Addressing hepatitis delta in primary care practices in the US: a narrative review.

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.

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.

Diagnosis and Management of Hepatitis Delta Virus Infection.

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

EASL Clinical Practice Guidelines on hepatitis delta virus.

Hepatitis D virus (HDV) is a defective virus that requires the hepatitis B virus to complete its life cycle and cause liver damage in humans. HDV is responsible for rare acute and chronic liver diseases and is considered the most aggressive hepatitis virus. Acute infection can cause acute liver failure, while persistent infection typically causes a severe form of chronic hepatitis which is associated with rapid and frequent progression to cirrhosis and its end-stage complications, hepatic decompensation and hepatocellular carcinoma. Major diagnostic and therapeutic innovations prompted the EASL Governing Board to commission specific Clinical Practice Guidelines on the identification, virologic and clinical characterisation, prognostic assessment, and appropriate clinical and therapeutic management of HDV-infected individuals.

Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease.

Approximately 5% of individuals infected with hepatitis B virus (HBV) are coinfected with hepatitis D virus (HDV). Chronic HBV/HDV coinfection is associated with an unfavourable outcome, with many patients developing liver cirrhosis, liver failure and eventually hepatocellular carcinoma within 5-10 years. The identification of the HBV/HDV receptor and the development of novel in vitro and animal infection models allowed a more detailed study of the HDV life cycle in recent years, facilitating the development of specific antiviral drugs. The characterisation of HDV-specific CD4+ and CD8+T cell epitopes in untreated and treated patients also permitted a more precise understanding of HDV immunobiology and possibly paves the way for immunotherapeutic strategies to support upcoming specific therapies targeting viral or host factors. Pegylated interferon-α has been used for treating HDV patients for the last 30 years with only limited sustained responses. Here we describe novel treatment options with regard to their mode of action and their clinical effectiveness. Of those, the entry-inhibitor bulevirtide (formerly known as myrcludex B) received conditional marketing authorisation in the European Union (EU) in 2020 (Hepcludex). One additional drug, the prenylation inhibitor lonafarnib, is currently under investigation in phase III clinical trials. Other treatment strategies aim at targeting hepatitis B surface antigen, including the nucleic acid polymer REP2139Ca. These recent advances in HDV virology, immunology and treatment are important steps to make HDV a less difficult-to-treat virus and will be discussed.

Hepatitis Delta: Prevalence, Natural History, and Treatment Options.

Half a century after its discovery, hepatitis delta remains a pertinent global health issue with a major clinical impact in endemic regions and an underestimated prevalence worldwide. Hepatitis delta virus infection follows a challenging clinical course and is responsible for significant liver-related morbidity. Although the only currently available treatment (pegylated interferon) does not provide consistent results, emerging therapeutic options are promising. This article explores the epidemiology, natural history, as well as current and potential therapeutic options for hepatitis delta virus infection.

[Recent advances in managing hepatitis D]. / Nouveaux aspects de la prise en charge de l'hépatite D.

Discovered in 1977, Hepatitis D is the most severe form of chronic hepatitis, with rapid development of cirrhosis, hepatic failure and hepatocellular carcinoma. Despite all this, it is still largely underdiagnosed and there is no standardised management. The current treatment options are scarce and bear frequent side-effects, but the early diagnosis and an optimal follow-up with identification of the patients suitable for treatment improve significantly their survival rate and quality of life. Moreover, new promising treatments are entering phase III trials and offer new perspectives for our patients.

Découvert en 1977, le virus de l'hépatite D (VHD) est responsable de la forme la plus sévère des hépatites chroniques, avec une évolution rapide vers la cirrhose, la défaillance hépatique et le carcinome hépatocellulaire. Pourtant, le VHD est encore largement sous-diagnostiqué et la prise en charge peu standardisée. Malgré un traitement actuel sous-optimal et lourd, un diagnostic précoce, un suivi rapproché et l'identification des personnes à traiter permettent d'améliorer leur qualité de vie et d'allonger la survie. En outre, de nouveaux traitements prometteurs entrent en études de phase III, auxquelles participent également des centres suisses, ouvrant de nouvelles perspectives pour nos patients.

[Current and Future Therapy of Hepatitis B and D]. / Hepatitis B und D: aktuelle und zukünftige Therapien.

With approximately 240 million chronically infected people, hepatitis B virus (HBV) infection is a leading cause of cirrhosis and hepatocellular carcinoma in the world. Chronic HBV infection should be treated with antivirals, if either liver cirrhosis with detectable HBV DNA or relevant viral load (HBV DNA > 2000 IU/ml) and signs of liver damage (transaminase elevation, fibrosis, risk of liver cancer or similar) are present. The current standard therapy is a long-term treatment with nucleoside or nucleotide analogues such as entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide, while in selected cases interferon treatment (for 48 weeks) may be useful. Entecavir and the new drug tenofovir alafenamide (TAF) are to be preferred over tenofovir disoproxil fumarate in patients with concomitant renal insufficiency or osteoporosis. Pregnant women with high viral load (> 200 000 IU/ml) should be treated with tenofovir in the third trimester to minimize the risk of neonatal transmission (in addition to immediate active-passive immunization). In conditions of immunosuppression (e. g. chemotherapy, rituximab, anti-TNF), even a "healed" HBV infection may reactivate in a life-threatening manner, requiring prophylactic antiviral therapy in addition to testing for HBV in high-risk situations. The current therapies primarily achieve virus suppression, but rarely the loss of HBs antigen, which is considered a functional cure. New strategies such as discontinuation of long-term antiviral therapy with provoked reactivation and also completely new drugs are currently in clinical trials. The most serious form of viral hepatitis is the co-/superinfection of HBV with the delta virus (HDV). Standard therapy for delta hepatitis is pegylated interferon-alfa, but the approval of new drugs such as the HBV entry inhibitor Myrcludex is expected in the near future.

The balance of type 1 and type 2 immune responses in the contexts of hepatitis B infection and hepatitis D infection.

BACKGROUND AND AIM: Hepatitis delta virus (HDV) infection is the most rapidly progressive chronic viral hepatitis. Little is understood about the immune responses to HDV. This study aims to characterize the systemic immune environments of hepatitis B virus (HBV) and HDV patients at various disease stages. METHODS: A total of 129 subjects were evaluated: 53 HBV, 43 HDV, and 33 healthy controls. HBV and HDV subjects were categorized by aspartate aminotransferase to platelet ratio index (APRI) into mild (APRI < 0.5), moderate, and severe (APRI > 1.0). Serum cytokines and immune markers were assessed at a single treatment-naïve time-point. RESULTS: Type 1 cytokines are elevated in both HBV and HDV. Both groups show higher tumor necrosis factor-α (TNF-α), interleukin (IL)-12p40, and C-X-C motif chemokine ligand 9 when compared with controls (all P < 0.05). However, only HBV group displayed elevated γ-interferon compared with controls. Type 2 cytokines are elevated in HBV. HBV group shows higher IL-4, IL-13, and C-C motif chemokine ligand (CCL) 26 compared with healthy controls and HDV. Chemokines CCL2 and CCL13 are lower in HDV. When assessing ratios, HDV displays higher γ-interferon/IL-4, TNF-α/IL-4, and TNF-α/IL-13 ratios than HBV and controls. CONCLUSION: Hepatitis B virus and HDV subjects show similarly elevated type 1 cytokines. HDV subjects display relatively lower type 2 cytokines. These differences in the systemic immune environments, particularly the predominance of type 1 responses, may contribute to the comparatively rapid progression of HDV disease. Characterization of the imbalance in type 1 and type 2 immunity unique HDV has the potential to provide immunological insights for designing therapeutic targets in HDV-associated disease progression.

Hepatitis delta: virological and clinical aspects.

There are an estimated 400 million chronic carriers of HBV worldwide; between 15 and 20 million have serological evidence of exposure to HDV. Traditionally, regions with high rates of endemicity are central and northern Africa, the Amazon Basin, eastern Europe and the Mediterranean, the Middle East and parts of Asia. There are two types of HDV/HBV infection which are differentiated by the previous status infection by HBV for the individual. Individuals with acute HBV infection contaminated by HDV is an HDV/HBV co-infection, while individuals with chronic HBV infection contaminated by HDV represent an HDV/HBV super-infection. The appropriate treatment for chronic hepatitis delta is still widely discussed since it does not have an effective drug. Alpha interferon is currently the only licensed therapy for the treatment of chronic hepatitis D. The most widely used drug is pegylated interferon but only approximately 25% of patients maintain a sustained viral response after 1 year of treatment. The best marker of therapeutic success would be the clearance of HBsAg, but this data is rare in clinical practice. Therefore, the best way to predict a sustained virologic response is the maintenance of undetectable HDV RNA levels.

Modeling hepatitis virus infections and treatment strategies in humanized mice.

Hepatitis viruses cause chronic liver diseases such as fibrosis, cirrhosis and hepatocellular carcinomas that are difficult to treat and constitute a global health problem. Species-specific viral tropism has limited the usefulness of small animal models to study the impact of viral hepatitis. Immunodeficient mice grafted with human hepatocytes are susceptible to hepatitis viruses B, C, D and E (HBV, HCV, HDV and HEV), developing full viral life cycles, and delivering a means to investigate virus-host interactions and antiviral treatments. These chimeric humanized mouse models have been further grafted with humanized immune systems to decipher immune responses following hepatotropic viral infections, the ensuing pathophysiology, and to test novel therapeutic strategies.

[The return of the hepatitis delta virus]. / De terugkeer van het hepatitis delta-virus.

- There are several regions worldwide with a high prevalence of infection with the hepatitis delta virus (HDV) in hepatitis B virus (HBV) carriers.- Chronic HDV infection is occurring with increasing frequency due to increased immigration.- HDV transmission can take place through the same routes as HBV by simultaneous infection with both viruses (co-infection) or infection of an HBV carrier with HDV (superinfection).- Delta hepatitis is considered as the most severe form of viral hepatitis with a high risk of progression to cirrhosis and hepatocellular carcinoma.- Chronic delta hepatitis is exclusively observed in patients who are HBV carriers.- Pegylated interferon is currently the only registered therapy for patients with delta hepatitis, but leads to a persistent virological response in only a minority of them, and rarely leads to a complete cure.- New antivirals, such as viral entry blockers, prenylation inhibitors and anti-sense oligonucleotides are promising and currently being investigated in phase 2 trials.

Hepatitis delta virus testing, epidemiology and management: a multicentre cross-sectional study of patients in London.

BACKGROUND: Hepatitis delta virus (HDV) testing is recommended for all patients with hepatitis B virus (HBV) infection. HDV infection is associated with severe liver disease and interferon is the only available treatment. OBJECTIVES: To determine the rate of anti-HDV antibody testing in HBV patients; and to describe the epidemiology, clinical characteristics and management of HDV-infected patients at four hospitals in London. STUDY DESIGN: The anti-HDV testing rate was estimated by reviewing clinical and laboratory data. Cross-sectional data collection identified HDV-infected patients who had attended the study centres between 2005 and 2012. RESULTS: At a centre with clinic-led anti-HDV testing, 40% (67/168) of HBV patients were tested. Recently diagnosed HBV patients were more likely to be screened than those under long-term follow-up (62% vs 36%, P=0.01). At a centre with reflex laboratory testing, 99.4% (3543/3563) of first hepatitis B surface antigen positive samples were tested for anti-HDV. Across the four study centres there were 55 HDV-infected patients, of whom 50 (91%) had immigrated to the UK and 27 (49%) had evidence of cirrhosis. 31 patients received interferon therapy for HDV with an end of treatment virological response observed in 10 (32%). CONCLUSIONS: The anti-HDV testing rate was low in a centre with clinic-led testing, but could not be evaluated in all centres. The HDV-infected patients were of diverse ethnicity, with extensive histological evidence of liver disease and poor therapeutic responses. Future recommendations include reflex laboratory testing algorithms and a prospective cohort study to optimise the investigation and management of these patients.

[Viral hepatitis delta. Is there the delta infection problem in the Russian Federation?].

Hepatitis delta (HD) is characterized by rapid progression to fibrosis, and development of hepatocellular carcinoma, and a high mortality rate. The article presents data on the epidemiology, diagnosis, treatment of HD. The views of the epidemiological, clinical and virological characteristics of HD-infection among population of the Russian Federation (RF) are limited due to absence of official HD registration and detection of antibodies to the HD virus (anti-HDV) in HBsAg-positive individuals. However, some areas of the country are characterized by a high HDV circulation (Republic Tyva (RT) - 46,5%, Republic Sakha (Yakutia) - 12,5%) according to our studies conducted in 6 regions of Russia. Clinical-epidemiological situation of HDV infection in RT can be considered as a model to create a program of optimize diagnosis, prevention and treatment of HDV-infection in the Russian Federation.

An update on HDV: virology, pathogenesis and treatment.

Hepatitis delta is an inflammatory liver disease caused by infection with HDV. HDV is a single-stranded circular RNA pathogen with a diameter of 36 nm. HDV is classified in the genus Deltavirus and is still awaiting a final taxonomic classification up to the family level. HDV shares similarities with satellite RNA and viroids including a small circular single-stranded RNA with secondary structure that replicates through the 'double rolling circle' mechanism. The HDV RNA genome is capable of self-cleavage through a ribozyme and encodes only one structural protein, the hepatitis delta antigen (HDAg), from the antigenomic RNA. There are two forms of HDAg, a shorter (S; 22 kDa) and a longer (L; 24 kDa) form, the latter generated from an RNA editing mechanism. The S form is essential for viral genomic replication. The L form participates in the assembly and formation of HDV. For complete replication and transmission, HDV requires the hepatitis B surface antigen (HBsAg). Thus, HDV infection only occurs in HBsAg-positive individuals, either as acute coinfection in treatment-naive HBV-infected persons, or as superinfection in patients with pre-existing chronic hepatitis B (CHB). HDV is found throughout the world, but its prevalence, incidence, clinical features and epidemiological characteristics vary by geographic region. There are eight genotypes (1 to 8) distributed over different geographic areas: HDV-1 is distributed worldwide, whereas HDV-2 to 8 are seen more regionally. Levels of HDV viraemia change over the course of HDV infection, being significantly higher in patients with early chronic hepatitis than in cirrhosis. Chronic HDV infection leads to more severe liver disease than chronic HBV monoinfection with an accelerated course of fibrosis progression, an increased risk of hepatocellular carcinoma and early decompensation in the setting of established cirrhosis. Current treatments include pegylated interferon-α and liver transplantation; the latter of which can be curative. Further studies are needed to develop better treatment strategies for this challenging disease.

[Hepatitis D: forgotten but not gone]. / Hépatite D:oubliée mais pas disparue.

Hepatitis D virus (HDV) is a subviral agent which depends on the envelope proteins (HBsAg) of hepatitis B virus (HBV). Therefore, hepatitis D is observed only in patients infected with HBV. Chronic hepatitis D is the least frequent albeit most severe form of chronic viral hepatitis. A resurgence of chronic hepatitis D has been observed in Northern and Central Europe, mainly due to immigration of patients from regions with high prevalence. Every HBsAg-positive patient should be screened for concurrent HDV infection. Standard treatment consists of pegylated interferon-alpha for at least one year. Sustained virological response rates are approximately 20%. Liver transplantation should be considered in patients with advanced cirrhosis or limited hepatocellular carcinoma. Preventive measures for hepatitis D are the same as for hepatitis B.

Hepatitis delta: immunopathogenesis and clinical challenges.

Hepatitis delta is caused by infection with the hepatitis D virus (HDV) and is considered to be the most severe form of viral hepatitis in humans. Hepatitis delta occurs only in hepatitis B virus (HBV) surface antigen (HBsAg)-positive individuals as HDV is a defective RNA virus which requires the HBsAg for complete replication and transmission. Eight different HDV genotypes have been described with specific geographic distributions and distinct clinical courses. HDV/HBV co-infection can be associated with complex and dynamic viral dominance patterns. While HDV is frequently the dominating virus not only in HBV/HDV co-infection, but also in HBV/HCV/HDV triple-infected patients, the fluctuating courses of HDV and HBV viremia can be observed in other patients. Chronic HDV infection leads to more severe liver disease than HBV monoinfection with accelerated fibrosis progression, earlier hepatic decompensation and an increased risk for the development of hepatocellular carcinoma. However and in contrast to HCV infection, hepatic decompensation, rather than development of liver cancer, is the first clinical endpoint that develops during the course of infection. So far, only interferon-alpha treatment has proven antiviral activity against HDV in humans and has been linked to improved long-term outcome. Recent studies on the use of pegylated interferon showed a sustained virological response concerning HDV-RNA in about one quarter of the patients. HDV-specific immune responses might be associated with the response to treatment. Novel alternative treatment options, including prenylation inhibitors, are still awaiting clinical development for delta hepatitis. So far, only few studies have investigated immune responses against HDV and HBV in humans.

Hepatitis D: clinical features and therapy.

Surveys in the 1980s showed that the hepatitis D virus (HDV) is endemic worldwide, though with prevalences and patterns of infection varying in different areas. Medical scrutiny confirmed that chronic hepatitis D usually runs a severe and progressive course, the prototype patient having HBsAg in blood, elevated ALT, a liver biopsy exhibiting aggressive hepatitis and markers of HDV (but no marker of HBV replication in serum). Although the circulation of HDV has declined significantly following the control of HBV achieved over the last 20 years, depriving HDV of the HBV network necessary to propagate its infection, there is still a consistent reservoir of the virus in Europe, sustained by two different pools of HDV-infected patients: the residual ageing domestic pool that survived the brunt of the hepatitis D epidemic in the 1970s and 1980s and the population of young patients with recent HDV infections migrating to Europe. Therapy of hepatitis D remains an unsolved business. The therapy available today is not different from the limited interferon treatment attempted more than 20 years ago. The problem is formidable as HDV has no enzymatic protein to be targeted by conventional antiviral therapy. A potential target of therapy is offered by the process of hepatitis D virion assembly.