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Avatar universal

hepatitisresearcher

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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Avatar universal
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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144210 tn?1273088782
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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Avatar universal
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?1273088782
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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Avatar universal
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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179856 tn?1333547362
"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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Avatar universal
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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Avatar universal
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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Avatar universal
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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233616 tn?1312787196
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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Avatar universal
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?1312787196
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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233616 tn?1312787196
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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Avatar universal
MEDICAL PROFESSIONAL
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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Avatar universal
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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Avatar universal
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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Avatar universal
MEDICAL PROFESSIONAL
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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Avatar universal
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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Avatar universal
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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Avatar universal
Please ignore the accidental copy and paste below my name in the post above.
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Avatar universal
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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Avatar universal
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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Avatar universal
MEDICAL PROFESSIONAL
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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Avatar universal
MEDICAL PROFESSIONAL
"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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