Hep C Discussion Forum

Members Login
Username 
 
Password 
    Remember Me  
Chatbox
Please log in to join the chat!
Post Info TOPIC: RAVs at NS-5A- the missing bit of the puzzle?
Tig


Admin

Status: Online
Posts: 8366
Date:
RAVs at NS-5A- the missing bit of the puzzle?
Permalink  
 


I found some additional information on viral resistance provided by Merck. It helps to understand how they can impact your treatment success.

What is an NS5A resistance blood test?

The NS5A resistance test is a simple blood test used to identify certain changes to your hep C virus. For patients with hep C genotype 1a infection, the results of this test can help your health care provider in determining your hep C treatment plan. Your health care provider may be able to request the test at the same time other blood work is being done.

Hep C Resistance



__________________

Tig

62 yo GT1A - 5 Mil - A2/F3 - (1996) Intron A - Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 1-4 years!

Hep C FAQ   Lab Ref. Ranges

Signature Line Set Up/Abbreviations   Payment Assistance

 



Guru

Status: Offline
Posts: 791
Date:
Permalink  
 

Great post!

cheers Malcolm



__________________

GT 3 dg. 08-2012 / FibroScan: 5 kPa F1 / FibroTest: F0-1 A1 / SoC TX: PegInt 120mcg+Riba 1000mg UND from w8 relapse EOT+4w
01-2016 Sof+Dac+Riba UND from w8, SVR24!




Guru

Status: Offline
Posts: 5601
Date:
Permalink  
 

Another excellent post, thanks Malcolm, and I absolutely agree with what everyone else has said, we`re very grateful to you as always for taking the time to share your knowledge with us here.

I've made this post a `sticky`, this information is too valuable to let it get `buried`.  smile

 



__________________

Jill 

(68 yo, lives in UK)

Was Gen 3a, 

24wks Peg/Riba, Sep 2010 - Mch 2011

UND @ Wk.4, UND @ EOT, 

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

 

 



Guru

Status: Offline
Posts: 679
Date:
Permalink  
 

Tig56 wrote:

Excellent post, thanks Malcolm! This gives me food for thought. One digested, I'll have a question, maybe! I always appreciate the time and knowledge you share so willingly. Your help makes this forum the best it can be! smile


         I just want to echo what Tig56 said. We are indeed fortunate to have such expertise here. Thank you.



__________________

65 yo, GT1A, , Cirrhosis, F-Scan F4 33.5, TX Naive Harvoni 12 wks

SOT 2/9/16 / ALT 187 AST 114 VL 2.3M.    POSTS

EOT 5/2/16  ALT 35/ AST/25  platlets 126 C/B VL UND

EOT +12 7/26/16  ALT 25 /AST 22/ ALP 83  platlets 129 C/B VL UND

EOT + 24 10/18/16 ALT 27/ AST 20/ ALP 71 platlets 153 C UND

 * SVR *

Tig


Admin

Status: Online
Posts: 8366
Date:
Permalink  
 

Excellent post, thanks Malcolm! This gives me food for thought. Once digested, I'll have a question, maybe! I always appreciate the time and knowledge you share so willingly. Your help makes this forum the best it can be! smile



__________________

Tig

62 yo GT1A - 5 Mil - A2/F3 - (1996) Intron A - Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 1-4 years!

Hep C FAQ   Lab Ref. Ranges

Signature Line Set Up/Abbreviations   Payment Assistance

 



Guru

Status: Offline
Posts: 1515
Date:
Permalink  
 

Hello Malcolm,

I won't pretend to understand everything here but this does help to paint a picture of some of what goes on to cause relapse.

As technical as it is, it's nice to have a portal into the process of how these DAA's and drug combinations work to get us to SVR.

Posts like these are helpful and encouraging in that they allow us, as patients, see that research is ongoing and getting closer all the time to finding that pan-genotypic, magic bullet that will cure every case, every time.

Thank you for sharing this information, it's appreciated!

 

Dave

 



__________________

63yy,HCV,2b,F3-A1, Sof/Riba,12wks Tx   SOT: 1/20/16, HCV-RNA 9,816,581, ALT 56, Hb 14.6

4wk: HCV-RNA <15 Detected, ALT 15, AST 17, Hb 13.6 EOT: 4/12/16, ALT 18 , Hb 12.9176a2f85d05d9c965eafe199f2ba9ba5.jpg SVR Achieved 7/8/16

 



Guru

Status: Offline
Posts: 3393
Date:
Permalink  
 

Hi all,

To eliminate HCV from the world, we need an affordable drug or drug combination with a 100% SVR rate with minimal side effects. We are not there yet, but 80-90% SVR rates are now possible. NS-5A RAVs seem to be the holdup.

I've had some questions about RAV's so I'll do a short post with the latest information. It's a bit technical.

RAVs from the early antiproteases(Victrelis and Incivek) were well documented, with the specific RAVs for each drug and genotype named. These are now not regarded as very significant. Most were not very fit and had a limited survival time.

RAVs from the NS-5A site are very different. We now have a list of these RAVs, for each DAA and for each genotype. There is considerable overlap- for genotype 1a,1b, 2 or 3, many of the same RAVs are found after treatment-failure with either Ledipasvir, Ombitasvir or Daclatasvir. Among the worst of these are RAVs Y93H and L31V/M.

Explanation: The NS-5A complex is an unstable, 447 aminoacid long phospho-protein. It has a terminal helix with three structurally distinct domains. We are only interested in the first 100 aminoacids in Domain 1. This is remarkably preserved across all genotypes. NS-5A blockers bind closely with Domain 1, preventing polymerase activity.  The number for each RAV is the position in the domain and the letters indicate the substitution (caused by the faulty viral replication). Thus Y93H means the amino acid at site 93 has been changed from tyrosine to histidine. For L31V, leucine has been changed to valine.(Sorry, someone asked how these weird names came about). An amino acid substitution as virtually any site can produce a RAV, so there are hundreds or thousands of these RAVs produced. Lets just concentrate on RAV Y93H.

Y93H can be found in Rx-naive patients, and can make up 10-20% of the viral population. This is a very fit mutation, able to enter cells and replicate. It is found in every patient who fails treatment with an NS-5A blocker, irrespective of genotype (some say Geno 1b is less of a problem).  It persists, and can be found 48 months after relapse. It reduces the effectiveness of the DAA by a factor of between 10 and 1000 (or more in Geno 3's). Any monotherapy with an NS-5A blocker has shown a massive selection of Y93H in a matter of days.

The obvious answer is to use a DAA that is effective against Y93H. The newer NS-5A inhibitors, Velpatasvir and Elbasvir seem to have better activity against this RAV, and to decrease the chance of it's selection.  However, if Y93H is found at baseline, Merck suggest treatment should be extended from 12 to 16 weeks and Ribavirin added with it's new drug , Zepatier. The other answer is to use a DAA that blocks a different site and is effective against Y93H.  Sovaldi can be that drug and will work, provided Sovaldi is not blocked by NS-5B RAVs. Merck hope Grazoprevir will do the same, again hoping NS-3 RAVs don't interfere. It is interesting that Ribavirin and Interferon are both highly effective against Y93H, but we don't want to go there.

Essentially, NS-5A RAVs are the reason we cannot achieve a 100% SVR rate. Pre-treatment testing for RAVs has been suggested. Population Sequencing is now pretty cheap, and may be preferable to expensive deep sequencing assays. IL-28B gene testing has been overlooked lately, but it has been shown that those with the TT allele are much more likely to have these RAVs.

If Y93H and the L31 RAVs are present at baseline, treatment may have to be extended and/or Ribavirin added. A nucleoside NS-5B blocker may need to be part of the DAA combo. I'm really looking forward to the new Sovaldi, MK-3682. It should be approved later in 2016.

Does it all matter? Patients may be happy to get their Harvoni/V-Pak or Zetapier and expect an SVR rate of about 90%. It's only when they relapse that questions are asked. This whole article is supposed to explain why that can happen. Hope it makes sense. Cheers.



__________________

Geno 1b, IL28B CT,  x3 prior relapser,  ex-cirrhotic, 74 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 +4 years

Malcolm

Page 1 of 1  sorted by
 
Quick Reply

Please log in to post quick replies.

Legal Disclaimer:

THIS FORUM, IT'S OWNERS, ADMINISTRATORS, MODERATORS AND MEMBERS DO NOT AT ANY TIME GIVE MEDICAL ADVICE AND IN ALL CASES REFER ANYONE HERE TO SEEK APPROPRIATE MEDICAL ADVICE FROM THEIR DOCTOR.