Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection
Autor: | Lisa A Bauman, Eckart Schott, Bradley M. Kerr, Yves Horsmans, Tobias Mueller, Kevin R. Steffy, Averett Devron R, Simon P. Fletcher, Jean-Pierre Desager, Thomas Berg |
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Rok vydání: | 2005 |
Předmět: |
Agonist
medicine.drug_class Hepacivirus Hepatitis C virus Receptors Cell Surface medicine.disease_cause Antiviral Agents Virus Immune system medicine Humans Membrane Glycoproteins Dose-Response Relationship Drug Guanosine Hepatology biology Toll-Like Receptors Hepatitis C Hepatitis C Chronic Viral Load biology.organism_classification medicine.disease Gene Expression Regulation Toll-Like Receptor 7 Immunology RNA Viral Viral disease Viral load |
Zdroj: | Hepatology. 42:724-731 |
ISSN: | 1527-3350 0270-9139 |
Popis: | Immune-based therapy is the mainstay treatment for chronic hepatitis C virus (HCV) infection but causes multiple side effects and achieves durable viral clearance in only approximately 50% of patients. Most new investigational anti-HCV compounds are direct-acting antivirals for which durability of response and risk of viral mutations and resistance are not yet known. Therefore, continuing discovery and development of new immune-based treatments is desirable. Toll-like receptors (TLRs) are pathogen recognition receptors that initiate the innate immune response. The responsiveness of HCV or other ongoing chronic systemic infections to treatment with a selective TLR agonist has not been reported. Isatoribine is a selective agonist of TLR7. In a proof-of-concept study, we found that once-daily 7-day treatment with intravenous isatoribine 800 mg caused a significant (P = .001) reduction of plasma HCV RNA (mean, -0.76; range, -2.85 to +0.21 log(10) units) in otherwise untreated patients (n = 12) who were chronically infected with HCV. Viral load reduction occurred in patients infected with genotype 1 as well as non-genotype 1 HCV. The reduction of viral load was correlated with induction of markers of a heightened immune antiviral state, including 2'-, 5'- oligoadenylate synthetase levels in whole blood. This treatment was well tolerated, with a low frequency of mild to moderate adverse events. In conclusion, systemic administration of the selective TLR7 agonist isatoribine resulted in dose-dependent changes in immunologic biomarkers and a statistically significant antiviral effect with relatively few and mild side effects. |
Databáze: | OpenAIRE |
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