Delayed anti-HDV test >5 years was independently associated with worsened liver-related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8-31.6)., Conclusion: Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low-endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: Hepatitis D virus (HDV) infection causes the most severe form of chronic viral hepatitis. However, it is still unclear to what extent the underlying cirrhosis may contribute to disease progression. The aim of this study was to compare the long-term outcome of HDV infection with HBV monoinfection in a single-center cohort of both non-cirrhotic and cirrhotic patients., Method: We retrospectively studied 175 patients with chronic hepatitis D (CHD) who were followed for at least 6 months (median of 6.3 (0.6-23.6) years). In addition, we selected 175 patients with HBV monoinfection (CHB) who were matched for gender, age, region of origin, HBeAg status, and bilirubin. Liver-related clinical end points were defined as hepatic decompensation (ascites, encephalopathy, variceal bleeding), liver transplantation, HCC, or liver-related death., Results: Clinical complications developed earlier (4.6 vs. 6.2 years) and more frequently (35.4% vs. 12.6%, p < 0.01) in CHD patients. In a multivariate Cox regression, HDV infection was independently associated with the development of end points (p < 0.01; HR: 3.0; 95% CI 1.4-6.4). However, in cirrhotic patients there were no significant differences between HBV and HDV in the development of end points. Besides, CHB patients with cirrhosis developed more frequently HCC (35.5%) than CHD patients with cirrhosis (18.5%)., Conclusion: Our results confirmed that HDV leads to a faster progression to cirrhosis compared to HBV. However, once cirrhosis is present, not HDV but the underlying cirrhosis is the dominate intrinsic risk factor for the development of liver-related end points and for the progression to HCC., (© 2023. The Author(s).)

Hepatitis delta virus (HDV) only infects patients with hepatitis B virus (HBV) due to its reliance on HBV surface proteins to form its envelope. With shared routes of transmission, HDV coinfection is estimated to occur in 15% of patients with HIV and HBV. However, HDV is often underdiagnosed and may be missed particularly in people living with HIV (PLWH) who are already on antiretroviral therapy with anti-HBV activity and coincidental HBV suppression. At the same time, HDV causes the most severe form of chronic viral hepatitis and leads to faster progression of liver disease and hepatocellular carcinoma. Thus, increased recognition and effective treatment are paramount, and as novel treatment options approach global markets, the study of their efficacy in PLWH should be pursued., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The association of hepatitis delta virus (HDV) infection with positive autoantibodies and autoimmune features has been known for decades. However, to date, very few cases of clinical autoimmune hepatitis (AIH) have been reported in association with HDV infection, most of them being in the context of treatment with peginterferon., Case Report: This case refers to a 46-year-old woman born in Guinea-Bissau who moved to Portugal in 2018 to investigate complaints of diffuse abdominal discomfort and nausea. Her initial work-up, including laboratory and liver histology, was consistent with type 1 AIH. She had HBe antigen-negative chronic hepatitis B virus infection with negative DNA and also a positive total anti-HDV antibody, with negative IgM and undetectable RNA. Therefore, after initiating prophylactic tenofovir difumarate, she was started on prednisolone followed by azathioprine, which was later stopped due to presumed hepatotoxicity. Repeated histology showed signs of viral superinfection, and she was treated with acyclovir due to a positive herpes simplex IgM, with HDV RNA remaining negative. A third flare in transaminases prompted the introduction of mycophenolate mofetil (MMF) after a thorough exclusion of additional causes of liver disease. About 6 months later, during another bout of hepatitis, HDV RNA was finally positive and classified as genotype 5. MMF was stopped, and, considering a contraindication to interferon, the patient was offered therapy with bulevirtide, which she refused for personal reasons as she is currently living in her home country., Discussion: This is a challenging case of autoimmune or "autoimmune-like" hepatitis, probably induced by chronic HDV infection. High suspicion of HDV was essential because, had the case been interpreted as refractory AIH, with escalation of immunosuppression, a more severe course of the viral infection might have ensued. Recently, HDV suppression with bulevirtide was shown to reverse autoimmune liver disease. We hypothesize that the same could have happened to our patient, had she accepted this treatment., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Author(s).Published by S. Karger AG, Basel.)

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., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Hepatitis delta virus (HDV) is a defective agent that only infects individuals with hepatitis B virus (HBV). Around 5-10% of chronic hepatitis B patients worldwide are superinfected with HDV, which means 15-25 million people. Hepatitis delta is the most severe of all chronic viral hepatitis, leading to cirrhosis, liver cancer and/or transplantation in most patients. Despite it, many HDV patients remain undiagnosed. The only treatment available until recently was peginterferon alfa, with poor results and significant side effects. The recent approval of bulevirtide, a lipopeptide that blocks HBV/HDV entry, has revolutionized the field. Another drug, lonafarnib, already approved to treat progeria, is expected to be available soon as HDV therapy. Since there is no cell reservoir for the HDV RNA genome, hypothetically viral clearance could be achieved if complete blocking of viral replication occurs for a minimum time frame. This is what happens in hepatitis C using direct-acting antivirals, with the achievement of cure in nearly all treated patients. We envision the cure of hepatitis delta using combination antiviral therapy. Given that sexual and parenteral transmission routes are the most frequent for the acquisition of HBV and HDV, shared with HIV infection and HBV/HDV and HIV coinfection. The clinical outcome of hepatitis delta is worst in the HIV setting, with more frequent liver complications. Since most persons infected with HIV are on regular health care follow-up, we propose that HIV-HDV patients should be prioritized for moving forward new and potentially curative treatments for hepatitis delta., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

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., (© 2023 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Introduction: Hepatitis delta virus (HDV) causes acute and chronic liver disease that requires the co-infection of the Hepatitis B virus and can lead to significant morbidity and mortality. Bulevirtide is a recently introduced entry inhibitor drug that acts on the sodium taurocholate cotransporting peptide, thereby preventing viral entry to target cells in chronic HDV infection. The mainstay of chronic HDV therapy prior to bulevirtide was interferon alpha, which has an undesirable side effect profile., Areas Covered: We review bulevirtide data from recent clinical trials in Europe and the United States. Challenges to development and implementation of bulevirtide are discussed. Additionally, we review ongoing trials of emerging drugs for HDV, such as pegylated interferon lambda and lonafarnib., Expert Opinion: Bulevirtide represents a major shift in treatment for chronic HDV, for which there is significant unmet need. Trials that compared bulevirtide in combination with interferon alpha vs interferon alpha monotherapy demonstrated significant increase in virologic response. Overall, treatment with different doses of bulevirtide were comparable. Bulevirtide was generally well tolerated, and no serious adverse events occurred. Understanding the true prevalence of HDV, as well as continued studies of emerging drugs will prove valuable to the larger goal of eradication of Hepatitis D.

Objectives: The study measures trends in the profile of patients with chronic hepatitis B virus linked to care in Italy., Methods: A cross-sectional, multicenter, observational cohort (PITER cohort) of consecutive patients with hepatitis B surface antigen (HBsAg) over the period 2019-2021 from 46 centers was evaluated. The reference was the MASTER cohort collected over the years 2012-2015. Standard statistical methods were used., Results: The PITER cohort enrolled 4583 patients, of whom 21.8% were non-Italian natives. Compared with those in MASTER, the patients were older and more often female. The prevalence of hepatitis B e antigen (HBeAg) declined (7.2% vs 12.3; P <0.0001) and that of anti-hepatitis D virus (HDV) remained stable (9.3% vs 8.3%). In both cohorts, about 25% of the patients had cirrhosis, and those in the PITER cohort were older. HBeAg-positive was 5.0% vs 12.6% (P <0.0001) and anti-HDV positive 24.8% vs 17.5% (P <0.0017). In the logistic model, the variables associated with cirrhosis were anti-HDV-positive (odds ratio = 10.08; confidence interval 7.63-13.43), age, sex, and body mass index; the likelihood of cirrhosis was reduced by 40% in the PITER cohort. Among non-Italians, 12.3% were HBeAg-positive (vs 23.4% in the MASTER cohort; P <0.0001), and 12.3% were anti-HDV-positive (vs 11.1%). Overall, the adherence to the European Association for the Study of the Liver recommendations for antiviral treatment increased over time., Conclusion: Chronic hepatitis B virus infection appears to be in the process of becoming under control in Italy; however, HDV infection is still a health concern in patients with cirrhosis and in migrants., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (© 2023 John Wiley & Sons Ltd.)

The entry inhibitor bulevirtide (BLV) is a new treatment option for patients with chronic hepatitis D virus (HDV) infection and compensated liver disease. The aim of this study was to investigate the kinetic and predictive value of markers reflecting HBV cccDNA transcriptional activity and host immune response activity during BLV treatment in a real-life cohort of HDV infected patients. Levels of HDV RNA, HBV RNA, hepatitis B core related antigen (HBcrAg) and hepatitis B core antibodies (anti-HBc) were measured in 16 patients before (BL), after three (3M) and six (6M) months of treatment with BLV. All patients received nucleos(t)ide analogue treatment. HDV RNA declined in all patients during treatment. 38% (6/16) showed ≥ 2 log HDV RNA decline from BL to 6M and 11 patients (69%) normalized ALT levels. HBV RNA levels were low and only detectable in two to four patients. HBcrAg levels declined in 75% (12/16) of patients. Median HBcrAg levels declined significantly from BL to 6M (3.75 logU/ml (IQR 2.93-4.78) vs. 3.4 logU/ml (IQR 2-4.68), p=0.002). A similar trend was shown for anti-HBc between BL and 6M. Levels of HBcrAg or anti-HBc did not differ significantly between patients with or without ≥ 2 log HDV RNA decline from BL to 6M.After 6 months treatment with BLV, levels of HBcrAg showed a significant decline, while HBV RNA and anti-HBc levels did not change. Reduction of HBV cccDNA transcriptional activity and immunological effects of antiviral treatment might explain these changes., (© 2023 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Background and Aims: A high prevalence of hepatitis delta virus (HDV) infection, the most severe form of viral hepatitis, has been reported among persons living with HIV (PLWH) in Europe. We analysed data from a large HIV cohort collaboration to characterize HDV epidemiological trends across Europe, as well as its impact on clinical outcomes., Methods: All PLWH with a positive hepatitis B surface antigen (HBsAg) in the Swiss HIV Cohort Study and EuroSIDA between 1988 and 2019 were tested for anti-HDV antibodies and, if positive, for HDV RNA. Demographic and clinical characteristics at initiation of antiretroviral therapy were compared between HDV-positive and HDV-negative individuals using descriptive statistics. The associations between HDV infection and overall mortality, liver-related mortality as well as hepatocellular carcinoma (HCC) were assessed using cumulative incidence plots and cause-specific multivariable Cox regression., Results: Of 2793 HBsAg-positive participants, 1556 (56%) had stored serum available and were included. The prevalence of HDV coinfection was 15.2% (237/1556, 95% confidence interval [CI]: 13.5%-17.1%) and 66% (132/200) of HDV-positive individuals had active HDV replication. Among persons who inject drugs (PWID), the prevalence of HDV coinfection was 50.5% (182/360, 95% CI: 45.3%-55.7%), with similar estimates across Europe, compared to 4.7% (52/1109, 95% CI: 3.5%-5.9%) among other participants. During a median follow-up of 10.8 years (interquartile range 5.6-17.8), 82 (34.6%) HDV-positive and 265 (20.1%) HDV-negative individuals died. 41.5% (34/82) of deaths were liver-related in HDV-positive individuals compared to 17.7% (47/265) in HDV-negative individuals. HDV infection was associated with overall mortality (adjusted hazard ratio 1.6; 95% CI 1.2-2.1), liver-related death (2.9, 1.6-5.0) and HCC (6.3, 2.5-16.0)., Conclusion: We found a very high prevalence of hepatitis delta among PWID across Europe. Among PLWH who do not inject drugs, the prevalence was similar to that reported from populations without HIV. HDV coinfection was associated with liver-related mortality and HCC incidence., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Hepatitis Delta virus (HDV) causes severe liver disease. Due to similarities in transmission routes, persons living with HIV (PLWH) are at risk of HDV infection. This analysis investigates the prevalence and the long-term clinical outcome of people with HDV in a large cohort of PLWH. We retrieved HBsAg ± anti-HDV positive PLWH enrolled from 1997 to 2015 in the multicentre, prospective ICONA study. The primary endpoint was a composite clinical outcome (CCO = having experienced ≥1 of the following: Fib4 score >3.25; diagnosis of cirrhosis; decompensation; hepatocellular carcinoma or liver-related death). Kaplan-Meier curves and unweighted and weighted Cox regression models were used for data analysis. Less than half of HBsAg positive patients had been tested for anti-HDV in clinical practice. After testing stored sera, among 617 HBV/HIV cases, 115 (19%) were anti-HDV positive; 405 (65%) HBV monoinfected; 99 (16%) undeterminate. The prevalence declined over the observation period. HDV patients were more often males, intravenous drug users, HCV coinfected. After a median of 26 months, 55/115 (48%) developed CCO among HDV+; 98/403 (24%) among HBV monoinfected; 18/99 (18%) in HDV unknown (p < 0.001). After controlling for geographical region, alcohol consumption, CD4 count, anti-HCV status and IFN-based therapies, the association with HDV retained statistical significance [HR = 1.67 (1.15, 2.95; p = 0.025)]. HDV infection among PLWH is underdiagnosed, although HDV entails an high risk of liver disease progression. Because effective drugs to treat HDV are now available, it is even more crucial to identify PLWH at an early stage of liver disease.

Hepatitis B virus (HBV) and hepatitis D virus are leading causes of morbidity and mortality worldwide. Despite the availability of HBV vaccinations that are 98% to 100% effective, an estimated 820,000 annual deaths were attributed to HBV in 2019, mainly related to the sequelae of cirrhosis and hepatocellular carcinoma. Because disease prevalence is concentrated outside of the United States, it is overlooked, but with expanded vaccination recommendations provided by the Centers for Disease Control and Prevention and recommended screening, as well as heightened awareness by health care providers, we can work toward the eradication of this preventable disease., Competing Interests: Disclosure A. Robinson: This author has nothing to disclose. R. Wong: research funding (to his institution) from Gilead Sciences, United States; he has served as a consultant and on advisory board for Gilead Sciences. R.G. Gish: He has served as a consultant and/or advisor for Gilead Sciences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Chronic Hepatitis D virus (HDV) infection remains an important global public health problem, with a changing epidemiological landscape over the past decade along with widespread implementation of hepatitis B vaccination and human migration. The landscape of HDV treatments has been changing, with therapies that have been under development for the last decade now in late stage clinical trials. The anticipated availability of these new therapies will hopefully replace the current therapies which are minimally effective., Areas Covered: This narrative review discusses the clinical course, screening and diagnosis, transmission risk factors, epidemiology, current and investigational therapies, and liver transplantation in HDV. Literature review was performed using PubMed and ClinicalTrials.gov and includes relevant articles from 1977 to 2022., Expert Opinion: HDV infection is an important global public health issue with a true prevalence that is still unknown. The distribution of HDV infection has changed globally with the availability of HBV vaccination and patterns of human migration. As HDV infection is associated with accelerated disease courses and poor outcomes, the global community needs to agree upon a uniform HDV screening strategy to understand the truth of global prevalence such that new therapies can target appropriate individuals as they become available in the future.

It has been ten years since the identification of NTCP as the cell surface receptor for HBV and HDV entry into hepatocytes. The search for molecules interfering with the binding of NTCP and HBV/HDV led to design bulevirtide (BLV). This large polypeptide mimics a region of the pre-S1 HBsAg and blocks viral entry by inhibitory competition. BLV was initially tested in cell cultures, animal models and more recently in Phase I-III human trials (called 'MYRS'). As monotherapy or in combination with peginterferon, BLV is well tolerated and exhibits potent antiviral activity. Plasma viremia significantly declines and/or becomes undetectable in more than 75% of patients treated for >24 weeks. However, serum HBsAg concentrations remain unchanged. No selection of BLV resistance in HBV/HDV has been reported in vivo to date. BLV is administered subcutaneously once daily at doses between 2 and 10 mg. BLV received conditional approval in Europe in 2020 to treat chronic hepatitis delta. The advent of peginterferon lambda or new specific anti-HDV antivirals (lonafarnib, etc.) will open the door for combination therapies with BLV. Since there is no stable reservoir for HDV-RNA within infected hepatocytes, viral clearance might be achieved using antivirals for a minimum timeframe. This is what happens in hepatitis C combining several antivirals, curing nearly all patients treated for 3 months. Clearance of HDV-RNA genomes may occur despite HBV persistence as cccDNA or chromosome integrated HBV-DNA within hepatocytes. This is supported by cases of HDV elimination using BLV despite persistence of serum HBsAg. Another path for HDV cure will derive from achieving HBsAg clearance, the goal of new promising anti-HBV gene therapies (bepirovirsen, etc.). In summary, the advent of BLV has triggered a renovated interest for antiviral therapy in hepatitis delta. We envision combination therapies that will lead to HDV cure in the near future., Competing Interests: The authors declare no conflicts of interest, financial or otherwise for this study., (© 2023 Soriano et al.)

Coinfection with hepatitis viruses A to E is frequent in persons living with HIV (PLWH) and causes significant morbidity and mortality. Oro-fecal transmissible hepatitis A and E mostly produce acute self-limited episodes in poor income regions and in non-vaccinated travelers. In high-income countries, outbreaks of hepatitis A occur in men having sex with men (MSM) and chronic hepatitis E is occasionally reported among PLWH with severe immunodeficiency. Chronic hepatitis B, C, and D are frequent in PLWH in highly endemic regions and globally in persons who inject drugs (PWID) and MSM. Progression to liver cirrhosis and development of hepatocellular carcinoma (HCC) is major clinical complications in coinfected patients. Current estimates for PLWH are of 38 million worldwide. Roughly 12% have chronic viral hepatitis (5 million). Coinfection figures are of 5-10% for HBV (2-4 million), 4% for HCV (1.5 million), and 15% of HBsAg+ for HDV (0.5 million). Oral direct-acting antivirals (DAA) cure almost all treated patients with hepatitis C. However, given that there is no protective HCV immunity, PLWH with high-risk behaviors may experience HCV reinfection episodes. Tenofovir is the drug of choice in PLWH with chronic hepatitis B, given its dual effect on HIV and HBV. Lifelong oral tenofovir suppresses HBV replication and ameliorate liver damage. However, the risk of HCC persists even in the absence of cirrhosis. Finally, HDV causes the worst of viral hepatitis with faster progression to cirrhosis and HCC. An entry inhibitor, bulevirtide, has recently been approved and another drug, lonafarnib, is completing Phase 3 trials. Combination antiviral therapy for hepatitis D could improve dramatically the poor prognosis of HIV-HDV coinfected patients. The resumption of good medical practices in PLWH after the big disruption caused by COVID-19 will reduce the burden of viral hepatitis coinfections. Renewed efforts on HAV and HBV vaccination of susceptible individuals and earlier and wider prescription of antiviral therapy for HBV, HCV, and/or HDV coinfection should be prioritized in PLWH. The benefits of innovative strategies for viral hepatitis, including pre-exposure prophylaxis or use of long-acting antivirals, warrant further consideration in PLWH., (Copyright: © 2023 Permanyer.)

Hepatitis Delta virus is the smallest known human virus, exploiting the HBV surface proteins (HBsAg) for the release of its progeny and de novo entry into hepatocytes. Ever growing evidence have highlighted the existence of multiple mechanisms underlying HDV persistence including integrated HBV-DNA as a source of HBsAg production and the capability of the HDV genome to propagate through cell proliferation, thus supporting a potential HDV persistence even in the absence of HBV. Chronic HDV-infection causes the most severe form of viral hepatitis, leading to the development of cirrhosis in 15% of cases within 1-2 years and in 50%-60% of cases within 5-10 years. The rates of hepatocellular carcinoma and hepatic decompensation are also 2-3-fold higher than for HBV mono-infection. There is the evidence that persistent viral replication plays a key role in triggering liver injury, suggesting the existence of direct viral cytopathic properties that can modulate, synergistically with immune-responses, the progression towards end-stage liver diseases. All these aspects can be further exacerbated by the extraordinary degree of viral genetic variability that can promote HDV evasion from immune responses and has enabled viral differentiation into genotypes and subgenotypes with potential different pathobiological properties. In this light, this review aims at providing comprehensive insights of mechanisms (with a focus on virological factors) underlying HDV persistence and pathogenesis, critical in shaping the clinical outcome of the infection. Dissecting these mechanisms is pivotal to optimize therapeutic strategies aimed at fully counteracting this fascinating and fearsome virus., (© 2022 John Wiley & Sons Ltd.)

Background: Chronic viral hepatitis B, C, and D are the main causes of decompensated cirrhosis and liver cancer worldwide. Newborn HBV vaccination was implemented more than 2 decades ago in most EU countries. Furthermore, potent oral antivirals have been available to treat HBV for 15 years and to cure HCV since 2014. The real-life clinical benefits of these interventions at country level have not been assessed, especially regarding major hepatic outcomes such as cirrhotic decompensation events and hepatocellular carcinoma (HCC)., Methods: Retrospective study of all hospitalizations in Spain having HBV, HCV, and HDV as diagnosis using the Spanish National Registry of Hospital Discharges. Information was retrieved from 1997 up to 2017., Results: From a total of 73,939,642 hospital admissions during the study period, a diagnosis of HBV, HCV, and HDV was made in 124,915 (1.7‰), 981,985 (13.3‰), and 4850 (0.07‰) patients, respectively. The median age of patients hospitalized within each group was 53.2, 55.9, and 47.0 years, respectively. Significant increases in mean age at hospitalization occurred in all groups (0.6 years older per calendar year on average). The overall rate of hepatic decompensation events for HBV, HCV, and HDV was 12.1%, 14.1%, and 18.8%, respectively. For HCC hospitalizations, these figures were 6.7%, 8.0%, and 7.8%, respectively. Whereas, the rate of decompensation events declined in recent years for HBV, and more recently for HCV, it continued rising up for HDV. Likewise, liver cancer rates recently plateaued for HBV and HCV, but kept growing for HDV., Conclusion: The rate of hepatic decompensation events and liver cancer has declined and/or plateaued in recent years for patients hospitalized with HBV and HCV infections, following the widespread use of oral antiviral therapies for these viruses. In contrast, the rate of decompensated cirrhotic events and HCC has kept rising up for patients with hepatitis delta, for which effective antiviral treatment does not exist yet., (© 2022. Asian Pacific Association for the Study of the Liver.)

Background & Aims: Among people living with HBV, only a subset of individuals with chronic hepatitis is in need of treatment, and this proportion varies according to the population, region, and setting. No estimates of the proportion of people who are infected with HBV and meet the treatment eligibility criteria in France are available., Methods: 552 treatment-naïve individuals with chronic HBV infection referred for the first time to a hepatology reference centre between 2008 and 2012 were prospectively included. Demographic, clinical, and laboratory data were analysed., Results: In total, 61.1% of patients were males, with a median age of 37.5 years. Moreover, 64% were born in an intermediate- or high-HBV endemicity country, and 90% were HBeAg-negative. At referral, median HBV DNA and HBsAg levels were 3.3 and 3.6 log IU/ml, respectively; 37.8% of patients had alanine aminotransferase >40 U/L, and 29.0% had moderate or severe fibrosis (≥F2), including 9.4% with cirrhosis. The most prevalent genotypes were D (34.7%), E (27.4%), and A (25.7%). Coinfections were rare: 2.4% were HIV-positive, 4.0% were HCV-positive, and 6.0% were HDV-positive. According to the 2017 EASL Clinical Practice Guidelines, using a single time point analysis, 2.7% of patients were classified as HBeAg-positive chronic infection, 6.1% as HBeAg-positive chronic hepatitis B, 26.5% as HBeAg-negative chronic hepatitis B, and 61.1% as HBeAg-negative chronic infection, whereas 3.6% patients could not be classified. The performance of HBsAg level quantification to identify individuals with HBeAg-negative chronic hepatitis B was poor. A total of 29.1% met the criteria for initiation of antiviral treatment, whereas 66.5% remained under routine clinical surveillance. Most eligible patients initiated recommended first-line therapies, including tenofovir (45.3%), entecavir (36.8%), or pegylated interferon alpha (11.6%)., Conclusions: Of all cases, 9.4% had cirrhosis at presentation and 29.1% met the 2017 EASL Clinical Practice Guidelines treatment criteria. HBsAg levels failed to accurately identify individuals with HBeAg-negative chronic infection., Lay Summary: Among French adults chronically infected with HBV referred for the first time to hepatology reference centres, about one-third had a significant liver disease. Approximately one-third of individuals met criteria for initiation of antiviral treatment based on entecavir or tenofovir or, occasionally, pegylated interferon alpha., Competing Interests: The authors declare no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Background: Located in southwestern Indian Ocean, Mayotte is a French territory, with a very specific demographic, social and health context. To date, epidemiological data on infections by hepatitis B (HBV), C (HCV), and delta (HDV) viruses in Mayotte have been sparse. We aimed to estimate, in the 15-69-year-old general population living in Mayotte, the prevalence of infections by hepatitis B (HBV), C (HCV), and delta (HDV) viruses and the distribution of HBV status: current infection with positive HBs antigen (Ag); resolved infection with positive HBc antibodies and negative HBsAg; immunisation by vaccination with only positive HBs antibodies; and no infection/no immunisation with negative markers. We also described the characteristics of infected people and assessed the determinants of lifetime HBV infection., Methods: The Unono Wa Maore survey, implemented in a random sample of the general population in 2018-2019, consisted of an at-home collection of epidemiological data and venous blood samples. Detection of hepatitis B, C, and delta serological and molecular markers was performed., Results: Among 5207 eligible people, 4643 responded to the questionnaire (89.2%), with 2917 being tested for HBV and HCV (62.8%). Estimated HBV status was as follows: current infection 3.0% (95% confidence interval [CI]: 2.3-3.9%) (n = 76); resolved infection 27.8% (95% CI: 25.8-29.9); immunisation by vaccination 27.7% (95% CI: 25.9-29.7); and no infection/no immunisation 41.5% (95% CI: 39.3-43.7). One participant was positive for HDV antibodies (Ab) (0.65%) with a negative HDV-RNA viral load. The risk of lifetime HBV infection was higher in men (adjusted prevalence ratio (aPR): 1.55, 95% CI: 1.29-1.89); in people aged 30-49 years (aPR: 3.83, 95% CI: 1.49-9.81) or 50-69 years (aPR: 4.52, 95% CI: 1.77-11.53) compared to those under 20; in individuals who reported no condom use during their first sexual intercourse (aPR: 1.46, 95% CI: 1.01-2.14); and in those living in Dembeni-Mamoudzou (aPR: 1.40, 95% CI: 1.09-1.80) compared to the West-Centre of Mayotte. Finally, six individuals were positive for HCV antibodies (0.21%), including three positive for HCV RNA., Conclusions: Mayotte is an area of intermediate endemicity for HBV and low endemicity for HCV and HDV. With a prevalence of HBsAg 10 times higher than in mainland France, a high proportion of people susceptible to HBV infection, and a demographic, health, and social context that may favour its transmission, hepatitis B is a major public health concern in Mayotte., (© 2022. The Author(s).)

Background: The hepatitis B and D virus (HBV/HDV) hepatocyte entry inhibitor bulevirtide (BLV) has been available in Europe since July 2020, after the registrational trial MYR202. Real-life data on the efficacy and safety of BLV are sparse. Methods: We have analysed the course of treatment with BLV (2 mg/day) plus tenofovir disoproxil fumarate (TDF) (245 mg/day) in patients with chronic hepatitis delta (CHD). Virologic (≥2 log reduction in HDV RNA or suppression of HDV RNA below the lower limit of detection) and biochemical (normalisation of serum ALT) treatment responses after 24 weeks were defined according to the MYR202 trial. Results: Seven patients were recruited (four with liver cirrhosis Child−Pugh A). After 24 weeks, a virologic response was observed in five of seven and a biochemical response was seen in three of six patients with elevated serum ALT at baseline. Extended treatment data > 48 weeks were available in three cases: two presented with continuous virologic and biochemical responses and in one individual an HDV-RNA breakthrough was observed. Adverse effects were not recorded. Conclusions: The first real-life data of the approved dosage of 2 mg of BLV in combination with TDF confirm the safety, tolerability, and efficacy of the registrational trial MYR202 for a treatment period of 24 weeks and beyond.

In 1977 the viral Delta agent was discovered and subsequently characterized as the hepatitis Delta virus (HDV). HDV infection is associated with HBV infection since the defective HDV needs HBV to infect and replicate in the liver. Even if not a frequent cause of chronic liver disease, HDV infection is responsible for an aggressive progression of hepatitis towards advanced liver disease. At present, no FDA approved treatment exists for this specific form of hepatitis. Interferon alfa has been recommended as off-label therapy by major scientific societies (AASLD, EASL and APASL) and has proved effective in about one quarter of patients. In recent years, new therapeutic approaches have been studied, and EMA has approved a new drug (bulevirtide) for Delta hepatitis. In this review, we encompass the 45-year journey of managing Delta hepatitis and address the most recent developments in treating this severe and aggressive liver disease.

Chronic delta hepatitis (CDH) has a worse outcome than other types of viral hepatitis. High-dose, long-term alpha interferon (IFN-α) is the approved treatment and may ameliorate the course of infection. We evaluated long-term histological outcomes of CDH patients treated with IFN-α. Patients with histologically proved noncirrhotic CDH who were treated with high-dose IFN-α for at least 1 year were classified as cirrhotic or noncirrhotic at the end of treatment. Noncirrhotic patients also had posttreatment liver biopsies. Patients were designated histologically responsive or nonresponsive on the basis of fibrosis status. Histological, virological, and biochemical courses were analyzed. Forty-eight patients were treated with IFN-α (conventional and/or pegylated) for a median of 24 months with a posttreatment follow-up of 5 years. During the follow-up, cirrhosis developed in 24 patients, 5 of whom were decompensated. There was no difference between pre- and posttreatment fibrosis scores for 24 noncirrhotic patients at the end of follow-up. Among patients, 13% ( n = 6) had decreased, 21% ( n = 10) had steady, and 16% ( n = 8) had increased fibrosis scores. Persistent viral response (PVR) was achieved in 16 patients (33%). Twenty percent of the entire group was histologically responsive (decreasing or steady fibrosis scores with improved necroinflammatory scores), while nearly 80% had histological progression/cirrhosis. PVR was significantly associated with histological response. The long-term natural course of patients who were treated with high dose IFN-α for at least 1 year was evaluated clinically and histologically. Despite the association of PVR with histological response, IFN-α treatment did not change the natural course of CDH; clinical and histological progression continued in two-thirds of the cases despite treatment.

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come., (© 2021 John Wiley & Sons Ltd.)

The molecular profile of hepatitis Delta in Afghanistan remains unclear yet, therefore this study addresses the genotype of HDV among HBsAg carriers in Afghanistan. In total 234 HBsAg-positive sera were examined by chemiluminescent micro-particle immunoassay to detect Anti-HDV antibodies. Serologically positive samples were later approved via real-time PCR test and subsequently, a 731 bp segment of the HDV Delta antigen RNA region was sequenced in the Illumina platform. The isolates were genotyped via distance matrix/UPGMA analysis using Kimura 2-parameter by MEGA7 software package program. The HBV/HDV coinfection rate among HBsAg carriers in Afghanistan was 2.1%. Finally, 4 samples successfully amplified Hepatitis delta antigen (HDAg) which Later in phylogenetic analysis, all resided in branch genotype I and were stored at GenBank with accession numbers MK799645, MK799646, MK799647, MK799648. The HDV genotypic variations in the Afghan HBsAg carriers may be homogenous and HDV-1 may be the predominant genotype in Afghanistan., Competing Interests: The authors have no conflict of interest to declare.

Chronic hepatitis D virus (HDV) infection is the most severe form of viral hepatitis with high rates of end-stage liver disease and hepatocellular carcinoma. Therefore, effective antiviral treatment strategies are needed desperately. Until recently, antiviral treatment was limited to pegylated interferon-alpha. With the conditional approval of the entry inhibitor bulevirtide by the European Medicines Agency, new treatment options are now available. In addition, multiple other antiviral compounds are currently tested in clinical phase II and III trials and represent promising agents for the treatment of chronic HDV infection., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Co-infection between hepatitis B virus (HBV) and hepatitis delta virus (HDV) causes the severest chronic hepatitis and is associated with a high risk of cirrhosis and hepatocellular carcinoma (HCC). The Global Health Sector Strategy on Viral Hepatitis called for the elimination of hepatitis (- 65% mortality and - 90% incidence) by 2030. Our aims were to summarize key points of knowledge and to identify the gaps that need to be addressed to mount a public health response to HDV., Methods: We performed a current literature review in terms of epidemiology by WHO regions, genotypes distribution and their pathogenicity, factors associated with HDV infection, mortality due to HDV infection, testing strategies and treatment., Results: Prevalence of infection and genotypes are heterogeneous distributed, with highest prevalence in foci around the Mediterranean, in the Middle East, and in Central, Northern Asia and Eastern Asia. Persons who inject drugs (PWID) and migrants from highly endemic areas are highly affected. While antibody detection tests are available, HDV RNA tests of current infection are not standardized nor widely available. The few therapeutic options, including lofartinib, are not widely available; however several new and promising agents have entered clinical trials., Conclusion: HDV infection is an poorly known cause of chronic liver disease. To mount a public health response, we need a better description of the HDV epidemic, standardized testing strategies and better treatment options., (© 2021. The Author(s).)

Hepatitis D virus (HDV) infection causes a severe chronic viral hepatitis with accelerated development of liver cirrhosis and decompensation, but whether it further increases the risk of hepatocellular carcinoma (HCC) is unclear. We performed a comprehensive systematic review of the published literature and meta-analysis to assess the risk of HCC in HDV and hepatitis B virus (HBV) co-infected, compared to HBV mono-infected patients. The study was conducted per a priori defined protocol, including only longitudinal studies, thus excluding cross-sectional studies. Random-effects models were used to determine aggregate effect sizes (ES) with 95% confidence intervals (CI). Meta-regression was used to examine the associations among study level characteristics. Twelve cohort studies comprising a total of 6099 HBV/HDV co-infected and 57,620 chronic HBV mono-infected patients were analysed. The overall pooled ES showed that HBV/HDV co-infected patients were at 2-fold increased risk of HCC compared to HBV mono-infected patients (ES = 2.12, 95% CI 1.14-3.95, I 2  = 72%, N = 12). A six-fold significant increased risk of HCC was noted among HIV/HBV/HDV triple-infected, compared to HIV/HBV co-infected patients. The magnitude of ES did not differ significantly after adjustment for study design and quality, publication year and follow-up duration in univariable meta-regression analysis. This systematic review and meta-analysis shows that infection with HDV is associated with a 2-fold higher risk of HCC development compared to HBV mono-infection. HCC surveillance strategies taking this increased risk into account, and new treatment options against HDV, are warranted., (© 2021 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Background & Aims: Hepatitis D virus infection (HDV) is considered the most severe form of viral hepatitis. In this study, we aimed to evaluate the prevalence of HDV infection in a tertiary center of a large, multi-ethnic city in the Netherlands. Moreover, we validate the reliability of a novel anti-HDV CLIA assay., Methods: All HBsAg-positive patients visiting the outpatient clinic between 2017 and 2019 were tested for HDV serology. Seropositive serum samples were further assessed by HDV RNA PCR and Sanger sequencing to identify the HDV genotype., Results: The CLIA assay was 100% sensitive and 98% specific. Out of 925 patients 3.7% tested seropositive for HDV, and HDV viremia was confirmed in 2.0%. The majority of patients had a non-Dutch background and did not speak English or Dutch. We detected HDV genotype 5 (N = 3), and genotype 1 (N = 15). Phylogenetic analysis demonstrated HDV1 clusters composed of sub-Saharan Africa isolates, central Asian, Turkish, Iranian and European isolates., Conclusions: The prevalence of HDV infection in a tertiary center in the Netherlands was 2.0% among HBsAg-positive individuals, and mainly in non-Dutch individuals. Only HDV genotype 1 and 5 isolates were detected, which was found to match with the patient's country of origin., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)