Author Topic: NS5A Resistance predicts Harvoni Failure/relapase (Read 19968 times)

charly8 · « **on:** February 18, 2015, 01:58:47 pm »

Is there a test for determining NS5A resistance? I am assuming that it tests the virus for this "resistance" and therefore in can only be tested after a relapse.

From the NDA filing report for HARVONI. It appears that nearly all the relapsers had this resistance.

In the report is also says the following:

"In the HCV GT 1 treatment-experienced, non-cirrhotic subject subset with baseline NS5A resistance associated polymorphisms, no relapse occurs in the LDV/SOF 24 week and LDV/SOF+RBV 12 week arms compared with 21% relapse rate in the LDV/SOF 12 week arm, suggesting that extending treatment duration or adding RBV may optimize response rates in this subset."

Also the following link (bottom table 12):

http://hepatitiscnewdrugresearch.com/harvoni--svr-ratesdosagedrug-interactionsside-effects.html

apache · « **Reply #1 on:** February 18, 2015, 05:56:51 pm »

Hi Charly8,

Very good question!

In the Harvoni detailed product insert:
http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf

it actually does discuss a method for (possibly) testing for NS5A resistance.

If you search for the string "deep sequencing", they talk about the characteristics of the hep C virus found in the 37 patients where Harvoni failed.

Quote

Of the 29 genotype 1a virologic failure subjects, 55% (16/29) of subjects had virus with emergent NS5A resistance-associated substitutions K24R, M28T/V, Q30R/H/K/L, L31M, or Y93H/N at failure. Five of these 16 subjects also had baseline NS5A polymorphisms at resistance-associated amino acid positions. The most common substitutions detected at failure were Q30R, Y93H or N, and L31M

Of the 8 genotype 1b virologic failure subjects, 88% (7/8) had virus with emergent NS5A resistance-associated substitutions L31V/M/I or Y93H at failure. Three of these 7 subjects also had baseline NS5A polymorphisms at resistance-associated positions. The most common substitution detected at failure was Y93H.

At failure, 38% (14/37) of virologic failure subjects had 2 or more NS5A substitutions at resistance-associated positions.
...

So that means it is technically possible to test for NS5A resistance, by doing "deep sequencing" of the patient's DNA. I have no idea if that is realistically possible (eg, is this something a typical gastroenterologist can order, or is this a special task only possible in R&D facilities?) Nor do I have any clue as to how much $ it might cost.

But... one has to question as to whether or not this is even a scientifically valid method of detecting NS5A resistance. Setting aside for the moment the cost factor, there seems to be a logic flaw here: did they do "deep sequencing" on the patients for whom Harvoni worked, and verify that they did not have these same genetic mutations?

If not, then it could be the case... that perhaps many of the SVR patients did have these genetic mutations, and yet the Harvoni worked anyway. Which would mean that these genetic mutations are not as good an indicator of treatment failure as one would otherwise believe.

MEG · « **Reply #2 on:** February 18, 2015, 07:20:36 pm »

Hi Charly and Apache...I just spent close to 2 hours reading that document and I think we don't have enough information to know what is going on. Some people with NS5A mutations did fine, others didn't.

I'm going to add this to the list of q's I have for my doc when he returns from vacation.

He did test me for sensitivity for Olysio last year when he thought that he may be able to prescribe it along with Sovaldi. I was sensitive for the Olysio but it targets the NS4A protein. I'm also sensitive for NS3 drug targets..Again, regards NS5A???

Bituman · « **Reply #3 on:** February 18, 2015, 08:23:32 pm »

Quote from: apache on February 18, 2015, 05:56:51 pm

But... one has to question as to whether or not this is even a scientifically valid method of detecting NS5A resistance. Setting aside for the moment the cost factor, there seems to be a logic flaw here: did they do "deep sequencing" on the patients for whom Harvoni worked, and verify that they did not have these same genetic mutations?

If not, then it could be the case... that perhaps many of the SVR patients did have these genetic mutations, and yet the Harvoni worked anyway. Which would mean that these genetic mutations are not as good an indicator of treatment failure as one would otherwise believe.

This^^^^^^

MEG · « **Reply #4 on:** February 18, 2015, 08:38:48 pm »

Hi all, I was just reading this document from Washington U where they discuss the resistance. It looks like they did test patients at baseline and 90% who showed NS5A resistance achieved SVR. And 65% of the relapsers had the variant.

Apache, you are correct. It appears like we can have the variant but can clear the virus....again,it sounds like we need more data re: pre-treatment testing---and we are the one giving it to them....we truly are a continuation of the Phase 3 trials, imo. I imagine they will figure out the signals, biomarkers in the not too distant future. They already know so much about this virus.

Add: The below is from the Ion3 trial analysis.

________
NS5A resistant variants
- Baseline resistance in 116 (18%) of 647 patients
- SVR12 in 104 (90%) of 116 patients with NS5A resistance
- Of the 23 patients who had viral relapse, 15 (65%) had NS5A-resistant
variants at time of relapse

http://depts.washington.edu/hepstudy/presentations/uploads/103/ledipasvir_sofosbuvir_master.pdf

Tpropane · « **Reply #5 on:** February 18, 2015, 08:53:07 pm »

This is scary. Did my 4 week labs today. Makes me glad I'm doing 24 weeks!

MEG · « **Reply #6 on:** February 18, 2015, 10:09:48 pm »

@Tpropane...you sure are to be getting the max regimen! With the minimal side effects, I'll take 24 weeks in a heart beat!

Truth is that I don't think it's as scary as it may seem. Overall, an overwhelming majority of all trial participants, 95-100%, achieved SVR...I'm rooting for all of us to be part of the 95%.

But even if one does relapse, there are 100% SVR rates being achieved with Gilead's next generation of medication. I need to keep remembering this when I begin to doubt---like today.

Lynn K · « **Reply #7 on:** February 19, 2015, 04:43:15 am »

I sure hope it works for me.

So far I haven't had a lot of luck even with sovaldi olysio for 12 weeks

Amj1951 · « **Reply #8 on:** February 19, 2015, 07:44:08 am »

This is an interesting topic. My liver doctor did a lot of tests I've never had done or not that I know of right before I started the treatment and one of the tests is a double strand DNA type test that came back negative (I love that word : ) but I wonder if that had anything do to with this discussion? It may have nothing to do with it. I'll have to ask her about this.

Either way I am undetected as of now and pray I stay that way. Actually, I am praying we all do!!!

Meredith

MEG · « **Reply #9 on:** February 19, 2015, 09:58:04 am »

Meredith, Were you on Harvoni or S/O? Not sure if you saw one of my posts upthread that said how when my doc wanted to see if I'll qualify for S/O he did a series of tests also. One was whether I had a mutation called Q80K(which was negative, meaning I was sensitive to it) and then tested my sensitivity to NS3-NS4 proteins---which came back positive. But no testing re: NS5A....which according to the studies has only small? relevance since folk with the NS5A area mutation also had SVR's. I imagine the doc's are confused about this too.!

I suppose the learning curve continues(!) until this virus is eventually eradicated.

Wishing you continued and forever SVR.

MEG · « **Reply #10 on:** February 19, 2015, 10:01:42 am »

I surely hope it works for you too, Lynn. You've been through so much yet here you are taking care of yourself and supporting us.

Just a quick q...what was the rationale for adding Riba?

Wishing you a peaceful day.

Lynn K · « **Reply #11 on:** February 19, 2015, 11:34:01 am »

I saw a rounds table discussion of several experts in the field just after the liver conference discussing different situations for patients part way in the were discussibg my situation a nul responder to interferon with cirrhosis who relapsed on a Sovaldi based regimen with long standing cirrhosis and the concessions was on riba or not to give this patient their best chance for a cure.

I may need the faction of a percentage point of improvement in my odds that adding riba gives me and honestly at this point if I don't clear hep c this time I could be running out of time before I decompensate. If this doesn't work for a patient like me what will and when will it be here?

Mike · « **Reply #12 on:** February 19, 2015, 11:44:44 am »

Hi Lynn,

It will work for you and everything is pointing that way.

Not that you need it, but I'll send a little extra prayer upstairs for you for good measure.

Best wishes, Mike

Amj1951 · « **Reply #13 on:** February 19, 2015, 12:51:14 pm »

Quote from: MEG on February 19, 2015, 09:58:04 am

Meredith, Were you on Harvoni or S/O? Not sure if you saw one of my posts upthread that said how when my doc wanted to see if I'll qualify for S/O he did a series of tests also. One was whether I had a mutation called Q80K(which was negative, meaning I was sensitive to it) and then tested my sensitivity to NS3-NS4 proteins---which came back positive. But no testing re: NS5A....which according to the studies has only small? relevance since folk with the NS5A area mutation also had SVR's. I imagine the doc's are confused about this too.!

I suppose the learning curve continues(!) until this virus is eventually eradicated.

Wishing you continued and forever SVR.

Hi MEG, I am taking the Harvoni for 12 weeks. This is my first and fingers crossed last treatment! : )

Meredith

lporterrn · « **Reply #14 on:** February 19, 2015, 02:36:01 pm »

Tests that detect genetic variations such as resistance are widely used in clinical trials, and sometimes they are available - I know that the major academic institutions use them for their nonclinical trial patients.

MEG · « **Reply #15 on:** February 19, 2015, 08:06:07 pm »

Hi Meredith---I wish that for you too. Virodemon be gone!

MEG · « **Reply #16 on:** February 19, 2015, 08:10:20 pm »

Thanks Lucinda, ya, the kind of testing and on-treatment evaluation seems to vary from place to place. Makes for confusion on forums like this---leaving us wondering if we're indeed getting the proper care....

Hopefully, as the DAA therapy matures that more consistency will emerge?

Lynn K · « **Reply #17 on:** February 20, 2015, 03:12:01 am »

Thanks Mike

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