Why IL28B Genotype Remains Important With DAA Regimens

[pooh55811]

From Clinical Care Options:

Why IL28B Genotype Remains Important With DAA Regimens
Raymond T. Chung MD - 11/1/2012

"One of the most interesting questions attending the remarkable pace of new therapies for patients with chronic hepatitis C is to what extent  IL28B genotype plays a role in management—both now and in the future.

IL28B: Still Important With PI Therapy
How do I currently use IL28B genotype in my practice? In the era of peginterferon/ribavirin plus protease inhibitor therapy, IL28B can be used to provide an increment of additional data that may assist with decision making. For the patient who needs to be treated (advanced fibrosis) or who really wants to be treated, I will not be deterred from starting therapy, so the test has limited value. On the other hand, for the patient with more limited disease in whom we could justifiably defer therapy, the finding of a CC genotype may persuade the patient toward giving treatment a try, particularly given the high likelihood of being able to abbreviate treatment to 24 weeks. If it’s clear that the patient has no inclination to consider interferon-containing therapy, then again the test has little value.

IL28B With Investigational Therapies
Given the postulated mechanisms of direct-acting agents (DAAs)—offering a stranglehold on virus replication by means of blocking enzymes or proteins that contribute to the replication machinery—the use of DAAs should “level the playing field” by halting replication until it’s extinguished. Under this scenario, we might then expect the contribution of IL28B genotype to be rendered either irrelevant or minimally relevant, given that it was discovered due to its relationship with interferon responsiveness. However, in recent phase II DAA studies, IL28B status still mattered in predicting outcome in genotype 1 patients being treated with interferon-free regimens. I found this to be somewhat unexpected but quite revealing about the role of this polymorphism in dictating outcome.

Contribution of HCV Subtype
How might IL28B be contributing to success under these circumstances? Let’s drill down somewhat deeper. In SOUND-C2, a study of the combination of a protease inhibitor plus nonnucleoside polymerase inhibitor with or without ribavirin, it appeared that in subtype 1b patients, responsiveness was excellent across the board, regardless IL28B status. By contrast, those subtype 1a patients with non-CC IL28B genotypes did poorly compared with those with the CC genotype who performed as well as the 1b subjects. This suggests to me that genotype 1 may need to be cleaved further into 1a/1b subtype distinctions for future clinical trials, and I can envision that DAA regimens may even be tailored to HCV subtype. In current practice, we routinely obtain subtype information with our genotype assays, so no additional information generally needs to be requested. However, subtype has less bearing presently on the decision to treat with current regimens, since overall SVR rates with these regimens are not terrifically different between subtypes.

The findings also suggest that HCV subtype 1a is an inherently more difficult-to-treat virus and that the right innate immune “equipment”—in this case, represented by IL28B genotype—is essential to maximize response for this group of patients. These data further imply to me that IL28B status does matter even in the absence of exogenous interferon. In the case of a virus with a low barrier to resistance development, such as HCV subtype 1a, the strength of the innate response coupled with antiviral therapy becomes critical. This might be reflected in an enhanced ability to respond to locally produced interferon and to minimize breakthrough of resistant viral variants. By contrast, in the case of HCV subtype 1b, where there is a generally higher barrier to virally encoded resistance, the DAA regimen alone may suffice, given the lower hurdle presented to the regimen.

Of course, these hypotheses are nothing more than that until we understand more precisely how IL28B genotype functionally produces its phenotype. Until then, we are left stratifying for subtype and IL28B in upcoming trials. Of course, the development of regimens that present ever higher barriers to resistance, including those that contain nucleotide polymerase inhibitors, may overcome these concerns at the end of the day."  


http://hepatitiscnewdrugs.blogspot.com/2012/11/hepatitis-c-why-il28b-genotype-remains.html

[dointime]

Jules, sorry, what I meant to say was:
" The new drugs that are eventually approved will be at least as good as what is available currently for all subtypes and categories, so that leaves a level playing field. "

I completely agree with you here:
"As for the IL28B I think the more information we have about ourselves the better informed decision we can make concerning treatment"

However, that is only one of the factors we need before we can make an informed decision.  Additionally, we still need the complete trial results of the drugs being proposed and the parameters within which they are effective, ie. the subtypes, genotypes, categories of patient, etc.  We have that data for the approved drugs but not for the drugs still in testing.  For example if you are a 1b and a CT then you still need that complete drug data to find out if you have a fighting chance with that particular drug.  If  you don't have it then knowing that you are a 1b and a CT is of no practical use to you.

I suspect that we are both on the same page with this but maybe I expressed it in a clumsy way and got myself misunderstood.
Anyway, seems that you made your decision and went for the bird in the hand, not the 2 in the bush.  Congratulations on your UND status,

dointime

    

[dooklebug]

Thank you, Pooh.  You always make things so much easier to understand and deal with.  Have I said lately that I love this site?

[pooh55811]

Don't worry about your CT status. You cannot do anything about it. You have what you have. I agree, you are probably Genotype 1 since that is the most common Genotype in the US. That is sub-typed further to 1a or 1b.

But, the main thing is, don't let the Genotype and the subtypes bother you or scare you. (Easier said than done, I know.) A person just has to move forward.

I was Genotype 1 but I have no idea if I was 1a or 1b and I have no idea if I was CC, CT, TT. I still started treatment because I wanted to get rid of Hep C. I did not clear until 8 weeks so I doubt I had the easy type, LOL.  However, I became UND at week 8 and stayed that way throughout the 48 weeks of Tx. I was also UND at 12 weeks post EOTand that gives me a 99.7 % chance at SVR.

As far as the study jargon .....

Those who have Genotype 1 can be sub-typed further into Genotype 1a or Genotype 1b. Genotype 1b is easier to cure than Genotype 1a. The reason for this is that the resistant strains do not develop as easily in those with Genotype 1b as they do in Genotype 1a.  One can also be sub-typed further into CC, CT, or TT. CC is easiest to treat.

However, all of this does not mean people with Genotype 1a who are also CT or TT cannot be cured. They can be. People with CT have about a 71% cure rate and that is very good. Many on this forum have these subtypes and they are treating and many are attaining SVR.

So the important thing is to move forward. Try not to worry about the subtypes since you cannot do anything about them. (You have what you have, just like the rest of us have what we have.)

Here is a link to an excellent article discussing Hep C, and everything about Hep C and treatment. Just keep turing the pages and you will obtain a lot of information:

http://www.clinicaloptions.com/inPractice/Hepatology/Hepatology/ch8_Mgmt_of_Hep_C_Infection/Pages/Page%202.aspx

I will attach a link that talks about resistance.

http://74.43.177.57/courses/2010/pg/pawlotsky/player.html

[dooklebug]

I know that I am IL28B-CT, but I have yet to know my genotype.  I am assuming it is 1 since that is the most common in the US.  My brain is simply not programmed (yet) to understand this study jargon, much less relate it to my condition.  Can someone explain, please?  From what I did gather, being CT is not a good thing.

[jules2551]

" The new drugs will be at least as good as what is available currently for all subtypes and categories, so that leaves a level playing field. "
*******
Dointime - I don't believe that is true because IF that were the case the new drugs would have already been approved by the FDA.  It's still too soon with the smaller trials being reported and a lot of what-ifs.

As for the IL28B I think the more information we have about ourselves the better informed decision we can make concerning treatment.  I am a 1b and CT so I knew up front that tx may prove difficult.  I am UND as of week 24.

[dointime]

"I think this is important because people are being encouraged to wait regardless of Genotype subtypes (1a or 1b or IL28B). Most of us do not even know if we are CC, CT, or TT. Some of us do not know if we are 1a or 1b. Waiting may work out for some people. But waiting is also a gamble, more so  for some. When will the new drugs be out? On whom will the new drugs work? How fast will I progress (fibrosis) while I am waiting? Will they work on CT and TT? How will Cirrhotics do with the new drugs? And so on."

Pooh - I don't see that the decision to wait or go needs to ask all of the above questions.  The new drugs will be at least as good as what is available currently for all subtypes and categories, so that leaves a level playing field.

The only relevant clinical question on when to treat is whether or not one has the liver time to wait.  Some people don't unfortunately and they have to go for tx asap.  Others do have the liver time which gives them a choice for as long as that happy circumstance prevails.

dointime

[pooh55811]

Yes, those are all good articles and I read them as they are published.

I think the point of the article I posted is being missed by some. However, I am not going to belabor the point. Those who read it and understand what is being said, great. Those who don't, well, I cannot do anything about that.

[Cheesegrater]

" In the case of a virus with a low barrier to resistance development, such as HCV subtype 1a, the strength of the innate response coupled with antiviral therapy becomes critical."

Very true with DAAs that offer low barrier to resistance to GT1a.

But not so critical when DAAs with high barrier or a combo with high barrier to resistance AND sufficient treatment time. 12 weeks may not be enough.
Some  studies have shown that while 12 weeks all DAA may be sufficient for GT1b,  GT1a have been seen to relapse from UND 4 to 36 weeks post treatment. Certainly, some combinations of DAAs will be less effective than others for short term treatment with GT1a.

A collection of interferon free studies have been reviewed at

http://www.hepatitiscnewdrugresearch.com/interferon-free-combinations.html

which those following this thread may find interesting.

Also
http://www.sciencedaily.com/releases/2013/01/130107190754.htm

[pooh55811]

One reason I posted this article is that it is interesting and informative. Another reason I posted it is because many people on this forum encourage people to wait for the new treatments, that they are just around the corner, and they are much better and easier. Well, some of that may be true.  However, we do not know when the new treatments will be available.  We also do not know if they will work on everyone. The trials are notoriously small and the most difficult to treat patients are often not in the trials or are only a tiny minority of participants.

What I found important in this article is this:

".....in recent phase II DAA studies, IL28B status still mattered in predicting outcome in genotype 1 patients being treated with interferon-free regimens. .....subtype 1b patients, responsiveness was excellent across the board, regardless IL28B status. By contrast, those subtype 1a patients with non-CC IL28B genotypes did poorly compared with those with the CC genotype who performed as well as the 1b subjects. This suggests to me that genotype 1 may need to be cleaved further into 1a/1b subtype distinctions for future clinical trials, and I can envision that DAA regimens may even be tailored to HCV subtype. .....The findings also suggest that HCV subtype 1a is an inherently more difficult-to-treat virus and that the right innate immune “equipment”—in this case, represented by IL28B genotype—is essential to maximize response for this group of patients. These data further imply to me that IL28B status does matter even in the absence of exogenous interferon. In the case of a virus with a low barrier to resistance development, such as HCV subtype 1a, the strength of the innate response coupled with antiviral therapy becomes critical."

I think this is important because people are being encouraged to wait regardless of Genotype subtypes (1a or 1b or IL28B). Most of us do not even know if we are CC, CT, or TT. Some of us do not know if we are 1a or 1b. Waiting may work out for some people. But waiting is also a gamble, more so  for some. When will the new drugs be out? On whom will the new drugs work? How fast will I progress (fibrosis) while I am waiting? Will they work on CT and TT? How will Cirrhotics do with the new drugs? And so on.

I do think people need to think very long and hard about the benefits from treating now versus waiting for future treatments which may or may not work for them.

I think it is important to realize that the new drugs now in trial may be excellent for some people, but they may not be available in time for everyone, and they may not work well for everyone, and they may not end up being the silver bullet to rid everyone of his/her own werewolf.

[Idyllic]

"On the other hand, for the patient with more limited disease in whom we could justifiably defer therapy, the finding of a CC genotype may persuade the patient toward giving treatment a try, particularly given the high likelihood of being able to abbreviate treatment to 24 weeks. "
_______________________
It is weird since prior to treatment (and even during) I thought the same way. Oddly after finishing 48 weeks I tend to encourage the person who can justifiably deter therapy to do just that.

I say that since I would encourage that same CC Genotype person (who is not advanced or with extrahepatic symptoms) who is not UND by the necessary milestones with the DAAs to adhere to response guided therapy.

Still, Thanks for the link. I would like to have known my IL28B gene polymorphism even though I knew I was going to treat anyway. I do not think many doctors utilize the IL28B in pre-treatment assessments. I am often surprised how many people post who mention they are getting ready to treat who do not have their level of fibrosis assessed.

__________
**Thought I would add this since Insulin Resistance (HOMA-IR) is another independent pretreatment indicator of SVR:
http://www.ncbi.nlm.nih.gov/pubmed/22613000

[1swimmer]

I found this interesting as well. Thanx for the post.

[dointime]

Informative article pooh, thanks for posting.
dointime

[Cheesegrater]

An interesting observation.

The compounds used in the Sound-C2 study, a protease inhibitor and a non-nucleotide polymerase inhibitor both give the virus a chance to develop resistance. If the patient's own immune system cannot eradicate these resistant strains which are resistant to the treatment, then breakthrough and treatment failure is certain. If the CC trait offers  an edge to the patient's immune response in fighting the virus, then those with the CC trait would be expected to do better than those without.

With some of the newer combinations that to date, have shown no evidence of viral resistance in vivo, it is being shown that SVR is being attained equally by all CC/CT/TT patients, and that viral breakthrough can be extremely rare. In this case the length of treatment is more important than CC/CT/TT type, but it is possible, if treatment time is cut too short and although UND a small population of virus remains, the  CC trait may show to be a factor.  
I strongly think it is in everybody's best interest to make the treatment duration long enough (more than 12 weeks) to be completely effective.