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

Hepatology. 2005 Sep;42(3):724-31. doi: 10.1002/hep.20839.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

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


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