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.

Chronische Hepatitis-B-Virusinfektion: aktuelle und zukünftige Therapieansätze

ZusammenfassungZur Therapie der chronischen Hepatitis-B-Virus-(HBV-)Infektion stehen aktuell pegyliertes Interferon-Alpha und Nucleosid‑/Nucleotidanaloga (Entecavir und Tenofovir) zur Verfügung. Diese Medikamente ermöglichen eine Virussuppression und eine Normalisierung des Leberenzyms Glutamat-Pyruvat-Transaminase (GPT) und verhindern ein Fortschreiten der Lebererkrankung. Zahlreiche noch in klinischer Entwicklung befindliche Therapiestrategien haben jedoch eine funktionelle Heilung zum Ziel. Dabei soll erreicht werden, dass das HBV-Hüllprotein HBsAg im Blutserum nicht mehr nachweisbar ist („ausgeheilte“ Hepatitis B). Der vorliegende Beitrag gibt eine Übersicht über aktuelle und mögliche zukünftige antivirale Therapien gegen die chronische HBV-Infektion. Als Grundlage diente eine Literaturrecherche unter besonderer Berücksichtigung der aktuellen Leitlinien sowie aktueller Kongressbeiträge.Die aktuell verfügbaren antiviralen Therapien führen nur sehr selten zur Elimination von HBsAg (funktionelle Heilung). Auch ist bisher weitgehend unklar, bei welchen Patienten ein Absetzen der Langzeittherapie mit Entecavir bzw. Tenofovir sinnvoll ist. Neue Therapiestrategien in klinischer Entwicklung führen bei einem höheren Anteil der Patienten zur funktionellen Heilung. Wahrscheinlich ist aber eine Kombination mehrerer antiviraler Strategien erforderlich, um die funktionelle Heilung für die Mehrheit der Patienten zu erreichen. Eine solche Therapie kann voraussichtlich in den nächsten 5–10 Jahren vorliegen.

The Effects From Oral Administration of Recombinant Interferon-alpha on Piglet Daily Care

The administration of interferon has improved the antiviral and immunomodulatory abilities of piglets, which is conductive to conductive to the prevention of potential diseases or delay the appearance of clinical symptoms. This study aimed to evaluate the effects from administration of recombinant interferon-alpha (IFN-α) on the daily care of piglets. The results were compared with compound Chinese herbal, which was proved to improve serum interferon level. Further, the administration routes were compared between oral administration and intramuscular injection. Forty (40) piglets with equal age and weight were randomly divided into four groups: Control group (Group C, without treatment), Group H (treated with compound Chinese herbal), Group K (administered orally with recombinant IFN-α, 1500 IU per day per piglet), and Group J (administered intramuscularly with IFN-α, 4× 106 IU per day per piglet). After the treatment of 15 days, both oral and intramuscular treatment of recombinant IFN-α significantly improved the secretion of IFN-gamma (IFN-γ) (P<0.05), and the effects of intramuscular pathway were faster. In addition, the expression levels of IFN-stimulated genes (MX1 and ISG15) were significantly enhanced (P<0.01), independently of IFN-α treatment time and serum IFN-γ level. Different from other studies, compound Chinese herbal showed weaker effects on interferon stimulation in piglets. The results indicated that oral administration of recombinant IFN-α improved interferon-induced response of piglets at both serum and molecular levels, which may be applied for improving autoimmunity of piglets.

IN SILICO CHARACTERIZATION OF HUMAN INTERFERON ALPHA/BETA RECEPTOR 2 (ISOFORM A, B AND C) PROTEIN

Objective: To predict the tertiary structure of human interferon alpha/beta receptor 2 protein. Study Design: Structure prediction by using bio informatics tools. Place and Duration of Study: Department of Biochemistry, Swat Medical College (STMC), Saidu Shareef, Swat, Pakistan, from Aug 2019 to Dec 2019. Methodology: All protein sequences of human interferon alpha/beta receptor 2 (isoforma, b and c) (IFNAR-2) were retrieved through the BLAST search (The Basic Local Alignment Search Tool) from available databases ‘NCBI’ (National Centre for Biotechnology Information) and ‘Uni Prot KB’ (The Universal Protein Resource). Sequence alignment was conducted by using Clustal Omega, to get the consensus sequence for IFNAR-2 protein. Consensus protein sequence of human IFNAR-2 was used for the prediction of the three-dimensional structure by employing Swiss-Model Server. Moreover, subcellular localization analysis was also performed by using CELLO2GO program. Results: Structural model of human IFNAR-2 protein was predicted and evaluated by Ramachandran dimension. Cellular localization of tertiary topological domains of the predicted models were revealed probability of localization of IFNAR-2 protein (isoform a, b & c) is highest in the plasma membrane due to the presence of the transmembrane alpha helical regions. Conclusion: This study predicted the tertiary structural dimensions of human IFNAR-2 protein, including the specific topological domains that contribute towards the subcellular compartmentalization and functional characteristics.

Giant cell angioblastoma

Giant cell angioblastoma is an extremely rare tumor of vascular origin, described at the end of the 20th century. It belongs to tumors with intermediate malignant potential and is characterized by locally infiltrative growth. The tumor doesn’t have any clear distinctive clinical characteristics. The diagnosis is established on the basis of histological examination. Two main treatment options for this pathology are discussed in the literature: radical removal of the tumor and therapy with low doses of interferon alpha. As a rule, this is a combination treatment. This article describes our own clinical case. The patient’s parents gave their consent to the use of their child’s data, including photographs, for research purposes and in publications. Interest is in the rarity of the disease and the features of the clinical characteristics of this case, specifically the extremely unfavorable localization in the oropharynx region and, accordingly, the impossibility of carrying out not only a radical removal of the tumor, but also its resection. The high probability of developing irreversible neurological complications in this age group associated with interferon alpha therapy questioned the possibility of its use. For the first time in this histological variant of a vascular tumor, chemotherapy was applied, including metronomic therapy with cyclophosphamide and vinblastine in combination with a liposomal form of doxorubicin. After 8 courses of chemotherapy, a complete clinical response was obtained with the restoration of the patency of the respiratory and digestive tracts. The observation period at the time writing of this article was 36 months.

Delta-tocotrienol enhances the antitumor effects of interferon alpha through ROS and Erk/MAPK signaling pathways in hepatocellular carcinoma cells

The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN α) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (δ-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of δ-tocotrienol with IFN α displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared to single therapies. Combining δ-tocotrienol and IFN α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinases MMP-7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and ROS generation. δ-tocotrienol induced Notch1 activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anticancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN α therapy showed promising results for HCC cells treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.

Clinical and immunological features of the combined course of pertussis and rhinovirus infection in children

The association of pertussis with various respiratory infections in children is the leading factor determining the complicated course and unfavorable outcome of the disease.Objective. To analyze clinical and immunological features of the combined course of pertussis and rhinovirus infection.Children characteristics and research methods. The authors observed 20 patients: 10 (50%) children were under the age of 1 year, 5 (25%) children of 1–3 years old, 3 (15%) children of 4–6 years, 2 (10%) children of 7 -14 years old.Results. The rhinovirus infection developed mainly at 1-2 weeks of illness in 18 (90%) children. Bronchitis developed in 11 (55%) children, pneumonia – in 4 (20%). Special attention was drawn to the low content of NK cells in 82.4% of patients when assessing the subpopulation composition of lymphocytes. The cytokine profile was characterized by a low level of interferon-gamma and interferon-alpha production – in 94.4 and 61.1% of patients, respectively.Conclusion. The combination of pertussis and rhinovirus infection in children contributes to the uneven course of the disease, the frequent development of bronchopulmonary complications.