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Spotlight Series on Hepatitis C

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Enter Ledipasvir

April 2015

After the hepatitis C virus (HCV) infects a cell, the virus's genetic information is read and translated into multiple proteins that are then linked together in a complex. The complex is then broken down into many proteins. Some of these proteins are useful for helping to force the infected cell to build new copies of correctly formed HCV. Such proteins that help do this work are called structural proteins and are labelled E1, E2 and so on by researchers.

Other proteins generally help play a role in the production of new copies of HCV. These are called non-structural proteins and are labelled as follows:

  • NS2
  • NS3
  • NS4A
  • NS4B
  • NS5A
  • NS5B


Focus on NS5A

The exact role that NS5A plays is not known, but scientists think that it may help an infected cell assemble and release new copies of HCV. However, NS5A also appears to have more problematic qualities such as the following:

  • It appears to interact unfavourably with the immune system.
  • In cells that are infected with HCV, NS5A stops them from initiating a self-destruct cycle or program. This self-destruct program is something that many cells can undergo when they become infected with a virus in order to help stop the spread of infection. Over time, some viruses have evolved to subvert this defence system.
  • It helps to promote the growth of tumours (the risk for liver cancer is elevated because of HCV infection).


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Ledipasvir in the Lab

Formerly called GS-5885, ledipasvir has been partnered with a slightly older drug, sofosbuvir (Sovaldi), and both drugs are sold as a fixed-dose combination called Harvoni.

In laboratory studies with cells and HCV, ledipasvir is extremely potent against the following sub-types or strains of HCV: 1a, 1b, 4a and 6a. Lab experiments also suggest that ledipasvir is less effective against genotypes 2 and 3. Bear in mind that as promising as laboratory experiments are, results in a test tube may not always be replicated in studies in people with HCV.

Ledipasvir is well tolerated by cells.


Ledipasvir -- Early Studies in People

In experiments, when taken orally ledipasvir reaches very high concentrations within the body between four and six hours after it is swallowed.

Most ledipasvir (70%) leaves the body in the feces unchanged (not broken down).

In clinical trials with people, ledipasvir's absorption is similar regardless of the degree of liver dysfunction caused by HCV. This means that, in practice, experts predict that doctors will not need to adjust the dose in people with severe liver injury.

There are no interactions between sofosbuvir and ledipasvir. As sofosbuvir works in a different way against HCV than ledipasvir, these drugs can be used together in treatment.


Ledipasvir -- Clinical Trials

In studies with people, ledipasvir was used as the only anti-HCV drug (monotherapy) to gauge its effect over three days with once-daily dosing. The doses tested ranged between 1 mg and 90 mg.

The drug has powerful anti-HCV activity, reducing the amount of HCV in the blood one-thousand-fold. No serious side effects were reported and side effects that did occur were generally of mild or moderate intensity. The most common side effect was headache.

When used in combination with peginterferon and ribavirin for between 12 and 24 weeks, ledipasvir resulted in cure rates of between 70% and 100% in participants with HCV genotype 1 who did not have severe liver injury. Most participants in these trials had not previously been exposed to HCV treatment.

In interferon-free regimens where ledipasvir was combined with sofosbuvir or ribavirin or both, cure rates were between 68% and 100%.


Tolerability

In studies of ledipasvir as part of HCV combination therapy, it is generally well tolerated.

Many reports in this issue of TreatmentUpdate feature HCV treatment combinations containing ledipasvir and recent clinical trial results.


Reference

Gentile I, Buonomo AR, Borgia F, et al. Ledipasvir: a novel synthetic antiviral for the treatment of HCV infection. Expert Opinion on Investigational Drugs. 2014 Apr;23(4):561-71.




This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication TreatmentUpdate. Visit CATIE's Web site to find out more about their activities, publications and services.

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