OBJECTIVE: Chronic hepatitis D (CHD) is a severe form of chronic viral hepatitis. The estimated HDV 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.
METHODS: 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.
CONCLUSIONS: 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.

OBJECTIVE: Sodium taurocholate cotransporting peptide (NTCP) genetic polymorphisms have been described, but their role in untreated and treated patients with Chronic Hepatitis Delta (CHD) remains unknown. Virological response (VR) to NTCP inhibitor Bulevirtide (BLV) was achieved at week 48 by >70% of CHD patients, but nearly 15% experienced virological nonresponse (VNR) or partial response (PR). This study aimed to evaluate whether NTCP genetic polymorphisms affect baseline HDV RNA load and response to BLV in CHD patients.
METHODS: Untreated and BLV 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 6 NTCP polymorphisms studied in 209 CHD untreated patients, carriers of rs17556915 TT/CC (N=142) compared to CT (N=67) genotype presented higher median HDV RNA levels (5.39 vs. 4.75 log10 IU/mL, p=0.004). 76 out of 209 patients receiving BLV monotherapy at 2 mg/day were evaluated at week 24 and 40 of them 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.
CONCLUSIONS: The NTCP rs17556915 C>T genetic polymorphisms may influence baseline HDV RNA load both in untreated and BLV treated patients with CHD and may contribute to identify patients with different early virological responses to BLV.

OBJECTIVE: 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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: A associação da infeção pelo vírus da hepatite delta (VHD) com a presença de autoanticorpos e outros aspetos de autoimunidade é conhecida desde há várias décadas. Contudo, até à data, muito poucos casos de hepatite autoimune (HAI) clínica foram reportados em relação com a infeção VHD, sendo a maioria destes no contexto de terapêutica com interferão peguilado.
UNASSIGNED: O caso refere-se a uma mulher de 46 anos natural da Guiné-Bissau, que se mudou para Portugal em 2018 para investigação de queixas de desconforto abdominal difuso e náuseas. A avaliação laboratorial inicial e a histologia hepática foram compatíveis com HAI tipo 1. A doente apresentava também infeção crónica a VHB (vírus da hepatite B) antigénio HBe negativa, com DNA negativo, e anti-VHD (vírus da hepatite delta) total positivo, com IgM negativo e RNA indetetável. Assim, após início de tenofovir difumarato profilático, foi iniciada terapêutica com prednisolona seguida de azatioprina, que posteriormente se interrompeu por presumível hepatotoxicidade. Uma segunda biópsia mostrou aspetos de superinfeção viral e como tal a doente foi tratada com aciclovir, tendo em conta IgM positivo para Herpes Simplex, mantendo-se o RNA VHD negativo. Um terceiro flare de transaminases motivou o início de micofenolato de mofetil, após extensa investigação e exclusão de outras causas de doença hepática. Cerca de 6 meses mais tarde, durante novo episódio de hepatite, o RNA VHD revelou-se finalmente positivo e este foi classificado como genotipo 5. O MMF foi suspenso e, considerando a contra-indicação para interferão, foi proposto à doente tratamento com bulevirtide, que esta recusou, alegando motivos pessoais, visto estar atualmente a residir no seu país de origem.
UNASSIGNED: Este é um caso desafiante de hepatite autoimune, ou autoimune-like, provavelmente induzida pela infeção crónica pelo VHD. Um elevado índice de suspeição para VHD foi essencial porque, se o caso tivesse sido interpretado como HAI refratária, com incremento de imunossupressão, poderia ter-se verificado um agravamento da hepatite viral. Recentemente, foi reportado que a supressão do VHD pelo bulevirtide pode reverter a doença hepática autoimune. Questionamo-nos se o mesmo poderia ter sucedido com a nossa doente, caso esta tivesse aceite este tratamento.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

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.

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.

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.
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.
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.
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.
Hepatitis delta virus (HDV) infection only occurs in the presence of hepatitis B virus (HBV) infection. People with an HDV infection are at higher risk for severe liver disease, liver transplant, and death compared to those who only have an HBV infection. The estimated global prevalence of HDV infection ranges from 5% to 15% among people living with HBV. These measurements vary due to different study methods, inconsistent HDV screening guidelines, and patient risk factors for infection.In the US, primary care providers (PCPs) play an important role in improving community access to HDV information and testing. However, poor funding and inadequate resources have created a lack of awareness and insufficient adherence by PCPs to current recommendations for screening and management of HDV infection. This narrative review aims to fill this gap by providing an overview of HDV infection, patient risk factors, and practice guidelines for PCPs.The recommendations for PCPs in this review include providing universal screening for HDV to people with an HBV infection, especially those at high risk. PCPs can educate and comanage patients with liver specialists. Topics to discuss with patients include expected disease outcomes, lifestyle factors that may influence liver health, and the need for consistent follow-up appointments. Patient risk of disease transmission can also be discussed to identify sexual partners, household contacts, and family members who will need screening and HBV vaccination. While there are no FDA-approved therapies for treating HDV infection, we provide an overview of available and emerging HDV treatments.

UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: Research Delegation of French Polynesia.