title: 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.affiliation: Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Unit de Pharmacologie Clinique, Brussels, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Horsmans
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Desager
authors.forename: Tobias
authors.initials: T
authors.lastname: Mueller
authors.forename: Eckart
authors.initials: E
authors.lastname: Schott
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fletcher
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Steffy
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Bauman
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Kerr
authors.forename: Devron R
authors.initials: DR
authors.lastname: Averett
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006151:Guanosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D008562:Membrane Glycoproteins / Q000819:agonists*; D012367:RNA, Viral / Q000097:blood / Q000187:drug effects / Q000235:genetics; D011956:Receptors, Cell Surface / Q000819:agonists*; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D008562:Membrane Glycoproteins; D012367:RNA, Viral; D011956:Receptors, Cell Surface; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D006151:Guanosine; C061136:isatoribine