Bulevirtide als erster spezifischer Wirkstoff gegen Hepatitis-D-Virusinfektionen – Mechanismus und klinische Wirkung

ZusammenfassungDie Blockade des Zelleintritts von Krankheitserregern ist ein geeigneter Ansatz, um Neuinfektionen zu verhindern. Der therapeutische Einsatz von Eintrittsinhibitoren bei chronisch infizierten Patienten war jedoch bisher nur begrenzt erfolgreich. Zur Behandlung von chronischen Hepatitis-D-Virus-(HDV-)Infektionen wurde im Juli 2020 mit Bulevirtide (BLV) ein vielversprechender Wirkstoff bedingt zugelassen, der auf diesem Wirkprinzip beruht. Zuvor hatten für HDV keine gezielte Medikation zur Verfügung gestanden und die Behandlung beruhte auf dem Off-Label-Einsatz von Interferon-Alpha/Peginterferon-Alpha (IFNα/Peg-IFNα). In diesem Beitrag wird ein Überblick über die Grundlagen des Wirkmechanismus von BLV gegeben und bisher vorliegende klinische Daten werden zusammengefasst.Eine HDV-Infektion manifestiert sich als Ko- oder Superinfektion bei Hepatitis-B-Virus-(HBV-)Infektionen und betrifft 4,5–15 % der HBV-Patienten weltweit. HDV nutzt die Hüllproteine von HBV zur Verbreitung. BLV wirkt, indem es den HBV/HDV-Rezeptor natriumtaurocholat-co-transportierendes Polypeptid (NTCP) blockiert und so den Eintritt von HBV/HDV in Hepatozyten verhindert. BLV senkt die HDV-Serum-RNA-Spiegel und führt bei HBV/HDV-infizierten Personen zur Normalisierung der Alanin-Aminotransferase-(ALT-)Werte. Es hat ein ausgezeichnetes Sicherheitsprofil, selbst wenn es über 48 Wochen in hohen Dosen (10 mg täglich) verabreicht wird. In Kombination mit Peg-IFNα zeigt BLV synergistische Effekte auf die Senkung der HDV-RNA im Serum, aber auch auf die Hepatitis-B-Oberflächenantigen-(HBsAg‑)Spiegel. Dies führte bei einer Untergruppe von Patienten zu einer funktionellen Heilung, wenn 2 mg BLV plus Peg-IFNα verabreicht wurden. Der Mechanismus dieser wahrscheinlich immunvermittelten Eliminierung wird in Folgestudien untersucht.

Hepatitis-D Virus Infection Is Not Impaired by Innate Immunity but Increases Cytotoxic T-Cell Activity

Approximately 70 million humans worldwide are affected by chronic hepatitis D, which rapidly leads to liver cirrhosis and hepatocellular carcinoma due to chronic inflammation. The triggers and consequences of this chronic inflammation, induced by co-infection with the hepatitis D virus (HDV) and the hepatitis B virus (HBV), are poorly understood. Using CRISPR technology, we characterized the recognition of HDV mono- and co-infection by intracellular innate immunity and determined its influence on the viral life cycle and effector T-cell responses using different HBV and HDV permissive hepatoma cell lines. We showed that HDV infection is detected by MDA5 and -after a lag phase -induces a profound type I interferon response in the infected cells. The type I interferon response, however, was not able to suppress HDV replication or spread, thus providing a persistent trigger. Using engineered T-cells directed against the envelope proteins commonly used by HBV and HDV, we found that HDV immune recognition enhanced T-cell cytotoxicity. Interestingly, the T-cell effector function was enhanced independently of antigen presentation. These findings help to explain immune mediated tissue damage in chronic hepatitis D patients and indicate that combining innate triggers with T-cell activating therapies might allow for a curative approach.

The Prevalence of Hepatitis D Virus in Reactive HBsAg Blood Donors at Department of Pathology, LUMHS Jamshoro

Background: The hepatitis delta virus (HDV) is a defective hepatotropic virus that only affects patients infected with the hepatitis B virus (HBV). Infection with the hepatitis delta virus can cause acute hepatitis, including the fulminant presentation or spontaneously resolving infection and chronic infection Aim: The present study's aim was to determine the prevalence of the Hepatitis D virus in reactive HBsAg blood donors at Diagnostic and Research Lab Hyderabad. Materials and Methods: This cross-sectional study was conducted on 434 blood donors at the Pathology department (Diagnostic and Research Laboratory) Civil Hospital, Hyderabad from January 2017 to December 2017. All the healthy individuals who visited at Diagnostic and Research Laboratory of Civil Hospital, LUMHS Hyderabad as blood donors with specific age groups of either gender were included in this study. All the individuals underwent Hepatitis screening. All of those cases that were noted with positive HBV further underwent HDV screening test. All the data was recorded in the proforma for the purposed of analysis. SPSS version 20 was used for data analysis. Results: Of the total 434 blood donors, 420 (96.8%) were male and 14 (3.2%) were female. The overall mean age was 31.65±4.67 years with an age range of 18 to 60 years. Out of 434, the incidence of positive delta virus was 62 (14.3%) while the remaining 372 (85.7%) were negative delta hepatitis blood donors. The prevalence of delta hepatitis blood donors with respect to age distribution were as follows; 18-30 years had 208 (48%), 31-40 years had 188 (27%), 41-50 years 69 (16%), and 51-60 years 39 (9%). Of the total 62 positive delta hepatitis, the prevalence of males and females was 98.4% and 1.6% respectively. All the donor’s blood group was divided into +O, +B, +A, +AB, -O, -A, and –B with their respective prevalence was 48.6%, 22.6%. 11.5%, 8.8%, 2.5%, 3.5%, and 2.5% whereas their frequency in positive tested delta hepatitis was 36 (58.1%), 7 (11.3%), 10 (16.1%), 6 (9.7%), 1 (1.6%), 2 (3.2%), and 0 (0%) respectively. Conclusion: It is concluded that the prevalence of HDV is 14.3% in Hepatitis B reactive healthy donors. This is a higher prevalence as compared to previously published studies. No such adequate recent data is available at the local level. More research is needed on this event, to provide adequate knowledge, which will be helpful to clinical and laboratory investigators, and physicians to reduce the burden of liver disease caused by HBV and HDV co-infection. Keywords: Hepatitis delta virus; HBsAg reactivity; Blood donors;