Hi Matt,

I had missed that Abbvie Trial so thanks. By eliminating patients with RAV's at sites 155, 156 and 168 they should have their bases covered for the antiprotease.  It seems the RAV's against ABT-450 are similar to those  that arise from Victrelis and Incivek. I'm sure you will be thrilled, but have a look at these 2 links. Forget the SVR rates quoted, and try to struggle through the Plos technical stuff.  You'll understand why I have been so keen on MK-5172, as the figures look good, even for Genotype 3.

There is another article in Virology that I can't post a link, as it hasn't been released yet. It talks about the new, improved deep sequencing techniques that have revealed RAV's in patients that tested negative in normal deep sequencing. I suspect that all patients who fail Rx with a DAA will have RAV's (as yet undetected).

http://www.aphc.info/pdf/JOUR1/D_NELSON.pdf

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002832

Hello Members

After digging around Abbvie's trials I think we have a partial answer to the question.

Trial # NCT01609933    http://clinicaltrials.gov/ct2/show/study/NCT01609933?term=HEPATITIS+C&spons=Abbvie&rank=6#locn

This trial is for Abbvie Subjects Who Have Experienced Virologic Failure in a Previous AbbVie or Abbott DAA Combination Study.

This study might be the rescue program for us who relapsed on the Turquoise II or the Sapphire trials, my trial location has not yet told me the name or number but this trial is by invitation only so it might be it.

Well back to to question / answer, Abbvie  on this trial will be treating with 2 of the 3 DAA's (ABT450 and ABT267) plus pegylated interferon alpha-2a (pegIFN) and Ribavirin (RBV) the key to the answer is in the Exclusion Criteria it say that if any of a particular Rav's are present then the person would not qualify. Here is the paragraph : In subjects with a prior null or partial response to pegIFN/RBV treatment at any time prior to pre-screening for this study or any prior failure with pegIFN/RBV plus telaprevir, the presence of variants relative to the appropriate prototypic reference sequence (H77 for 1a or Con1 for 1b) at any of the following positions: NS3 155, 156, or 168; or NS5A 28, 29, 30, 31, 32, 58, or 93.  

These locations NS3 and NS5A are exactly what Malcolm mentioned in his post ("Given that sites NS-3/4A and NS-5A are unstable proteins that are highly susceptible to RAV's, they must have some idea by now.") Malcolm these might be Abbvies list of undisclosed Rav's that you mentioned. It leads me to believe that Abbvie thinks as long as these Rav's are not found in the gene sequencing on the patient labs that they will treat them again.

The part we need to be aware of is Abbvie is including PegIFN and Ribavirin to insure there treatment has better percentage of cure and control the Rav's in this second treatment which is smart especially for cirrhotic patients. Perhaps sometime in the next five years we will see Drugs like Mercks MK-5172 and a improved Sofosbuvir that can deal with most of the Rav's and eliminate Interferon altogether.

The other unanswered question is, if we had Rav's and we waited until they died off could we then be retreated, who knows.  I speculate that the best approach might be to go to a drug that attacks the HEP virus at a different part of the protein or go a entirely different way like Miravirsen the first Micro RNA targeted drug.

Hopefully we will never even need to worry about this because there will be such a high cure percentage like 99% that it will hardly ever be needed.

Matt               

Matt, well done you for finding this!! I know how time consuming it is to sift through all the different google hits. It makes very interesting reading.

Thanks for the explanation. But my head is spinning...LOL

Hi Marian,

That is correct. The 'wild-type' virus dominates because it is the most efficient form of the virus. Many of the mutations 'die' quickly, as they cannot replicate or survive as well. The RAV's obviously can replicate, enter host cells, and are 'good copies', but over time, they will be replaced by the 'wild-type' virus.  How long this takes is the question. This is the problem with an RNA virus. It has no blueprint to follow ( only DNA stores information) so when it replicates it makes mistakes and so we get the 'family' of similar but slightly different viral structures. Cheers.

Thank you Malcolm, that's the first explanation of RAVs and the workings of DAA's that I've actually understood. I thought I had seen somewhere a statement  that RAV's eventually revert back to the original virus, is this right?

Hi Matt,

It's a very interesting topic and one that doesn't have any answers as yet. With Victrelis and Incivek, the RAV's are well documented eg for Geno 1a, Resistant Mutations R155K and V36M are the important ones.  For Geno 1b, Mutations T54A and T54S are the most important. It is interesting that these RAV's develop in both Victrelis and Incivek patients, and are Genotype -specific. PreRx testing has shown that these mutations may exist in the family of mutations that accompany any wild-type virus. Once the DAA knocks out the wild-type virus, these mutations become dominant and we rely on Peg. and Riba to control these. If the Peg. and Riba don't work, SVR is impossible. How long these mutations last is another question. RAV's have been found up to 2 years after Rx failure. Obviously, as long as these RAV's are around, re-treatment with Victrelis or Incivek won't work. Sticking with the antiproteases, enter Merck's MK-5172. It is active against all of the RAV's mentioned above, as well as some others I haven't mentioned. So, in theory, Rx failures with Vict. and Inciv. could be re-treated with MK-5172.

Do all Rx-failure patients develop RAV's to the DAA used? The answer must be yes, or else the DAA doesn't work. Some studies found the usual RAV's are not found in some RX-failure patients. It's probable that the RAV's have not been identified.

For Sofosbuvir, Gilead are rightly paranoid about it's only known RAV, S282T. Some Gilead Trials are insisting on pre-Trial screening for this RAV.  It's like penicillin- once a wonder drug that killed all bacteria, resistant strains now make it useless for many bacteria.

As for the Abbvie drugs, there has not been a single publication about specific RAV's to it's drugs. Given that sites NS-3/4A and NS-5A are unstable proteins that are highly susceptible to RAV's, they must have some idea by now. Site NS-5B is said to be highly resistant to RAV's if a Nucleoside Antagonist (like Sofosbuvir) is used, but not if a non-Nucleoside antagonist is used (ABT-333).  Abbvie's reasoning that blocking 3 viral replication sites make it mathematically more difficult to develop a RAV to all 3 sites. Until we find out, retreatment with the same type of DAA has been put on hold. I see that Abbvie have now added previous Rx with an antiprotease or NS-5A blocker to their exclusion criteria.

I don't think we'll get any answers until the FDA approvals are given. Then we might get some honest information from the DrugCos.

Hello Friends

After reading Jumpy's post about relapse in Genotype 1 from the Abbvie Aviator study I found myself with this question about relapsed patients.

" If you relapsed and did not develop Rav's can you be treated with the same type of DAA'S drugs?"

Here is the URL that Jumpy listed  http://www.natap.org/2013/CROI/croi_06.htm

I wondering if anyone has encounter any information on this question. From time to time we hear about not being able to be treated with the same type of DAA again because of mutations or Rav's that would have likely developed during the first treatment, but what if they never developed or what if they disappeared within a year time could one retreat?

These will be important questions as time go's on because of the use of many more DAA's in HCV treatment.

Any thoughts?

Matt