Think you could add pi's later in treatment?

[Upbeat]

I have often wondered if a person was already doing SOC and the pi's became availible could you then throw them into the mix?  I know a lot of people are putting off treatment waiting on the pi's but if you could add it later it might make since to go ahead and start early.

[Cory255]

HCV replicates at over 1 trillion copies per day.  I agree, it's also possible for HCV to replicate even up to 10 trillion copies of itself each day too.  Virons dying could account for general fluctuation.    

Telaprevir blocks an enzyme that the hep C virus needs in order to replicate itself, Ribaviron works to prevent viral breakthrough, and Interferon is a natural substance combating the virus via immune response.

I concur, the wild-types are quickly removed due to the PI's direct targeting capabilities.  I believe monotherapy is more likely to develop resistant mutations, due to lack of Ribaviron, resulting in breakthrough occurances with the possibility of resistance occuring.  These rare occurances are when the resistant strains can't be eliminated.  At some point, yes they can revert back to the wild-type.      

Since our immune systems strength is a variable in the elimination of resistant strains, it would be logical to also conclude the IL28b as yet another variable to consider.  TT allele's are the rarest, and have a 41% SVR rate with Standard of Care.  The research studies for Geno 1's have determined CC allele's have an 85% SVR rate, with CT's somewhere in the middle around 45%.

[Andiamo1]

HCV replicates at over 1 trillion copies per day.  Most copies are not viable and die off immediately.

The PIs target wild type virions and almost all are eliminated in the first few days leaving only resistant strains.  The combination of interferon, ribaviron and our immune systems eliminate the rest in most cases.

The variables in the elimination of the resistant strains are our immune systems strength, the absorption rate of the drugs, the viability of the resistant strain and our bodes ability to deliver the drugs to the targets.

Most resistant strains are weaker than wild type and are eliminated in the weeks of interferon and ribaviron treatment following the initial course of treatment with the PI.

There is evidence that treatment failures will eventually revert back to predominately wild type virions.  We certainly need much more data on this subject.

[Cory255]

I might have read a different abstract, there's too many to sort thru at the moment.  According to Pubmed Abstract,  http://www.ncbi.nlm.nih.gov/pubmed/20445200  , I think it reported that drug-resistant variants emerge in 5-20% of the population as early as Day 2 starting with Telaprevir based on clinical trials.  That part was interesting to read, although the reward outweighs the risks with the protease inhibitors.  

Cory  

[willing]

>there seems to be plenty of  countering evidence to indicate they have benefit
well, quite possibly I haven't looked around enough, If  you've seen evidence of documented statin benefit in patients - as opposed to viral suppression in cell culture - please post. No sense ignoring statins if the evidence is there, but from what I saw Enzo's comment seemed to sum up the case.

And I agree completely about the need for better testing of hcv-related supplements, particularly in the area of anti-fibrotics. However, I don't see this happening anytime soon - in many cases the benefits are slight and the metric (fibrosis reduction) very difficult to quantify. Most of the arguments about supplements around here are painted in black and white whereas the reality seems more fog-like. The subjective viewpoint may really be the most important -  if you think they help, they do!

[Trish77]

I disagree with Enzo's contention on statins - there seems to be plenty of  countering evidence to indicate they have benefit rather than harm - however the  investigation into statins is still in relative infancy and one has to weigh the risks at their own moment in time.  Alinia has much better knowns than unknowns at this point, for sure.  

"With a lot of these supplements, the effect seems to be similar to trying to steer a toy boat across a pond by throwing in rocks - plunk, plunk, plunk - is it helping?"

Hard, isn't it?  A person ends up being their own clinical trial.  Various societies like the Cancer Society, the MS society, etc. fund research into areas that are of relevance to their own.  Perhaps Hep C needs something similar so that we can fund clinical trials into supplements that give us valuable data.  Pharmaceuticals have their own motivator so that seems covered.

[willing]

Trish: finally got around to doing a bit of reading re statins; looks like there might be something promising there but there's enough murkiness that I'm going to pass - I think the following comment by
Enzo sums it up well:

http://www3.interscience.wiley.com/cgi-bin/fulltext/122394602/HTMLSTART

There's enough indications that statins either have no HCV effect
http://www.ncbi.nlm.nih.gov/pubmed/19859994
or may actually promote hcv rna (though I think Bader's criticisms of that result seem valid) to scare me off.

Viaduk: good news! Mike716 posted a good list of ntz sources on this thread:
http://www.medhelp.org/posts/Hepatitis-C/Alinia-Nitazoxanide-Sources/show/1124364
My current plans are to start 1st ifn injection 10/18 and ntz/rbv mid Sept. so I'll check on ins. co. approval mid Aug.  - we'll see what they say. Likewise, if a good trial option comes up between now and then I would change plans - but I can't see anything promising  open to relapsers for now.

I'm also planning on the SAMe, mostly based on the strength of
http://www.ncbi.nlm.nih.gov/pubmed/16557551
though I'm starting to wonder about why there hasn't been more confirmation of this over the past four years. Still no results from that SAMe/HCV clinical trial:
http://clinicaltrials.gov/ct2/show/NCT00475176

The other supplement I'm taking is 100mg of quercetin, based on:
http://www.ncbi.nlm.nih.gov/pubmed/19839005
though again, it would be nice to see more data.

With a lot of these supplements, the effect seems to be similar to trying to steer a toy boat across a pond by throwing in rocks - plunk, plunk, plunk - is it helping?

[viaduk]

So, I took the Alinia  Rx to the pharmacy and, to my surprise,  it was covered by my insurance!  I have two refills on this script, and will wait to get one refill before starting. Just hedging my bet, so that I have one month of back up in case it's denied in the future and I have to go to the online sources.  If it seems that I'm overthinking this, you're probably right

I also have a visit with Dr. D. in three weeks --- a last attempt to see if any new trials are looming before I fully commit to this.   I'll also get his opinion about this approach and post it here.  

[viaduk]

I am planning to add vitamin D ( recent bloodwork shows that I'm deficient) and Omega 3.  I'm also considering continuing with the SAMe and wheat grass juice that I have been taking, but stopping everything else.   I would add PPC, but when I tried it earlier my LFTs went up considerably.  I'm prettty sure that I'll need neupogen, as I needed it during previous treatment. Hopefully my platelets won't tank (currently 79).

I received my Rx for NTZ by mail today and will see what happens when I try to fill it.  Regardless of what happens with the PIs, my hepatologist thinks that I should predose NTZ for a month and continue treatment for 48 weeks AFTER undetectible status.  I responded pretty quickly last time, and hope to do so again.

[willing]

Trish: eh. no problem, I post mistakes all the time (but thanks for the  kind response;  the usual response to an acknowledgement is "duh.. took you a while" ). Anyway I still haven't had a chance to read through the recent statins papers but agree there might well be something promising there.

Viaduk: good question. I've been wondering whether there  might be good reasons to *not* have a w4 VL test in my chart. Are you planning on adding anything to SOC during the (long) lead-in?

Cory/Moahunter: I could be way off on this, but believe the two recent modeling papers in the post to Bali above do a very good job of capturing vl decline in the presence of different tx regimes.

[Trish77]

Isn't it possible that adding PI's later in treatment would tackle any of those harder to die virii ?  That would be my reason for adding a PI if it became available later in treatment.  I'd want to hit it with whatever firepower I had to make sure this is a one-shot deal.  It would depend on when the PI became available and how early I'd cleared, however.  

[moahunter]

I did monothearpy (as acute), and when that failed, the doctors took me off, then restarted a month later with Riba. It was explained to me that the most critical time is the first few weeks, that's when you have to get a response. Adding PI's later in treatment probably isn't going to do anything but maybe make you imune to them. If treatment isn't working, then stop and try something else.

[viaduk]

I appreciate your comment. It ois I who should be embarrased. The question was only addressed to willing because he/she is also considering this approach. I was hoping to get opinions on the possibility  of problems with insurance. As the kids say these days: "My bad!"

[Trish77]

*embarrassed* - I didn't notice your question was to willing and answered it.  I'm sure willing will get around to it soon enough.

[Trish77]

I wouldn't think so.  It's simply adding meds that are found to make treatment even more effective ... kind of like adding a rescue drug like procrit or neupogen so that you don't have to reduce dosages.  That would be my logic on it at least, if I was going to present it.   A new and even more effective drug comes onto the market that increases chances of success exponentially ... can't see any reason for refusing something like that.

[viaduk]

I wonder if an insurance company would deny payment for the PI if it was used later in treatment.  Assuming that we time it right, start tx after the summer, and the PI meds are approved spring 2011, would the insurance company reject paying for the PI because it's being used in this way?  

[Trish77]

"yes you're  quite right (AGAIN!) "

A man telling a woman that is sweet indeed (as is the reverse, I'm sure) so I hope you don't mind if I quote that and savour it a bit. :)   Okay....moving on to the IMPORTANT stuff now...

"Still, this is clear as mud to me at the moment. Why the difference between in-vitro and in-vivo results? and which statins have the strongest effect? Here they found only a moderate effect for fluvastatin:
http://www.ncbi.nlm.nih.gov/pubmed/19437494 "

Well that article you're quoting HERE is even MORE exciting.  I like it!!  Statins on the whole are known to have an impact on reducing viral load and up until recently it was Fluvastatin.  However this study you've quoted looks at additional statins that do even better it seems which is great news.  

"We here report that, of five statins studied, mevastatin and simvastatin exhibit the strongest in vitro anti-HCV activity"

So hey, if Fluvastatin was the one to be excited about in times past and these do even better then that's good news, yes?  

As for the difference between in vitro and in vivo ... man, do you ever make a girl research.  Kinda like that quality in a man...but anyway..you made me curious so I went digging.  Not sure if I can make any sense out of it but I sure wanted to understand it.  I found this article on in vitro and in vivo and it *seems* to say that in vitro is in the actual organism while in vivo is simulating the actual organism?  Is that what you get out of this?

http://science.jrank.org/pages/3541/In-Vitro-in-Vivo.html

[Cory255]

Yes, the idea of the PI is to stop replication, but what if you are replicating later in treatment... Being a slow responder you wouldn't get a 2 log drop at week 12, and then a non-responder doesn't get a 2 log drop by week 12.  Given the risk of a PI altering the virus, and not being able to treat again with it, it may be beneficial...  What if you experience a breakthrough?  You clear the virus then it comes back during tx.  In this case it may be beneficial to then add in a PI.   Again, you'd have to consider the risk of not being able to treat with a PI, if you fail...

[willing]

yes you're  quite right (AGAIN!) I mixed up the two refs. The one Bader is unhappy with is
http://www.ncbi.nlm.nih.gov/pubmed/19215577
not the more recent
http://www.ncbi.nlm.nih.gov/pubmed/20118492

Still, this is clear as mud to me at the moment. Why the difference between in-vitro and in-vivo results? and which statins have the strongest effect? Here they found only a moderate effect for fluvastatin:
http://www.ncbi.nlm.nih.gov/pubmed/19437494

[Trish77]

It seems the study that Bader is commenting on is a 2nd different study that Milazzo participated in, the one you provided a link to and not the same one as the one in the link I sent you.  You'll note that the researchers are different for each one, for one thing.  

This is the study Bader is commenting on, or at least seems that way to me:

http://www.ncbi.nlm.nih.gov/pubmed/19215577

Aside from that, interesting how the conclusions differ between the two Milazzo studies.  You're right. Something to chew on, as that would be the first study to show negative effects from Fluvastatin and I have to say I'm rather skeptical on that outcome.

Trish

[Bali05]

thanks willing,

looking back i would have done peg x2 wk vs x1wk for the first 4 weeks.

would have most likely been und at 2wk which would have been excellent.

i was so concerned with sx that i did not do that and now i wish i did .

[willing]

this is going to take a bit to sort out: in a letter commenting on the recent Milazzo'10 study (the 1st of the two links), Ted Bader, author of the '08 paper (2nd link) writes:

"To the Editor:

The major endpoint of a prospective controlled trial is to compare the outcome between the observed and the intervention groups. It is puzzling as to why this was not performed in the article by Milazzo et al. [1]. The suspected reason is that the comparison between these two groups (Figure 1, Table 2) would show no statistical difference (the standard error of the mean of the intervention group is less than the control group) and thus their conclusion would be negative.

The authors compare the beginning and ending values for their intervention and control groups. The only statistical difference found is in the change between the beginning and ending values of their intervention group, a secondary finding that has uncertain meaning. However, the results of both groups are quite similar to those of published studies on HCV RNA levels in untreated and control groups in HCV mono-infected patients. Their report extends this observed natural variation in HCV RNA levels into the co-infection population [2–4].

The methodology is inadequate with only one intervention point being measured. Viral kinetic studies (i.e. significant changes in viral load) certainly require many more time points before sufficient validity would be approached [5].

The implied answer to their article title seems no doubt to be 'yes' in the abstract, but then 'no' when the article is read and analysed."

from
http://www.ncbi.nlm.nih.gov/pubmed/19758277

not quite sure who to believe yet.

[Trish77]

Re: Canadian online pharmacies for NTZ - I would have needed a prescription and that's why initially was looking at Mexico for over-the-counter.

Dosage for Fluvastatin has been settled in clinical trial to be 80mg / day - that's why I asked if 80mg was considered high when you mentioned one of the concerns was the high dosage required.  A couple o' links:

http://jac.oxfordjournals.org/cgi/content/abstract/65/4/735
http://www.lipidsonline.org/news/article.cfm?aid=6344

"As no specific benefit was observed for doses above 80 mg/day, for the second part of the study researchers concentrated on fluvastatin doses around this level."

[willing]

dointime: thanks for the kind word and good wishes. I hope your wait doesn't drag on much longer - I think we've all shown we're thoroughly rehabilitated by now, don't present any danger to the community, have paid our debt to society with excess interest and consequently should be paroled pronto. As for the NTZ relapse rates they're from the table in
http://www.kenes.com/easl2010/Posters/Abstract130.htm
Of the 23, it looks like 21 got to  EVR or cEVR, only 15 made it to w24  und but all those went on to svr. Why they lost 6 between the w12 evr check and the w24 und check is a mystery. I'm going to try following up with authors on that.

Trish/Desrt: eh, basic answer is I don't know on both counts - but will be investigating both (and Desrt thanks for that warning letter - very on point). I was concocting all manner of hare-brained schemes in case my Dr. didn't write the rx for ntz, but now it looks like cost (assuming ins co denial) is the remaining hurdle and I will check out the Mexican pharmacy prices (I take it online Canadian pharmacies were not an option?). Likewise, with the statins, need to check at what dosage they would be likely to have effect.

Bali: looking very good - best wishes! BTW two recently published papers have driven home the practical usefulness of kinetic modeling in predicting tx outcome and pi mutation changes:
http://www.ncbi.nlm.nih.gov/pubmed/20463660
http://www.ncbi.nlm.nih.gov/pubmed/20445200
and there's a good near-free diff-eq solver here
http://www.berkeleymadonna.com
(the one used by the Rong/Perelson paper).

[dointime]

"IMHO, the most impressive result from the Romark study was not the 56% SVR but the 0% relapse (which would normally run 25-30% of eot-und for naives and up to 60% for those without cEVR)."

Willing - do you have a reference for this 0% relapse result?  I don't see it in the Romark study.

Thanks,
Dointime