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Hep C Discussion Forum -> On Treatment -> q80K?
Post Info TOPIC: q80K?
jimbob


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RE: q80K?
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Well Isis, I may have to change my previous answer. I've been seaching for some direct connection between q80k and AA's. In the SYNERGY trial Dr. Anita Kohli mentioned AA's as historically having been a difficult group to treat, but I believe she was referring to the INF/RIB based txs. As my triple tx involved INF/RIB, my NP may have been referring to that. I still haven't found direct link between q80K and AA's yet.

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jimbob: 64 y/o, GT 1A, F1-F2, diagnosed 1996. Since 1970. SOT 3.5 mil VL on 3/10/14 with Sov/Rib/Peg for 12 weeks. Tx naive. UND @ week 4,8,12. EOT 6/2/14.
jimbob


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Isiscat2011 wrote:
jimbob wrote:

I'm reminded of a conversation I had with my NP just prior to starting tx. I asked her about the Q80K and her response was (basically, don't worry) "that occurs in predominantly African- Americans". Ive pretty much doubted most of her answers from the beginning and wonder if there is any truth to this?

The Q80K polymorphism is seen primarily in genotype 1a North Americans.  I once read it is found in up to 17% of the Euro 1a population and up to 48% of the US population.

It isn't racially determined but is geographically concentrated.

 Thank you Isis. Told ja I had reason not to trust her....



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jimbob: 64 y/o, GT 1A, F1-F2, diagnosed 1996. Since 1970. SOT 3.5 mil VL on 3/10/14 with Sov/Rib/Peg for 12 weeks. Tx naive. UND @ week 4,8,12. EOT 6/2/14.
Fireman Rob


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Thanks Isiscat,

I have read the cosmos trials but wondered if there has been anything else a little more recent that focuses more on the S/O tx and it's ability to defeat the Q80K mutation specifically.



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Age 33, Male. GT-1 for ten years. Diagnosed in March, 2014.

Treated with Sovaldi/Olysio: SVR 24 on February 16, 2015!
Isiscat2011


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Good summary, Jill.  I also find this fascinating and from a treatment perspective it is very important.  I recently read that ALL TREATMENT FAILURES will be linked to naturally occurring polymorphisms and treatment induced RAVs  (apparently the wild type are easier to kill)  so the key is to find the perfect combo that will defeat them all.  The RAV terminator!!  

It is very complex and I am slowly learning more.  Microbiology doesn't come naturally to me so it is a bit like learning a complex foreign language.   



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Diagnosed in 2011, Incivek triple in 2011, tx discontinued, Genotype 1a, CT, VL 7mill, cirrhosis dx in 2012, age 67, waiting for new DAAs.
Isiscat2011


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jimbob wrote:

I'm reminded of a conversation I had with my NP just prior to starting tx. I asked her about the Q80K and her response was (basically, don't worry) "that occurs in predominantly African- Americans". Ive pretty much doubted most of her answers from the beginning and wonder if there is any truth to this?

The Q80K polymorphism is seen primarily in genotype 1a North Americans.  I once read it is found in up to 17% of the Euro 1a population and up to 48% of the US population.

It isn't racially determined but is geographically concentrated.



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Diagnosed in 2011, Incivek triple in 2011, tx discontinued, Genotype 1a, CT, VL 7mill, cirrhosis dx in 2012, age 67, waiting for new DAAs.
Isiscat2011


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Fireman Rob wrote:

Since this thread began, I've been trying to find formal studies and direct correlations to S/O treatment and effectiveness and haven't turned up much. This topic is very interesting and tx success stats might be changing in the near future? 

Anyone have any luck finding any such and recent studies?

 Hi Rob:  

The S/O combo clinical trials were quite limited.  The phase 2 trial was called COSMOS and that is as far as has been reported.  If you haven't read the COSMO data we can link you up with that information.  

Assuming the S/O combo receives FDA approval (for which it has applied) there will be more information available.  I'm not sure how aggressively the S/O combo approval is now being sought because there are other combos, also awaiting FDA approval, that are pushing the S/O combo to the sidelines. 



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Diagnosed in 2011, Incivek triple in 2011, tx discontinued, Genotype 1a, CT, VL 7mill, cirrhosis dx in 2012, age 67, waiting for new DAAs.
Fireman Rob


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Since this thread began, I've been trying to find formal studies and direct correlations to S/O treatment and effectiveness and haven't turned up much. This topic is very interesting and tx success stats might be changing in the near future? 

Anyone have any luck finding any such and recent studies?



__________________

Age 33, Male. GT-1 for ten years. Diagnosed in March, 2014.

Treated with Sovaldi/Olysio: SVR 24 on February 16, 2015!
jimbob


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I'm reminded of a conversation I had with my NP just prior to starting tx. I asked her about the Q80K and her response was (basically, don't worry) "that occurs in predominantly African- Americans". Ive pretty much doubted most of her answers from the beginning and wonder if there is any truth to this?

__________________

jimbob: 64 y/o, GT 1A, F1-F2, diagnosed 1996. Since 1970. SOT 3.5 mil VL on 3/10/14 with Sov/Rib/Peg for 12 weeks. Tx naive. UND @ week 4,8,12. EOT 6/2/14.
Huey


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That makes since Jill,,,



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  HCV Genotype 3a , now Psot-Tx was on S/riba. First VL was 5.8 mil on 7-5-13 then "und" at 3.8 weeks. 06/13/14 still und. off meds 3 days back on 7/29 Last pill 08/10/14 SVR+4

 
Cinnamon Girl


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Hi there Huey, I`m certainly not an expert but as I understand it new viral mutations (RAV`s) can arise following treatment with the new protease inhibitors and DAA`s, but that`s not the same thing as naturally occuring viral mutations that happen within our bodies and which are not related to treatment drugs.  These are called `polymorphisms` and Q80K is one of those.  These naturally occurring mutations happen quite randomly and so there can be no such thing as a `pure` version of the virus.



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Jill 

(71 yo, lives in UK)

Was Gen 3a, 

24wks Peg Ifn/Riba, Sep 2010 - Mch 2011

UND @ Wk.4, UND @ EOT, 

SVR Nov 2011 --> Still UND @ EOT + 4 yrs.

 

 
Huey


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What I mean by Pure,,,"trying to explain"  my hcv most likely came from a blood transfusion to my mother , then I got it from her.  No one in this scenario has ever had any DAA, There was none at the time.  Compared to someone who has been in trials and now have new mutations caused by the DAA's /  So can i contribute my good reaction to the sovaldi as because my virus was "PURE" and not influenced by any of the failed DAA that proceeded Sovaldi.



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  HCV Genotype 3a , now Psot-Tx was on S/riba. First VL was 5.8 mil on 7-5-13 then "und" at 3.8 weeks. 06/13/14 still und. off meds 3 days back on 7/29 Last pill 08/10/14 SVR+4

 
mallani


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'Knowledge' cannot be stored in RNA. Consequently, when it comes to assembling the 'building blocks' by the NS-5B polymerase, errors are made as the virus has no 'blueprint'. Putting aminoacids in the wrong order leads to the polymorphisms. This is why a vaccine is so elusive. HBV is a DNA virus, so replicates perfectly- this is why an effective vaccine is available.

Here is a link to common RAV's for different DAA's. Another link is to the MK-5172 RAV's.

Testing for significant RAV populations is expensive. Testing for Q80K is being done but when Sovaldi is used, this RAV question seems less important at the moment.

In the Sovaldi Phase 1 Trials, Sovaldi was given as monotherapy for various periods. Viral clearance was remarkable but all patients relapsed. Gilead have never published the list of RAV's found in the relapsers- they mention only one patient with the S282T RAV. Sorry, this probably doesn't interest most Members.

http://www.idsociety.org/uploadedFiles/IDSA/Hepatitis_C/For_IDSA_Members/ForumforCollaborativeHIV-ClinicallyRelevantHCVDrug.pdf

http://www.iapac.org/icvh/presentations/ICVH2013_OA25.pdf



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Geno 1b, IL28B CT,  x3 prior relapser,  ex-cirrhotic, 75 yo, did 48 weeks with Victrelis/Peg./Riba.  VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30  and 48 weeks.  EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR!  Still Undet. at EOT +5 years

Malcolm
Isiscat2011


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Huey wrote:

I have strong suspicions that I got hcv from my mother who had hep non a and non b.   From what your saying , My exposure having came from pure virus stock has no mutations, where as those who 's exposure was from a hybrid source then the mutations are present, at least that is your hypothesize 

  I can tell you that my rapid viral response was vary quick and fast, all in all my treatment has been going vary well, This may be a factor,

I'm no scientist but this sounds wrong to me.  I don't think a "pure virus stock" exists because these mutations occur naturally in our bodies.  These mutations happen because the genetic information of the virus is stored in RNA which is not as stable as DNA.  In other words, the hepc virus is prone to making replication errors which become mutations.  



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Diagnosed in 2011, Incivek triple in 2011, tx discontinued, Genotype 1a, CT, VL 7mill, cirrhosis dx in 2012, age 67, waiting for new DAAs.
Isiscat2011


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Scruffy wrote:

Food for thought

I wonder if any one did any kind of investigation as to the cure rate of ppl who caught hep c long ago before there was any kind of treatment.  Opposed to people who caught it from some one who failed treatment.  Would be interesting to see if the Q80K is present in people that were infected before there was treatment and weren't exposed to it after that.

_________________________________________________________________________________________________________

This is my understanding and I hope Malcolm will correct me if I am mistaken:  Viral mutations occur naturally in our bodies and there are many different types of mutations.  No one produces or has only the original (a/k/a "wild") type virus because there are naturally occurring errors in the replication process. We all are infected by and produce various combinations of the virus.  How long particular mutations survive in our bodies is not definitively known but producing mutations is an ongoing process.  Adding treatment drugs can further complicate the replication process. 

Up to roughly half of Genotype 1as have the Q80K mutation (polymorphism) and that particular mutation is almost exclusive to Genotype 1as.  A person can have the Q80K polymorphism without ever having been treated.     

What baffles me is that we aren't routinely checked for RAVs before treatment because that technology is now available.  Perhaps screening will become more common as more drugs are developed to deal with specific RAVs.  Historically hepc tx has been done in assembly line fashion as opposed to an individualized approach.  When the first PIs came out docs were not even testing for the IL28B type.  Some still aren't, nor are they testing for the various polymorphisms.   Naturally, results will be more hit and miss with that approach.



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Diagnosed in 2011, Incivek triple in 2011, tx discontinued, Genotype 1a, CT, VL 7mill, cirrhosis dx in 2012, age 67, waiting for new DAAs.
mallani


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When we're infected, it will be by a 'wild-type ' virus as the predominant structure, along with hundreds of polymorphisms, each with a slightly different structure.(the quasi-species).

The wild-type structure will determine our Genotype.

As the virus replicates, it makes mistakes so we end up with a family of viral structures. Only the fit viral structures survive.

We are mostly interested in the Non-Structural viral sites called NS-3, NS-5A and NS-5B.

NS-3 is a protease, responsible for cleaving the hepatocyte cytoplasm to make the 'building blocks' for a new virus. The antiprotease drugs like Olysio block this site.

However a single amino-acid substitution (mistake) at NS-3, may mean that Olysio no longer works. Each protein at the site has been numbered eg site 155 at NS-3. Depending on the substitution, these are given letters at each end. So we could end up with a R155K substitution in Genotype 1a, which means Olysio doesn't work. Similarly, at site 80, the Q80K substitution interferes with the blockage of the site.

Many of these substitutions occur naturally. Screening to detect these possible RAV's has been discussed. If the Q80K polymorphism is found, Olysio shouldn't be used as the primary DAA. Patients who fail treatment with Victrelis or Incivek, will have RAV's to these drugs. How long these persist is still uncertain.

RAV's to sites NS-5A may pre-exist or be formed by a single amino-acid substitution. The active site at NS-5B is said to be 'highly preserved', meaning it is difficult to change. It can't be that difficult, otherwise Sovaldi could be used as monotherapy!



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Geno 1b, IL28B CT,  x3 prior relapser,  ex-cirrhotic, 75 yo, did 48 weeks with Victrelis/Peg./Riba.  VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30  and 48 weeks.  EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR!  Still Undet. at EOT +5 years

Malcolm
Huey


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I have strong suspicions that I got hcv from my mother who had hep non a and non b.   From what your saying , My exposure having came from pure virus stock has no mutations, where as those who 's exposure was from a hybrid source then the mutations are present, at least that is your hypothesize 

  I can tell you that my rapid viral response was vary quick and fast, all in all my treatment has been going vary well, This may be a factor,



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  HCV Genotype 3a , now Psot-Tx was on S/riba. First VL was 5.8 mil on 7-5-13 then "und" at 3.8 weeks. 06/13/14 still und. off meds 3 days back on 7/29 Last pill 08/10/14 SVR+4

 
Marypetrecz


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Well that's pretty thought provoking scruffy.



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Scruffy


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Food for thought

 I wonder if any one did any kind of investigation as to the cure rate of ppl who caught hep c long ago before there was any kind of treatment.  Opposed to people who caught it from some one who failed treatment.  Would be interesting to see if the Q80K is present in people that were infected before there was treatment and weren't exposed to it after that.



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Geno 1a null responder 2004 inter/riba   finished incivek,peg/riba 48 weeks May 17th 2014. undetect weeks 4-12-32.  EOT+7 undetect. EOT+24 SVR!!!!! EOT+!YEAR SVR!!!!
Marypetrecz


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Whew.....so glad you two are here with your wealth of knowledge.  It hasn't even occurred to me that I could relapse,  I guess I live in the ignorance is bliss world.....and I'm loving my new found life.  ok...I'm going back to my ignorant state and being cured is in my reach with less than 5 weeks to go.  

are we treated for the q80k before we start?  Or will the newer drugs coming make that obsolete And mute?



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Cinnamon Girl


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Hi Mary, don`t forget that even though 40-50 % of people with Hep C in the US have the Q80K polymorphism that doesn`t mean that many of them will be doing treatment with S/O, or even doing treatment at all.  That figure doesn`t apply to treatment success or failure rates.



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Jill 

(71 yo, lives in UK)

Was Gen 3a, 

24wks Peg Ifn/Riba, Sep 2010 - Mch 2011

UND @ Wk.4, UND @ EOT, 

SVR Nov 2011 --> Still UND @ EOT + 4 yrs.

 

 
Tig


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Mary,

The relapse rate is the smaller of the two. 40-50% of the G1a's in the USA carry the Q80K polymorphism. Typically relapse rates are sub 5% and falling fast.

Tig



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Tig

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Marypetrecz


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So does this mean that 40-50% of people on S/O are going to relapse? Or is it the really small number......like 6%...relapse.......94% cured?



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TazKat


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by the way good pic Malcolm!!!!  smile wish I was that close to some water. that has got to be soothing.. 



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TazKat Genotype 1A null responder x 3 riba & iterferon twice, relapsed from Incivek 2012 with only 12 weeks left to do. stage 4 mild cirrhosis 4/25/2014/ started sovaldi riba & interferon.. finished treatment 7/17/14  results 7/25  cleared..

 

 
TazKat


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I love ya'll...  seriously.. because I had done the incevik & olysio is a cousin to it. this gives me a better feeling. I have now heard of 2 relapses with olysio & solvaldi.  You never stop learning. never stop.. smile   I sure hope my stuff for me has worked. my hepa gave me a thumbs up right at start of treatment.  these last two weeks are problay going to be the most nervous & nauseas time for me. specially with the terrible unwanted & could have been prevented stress that I have had to deal with. (meds & son's crazy wife).. lol   I go for a labs in a little while.. just reg stuff.  Taz



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TazKat Genotype 1A null responder x 3 riba & iterferon twice, relapsed from Incivek 2012 with only 12 weeks left to do. stage 4 mild cirrhosis 4/25/2014/ started sovaldi riba & interferon.. finished treatment 7/17/14  results 7/25  cleared..

 

 
Isiscat2011


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Just adding to what Malcolm stated: In a clinical trial where Sovaldi was used with Olysio the SVR rates were not significantly reduced where the Q80K polymorphism was present.  

Having said that, my Hepatologist recently expressed some concerns about this.  She didn't appear to be 100% convinced that Sovaldi would cancel out the potential to reduce SVR for Q80K carriers using the S/O combo.

So much of the information on the new DAAs is still speculative.



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Diagnosed in 2011, Incivek triple in 2011, tx discontinued, Genotype 1a, CT, VL 7mill, cirrhosis dx in 2012, age 67, waiting for new DAAs.
mallani


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Hi Taz,

Q80K is the name given to a polymorphism of the HepC virus. It is found almost exclusively in Geno 1a, and 40-50% of patients in the USA have this form in the family of viruses.

This form of the virus shows resistance to Olysio, and SVR rates are decreased when Olysio is the primary DAA.  Cheers.



__________________

Geno 1b, IL28B CT,  x3 prior relapser,  ex-cirrhotic, 75 yo, did 48 weeks with Victrelis/Peg./Riba.  VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30  and 48 weeks.  EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR!  Still Undet. at EOT +5 years

Malcolm
TazKat


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what does this mean?



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TazKat Genotype 1A null responder x 3 riba & iterferon twice, relapsed from Incivek 2012 with only 12 weeks left to do. stage 4 mild cirrhosis 4/25/2014/ started sovaldi riba & interferon.. finished treatment 7/17/14  results 7/25  cleared..

 

 
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