Effect of interferon treatment on serum 2?,5?-oligoadenylate synthetase levels in hepatitis C-infected patients

Murashima, Shiro; Kumashiro, Ryukichi; Ide, Tatsuya; Miyajima, Ichiro; Hino, Teruko; Koga, Yuriko; Ishii, Kunihide; Ueno, Takato; Sakisaka, Shotaro; Sata, Michio

doi:10.1002/1096-9071(200010)62:2<185::aid-jmv9>3.0.co;2-x

Cited by 22 publications

(15 citation statements)

References 37 publications

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“…Other studies in HCV-infected patients have shown that interferon-based therapy is associated with upregulation of OAS and ISG15, although this does not necessarily predict long-term outcomes. [26][27][28][29] In this study, we did not observe substantive increases in these markers after a single dose of isatoribine; however, dose-related increases in expression of both OAS (Fig. 3) and ISG15 Fig.…”

Section: Resultscontrasting

confidence: 65%

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

et al. 2005

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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...

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Section: Resultscontrasting

confidence: 65%

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

et al. 2005

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“…Its antiviral effects are initiated by synthesis of 2Ј,5Ј-oligoadenylates that activate an endoribonuclease to cleave double-stranded viral RNA. 2Ј,5Ј-OAS is considered to be a reliable biomarker of IFN-␣ exposure, although its relationship to long-term clinical response is not clear (Moritz et al, 1992;Fischer et al, 1996;Murashima et al, 2000). 2Ј,5Ј-OAS mRNA levels were significantly higher after a single Albuferon injection than after three 40 g/kg IFN-␣ injections every other day, and the duration of effect was also longer (up to 10 days).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

Osborn¹,

Olsen²,

Nardelli³

et al. 2002

J Pharmacol Exp Ther

192

105

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Interferon-␣ (IFN-␣) is indicated for the treatment of certain viral infections including hepatitis B and C, and cancers such as melanoma. The short circulating half-life of unmodified IFN-␣ makes frequent dosing (daily or three times weekly) over an extended period (6 -12 months or more) necessary. To improve the pharmacokinetics of IFN-␣ and decrease dosing frequency, IFN-␣ was fused to human serum albumin producing a new protein, Albuferon. In vitro comparisons of Albuferon and IFN-␣ showed similar antiviral and antiproliferative activities, although Albuferon was less potent on a molar basis than IFN-␣. Pharmacokinetic and pharmacodynamic properties of the fusion protein were enhanced in monkeys. After a single intravenous injection (30 g/kg,) clearance was 0.9 ml/h/kg, and the terminal half-life was 68 h. After 30 g/kg subcutaneous injection, apparent clearance (clearance divided by bioavailability) was 1.4 ml/h/kg, the terminal half-life was 93 h, and bioavailability was 64%. The rate of clearance of Albuferon was approximately 140-fold slower, and the half-life 18-fold longer, than for IFN-␣ given by the subcutaneous route in other monkey studies. Sera from Albuferon-treated monkeys demonstrated doserelated antiviral activity for Ն8 days based on an in vitro bioassay, whereas antiviral activity from IFN-␣-treated animals was only slightly elevated relative to vehicle on day 0. Significant increases in 2Ј,5Ј-oligoadenylate synthetase mRNA relative to IFN-␣-or vehicle-treated animals were maintained for Ն10 days after subcutaneous dosing. The improved pharmacokinetics of Albuferon are accompanied by an improved pharmacodynamic response suggesting that Albuferon may offer the benefits of less frequent dosing and a potentially improved efficacy profile compared with IFN-␣.

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“…HCV cell-based expression models show inhibition of IFN-␣-induced signal transduction through the Jak/STAT pathway (22,26,55,76). Among all ISGs, the best characterized effector proteins are the double-stranded RNA-activated protein kinase (PKR) (41), the 2Ј,5Ј-oligoadenylate synthetase (92), and the Mx proteins (134). Besides its antiviral activities, IFN-␣ also affects processes that regulate cell growth and the modulation of the immune response.…”

Section: Ifn-␣ Signal Transductionmentioning

confidence: 99%

Viral Determinants of Resistance to Treatment in Patients with Hepatitis C

2007

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SUMMARY Chronic hepatitis C virus (HCV) infection affects more than 170 million persons worldwide and is responsible for the development of liver cirrhosis in many cases. Standard treatment with pegylated alpha interferon (IFN-α) in combination with the nucleoside analogue ribavirin leads to a sustained virologic response in approximately half of the patients. IFN-α is classified as an indirect treatment, as it interacts with the host's immune response. The mechanism of action of ribavirin is still unknown. The benefit of triple therapy by adding other antiviral agents, e.g., amantadine, is controversial. Currently, new direct antiviral drugs (HCV protease/polymerase inhibitors) are being evaluated in phase 1/phase 2 trials. Phenotypic resistance to antiviral therapy has been attributed to amino acid variations within distinct regions of the HCV polyprotein. While sensitivity to IFN-α-based antiviral therapy in vivo is clearly correlated with the number of mutations within the HCV NS5A protein, the underlying functional mechanisms for this association are unknown. In turn, in vitro, several mechanisms to circumvent the host immune defense or to block treatment-induced antiviral activities have been described for different HCV proteins. By the introduction of direct antiviral drugs, hepatitis C therapy now is entering a new era in which the development of resistance may become the most important parameter for treatment success or failure.

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Effect of interferon treatment on serum 2?,5?-oligoadenylate synthetase levels in hepatitis C-infected patients

Cited by 22 publications

References 37 publications

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

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

Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

Viral Determinants of Resistance to Treatment in Patients with Hepatitis C

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