I just shared this in another thread and found it very informative. ( For us Hep C nerds) It gives a detailed and might be hard for some to follow, but give it a read and I’m sure it will help you unravel some of the peculiarities with viral resistances.
Thank you, Tig. I really didn't think it could affect it-just wishful thinking on my part! This process would be a little simpler if I didn't have the mutations but I guess it's preferable to finding out now rather than after treatment!
Tig said
Aug 6, 2017
Hi Lindsay,
Malcolm may not reply, he hasn't been active for quite awhile. He really was a wealth of knowledge and contributed here for years.
I don't believe there is any reason to believe the steroid injection would have altered the RAS testing in any way. It could result in a lower ALT, because it is a systemic anti inflammatory medication. Mutations aren't altered or changed in that fashion.
Lindsmatt52 said
Aug 6, 2017
Hi Malcolm- I know you wrote about RAV's a while ago, but hope you're still available to answer questions. I was tested for NS5A resistance and was determined to be resistant to both Harvoni and Zepatier. The mutations detected were: Q30H/Y and H58Q. You seem to have an amazing amount of knowledge about these tests and it is like a foreign language to me, but I do have a question. It is rather specific and may not have a clear answer, but the day before I had the NS5A testing done, I had a steroid shot in my hand by my orthopedist. Could that have affected my blood work the following day in any way? I've tried to research this online but have come up with nothing. Thank you so much!
Matt Chris said
Aug 19, 2015
Hey Tig
Thanks for updating this information regarding RAV's at the NS5A site.
Its a long article on various studies about HCV treatments, but near the end it has some insightful updates on RAV's. Here are some of the condensed points.
Overall, presence of cirrhosis had no impact on achieving SVR12, whereas prior longer treatment duration and presence of baseline RAVs had a clear impact on chance to achieve SVR12. Obviously longer prior treatment duration was associated with higher risk for developing RAVs upon relapse so these two events are somewhat linked. As in treatment-naïve patients with low HCV RNA levels shorter treatment duration of 8 weeks can be selected this would at least imply that in case of virological failure retreatment may be easier as risk of developing RAVs is lower. However, it also becomes apparent that once RAVs are there, future retreatment will be difficult, particularly as NS5A RAVs tend to persist (see studies above). Clinically the next important question then becomes are all RAVs the same or are there some which are more impactful in affecting SVR12 probability? Figure 53 shows SVR12 rates depending on number and type of RAVs from this study. [from Jules: another important question is what will be the effectiveness against this NS5A resistance by new 2nd generation NS5A inhibitors: Merck's MK8408, Abbvie's (ABT-530 and Achillion's ACH-3102 (now belongs to J&J); and for that matter what affect the little NS3 resistance we see will have if any.]
In GT1a patients who have developed virological failure under DAA therapy the proportion of subjects with RAVs in NS3 declined over time, while most subjects with RAVs in NS5A and NS5B had these variants detectable through Post-Treatment Week 48
NS5A variants can persist for >96 weeks post-treatment in subjects who relapse to regimens containing NS5A inhibitor suggesting high fitness of the NS5A RAVs
Number of RAVs after failure to a NS5A inhibitor based therapy matter. In particular detection of the L31M and/or Y93H/N is associated with a higher risk for developing virological failure if retreatment is done with ledipasvir/sofosbuvir. This implies that after all oral DAA therapy including a NS5A inhibitor genotypic resistance testing indeed can be helpful to select the most active and promising retreatment therapy.
matt
dragonfly said
Aug 19, 2015
I'm sorry, looking back over your thread - I may have misunderstood your query. I apologise for any confusion.
Nirmalee
dragonfly said
Aug 19, 2015
Without any medical knowledge whatsoever I would reiterate that diet has very little to do with SVR on the new drugs. However a good diet will alleviate the SX. I am coming to this from a different angle never being a big eater - I just ate what I fancied supplemented by lots of veggie juice. Obviously a low salt regime is recommended it you have fluid on your belly. I understand from talks with my nurse that the protease inhibitor drugs activate the 'stop' codon on the molecular structure of the virus but again Malcolm is more qualified to deliver this kind of information. But if this is so, your diet has very little to do with SVR unless you wash down your breakfast with a beer!
Good luck,
Nirmalee
Tig said
Aug 18, 2015
I was looking up information regarding RAV's, post DAA treatment (failures) and came across this EASL article. It's a long read, but full of different information on just about everything. Toward the end of it (Fig 46), there is mention of various RAV's and how long they have been present post tx. Longer than I realized, particularly the NS5A's. Hard to say what retreatment holds for some. The newest of the DAA's in the pipeline seem to hold a lot of hope. The summary is informational. These new protocols hold a lot of hope, as well as a lot of unknowns. As we like to say, we are all pioneers at some point in our treatment process. What we do today, makes tomorrow easier for someone else. Keep up the good fight....
http://www.natap.org/2015/EASL/EASL_155.htm
Rubye said
Jan 2, 2015
It does indeed help Matt. Thank you.
Matt Chris said
Jan 2, 2015
Hello Ruby
My assertion was that I would hope that some day we could restrain the Rav's that we get via treatment or have already by discovering the factors that we can control. I included genetics, diet, stress, peptides, or drugs as possible areas that might be included in the search, its was strickly conjecture or hypothesis on my part not a causal conclusion.
Matt Chris wrote:
My wish is to find out what deficiencies within our body, be it genetics or other factors that we can control via diet, stress, peptides or drugs that can restrain the polymorphism process.
I hope this helps
matt
Rubye said
Jan 2, 2015
Just to clarify Matt, I am easily confused. So if one paragraph says rav's and the other says diet, I think the two must be connected. Duh. Perhaps my mind will come back after tx. :)
Thanks Malcolm. I am so stumbling around in this area, but I appreciate everything you guys have to say. At least I have a semblance of an understanding of what's going on. Maybe not. Still, I find it interesting.
Just one last question. How much do you think q80k affects svr odds with regard to tx with Sovaldi and Olysio only?
mallani said
Jan 2, 2015
Hi Ruby,
Just to clarify. A 'RAV'(Resistance Associated Variant) is just the virus with a slightly chemical structure. This particular structure makes it resistant to the action of one of the DAA's. These 'RAVs' may be found naturally as part of the family associated with the wild-type virus. They become of interest when they take over as the predominant form, as the DAA may no longer work.
Each RAV is specific to a certain DAA and genotype. The example you gave, Q80K, is a mutation at the antiprotease site (NS-3A) and is only found in Genotype 1a.
There are no 'RAVs' to Interferon. Although the action is still poorly understood, Interferon is effective against ALL wild-type virus and their mutations ( in certain patients, and when used for long enough).
Having the Q80K RAV at baseline makes Olysio less effective. These patients need to rely on Interferon and Ribavirin to look after this RAV. This RAV also develops when Olysio is used. Patients that are not Interferon sensitive (eg TT's at IL28B) are unlikely to do well.
Diet has nothing to do with RAVs.
Sovaldi obviously causes RAVs, otherwise it would have a 100% SVR rate used on its own. These are usually short-lived and only one, S282T, is known to persist. Basically, RAVs from Sovaldi should be ignored, so Sovaldi can be re-used. Sovaldi has been shown to be effective against all known RAVs from other DAAs. Hope this helps.
Matt Chris said
Jan 2, 2015
Hello Ruby
Just to clarify I have not indicated that either baseline resistance or resistance after treatment is due to any sort of diet. Resistance or Rav's have never been linked to a particular type of diet. Rav's typically develop due to exposure to DAA's
matt
Rubye said
Jan 2, 2015
Hi Malcolm,
This is very interesting and thank you for posting it here. It makes me wonder though.
If the q80k variant is a RAV with regard to interferon, then why is it not a RAV with Olysio or Harvoni? I say this because I read something about q80k being inconsequential with Olysio. And if a person is treatment naive then how do variants come about in the first place? New exposure to the virus?
From what Matt says, it sounds like perhaps the q80k mutation could have possibly come about from something as simple as diet. I'm talking about q80k in particular because I have it.
I think "they" say if you've treated with Sovaldi, then you can't do the Viekera Pak because the Sovaldi causes a resistance to one of the components in the pak. Is that because the Sovaldi may have changed the virus to a RAV.
Yes, I really don't know what I'm talking about here but I'm trying to learn. :)
Matt Chris said
Jan 1, 2015
Hey Malcolm
This whole Rav's issue is so hard to find solid well founded certainties. For example one of the trials (Electron 2) mentioned that baseline labs show that 11 patients already had resistance issues at Y93H found at the NS5A address but 10 of the 11 achieved SVR anyway.
My wish is to find out what deficiencies within our body, be it genetics or other factors that we can control via diet, stress, peptides or drugs that can restrain the polymorphism process.
This link shows what I am referencing - http://www.natap.org/2014/AASLD/AASLD_13.htm
matt
pl1952 said
Jan 1, 2015
Thanks Malcom...I'll will certainly ask my doctor about this....Thank you!
mallani said
Jan 1, 2015
Hi pl1952,
I'm trying to understand treatment failures, and whether different treatments using the same type of DAA will be effective.
In particular, if you relapse after the Viekira, will that affect your chances of retreatment with Harvoni. Probably not, but there's not a lot available about resistance to the NS-5A blockers. This article suggests the RAV's may persist for at least 48 weeks:
I think that as long as Sovaldi is included, these RAVs may not be significant. Cheers.
pl1952 said
Jan 1, 2015
Hi Malcolm, I'm in the <1%....only because Matt mentioned NS-5a in his answer to me concerning Viekira. I have no idea what that is and I'll be honest, I read what you wrote about 5 times, and I just don't understand it. Can you dumb it down considerably so I can try to understand it, if it does in fact pertain to my question about using Abbvie's Viekira Pak..Thanks!
mallani said
Jan 1, 2015
Hi all,
I'm sitting on the boat, it's 36C, steamy, with not a breath of wind. For once, I wish I was in the Northern Hemisphere.<1% of Forum members will be interested in this, so be warned.
I've been wondering about retreatment options after relapse after previous NS-5A treatment (Daclatasvir, Ledipasvir and Ombitasvir). Little data has been released.
Obviously RAV's to the NS-5A site is the question. How long do they last, is there cross-resistance etc.
Looking at the structure of NS-5A, it's a complex phosphoprotein containing 447 amino acids. It is divided into 3 distinct domains, and it is Domain 1 (amino acids 33 to 213) that is of most interest. Although Daclatasvir is the only DAA that has been studied in detail (that I can find), the broad statement is made that the other NS-5A blockers have the same results. Significant RAV's develop at amino acid sites 31 and 93. These interfere with the blocking action of Daclatasvir. The most significant are called L31V and Y93H. Remember the letters just stand for the amino acid substitution: L = leucine, V = valine, Y = tyrosine and H = histidine. Other RAVs are Y93N (asparagine) and L31M(methionine).
From what I can find, there appears to be little difference between Geno 1a and Geno 1b. Looking at the structure of the various NS-5A blockers, they all appear to block the same region of Domain 1, so RAV's should be common to all drugs currently used. I cannot find any documentation about time frame of persistence of these RAVs. Hopefully it's short.
For those who are interested, here's a link to some research:
I just shared this in another thread and found it very informative. ( For us Hep C nerds) It gives a detailed and might be hard for some to follow, but give it a read and I’m sure it will help you unravel some of the peculiarities with viral resistances.
HCV Resistance Primer
Thank you, Tig. I really didn't think it could affect it-just wishful thinking on my part!
This process would be a little simpler if I didn't have the mutations but I guess it's preferable to finding out now rather than after treatment!
Hi Lindsay,
Malcolm may not reply, he hasn't been active for quite awhile. He really was a wealth of knowledge and contributed here for years.
I don't believe there is any reason to believe the steroid injection would have altered the RAS testing in any way. It could result in a lower ALT, because it is a systemic anti inflammatory medication. Mutations aren't altered or changed in that fashion.
Hi Malcolm- I know you wrote about RAV's a while ago, but hope you're still available to answer questions. I was tested for NS5A resistance and was determined to be resistant to both Harvoni and Zepatier. The mutations detected were: Q30H/Y and H58Q. You seem to have an amazing amount of knowledge about these tests and it is like a foreign language to me, but I do have a question. It is rather specific and may not have a clear answer, but the day before I had the NS5A testing done, I had a steroid shot in my hand by my orthopedist. Could that have affected my blood work the following day in any way? I've tried to research this online but have come up with nothing. Thank you so much!
Hey Tig
Thanks for updating this information regarding RAV's at the NS5A site.
Its a long article on various studies about HCV treatments, but near the end it has some insightful updates on RAV's. Here are some of the condensed points.
Overall, presence of cirrhosis had no impact on achieving SVR12, whereas prior longer treatment duration and presence of baseline RAVs had a clear impact on chance to achieve SVR12. Obviously longer prior treatment duration was associated with higher risk for developing RAVs upon relapse so these two events are somewhat linked. As in treatment-naïve patients with low HCV RNA levels shorter treatment duration of 8 weeks can be selected this would at least imply that in case of virological failure retreatment may be easier as risk of developing RAVs is lower. However, it also becomes apparent that once RAVs are there, future retreatment will be difficult, particularly as NS5A RAVs tend to persist (see studies above). Clinically the next important question then becomes are all RAVs the same or are there some which are more impactful in affecting SVR12 probability? Figure 53 shows SVR12 rates depending on number and type of RAVs from this study. [from Jules: another important question is what will be the effectiveness against this NS5A resistance by new 2nd generation NS5A inhibitors: Merck's MK8408, Abbvie's (ABT-530 and Achillion's ACH-3102 (now belongs to J&J); and for that matter what affect the little NS3 resistance we see will have if any.]
In GT1a patients who have developed virological failure under DAA therapy the proportion of subjects with RAVs in NS3 declined over time, while most subjects with RAVs in NS5A and NS5B had these variants detectable through Post-Treatment Week 48
NS5A variants can persist for >96 weeks post-treatment in subjects who relapse to regimens containing NS5A inhibitor suggesting high fitness of the NS5A RAVs
Number of RAVs after failure to a NS5A inhibitor based therapy matter. In particular detection of the L31M and/or Y93H/N is associated with a higher risk for developing virological failure if retreatment is done with ledipasvir/sofosbuvir. This implies that after all oral DAA therapy including a NS5A inhibitor genotypic resistance testing indeed can be helpful to select the most active and promising retreatment therapy.
matt
I'm sorry, looking back over your thread - I may have misunderstood your query. I apologise for any confusion.
Nirmalee
Without any medical knowledge whatsoever I would reiterate that diet has very little to do with SVR on the new drugs. However a good diet will alleviate the SX. I am coming to this from a different angle never being a big eater - I just ate what I fancied supplemented by lots of veggie juice. Obviously a low salt regime is recommended it you have fluid on your belly. I understand from talks with my nurse that the protease inhibitor drugs activate the 'stop' codon on the molecular structure of the virus but again Malcolm is more qualified to deliver this kind of information. But if this is so, your diet has very little to do with SVR unless you wash down your breakfast with a beer!
Good luck,
Nirmalee
I was looking up information regarding RAV's, post DAA treatment (failures) and came across this EASL article. It's a long read, but full of different information on just about everything. Toward the end of it (Fig 46), there is mention of various RAV's and how long they have been present post tx. Longer than I realized, particularly the NS5A's. Hard to say what retreatment holds for some. The newest of the DAA's in the pipeline seem to hold a lot of hope. The summary is informational. These new protocols hold a lot of hope, as well as a lot of unknowns. As we like to say, we are all pioneers at some point in our treatment process. What we do today, makes tomorrow easier for someone else. Keep up the good fight....
http://www.natap.org/2015/EASL/EASL_155.htm
It does indeed help Matt. Thank you.
I hope this helps
matt
Just to clarify Matt, I am easily confused. So if one paragraph says rav's and the other says diet, I think the two must be connected. Duh. Perhaps my mind will come back after tx. :)
Thanks Malcolm. I am so stumbling around in this area, but I appreciate everything you guys have to say. At least I have a semblance of an understanding of what's going on. Maybe not. Still, I find it interesting.
Just one last question. How much do you think q80k affects svr odds with regard to tx with Sovaldi and Olysio only?
Hi Ruby,
Just to clarify. A 'RAV'(Resistance Associated Variant) is just the virus with a slightly chemical structure. This particular structure makes it resistant to the action of one of the DAA's. These 'RAVs' may be found naturally as part of the family associated with the wild-type virus. They become of interest when they take over as the predominant form, as the DAA may no longer work.
Each RAV is specific to a certain DAA and genotype. The example you gave, Q80K, is a mutation at the antiprotease site (NS-3A) and is only found in Genotype 1a.
There are no 'RAVs' to Interferon. Although the action is still poorly understood, Interferon is effective against ALL wild-type virus and their mutations ( in certain patients, and when used for long enough).
Having the Q80K RAV at baseline makes Olysio less effective. These patients need to rely on Interferon and Ribavirin to look after this RAV. This RAV also develops when Olysio is used. Patients that are not Interferon sensitive (eg TT's at IL28B) are unlikely to do well.
Diet has nothing to do with RAVs.
Sovaldi obviously causes RAVs, otherwise it would have a 100% SVR rate used on its own. These are usually short-lived and only one, S282T, is known to persist. Basically, RAVs from Sovaldi should be ignored, so Sovaldi can be re-used. Sovaldi has been shown to be effective against all known RAVs from other DAAs. Hope this helps.
Hello Ruby
Just to clarify I have not indicated that either baseline resistance or resistance after treatment is due to any sort of diet. Resistance or Rav's have never been linked to a particular type of diet. Rav's typically develop due to exposure to DAA's
matt
Hi Malcolm,
This is very interesting and thank you for posting it here. It makes me wonder though.
If the q80k variant is a RAV with regard to interferon, then why is it not a RAV with Olysio or Harvoni? I say this because I read something about q80k being inconsequential with Olysio. And if a person is treatment naive then how do variants come about in the first place? New exposure to the virus?
From what Matt says, it sounds like perhaps the q80k mutation could have possibly come about from something as simple as diet. I'm talking about q80k in particular because I have it.
I think "they" say if you've treated with Sovaldi, then you can't do the Viekera Pak because the Sovaldi causes a resistance to one of the components in the pak. Is that because the Sovaldi may have changed the virus to a RAV.
Yes, I really don't know what I'm talking about here but I'm trying to learn. :)
Hey Malcolm
This whole Rav's issue is so hard to find solid well founded certainties. For example one of the trials (Electron 2) mentioned that baseline labs show that 11 patients already had resistance issues at Y93H found at the NS5A address but 10 of the 11 achieved SVR anyway.
My wish is to find out what deficiencies within our body, be it genetics or other factors that we can control via diet, stress, peptides or drugs that can restrain the polymorphism process.
This link shows what I am referencing - http://www.natap.org/2014/AASLD/AASLD_13.htm
matt
Thanks Malcom...I'll will certainly ask my doctor about this....Thank you!
Hi pl1952,
I'm trying to understand treatment failures, and whether different treatments using the same type of DAA will be effective.
In particular, if you relapse after the Viekira, will that affect your chances of retreatment with Harvoni. Probably not, but there's not a lot available about resistance to the NS-5A blockers. This article suggests the RAV's may persist for at least 48 weeks:
http://hepatitiscresearchandnewsupdates.blogspot.com.au/2013/07/selection-of-resistantassociated.html
I think that as long as Sovaldi is included, these RAVs may not be significant. Cheers.
Hi Malcolm, I'm in the <1%....only because Matt mentioned NS-5a in his answer to me concerning Viekira. I have no idea what that is and I'll be honest, I read what you wrote about 5 times, and I just don't understand it. Can you dumb it down considerably so I can try to understand it, if it does in fact pertain to my question about using Abbvie's Viekira Pak..Thanks!
Hi all,
I'm sitting on the boat, it's 36C, steamy, with not a breath of wind. For once, I wish I was in the Northern Hemisphere.<1% of Forum members will be interested in this, so be warned.
I've been wondering about retreatment options after relapse after previous NS-5A treatment (Daclatasvir, Ledipasvir and Ombitasvir). Little data has been released.
Obviously RAV's to the NS-5A site is the question. How long do they last, is there cross-resistance etc.
Looking at the structure of NS-5A, it's a complex phosphoprotein containing 447 amino acids. It is divided into 3 distinct domains, and it is Domain 1 (amino acids 33 to 213) that is of most interest. Although Daclatasvir is the only DAA that has been studied in detail (that I can find), the broad statement is made that the other NS-5A blockers have the same results. Significant RAV's develop at amino acid sites 31 and 93. These interfere with the blocking action of Daclatasvir. The most significant are called L31V and Y93H. Remember the letters just stand for the amino acid substitution: L = leucine, V = valine, Y = tyrosine and H = histidine. Other RAVs are Y93N (asparagine) and L31M(methionine).
From what I can find, there appears to be little difference between Geno 1a and Geno 1b. Looking at the structure of the various NS-5A blockers, they all appear to block the same region of Domain 1, so RAV's should be common to all drugs currently used. I cannot find any documentation about time frame of persistence of these RAVs. Hopefully it's short.
For those who are interested, here's a link to some research:
http://www.nature.com/srep/2014/140423/srep04765/full/srep04765.html