Resistance in 2-DAA combos

[dointime]

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.

[Trish77]

"Thanks Lynda for elaborating.  I just don't understand the "and/or" of the 4 and/or 12 weeks.   In other words, which is it.....4 or 12?  I'm assuming the measurement has to do with when the DAA is added to the mix, but not sure. "

To echo Lynda's comments - you can be detectable but <1000IU/ml at 4 weeks and still be there at 12 weeks.  Some people hit a plateau of sorts and viral load drops very slowly.  So I believe what they're doing is indicating treatment direction based on viral load at the 4 week and 12 week markers.

[Trish77]

" There is also no way to accurately calculate in my improved immune health for my odds of success....It's all best guesstimate type stuff.  I suppose a biopsy may be the final deciding factor, but nothing points to having progressed from my stage 1, six years ago.  "

I'm not sure what evidence you expect to see or experience?  Many many people have no idea of the extent of their liver damage until a biopsy.  There are some biological markers that might indicate but are incomplete taken on their own.  If you haven't had a biopsy in six years, I'd like to strongly suggest you go for one, hoping you have no physical reason why you can't be doing this.

[willbb]

I believe you are right on with that....by Pharma"s own data aprrox 1 in every 4 will be unsuccessful at triple.....  the sample group will unfortunately be huge  and they can"t have everyone wondering around with this issue ... thx again for all your input

Will

[Willy50]

Nawww....I just meant it generically for everybody, not you specifically.  

Now that approval has happened they can look into this further.  Maybe the theories will be put to a test soon.  The sample group of people with potential resistance is going to get bigger and it is a question which may be answered soon.  

I hope so.

willy

[willbb]

Willy..I have certainly not lost hope in the least... possibly you interpreted my post  as a bit pessimistic.   That is not the case at all ..I am an eternal optimist and there is no doubt in my mind that I will treat succesfully in the future  :)   My concern was actually for others that are thinking of entering treatment  with  again no liver damage.... just to be  as aware as one can be in todays landscape..

Thx for the concern tho   :)

Will

[Willy50]

(wrote) "Willy.. yes ....lets hope as you say the  resistance issue  not as big a specter as in some people minds."
==========================

I think that my point is that *simply* because one has resistance does not mean the are out of luck.

For instance waiting *could* get you back to wild type after a time,

Adding a 3rd or 4th component to the treatment could essentially "trump" the established resistance.

I believe that other improvements are being made even to current SOC (IFN and RBV) treatments, such as IR work, vitamin levels prior, such as Vit D. coffee etc.

Even the  work on the inoculation trial Hep vaccinations are showing some promise and may also be used as adjuncts with treatments.

The blank look you get from those in your treatment team just means that they are professional enough to not venture an unsupported opinion, although I'm sure they have one as well as hopes for us all.  

I think that the easiest to treat group, in theory would be the best responding group from the Vertex trials that were in a no riba arm.  I would think that they would start with this group and try to cure them.  If you can't successfully use a PI again on this group it would not bode well for other groups unless you could add other components to essentially provide a stronger treatment than the prior.

I also wonder how Taribavirin (viramidine) may be used to augment these new PI's,  It may be that anemia and dose reductions with riba will be less when combined with this trial drug, if so the SVR/success rate could improve.  It would remain to be side how the rash would be affected, but riba dose reductions could be further reduced thereby increasing the success rate.

Lots of good things are coming and as they get approved things are more likely to be able to be combined.  Don't lose hope....

willy

willy