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Charakteristika des Hepatitis-C-Virus und virale Prädiktoren der therapeutischen Intervention

Characteristics of hepatitis C-Virus and viral predictors of therapeutical response

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Zusammenfassung

□ Pathogenese der HCV-Infektion und virale Charakteristika

Das Hepatitis-C-Virus (HCV) gilt weltweit als häufigster Verursacher der chronischen Non-A-non-B-Hepatitis, die schleichend in eine Leberzirrhose übergehen kann und mit einem erhöhten Risiko zum primären Leberzellkarzinom assoziiert ist. Der hohe Anteil chronifizierender Verläufe nach HCV-Infektion läßt sich durch die ausgeprägte Variabilität antigener Virusepitope erklären, die nur eine unzureichende Immunantwort induzieren und so das konsekutive Persistieren des Virus im Wirtsorganismus ermöglichen. Die Heterogenität von HCV innerhalb einer Viruspopulation bzw. zwischen verschiedenen HCV-Isolaten läßt sich auf genomischer Ebene charakterisieren: man differenziert HCV-Varianten innerhalb einer Viruspopulation mit Sequenzunterschieden von weniger als 5% (sogenannte HCV-Quasispezies) von HCV-Isolaten mit Sequenzdivergenzen zwischen 10 und 20% (HCV-Genotypen bzw._-Subtypen). Insbesondere zwischen HCV-Genotypen zeigen sich Unterschiede sowohl in Antigenität und therapeutischer Empfindlichekeit als auch in ihrer geographischen Verteilung.

□ Virale Prädiktoren der HCV-Therapie

In einer Metaanalyse von 18 Therapiestudien zeigt sich, daß der Erfolg der Interferontherapie von HCV-Infektionen wesentlich determiniert wird durch HCV-Genotyp 1 und hohe HCV-RNA-Titer (>106 Genomäquivalente/ml). Einen wesentlichen Fortschritt in der Therapie von Patienten mit chronischer HCV-Infektion scheint die Kombinationstherapie aus Interferon und Ribavirin zu bringen. In den beiden bislang publizierten multizentrischen Studien profitierten insbesondere Patienten mit ungünstigen viralen Prädiktoren — HCV-Genotyp 1 oder hohe HCV-RNA-Titer — dauerhaft von einer Kombinationstherapie.

□ Schlußfolgerung und Ausblick

Sowohl aus virologischer als auch aus klinischer Sicht stellt die HCV-Infektion eine Herausforderung dar. Die Kombinationstherapie aus Interferon und Ribavirin stellt einen entscheidenden Fortschritt sowohl in der Retherapie als auch in der Primärtherapie der Hepatitis C dar. Trotz dieses neuen Therapiekonzepts müssen weitere Strategien zur Verbesserung der therapeutischen Ergebnisse entwickelt werden. Hierzu zählen Therapien mit Modifikationen der Interferongaben (höhere und tägliche Dosierungen, längere Therapiedauer, Verwendung von pegylierten Interferonen mit verzögerter Freisetzung), Kombinationstherapien von Interferon mit anderen bekannten antiviralen Substanzen (Amantadin), mit Immunodulatoren (GM-CSF, Thymosin α1), die Entwicklung von neuartigen antiviralen Hemmstoffen (Hemmung der viralen Protease, Helikase oder Polymerase) sowie die Exploration antiviraler molekularer Strategien, wie die Gabe von spezifischen Ribozymen, Antisenseoligonukleotiden oder der DNA-Vakzinierung. Endgültiges Ziel ist und bleibt allerdings die Entwicklung einer wirksamen Impfprophylaxe.

Abstract

□ Natural History of Hepatitis C-Infection and Viral Characteristics

Hepatitis C-virus (HCV) infection is a major cause of non-A, non-B-hepatitis and, additionally, is associated with liver cirrhosis and hepato-cellular carcinoma. The high degree of chronificity of HCV-infection is reasonable due to antigenic variability of neutralizing epitopes leading to incomplete immunoresponse with subsequent virus persistence. Besides genetic variants of HCV within a virus population (quasispecies nature of HCV), different genotypes are classified being genetically and phenotypically distinct, and geographically restricted in part. Genotyping of HCV is not only important for phylogenetic and epidemiological studies, but also a predictive marker for pathogenesis and therapy.

□ Viral Predictors of HCV Therapy

In a meta-analysis of 18 therapeutical studies of chronical HCV infections, genotype 1 and high levels of viremia determined markedly the response to interferon therapy. In this context, clinical trials have proven the effect of a combined therapy with interferon and ribavirin. Especially patients with HCV genotype 1 or high levels of viremia had a real benefit from combined antiviral therapy in comparison to monotherapy with interferon.

□ Conclusion and Future Concepts

Besides recent concepts improving the therapeutical response to HCV infection, further effort is necessary to develop more successful strategies for eradication of hepatitis C virus. In this context, variations of interferon therapy should be evaluated (e. g. higher and daily doses, longer duration of interferon therapy, “retarded” interferon (PEG-IFN). In addition, new therapeutical concepts should be performed including a combination of interferon with other known antiviral agents (amantadine), a combination with immunomodulators (GM-CSF, thymosin α1), the development of new antiviral agents (inhibitors of viral proteases, helicases and polymerases) and the exploration of anti-viral, molecular strategies (specific ribozymes, antisense oligonucleotides and DNA-vaccination). Nevertheless, the development of an effective vaccination should be the most important challenge for the future.

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    Andreas Ambrosch & Wolfgang König

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Ambrosch, A., König, W. Charakteristika des Hepatitis-C-Virus und virale Prädiktoren der therapeutischen Intervention. Med Klin 94, 626–632 (1999). https://doi.org/10.1007/BF03045003

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