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.

The changing context of hepatitis D.

The global epidemiology of hepatitis D is changing with the widespread implementation of vaccination against hepatitis B. In high-income countries that achieved optimal control of HBV, the epidemiology of hepatitis D is dual, consisting of an ageing cohort of domestic patients with advanced liver fibrosis who represent the end stage of the natural history of HDV, and of a younger generation of immigrants from endemic countries who account for the majority of new infections. As observed in Europe in the 1980s, the distinctive clinical characteristic of chronic hepatitis D in endemic countries is the accelerated progression to cirrhosis and hepatocellular carcinoma. Despite some recent progress, the therapeutic management of HDV remains unsatisfactory, as most patients are not cured of HDV with currently available medicines. This review article describes the current epidemiology and clinical features of chronic hepatitis D, based on the literature published in the last 10 years.

Effectiveness of pegylated interferon monotherapy in the treatment of chronic hepatitis D virus infection: A meta-analysis.

Chronic HDV infection often is associated with aggressive form of liver disease, compared to chronic HBV mono-infection. However, chronic HDV treatment is challenging because currently there is no approved regimen for affected patients. While standard interferon with/without nucleos(t)ide analogues were reported to be inferior to pegylated interferon (peginterferon) as HDV treatment according to few randomized clinical trials. This meta-analysis will summarize the results of studies on the effectiveness of peginterferon as HDV treatment regimen. An electronic search was performed using PubMed, Cochrane Library, Research Gate, and Medline databases. Studies involving patients who received peginterferon therapy for at least 48 weeks and followed up for 24 weeks post-therapy were included. All analyses were conducted using Review Manager 5.3 designed for Cochrane Reviews. The primary efficacy endpoint was virological response (VR) or HDV-RNA negativity at the end of the follow-up period, whereas secondary efficacy endpoints were biochemical response (BR) or ALT normalization and HBsAg clearance with seroconversion to anti-HBs at the end of follow-up period. Data were abstracted from 13 relevant studies with a total of 475 patients who were treated with peginterferon alpha-2a or -2b. At the end of 24-week post-treatment the pooled VR was achieved in 29% of patients with 95% CI [24%; 34%], BR was reached in 33% of patients [95% CI 27%; 40%] and HBsAg clearance with seroconversion to anti-HBs was achieved in 1% of patients with 95% CI [-0.02; 0.05]. In conclusion, this study showed that peginterferon has limited effectiveness in HDV treatment, since only one-third of chronic HDV patients achieved viral clearance and normalized ALT levels. Morever, HBsAg clearance with seroconversion to anti-HBs has been rarely observed among chronic HDV patients.

Origin, HDV genotype and persistent viremia determine outcome and treatment response in patients with chronic hepatitis delta.

BACKGROUND & AIMS: HDV infection causes severe chronic liver disease in individuals infected with HBV. However, the factors associated with poor prognosis are largely unknown. Thus, we aimed to identify prognostic factors in patients with HDV infection. METHODS: The French National Reference Centre for HDV performed a nationwide retrospective study on 1,112 HDV-infected patients, collecting epidemiological, clinical, virological and histological data from the initial referral to the last recorded follow-up. RESULTS: The median age of our cohort was 36.5 (29.9-43.2) years and 68.6% of our cohort were male. Most patients whose birthplace was known were immigrants from sub-Saharan Africa (52.5%), southern and eastern Europe (21.3%), northern Africa and the Middle East (6.2%), Asia (5.9%) and South America (0.3%). Only 150 patients (13.8%) were French native. HDV load was positive in 659 of 748 tested patients (88.1%). HDV-1 was predominant (75.9%), followed by sub-Saharan genotypes: HDV-5 (17.6%), HDV-7 (2.9%), HDV-6 (1.8%) and HDV-8 (1.6%). At referral, 312 patients (28.2%) had cirrhosis, half having experienced at least 1 episode of hepatic decompensation. Cirrhosis was significantly less frequent in African than in European patients regardless of HDV genotype. At the end of follow-up (median 3.0 [0.8-7.2] years), 48.8% of the patients had developed cirrhosis, 24.2% had ≥1 episode(s) of decompensation and 9.2% had hepatocellular carcinoma. European HDV-1 and African HDV-5 patients were more at risk of developing cirrhosis. Persistent replicative HDV infection was associated with decompensation, hepatocellular carcinoma and death. African patients displayed better response to interferon therapy than non-African patients (46.4% vs. 29.1%, p <0.001). HDV viral load at baseline was significantly lower in responders than in non-responders. CONCLUSION: Place of birth, HDV genotype and persistent viremia constitute the main determinants of liver involvement and response to treatment in chronic HDV-infected patients. LAY SUMMARY: Chronic liver infection by hepatitis delta virus (HDV) is the most severe form of chronic viral hepatitis. Despite the fact that at least 15-20 million people are chronically infected by HDV worldwide, factors determining the severity of liver involvement are largely unknown. By investigating a large cohort of 1,112 HDV-infected patients followed-up in France, but coming from different areas of the world, we were able to determine that HDV genotype, place of birth (reflecting both viral and host-related factors) and persistent viremia constitute the main determinants of liver involvement and response to treatment.

Chronic Hepatitis B, C, and D.

Chronic hepatitis B, C, and D virus infections contribute significantly to the morbidity and mortality of immunocompromised individuals. To contextualize discussion of these infections in immunocompromised patients, this paper provides an overview of aspects of infection in normal hosts. It then describes differences in disease, diagnostic testing, and therapeutic management observed in immunocompromised patients.

Autoimmune hepatitis in patients with chronic HBV and HCV infections: patterns of clinical characteristics, disease progression and outcome.

We retrospectively investigated the characteristics, patterns of disease progression, outcome and difficulties in the management in 11 patients with concurrent autoimmune hepatitis (AIH) and HBV or HCV infections (5 HCV and 6 HBV including 2 with HDV co-infection) since there are scarce data on this issue. HCV or HBV diagnosis preceded that of AIH in all patients by many years. At initial clinical and histological assessment almost half of patients had cirrhosis (45.5%) with the group of AIH and HCV carrying the highest frequency (4/5; 80%). In two thirds of patients, mostly with HCV and HBV/HDV, AIH was assumed to be IFNalpha-induced and experienced difficulties in achieving sustained virological response. On the contrary, the outcome of patients with HBV and AIH was better compared to those with AIH and HCV or HDV. In conclusion, chronic viral hepatitis infections concomitant with AIH are often very difficult to recognize and therefore, a significant delay in AIH diagnosis in this specific group of patients is usual. HBV patients with concomitant AIH seem to carry the most favorable outcome compared to those with HCV probably because of the use of nucleos(t)ide analogues which contrary to IFN-alpha can control HBV replication with no adjacent effect, related to exacerbation of autoimmune phenomena.

Hepatitis D virus: an update.

Hepatitis D virus (HDV) infection involves a distinct subgroup of individuals simultaneously infected with the hepatitis B virus (HBV) and characterized by an often severe chronic liver disease. HDV is a defective RNA agent needing the presence of HBV for its life cycle. HDV is present worldwide, but the distribution pattern is not uniform. Different strains are classified into eight genotypes represented in specific regions and associated with peculiar disease outcome. Two major specific patterns of infection can occur, i.e. co-infection with HDV and HBV or HDV superinfection of a chronic HBV carrier. Co-infection often leads to eradication of both agents, whereas superinfection mostly evolves to HDV chronicity. HDV-associated chronic liver disease (chronic hepatitis D) is characterized by necro-inflammation and relentless deposition of fibrosis, which may, over decades, result in the development of cirrhosis. HDV has a single-stranded, circular RNA genome. The virion is composed of an envelope, provided by the helper HBV and surrounding the RNA genome and the HDV antigen (HDAg). Replication occurs in the hepatocyte nucleus using cellular polymerases and via a rolling circle process, during which the RNA genome is copied into a full-length, complementary RNA. HDV infection can be diagnosed by the presence of antibodies directed against HDAg (anti-HD) and HDV RNA in serum. Treatment involves the administration of pegylated interferon-α and is effective in only about 20% of patients. Liver transplantation is indicated in case of liver failure.

Interferon-alpha treatment of hepatitis D induces tuberculosis exacerbation in an immigrant.

This report describes the case of a young Romanian patient who developed a severe exacerbation of pulmonary tuberculosis during interferon-alpha treatment for chronic hepatitis D. While this occurrence underscores that clinical guidelines should be applied with caution in immigrants from underdeveloped countries, due to the possible presence of unrecognized or unreported comorbidity, the mechanisms for an interferon-related exacerbation of pulmonary tuberculosis are also examined. We propose that IFN-induced weight loss and anorexia may have played an important role in promoting clinical manifestations of tuberculosis in our patient.

Chronic viral hepatitis.

Both hepatitis B and hepatitis C are spread parenterally. Chronic hepatitis C is fast becoming the leading indication for liver transplantation. Most infected patients go on to develop chronic hepatitis, with approximately 20% developing liver cirrhosis or hepatocellular carcinoma after 20 years. Standard treatment now is with a combination of alpha-interferon and ribavirin, which is successful in up to 40% of patients. A vaccine is still a remote possibility and prevention remains all-important. Despite having a successful vaccine, chronic hepatitis B remains an important cause of liver cirrhosis and hepatocellular carcinoma. Treatments for active hepatitis include alpha-interferon and the newer nucleoside analogues such as lamivudine and adefovir. In patients undergoing liver transplantation, recurrence of hepatitis B in the graft can be reduced with a combination of hepatitis B immunoglobulin and these nucleoside analogues.

Hepatitis delta virus: the molecular basis of laboratory diagnosis.

Infection with hepatitis delta virus (HDV), a satellite virus of hepatitis B virus (HBV), is associated with severe and sometimes fulminant hepatitis. The traditional methods for the diagnosis of HDV infection, such as detection of serum anti-HD antibodies, are sufficient for the clinical diagnosis of delta infection. However, such techniques lack the sensitivity and specificity required to more accurately characterize the nature of HDV infection and to assess the efficacy of therapies. Recent improvements in molecular techniques, such as HDV RNA hybridization and RT-PCR, have provided increased diagnostic precision and a more thorough understanding of the natural course of HDV infection. These advances have enhanced the clinician's ability to accurately evaluate the stage of HDV infection, response to therapy, and occurrence of reinfection after orthotopic liver transplant. This review focuses on the recent advances in the understanding of the molecular biology of HDV and in the laboratory diagnosis of HDV infection.

[Chronic viral hepatitis--diagnosis, therapy and prognosis]. / Chronische Virushepatitis--Diagnostik, Therapie und Prognose.

Infections with the hepatitis B, C or D virus can all lead to chronic hepatitis. Serological and molecular methods are essential for diagnosis and for differentiation between the different forms of chronic virus hepatitis. In adults between 5 and 10% of all infections with the hepatitis B virus become chronic while the rate is as high as 80% with the hepatitis C virus. All forms of chronic hepatitis are frequently asymptomatic for a long period of time. Complications are liver cirrhosis and hepatocellular carcinoma. During chronic hepatitis B infection in around 1% of the patients per year the virus is eliminated spontaneously while virus elimination occurs rarely in patients with chronic hepatitis C infection. In patients with chronic hepatitis C infection over a period of 30 years around 3% of the patients die due to chronic hepatitis C infection. As soon as chronic virus hepatitis is diagnosed treatment should be considered. Standard therapy for all forms of chronic viral hepatitis is interferon alpha. Additionally recent results indicate that nucleoside analogous are effective for chronic hepatitis B and C virus infection. For chronic hepatitis B infection studies with famciclovir and lamivudine show that viral replication can be effectively blocked. For chronic hepatitis C infection a combination therapy with interferon and ribavirin has been shown to reach higher elimination rates compared to interferon mono-therapy. The last treatment option for all forms of viral hepatitis is liver transplantation.

Exacerbation of chronic hepatitis D during interferon alpha administration.

Acute and severe impairment of liver function with jaundice and ascites occurred in two out of seven patients with chronic hepatitis D during interferon alpha administration (10 MU three times a week). Both of them were young women with histological diagnoses of moderate to severe chronic hepatitis and cirrhosis with no signs of portal hypertension. Only a slow and partial recovery was observed after interferon withdrawal. Autoantibodies against basal cell layer tested positive in these two patients. In the remaining five patients with hepatitis D who did not experience liver impairment during interferon administration, basal cell layer antibodies were found only in one case. We conclude that severe decompensation of liver cirrhosis related to hepatitis D may occur during interferon administration. Positivity of basal cell layer antibodies may be associated with the risk of developing such an adverse event but our data are not sufficient to prove this association.

Hepatitis crónica viral: diagnóstico, evolución y tratamiento / Cronic viral hepatitis: diagnosis, natural history and treatment

La infección crónica por los virus de la hepatitis B, C y D puede prvocar un proceso necro-inflamatorio hepático persistente y progresivo. La hepatitis crónica viral constituye una de las primeras causas de enfermedad hepática avanzada a nivel mundial. Por lo general asintomátivca, solo se hace clínicamente aparente cuando ya existe cirrosis o sus complicaciones. Se sospecha frecuentemente al detectarse elevación de las transaminasas. La evolucíon es muy variable pero un grupo significativo de pacientes progresan hacia cirrosis y hepatocarcinoma, generalmente en cuestión de décadas. El diagnóstico se basa fundamentalmente en el laboratorio en especial en los marcadores virales, pudiendo ser útiles los hallazgos de la biopsia. El tratamiento aceptado es con interferón que inhibe la replicación viral y reduce la lesión hepática, sin embargo, esto solo sucede en un subgrupo de enfermos, siendo frecuentes las recaídas especialmente en las infecciones provocadas por el virus C. Se están investigando nuevas modalidades terapéuticas entre las cuales destaca el uso de antivirales como los nucleósidos análogos utilizados por lo general combinados con interferón