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

Authors


  • Potential conflict of interest: DR Averett, SP Fletcher, BM Kerr, LA Bauman, and KR Steffy own stock in and are employed by Anadys Pharmaceuticals. Y Horsmans, T Berg, JP Desager, T Mueller, and E Schott were compensated by Anadys for clinical study services. T Berg and E Schott received a research grant from Anadys. Y Horsmans and T Berg are consultants to Anadys.

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 log10 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. (HEPATOLOGY 2005;42:724–731.)

Ancillary