Bumping it forward.....

Hi guys,

Treatment duration for cirrhotics has been recently discussed by Matt Chris. In his case, the absence of RAV's post relapse, shows the importance of sustained drug exposure required by cirrhotics. The decreased perfusion, plus the thickened limiting plate ( between the blood sinusoids and hepatocytes) suggests long term treatment may be required for some patients.

Once the Trials have finished and the drugs approved, we will see how this translates into clinical practice. In the real world, the Trials for Incivek and Victrelis were shown to be flawed.

Merck have been unable to get much publicity for it's excellent drugs. They seem pretty hopeless and that helped Vertex to make a killing with Incivek. MK-5172 may get a few patients if it is priced accordingly.

Based on this article, my perfect treatment would be 24 weeks of Sovaldi/ Ledipasvir (for cirrhotics). However I doubt whether Government or Insurance will be willing to pay for this.

http://www.medscape.com/viewarticle/818806_5

Malcolm: I re-read and you stated 12 weeks with the MK-5172 would probably suffice so scratch that question.  How about 12 on the S/L and if that doesn't do it then 12 on the MK-5172 + S + new second combo?

This is some good information.  Thank you, Malcolm (and PW for bumping it).  

Malcolm: So, your thinking is that, at least for cirrhotics, it is best to combine an anti-protease with the S/L combo for long term success?   Is this because the S/L combo is only hitting the NS-5A and 5B sites?  This makes perfect sense.  

I don't think I'd want to try Riba again because my Hgb dropped quite low--I think at its lowest it wa about 6.5--and adding rescue drugs is also adding more risks.

MK-5172 has received breakthrough status but I don't know how far along they are in the trials.  How is that looking in terms of safety and availability? 

I'm wondering about treating 12 weeks on the S/L combo and if that doesn't do it come back for another 12 with an anti-protease addition (like MK-5172). Is that realistic or do you think the 24 weeks need to be continuous?

Btw, I'm seeing an ID doc tomorrow to discuss all this new and exciting stuff.  Word in my neck of the woods is the IDs are going to be lending an even bigger hand to HepC tx in the future and all help is appreciated. 

I'm bumping this thread as this has come up recently.  Really good info.  In fact I think it's a good sticky candidate myself.

Thanks for this, Malcolm. Visiting the doc tomorrow and you've enabled a couple more questions I can add to my list.  It's appreciated...

Hi all,

RAV= Resistance Associated Variant. Also called mutations, treatment-induced variants or viral polymorphisms. When infected by HCV, we know there is a dominant viral structure called the 'Wild-Type', and it has a family of very similar viruses, with substitutions of an amino acid or two in vital spots. These substitutions are due to an error in replication. Many are poor copies and cannot replicate or enter cells, so these quickly disappear. It's survival of the fittest. We are probably left with a few dozen mutations ( forming 5-10% of the VL), and some of these may have changes at replication sites. Significant RAV's have been named, using the protein number where the changes have occurred. The type of protein change is identified by two letters, so we have names like 'RAV S282T'.

With the loss of Interferon, and hopefully Ribavirin, these RAV's are now the subject of countless papers. RAV's are drug and Genotype specific, and probably account for most treatment failures or relapses.

Pre-Treatment Screening: With Olysio, we have seen the advice to check for the Q80K RAV. This only occurs in Geno 1a, and is present naturally in up to 50% of US patients. As Olysio is unlikely to get much use, except with another DAA until better drugs are approved, this is probably of no significance. Naturally occurring RAV's to virtually every DAA have been found. There is debate as to whether this matters, as no DAA will be used as monotherapy. It is of interest to researchers, but in practice this is expensive and unjustified.

Anti-proteases: From the replicon studies, this NS-3 site was found to be easy to block. The first generation antiproteases, Incivek and Victrelis, lifted the SVR rates significantly for Geno1. Incivek has some nasty side-effects, and Victrelis was less potent and needed thrice daily dosing, and only worked after the VL was reduced by a leadin with Peg and Riba. RAV's quickly developed to both and the Geno 1a's were most at risk. The specific RAV's are well-documented, and I have discussed these in previous posts. Patients on these early drugs had the safeguard of Peg and Riba to destroy the RAV's, providing the patient was Interferon-sensitive, and Ribavirin was at adequate blood levels. The antiproteases RAV's were said to have reduced 'fitness', but Geno 1b RAV's persisted for up to 6 months, and 1a RAV's persisted for up to 2 years.

Enter the second generation antiproteases. These were meant to have a more complex structure, reducing the likelihood of RAV production. They were also intended to be pan-genotype, and free of nasty side-effects. The only one that comes close is Merck's MK-5172. This is active against all known RAV's from other antiproteases, but not much has been said about any RAV's it may produce.

NS-5A inhibitors: Again, this is a complex, unstable site. Potent blockers have been developed, and Ledipasvir and Daclatasvir are well known. Pretreatment screening has shown naturally occurring RAV's at protein sites 28, 30, 31 and 93. Significant RAV's are M28V and Y93H. As these drugs will be always used with another DAA, the significance of these RAV's is uncertain. A number of treatment-induced RAV's have been identified, but these should be destroyed by the other DAA, e.g. Sovaldi.

NS-5B inhibitors: Here we have the non-nucleosides( e.g ABT-333) and the nucleosides (e.g. Sovaldi). The non-nucs have a low barrier to resistance, and RAV's rapidly appear, particularly at sites 452, 316 and 159. Again, we hope the additional DAA's will take care of these. The nucs, like Sovaldi, have an inherently high barrier to RAV's but they do occur.

So what does all this mean. Basically, I think pre-treatment screening for RAV's is a waste of time and money. Assuming Peg and Riba are not used, the choice of drugs is important. Until drugs like Ledispavir and MK-5172 are approved, we have to go what we've got. Forgetting cost, we want the drugs with the least chance of treatment failure, and with the fewest side-effects. My choice would be Sovaldi and Olysio, and as a cirrhotic, I'd want Riba as well- Rx duration of 24 weeks! Down the road, I'd want Sovaldi and Ledipasvir +/- MK-5172. Maybe 12 weeks of that would suffice.

For treatment failures, Sovaldi can be re-used. You would need a different second, and possibly third DAA ( to protect against surviving RAV's). Antiprotease failures should switch to another site. Treatment duration has not been established, and cirrhotics may need 24 weeks.

All this stuff is complex and still far from clear. I understand patients can't walk into a Hepatologist's office and demand a certain drug regime. It's just information. Cheers.