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 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.
Horsmans
Yves
Y
Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Unit de Pharmacologie Clinique, Brussels, Belgium.
Berg
Thomas
T
Desager
Jean-Pierre
JP
Mueller
Tobias
T
Schott
Eckart
E
Fletcher
Simon P
SP
Steffy
Kevin R
KR
Bauman
Lisa A
LA
Kerr
Bradley M
BM
Averett
Devron R
DR
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
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