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Emerging Targets for Hepatitis C -Part 2

August 6, 2013 7:00 am

The best review on new therapies for HCV that I’ve read in quite a long time:

Hepatology 2013; 58: 428-38

First the abbreviations:

• ASV -Asunaprevir
• BOC -boceprevir
• DAA -direct-acting antiviral
• DCV -daclatasvir
• DNV -danoprevir
• NI -nucleos(t)ide inhibitor
• NNI -nonnucleos(t)ide inhibitor
• SIL -silibinin
• SOF -sofosbuvir
• TVR -telaprevir

More terminology:

• First-generation NS3/4A protease inhibitors (TVR, BOC) are “defined as agents that display potent activity on HCV-1 but oppose a low barrier to selection of resistant viral variants and are not effective on all viral genotypes.”
• Second generation NS3/4A protease inhibitors are “defined as agents that pose a high barrier to the development of viral resistance, retain activity against the viral variants that are resistant to first-generation compounds, and are active across all HCV genotypes.”
• First-wave therapies are covalent linear inhibitors and second-wave therapies are either non covalent linear or macrocyclic inhibitors.

What are the weapons?

Some second-wave, first generation NS3/4A PIs: faldaprevir, asunaprevir, sovaprevir, simeprevir, danoprevir, and vaniprevir.  These agents have similar clinical efficacy as BOC and TVR but are easier to administer, usually once-a-day.  Some of these agents have better activity  against several genotypes.

MK-5172, 2nd-generation NS3/4A PI,  has pan-genotype activity & maintains antiviral activity against most mutations that confer resistance to 1st-generation PIs.

DCV, a NS5A inhibitor, has potent HCV activity but a low barrier for viral resistance; thus, it is likely to be used in combination with other agents.  Multiple NS5A inhibitors are in development.

SOF, a NS5B polymerase inhibitor, is being studied in interferon-free combinations.  Viral resistance has been rare in clinical studies with this agent.  Multiple other agents in this class are in study.

NS5B polymerase inhibitor NNIs bind to less conserved sites on HCV; thus, initial results have not been as promising.  Several NNIs, including setrobuvir and lomibuvir (& others), are being tested in combination in all-oral, interferon-free regimens.

SIL, a NS4B binding inhibitor, is an intravenous agent that has shown some efficacy in liver transplant patients.  Other oral agents, like clemizole, are being investigated.

How these agents may be useful:

1. “The first step forward in anti-HCV therapy will be the introduction of a second-wave PI to used in combination with PEG-IFN/RBV.” Simeprevir, faldaprevir, and ritonavir-boosted danoprevir (DNV) will be easier to administer than TVR or BOC as they can be given once-daily.  In addition, these drugs are more active against genotypes 2, 4, 5, and 6.  In fact, ritonavir-boosted DNV in combination with PEG-IFN/RBV had 100% SVR efficacy for patients with HCV-4 in one trial.
2. Next, will be NS5A and NS5B inhibitors to be used in combination with previous agents.  These agents will compete with second-wave PIs but “whether they will provide a true innovation in terms of viral cure rates, safety profile, or patient tolerability is still to be demonstrated.”  These agents work better with other DAAs.
3. Finally, all-oral combinations will enter the market.  “The first all-oral anti-HCV regimen will be likely available in 2014 for HCV-2 and HCV-3 patients.”  SOF with RBV has had good success rates in previous studies.

Potential Problems:

• Many of these investigational agents have been studied in easy-to-cure populations.
• Lack of data in advanced fibrosis/cirrhosis.
• Safety questions in post-transplant populations.
• Affordability.  “It is possible that these innovative regimens will be confined to groups of patients in whom TVR/BOC or PEG-IFN/RBV are either ineffective or unsafe.”  Some patients may receive ‘maginally less effective and less tolerable drugs for cost-containing issues.’
• Drug resistance.  This is likely to become a clinical problem with all oral IFN-free regimens. with TVR/BOC, resistance has limited significance due to HCV quasispecies reverting back to wild-type virus after stopping TVR or BOC.  It is unclear if this will be the case with other DAAs.

Posted by gutsandgrowth

Categories: hepatitis C, Hepatology

Tags: boceprevir, danoprevir, faldeprevir, silibinin, simeprevir, sofosbuvir, telaprevir

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3 Responses to “Emerging Targets for Hepatitis C -Part 2”

1. […] Emerging Targets for Hepatitis C -Part 2 | gutsandgrowth […]

   By Big Interferon-free Hepatitis C Study | gutsandgrowth on August 28, 2013 at 7:06 am

2. […] Emerging Targets for Hepatitis C -Part 2 | gutsandgrowth […]

   By Better HCV Treatments Approved | gutsandgrowth on October 27, 2013 at 10:03 am

3. […] Emerging Targets for Hepatitis C -Part 2 | gutsandgrowth […]

   By Progression of Hepatitis C in Children | gutsandgrowth on November 21, 2013 at 7:01 am

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