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Your opinion please? Lets say a patient went thru treatment (1b) pegasys/copegus 180/1200 for 48 weeks, starting VL was 10 mil, middle aged male, slight liver damage, still detectable at 600 week 12, clear week 16 (less than 50), relapsed, waited 3 months and started treatment over, VL 500,000, double dose pegasys 4 weeks, 1400 copegus, no VL detected at week 4 using heptimax, did shot every five days from week 4 thru week 12, did 1600 copegus for month and half, waited full seven days at week 12 and got negative heptimax, doing 180/1200 rest of treatment, ast/alt normal at week 12, does this person have the same chance with RVR statistics (as high as 85% SVR) with 48 weeks, or are those RVR statistics only good for someone who does treatment the first time using the SOC? I hope you can understand what I’m asking here?
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Willing: starts to quantify the significance of occasional breakthroughs from high-sensitivity tests during tx. Looks like  breakthrough  is not catastrophic (10/23 still SVRrd) but definitely not good.  Yeah, I know, I know, you already knew all that..
----------------
Well, well, this could be a very boring New Year with nothing to quibble about. No doubt this was the reasoning behind my docs' noting the importance of monthly TMA's after UND.

-- Jim
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Hi Spcest2

I was wondering if the increased doses were something that your doctor recommended or is this something that was your idea/ Also do you know if this is a common approach for persons who fail tx the first time?
Is this something that most doctors will agree to or do you have to seek out a doctor  who will treat with this method?
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mike - thanks for the word; good to hear from you as always. I hope you are keeping well.

spcecst2: for a re-tx that seems as sound a plan as I can think of, both with respect to the initial dosing  and duration. Even if the RVR/SVR correlation is not the same under a more intense regime as for SOC,  RVR remains a definite sign that you *are* responding to presence of the ifn. The extra time seems the right investment, particularly if the initial tx failed on relapse.
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Welcome back. I am sorry, but the following is a critical isue:

I think there is a small but important mistake: You wrote:

Gelderblom HC, Reesink HW, Beld MG, Weegink CJ, Jansen PL, Dijkgraaf MG, Zaaijer HL.Low-level HCV viraemia after initial response during antiviral therapy: transcription-mediated amplification predicts treatment failure.Antivir Ther. 2007;12(3):423-7. PMID: 17591033

which (finally I might add) starts to qunatify the significance of occasional breakthroughs from high-sensitivity tests during tx.

"Looks like  breakthrough  is not catastrophic (10/23 still SVRrd)"

but definitely not good.  

No, breakthrough IS catastrophic according to this paper, none of the SVR had breakthrough,

BUT SOME, EVEN WITHOUT BREAKTHROUGH still did NOT have SVR. That is the correct conclusion...
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I also agree with both your comments on the 'renegotiated truce' with the virus after SVR, and that the virus seems to now be almost 'proven' to still live on in the body in most patients, long after SVR.  What I continue to be unclear about is just why the mainstream docs continue to ignore, or even worse mis-interpret the data on viral persistence after SVR.  If the non-research oriented medical experts dealing with HCV are unwilling (no pun intended) to acknowledge this phenomenon, then how will we ever really understand true viral behavior, and find out what the presistent virus might be capable of in those who are long term SVR's?

I also think that many HCV treaters also tend to want to ignore the recent studies, and the concept of a viral 'remission' relating to treatment of HCV.  I think the persistent viral concept potentially explains many issues that often confront the SVR, or even the spontaneous clearer.  There may be ongoing immune system actions that are geared toward containing or controlling the sub-detectable virus, which might also exert a negative effect on our overall health...maybe by stimulating autoimmune activity, or in other less understood ways.  The problem is that if no one in the mainstream will consider the realities of recent research, then the virus continues to be understood in an inaccurate manner, and further research and discussion is effectively discouraged.

By the way, its always great to hear form both of you guys, and I always appreciate your comments on current issues.  Have a great holiday season!

DoubleDose
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DD: Of course, I'm sure many "mainstream" docs do "ignore" or "mis-interpret" data on viral persistence after SVR, and possibly many simply haven't heard of it. However, I've spoken to another sub-set of docs -- who are aware, but may differ from you on the relevance of the conclusions, especially in the clinical arena. In fact, even the authors of the supportive papers, usually end with something akin "no clinical relevance established. More studies needed".

-- Jim
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HR : yes, you are absolutely correct - my initial quick read of the abstract was wrong.  Thank you for the correction. I don't have access to the full text of the journal, but the main result is clear "Reappearance of low levels of HCV RNA in patients with IVR (initial viral response) predicts treatment failure. ".
  
By way of background, this has been an issue that Jim and I have sparred over repeatedly. Whereas Jim has argued for high-sensivity tests throughout tx, I have objected that  up to now there has been no data against which to interpret the clinical significance of say a single VL of 5 at week 20. Given the accepted 1log variability of serum VL, are occasional spikes above the level of detection for sensitive tests part of the normal course of tx? This paper starts to provide a definite answer to that question. A related topic in interpreting these results is the false positive rate of TMA tests. Interestingly, post EOT spikes don't  seem as predictive. On my time on this board I believe two patienst (nygirl is one) reported post EOT VL but went on to SVR.

DD: good to hear from you. I believe the lack of attention to this topic only reflects the fact that the clinical impact of remaining infection is, to all appearances,  so much smaller than the impact of unchecked infection. It's hard to see Roche or Schering finding it in their interest to fund studies on residual virus and government funds are presumably better spent on proposals with a higher cost/benefit profile. The focus of Pham's lab seems to be more on basic virology than on clinical work.
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willing--it's all I can do!

DD---You have a very valid point with lots of info pointing in that direction but what ever they call it I could live very happy with 5 years or hopefully more of keeping it at bay, 10 years would do me better and by then hopefully they could find something better, in keeping with the idea that the host immune system plays a huge role I read --ScienceDaily (May 19, 2006) — A team of scientists at The Scripps Research Institute has shed light on one mechanism the hepatitis C virus uses to inhibit the immune system and promote its own survival. Results of the study may help in the development of new approaches to the treatment of hepatitis C virus--

According to Mitchell Shiffman,
“The use of peginterferon alone, or in combination with ribavirin, points to a cure for Hepatitis C, the leading cause of cirrhosis, liver cancer and the need for liver transplant. This paper strongly suggests, for the first time, that Hepatitis C is a curable disease. After treatment, 99.6 percent of the patients remained virus undetectable for over five years.”

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willing:
A related topic in interpreting these results is the false positive rate of TMA tests

Yes, extremely important in this context. Thats why i have pointed 3 times already at the false positivity problem of theTMA and described the incredible cumbersome means to avoid false positives using  the supersensitive PCR test  (below 2 iU) at Labcorp/NGI. It is forgotten in  a few days.

You hint, quite correctly IMO, at the fact that a tiny part of the preexisting quasispecies might not respond to treatment, because it has a priori evaded the cytotoxic CD-8 T cell response by shedding its class 1 effective CTL epitopes, as a means to evade.
Upon treatment, the main HCV quasispecies portion drops rapidly - RVR- but the small unaffected portions stays almost the same. Hence the true VL curve hits, after initial rapid decline, a deep plateau, when it encounters the non susceptible portion.
There are of course ten shades of gray in between this black and white picture. But the CTL epitope evasion theory has the best chance to reflect the actual reality behind all these phenoma.

The real important effect of riba, IMO, is that it might drive the viral proteome (sum of all proteins) into a state, where

new effective  HCV CTL epitopes are de novo ( not existing before treatment) created by hypermutation.

By the collateral effect of activated ( by hepatocytes  carrying these new reactive epitopes)  CTLs on other  nearby infected  " pseudoclean=no CTL epitopes displayed)" hepatocytes, by " noncytolytic" clearance, due to intense local cytokine production by the positively TCR engaged  CTLs,

broad clearance/antiviral effectiveness is now provided.
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Regarding mutated virus - this was something that the Big U doc my husband visited last week alluded to and implied might be what has happened to my husband during Treatment 1 and possibly now during treatment 2.  Is the only hope for someone with potential mutated virus to wait for new drugs on the market if there are no new studies on the horizon?  H has used PegIntron now for both treatments, Big U doc suggested clearing out his system for 2 months and trying Pegasys?  What ever happened to the side by side study of Peg vs. Intron and did that study only deal with treatment naieve patients - I'm not finding any reference in the threads....also wondering about changing from PegIntron to Pegasys mid-stream with no 2 month cleansing....thoughts anyone.
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DDquote: "What I continue to be unclear about is just why the mainstream docs continue to ignore, or even worse mis-interpret the data on viral persistence after SVR."

Can't speak for how most doctors feel about the persistent low level virus schpiel, but my doctor openly acknowledges the Castillo et al findings and does not ignore them. But he does not currently accept them as an irrefutable fact either, he says more study is needed and that by all appearances the vast majority who achieve SVR are cured (and the word "cured" is freely used by many top tier research doctors too). And even if there is a low lying ongoing infection, effectively SVR patients by and large are cured of liver disease (in stark contrast to their condition prior to achieving SVR). Also, assuming there is ongoing low level persistence after achieving SVR, realistically what can be done about it? Nothing that I know about. And more importantly, what should be done about it? Should another phase of antiviral treatment be developed to go for that second tier *deep cleansing* that all us SVR's really need in order to get our health back?

DDqote: "If the non-research oriented medical experts dealing with HCV are unwilling (no pun intended) to acknowledge this phenomenon, then how will we ever really understand true viral behavior..."

By "acknowledge the phenomenon", you mean simply accept this is an irrefutable fact without any further debate or research to help resolve the issue with more clarity and certainty? If so I certainly don't agree with that, and I know that many well educated hepatologists don't either. And also, why would it be so important for "non-research oriented medical experts" to accept this theory as fact? Wouldn't it be more important for research oriented medical experts to take it more seriously and to devote more study to it? Working doctors primarily deal with what treatments/drugs are available today and they also tend to focus on things they have some control and influence over. They also tend to only treat patients who need their care and expertise. SVR's often don't require their care and expertise, at least in regards to the issues associated with an ongoing HCV infection (obviously because they're SVR). So why would it be so important for non-research oriented working level doctors to be so wrapped up into the whole viral persistence debate?

DDquote: "...and find out what the presistent virus might be capable of in those who are long term SVR's?"

You mean like SVR's transmitting the virus to others vis-a-vis casual contact? That pet theory of yours is not accepted within the scientific community at all, and there is no real evidence to prove that's true. Those are the facts.

DDquote: "I also think that many HCV treaters also tend to want to ignore the recent studies, and the concept of a viral 'remission' relating to treatment of HCV."

Really, like who? Certainly not me, nor anyone else I know who is SVR (and is aware of the studies). Although I will admit to experiencing a building feeling of extreme confidence that I'm not going to relapse and I will admit to the onset of boredom pangs with the whole concept that I'm just in remission and I'll relapse at any time. But is there a perfectly rational and scientifically sound reason for me feeling that way? Absolutely there is! SVR is durable, SVR infers histological improvement, SVR often infers resolution of HCV related symptoms, SVR means more LIFE - SVR is fabulous. Furthermore, aren't there also just a few SVR's who literally *need* to believe in the viral persistence theory in order to rationalize and justify certain hypochondrial-like anxieties? I think so, don't you? And you don't even have to be SVR either, in fact you don't even have to have ever been infected with HCV in order to become obsessed about this sort of thing. Just look around on this forum, and you'll see that's true.

RELAX DUDE.  http://youtube.com/watch?v=yjnvSQuv-H4
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Why, you would have thought that I had put a big MREMEET tag on the subject line of my post!  WOW!  Sensitive, sensitive, sensitive! I make a few comments, echoing what Willing and Mike had stated, and ask a few reasonable questions...and as usual, you jump out of your skin to refute or qualify my statements, and to make personal attacks on my own motivations, etc.  Don't you think you are being a bit overwrought?  I understand completely the issues you pointed out, and always have.  But I also do see the behaviors in the HCV medical community that I pointed out.

  And, by the way, Castillo is NOT the only researcher who has discovered replicating virus after SVR. Far from it.  There have probably been more than eight or nine researchers finding similar viral behaviors after SVR, in recent years.   I am not having a hypochondriacal fit, or anything of the sort.  Merely pointing out my particular observations and opinions.  I hope you can live with that.  That's all we have here, is our opinions.  You are about as much a medical expert as any other person posting on this forum, and by your tendency to attack others who you disagree with, I would say you might benefit FROM some medical expertise!  I am not quite sure what your problem is.

DD
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it's very appropriate that an HCV forum have such limited memory, in fact it's one of the most endearing aspects of this place as it allows one the joy of rediscovering fundamental  truths on a regular basis! However, I can assure you your warnings about contamination were not forgotten - I think about them every time I'm pipetting, though I can't manage the luxury of separate benches, let alone buildings.

The hypothesis of riba as a facilitator for bystander killing of the residual stealth virions by promoting "loud-mouthed" mutations  is indeed attractive  A fly in in the ointment is that Crotty's "error catastrophe" theory seems to have come under attack, by Pawlotsky's lab among others:

Chevaliez S, Brillet R, Lázaro E, Hézode C, Pawlotsky JM.
Analysis of ribavirin mutagenicity in human hepatitis C virus infection.
J Virol. 2007 Jul;81(14):7732-41. Epub 2007 May 9.
PMID: 17494069

and
Chang KO, George DW.
Interferons and ribavirin effectively inhibit Norwalk virus replication in replicon-bearing cells.
J Virol. 2007 Nov;81(22):12111-8. Epub 2007 Sep 12.
PMID: 17855555

Also I wonder whether the relative size of the population resistant to SOC is a function of the host or of the quasispecies distribution. As I noted above, my interpretation of the success of the gene-expression predictors of SVR outcome is that the prevalence of "stealth" virions may depend more on the host's HLA alleles than on the original viral genome.

BTW, on the subject of testing,  it would be interesting to hear your thoughts on

Kretzschmar E, Chudy M, Nübling CM, Ross RS, Kruse F, Trobisch H.
First case of hepatitis C virus transmission by a red blood cell concentrate after introduction of nucleic acid amplification technique screening in Germany: a comparative study with various assays.
Vox Sang. 2007 May;92(4):297-301.
PMID: 17456153

or
Grabarczyk P, Gronowska A, Brojer E, Letowska M, Radziwon P.
Sequence analysis confirmation of transfusion-transmitted hepatitis C by red blood cells that tested negative by minipool hepatitis C virus nucleic acid testing.
Transfusion. 2007 Jun;47(6):1102-4.
PMID: 17524106

while sensitivity  of tests is important to patients, it's presumably all the more so to those managing the blood supply.
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DDquote: "I make a few comments, echoing what Willing and Mike had stated..."

Mike and willing echoed your sentiments that HCV is passed on by SVR's to uninfected people via casual contact? Sorry but I didn't see them state nor infer that. And I seriously doubt they believe that either, although I'll let them speak for themselves.

DDquote: "And, by the way, Castillo is NOT the only researcher who has discovered replicating virus after SVR."

Sure, that's why I said "et al" above. You know what et al means, right? And it has nothing to do with hungry cannibals, either.

DDquote: "I am not having a hypochondriacal fit, or anything of the sort.  Merely pointing out my particular observations and opinions."

I'm not saying you are having a hypochondriacal fit. But your belief that you're passing on the HCV virus (or symptoms) to those around you via casual contact, especially now that you're SVR, frankly is hypochondrial-like. I think most well informed and reasonable people would agree. And that's just me pointing out my observations and opinions.

DDquote: " I hope you can live with that"

I can live with it, and I hope you can live with being confronted with plain facts and thoughts that are contrary to your casual contact theory. And also concerning the stalwartness of the viral persistence theory that ties into your casual contact nervosa. Also, I've passed on commenting on many of your posts of this nature in the past. But you voice this theory so frequently that I've just got to say something about it. I mean, why not? This is an open forum, I am allowed to discuss it with you or anyone else for that matter. Like I said before, you're a good person and a nice man. But you being a good person does not immunize your theories from being open to critical debate. Especially when they'e as far out as your pet theory is. Besides, it's good for you to hear it. It might remind you that your worries are overblown and perhaps you'll be brought to understand there is an element of anxiety in your fears. I mean, you remember that really nice guy that had bad BO in highscool, and yet no one told him he had bad BO? Wouldn't it be better for someone to gently tell him? No one was doing mr stinky any favors by being politely silent. C'mon now, huh??!  ;-)
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But I do believe that my comments above were strictly limited to viral persistence.  I don't think that I injected any 'pet theories' or anything other than my perception of how the viral persistence issue is dealt with in the HCV medical (treatment vs. research) community.  When I do mention any other off the wall theories, or guilt-driven scenarios, please, by all means, do jump right in, and criticize them as much as you like.  I'm fine with that.  Just don't add unrelated information to my statements, or infer motivations as to why I commented on a particular issue.  That is just your own projection.

The fact that I have asked unusual questions, in the past, about a very unquestioned, carved in stone,  clearly agreed upon issue (casual transmission other than blood/blood), does not preclude other comments that I make from being uniquely relevant, or valid.  And as for some of my more 'far-fetched' concerns about atypical infection, and cellular transmission.......I take full responsibility for asking those questions....and you never know....in many scientific fields, clearly defined truths have in some cases been shown to be entirely different than was previously believed.  Unless you ask 'out of the box' questions, and don't accept all the 'known truths', you may never discover the full realities.  

That's not to claim my theories are valid.  I have never claimed that...but I have had observations that have provoked my questions.  If one always accepts the status quo as absolute truth, there will never be any new discoveries.  And, by the way, a major, nationally known hepatologist, is designing a study to look at 'cellular immune reactions to HCV' in family members and close contacts of those infected with HCV.  I believe he is also looking to determine what significance these 'cellular reactions, specific to HCV' might hold.  Now, if I am being absolutely hypochondriacal, and projecting my guilt, then what would you say this doctor's study is based on?  



DD
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And, in case you would like to read a very interesting research article regarding 'HCV cellular immune reactions' in family members, and the findings of one study, then read this one:  Also, note comments about 'conversion' to full HCV infection in some of the people studied.  Here it is:

http://www.ajtmh.org/cgi/content/full/73/1/44

You might find some possible reasons for my 'hypochondriacal rantings' buried throughout this article.  There are a few more, like this one, that have been published in the last few years.  One is US based, and hopefully, there will be new, and more comprehensive data from the study that is being developed currently.


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And for your amusement, and enlightenment,here is just one paragraph from the formal discussion in the above cited research article with some possible scenarios or explanations for what the HCV cellular immune responses in sero-negative family members might represent,  verbatim, from the discussion section:

"None of the subjects with HCV-specific CMI responses had a history of hepatitis or symptoms compatible with hepatic disease. The majority of HCV infections are asymptomatic, even during the acute phase.2 Therefore, we speculate that our CMI-positive seronegative subjects had a transient very mild infection, possibly associated with low-dose exposure to the virus, which was cleared. Infection is supported by most of the immune responses being to non-structural epitopes of HCV, an indication of replicating virus. A less likely, in our opinion, alternative is the CMI positive individuals have a healthy carrier state with the virus being present in some body compartment (i.e., in the liver) and not in the blood or it is replicating at levels below the sensitivity of our PCR assay (100 copies/mL).


Mremeet....did you catch the less likely alternative possibility that the researchers pose above????  Sound a little like a nutcase crackpot, hypochondriacal theory put forth by some angst ridden member here?  Gee, I guess there are nutcase research experts out there too, huh?

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I agree with your assessment of why there is little attention given to the persistent viral issue, and indeed there does seem to be little clinical relevance, so far, in having this post-SVR viral presence, especially compared to the unchecked infection.  My concerns are more focused on understanding how the virus operates, along with the immune system, and what governs when and why a person gains 'control' of the virus, and thus SVR, vs. relapse.  I also think that understanding exactly what this persistent viral presence means in the long term might be useful as it relates to immune system function over a period of decades.  Also, the issue of potential relapse, or probably more like a 'reactivation' needs to either be absolutely ruled out, or if there is a very small probability for this happening, it needs to be determined exactly which behaviors, medications, illnesses, etc. might have the potential to cause it.  I know that so far we are seeing about a 99%, give or take, durability rate for SVR...but this needs to be viewed over decades, and under more circumstances of extreme behavior or medical duress, to determine IF 'reactivation is at all possible.  We have all read the random story or two about viral recurrance from very high dose immune suppression therapy, and there seem to be few additional details relating to those cases to really make any clear determination.  I am curious about these issues because I think they can lead to a better understanding of how tx really works, and WHY it works, but beyond that, how some people are able to spontaneously place the virus under immune system control, from the beginning.  Maybe a fuller understanding of how that works, could lead to another line of medical treatments, based on newer gene alteration technology, or as yet unknown future medical breakthroughs.  I guess I think that it is not very beneficial for medical scientists to overlook the importance of the viral persistence mechanism, or to act as if it does not occur.  


Best wishes to you!

DoubleDose
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yes, I have to confess that my own fascination with all things "occult" has a very pragmatic objective : I simply would like to understand what factors play into the  SVR vs relapse outcome post EOT. In this regard, it seems a bit strange that none of the persistence researchers have found it worthwhile to examine EOT patients, look carefully at where the relapse-inducing virions live (PBMCs, liver, other tissues?) and what aspects of their  sequence has enabled them to survive the long ifn storm. This sort of "detailed interview of the survivors", once correlated with the eventual SVR/relapse outcome might go  a long way towards unraveling how the virus manages to get the upper hand again.
BTW, that Egyptian article was very interesting. I couldn't make sense of their CMI measurements, but will keep trying.
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I just looked ot the CMI measurements in this Egyptian study, they used elispots and, independently, intracellular gamma Interferon staining/flow cytometry evaluation of the response to HCV  specific overlapping peptide pools of the major HCV proteins. I assume that the New York Blood Institute Researchrs participating in this study did the major work of this kind, but not sure. As far as I could see, there was nothing wrong with their testing technology. Any specific concerns?

The paper by Pawlotsky finding that riba does not introduce an error cartastrophy type of increased mutations in vivo in HCV patients treated with Riba suffers from the problem that the noise introduced into the sequencing results by nested PCR might have been of such a magnitude, that a mild effect, not causing an "error catastrophy" byt indeed some mild speed up of mutational rate, enough to cause a switchback to wild type or otherwise CTL recognizable epitopes could not be seen.

Indeed, from other experiments surrounding this issue, we can deduct,

that a certain degree of mutations will be introduced, at concentrations that are attainable in vivo, because such a mutagenic effect will semilinearly depend on concentration,

by extrapolation,   from the higher  toxic riba concentrations , used n cellular systems/riba experiments  that definitely cause a clearly and robustly  higher mutation rate..

Thus my assumption is that it is not an error catasrophy type, that drives many HCV genomes into extinction, thereby causing an antiviral effect, but rather that a much more minor, subtle riba driven increase in mutation rate will drive the constant equilibrium of epitope loss and gain towards de novo recognizable HCV CTL epitop generation, with the net effect that the T cell system, the most important effector of the anti HCV efforts of the immune system, will regain and maintain control of the dramatically reduced viral population towards or at EOT.
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it occurred to me that, if this theory is correct, continuing riba post eot is presumably of greater value than ifn. Cells infected with residual, "stealth" virus, ie virus missing recognizable CTL epitopes (BTW there is a nice databse of known epitopes at the lanl hcv database: http://hcv.lanl.gov/content/immuno/tables/ctl_summary.html ) might still be able to activate the ifn expression pathways, and thus partly compensate for absence of the dosed ifn, however there's no way they could make up for the missing riba.

However the larger question seems to be whether there is evidence that riba is an HCV mutagen at in-vivo concentrations. Understood that the level of mutation required to construct de novo recognizable CTL epitopes is much milder than that postulated by Crotty's original "error catastrophe" hypothesis. However my read of the Pawlotsky paper is that they could find no evidence of any mutagenic effect above  the baseline induced by the HCV RNAP error rate in the NS3 and NS5A genes they sequenced. Their discussion section notes that their results in this regard are more reliable than either the preliminary ones based on vitro studies, since the concentrations used there,  50-100uM,  could never be reached in-vivo (though some of the riba dosing used during the SARS epidemic is impressive), or the results of an  earlier in-vivo study by Asahina in '05. They claim to be superior to the latter, in part,  because their analysis explicitly   accounted for quasispecies diversity as opposed to mutation-induced variation. I haven't yet been able to understand the paper in enough detail to decide if this claim is justified, but the challenge of separating the alleged riba-induced mutation from  a noisy  background generated by quasispecies differences, the ongoing RNAP error rate and the sequencing errors you mentioned seems to require some fine-tuned data analysis. In this regard, HCV patients everywhere would be enormously grateful if researchers would *release their damn data* and let others have a shot at analyzing it! (sorry, but this is one of my ongoing gripes).

Unfortunately, I can't get access to the full text of that Chang'07 paper, but from the abstract it appears they also support the no-mutagenic-effect-in-vivo position (here with a different virus, but presumably this is not relevant if mutations are based on riba as a generic guanosine analog) : "Sequencing analysis of the conserved polymerase regions of NV in the ribavirin-treated (100 microM) and nontreated groups showed that the mutation rates were similar and indicated that ribavirin did not induce catastrophic mutations."

As above, "similar" could possibly well be masking a  mild mutagenic effect.

Are there other data  that clearly support  a role for riba an an HCV mutagen at in-vivo concentrations?
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sorry, with regard to the Chang paper,  the analysis is on a cell-based system, not in-vivo. But still: no mutagenic effect observed at 100microM.
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OK, I'm working hard on extracting-foot-from-mouth;  it's not easy. On re-read of that article they did in fact deposit sequences for the derived clones in genbak with accession numbers AM400248-AM400838 and AM401639-AM402384. This means anyone interested can rerun their stats along with whatever other tests they choose to determine whether there is or not evidence that riba accelerated the pre-tx rate of mutation in those two genes. Nevertheless...IMHO this is very much a rarity, most summaries of clinical trial results *do not* publish their original data
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Any thoughts on the Egyptian study, that looked at Cellular Immune Responses?  I guess the crux of the article for me is: what to make of this phenomenon, and whether the researchers' second 'possibility' might have some possibility for being valid.  I also wonder how this 'mild infection' was transmitted, because they did not really pose any theories on why there would be a 'cellular' reaction, versus a full humoral reaction, which would have likely provoked HCV blood antibodies, or a full fledged HCV infection.  Do either of you see any 'holes' in the research?  From my perspective the study appears to be saying that a significant percentage of people living in close contact with HCV infected persons, in this study, came away from this association with some 'other' sort of either ' lasting immune reaction specific to HCV', or possibly some sort of 'controlled, compartmentalized inffection', not of the typical blood/liver variety.  I am still very intrigued by this study, and this subject.  I think there has to be some significance attached to it...even if the consequences of this cellular reaction are either still unknown, or presumed to be minimal, or absent.

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all I meant by "couldn't make sense of the CMI measurements" was that I'm not familiar with IFN-gamma elispot assay - simple ignorance on my part, not skepticism. I'll make an attempt at correcting that and follow up some of their refs.
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I just read a post on the other side of this forum from someone who has relapsed and is now in their 36th week of vertex which I assume from the post ends at 48 weeks, what would be the difference from vertex after relapse and me doing high dose and stopping at 48 weeks with 4 week rvr? I am planning on doing the 72, but I wonder what exactly is the difference from vertex knocking it down hard and fast and myself high dosing SOC and knocking it down hard and fast?
Thanks,
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"hard and fast" are not really quantitative expressions. Vertex reduces  the replication speed by a factor of 10000 for those HCVs that are not resistant to its action. So the Vl goes down even much much faster than on high dosing SOC. This reduces the chance for adaptive mutations, except for the a priori telaprevir resistant HCV portion.
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You might want to take a look at the current "vaccine" thread where the cellular immune response is explained in more detail, it can explain, how household contacts could show only Cell Mediated Immune responses (CMI) as shown in the Egyptian study.
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more food for the soul...another excellent discussion

i have an interesting (at least to me) curve ball to throw into this. time will tell if perhaps the CTL sentries that are still on patrol in my SVR status will continue the good work of maintaing my SVR.
assuming that occult hcv is a fact as research clearly shows and i have occult fragments status SVR

Hr am i assuming incorrectly that in SVR the occult fragments that are present are held in check by the primed CTL's successfully preventing any occult fragments that "could replicate" , find their way to happy hunting grounds in the hepatocyte and cause pathology?

for me this may be a mighty big news. sucessful treatment EOT 7/06. negative PCRs since week 4 of treatment. .
start of humira  4/07 which is tumor necrosis factor inhibitor.  this med is known to activate hepb and TB in clinical remission.

consult with 3 docs (2GI's and 1 Hep) before starting and ALL said this med would NOT affect my SVR.  i specifcally asked in view of occult hcv studies if the med could suppress immune function that could cause successful replication and activation of any occult virons left. again the answer was NO.  also i wrote the pharm co and they said there was no evidence of it reactivating HCV.
however my rheumy was concerned and would not give me the same reassurance. the need for intervention was considered and because of the GI docs go ahead i started med.

now after a better understanding of the cellular immune response (thanks HR) and perhaps any occult virons left after SVR perhaps controlled by primed sentinal CTL's vs adaptive anitbodies present,  i now might be a guinea pig.

although i do not have a clear understanding of the role of TNFa except as it being a key pro inflammatory cytokine in the inflammatory immune response; increases liver inflammation and apoptosis.  i have failed trying to figure the interactions of all those cytokines. geesh they "talk " a different language i have yet mastered)  i can't figure by my research if it is associated more with the TH1 vs TH2 response. ( my guess it is TH2 but am not sure of this or how it affects T cells? )                                                            

i had a PCR done 3 months after starting humira= undetected july 07
will request another Jan 08 instead of waitiing till july.

the result might be interesting in view of the occult phenomenon. i am a bit more nervous now.
why would my docs give me the heads up knowing occult studies, immune response, that this med would not reactivate hcv?
btw...i know of another person hepc SVR on the same med and after 2 yrs on treatment has sustained SVR.

HR...am i being paranoid or do you think my concerns have any merit?
also.......considering telaprevir effects in decreasing hcv replication (however not on resistant populations) would the T-cell vaccines be adjunctive to these resistants...any resistants; or are the resistants present by their morpholgy not able to stick to receptors on the MCH1 molecules thus to designed Tcells no matter how programmed?

DD maybe my situation might bring in more information about the significance of occult hcv.
if this med reactivate's  HBV i may be in for another ride on the tx rollercaster in regards to HCV reactivation. >0<  



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Wh: why would my docs give me the heads up knowing occult studies, immune response, that this med would not reactivate hcv?
-----------------------------------------------------------------------
If the question is will Humira reactivate HCV in someone who is SVR, I think you can go to bed at night with the knowledge that there is no clinical basis to worry, as related to you by your doctors and pharn company.

That's because SVR has been shown over and over again to be durable in studies going out 8-10 years. As far as I know, there have only been 2-3 documented cases where the virus was reactivated because of immunosuppressive treatments.

-- Jim


btw...i know of another person hepc SVR on the same med and after 2 yrs on treatment has sustained SVR.

HR...am i being paranoid or do you think my concerns have any merit?
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Please ignore the accidental copy and paste below my name in the post above.
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thank you for the reassurance, much appreciated. the only glitch is i am not sure humira and HCV are considered in the stats of durable SVR. i can not find exactly what the immunosuppressvie treatments were that factored in SVR relapse...do you by chance know?

however like DD, i have an uncomfortable lingering wonder what the significance of occult hcv is really all about. i am not losing sleep though...just that uncomfortable question lurking and waiting for more information in the sea of conscious random thoughts, lol
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you might want to flag mikesimon and discuss his personal experience with the tradeoff between immuno-suppressants  and hcv rebound. I only investigated this briefly but my impression was that among liver-transplant patients rebound of VL in response to the drugs required to prevent rejection is fairly common. The good news for you should be that, having developed those magic activated T cells they'll stay with you for life - reduce the immuno-suppressant dose and the VL should drop to UND.
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A permanent supression/control of remnant virions aftert SVR by an established vigorous Class I and II T cell response tends to be very stable and not very dependent on TNFalpha/unspecific proinflammatory signals. Therefore chances that Humira will cause a HCV breakthough/SVR loss are extremely slim.
With respect to the "occult" "remnant" infection, it has to be clearly stated, that in all likelyhood we are dealing with a huge range of differences within the remaining viral genomes, from close to Zero to many millions, without a simple way to check for that, other than sending a biopsy to Castillo in Spain. What matters its the apparent stability of SVR in almost everyone, regardless where they might be in that range.
Nevertheless your concern is not totally unfounded and only after many years of many SVR  patients on Humira we will know for sure.( Provided someone publishes/collects that data. Not the company that makes Humira, I would assume)
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151263 tn?1243377877
FYI I took large amounts of prednisone starting at about week 7 during my tx (VX950 trial) to control a telaprevir rash. And I took gobs of the stuff for well over a month afterwards, with doses ranging up to 80mg/day (that's a LOT). Then I stopped the VX950 early (by week 8) and was no longer anti-virologically covered afterwards by it (VX950 leaves your body very quickly). Then I stopped taking ribavirin for several days, and then only continued with a reduced dose afterwards (800mg vs 1200mg). And this all happened by about week 8. Then another week later I had to get a jolt of a powerful IV immunosuppressant called solumedrol (much more powerful than prednisone, but in the same steroidal class of drugs). And this all happened between about week 7 and week 12, right smack in the middle of the most critical phase of tx (for SOC anyway). And yet I maintained my UND status during all of this and went on to SVR after 41 weeks of tx (with sub-weight based riba during the remaining tx). As you can see powerful immunosuppressants like prednisone and solumedrol don't even seem to be able to unhinge an SVR, even though I didn't (technically) have my SVR at all yet. I don't know how powerful humira is, or what doses you'll be taking, but I doubt it will have the immunosuppressive power of what I was adminstered. I'd trust your docs on this one. You don't want to take immunosuppressants willy nilly that's for sure, but if I really needed them again I would use them judiciously as required, and would do so without too much fear. From where I stand, if SVR doesn't truly mean complete eradication, it sure puts on a reasonable facsimile thereof.
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You said to whrose ""having developed those magic activated T cells"" I read this  ""Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia"" if you have a minute could you explain a couple of things? How does one's body ""develope"" these ""magic activated T cells"" is this what happens (to some) when we are on treatment ((in lay terms please)) and is this ""the negotiation between virus and host immune response that determines SVR"" you spoke of earlier?
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You might want to read the explanation on how the HCV specific activated T cells are developed in the recent "vaccine"  thread, where I explain it in the necessary detail, as "laytermy" as possible without loosing it all,  building it up from scatch..
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233616 tn?1312790796
I'm curious as to why they didn't try to suppress your rash with some of the stronger allergy drugs rather than steroids, known to harm the liver?
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233616 tn?1312790796
yes, please, tell us how they all turn into "Mr. Anderson's"  (the Matrix)!!!!!!!!

I'm wondering if my T-cells were kicked into a higher gear by going on the HGH since this is when the fevers/sweats became pronounced. Is it possible that HGH could be aiding in T-cell response?

Mary
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151263 tn?1243377877
Well the steroids I was on were pretty strong, especially the bolus solumedrol (that's what they give people in the ER that are having potentially lethal allergic reactions to bee stings etc). And to my knowledge prednisone can be a very potent immunosuppressant, it just depends on what dose you take (and 80mg/day is a lot). So I don't know what immunosuppressants would have been better or more effective than these for controlling my runaway rash. Also, of course both me and my doctor did not want to overdo immunosuppressants considering I was knee deep in tx and a steroid jamboree could have nixed my SVR for good. So as far as I know what they gave me was what would commonlpy be used for that sort of thing. Why, do you think another type of immunosuppressant would have been better?  
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233616 tn?1312790796
I wish I could tell you of what else might have worked, certainly if your rash was to the anaphylaxis stage probably nothing else would have, but you didn't say that at first.

Don't know what the current thinking is, having not kept up on the reactions field, at one time I had to.......but it used to be no steroids for folk under 80, when the first liver studies came out.
I had chosen to forego steroids in my 20's even with raw grapefruit sized patches on my skin, based solely on the reports of liver damage.....so even then I was "being careful" as I could be.

I know that whole bad rap is much underplayed now, and certainly people want relief, but the public at large I do not think know, nor are they warned as to how cummulative steroid damage is to the liver.
Even though, when you think about it, with all the athletic abuse it should be common knowledge.

Of course if your rash was bringing lots of fluid to your skin surface, that means it could also swell your throat and make your heart stop...in those cases what's worse is thrown out, it's what will stop the allergic reaction in time to save life, and darn the torpedos. I've been there too.

I guess I was questioning, only based on your veriage of "bad rash". Obviously there's bad, and then there is BAD.
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yes, development of  an effective immune response to the various "efficient" forms of the virus is the negotiation I believe is at the heart of SVR. I think of each tx as a sort of  rerun of "High Noon" - after 48 (or 72) weeks of hell the streets are deserted. All that's left is a few surviving virions (black hat) and the DC and lymphocytes (white hat), just like at the time of the original acute infection. This time will the guy with the white hat (finally!) manage to get his act together or will  the banditos run amok all over town once more?  and so the story continues.  HR's summary of the mechanics of T cell activation in that vaccine thread doesn't bear improving on - check it out.

Also, re your question  about the relative damage done to the virus by vertex vs soc unnfortunately I don't believe there's an answer. The virus' greatest strength is an error-prone way of making copies of itself (there's some deep philosophical insight here about the fundamental importance of change) and this error rate per virion is pretty much constant. If you could knock off enough of the total virus quickly enough there might be so few survirors left they might not be able to find the necessary escape mutation in time. For vx this doesn't seem to be the case, within a few weeks the survirors have found the way out - but possibly with other drugs.  How quickly is quick enough isn't known as best I can tell. In principle the simple but effective models used to predict the virus' steady-state population could be adapted, but I don't believe this has been done.
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151263 tn?1243377877
willingquote: "If you could knock off enough of the total virus quickly enough there might be so few survirors left they might not be able to find the necessary escape mutation in time. For vx this doesn't seem to be the case, within a few weeks the survirors have found the way out..."

Not to nitpick, but the virus does not necessarily have to come up with a telaprevir resistant strain "on the fly" in order to survive after the anti-viral onslaught initiates in all patients. Many patients were tested for PI/telaprevir resistant virus prior to being given telaprevir (and other PI's), and in a fair number of them either a partially or wholly resistant virus was found to already be in existence (albeit in very small numbers). So the mechanism for survival in the face of a PI attack wouldn't necessarily always be a purely adaptive one borne of a ferocious rate of mutative iterations and managing to come up with that "one in a trillion" just in the nick of time during the onslaught. It could simply be a case of the non-resistant variants being wiped out, and the very few pre-existing resistant types simply moving in and taking over (especially in the case of PI monotherapy). That is unless there are mutliple anti-viral modes of efficacy in play to keep this from happening, as in VX+SOC.
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yes - good point - in fact given the high rate of polymorphism in the genome distribution of a typical infection it may well be the case that nearly all viable genomes already exist. Thus time may not be as relevant a factor as simply the size of the survivor population and the extent of its handicaps (the "one legged, two-fingered, tongueless" Will Smiths of  viral Manhattan). From AASLD abstract LB8 on TVR mutations :

"In the TVR groups, viral breakthroughs were associated with the selection of known TVR-resistant variants. The breakthrough rate in the TVR/P group was higher than in the TVR/P/R groups, suggesting that suboptimal inhibition of viral replication provides a greater probability for selection of TVR-resistant variants. Some subjects with viral breakthrough on TVR had a subsequent decline in HCV RNA during treatment with P/R, indicating that emergence of TVR-resistance does not preclude response to P/R."
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179856 tn?1333550962
"SVR's often don't require their care and expertise, at least in regards to the issues associated with an ongoing HCV infection (obviously because they're SVR)"

But isn't that sort of the point?
Wouldn't this statement sort of be like comparing antibodies to active viral liver eating HCV?  

As a research tool to understand (and hopefully learn to RAELLY eradicate the virus) it seems that it would be of major importance - however with the lacking of funding and any government care of this ongoing plague that is attacking the world today - I'd rather doctors work towards effectively gainning a greater portion of our population achieve SVR, whether it be TVR or any of the new medications that are being developed or just improving on SOC and tweaking it out with extended time or testing or anything.

Until the time a greater majority of the world realizes exactly what is going on and how prevalent this disease truly is - it sort of seems like putting the cart before the apple to me.  A great discussion but certainly getting everyone to the point where the disease is no longer rampantly destroying the liver seems to me is numero uno important and this may still be somewhere down the list.

If indeed my 72 weeks of treatment completed leaving 'mutant but non-destroying' viral cells inside that's fine but it's when it comes back to viral infection and liver damage that I care.

I'm sure i live with so many bacteria and virus' inside this old body that I don't care a whit about one more...as long as it stays suppressed or whatever the right word is - is all I care about.

I consider that 100% cured.  Let the suckers stay in there sound asleep for all I care...as long as the viral replication and infection and liver death aren't a part of it, I'm fine.

Just get everyone there first.  White Hats rock on - however I do worry that with TVR it seems to me that the White Hats might just need a little more time after wiping out those Black Hats with some regular old SOC perhaps as the taper down mechanism just to make sure they don't find any grey hats have been born.  (just couldn't resist).

But then I can't understand 99% of what is really going on in this thread as usual.  Willing and HepR'r and Meet and Mike and Jim..........have at it you guys are just too smart for me.

I can only deal with black and white and grey hats for now :)
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151263 tn?1243377877
You probably are already aware of this, but the boceprevir team has utilized a unique dosing strategy of an initial 4 weeks of SOC followed up with another 24 weeks of SOC + boceprevir. From memory one of the researchers hinted that it was important to get those IFN molecules up to strength prior to dosing the BCVR (or something to that extent). And he seemed pretty coy about the whole thing, as if it was his big juicy secret (and he had all the prelim viral response data at that point in time too). His boss cut him off before he said anymore about it. I suspect SP came up with that strategy in an attempt to pre-emptively deal with the resistance issues that they undoubtably learned about from the Vertex trials and from their own mono-therapy trials, especially considering that SCH503034 is less effective in vitro than VX-950 was (as far as I know).

Anyway, I can't help but keep thinking about that delayed PI dose strategy. I think it might have merit and it might help to alleviate the problem of PI viral resistance. I could see where there would be a real benefit for the patient to start out with SOC and to get the IFN and riba serum levels fully ramped up, and to get their respective referred immune responses near fully engaged FIRST. Also, the VL is likely to drop at least a log or two (and usually more) within that same timeframe - obviously (1) reducing future resistance breeding stock, (2) killing off most (or all) pre-existing PI resistant strains, and perhaps (3) letting the riba work it's "unfitness" magic on what breeding stock remains (assuming riba actually produces that effect in a meaningful way). THEN imagine the PI being brought into the picture at that point in time? Seems pretty clear that as long as the SOC drugs are working at least reasonably well, the virus will have an awfully hard time playing catch up after the anti-viral equivalent of "say hello to my little friend" takes place.

Also, examining typical viral responses during PI monotherapy, the PI has immediate and strong efficacy up front. But within just a few weeks it invariably wanes and soon afterwards there's a full VL rebound to pre-tx levels. The whole shootin' match is usually over in less than 4 weeks. I noticed that the viral responses of those (in prove 1/2) who did not receive ribavirin were very similar to this, except the VL rebound had a greatly damped and somewhat delayed action. But you could still see the same basic dynamic there, where there would be a fabulous initial dropoff, then a tapering off, then maybe even UND for a bit, then re-emergence, and then the VL floats along at low detectable levels after that (obviously being suppressed by IFN alone). And in the relative few who experienced this same phenom with the riba included, it was probably due to being relatively insensitive to the effects of SOC (or they simply weren't taking their meds like they should have been). And that's another reason I think the delayed intro of the PI could be good.

Someone who is relatively insensitive to the effects of SOC are most vulnerable to developing a PI resistant strain (when PI's are dosed concurrently). Either they are slow to respond to the referred effects of SOC and/or their total response once the drugs are fully in play is lacklustre and sub-par. It seems clear to me at this point that the PI has a precious and fleeting window of efficacy that doesn't last very long. If it's given concurrently to those who fall into the SOC insensitive category, by the time whatever response they are going to have is fully elicited, it's too late - the PI has already shot its wad and the game is over. The resistant strains have gotten a footing, and the SOC is flying solo at that point. And because the person is SOC insensitive, that’s it - failed tx. But on the flipside, if the SOC insensitive person is allowed enough time to ramp up whatever response they're going to get out of SOC (by commencing SOC tx for at least 4 weeks first) and then the PI is introduced when the SOC drugs are at the peak of their powers - THEN I could see where even these tough to treaters might have a shot at SVR redemption.

Bottom line is that it just seems that the major problem that gives rise to the production of resistant strains is linked to the simple fact that the PI's up front strong efficacy that rapidly wanes afterwards is not properly coordinated with SOC's relatively slow up front efficacy. If the two modes could be synchronized so that SOC is fully brought to bear first after ~4 weeks and only then the PI is brought on board, I suspect this could pay dividends. That way both modes are additive and are synergistically synchronized at the peak of their powers, instead of having one mode slowly ramp up while the other fairly rapidly ramps down.

Anyway not to go off on a tangent, but the quote you referenced above made me think of what that SP researcher said. I really hope we hear more about the staggered dosing strategy, I’m hoping it bears fruit, especially for those who are relatively insensitive to SOC.
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144210 tn?1273092382
Interesting. I have wondered the same in theory only with the Alinia. It seems to make sense that as a former responder to SOC, perhaps knocking down the virus levels and then introducing the Alinia to "mop up" the more resistant virions might work best. But, I also know that a common sense approach might just be the wrong thing to do and will simply trust the advice of HR on this, of course. Do you have any thoughts on how Alinia might best be introduced into SOC?
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151263 tn?1243377877
I really know nothing at all about the antiviral kinetics of alinia, whereas I've seen quite a bit of data on PI's (and experienced VX950 firsthand). Based on what I've heard from HR on it, alinia's anti-viral mode of action is definitely entirely different than a PI, so I would not apply the delayed introduction theory above to alinia (and the theory posed above is just that until more is known anyway). At least not without knowing a whole lot more about Alinia and with information in hand to suggest that it would be a good idea. No, I'd say if I were treating with alinia I'd take it concurrently with SOC just like I believe HR suggested (although I'd predose riba, and probably doubledose IFN for a few weeks too). Plus since you already know you're not SOC insensitive, the benefits of a postponed introduction would probably be for nought anyway. The majority of people who took VX950 with SOC concurrently quickly went UND and later went on to SVR (those who were sufficiently sensitive to SOC that is)...and they did so without the staggered dosing. So until we hear more I would definitely leave the staggered dosing to the PI theoreticians, and just keep it simple by taking all of the drugs at once. My $0.02 anyway, let us know when you decide to get started dude, it'll be interesting to get a blow by blow alinia + SOC tx account.
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144210 tn?1273092382
I will see the doc after the holidays and try to get him on board with Alinia. If he does, then I will probably start tx soon after. If not, well, I will have to go doc shopping.  I'd like to drop another 10 lbs as well, which will give me a grand total of 45 lost. I will definately be around here during treatment and thanks my friend.
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nygirl: hey as long as the guy with the white hat wins in the  end all is cool!

mremeet,gauf:
yes, I definitely agree that as the number of tx options increases (and I'm still a big fan of both r1626 and ntz)
http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Investigational%20HCV/Capsules/167.aspx
determining an optimal strategy for how/when to combine is very much an open question. Some key variables per drug seem to be the proportion of the viral population susceptible, the amount of time required to reach maximum efficacy and the fitness of the  survivors, that is their  ability of survivors to repopulate. TVR and SOC have very different profiles on those three indicators. A good strategy might be to delay TVR until either prior to  EOT or first  evidence of a flattening of the VL curve.

That is, as long as SOC is working give it a chance to eliminate as many genomes as possible and when it either appears that soc is encountering resistance (ie weekly log drop is lt 1 ) or as insurance against relapse at EOT apply the TVR. As far as I know TVR has no general anti-viral effect, it can be simply counted on to quickly eliminate the X% of virus that does not include the necessary survival mutations. Deploying it when the number of survivors that will survive its effect is as small as possible makes good sense.

On the other hand, NTZ's effect, due to inhibiting dephosphorylation of eukaryotic initiation factor 2α, seems non-specific and complementary to ifn. Thus it would seem to make more sense to include it as an adjunct throughout soc.

As someone  counting on the independent and thus additive effect of multiple drugs for my next tx this question is of great interest, but I don't believe there's much guidance yet.
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