I'll post more accurate numbers later (hubbie has dinner ready!), but in monotherapy in '98 I had cleared at week 4.  I think my starting VL was 2.9 million and week 24 was less than 100,000?  I argued to stay on drug and be labeled a partial responder, but they adamantly asserted I was a non-responder.  '00 starting VL was about the same, 2.9 million, never cleared, taken off treatment at week 24 at 200,000?  Again, docs insisted I was non-responder rather than partial.  No eye problems up to this point.

Infergen starting VL was 3.5 million (?), at week 4 750,000?  Doc thought this was a bad sign as far as clearing.  Daily Infergen at 15 mcg per day, Riba at 1,000 mg per day (same Riba dose as with Peg in second treatment), developed eye problems at week 9 and was stopped.  Ending VL 6.5 million.  Local doc and best-in-world doc in Boston said NO current treatments are going to work for me, and predicted my chance at having cleared on Infergen/Riba at about 3%.  That's why he said I'm an excellent candidate for VX-950.

I weigh 130 pounds, 5'5", though have intentionally put on 10 pounds so I can afford to lose it if I get sick during VX-950.  Now I'm trying to lose it again since my gut feeling is they're not going to let me in.  I'm interested in your thoughts, HCA.

Jim, I couldn't agree with you more.  I can only say that I'm suspicious and mistrustful that David Crosby got a liver transplant while others undoubtedly on the waiting list for much longer than he was were passed over, and then Steven Tyler clears, just like that.  Tyler could have been more of an advocate for us in the difficulties with treatment and the urgent need for a cure for us.  I think the U.S. is disgusting in its health care system (or lack thereof) when compared to other countries.

I'll get more accurate numbers and post them after din-din, as they're sitting right here.  I just have to find them!

Chris,

Ever watch "House" on TV? You know, four doctors (and one of them a hottie) 24/7 on on patient for as long as it takes to get them cured, often throwing SOC out the door and trying any and everything reasonable? Well, that's a TV fantasy -- or maybe the kind of care Bill Gates might receive or someone with a very "interesting" disease -- interesting to the doctors that is. Still, in the real world, I think if Hep C was treated as agressively as certain cancers in those with significant liver damage, we could see a much higher SVR rate. Maybe it's as simple as cancer got the funds and HCV didn't. This self-injection and pills twice a day sh*t (and only three PCRs during tx by many doctors) seems second rate treatment given today's medical technology.

Sorry you didn't clear this round either. I'm also curious if you relapsed or simply didn't respond. Also, how much ribavirin did you titer up to and what was your weight?

HCA,

Some of the Sweedish rib studies seem to suggest that less than optimal levels of ribavirin could account for either non-response or relapse. I think the doctors here aren't all that much interested in riba research because both the big prize and the big bucks seems to be with the protease inhibitors supported by major trial money. Why fix the old car when you can get a new one :) Not that I wouldn't like to see ribavirin replaced, but I still think interferon is worse in terms of long term side effects. Hopefully, they will develop a treatment without neither although everyone seems all too comfortable keeping interferon along side the PI's based on efficacy with IMO not enough consideration to long term side effects.

-- Jim

The key point here is whether the treatment failed because you cleared and relapsed or because you did not achueve viable levels of viral eradication.
The mention of Infergen strongly suggests the latter,but if it was a relapse perhaps you could let us know.

First correction: typo in last sentence "if IFN  should be "of IFN". Riba ahead of IFN,

Jim, you see correctly that - if accepting the simulstart combo paradigm - there is a fundamental problem with a drug that builds up to its effective levels over weeks. IV riba would make sense, but is just one of those possible  variations that could provide SVR benefit, but are probably never done due to the trial limitations.

Riba is a special case in several ways. It is not a good HCV antiviral by itself - its monotrials showed only marginal reductions in VL.  Considering this, there might not be such a phenomenon as resistance to riba - very weak antiviral dont breed resistance, since there is no gain for the resistant virus.
Of course, one could make just the opposite argument: A semiweak antiviral breeds dead sure resistance, since the remaining adaptive power is enormous.
The mechanism of action of riba in the combo is still a matter of debate - Fostering Th-1 cytokines/immune propensity or hypermutating the already error prone replication mechanism, thus driving many HCV offspring into abortion/reduced fitness/new epitopes. This pertains to the question of ribas resistance participation in the combo, since resistance against ribas more indirect antiviral effects might be hard to come by, even for HCV. Like to invent a less error prone Polymerase or a proofreading mechanism, this type of adaptation is not as easy as simply sticking out a new amino acid side chain where a proteinase or Polymerase inhibitor wants to bind/snuggle in.

While the simulcombo paradigm still holds, it might therefore be more important to reach effective  riba levels before IFN kicks in. A compromise to the purist and I would prefer the IV riba approach.

HR: A compromise to the purist and I would prefer the IV riba approach.
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Is it possible then to safely administer ribavirin IV to reach let's say a target serum riba level as measured by HPLC? I mention this because I imagine that a quick rise in serum riba levels would also be accompanied by a quick drop in hemoglobin without the body having time to adjust for the lower hgb levels as it does now with the current oral dosing and slow buildup.

But assuming it is safe, and the anemia issue can be addressed via  prophactive administration of Procrit and/or standby transfusion, I'm surprised this hasn't been tried. I do understand financial considerations, but if cancer patients can be hospitalized for very agressive short-term treatments, then why can't HCV patients get the same attention? Purely financial? Political? A combination?

Personally, I'd rather spend ten days or so in the hospital if it dramatically cut my treatment time down (and SVR chances up) than spend over a year on my couch from the current treatment approach.

Thanks for all your help.

-- Jim

Jim,

I agree with you about being hospitalized for a shorter course of treatment.

I don't know if this is relevant, but when I did Infergen/Riba last year, I started the Riba dosing gradually for four weeks before starting Infergen, so that at 1st Infergen shot I was at full dose Riba.  The reason was because the Riba had me so nauseated in '00 with Peg that I actually had to quit treatment for a week altogether, then gradually "sneak" the Riba back into my system a little at a time till I get could to the full Riba dose.  I never had to reduce dose after that.  Unfortunately, I failed that treatment just as I have all of the others.  I didn't know if this treatment would be helpful.

HCA: I was of course suggesting that pre-dosing riba may confound the creation of the INF resistant sub-strain by building up sufficient riba to corrupt the mutational ability by the time the INF hits.
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That would be my thinking as well along the lines discussed. But even if riba works its magic along different lines -- some suggest the exact mechanism isn't known -- the fact remains that there seems to be some relationship between serum riba levels and RVR and therefore SVR. So, it seems to make sense that getting the serum riba levels up prior to the first Peg shot will further the viral eradication process.

-- Jim

I infered from HR's response to my query that a fundamental of combination therapy is to fire all of your guns at once.
I was of course suggesting that pre-dosing riba may confound the creation of the INF resistant sub-strain by building up sufficient riba to corrupt the mutational ability by the time the INF hits.
If I have misunderstood I would appreciate clarification.
The theory that the seeds of relapse are sown at the very moment the virus is first mown down has been on my mind a great deal.
The suggestion is wholly compatible with the known facts that SVR follows RVR and relapse equates with slow response.
It would also appear to bode well for the efficacy of the Vertex compound in upping SVR rates.
(not much mention of the 'rash' on P.R front,particularly when bearing in mind the alarming first hand accounts of this phenomenon that have appeared on this forum)

I think I followed you up to the last sentence.

Are you saying that pre-dosing riba prior to SOC is a good or bad idea?
-----------------------------------

If it's the latter (bad idea) is the logic by your analysis that you're starting with mono therapy which might allow mutants to arise?  

However, aren't you in a sense starting with mono therapy in SOC since it takes several week for riba to reach its maxium level per prescribed dose in plamsa? Or are you differentiating between interferon monotherapy and riba monotherapy because interferon works directly on the immune system? Is there a possible happy medium then where pre-dosing might be effective if started not too far in advance -- say maybe 2-3 weeks? This is where I come out on a purely intuitive basis.

Lastly, is there a way to get ribavirin up to maxium prescirbed serum levels concurrent with the first peg shot by let's say IV injection and has it ever been tried?  

Around a year ago, I believe someone's wife posted here that her husband was in a trial that sounded like they were pre-dosing ribavirin 3 weeks prior to treatment.  I tried finding it over at "clinicaltrials.gov" but drew a blank. Do you have another source?

Thanks for all your help.

-- Jim

thank you for that enlightening analysis...well said!

The evasion from the T cell response is one important component of viral defense, but equally important is the evasion from intracellular antiviral mechanisms.  
The T cell evasion is mostly caused by mutations in the critical epitopes AA sequence. The idea that fibrosis causes a diminished access capacity of migration through the liver  for T cells to screen for the presence of infected cells might have some validity, but cannot be the primary reason for leaving some HCV behind in the removal process. It is rather a tricky adaptation of its vulnerable parts that makes the virus both "invisible" to the T cell system and still allows it to shut off the intracellular antiviral defense mechanisms at the same time without loosing all fitness to replicate. That is difficult even for HCV, but one or a few of its trillion children - if the virus can make that many in the short time it has while under multiple attack- do come up with this supercontorted trick. Some think that this mutant is already preexistent, but, against a multiple combo, this is unlikely. So of this HCV supermutant -produced in the few days before the adaptive power of HCV  has vanished- very very tiny amounts are present initially, but it has the capacity to wait it out, while its brethren are dying by the million per second.
Thus everything important probably happens while the virus still can breed large amounts, a capacity that is lost within days if powerful combos are used.  Riba ahead if IFN is not a concept that fits the fundamental paradigm of combo therapy.

I was struck by your proposition that the mutant species that cause relapse may be created in response to first wave of anti-viral therapy.
Popular conception (among patients at least) is that relapse is caused by residual viremia lurking in fibrotic or cirrhotic tissue where it can evade the T-cells.These two ideas are not,of course,incompatible.
Your suggestion appears to make sense insofar as rapid and brutal eradication of viral serum would give the mutatation less opportunity to enter the fray.
Could this be an argument for pre-dosing with ribavirin?

Considering the incredible adaptive power of HCV any kind of monotherapy is likely to fail. If you followed carefully what was previously presented here, one of the "official" new HCV antivirals supressed the virus by 99% after 4 days and yet after a mere 2 weeks , under ccontinuous dosing, all trial participants returned to baseline VLs- total resistance in all participants! And the AASLD abstract 92 by Tara Keiffer of Vertex showed that out of 8 patients receiving 950 Monotherapy, 4 experienced viral breakthrough or plateau response after two weeks, all with respective resistance mutations.

While the resistance propensity of antivirals differs widely due to mechanism, suppressive power, molecular target and the ease with which HCV can produce mutants fit enough to suceed, the working hypothesis must be that no mono and likely no simple dual therapy can retain this virus from adapting. Note that IFN is not just a " monotherapy" but has multiple , complex activity against HCV, classifying it a priori as " pseudocombotherapy).Apparantly not comboish enough, however. Thats why riba helps and more elaborate cocktails will help even more, if used properly.

The second problem with monotherapy - and that goes most likely for Alinia as well - is that, once resistance has set in, even in the past and even after no drug was given for prolonged periods of time its future use in a combo is clouded with a quick return of the resistant variant that has been" archived" as Doug Richman puts it. Same for HCV and HBV and HIV.

A combo treatment cocktail needs to be given in combo from the start and ideally the virus has never seen any of the drugs before.
Thus any of the official helper drugs or the Alinia or perhaps the oxymatrine should never be used without the IFN/riba combo, started simultaneously and should never be used before in mono form.  
Rapid supression of the adaptive evolutionary power of HCV must be the guiding concept to combat HCV. The mutants that eventually stage the HCV combeback when treaters relapse after a full year of therapy with even "UND" for 6 month are PROBABLY CREATED WITHIN THE FIRST DAYS AFTER THE IFN/RIBA WAS STARTED, in tiny amounts. If you cut -by using additional replication reducing drugs("helpers") - the adaptive power by a factor of 100 or 1000, then these early mutants probably never come to live.
HCV is an incredible sophisticated huge molecular machine that has a milion times a million! offspring and mutants per day. There is nothing trivial about that and we must use all levels of sophistication to combat it. No mistakes are forgiven.

Re Alinia, with all due respect, the approach by the company to pretreat for three month and then add Pegasys for 6 month is prone to breed Alinia resistance.

I also believe that Alina will eventually be used in a cocktail with a variety of antivirals. There was a study in Eqypt that used Alina as monotherapy and several here that are not really big studies that are using Alina with Inf and Riba in some cases, I believe. The study in Eqypt showed a great responce to the virus, but I don't believe it was sustainable over time, therefore the need for others. I believe this is one of the problems they are having with VERTEX. I haven't heard resistance problems in Alina, but have in VX950. Please HR correct any mistakes I have made here, this is off the top of my head. Thanks.

I'm really obsessive as you know. It's going to be a LOT of hard work for me to not be running in for a PCR constantly.

I'm thinking that probably I'll do about the same schedule for PCRS post treatment as I did during treatment (4, 12, 24...) if I can. I haven't talked to the doc and don't really know what is considered "typical" but I'll TRY to stick to it. I don't want to go to jail for forging Medical Orders for PCRs ;)

Of course - I have to convince the doctor what I want but I don't think it will be much of a problem. I do intend to get frequent CBCs though (although I am SO lazy about actually going to the blood suckers!) it's important to figure out when the hemo comes up and get off this epogen asap! No more needles is my motto!

There is someone posting here who is doing Alinia and IFN, I believe the reasoning is the Alinia will whack the virus while the IFN hyperstimulates the immune system.  But I'm thinking they aren't having a lot of luck.  

nygirl, there is some research out about the anti-viral effects of Alinia, but like riba, you are correct, it doesn't work alone.  As far as the virus mutating against Alinia, seems like once IFN was added, none of that would be a concern.  But then I'm a housewife, not a doctor.

There are so many thoughts about ways to remove riba from the equation and I, for one, am darn glad of it.  Perhaps when I am lucky or sick enough to have to do treatment again, riba will be replaced with something better.  I know that Prove III will have an arm, small arm, but an arm that does IFN and VX950 only.  Gotta find a new crystal to see if I can make that one happen in the near future!!

Willow

p.s.  I was only foolin about the crystal.

Hello, may I ask what your plan is as far as follow up pcr? every 4 weeks... Thanks Pam

Alinia is an anti diahhrea (spelling?) medicine. There was some suggestion that it might help eradicate the virus but as far as I know it was never intended that it be a monotherapy. It's not been proven in any means and most of us after looking at it decided it wasn't worth it. That's the short course explanation on what I know (which ain't much).  I'm sure someone will explain it better.

I cant believe I only have two shots left. I'm so excited but also SCARED too. Now I see what people go through. you do worry that it will come back. I mean I haven't had a PCR in months and now playing that waiting game again...ugh!

I got my last script in the mail yesterday and for some stupid reason they sent me the redi-pens. In a big cooler with ice packs!  I was mad because I knew I'd have 3 extra shots left and I want to pass them on when somebody has an emergency and needs them and the Riba (I have tons extra). So now I'll have to pack them up in a cooler pack instead of just mailing the syringes!

I felt like they KNEW I wanted to pass the remainders on or something! Plus I hate those redi-pens gah!

Hey that should be my worse problems.

;)

I don't know anything about Alina but would like to since it has been mentioned on this forum many times.  How does it work and what category does it fall under?  I hope you have a good doctor that can put you in touch with the standard of care treatment.
   I'll be needing those cookies lol

NY girl -  you are getting to be a real "short-termer", aren't you.  How do you feel in general at the end of such a long coarse. If I remember right just 1 or 2 more weeks, right?

ps Have you ever done real treatment (Interferon and Rebetol?) That is the only thing that is proven to work right now.

The only thing that kills the virus is Interferon. That is the ONLY proven cure. Taking Alinia as a monotherapy has never been advised by any medical professional anywhere.