Aa
HCV, HIV, HBV and the effectiveness of PIs
I just went to Mt Sinai for my post 2 week physical and blood draw. I asked the doctors a lot of questions about these viruses and the effectiveness of PIs in treating them. There has been a lot of confusion on these boards in some recent threads and I include myself among the confused.
So, from the horses mouth:
HCV and HIV are RNA retroviruses.
HBV is a DNA virus.
However, HBV and HIV only reproduce within cells. HIV uses the DNA of the host cell to reproduce.
HCV reproduces free in the bloodstream and not within a cell.
This makes HCV much easier to treat with PIs since the virus is exposed during reproduction and the other two are hidden. This is the reason it is possible to cure HCV with a PI, but HIV and HBV are not curable with PIs.
The current PIs attack the Ns3 protease within the RNA and since they are very selective, the can't inhibit reproduction of all mutations of the virus; thus, SOC is required along with the PI. The newer PIs in early stages, attack a broader range and the polymerase inhibitors take an entirely different approach. All the Capo Grandes I spoke with think that in the next few years a cure will be available that no longer requires SOC - thank God!!
Eric
So, from the horses mouth:
HCV and HIV are RNA retroviruses.
HBV is a DNA virus.
However, HBV and HIV only reproduce within cells. HIV uses the DNA of the host cell to reproduce.
HCV reproduces free in the bloodstream and not within a cell.
This makes HCV much easier to treat with PIs since the virus is exposed during reproduction and the other two are hidden. This is the reason it is possible to cure HCV with a PI, but HIV and HBV are not curable with PIs.
The current PIs attack the Ns3 protease within the RNA and since they are very selective, the can't inhibit reproduction of all mutations of the virus; thus, SOC is required along with the PI. The newer PIs in early stages, attack a broader range and the polymerase inhibitors take an entirely different approach. All the Capo Grandes I spoke with think that in the next few years a cure will be available that no longer requires SOC - thank God!!
Eric
It is a good question you asked, whether raised ALT and AST could indicate increased cell death from increased immune attack. I never looked at that much because my levels are not increased, despite my biopsy showing medium liver inflammation. I suspect that much more research would be needed into the mechanism to get any kind of a take on this subject.
Regarding the telaprevir-resistant strains being easier to wipe out. This may be true in the majority of cases. Unfortunately not for me.
In any case, if 'wiped out' means halted from replicating then there's still the question of how long it takes after that for infected cells to get cleared out. But yes I agree, every mechanism of action helps, doesn't it. The sooner replication is stopped, the less infected cells there will be in line for elimination. Somehow I like the conclusion of the Drusano study which says it takes 36 weeks after UND. I suppose that means 36 weeks for infected cells to be cleared after replication has been halted. I can't say why I like this best, contrary to Vertex's 24 weeks, it just seems about right to me.
dointime
Regarding the telaprevir-resistant strains being easier to wipe out. This may be true in the majority of cases. Unfortunately not for me.
In any case, if 'wiped out' means halted from replicating then there's still the question of how long it takes after that for infected cells to get cleared out. But yes I agree, every mechanism of action helps, doesn't it. The sooner replication is stopped, the less infected cells there will be in line for elimination. Somehow I like the conclusion of the Drusano study which says it takes 36 weeks after UND. I suppose that means 36 weeks for infected cells to be cleared after replication has been halted. I can't say why I like this best, contrary to Vertex's 24 weeks, it just seems about right to me.
dointime
Thanks for the interesting link. I find this paragraph:
" Results so far for telaprevir/interferon/ribavirin are encouraging, with only a 5% rate of viral breakthrough in phase 2. Short-term studies at Vertex show that variants that are highly resistant to telaprevir tend to be less fit for replication and hopefully can be wiped out by interferon and ribavirin. The phase 3 telaprevir trial should give definitive answers."
Perhaps this is the reason for the effectiveness of the shortened treatment.
" Results so far for telaprevir/interferon/ribavirin are encouraging, with only a 5% rate of viral breakthrough in phase 2. Short-term studies at Vertex show that variants that are highly resistant to telaprevir tend to be less fit for replication and hopefully can be wiped out by interferon and ribavirin. The phase 3 telaprevir trial should give definitive answers."
Perhaps this is the reason for the effectiveness of the shortened treatment.
From medicine.net:
"AST: 1. Aspartate aminotransferase, an enzyme normally present in liver and heart cells. AST is released into blood when the liver or heart is damaged. The blood AST levels are thus elevated with liver damage (for example, from viral hepatitis) or with an insult to the heart (for example, from a heart attack). Some medications can also raise AST levels. AST is also known as serum glutamic oxaloacetic transaminase"
My impression was that the enzyme was released upon the death of the cell. That is why I asked the question about the enzymes being raised when an increased immune system attack is underway. The definition here says "damaged" not killed, so perhpas I don't understand the mechanism. There also appears to be no direct relationship between viral load and enzyme levels as I would have expected.
Eric
"AST: 1. Aspartate aminotransferase, an enzyme normally present in liver and heart cells. AST is released into blood when the liver or heart is damaged. The blood AST levels are thus elevated with liver damage (for example, from viral hepatitis) or with an insult to the heart (for example, from a heart attack). Some medications can also raise AST levels. AST is also known as serum glutamic oxaloacetic transaminase"
My impression was that the enzyme was released upon the death of the cell. That is why I asked the question about the enzymes being raised when an increased immune system attack is underway. The definition here says "damaged" not killed, so perhpas I don't understand the mechanism. There also appears to be no direct relationship between viral load and enzyme levels as I would have expected.
Eric
Andiamo - I honestly don't know the exact mechanism of how AST and ALT get raised with HCV infection. Can you point me to a reference which explains how that works?
I found another link to a relevant discussion:
http://www.nature.com/nbt/journal/v25/n12/full/nbt1207-1379.html
"A seemingly bedrock truth about HCV is that it's not enough to stop RNA replication (the goal of targeted therapies like telaprevir); one must also eradicate the virus from the body by harnessing the immune system to clear infected cells."
"The 24-week telaprevir treatment is controversial—and potentially paradigm shifting—because it challenges conventional wisdom, which holds that the adaptive immune system needs the full year to clear infected hepatocytes. Telaprevir's superior SVR rates in phase 2 compared with interferon and ribavirin alone suggests that the immune system plays a much smaller role than previously thought and that just stopping RNA replication may be enough to cure patients."
"a second function of the NS3 protease, discovered in 2003: it blocks the double-stranded RNA-sensing pathway of interferon regulatory factor-3 (IRF-3), at least in vitro2. By giving telaprevir, speculates Alam, "you're de-repressing those pathways" and enabling interferon to work again against the virus."
So, bottom line, there is plenty of reason to speculate that the ns3 protease inhibitors will reduce the relapse rates, not just by halting replication but also by enabling interferon to clear infected cells faster. Hopefully further results from the trials will confirm better relapse rates. Even if confirmed, it may be difficult to prove the mechanisms involved. Maybe it will become like ribavirin - we know it works but we don't totally know how it works.
dointime
I found another link to a relevant discussion:
http://www.nature.com/nbt/journal/v25/n12/full/nbt1207-1379.html
"A seemingly bedrock truth about HCV is that it's not enough to stop RNA replication (the goal of targeted therapies like telaprevir); one must also eradicate the virus from the body by harnessing the immune system to clear infected cells."
"The 24-week telaprevir treatment is controversial—and potentially paradigm shifting—because it challenges conventional wisdom, which holds that the adaptive immune system needs the full year to clear infected hepatocytes. Telaprevir's superior SVR rates in phase 2 compared with interferon and ribavirin alone suggests that the immune system plays a much smaller role than previously thought and that just stopping RNA replication may be enough to cure patients."
"a second function of the NS3 protease, discovered in 2003: it blocks the double-stranded RNA-sensing pathway of interferon regulatory factor-3 (IRF-3), at least in vitro2. By giving telaprevir, speculates Alam, "you're de-repressing those pathways" and enabling interferon to work again against the virus."
So, bottom line, there is plenty of reason to speculate that the ns3 protease inhibitors will reduce the relapse rates, not just by halting replication but also by enabling interferon to clear infected cells faster. Hopefully further results from the trials will confirm better relapse rates. Even if confirmed, it may be difficult to prove the mechanisms involved. Maybe it will become like ribavirin - we know it works but we don't totally know how it works.
dointime
So the PI delivers a double whammy to the virus, ie. it prevents it cleaving and it reinstated the signalling process making the virus visible to the immune system, ie. restoring innate immunity. This could be a reason why infected cells are eliminated more quickly and thus the tx takes 24 weeks, not 48.
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If this were the case, wouldn't there be a rise in AST and ALT? My enzymes normalized within a week and then elevated at week 40.
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If this were the case, wouldn't there be a rise in AST and ALT? My enzymes normalized within a week and then elevated at week 40.
Oops - correction to my last post.
The speed of going UND does not necessarily say anything about the eventual death of the infected cell, just that the production of new virions has been halted.
Hard to see from the viewpoint of my limited understanding how it could be shown in-vivo, that cell death occurred quickly as a result of restoration of innate immunity by the ns3 antiviral.
The speed of going UND does not necessarily say anything about the eventual death of the infected cell, just that the production of new virions has been halted.
Hard to see from the viewpoint of my limited understanding how it could be shown in-vivo, that cell death occurred quickly as a result of restoration of innate immunity by the ns3 antiviral.
I'll reread the paper I signed on the use of my data by Vertex, see if I have a case for the ethics committee. Meanwhile my study doc is a big player in the hepC world and I suspect he'll be campaigning at EASL, so I'll see what he comes up with first.
" has VX already been shown to restore the function of the interferon regulatory factor or is this an assumed benefit?"
Good question. Here's a link to a laymans take on this subject.
http://www.businessweek.com/technology/content/feb2006/tc20060221_196821.htm
I can't remember if I ever came across a study which demonstrated restoration of the immune signalling pathways for sure, using VX950. I believe that the very fast knockdown of the virus obtained with VX has been partially attributed to it's alleged ability to restore the cell's signalling pathway to the immune system. In that case you would not expect this speed with a drug which targets the ns5b, and that is what we are seeing. Anyway as it is very relevant to the 'long drawn out end-game' concept, it is certainly worth following up. But even if this mechanism is proved, there's still those pesky telaprevir-resistant mutations and their infected cells left to get rid of. The hope is that their numbers are far fewer.
dointime
" has VX already been shown to restore the function of the interferon regulatory factor or is this an assumed benefit?"
Good question. Here's a link to a laymans take on this subject.
http://www.businessweek.com/technology/content/feb2006/tc20060221_196821.htm
I can't remember if I ever came across a study which demonstrated restoration of the immune signalling pathways for sure, using VX950. I believe that the very fast knockdown of the virus obtained with VX has been partially attributed to it's alleged ability to restore the cell's signalling pathway to the immune system. In that case you would not expect this speed with a drug which targets the ns5b, and that is what we are seeing. Anyway as it is very relevant to the 'long drawn out end-game' concept, it is certainly worth following up. But even if this mechanism is proved, there's still those pesky telaprevir-resistant mutations and their infected cells left to get rid of. The hope is that their numbers are far fewer.
dointime
dointime: I hope your request is successul. If Vertex balks at releasing it, I would suggest taking up your request with the Ethics Review Board responsible for approving the study design (see eg how their recommendations affected the BC re-tx study). I believe this is important precedent - as a patient you should have full access to information collected from you, particularly insofar as it affects your future tx outlook. There has been a flurry of recent research on drug resistance and this area will get much more attention in the future.
Your comments about VX and NS3's blocking of IRF3 are interesting - has VX already been shown to restore the function of the interferon regulatory factor or is this an assumed benefit?
And thanks for the thoughts re the fs - good or bad I guess it's better to be aware.
Barry - thanks for those references - sounds like the vx focus on g1s is entirely due to patient selection, not biochem.
Your comments about VX and NS3's blocking of IRF3 are interesting - has VX already been shown to restore the function of the interferon regulatory factor or is this an assumed benefit?
And thanks for the thoughts re the fs - good or bad I guess it's better to be aware.
Barry - thanks for those references - sounds like the vx focus on g1s is entirely due to patient selection, not biochem.
willing - I posted this a while ago to see if there was much interest in getting data from Vertex.
http://www.medhelp.org/posts/show/392306
My study doc forwarded my request to Vertex and has been arguing the case himself for study participants to get their resistance data. I continue to think it could be very important to have it, as it could be make or break for the next tx.
It is very interesting what you write about the importance of the end game. There's one factor about the ns3 PI that is relevant here. the ns3 is responsible for turning off the signaling to the immune system that there is a pathogen present. So the PI delivers a double whammy to the virus, ie. it prevents it cleaving and it reinstated the signalling process making the virus visible to the immune system, ie. restoring innate immunity. This could be a reason why infected cells are eliminated more quickly and thus the tx takes 24 weeks, not 48.
But yes I agree, we are still really clueless about how long is long enough. Sure we have some stats but the new drugs are a new ball game, although the virus is not. At an individual level I've been in the small minority all along this road, so I'm not putting much faith in the stats when it comes to my next tx. I more appreciate your input and the pooled knowledge within this forum. I never got as far as worrying about relapse last time but I'm really taking this information about the elimination phase on board for next time.
Fingers crossed for your fibroscan.
Barry - many thanks for the information on the studies for the other genotypes. Interesting. I'm genotype 1 so tend to be myopic on that one, but I do like to know what's going on.
dointime
http://www.medhelp.org/posts/show/392306
My study doc forwarded my request to Vertex and has been arguing the case himself for study participants to get their resistance data. I continue to think it could be very important to have it, as it could be make or break for the next tx.
It is very interesting what you write about the importance of the end game. There's one factor about the ns3 PI that is relevant here. the ns3 is responsible for turning off the signaling to the immune system that there is a pathogen present. So the PI delivers a double whammy to the virus, ie. it prevents it cleaving and it reinstated the signalling process making the virus visible to the immune system, ie. restoring innate immunity. This could be a reason why infected cells are eliminated more quickly and thus the tx takes 24 weeks, not 48.
But yes I agree, we are still really clueless about how long is long enough. Sure we have some stats but the new drugs are a new ball game, although the virus is not. At an individual level I've been in the small minority all along this road, so I'm not putting much faith in the stats when it comes to my next tx. I more appreciate your input and the pooled knowledge within this forum. I never got as far as worrying about relapse last time but I'm really taking this information about the elimination phase on board for next time.
Fingers crossed for your fibroscan.
Barry - many thanks for the information on the studies for the other genotypes. Interesting. I'm genotype 1 so tend to be myopic on that one, but I do like to know what's going on.
dointime
This is from the Vertex press release of this past January:
"Tibotec is also conducting a Phase II viral kinetics study in Europe to evaluate teleprevir in patients infected with genotype 2/3 HCV. Interim on treatment data are expected to be available in late 2008"
No mention of the cities. Also this is from a vertex release in April of last year
"Conclusions:These in vitro studies demonstrate that teleprevir is a potent inhibitor of ns3-4A proteases from genotypes 2,3 and 4.These results support the clinical investigation of the anti viral activity of teleprevir in patients infected with genotypes 2,3 and 4 HCV."
By the way isn't there a big Hepatitis c conference going on now where many pharnaceutical companies including Vertex are presenting? I wonder if any new announcements will come out of it.
Barry
"Tibotec is also conducting a Phase II viral kinetics study in Europe to evaluate teleprevir in patients infected with genotype 2/3 HCV. Interim on treatment data are expected to be available in late 2008"
No mention of the cities. Also this is from a vertex release in April of last year
"Conclusions:These in vitro studies demonstrate that teleprevir is a potent inhibitor of ns3-4A proteases from genotypes 2,3 and 4.These results support the clinical investigation of the anti viral activity of teleprevir in patients infected with genotypes 2,3 and 4 HCV."
By the way isn't there a big Hepatitis c conference going on now where many pharnaceutical companies including Vertex are presenting? I wonder if any new announcements will come out of it.
Barry
dointime: I'll try to dig up some of those BC/VX cross-resistance papers. The question about getting Vertex to release the sequencing data they collected from you is an interesting one. I've often thought we (collectively) should organize, and require public disclosure of all data collected from us as a condition of trial participation (lab rats of the world unite!) The fact that Roche/Schering/Vertex are now sitting on masses of "proprietary" sequence/resistance data collected as part of PI investigations which could be of benefit to more than their stock price (including the patient..) is something that needs to be changed.
Re the importance of the end-game, RVR is a great indicator of strong response to meds and thus a strong SVR predictor, but, here again there's a fly in the ointment : several recent induction dosing studies showed that heavy-duty up-front IFN dosing led to significantly better early response but had no detectable effect on final SVR rates.
I believe this reflects different phases of viral suppression, which are highlighted in that nice movie you posted. When the ifn first hits, many infected cells shut down translation, thus quickly blocking all viral production. The NS3 PIs presumably are a strong adjunct at this point - in cells where translation inhibition failed, the ribosome-produced polyprotein doesn't get cleaved. In principle, the flood of ifn should also be stimulating NK cells into eliminating infected cells. However, the length of time required for successful tx, relapse, and the extensive literature on occult all indicate that this phase is very drawn out (loss of hcv antibodies 20 years after infection may be a yardstick). I don't believe we yet understand why this elimination phase is so difficult : perhaps because of the failure of infected cells to announce their status via presentation of HCV epitopes (poor MHC binding? low-frequency of epitopes?) ; perhaps because of a failure to recognize the presented epitopes - but I 'm pretty sure strengthening this phase is the key to avoid relapse. The NS5b PIs should significantly reduce viral production in infected cells and thus seem a good adjunct while one patiently waits for the NK cells to find their prey.
On the other hand, I'm not quite sure, whether waiting for r1626 will be an option. Monday I'm having a long-delayed fibroscan - if it comes in at 11 or above, I may have to jump sooner.
Barry: do you have cites for those in-vitro studies? I vaguely remember that, in addition to the lack of g2/g3 testing now being addressed by the study you mention, there was some data showing reduced in-viro effectiveness for g2/g3, but am not sure.
Re the importance of the end-game, RVR is a great indicator of strong response to meds and thus a strong SVR predictor, but, here again there's a fly in the ointment : several recent induction dosing studies showed that heavy-duty up-front IFN dosing led to significantly better early response but had no detectable effect on final SVR rates.
I believe this reflects different phases of viral suppression, which are highlighted in that nice movie you posted. When the ifn first hits, many infected cells shut down translation, thus quickly blocking all viral production. The NS3 PIs presumably are a strong adjunct at this point - in cells where translation inhibition failed, the ribosome-produced polyprotein doesn't get cleaved. In principle, the flood of ifn should also be stimulating NK cells into eliminating infected cells. However, the length of time required for successful tx, relapse, and the extensive literature on occult all indicate that this phase is very drawn out (loss of hcv antibodies 20 years after infection may be a yardstick). I don't believe we yet understand why this elimination phase is so difficult : perhaps because of the failure of infected cells to announce their status via presentation of HCV epitopes (poor MHC binding? low-frequency of epitopes?) ; perhaps because of a failure to recognize the presented epitopes - but I 'm pretty sure strengthening this phase is the key to avoid relapse. The NS5b PIs should significantly reduce viral production in infected cells and thus seem a good adjunct while one patiently waits for the NK cells to find their prey.
On the other hand, I'm not quite sure, whether waiting for r1626 will be an option. Monday I'm having a long-delayed fibroscan - if it comes in at 11 or above, I may have to jump sooner.
Barry: do you have cites for those in-vitro studies? I vaguely remember that, in addition to the lack of g2/g3 testing now being addressed by the study you mention, there was some data showing reduced in-viro effectiveness for g2/g3, but am not sure.
Everything I've read about invitro studies is that Vetex-950(Teleprevir) is as effective for genotypes 2 and 3 it is are for 1. I know there is a clinical trial using 2s and 3s about to begin in Europe with just those genotypes.
Barry
Barry
hi - the airplane image is great! I keep hoping there will be a third option like - the virus won't really damage my liver at all - in my dreams!
That's good news about BC and R1626. If it all comes off like we hope then you could have plenty of company doing the combo from other members of this board, including me.
I would not use the ns3 PI for the whole time. I would try to get away with using that for 8 weeks only. Maybe even 4 weeks would be enough. I would want to use the ns5b for the whole time to keep the pressure on the virus.
The trial I am most excited about is the Alinia trial. It's efficacy is such an unknown quantity right now. Given that the sides are so small it would be great if ntz could even partially take the place of ribavirin. I got such a bad rash from the riba that I'd almost rather die than high dose it - almost.
Thanks for the heads up on cross-resistance. I have been looking at that and have asked Vertex to tell me exactly which mutations I have. (no answer yet). I figure that I could still use the VX if I had to, to kill the reverted wild-type virus and leave the mutations to be mopped up by the ns5b and ntz. I asked HR and he said that BC has a favourable cross-resistance to VX, so BC should be the better choice for me. I will really be digging into this question as and when the info. becomes available.
" I had no breakthrough as far as I know (std 48 week tx but with a slightly ominous inflection point in the vl curve around w8) so am more concerned about end-game reduction."
From my experience in the VX trial and also seeing how it went for others, I think that the key to not having a long drawn-out end game is to knock the virus down hard and fast at the beginning. So far it has been found that being clear in the first 4 weeks (RVR) is the best indication of SVR. Others in my group who got the triple therapy also had their VL curve go flat in the third week as the virus tried to fight back but they got RVR and SVR. If you are a relapser I think your chances of SVR with only VX and alinia and SOC should be very high. We'll know something when the Prove3 results are in, providing they divide them by non-responders and relapsers but my strong impression is that relapsers luck out with VX - good to keep in mind in case you don't want to or can't wait for R1626.
dointime
That's good news about BC and R1626. If it all comes off like we hope then you could have plenty of company doing the combo from other members of this board, including me.
I would not use the ns3 PI for the whole time. I would try to get away with using that for 8 weeks only. Maybe even 4 weeks would be enough. I would want to use the ns5b for the whole time to keep the pressure on the virus.
The trial I am most excited about is the Alinia trial. It's efficacy is such an unknown quantity right now. Given that the sides are so small it would be great if ntz could even partially take the place of ribavirin. I got such a bad rash from the riba that I'd almost rather die than high dose it - almost.
Thanks for the heads up on cross-resistance. I have been looking at that and have asked Vertex to tell me exactly which mutations I have. (no answer yet). I figure that I could still use the VX if I had to, to kill the reverted wild-type virus and leave the mutations to be mopped up by the ns5b and ntz. I asked HR and he said that BC has a favourable cross-resistance to VX, so BC should be the better choice for me. I will really be digging into this question as and when the info. becomes available.
" I had no breakthrough as far as I know (std 48 week tx but with a slightly ominous inflection point in the vl curve around w8) so am more concerned about end-game reduction."
From my experience in the VX trial and also seeing how it went for others, I think that the key to not having a long drawn-out end game is to knock the virus down hard and fast at the beginning. So far it has been found that being clear in the first 4 weeks (RVR) is the best indication of SVR. Others in my group who got the triple therapy also had their VL curve go flat in the third week as the virus tried to fight back but they got RVR and SVR. If you are a relapser I think your chances of SVR with only VX and alinia and SOC should be very high. We'll know something when the Prove3 results are in, providing they divide them by non-responders and relapsers but my strong impression is that relapsers luck out with VX - good to keep in mind in case you don't want to or can't wait for R1626.
dointime
Barry - you are quite right, Vertex is aiming to do a 24 week tx for genotype 1 treatment naive people who clear the virus within 4 weeks (RVR) of the triple therapy.
I was speaking only for myself and my own particular circumstances, ie. I am a non-responder because of viral breakthrough, and I already have telaprevir-resistant mutations. The Vertex Prove3 study is the first one done for a PI for non-responders and the results are not out yet. In any case, I think I need to go longer to beat those pesky resistant mutations.
I don't know of any PI's which have been designed or tested for geno2 or geno3.
dointime
I was speaking only for myself and my own particular circumstances, ie. I am a non-responder because of viral breakthrough, and I already have telaprevir-resistant mutations. The Vertex Prove3 study is the first one done for a PI for non-responders and the results are not out yet. In any case, I think I need to go longer to beat those pesky resistant mutations.
I don't know of any PI's which have been designed or tested for geno2 or geno3.
dointime
I'm confused by your posts. I thought the beauty of Vertex and other PIs, etc was that it was so potent it would LOWER the time needed for treatment. It seems that both your treatments with multiple PIs, and alinia the SOC still lasts 40+ weeks. Are you basically talking about Genotype1's who have either relapsed or never responded or are you talking about all 1s. I assume for 2s and 3s the time of treatment would be much lower, possibly only 12 weeks. Could you explain the long SOC with the PIs
Thanks,
Barry
Thanks,
Barry
I know what you mean about when it's time it's time. My mental image of re-tx planning is a bit like being on an airplane that's on fire and is losing altidude over shark-infested waters, but is approaching the coast: jump too soon and you're lunch but wait too late and you're toast. The EASL presentations are already online though I think the press embargo may limit publicity - there's a discussion of the results in that "Good news from Vertex" thread andiamo started 3/31.
My overall impression of BC's phase II (Sprint 1) relative to the VX Prove I and II results was comparable - particularly w12 stats with the 4 week soc lead in. Also the results on lack of resistance mutations to R1626 and w4rvr-eot correlation (84%!) are very encouraging. At this stage, my plan is to jump whenever both are available, and it looks like r1626 is the longest wait, particularly if vx gets early approval for re-tx patients on the basis of prove III results (Schering will probably not be able to do the same because their phase II results on tx-experienced are such a mess). I doubt we'll see much data on tolerabillity of multi-drug tx until after approval so I'm assuming it'll be my turn to be the lab rat on that one. Re. using the ns3 pi for the whole time, it'll be interesting to see whether the vx and bc 44-48 results differ from the 24 but my hunch is the NS3s PIs are so effective in eliminating all but resistant mutations that the extra time won't make a big difference - you're just extending the rash/nausea misery. It sounds like in your case resistant strains were quickly selected and then only partially eliminated by the addition of soc so starting with both ns3 and ns5b pis up front may be the better strategy - though there's also the question of how much your ifn response would be strengthened by the ntz. I had no breakthrough as far as I know (std 48 week tx but with a slightly ominous inflection point in the vl curve around w8) so am more concerned about end-game reduction.
One issue you'll probably want to investigate is cross resistance of vx,bc and itmn. There are a few papers on this and I haven't looked at the question in any detail but it may well be that the selection effect of the first tx may rule out both vx and bc in a re-tx since they are so similar.
My overall impression of BC's phase II (Sprint 1) relative to the VX Prove I and II results was comparable - particularly w12 stats with the 4 week soc lead in. Also the results on lack of resistance mutations to R1626 and w4rvr-eot correlation (84%!) are very encouraging. At this stage, my plan is to jump whenever both are available, and it looks like r1626 is the longest wait, particularly if vx gets early approval for re-tx patients on the basis of prove III results (Schering will probably not be able to do the same because their phase II results on tx-experienced are such a mess). I doubt we'll see much data on tolerabillity of multi-drug tx until after approval so I'm assuming it'll be my turn to be the lab rat on that one. Re. using the ns3 pi for the whole time, it'll be interesting to see whether the vx and bc 44-48 results differ from the 24 but my hunch is the NS3s PIs are so effective in eliminating all but resistant mutations that the extra time won't make a big difference - you're just extending the rash/nausea misery. It sounds like in your case resistant strains were quickly selected and then only partially eliminated by the addition of soc so starting with both ns3 and ns5b pis up front may be the better strategy - though there's also the question of how much your ifn response would be strengthened by the ntz. I had no breakthrough as far as I know (std 48 week tx but with a slightly ominous inflection point in the vl curve around w8) so am more concerned about end-game reduction.
One issue you'll probably want to investigate is cross resistance of vx,bc and itmn. There are a few papers on this and I haven't looked at the question in any detail but it may well be that the selection effect of the first tx may rule out both vx and bc in a re-tx since they are so similar.
There seems to be a question about boceprevir results. Maybe we will get clear results from EASLD at the end of the month. If they were comparable to VX950 for speedy VL knockdown then I'd go with boceprevir.
I'm not too keen on the neutropenia associated with R1626. I would need to see how the trials go using only a half dose of interferon. R7128 has so far not reported neutropenia, still it's early days for both those drugs. If I thought I could get through 40 weeks of R1626 and not have to use neupogen (yet another drug and another injection) then I'd go for R1626.
I guess the bottom line is that when my liver calls time I'll have to grab whatever is available and do the best I can with it.
I agree that the ifn response is probably the main determinant of the tx strategy. That said, most strategies probably should have a predosing phase, a killing phase and a mop-up phase.
The mop-up phase is the easiest to design. That phase is a war of attrition with the last few virions and, as you say, can last a long time. So drugs which don't develop resistance, like alinia, are most useful. Actually I am not sure about the resistance profile of R1626, another reason why I preferred R7128, which has not so far produced resistant mutations.
The killing phase will be the most individual I think. A lot will depend on how tolerable it will be to take both the protease inh. and the polymerase inh. at the same time. If it can be tolerated I don't see any advantage in holding off with R1626 till week 20. Why would you not just take it for all 48 weeks? I am depending on the virus not being able to mutate round both these drugs at the same time, so I would want to maximize the time that I took both together. The protease inh kills very quickly then develops resistance, so the timing of that strike could be important. Even after resistance has set in it still has the function of preventing the virus reverting back to wild-type, so there's one less place for the virus to hide and that is good because it is more likely to make fatal mistakes while mutating. My hope would be that the killing phase would kill every last one of the virions, making the mop-up phase purely for insurance.
I was UND at day 15 with VX950 and ifn (no riba) then had confirmed breakthrough by day 28. I then started SOC, was UND at week 6 and had another breakthrough around week 16. I think that if I had had the triple therapy all at once from the start it might have worked. From this, I believe that using all the active agents at once is more effective that using them serially within a tx.
Anyway, I know that I can go UND quickly, but that I have a job on my hands to hit the virus very hard and fast before it can get up again - and without killing myself in the process!
Did you do a previous tx? If so, what happened?
dointime
I'm not too keen on the neutropenia associated with R1626. I would need to see how the trials go using only a half dose of interferon. R7128 has so far not reported neutropenia, still it's early days for both those drugs. If I thought I could get through 40 weeks of R1626 and not have to use neupogen (yet another drug and another injection) then I'd go for R1626.
I guess the bottom line is that when my liver calls time I'll have to grab whatever is available and do the best I can with it.
I agree that the ifn response is probably the main determinant of the tx strategy. That said, most strategies probably should have a predosing phase, a killing phase and a mop-up phase.
The mop-up phase is the easiest to design. That phase is a war of attrition with the last few virions and, as you say, can last a long time. So drugs which don't develop resistance, like alinia, are most useful. Actually I am not sure about the resistance profile of R1626, another reason why I preferred R7128, which has not so far produced resistant mutations.
The killing phase will be the most individual I think. A lot will depend on how tolerable it will be to take both the protease inh. and the polymerase inh. at the same time. If it can be tolerated I don't see any advantage in holding off with R1626 till week 20. Why would you not just take it for all 48 weeks? I am depending on the virus not being able to mutate round both these drugs at the same time, so I would want to maximize the time that I took both together. The protease inh kills very quickly then develops resistance, so the timing of that strike could be important. Even after resistance has set in it still has the function of preventing the virus reverting back to wild-type, so there's one less place for the virus to hide and that is good because it is more likely to make fatal mistakes while mutating. My hope would be that the killing phase would kill every last one of the virions, making the mop-up phase purely for insurance.
I was UND at day 15 with VX950 and ifn (no riba) then had confirmed breakthrough by day 28. I then started SOC, was UND at week 6 and had another breakthrough around week 16. I think that if I had had the triple therapy all at once from the start it might have worked. From this, I believe that using all the active agents at once is more effective that using them serially within a tx.
Anyway, I know that I can go UND quickly, but that I have a job on my hands to hit the virus very hard and fast before it can get up again - and without killing myself in the process!
Did you do a previous tx? If so, what happened?
dointime
skin problems, primarily ifn-fueled escalation of otherwise dormant psoriasis, were a problem with me as well, which is why I think I'd rather risk the boceprevir nausea than the telaprevir rash. I'm curious why you would wait for itmn-191 and r7128 when boceprevir and r1626 are already in phase II, seem quite tolerable, and have given very encouraging data.
The options in mixing this cocktail seem open-ended, and it seems unlikely one size will fit all, the strength of one's ifn response probably being the main determinant. Unfortunately, the mechanisms of breakthrough and relapse are still mostly unknown, so planning the best path is still mostly speculation. My main reason for not wanting to use all the ammo up front is that it's pretty clear from relapse that a relatively small number of immune-undetected but infected cells can remain for a long time (consider the benefits observed in extended soc). Eliminating these seems to require more than soc, and r1626, with half-dose ifn seems an ideal candidate. How early on was your breakthrough?
The options in mixing this cocktail seem open-ended, and it seems unlikely one size will fit all, the strength of one's ifn response probably being the main determinant. Unfortunately, the mechanisms of breakthrough and relapse are still mostly unknown, so planning the best path is still mostly speculation. My main reason for not wanting to use all the ammo up front is that it's pretty clear from relapse that a relatively small number of immune-undetected but infected cells can remain for a long time (consider the benefits observed in extended soc). Eliminating these seems to require more than soc, and r1626, with half-dose ifn seems an ideal candidate. How early on was your breakthrough?
I've been thinking along much the same lines as you regarding my tx options and the timeline. I agree that in about 5years+ we will be looking at one protease and one polymerase inhibitor + SOC/alinia. That is unless one of the vaccines comes up trumps. There's also Locteron as the interferon which would be bi-weekly and not give so much injection site inflammation.
As I have aready had VX950 and don't fancy the rash again, I would like the protease to be either vx500 or itmn-191, both currently in phase 1 development. For the polymerase my choice would be Pharmasset's R7128 because of it's lack of sides and because there's no resistance to it been found. It is also in phase 1 development.
Your ideal tx is very interesting and gives me food for thought. I am a subscriber to the 'put the virus down hard and fast at the front of tx' school of thought. This may be because my 2 failed tx's were because of breakthrough so I need to nail the b****** before it can get up again. I would do:
week -4 : start alinia
week -2 : start high-dose rbv
week 0 : start inf + protease inh. + polymerase inh, drop riba to weight-based +200mg
week 8 - 12 stop the protease during this time depending on sides.
week 24: reduce riba and inf only if necessary because of sides
week 40: stop all, eot
I would stop at week 40 assuming RVR as that would be 36 weeks after UND. It would also cut down on exposure to inf and riba.
I guess that everyone's ideal tx would be different depending on how their virus behaved during their previous tx's. I got to UND with no problem but the virus just got up again and that was the end of that. For others, a slow and steady war of attrition may be the best approach.
Great topic you raised! I'd like to hear other's thoughts on combo strategies too.
dointime
As I have aready had VX950 and don't fancy the rash again, I would like the protease to be either vx500 or itmn-191, both currently in phase 1 development. For the polymerase my choice would be Pharmasset's R7128 because of it's lack of sides and because there's no resistance to it been found. It is also in phase 1 development.
Your ideal tx is very interesting and gives me food for thought. I am a subscriber to the 'put the virus down hard and fast at the front of tx' school of thought. This may be because my 2 failed tx's were because of breakthrough so I need to nail the b****** before it can get up again. I would do:
week -4 : start alinia
week -2 : start high-dose rbv
week 0 : start inf + protease inh. + polymerase inh, drop riba to weight-based +200mg
week 8 - 12 stop the protease during this time depending on sides.
week 24: reduce riba and inf only if necessary because of sides
week 40: stop all, eot
I would stop at week 40 assuming RVR as that would be 36 weeks after UND. It would also cut down on exposure to inf and riba.
I guess that everyone's ideal tx would be different depending on how their virus behaved during their previous tx's. I got to UND with no problem but the virus just got up again and that was the end of that. For others, a slow and steady war of attrition may be the best approach.
Great topic you raised! I'd like to hear other's thoughts on combo strategies too.
dointime
yes, lots of new stuff on the horizon : RNAi, ribozymes, peptides like the one Mike posted about recently, but... trouble is, the distance to the horizon isn't likely to get much shorter. For example, there was nothing particularly revolutionary about VX: inhibitors of serine proteases have been the poster story for rational drug design and Vertex got to build on much previous work, including BILN-2061. However, lab development was finished by 2003 or thereabout and the currently recruiting PhaseIII trial won't complete until March 2010, with FDA approval hopefully shortly thereafter. That stretch of time isn't likely to get shorter - and I'm not sure it should considering the number of recent candidates, including biln-2061 and hcv-796 , that have been discontinued because of adverse effects.
So unless you're willing to wait 10 years or more, it looks like the near-future tx landscape will consist of an ns3 inhibitor (vx or bc), an ns5b inhibitor (r1626), soc and ntz/alinia (drugs like ntz that already have fda approval and get redirected are a great short cut).
With VX in 2010, reasonable guesses are bc by 2012 and R1626 by 2014 - or 6 more years - and then there's the question of how to combine them. From what's available now my nomination for an ideal tx, would be:
week -4 : start ntz/alinia
week -1 : start weight-based rbv
week 0 : start soc
week 4 : add vx or bc (soc lead-in should work for either)
week 20: add r1626
week 24: stop vx/bc and drop ifn (but not rbv) to half dose
week 44: end r1626
week 48: end soc and ntz, eot
this gives 4 weeks where any resisting virions have to be cross-resistant to both types of inhibitors - a tough act to pull off. The one week rbv pre-dosing may or may not make a difference and could be replaced by beng careful about evenly distributing rbv pills through the day at start.
R1626 seems slightly more sluggish about killing off virus but resistance mutations are near non-existent, thus the 2nd 6 months, at half dose-ifn should be ample time to eliminate residual infected cells. I'd be curious to hear any thoughts about other combo strategies... now if I could just beg/borrow/steal the pills before 2012..
So unless you're willing to wait 10 years or more, it looks like the near-future tx landscape will consist of an ns3 inhibitor (vx or bc), an ns5b inhibitor (r1626), soc and ntz/alinia (drugs like ntz that already have fda approval and get redirected are a great short cut).
With VX in 2010, reasonable guesses are bc by 2012 and R1626 by 2014 - or 6 more years - and then there's the question of how to combine them. From what's available now my nomination for an ideal tx, would be:
week -4 : start ntz/alinia
week -1 : start weight-based rbv
week 0 : start soc
week 4 : add vx or bc (soc lead-in should work for either)
week 20: add r1626
week 24: stop vx/bc and drop ifn (but not rbv) to half dose
week 44: end r1626
week 48: end soc and ntz, eot
this gives 4 weeks where any resisting virions have to be cross-resistant to both types of inhibitors - a tough act to pull off. The one week rbv pre-dosing may or may not make a difference and could be replaced by beng careful about evenly distributing rbv pills through the day at start.
R1626 seems slightly more sluggish about killing off virus but resistance mutations are near non-existent, thus the 2nd 6 months, at half dose-ifn should be ample time to eliminate residual infected cells. I'd be curious to hear any thoughts about other combo strategies... now if I could just beg/borrow/steal the pills before 2012..
It is important to realize though that PI's are not the only promising lines of research at the moment. In addition to research on a vaccine, there seem to be new "discoveries" every other day in updates, as to potential lines that are promising. If a PI come's along, that eliminates the need for other drugs, that will be great. But, it is a bet that PI's will be first, and no more than that. The "lucky" thing for us is that a lot of people have Hep C, so there is money for big Pharma and small Pharma in exploring it. If we had instead had a rare disease, it is not so prommising, sadly.
I thank you for your clarification of the virus definitions.
I know next to nothing about biochemistry. In this post, I repeated what one of the research people told me without verifying it. I won't do that again, as I have no idea what she meant. I do know what she said and that is what I repeated.
All of them said that HBV and HIV reproduced in a different way than HCV even though HIV was an RNA virus, HBV a DNA virus and HCV an RNA virus. One of them definitely said that HBV and HIV were embedded within the host cells and hidden from the PIs. While HCV was exposed in the blood stream.
Perhaps I read in that they were embedded during reproduction and HCV was not and she meant during a different part of the life cycle.
In any case, I apologize if I came across as testy. I am feeling worse two weeks post treatment than I did during treatment. I will probably stop posting until I feel better and get some sleep.
I know next to nothing about biochemistry. In this post, I repeated what one of the research people told me without verifying it. I won't do that again, as I have no idea what she meant. I do know what she said and that is what I repeated.
All of them said that HBV and HIV reproduced in a different way than HCV even though HIV was an RNA virus, HBV a DNA virus and HCV an RNA virus. One of them definitely said that HBV and HIV were embedded within the host cells and hidden from the PIs. While HCV was exposed in the blood stream.
Perhaps I read in that they were embedded during reproduction and HCV was not and she meant during a different part of the life cycle.
In any case, I apologize if I came across as testy. I am feeling worse two weeks post treatment than I did during treatment. I will probably stop posting until I feel better and get some sleep.
dointime - nice movie - much clearer than the diagram.
andiamo: the main point of your post is very interesting. I've been so bogged down with hcv I haven't really taken the time to read much about hbv/hiv and their response to designed drugs. It seems encouraging that experts anticipate greater success with targeting PIs at hcv than at the other two viruses. (both nastier than hcv). And no, I'm not a biochemist - actually a computing-to-bio retread - the two are starting to look more alike every day.
andiamo: the main point of your post is very interesting. I've been so bogged down with hcv I haven't really taken the time to read much about hbv/hiv and their response to designed drugs. It seems encouraging that experts anticipate greater success with targeting PIs at hcv than at the other two viruses. (both nastier than hcv). And no, I'm not a biochemist - actually a computing-to-bio retread - the two are starting to look more alike every day.
Willing - thanks for weighing in here. I do think it is important to try and maintain accuracy about the basic facts of HCV.
Andiamo - here is a graphic description of the lifecycle of the HCV virus, showing in pictures the invasion of the hepatocyte and subsequent mechanism of replication.
Your wrote "I suggest you give a presentation to the research scientists at Mt Sinai. They might be enlightened by your explanation."
I would be happy for you to take this along to the researchers at Mt Sinai, although I doubt that they would not already know these facts.
http://hopkins-gi.org/multimedia/database/intro_293_VC-04.swf
dointime
Andiamo - here is a graphic description of the lifecycle of the HCV virus, showing in pictures the invasion of the hepatocyte and subsequent mechanism of replication.
Your wrote "I suggest you give a presentation to the research scientists at Mt Sinai. They might be enlightened by your explanation."
I would be happy for you to take this along to the researchers at Mt Sinai, although I doubt that they would not already know these facts.
http://hopkins-gi.org/multimedia/database/intro_293_VC-04.swf
dointime
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