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Resistance in 2-DAA combos

Following on from the discussion on resistance in another thread, I found this study.
http://www.pharmasset.com/assets/1/Page/ALam_combo_studies_invitro_7977_938_June10.pdf

"Selection study in replicon cells treated with the nucleotide analogs PSI-7977 and PSI-352938 did not select for resistance over a 120-day time period. Combining VX-950 plus HCV-796 selected for dually resistant HCV replicons within 46 days. Results suggest that combination therapies using complementary NS5B nucleotide analogs could provide a significant barrier to resistance selection that might not be seen with a combination of a protease inhibitor and a non-nucleoside inhibitor."

I think it is an important study because it is showing that if you don't get the 2-DAA combo right you could be looking at dually resistant mutations within 46 days of tx.  The viral superbugs already!  From experience with HIV we know that multiple drug resistance does emerge eventually, but it is the 46 days that I find such a shocker, such a short time.  

The good news is that the 2 NS5B nucleotide analogs used in the study did not produce any resistant mutations within 120 days of tx.  

Anyhow, this wrecks my previous complacency about 2-DAA combos being the magic bullet.  We are going to have to be very cautious about resistance with these combos - I presume even when there is SOC in the mix but poor ifn response.

dointime
PS - and thanks to willbb for waking me up.
134 Responses
Avatar universal

dointime...From what I see from your posts you are certainly wide awake and very well informed :)

The reason for my query in the first place ... was in all the articles I have read in regards to resistance ..especially cross resistance ...there  are still many unknowns.

And I agree with you entirely  we are going to have to tread very carefully imho  through the resistance maze until more is known and  studied.

Again ..thx for the input...hope all is well with you

Will

Avatar universal
Very interesting information.  Thanks for posting that.  With the next trials involving new DAA's and pairing of DAA's, it's important to get the information out there.  

ON this one...that might explain why Vertex seems to have stopped pursuing Telaprevir in combination with the also non-nucleoside VX-222 then.  If they could see resistance mutations developing very early for both the Telaprevir and the VX-222, that's a problem.  

One of the benefits of pairing DAA's is that what one becomes resistant to, the other one is not and they fight off each other's mutations.  So the fact that they develop mutations early doesn't necessarily render both drugs ineffective - other studies of DAA pairing show that the resistant mutations of the one drug were still vulnerable to the other drug - however minimizing resistance where possible is desirable and being aware of the resistance risks will be an important part of treatment decisions.  If I could choose a DAA pair that was equally effective and developed resistance mutations at a lower rate, that would be a no-brainer.  The greater issue is when the treatment hasn't worked - you're left with resistance mutations to both types of DAA.  And when these drugs are still in trial, the questions to ask when considering a trial become more complex.  

Another thing to consider, before people get too worried, is that the life of resistant mutations needs to be looked at also on an ongoing basis and monitored.  From what I've read...and I'll find the reference....Telaprevir mutations have a shelf life and when testing has been done, they've found no existence of them in many cases 2-3 years later.  So resistance isn't necessarily a permanent thing but that remains to be seen for ongoing study.  

Lots to know, many questions remain and nothing to be complacent about, as you suggest.  

Trish
Avatar universal
Thanks for weighing in on this, and on that previous thread.  I really appreciate all the help and insight that I can get on it.

I was wondering the same myself about the Vertex drugs.  This study does raise doubt where VX950 (telaprevir, incivek) is concerned.  

"One of the benefits of pairing DAA's is that what one becomes resistant to, the other one is not and they fight off each other's mutations."
Well that has been the theory, and it would be fine if it always worked like this.  But what this study shows is that each DAA pair must be evaluated on an individual basis.  Some pairs, like the one in this study, quickly select out dual resistant mutations.  We would obviously want to avoid those like the plague, for the reasons that you state.  

".Telaprevir mutations have a shelf life and when testing has been done, they've found no existence of them in many cases 2-3 years later."
This is ofcourse encouraging but it does not take into account a couple of things.  First there is the archival capability of viruses.  This was first documented in the HIV research - can't find a link for that right now but will look.  I heard about it from HR.  This is a kind of species memory.  Even if no mutations exist, the virus can 'remember' if it met the particular threat before and can figure out faster next time how to get round it.  The next thing is that many people have these mutations in their quasispecies from the start.  They may be too little to detect but they never completely go away.  So 2nd time out they are waiting to be selected again.  For these reasons I think that the whole argument about the life of mutations is fairly useless propaganda meant to calm us all down.  I think it would be better to just come clean and tell people that once they have resistance to a class of DAA then any drug in that class will be less effective for them in the future, although it may still be of some use in an intelligently targeted combo.

Lastly, I still remember one of HR's great posts a while back.  He sounded the warning bells then about these combos.  He said that while effective combos would eventually be found, there would be a period leading up when the danger would be for people who got unsuccessful combos and became multi-resistant to all the drugs.  There would be no help then for these people, while tx naive people would be stepping up and getting cured by the ultimately successful combo.  This was such an ominous prediction that I think it is well worth putting out there again, albeit paraphrased in my own words.  I wish medhelp was easier to search and I could find that post again as it has now come to such relevance.

dointime          



      
Avatar universal
46 days for the virus to effectively replicate  variants selected for  resistance to two "leaky" DAAs (in this case tela and vx222) seems in keeping with the predictions from Rong and Perelson:
http://www.ncbi.nlm.nih.gov/pubmed/20445200
It takes the virus a bit longer to figure out how to wriggle past two DAAs than one, but there's still no serious challenge.

However an important point for many null/partial responders wondering whether to risk triple or wait for quad is that the amount of ifn response required to reach SVR appears to be far less with quad than with triple. Data is still preliminary, but both the vertex quad results (87% rvr on naives)
http://www1.easl.eu/easl2011/program/Posters/Abstract3.htm
and the bms quad results (100% SVR on nulls)
http://natap.org/2011/EASL/EASL_28.htm
look very promising.

It looks likely that   those who can't tolerate ifn will need  to wait beyond 2 DAA tx (though  PSI 7977  may  be  a  game changer) but for the many null/partials left out by the recent approval of triple, quad looks good enough to do the job.
Avatar universal

Willing: thanks again...your breadth of knowledge and ability to sift  through some of the science-speak is always very helpful...I hope to enter the guad casino and come out leaving millions behind  :)

Will
Avatar universal
"millions of virons " that is
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