Die Anwendung von Interferonen in der Virus-Therapie

Die starke antivirale Aktivität der Interferone und ihre mögliche Wirkung gegen Tumorzellen sind der Grund, warum Interferone schon kurz nach ihrer Entdeckung als vielversprechende Medikamente betrachtet wurden. Die vermutlich medizinisch wichtigste Anwendung von Interferonen in der Virus-Therapie ist die Behandlung der chronisch-aktiven Hepatitis, die durch Hepatitis-B- oder -C-Viren ausgelöst wird. Bei Hepatitis C reagieren die viralen Serotypen allerdings sehr unterschiedlich auf eine Interferon-Therapie. Gute Erfolge konnten mit Interferon-α-2a oder Interferon-α-2b erzielt werden, besonders wenn diese in Kombination mit anderen antiviralen Medikamenten verabreicht werden, z.B. Protease-Inhibitoren. Mittlerweile sind auch so genannte pegylierte Interferone zugelassen, die aufgrund der Kopplung an das Polymer PEG¹⁾ im Körper nicht so schnell abgebaut werden und nur einmal in der Woche verabreicht werden müssen.

Die anfängliche Hoffnung, dass Interferone auch für die Therapie von HIV-Infekten erfolgreich sein könnten, erfüllte sich nicht. Abgesehen von der Wirkung auf Kaposi-Sarkome wurde der Krankheitsverlauf durch Interferon-α-2a oder Interferon-α-2b nicht signifikant verbessert. Kaposi-Sarkome sind bösartige Tumore, die oft im Zusammenhang mit einer HIV-Infektion auftreten und vom Humanen Herpes-Virus 8 (HHV-8) verursacht werden.

Eine Therapie mit Interferonen verursacht oft erhebliche Nebenwirkungen mit Grippe-ähnlichen Symptomen wie Fieber, Schüttelfrost, Müdigkeit, Kopfschmerzen und Gewichtsverlust, so dass viele Patienten die Therapie abbrechen. Ein vergleichsweise großer Anteil der Patienten von bis zu 40 % entwickelt im Verlauf der Therapie Antikörper gegen rekombinant produziertes Interferon-α oder die IFN-β-Ser-17-Variante²⁾, was in der älteren Literatur auch gelegentlich als Interferon-Resistenz beschrieben ist.

Literatur

Meager, A.; Das, R. G. (2005): Biological standardization of human interferon beta: establishment of a replacement world health organization international biological standard for human glycosylated interferon beta. In: J. Immunol. Methods. 306 , 1-15 Titel des Artikels Biological standardization of human interferon beta: establishment of a replacement world health organization international biological standard for human glycosylated interferon beta Abstract Human interferon beta (IFN-beta) has been developed as a major biotherapeutic agent for the treatment of multiple sclerosis. Since World Health Organization (WHO) international standards (IS) for IFN-beta were established several years prior to the development of clinical grade IFN-beta products, a number of scientific issues with regard to the biological standardisation of natural and recombinant IFN-beta products have emerged. In order to address these issues, an international collaborative study to evaluate WHO IS and candidate international standards (CIS) of IFN-beta was instigated by the National Institute for Biological Standards and Control (NIBSC) in 2000 and was carried out in the succeeding year. Sixteen expert laboratories from 8 countries worldwide participated in the study. They performed titrations on 8 different IFN-beta preparations, including IS and new CIS, in a variety of mainly antiviral- but also including some antiproliferative- and reporter gene-assays, and contributed raw data from these assays to NIBSC for statistical analysis and calculation of potencies. While both intra- and inter-laboratory variation of potency estimates was evident, overall validity of the study as a whole was clearly shown by comparison of two pairs of internal coded duplicates, which gave the expected relative potency of 1 and the lowest inter-laboratory variability of potency estimates in all assay types. The CIS containing Chinese hamster ovary (CHO) cell- or human fibroblast-derived, glycosylated, IFN-beta gave similar low inter-laboratory variation in potency estimates one to another as the coded duplicates, which was significantly less than to the 2nd WHO IS of IFN-beta, human fibroblast-derived, Gb23-902-531. One of these CIS, designated 00/572, containing CHO cell-derived IFN-beta and formulated with both bovine casein and human serum albumin, could be assigned a potency, consistent for all assay types, of 40,000 international units (IU) per ampoule relative to the IU of the 2nd IS of IFN-beta, Gb23-902-531. Other CIS containing glycosylated IFN-beta, either CHO cell- or human-fibroblast-derived, could also be assigned potency values that were continuous with the IU of Gb23-902-531 and 00/572. However, greater inter-laboratory variations in estimates were evident from comparisons of Gb23-902-531 or 00/572 with either the 1st IS for E. coli-derived, non-glycosylated, IFN-beta with serine substitution at position 17 (IFN-beta Ser 17 mutein), Gxb02-901-535, or with a CIS (00/574) containing IFN-beta Ser 17 mutein. Indeed, variations in potency estimates for preparations containing IFN-beta Ser 17 mutein were sufficiently large to indicate that assays could distinguish preparations of IFN-beta Ser 17 mutein from preparations of glycosylated IFN-beta. Thus, neither the 2nd IS of IFN-beta, Gb23-902-531, containing fibroblast-derived IFN-beta, nor CIS, 00/572, containing CHO cell-derived IFN-beta, was appropriate for standardisation of preparations of IFN-beta Ser 17 mutein. Conversely, neither the IS of IFN-beta Ser 17 mutein, Gxb02-901-535, or a CIS of IFN-beta Ser 17 mutein, 00/574, was appropriate for the standardisation of preparations of glycosylated IFN-beta. CIS 00/572, containing CHO cell-derived, glycosylated IFN-beta, was clearly shown to be suitable to serve as a primary standard for glycosylated forms of IFN-beta, especially clinical grade IFN-beta-1a products. It was further shown to exhibit high thermal and long-term stability. Since the CHO cell-derived IFN-beta used for preparation of 00/572 was of a greater purity than the IFN-beta used for the 2nd IS of IFN-beta, Gb23-902-531, it was recommended by the WHO Informal Consultation on the Standardisation of Cytokines, Growth Factors and Other Endocrinological Substances, which met in October 2003, that 00/572 should replace Gb23-902-531 as the IS for glycosylated IFN-beta. This recommendation was accepted by the WHO Expert Committee on Biological Standardization (ECBS) at its annual meeting in November 2003 and 00/572 was established as the 3rd IS for human glycosylated IFN-beta with an assigned potency of 40,000 IU. As this study identified no advantage to replacing the existing 1st IS for IFN-beta Ser 17 mutein, Gxb02-901-535, WHO ECBS accepted that this should continue to serve as the IS for this material.

Ishikawa, T. (2008): Secondary prevention of recurrence by interferon therapy after ablation therapy for hepatocellular carcinoma in chronic hepatitis C patients.. In: World J. Gastroenterol.. 14 , 6140-4 Titel des Artikels Secondary prevention of recurrence by interferon therapy after ablation therapy for hepatocellular carcinoma in chronic hepatitis C patients. Abstract Chronic hepatitis C is a leading cause of hepatocellular carcinoma (HCC) worldwide. Interferon (IFN) therapy decreases the incidence of HCC in patients with chronic hepatitis C. Prevention of chronic-hepatitis-C-related HCC is one of the most important issues in current hepatology. We have previously reported that male gender and high titer of hepatitis C virus (HCV) RNA are predictive factors for the development of HCC in HCV-related cirrhosis. Clinical efforts at eradicating or reducing the viral load may reduce the risk for HCC. Furthermore, because HCC often recurs after ablation therapy, we performed a trial of IFN in patients with chronic liver disease caused by HCV to see whether IFN therapy decreases recurrence after ablation therapy of HCV-related HCC. By using IFN therapy as a secondary prevention, patients with HCC who had received complete tumor ablation showed better survival, primarily as a result of the preservation of liver function and also probably prevention of recurrence. Postoperative IFN therapy appears to decrease recurrence after ablation therapy such as radiofrequency ablation (RFA) therapy of HCV-related HCC. We believe that there is a survival benefit in secondary prevention using IFN therapy. However, a controlled study is essential to obtain conclusive evidence of the efficacy of this strategy.