New HCV Therapies on the Horizon

[Guest guest]

http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2010.03430.x/abstract;jse\

ssionid=F3F41F0A251AF2E245DD8FAA3E8FB834.d02t02

New HCV Therapies on the Horizon

Johannes Vermehren, Christoph SarrazinDOI: 10.1111/j.1469-0691.2010.03430.x

European Society of Clinical Microbiology and Infectious

Issue

Clinical Microbiology and Infection

Accepted Article (Accepted, unedited articles published online for future

issues)

Abstract

Improved understanding of the hepatitis C virus (HCV) life-cycle has led to the

discovery of numerous potential targets for antiviral therapy. HCV polyprotein

processing and replication have been identified as the most promising viral

targets. However, viral entry and fusion, RNA translation, virus assembly and

release and several host cell factors may provide alternative attractive targets

for future anti-HCV therapies.

Inhibitors of the HCV NS3/4A protease are currently the most advanced in

clinical development. Monotherapy with protease inhibitors revealed high

antiviral activity but was associated with a frequent selection of resistant HCV

variants, often resulting in viral breakthrough. However, there is encouraging

evidence from phase 2/3 trials, indicating that the addition of a protease

inhibitor (e.g. telaprevir and boceprevir) to pegylated

interferon-alfa/ribavirin substantially improves sustained virologic response

rates in both treatment-naïve and -experienced patients with HCV genotype 1.

Nucleos(t)ide inhibitors of the HCV NS5B polymerase have shown variable

antiviral activity against different HCV genotypes but seem to have a higher

genetic barrier to resistance compared to protease inhibitors. In addition,

several allosteric binding sites have been identified for non-nucleoside

inhibitors of the NS5B polymerase. However, development of a substance with high

antiviral activity and a high genetic barrier to resistance seems to be

difficult. Among the different host-cell targeting compounds in early clinical

development, cyclophilin-inhibitors have shown the most promising results.

Although advances have also been made towards the improvement of interferons,

combinations of antiviral agents with different mechanisms of action may lead to

the eventual possibility of interferon-free regimens.

[Guest guest]

http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2010.03430.x/abstract;jse\

ssionid=F3F41F0A251AF2E245DD8FAA3E8FB834.d02t02

New HCV Therapies on the Horizon

Johannes Vermehren, Christoph SarrazinDOI: 10.1111/j.1469-0691.2010.03430.x

European Society of Clinical Microbiology and Infectious

Issue

Clinical Microbiology and Infection

Accepted Article (Accepted, unedited articles published online for future

issues)

Abstract

Improved understanding of the hepatitis C virus (HCV) life-cycle has led to the

discovery of numerous potential targets for antiviral therapy. HCV polyprotein

processing and replication have been identified as the most promising viral

targets. However, viral entry and fusion, RNA translation, virus assembly and

release and several host cell factors may provide alternative attractive targets

for future anti-HCV therapies.

Inhibitors of the HCV NS3/4A protease are currently the most advanced in

clinical development. Monotherapy with protease inhibitors revealed high

antiviral activity but was associated with a frequent selection of resistant HCV

variants, often resulting in viral breakthrough. However, there is encouraging

evidence from phase 2/3 trials, indicating that the addition of a protease

inhibitor (e.g. telaprevir and boceprevir) to pegylated

interferon-alfa/ribavirin substantially improves sustained virologic response

rates in both treatment-naïve and -experienced patients with HCV genotype 1.

Nucleos(t)ide inhibitors of the HCV NS5B polymerase have shown variable

antiviral activity against different HCV genotypes but seem to have a higher

genetic barrier to resistance compared to protease inhibitors. In addition,

several allosteric binding sites have been identified for non-nucleoside

inhibitors of the NS5B polymerase. However, development of a substance with high

antiviral activity and a high genetic barrier to resistance seems to be

difficult. Among the different host-cell targeting compounds in early clinical

development, cyclophilin-inhibitors have shown the most promising results.

Although advances have also been made towards the improvement of interferons,

combinations of antiviral agents with different mechanisms of action may lead to

the eventual possibility of interferon-free regimens.