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New treatments for genotype 1 chronic hepatitis C - focus on simeprevir.

Kanda T, Nakamoto S, Wu S, Yokosuka O - Ther Clin Risk Manag (2014)

Bottom Line: Chronic hepatitis C virus (HCV) infection causes end-stage liver diseases and hepato cellular carcinoma.In the USA, Canada, and Japan, simeprevir - one of the second-generation HCV NS3/4A protease inhibitors - in combination with peginterferon α-2a or 2b plus ribavirin has recently been approved for HCV genotype 1-infected patients and is now used in daily clinical practice.In the near future, the development of interferon-free regimens with simeprevir is expected.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan.

ABSTRACT
Chronic hepatitis C virus (HCV) infection causes end-stage liver diseases and hepato cellular carcinoma. In the USA, Canada, and Japan, simeprevir - one of the second-generation HCV NS3/4A protease inhibitors - in combination with peginterferon α-2a or 2b plus ribavirin has recently been approved for HCV genotype 1-infected patients and is now used in daily clinical practice. This review summarizes the mechanism of action of simeprevir and the results of clinical trials of simeprevir and peginterferon plus ribavirin for HCV genotype 1 patients. In general, the simeprevir and peginterferon plus ribavirin treatment is highly effective and its adverse events are similar to those of peginterferon plus ribavirin only, the exception being milder, reversible jaundice. In the near future, the development of interferon-free regimens with simeprevir is expected. Careful attention should be paid to new results of clinical trials with simeprevir.

No MeSH data available.


Related in: MedlinePlus

Structure of simeprevir.
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f1-tcrm-10-387: Structure of simeprevir.

Mentions: Simeprevir is an orally administered HCV NS3/4A protease inhibitor with a macrocyclic structure (Figure 1) and is one of the non-covalent inhibitors.11 HCV NS3/4A protease inhibitors are divided into two classes: reversibly covalent and non-covalent. Boceprevir and telaprevir are linear peptidomimetic structures incorporating an α-ketoamide.12 Simeprevir is a highly specific, potent HCV NS3/4A protease inhibitor, and biochemical assays have shown that HCV NS3/4A proteases of genotypes 1a and 1b, respectively, are inhibited with 0.5 nM and 0.4 nM of simeprevir.13 In genotypes except HCV genotype 3, simeprevir has been shown to be effective in vivo.14,15 This compound has synergistic effects with interferon-α and HCV NS5B inhibitor, and it has additive effects with ribavirin in HCV replicon cells.13 In rats, simeprevir was extensively distributed to the liver and intestinal tract, absolute bioavailability was 44% after a single oral administration, and compound concentrations were detected in both plasma and liver at 8 hours.13 It was reported in both in vivo and in vitro studies that amino acids V36M, Q41R, F43S, T54S, Q80K/R/L, R155K, A156T/V, and D168N/A/V/E/H/T were resistance mutations to simeprevir.16 R155K and D168E are the common resistance mutations in HCV genotypes 1a and 1b, respectively,17–19 although further studies will be needed. To prevent the resistant variants from emerging, simeprevir should be used in combination with peginterferon plus ribavirin, or other classes of direct-acting antivirals against HCV.20


New treatments for genotype 1 chronic hepatitis C - focus on simeprevir.

Kanda T, Nakamoto S, Wu S, Yokosuka O - Ther Clin Risk Manag (2014)

Structure of simeprevir.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043814&req=5

f1-tcrm-10-387: Structure of simeprevir.
Mentions: Simeprevir is an orally administered HCV NS3/4A protease inhibitor with a macrocyclic structure (Figure 1) and is one of the non-covalent inhibitors.11 HCV NS3/4A protease inhibitors are divided into two classes: reversibly covalent and non-covalent. Boceprevir and telaprevir are linear peptidomimetic structures incorporating an α-ketoamide.12 Simeprevir is a highly specific, potent HCV NS3/4A protease inhibitor, and biochemical assays have shown that HCV NS3/4A proteases of genotypes 1a and 1b, respectively, are inhibited with 0.5 nM and 0.4 nM of simeprevir.13 In genotypes except HCV genotype 3, simeprevir has been shown to be effective in vivo.14,15 This compound has synergistic effects with interferon-α and HCV NS5B inhibitor, and it has additive effects with ribavirin in HCV replicon cells.13 In rats, simeprevir was extensively distributed to the liver and intestinal tract, absolute bioavailability was 44% after a single oral administration, and compound concentrations were detected in both plasma and liver at 8 hours.13 It was reported in both in vivo and in vitro studies that amino acids V36M, Q41R, F43S, T54S, Q80K/R/L, R155K, A156T/V, and D168N/A/V/E/H/T were resistance mutations to simeprevir.16 R155K and D168E are the common resistance mutations in HCV genotypes 1a and 1b, respectively,17–19 although further studies will be needed. To prevent the resistant variants from emerging, simeprevir should be used in combination with peginterferon plus ribavirin, or other classes of direct-acting antivirals against HCV.20

Bottom Line: Chronic hepatitis C virus (HCV) infection causes end-stage liver diseases and hepato cellular carcinoma.In the USA, Canada, and Japan, simeprevir - one of the second-generation HCV NS3/4A protease inhibitors - in combination with peginterferon α-2a or 2b plus ribavirin has recently been approved for HCV genotype 1-infected patients and is now used in daily clinical practice.In the near future, the development of interferon-free regimens with simeprevir is expected.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan.

ABSTRACT
Chronic hepatitis C virus (HCV) infection causes end-stage liver diseases and hepato cellular carcinoma. In the USA, Canada, and Japan, simeprevir - one of the second-generation HCV NS3/4A protease inhibitors - in combination with peginterferon α-2a or 2b plus ribavirin has recently been approved for HCV genotype 1-infected patients and is now used in daily clinical practice. This review summarizes the mechanism of action of simeprevir and the results of clinical trials of simeprevir and peginterferon plus ribavirin for HCV genotype 1 patients. In general, the simeprevir and peginterferon plus ribavirin treatment is highly effective and its adverse events are similar to those of peginterferon plus ribavirin only, the exception being milder, reversible jaundice. In the near future, the development of interferon-free regimens with simeprevir is expected. Careful attention should be paid to new results of clinical trials with simeprevir.

No MeSH data available.


Related in: MedlinePlus