Therapy of chronic hepatitis C virus infection in the era of direct-acting and host-targeting antiviral agents

Conteduca, Vincenza; Sansonno, Domenico; Russi, Sabino; Pavone, Fabio; Dammacco, Franco

doi:10.1016/j.jinf.2013.08.019

Cited by 69 publications

(66 citation statements)

References 118 publications

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“…At present, 130-150 million people worldwide are chronically infected with this virus, and HCV infection is a serious public health problem. [2][3][4] HCV is classified into six major types of genomes (genotypes [1][2][3][4][5][6]. The previous standard treatment for HCV-infected patients is the combination therapy with pegylated interferon-a (peg-IFN-a) and ribavirin (RBV).…”

Section: Introductionmentioning

confidence: 99%

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Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative

Ito

Toyama

Okamoto

et al. 2015

Antivir Chem Chemother

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Background: The novel phenanthridinone derivative HA-719 has recently been identified as a highly potent and selective inhibitor of hepatitis C virus replication. To elucidate its mechanism of inhibition, we have isolated and analyzed a clone of hepatitis C virus replicon cells resistant to HA-719. Methods: To isolate HA-719-resistant replicon cells, Huh-7 cells containing subgenomic hepatitis C virus replicons (genotype 1b) with a luciferase reporter (LucNeo#2) were cultured in the presence of G418 and escalating concentrations of HA-719. After several passages, total RNA was extracted from the growing cells, and Huh-7 cells were transfected with the extracted RNA. Limiting dilution of the transfected cells was performed to obtain an HA-719-resistant clone. Results: The 50% effective concentration (EC 50 ) of HA-719 for hepatitis C virus replication was 0.058 AE 0.012 mM in LucNeo#2 cells. The replicon cells capable of growing in the presence of G418 and 3 mM HA-719 were obtained after 18 passages (72 days). The HA-719-resistant clone LucNeo719R showed 98.3-fold resistant to the compound (EC 50 ¼ 5.66 AE 0.92 mM), but the clone had no cross-resistance to telaprevir (NS3 inhibitor), daclatasvir (NS5A inhibitor), and VX-222 (NS5B inhibitor). The sequence analysis for the wild-type and LucNeo719R identified 3, 2 and 7 mutations in NS3/4 A, NS4B, and NS5A, respectively, but no mutations in NS5B. Conclusion: None of the amino acid mutations in the resistant clone corresponds to those reported to confer drugresistance to current anti-hepatitis C virus agents, suggesting that the target of HA-719 for hepatitis C virus inhibition differs from those of the existing agents.

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Section: Introductionmentioning

confidence: 99%

“…The previous standard treatment for HCV-infected patients is the combination therapy with pegylated interferon-a (peg-IFN-a) and ribavirin (RBV). 5 However, this interferon-based therapy is not always effective for all patients. In addition, it has serious side effects, such as flu-like symptoms, anemia, loss of appetite, and depression.…”

Section: Introductionmentioning

confidence: 99%

Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative

Ito

Toyama

Okamoto

et al. 2015

Antivir Chem Chemother

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“…These unsatisfactory therapeutic outcomes led to the development of direct-acting antivirals (DAAs), including boceprevir, telaprevir, simeprevir and sofosbuvir (4,5). Triple therapy with either of these DAAs in combination with Peg-IFN and RBV has been found to significantly improve SVR rates and shorten the duration of therapy (6). However, a percentage of the infected population is not eligible for treatment with this new therapy due to drug toxicities, drugdrug interactions, the induction of long-term viral resistance and economic burdens (7,8).…”

Section: Introductionmentioning

confidence: 99%

Long-term Pegylated Interferon Monotherapy Following 72 Weeks of Pegylated Interferon and Ribavirin in Hepatitis C Virus Genotype-1-infected Slow Responders

et al. 2015

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Objective Slow responders to pegylated interferon (Peg-IFN) and ribavirin (RBV) among patients infected with hepatitis C virus (HCV) genotype 1 may benefit from an extended treatment course. The aim of this study was to determine the efficacy of persistent negative serum HCV RNA over 96 weeks during long-term Peg-IFN monotherapy following 72 weeks of combination therapy. Methods A total of 46 HCV genotype 1-infected slow responders were treated for 72 weeks with Peg-IFN and RBV combination therapy alone (n=25) or additional long-term biweekly treatment with 90 μg of Peg-IFN-α2a (n=21). The criterion for the completion of long-term Peg-IFN monotherapy was defined as the attainment of constantly negative HCV RNA in the serum over 96 weeks during IFN treatment. Results The patients with sustained negative serum HCV RNA during 96 weeks of IFN treatment had a higher rate of sustained virological response (SVR) than those without (81 vs. 40%, p=0.012). A multivariate analysis identified sustained negativity of serum HCV RNA over 96 weeks of IFN treatment to be a predictive factor for SVR. Conclusion In the present study, sustained negative serum HCV RNA over 96 weeks during long-term Peg-IFN monotherapy following 72 weeks of combination therapy of Peg-IFN and RBV resulted in beneficial virological outcomes among HCV genotype 1-infected slow responders.

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“…3 The current treatment for genotype-1 with ~80% sustained virologic responses is a combination of pegylated interferon, ribavirin and boceprevir/telaprevir/simeprevir. 4 This therapy is associated with flu-like symptoms, anaemia, loss of appetite, depression etc. and need close monitoring.…”

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confidence: 99%

Synthesis and anti-HCV determinant motif identification in pyranone carboxamide scaffold

Balaraju

Konreddy

Parveen

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Therapy of chronic hepatitis C virus infection in the era of direct-acting and host-targeting antiviral agents

Cited by 69 publications

References 118 publications

Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative

Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative

Long-term Pegylated Interferon Monotherapy Following 72 Weeks of Pegylated Interferon and Ribavirin in Hepatitis C Virus Genotype-1-infected Slow Responders

Synthesis and anti-HCV determinant motif identification in pyranone carboxamide scaffold

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