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.
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.
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.
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.
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:
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.
interesting reading - thanks for posting. My proposal is to follow the alinia protocol report at easl 2010
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.