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. ( C hronic infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality, affecting 170 million persons worldwide. 1,2 Although chronic HCV infection is largely asymptomatic, persistent infection over many years significantly increases the risk of cirrhosis, hepatocellular carcinoma, and end-stage liver disease. [1][2][3][4] The current standard-of-care treatment for HCV infection is immune based, consisting of an injectable interferon-alpha product (a type 1 cytokine) in combination with the orally administered nucleoside analog ribavirin. 1,5,6 This treatment can durably clear HCV from approximately 50% of treated patients but has multiple side effects that often result in early abandonment of treatment. Thus, a need remains for novel anti-HCV therapies to improve response rates and reduce adverse effects.A variety of investigational anti-HCV compounds are approaching or undergoing clinical studies. 7 Aside from modified versions of interferon-alpha and ribavirin, most investigational compounds are direct-acting antivirals that bind to virally encoded targets. Whether durable virological responses can be achieved with direct-acting anti-HCV agents is unknown. Moreover, the high rate and low fidelity of HCV replication may lead to rapid emergence of resistance to direct-acting antivirals. 8,9 In light of these uncertainties, continuing to explore immune stimulation as an appro...

IFN‐α subtypes: distinct biological activities in anti‐viral therapy

“…They do induce type I IFN comparable with TLR3 or TLR9 ligands, show anti-viral potency and activate the host immune response (Horsmans et al, 2005;Pockros et al, 2007). Many clinical studies with agonists for TLR7 and TLR8 are under way, for example, against infections with HBV or HCV (refer to http://www.clinicaltrials.gov), which indicate their potential for future therapy of viral infections.…”

Potential adjuvantic properties of innate immune stimuli

“…191 Local and/or systemic toxicity is to be anticipated and is therefore a potential concern with potent TNFα-inducing molecules; indeed such an effect may have been contributory to the GI toxicity that has been observed with clinical trials on Isatoribine given orally. [201][202][203] Intracellular TLR9 Activation: CpG ds-DNA Unmethylated "CpG motifs" which are present at high frequency in bacterial but not mammalian DNA due to a combination of Gag-specific CD8 + CTL responses compared with animals immunized with HIV Gag protein and the TLR7 agonist as a noncovalent mixture. 173 It must be noted, however, the method of conjugation in the above-referenced study was by UV irradiation of antigenimidazoquinoline mixtures, followed by exhaustive dialysis.…”

Activation of anti-hepatitis C virus responses via Toll-like receptor 7

“…The pattern of TLR7 expression in liver may explain why SM360320 exerted direct anti-HCV effects, whereas six other TLR activators did not, including R848 or 7-thia-8-oxoguanosine, a TLR7 ligand in clinical trials in HCV-infected patients (31). Although immunoreactive TLR7 was detectable in HCV-infected hepatocytes, the levels of the antigen were much lower than those found in infiltrating mononuclear cells in the same specimens (data not shown).…”