Viral Resistance & and how DAAs work

[HectorSF]

Here is a great talk with audio and slide presentation from "The Best of The Liver Meeting® 2010 Postgraduate Course sessions" The doctor explains viral resistance and how treatment with DAAs works with peg-interferon and ribavirin.

Therapy of Hepatitis C: Viral Resistance and Remaining Challenges
http://74.43.177.57/courses/2010/pg/pawlotsky/player.html

Cheers!
Hector

[Dee1956]

Hi, thanks for much for the information, I am trying to learn as much as I can and as always your information is great
Much appreciated
Dee

[curiouslady1]

It was a great post Hector.  One can also look through other videos from that conference which are really helpful.

[flcyclist]

Another article to add related to HCV resistance.  Following is the summary in case the link below doesn't work.  

HCV Resistance: Similarities and Differences With HIV
Source: HIV and Hepatitis C Annual Update 2011
By: Stuart Ray, MD


Impact of Baseline Protease Inhibitor Resistance in Phase III Trials
In the pivotal phase III boceprevir trials, data on baseline viral sequences were available for 980 patients treated with boceprevir. An analysis of these sequences revealed that 43 patients (4%) had pretreatment detection of the high-level resistance-associated variants V36M, T54A/S, V55A, and/or R155K.[13] The sustained virological response (SVR) rate in this population was 65% (28/43). Among the 36 patients in this subgroup who experienced ≥ 1 log10 reduction in HCV RNA during 4-week peginterferon/ribavirin lead-in therapy (interferon responsive), the SVR rate was 78% (28/36), which was comparable to the 72.7% to 80.6% SVR rate observed in the overall population of interferon-responsive patients. Therefore, in this small subpopulation, response did not appear to be hampered by the presence of high-level resistance mutations at baseline, provided patients were responsive to lead-in peginterferon/ribavirin. In the 7 patients with high-level resistance mutations at baseline who were nonresponsive to interferon as defined by < 1 log10 reduction in HCV RNA during 4-week peginterferon/ribavirin lead-in therapy, SVR was not observed. By contrast, in the overall population, 27.8% to 37.9% of patients who were nonresponsive to interferon during the 4-week lead-in period achieved SVR. Therefore, it will be important to continue to collect data on the impact of baseline resistance in future studies to determine whether this information has predictive value either alone or in combination with Week 4 peginterferon/ribavirin lead-in response.

Among patients treated with telaprevir in the pivotal phase III studies, baseline resistance-associated substitutions (at positions V36, T54, R155, and/or D168) were observed in 5% of the available samples. However, an SVR analysis in this subgroup was not conducted because of the small patient numbers.[14]

In conclusion, only approximately 5% of patients will have detectable baseline protease inhibitor resistance-associated mutations. These substitutions may compromise the therapeutic efficacy of protease inhibitor–based combination regimens in only a subset of that population.

http://www.clinicaloptions.com/Hepatitis/Annual%20Updates/2011%20Annual%20Update/Modules/HCV%20Resistance/Pages/Page%206.aspx

[willbb]

Hector...thx for posting ...all articles (videos )  of this nature are helpful.
Will

[OC]

excellent, thanks for posting!

given the current triple therapy with incivek, if failed, would that preclude you from taking the all oral therapy in the future?

[curiouslady1]

Hello Pommes,

To answer your question about my trial (which has been touted in the forum over the last few weeks).  It is the NS5b which is given first and it is given for 6 days before the drug from a different class NS5a is introduced into the mix.  Day 1 of the trial I have 5 readings; baseline, 1 hour, 2 hours, 4 hours, 8 hours and then once daily for 6 days.  Day 7 there are 9 blood draws.  I am not sure of the spacing as I haven't gotten there yet.  In this way the interaction the drugs have with the virus is studied more carefully.  Correct no ifn unless you have to be rescued.  Then you get a quad.  

[dointime]

Great video Hector.  Thanks for posting.  

This video either answers or confirms most of the issues we've been trying to get to grips with for some time.  Much appreciated.

dointime  

[pommes]

Hi,

I'm going to stick my neck out and make a first stab at answering your questions.

For info on the NS3/4A test, see the 8/25 posting by willbb titled
"LabCorp Introduces HCV Resistance Testing through Monogram Biosciences with the Launch of HCV GenoSure® NS3/4A"

I'm hoping that somebody will explain the test to us.

As for the resistance issues, the protease inhibitors evidently are chemically very similar and exhibit extensive cross-resistance, meaning that once you have been treated unsuccessfully with one protease inhibitor, you will not be responsive to any other members of that drug class.

Not so with the polymerase inhibitors.   They have different targets and use different mechanisms, so presumably there is not the same problem of cross-resistance.   You should be able, in other words, to re-treat with a different polymerase inhibitor.

As for how much we should worry about resistance, it's been explained to me that with the prospects of so many novel drug treatments, it may not be such a big deal whether you become resistant to one particular class.    I don't know if I believe that myself, and I also wonder what happens when the Hapless Hepatologists have to keep track of all this in choosing new treatment options.

Good luck with your all-oral clinical trial!    We're all holding our breaths hoping for good results.

renata

[Ozgirl707]

Hi,
I don't know about this NS3/4A test? could you please tell me what that's for??

I've had the IL28B test (I'm CT)

I'm currently on an all oral clinical trial consisting of a Protease Inhibitor, Antiretroviral, Polymerase Inhibitor & Ribas.  I'm up to end of week 5 and no sides, but haven't had a result of the VL's taken at week 1, week, 2 week 4  yet.(still waiting) But AST, ALT, GGT been down to normal since end of week 1.

Now i'm worried about resistance. If this doesn't work, does that mean I'd have a resistance to PI's and Polymerase Inhibitors for ever?
Anyone know?
x

[HectorSF]

Not sure I understand your question.

As far as the first paragraph of your post...

" figure out whether the individual was unresponsive to INF or to the DAA or to both?" The DAAs is only effective on the wild virus. The majority HCV virus when treatment starts. Resistance is always the same whether SOC or DAAs. In all cases it is the variants that become the main viral load after treatment begins. So treatment failure is due to the interferon and ribavirin being unable to suppress the variants. That is why they are looking for DAAs that suppress the variants that multiply over treatment time.

"Boceprevir has an advantage over Telaprevir in that the SOC lead-in gives early info on likelihood of treatment success, and permits stopping before PTI-resistance develops."  
There is no "advantage" for Victrelis. Treatment will be stopped for both DAAs if a patient doesn't respond to treatment before resistance develops. That is why HCV-RNA level are taken at certain intervals.

Better?
Hector

[pommes]

So no INF in your study arm?   How long on the NS5a?  

And do they actually test you after 7 days and then after 14 days to figure out what strains are present?

That sounds like a fabulous cocktail.    Will hold my breath for the results.

renata

[pommes]

Thanks!

I understand (sorta) how the pattern of response to SOC can be used to predict success rate in SOC+DAA treatment, but I'm wondering whether it will be possible to do that same kind of analysis for failed triple Tx treatments.    In other words, look at the pattern of response (null responder, slow responder, breakthrough, relapser) for (failed) triple Tx, and figure out whether the individual was unresponsive to INF or to the DAA or to both?    So as to decide whether he/she can re-treat with same class of PTI, or another class of PI+INF, or other combination?   The consensus seems to be that re-treatment with a PTI is NOT possible because of evolved PTI-resistance, but the slides from Pawlotsky seem to say that testing in treatment failures for wild-type versus low- or high-resistance would be necessary in order to distinguish between the different kinds of resistance.

Don't mean to beat this horse into the ground, but I'm confused.    Also I may be drawing the wrong conclusion which is that for treatment-naive people, Boceprevir has an advantage over Telaprevir in that the SOC lead-in gives early info on likelihood of treatment success, and permits stopping before PTI-resistance develops.    Sounds too simple, tho, which is why I'm confused.    (If I were right, there wouldn't be a good rationale for starting with off with all three drugs, so I must be wrong, right??)

Looking forward to being educated on this!

renata

p.s.  Sure seems like IL28b and NS3/4A testing should be encouraged before treatment, not that anyone should be denied on the basis of test results but that people just might want to know!    I don't even understand why it is that the NS3/4A test is only coming out now---I get it that there are different pharma companies involved, but how can you justify providing the treatment without the prior responsiveness testing?   (Unless the test truly is a breakthrough result achieved, like, yesterday.)

[HectorSF]

It has been known for sometime this is how the DAA treatment works. As mentioned by the doctor, this is the same mechanism seen with HIV and HBV treatment. The drug cocktails that HIV patients take shows the efficacy of that approach. Different antivirals in the cocktail inhibit both the wild virus and the different variants. It is hoped that in the future we can eliminate interferon and ribavirin and take a cocktail of antvirals that are more effective and with less side effects.

IL28B is the best predictor of treatment response for those who have never treated before as it indicates response to interferon. In patients that have already treated and failed SOC treatment the type of response they had to peg-interferon and ribavirin (non-responder, partial responder, breakthrough, relapser) predicts chances of SVR in treatment with DAAs added.

How much IL28B testing is being done is unknown. It is a relatively new tool for doctors and many if not most gastroenterologist may not be aware of its use in preparing for treatment. I would think most hepatologist are aware of it and its purpose as it has been one of the biggest developments in the treatment of HCV secondary to the use of DAAs themselves. It is a learning curve for most docs who weren't involved in the clinical trials of the two DAAs on the market now.

There is only one class of antivirals available now. Protease HCV NS3/4A inhibitors (PIs). Incivek by Vertex and Victrelis by Merck are PIs.
Other drug classes including nucleoside polymerase inhibitors, NS5A inhibitors, cyclophylin inhibitors and non-nucleoside polymerase inhibitors are being studied now in clinical trials.

Hope that answers some of your questions, renata.
Cheers!
Hector

[curiouslady1]

Not sure of the answer to pommes question but in my research arm I am taking a NS5b inhibitor which has a very low tendency for resistant strains followed after 7 days with a NS5a with a higher tendency for resistant strains on the assumption that the 1st drug will perform most of the dirty work and the second will be used to mop up the few left behind which will not be resistant to it.  At least that is my understanding of the actions of the two drugs from what I have been told.  In any case, this research does not seem hit and miss to me.  

[pommes]

Great video.  

Interesting the argument that triple combo failure is primarily the result of insufficient antiviral IFN response.    I've heard arguments to the contrary (e.g., suggesting no reason to check IL28b).

Data seems to suggest testing for both IL28b and NS3/4A before starting triple Tx---is that happening clinically?

And how DO they figure out which drug classes to try out in combination with which other classes?    Or is it as hit-and-miss as it looks??

Thanks for posting,
renata