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

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.)