Aa
Think you could add pi's later in treatment?
I have often wondered if a person was already doing SOC and the pi's became availible could you then throw them into the mix? I know a lot of people are putting off treatment waiting on the pi's but if you could add it later it might make since to go ahead and start early.
The studies I know of have been using the PI's early on in tx. I think it goes back to the people that have had the most sucess with attaining SVR were those that cleared the virus fast. Hence the 4 week test and RVR is a good predictor of SVR
it is propably not ideal , but PIs sometimes are offered to placebo arms later on in trials
so i guess it can still be beneficial.
so i guess it can still be beneficial.
Well, to state the obvious, you'd have to have a date for the PI availability in order to time it right. But I wouldn't like to have a tx plan with a date in it that I couldn't trust.
However, in general I've wondered too how it would work out to do the PI in the last 4 weeks of tx when the virus is either already dead or on it's last legs, just to make sure and finish it off. That might work well for some potential relapsers. If I were txing with SOC and a PI became available I'd certainly ask my doc to add it to my mix.
dointime
However, in general I've wondered too how it would work out to do the PI in the last 4 weeks of tx when the virus is either already dead or on it's last legs, just to make sure and finish it off. That might work well for some potential relapsers. If I were txing with SOC and a PI became available I'd certainly ask my doc to add it to my mix.
dointime
No point in adding a PI if the virus is already undetectable. They interfere with viral replication. No virus replicating, side effects for nothing. I've heard of people in rollovers (trials where you are allowed to add the PI after 24 weeks or so if you've not gone undetectable while in the straight SOC placebo trial) making SVR with the addition of the PI and also others who did not SVR. The interferon is still the big gun in the picture and if you've already achieved UD early enough with the interferon there's no point exposing yourself to more side effects and the possibility that you'd become resistant to a PI. Once you've failed with them the current ones won't work for you again ever. If you aren't succeeding with SOC and have to add the PI late it would be better to stop, recover and then start fresh with SOC and the PI added at the proper time.
That is a great question! As a stage 4 relapser who is waiting for another go, this approach is more appealing than waiting till 2011/12 as my liver and overall health deteriorate.
Newleaf hits the nail right on the head.
As the other thread "http://www.medhelp.org/posts/Hepatitis-C/Bad-news-re-Vertexs-Telaprevir-and-all-the-PIs/show/1235495"; shows, HCV's known degree to be highly mutable make their effectivness limited.
Initial test were to use them as stand alones which failed miserably. Then tried in combo and showed some promise. However, because of limited period of their effectiveness due to viral mutation, the real benefit was seen by adding them at the beginning of TX.
The thought appears to be to couple them with Riba to double team the virus early in TX so that Interferon can quickly gain the upper hand. If the new meds should become ineffective due to viral mutation, hopefully enough ground has been gained over it's foothold to increase odds of attaining UND.
As the other thread "http://www.medhelp.org/posts/Hepatitis-C/Bad-news-re-Vertexs-Telaprevir-and-all-the-PIs/show/1235495"; shows, HCV's known degree to be highly mutable make their effectivness limited.
Initial test were to use them as stand alones which failed miserably. Then tried in combo and showed some promise. However, because of limited period of their effectiveness due to viral mutation, the real benefit was seen by adding them at the beginning of TX.
The thought appears to be to couple them with Riba to double team the virus early in TX so that Interferon can quickly gain the upper hand. If the new meds should become ineffective due to viral mutation, hopefully enough ground has been gained over it's foothold to increase odds of attaining UND.
I don't think it makes any sense - if the idea is to stop replication and add a layer of "hit it fast and hit it hard" to be UND by week 2 or 4 (which we all know makes all the difference) to use them later on just doesn't make sense. You'd still have to have been UND by 12 or 24 already....then do the 48 after all.....I don't know it just seems senseless to add it after you are already UND.
But....
As any relapser knows, undetectable does not mean virus-free.
To say that adding a PI would do no good later (even upon undetectable) might not be accurate. If there is no replication going on when someone reaches undetectatble, then why does treatment continue after achieving it?
As any relapser knows, undetectable does not mean virus-free.
To say that adding a PI would do no good later (even upon undetectable) might not be accurate. If there is no replication going on when someone reaches undetectatble, then why does treatment continue after achieving it?
Trials have showed better results starting a PI after a four week lead-in not at the beginning of tx.
very good question - I've been wondering this for a while. I may not be able to wait for the 1st gen PIs for ins. and other reasons and so will be asking my hepa next Monday whether he would be willing to add a PI after approval if I start on NTZ+SOC sometime before the end of this year. I believe the honest answer here is no one has a clue - there is zero data.
However a couple of points indicate the strategy may be a reasonable way to cut relapse-risk and/or shorten tx. At UND we know there is still a large population of cells teeming with healthy wild-type virus ready to bounce back. The goal of the long-winded search and destroy that goes on from UND to EOT is basically to eliminate the holdovers. Give up too quickly and we know what happens.
PIs are small molecules that can easily diffuse and will shut down viral production in every cell they enter (with the exception of course of viral strains blessed with the right resistant mutations). If there's a reason why this process should not be as, if not more, effective than SOC in eliminating the remaining virus I'd like to hear it.
BTW, have to disagree with newleaf's comment "Once you've failed with them the current ones won't work for you again ever." First I'm really not sure there is any much/any data on PI re-tx at this point. Also we do know, from data reported at EASL 2010 that the PI-resistant mutations are less-fit and eventually are replaced by PI-sensitive wild-type. See the graph below:
http://www.kenes.com/easl2010/Posters/Abstract16.htm
PIs will always have Uzi-like effectiveness on wild type, and the above shows the relative proportion of PI-resistant virus decreases over time. On the other hand, to breed a PI-resistant superstrain by multiple failed PI txs is clearly not a good idea.
However a couple of points indicate the strategy may be a reasonable way to cut relapse-risk and/or shorten tx. At UND we know there is still a large population of cells teeming with healthy wild-type virus ready to bounce back. The goal of the long-winded search and destroy that goes on from UND to EOT is basically to eliminate the holdovers. Give up too quickly and we know what happens.
PIs are small molecules that can easily diffuse and will shut down viral production in every cell they enter (with the exception of course of viral strains blessed with the right resistant mutations). If there's a reason why this process should not be as, if not more, effective than SOC in eliminating the remaining virus I'd like to hear it.
BTW, have to disagree with newleaf's comment "Once you've failed with them the current ones won't work for you again ever." First I'm really not sure there is any much/any data on PI re-tx at this point. Also we do know, from data reported at EASL 2010 that the PI-resistant mutations are less-fit and eventually are replaced by PI-sensitive wild-type. See the graph below:
http://www.kenes.com/easl2010/Posters/Abstract16.htm
PIs will always have Uzi-like effectiveness on wild type, and the above shows the relative proportion of PI-resistant virus decreases over time. On the other hand, to breed a PI-resistant superstrain by multiple failed PI txs is clearly not a good idea.
I think that this is an important question for the forum, and thanks to Upbeat for asking it, because there will be a lot of people in the middle of tx when the first PI hits the street who will be asking themselves the same question.
We have no data on using a PI later on in tx, but we do know certain things:-
-
UND does not mean virus free, or there would be no relapsers.
-
Pre-existing mutations are less fit than wild type virus, therefore they are likely to be the first to die with SOC. This was surmised by the success in the boceprevir trials of tx'ing with SOC alone for the first 4 weeks then adding the drug. The increased SVR rate from this strategy was thought to be due to having overcome pre-existing resistant mutations before starting the boceprevir.
-
There is a wealth of data on the probability of SVR with SOC alone, as measured at various stages, ie. RVR and EVR.
So looking at various stages of TX with SOC alone:-
-
People who get RVR are probably going to go on to SVR without any help from a PI.
-
People for whom SOC is not working, ie. non-responders and breakthroughs who are not UND by week 12, should probably give it up and start again another time using a PI at the beginning of tx in the proper tested way. Either that or they might have the option of 72 weeks of SOC.
-
I see the grey area as being people who have not got RVR but go UND before week 12, ie. people who have a greater than 10% probability of relapse depending on what week they go UND. I mean people who stay UND all the way after week 12 to EOT and then the virus comes back in the following 6 months.
I think that for these people there is a good argument for adding the PI to the last month of tx. By then we know that the pre-existing resistant mutations are most likely to be gone already. We know that the stragglers which would be responsible for a relapse have been worn down if not completely banished and that they are the strongest wild type. We know that the PI's cut down the wild type virus like a knife through butter.
Against this is the possibility of developing PI resistance, a small but real possibility. There's also the addition of extra sides just when the person is dragging through the last of tx, so definitely a consideration, especially if the sides are bad already and there's a risk of causing the whole tx to be discontinued.
So all this to be weighed up with the doc - if the doc is even willing to use a PI in a non-prescribed way. So that's something to discuss before even starting SOC tx. But I think that there's a definite window of opportunity in use of a PI at the end of tx for some people.
dointime
We have no data on using a PI later on in tx, but we do know certain things:-
-
UND does not mean virus free, or there would be no relapsers.
-
Pre-existing mutations are less fit than wild type virus, therefore they are likely to be the first to die with SOC. This was surmised by the success in the boceprevir trials of tx'ing with SOC alone for the first 4 weeks then adding the drug. The increased SVR rate from this strategy was thought to be due to having overcome pre-existing resistant mutations before starting the boceprevir.
-
There is a wealth of data on the probability of SVR with SOC alone, as measured at various stages, ie. RVR and EVR.
So looking at various stages of TX with SOC alone:-
-
People who get RVR are probably going to go on to SVR without any help from a PI.
-
People for whom SOC is not working, ie. non-responders and breakthroughs who are not UND by week 12, should probably give it up and start again another time using a PI at the beginning of tx in the proper tested way. Either that or they might have the option of 72 weeks of SOC.
-
I see the grey area as being people who have not got RVR but go UND before week 12, ie. people who have a greater than 10% probability of relapse depending on what week they go UND. I mean people who stay UND all the way after week 12 to EOT and then the virus comes back in the following 6 months.
I think that for these people there is a good argument for adding the PI to the last month of tx. By then we know that the pre-existing resistant mutations are most likely to be gone already. We know that the stragglers which would be responsible for a relapse have been worn down if not completely banished and that they are the strongest wild type. We know that the PI's cut down the wild type virus like a knife through butter.
Against this is the possibility of developing PI resistance, a small but real possibility. There's also the addition of extra sides just when the person is dragging through the last of tx, so definitely a consideration, especially if the sides are bad already and there's a risk of causing the whole tx to be discontinued.
So all this to be weighed up with the doc - if the doc is even willing to use a PI in a non-prescribed way. So that's something to discuss before even starting SOC tx. But I think that there's a definite window of opportunity in use of a PI at the end of tx for some people.
dointime
interesting reading - thanks for posting. My proposal is to follow the alinia protocol report at easl 2010
http://www.kenes.com/easl2010/Posters/Abstract130.htm
for the first 24w and then add a PI for 12w, hopefully boce but o/w tela. for a total of 36w of fun. If there are delays and neither is approved in time I would just finish out the standard 48w on soc. Not at all sure he'll agree but will post back the outcome.
I'm not sure one's ifn-response need be strong enough to reach und by w12 before benefiting from a PI however. GB is a great example of someone with limited ifn response who nevertheless sailed happily to SVR. Something around a 0.8 log drop by w4 may be the measure of how much ifn is needed to reliably mop up the mutiny.
This question may also come up for known non-responders who dive in anyway after boce/tela approval because there's no other choice and may have the option to add an NS5B/NS5A inhibitor during their tx.
http://www.kenes.com/easl2010/Posters/Abstract130.htm
for the first 24w and then add a PI for 12w, hopefully boce but o/w tela. for a total of 36w of fun. If there are delays and neither is approved in time I would just finish out the standard 48w on soc. Not at all sure he'll agree but will post back the outcome.
I'm not sure one's ifn-response need be strong enough to reach und by w12 before benefiting from a PI however. GB is a great example of someone with limited ifn response who nevertheless sailed happily to SVR. Something around a 0.8 log drop by w4 may be the measure of how much ifn is needed to reliably mop up the mutiny.
This question may also come up for known non-responders who dive in anyway after boce/tela approval because there's no other choice and may have the option to add an NS5B/NS5A inhibitor during their tx.
so I got an OK from my Drs to follow through with the above plan. Will start tx around Sept/Oct per the soc/high RBV/NTZ protocol above and add one of the two PIs sometime in spring as (and if!) they become available. I was pleasantly surprised one of them agreed to prescribe the NTZ as I had been hatching all sorts of of unlikely plan-B schemes - though there is a good chance the ins co won't pay for it as off label. I'm feeling better already!
The Dr. at Romark emailed tons of data to Joe's Insurance Co. and that is what persauded them to cover the Alinia. Their pharm Dr. was Dr. Jackson . It has been at least a year and a half ago since I talked to him so I don't know if he is still there or not. He was a very nice person.
Ev
Ev
If I understand correctly, you will do SOC with Alinia and add the PI if approved by spring?
If not approved say until late 2011 you will proceed with SOC and add the PI's at a later date? If the PI's aren't released will you proceed with SOC for 72 wks?
Are you basing this on liver damage and unable to wait for the release of the PI's. The reason I ask is because I'm stuck between a rock and a hard place myself in deciding what to do.
Trin
If not approved say until late 2011 you will proceed with SOC and add the PI's at a later date? If the PI's aren't released will you proceed with SOC for 72 wks?
Are you basing this on liver damage and unable to wait for the release of the PI's. The reason I ask is because I'm stuck between a rock and a hard place myself in deciding what to do.
Trin
evangelin: thanks, I won't find out about the ins. co issue until later in the summer but will PM you if I need ammunition. Unfortunately all that's available at this point is clinical trial data (and not much of it) so if they decide to deny it might be hard to force the issue.
trinity: though I was planning to wait for PI approval (and possibly for protease/polymerase approval in '14) increasing symptoms have forced an attitude adjustment - the days not overwhelmed by fatigue are getting further apart. The plan is to start with dosing as set out in the Alinia trial above. When to stop/add PI will depend on approval date and the vl curve. Last time I was an EVR (but possibly not a cEVR) and I'm assuming that will be the same. If I start Oct.15, a 48w tx would end Sept 16. Say approval happens by June, I would add the PI for the last 3 months. If approval is (hopefully) earlier the 12w PI would lead to a shorter total tx. This also depends in part on what the final tela/boce numbers say. It's definitely jumping the gun and has no support from existing data so I wouldn't recommend it unless forced. However, I haven't seen anything that suggests inhibiting replication won't be as effective at the later stages of tx as it as the outset.
trinity: though I was planning to wait for PI approval (and possibly for protease/polymerase approval in '14) increasing symptoms have forced an attitude adjustment - the days not overwhelmed by fatigue are getting further apart. The plan is to start with dosing as set out in the Alinia trial above. When to stop/add PI will depend on approval date and the vl curve. Last time I was an EVR (but possibly not a cEVR) and I'm assuming that will be the same. If I start Oct.15, a 48w tx would end Sept 16. Say approval happens by June, I would add the PI for the last 3 months. If approval is (hopefully) earlier the 12w PI would lead to a shorter total tx. This also depends in part on what the final tela/boce numbers say. It's definitely jumping the gun and has no support from existing data so I wouldn't recommend it unless forced. However, I haven't seen anything that suggests inhibiting replication won't be as effective at the later stages of tx as it as the outset.
i have ingested a fair share of NTZ. Was declined R7128 trial because of it.
As a geno 4 I was in direct contact with Dr. Emmet
Keefe @ Romark who was gracious enough to share the most detailed trial info I had
seen to that point. I decided to give the monotrial a go so I ended up predosing Alinia
for about 6 month.
Since hind sight is always 20/20 knowing what I know today I would have added
SOC after 5 weeks predosing Alinia. My ALT went down to 29 and AST 14 perfect
time to get out that heavy artillary !
Despite Alinia my viral load went back to its highest ever including ALT 75 in mid March
when I decided to treat.
Here is what I would do today:
Start Alinia for 3 weeks , than add hi dose Riba (as high as your HgB can tolerate)
than after two weeks of that , I would double dose my first Peg.shot. and keep going
on that riba according to HgB.
For prep check IR , BMI , Vit D
b
As a geno 4 I was in direct contact with Dr. Emmet
Keefe @ Romark who was gracious enough to share the most detailed trial info I had
seen to that point. I decided to give the monotrial a go so I ended up predosing Alinia
for about 6 month.
Since hind sight is always 20/20 knowing what I know today I would have added
SOC after 5 weeks predosing Alinia. My ALT went down to 29 and AST 14 perfect
time to get out that heavy artillary !
Despite Alinia my viral load went back to its highest ever including ALT 75 in mid March
when I decided to treat.
Here is what I would do today:
Start Alinia for 3 weeks , than add hi dose Riba (as high as your HgB can tolerate)
than after two weeks of that , I would double dose my first Peg.shot. and keep going
on that riba according to HgB.
For prep check IR , BMI , Vit D
b
Great discussion. Although I have tried to keep abreast of the PI progress and think this time next year I will be treating if the PI's are available, I have not done my homework on Alina and it looks like I better start.
Willing, I am sorry to hear you say you will not be able to wait for the PIs. However, I am very glad that your doctors okay'ed your plan and you can add them later as needed. I am sure you are not looking forward to the tx nightmare again. I appreciate your thoughtful posting.
Doin time - excellent info there too.
I may check with the old BC BS case worker I had while treating and see if he can dig out any information from Blue Cross as to what they will cover.
frijole
Willing, I am sorry to hear you say you will not be able to wait for the PIs. However, I am very glad that your doctors okay'ed your plan and you can add them later as needed. I am sure you are not looking forward to the tx nightmare again. I appreciate your thoughtful posting.
Doin time - excellent info there too.
I may check with the old BC BS case worker I had while treating and see if he can dig out any information from Blue Cross as to what they will cover.
frijole
I met with my hepatologist yesterday and discussed the possiblity of doing treatment in much the same way as Willing described above. He said that this approach seems reasonable to him, and he had been talking to another patient about this, but he thought that I would be unable to get the insurance company to cover the Alinia. I plan to meet with him again next month, and may begin the alinia at that point.
Has anyone had any luck with the generic companies that were mentioned in a previous post?
Has anyone had any luck with the generic companies that were mentioned in a previous post?
I like the two week lead-in for the ribavirin in your plan and the high RBV approach overall. You're close enough to the Mexican border and NTZ is over-the-counter there. Any possibilities of that working for you?
Have to ask.. since you're making use of what's available outside of a PI. Considered also adding Fluvastatin and wonder what your take on that is?
Trish
Have to ask.. since you're making use of what's available outside of a PI. Considered also adding Fluvastatin and wonder what your take on that is?
Trish
bali: good luck with your progress - have you started getting vl results yet? The protocol from the Romark clinical trial has 4w ntz and 2w rbv lead ins which is pretty close. As for my numbers, bmi 23.4, very low insulin, vitD25 43, so not much to do there. The 1400mg rbv per protocol is 16.7 mg/Kg which should be high enough (and I'm a bit scared to do more..)
frijole: yeah, sure looks like the svr train is coming in sight for you, though it's taking its sweet time. You might consider adding ntz to whatever PI you choose. IMHO, the most impressive result from the Romark study was not the 56% SVR but the 0% relapse (which would normally run 25-30% of eot-und for naives and up to 60% for those without cEVR). It's a bit ironic that after advocating w&w for the past 7 years I'm caving in just as the train's coming round the bend, but when it's time it's time.
viaduk: hope all goes well for you - it'll be great to have traveling companions!
trish - thanks. As to the statins, I believe the issues are (1) heavy dosage required and (b) significant sides which is why statins as add ons haven't received much attention since the initial reports.
frijole: yeah, sure looks like the svr train is coming in sight for you, though it's taking its sweet time. You might consider adding ntz to whatever PI you choose. IMHO, the most impressive result from the Romark study was not the 56% SVR but the 0% relapse (which would normally run 25-30% of eot-und for naives and up to 60% for those without cEVR). It's a bit ironic that after advocating w&w for the past 7 years I'm caving in just as the train's coming round the bend, but when it's time it's time.
viaduk: hope all goes well for you - it'll be great to have traveling companions!
trish - thanks. As to the statins, I believe the issues are (1) heavy dosage required and (b) significant sides which is why statins as add ons haven't received much attention since the initial reports.
"I'm not sure one's ifn-response need be strong enough to reach und by w12 before benefiting from a PI however. GB is a great example of someone with limited ifn response who nevertheless sailed happily to SVR. Something around a 0.8 log drop by w4 may be the measure of how much ifn is needed to reliably mop up the mutiny."
willing - you put your finger on what I think is one of the million dollar questions. One thing for sure is that we are going to get answers to it soon enough. For who could reach week 12 still not UND without being desperate enough to throw everything at the virus that they can get their hands on.
Anyway, here's wishing you all the best for your tx. You've helped me and a lot of other people here and I hope it is you turn now for SVR.
dointime
willing - you put your finger on what I think is one of the million dollar questions. One thing for sure is that we are going to get answers to it soon enough. For who could reach week 12 still not UND without being desperate enough to throw everything at the virus that they can get their hands on.
Anyway, here's wishing you all the best for your tx. You've helped me and a lot of other people here and I hope it is you turn now for SVR.
dointime
"have you started getting vl results yet?"
Come on now , I am seen as the obsessive "tester-holic" around here.
During predose 0.41 log drop , after 2 weeks INF another 1.39 log drop.
Right now estimated to reach UND at wk 6.
b
Come on now , I am seen as the obsessive "tester-holic" around here.
During predose 0.41 log drop , after 2 weeks INF another 1.39 log drop.
Right now estimated to reach UND at wk 6.
b
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