8 Potent HCV Protease Inhibitors With the Potential for Once-Daily Dosing and Broad Genotype Coverage

Jiang, Lijuan; Gai, Ying; Middleton, Tim; Kurtz, K.; Lü, Ling; Liu, S.; Phan, Truc K.; Luo, Xia; Poon, Tung Ping; Brasher, Bradley; McDaniel, Keith F.; Kempf, Dale J.; Or, Yat Sun

doi:10.1016/s0168-8278(09)60010-6

Cited by 3 publications

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“…In contrast, subtype identification has no clinical impact on current therapy. However, this is changing with the development of new specific inhibitors of HCV enzymes and functions that may yield different antiviral responses and resistance profiles according to the HCV genotype subtype [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] . Correct HCV genotype 1 subtype identification is mandatory in clinical trials where these drugs are tested alone, in combination, or in combination with pegylated IFN-α and ribavirin for stratification and interpretation purposes.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, several HCV inhibitors appear to have selective activity against different HCV genotype 1 subtypes, both in vitro and in vivo . Differences have been observed in vitro with NS3/4A protease inhibitors, non-nucleoside inhibitors of HCV RdRp and NS5A inhibitors [13] , [14] , [15] , [16] , [17] . For instance, BILB 1941, a non-nucleoside inhibitor of HCV RdRp, has been shown to have better antiviral efficacy in patients infected with HCV subtype 1b than in those infected with HCV subtype 1a, a finding reflecting in vitro experiments [13] .…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis C Virus (HCV) Genotype 1 Subtype Identification in New HCV Drug Development and Future Clinical Practice

et al. 2009

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BackgroundWith the development of new specific inhibitors of hepatitis C virus (HCV) enzymes and functions that may yield different antiviral responses and resistance profiles according to the HCV subtype, correct HCV genotype 1 subtype identification is mandatory in clinical trials for stratification and interpretation purposes and will likely become necessary in future clinical practice. The goal of this study was to identify the appropriate molecular tool(s) for accurate HCV genotype 1 subtype determination.Methodology/Principal FindingsA large cohort of 500 treatment-naïve patients eligible for HCV drug trials and infected with either subtype 1a or 1b was studied. Methods based on the sole analysis of the 5′ non-coding region (5′NCR) by sequence analysis or reverse hybridization failed to correctly identify HCV subtype 1a in 22.8%–29.5% of cases, and HCV subtype 1b in 9.5%–8.7% of cases. Natural polymorphisms at positions 107, 204 and/or 243 were responsible for mis-subtyping with these methods. A real-time PCR method using genotype- and subtype-specific primers and probes located in both the 5′NCR and the NS5B-coding region failed to correctly identify HCV genotype 1 subtype in approximately 10% of cases. The second-generation line probe assay, a reverse hybridization assay that uses probes targeting both the 5′NCR and core-coding region, correctly identified HCV subtypes 1a and 1b in more than 99% of cases.Conclusions/SignificanceIn the context of new HCV drug development, HCV genotyping methods based on the exclusive analysis of the 5′NCR should be avoided. The second-generation line probe assay is currently the best commercial assay for determination of HCV genotype 1 subtypes 1a and 1b in clinical trials and practice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hepatitis C Virus (HCV) Genotype 1 Subtype Identification in New HCV Drug Development and Future Clinical Practice

et al. 2009

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The Potential for Combination Treatment Using STAT-C Drugs

Wyles

2009

Curr Hepatitis Rep

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Given the limitations of pegylated interferon (IFN) and ribavirin (RBV) therapy for chronic hepatitis C virus (HCV) infection, new antiviral medication and treatment approaches are sought. Specifically targeted antiviral therapies for hepatitis C (STAT-C) refers to the use of these new inhibitors, either in combination with IFN and RBV or other STAT-C agents, to improve therapy for HCV. Although many classes of inhibitors are being developed, NS3 protease and NS5B polymerase inhibitors are likely to be among the first STAT-C agents approved. The preclinical and clinical characteristics of HCV protease and polymerase inhibitors are reviewed in this article. Strengths and weaknesses of each class in the context of developing future all-STAT-C regimens are explored, with a particular focus on viral resistance and the prospects for eliminating IFN and/or RBV.

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Impact of HCV genetic differences on pathobiology of disease

Ripoli

Pazienza

2011

Expert Review of Anti-infective Therapy

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Multiple HCV genotypes have been isolated worldwide. Genotype seems to be involved in the main pathological aspects of HCV infection. Insulin resistance, steatosis and progression toward cirrhosis, fibrosis and hepatocellular carcinoma establish and develop following genotype-specific mechanisms. Moreover genotype influences pharmacological treatment in term of dose and duration. Pathways involved in cell proliferation, apoptosis, lipid metabolism, insulin and interferon signaling are impaired to a different extent among genotypes, leading to distinct pathological settings. Genotype 1 is associated with a more aggressive disease with increased insulin resistance, worst response to therapy, higher risk of cirrhosis and hepatocellular carcinoma development, while genotype 3 is associated with increased steatosis and fibrosis. The identification and characterization of HCV types and subtypes provides insight into the different outcome of HCV infection and responsiveness to therapy. In the present article, we focused on the pathogenicity of HCV genotypes and their effect on disease progression and treatment.

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8 Potent HCV Protease Inhibitors With the Potential for Once-Daily Dosing and Broad Genotype Coverage

Cited by 3 publications

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Hepatitis C Virus (HCV) Genotype 1 Subtype Identification in New HCV Drug Development and Future Clinical Practice

Hepatitis C Virus (HCV) Genotype 1 Subtype Identification in New HCV Drug Development and Future Clinical Practice

The Potential for Combination Treatment Using STAT-C Drugs

Impact of HCV genetic differences on pathobiology of disease

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