Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus

McHutchison, John G.; Bacon, Bruce R.; Gordon, Stuart C.; Lawitz, Eric; Shiffman, Mitchell L.; Afdhal, Nezam H.; Jacobson, Ira M.; Muir, Andrew J.; Al‐Adhami, Mohammed; Morris, Mary L.; Lekstrom-Himes, Julie; Efler, Susan M.; Davis, Heather L.

doi:10.1002/hep.21773

Cited by 105 publications

(80 citation statements)

References 27 publications

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“…For induction of protective immune responses against intracellular pathogens such as HIV-1 and Mycobacterium tuberculosis for which both cellular and humoral responses may be critical, TLR ligands targeting nucleotide-sensing TLRs (i.e., TLR3, 7/8, and 9) are attractive. TLR ligands have shown efficacy as vaccine adjuvants in mice (8 -10, 14) and nonhuman primates (11)(12)(13), and several clinical trials are under way (15)(16)(17)(18). Optimal stimulation of immune responses may require stimulation of several DC subsets and B cells.…”

Section: Discussionmentioning

confidence: 99%

“…During natural infection, TLRs, along with other pattern recognition receptors, are used to sense invading pathogens and to activate an immune response (6,7). A number of preclinical vaccine studies have shown that natural or synthetic TLR ligands administered together with protein Ags results in the stimulation of potent Ag-specific immune responses (8 -14), and selected TLR ligands have been evaluated as vaccine components in human trials (15)(16)(17)(18).…”

mentioning

confidence: 99%

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Human B Cell Responses to TLR Ligands Are Differentially Modulated by Myeloid and Plasmacytoid Dendritic Cells

Douagi

Gujer

Sundling

et al. 2009

The Journal of Immunology

103

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Human B Cell Responses to TLR Ligands Are Differentially Modulated by Myeloid and Plasmacytoid Dendritic Cells

Douagi

Gujer

Sundling

et al. 2009

The Journal of Immunology

103

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“…Therefore, amantadine has no relevance in the antiviral treatment of chronic hepatitis C. Currently, direct antiviral agents such as inhibitors of the HCV serine protease and the RNA-dependent RNA polymerase are under clinical investigations, and initial phase I/II trials have shown that the combination of PEG IFN-␣ and ribavirin together with a direct antiviral compound can increase sustained virological response rates in genotype HCV-1-infected patients. [33][34][35][36][37] …”

Section: Discussionmentioning

confidence: 99%

Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection

Wagner¹,

Hofmann²,

Teuber³

et al. 2008

Hepatology

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The impact of amantadine on virologic response rates of interferon-based treatment of chronic hepatitis C is controversial. The aim of this study was to compare virological response rates in patients with chronic hepatitis C virus (HCV)-1 infection treated with 400 mg amantadine or placebo in combination with peginterferon alfa-2a (40 kD) and ribavirin for 48 weeks. Seven hundred four previously untreated chronically HCV-1-infected patients (mean age, 46 ؎ 12 years) were randomized to (A) amantadine-sulphate (400 mg/day) (n ‫؍‬ 352) or (B) placebo (n ‫؍‬ 352), both in combination with 180 g peginterferon alfa-2a once weekly and ribavirin (1000-1200 mg/day) for 48 weeks. End of treatment and sustained virological response after a 24-week follow-up period were assessed by qualitative reverse transcription polymerase chain reaction (RT-PCR) (sensitivity, 50 IU/mL). Demographic and baseline virological parameters were similar in both treatment groups. In groups A and B, 231 of 352 patients (66%) and 256 of 352 patients (72%) achieved an end of treatment response, and 171 of 352 patients (49 %) and 186 of 352 patients (53 %) a sustained virological response, respectively. On-treatment dropout rate in the amantadine group was significantly higher than in the placebo group (32% versus 23%; P ‫؍‬ 0.01). However, adverse events and laboratory abnormalities were similar between both groups. Per-protocol analysis revealed similar sustained virological response rates in both treatment groups (53% versus 55%). Conclusion: In this large placebo-controlled multicenter study, amantadine even at a dose of 400 mg/day did not improve virological response rates of peginterferon alfa-2a and ribavirin in patients with chronic genotype HCV-1 infection. (HEPATOLOGY 2008;

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“…Many studies with different TLR ligands were performed in cell culture or animal models for virus infections. Synthetic ligands for TLR3 and 9 (polyinosinic : polycytidylic acid (poly I : C) and CpG oligodeoxynucleotides respectively) were shown to be effective in treating viral infections like HIV, HBV, HCV, herpes virus or FV (McClary et al, 2000;Ashkar et al, 2004;Isogawa et al, 2005;Gill et al, 2006;Kraft et al, 2007;McHutchison et al, 2007;Trapp et al, 2009;Gibbert et al, 2010). We and others have shown in mice that the therapeutic effect of the TLR ligand used depends on the induction of type I IFN, as therapeutic treatment with the different TLR ligands is not effective in mice deficient in the type I IFN receptor (IFNAR -/-) (McClary et al, 2000;Isogawa et al, 2005;Gill et al, 2006;Gibbert et al, 2010).…”

Section: Drugs That Induce Endogenous Ifn-a Productionmentioning

confidence: 99%

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

Gibbert

Schlaak

Yang

et al. 2013

British J Pharmacology

153

138

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During most viral infections, the immediate host response is characterized by an induction of type I IFN. These cytokines have various biological activities, including anti‐viral, anti‐proliferative and immunomodulatory effects. After induction, they bind to their IFN‐α/β receptor, which leads to downstream signalling resulting in the expression of numerous different IFN‐stimulated genes. These genes encode anti‐viral proteins that directly inhibit viral replication as well as modulate immune function. Thus, the induction of type I IFN is a very powerful tool for the host to fight virus infections. Many viruses evade this response by various strategies like the direct suppression of IFN induction or inhibition of the IFN signalling pathway. Therefore, the therapeutic application of exogenous type I IFN or molecules that induce strong IFN responses should be of great potential for future immunotherapies against viral infections. Type I IFN is currently used as a treatment in chronic hepatitis B and C virus infection, but as yet is not widely utilized for other viral infections. One reason for this restricted clinical use is that type I IFN belongs to a multigene family that includes 13 different IFN‐α subtypes and IFN‐β, whose individual anti‐viral and immunomodulatory properties have so far not been investigated in detail to improve IFN therapy against viral infections in humans. In this review, we summarize the recent achievements in defining the distinct biological functions of type I IFN subtypes in cell culture and in animal models of viral infection as well as their clinical usage in chronic hepatitis virus infections.

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Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus

Cited by 105 publications

References 27 publications

Human B Cell Responses to TLR Ligands Are Differentially Modulated by Myeloid and Plasmacytoid Dendritic Cells

Human B Cell Responses to TLR Ligands Are Differentially Modulated by Myeloid and Plasmacytoid Dendritic Cells

Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection

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

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