Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection.

Abstract

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.

• Authors: Yves Horsmans, Thomas Berg, Jean-Pierre Desager, Tobias Mueller, Eckart Schott, Simon P Fletcher, Kevin R Steffy, Lisa A Bauman, Bradley M Kerr, Devron R Averett
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 42 Issue 3 Pg. 724-31 (Sep 2005) ISSN: 0270-9139 [Print] United States
• PMID: 16116638 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antiviral Agents
• Membrane Glycoproteins
• RNA, Viral
• Receptors, Cell Surface
• TLR7 protein, human
• Toll-Like Receptor 7
• Toll-Like Receptors
• Guanosine
• isatoribine

Topics

• Antiviral Agents (adverse effects, pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Gene Expression Regulation
• Guanosine (adverse effects, analogs & derivatives, therapeutic use)
• Hepacivirus (drug effects, genetics)
• Hepatitis C, Chronic (drug therapy)
• Humans
• Membrane Glycoproteins (agonists)
• RNA, Viral (blood, drug effects, genetics)
• Receptors, Cell Surface (agonists)
• Toll-Like Receptor 7
• Toll-Like Receptors
• Viral Load