Bad news re Vertex's Telaprevir (and all the PIs)

[A friend just sent me this rather discouraging news article from yesterday, on Telaprevir. I think it's still up in the air whether the PIs will be approved, because of this issue with it.

Vertex's Experimental Telaprevir Resisted by Some Strains of Hepatitis C
By Rob Waters - May 05, 2010

Vertex Pharmaceuticals Inc.’s experimental hepatitis C treatment knocks out so much of the rapidly mutating virus it lets drug-resistant strains grow instead, requiring multidrug cocktails to defeat it, a study said.

In patients infected by a common strain of the hepatitis C virus, as many as 20 percent of viral particles became resistant to Vertex’s telaprevir within two days of taking it, according to researchers at Los Alamos National Laboratory in New Mexico. They used patient data from clinical trials of the drug to create a mathematical model based on the number of virus mutations found during treatment.

Doctors and drugmakers are searching for new hepatitis C treatments because the standard two-drug therapy works in only half of patients and causes side effects that are hard for many to tolerate. The study published today suggests those current medicines still will be needed given the degree of resistance to telaprevir.

“That’s the most rapid drug resistance for any agent that’s ever been observed,” said Alan Perelson, a Los Alamos scientist and the senior author of the study published today in the journal Science Translational Medicine.

About 170 million people, 3 percent of the world population, are infected with hepatitis C, according to the World Health Organization. The liver disease, spread by contact with infected blood, develops slowly, scarring livers over years or decades and may lead to liver cancer and require a transplant.

Two-Drug Combination

Many people don’t know they’re infected and aren’t getting treatment. Among those who are, most take a two-drug combination of the generic antiviral pill ribavirin and alpha interferon, sold under the brand name Pegasys by Swiss drugmaker Roche Holding AG and as Pegintron by Whitehouse Station, New Jersey- based Merck & Co.

The two drugs fortify the immune system, helping it clear the virus from the patient’s blood, and generate about $2 billion a year in sales. They also can cause protracted flu-like symptoms and trigger anemia.

Telaprevir, from Cambridge, Massachusetts-based Vertex and its partner, Johnson & Johnson of New Brunswick, New Jersey, is racing against another experimental drug, boceprevir from Merck, to become the first new hepatitis C treatment approved in a decade. Both are so-called protease inhibitors, similar to drugs used against the AIDS virus HIV, that block an enzyme that viruses use to copy themselves.

1 Trillion Particles

Hepatitis C copies itself so quickly that the typical patient makes about 1 trillion viral particles a day, Perelson said. With each new copy, there’s a chance of a genetic mutation and some of these mutations make the virus resistant to drugs.

“You’re making so much virus that it is literally a certainty” that every letter of genetic code will be changed at least once in the course of a day, Perelson said.

When patients take telaprevir, it kills off the normal, unmutated viral particles. The few mutants that are resistant grow in number and become increasingly hard to kill, Perelson said in a telephone interview.

The findings are consistent with what Vertex has learned from its clinical trials, said Robert Kauffman, the company’s chief medical officer.

Cocktail Solution

“For all direct-acting antivirals against hepatitis C, resistance is likely to develop fairly quickly,” Kauffman said in a telephone interview yesterday. “The solution to that problem is a cocktail.”

Vertex fell 92 cents, or 2.4 percent, to $37.55 at 4 p.m. in Nasdaq Stock Market composite trading. The shares have fallen 12.4 percent this year.

For now, any drug combination, or cocktail, will need to include interferon and ribavirin and the side effects they cause, Perelson said. If the Vertex or Merck drugs are approved next year and become part of a patient’s cocktail, as company executives predict, it may reduce treatment time to six months from a year.

Treatment that avoids the current regimen may still be some years away, Kauffman said. Vertex this month began a trial of telaprevir with an experimental drug called VX-222, a different type of antiviral, to see if the two drugs can defeat the virus.

To contact the reporter on this story: Rob Waters in San Francisco at ***@****.

[Diamando6]

OK, but we all know, that this would be a triple therapy, anyway, wright?

[Diamando6]

besides, there are some people that should take care of this medication , to be on the shelves, maybe just the same as we wish! So we dont have to be preocupied that much, nothing depends on us, anyway. We can take care of food, lifestyle, and supplements, but therapy? It is on them. We dont know anyway, what we are getting in those medications. We need a little bit of luck too!

[nygirl7]

Vertex fell 92 cents, or 2.4 percent, to $37.55 at 4 p.m"

Considering what happened to the market today I wouldn't base anything on stock prices - Intermmune lost 78% of it's stock at one point last I read.

"For now, any drug combination, or cocktail, will need to include interferon and ribavirin and the side effects they cause,"

This is nothing new we always knew it wasnt a stand alone drug but a 3 drug mix anyway.  Still one trillion particles a day sounds like a lot of chances to have mutations either way....amazing to me that so many of us do get cured.

[Trinity4]

I don't see anything new here Mike.  The cure rate is still higher any way you stack it and I doubt that will hold up the release.  

[Diamando6]

I entirely agree with you. With this comment of trillion particles , and mutations, gee, I truly believe, that cured have been enormously lucky!

[RobertBeWell]

So, let's see. If the little buggers make a trillion copies a day, and my viral load is 550,000, I reckon the old immune system is doing a

DARN GOOD JOB.

Look on the bright side folks ;-)

[RobertBeWell]

"When patients take telaprevir, it kills off the normal, unmutated viral particles. The few mutants that are resistant grow in number and become increasingly hard to kill, Perelson said in a telephone interview. "

I'm not seeing how any of this is an issue. So, the mutants are not killed off.... they wouldn't be killed off whether a PI was present or not. Nothing here has changed in the overall equation.

If the virions lived forever, I could see the game changing, but the half-life of a hepatitis virion is 1 day...

So, what's the issue?

[jepperone]

For now, any drug combination, or cocktail, will need to include interferon and ribavirin and the side effects they cause, Perelson said.

If the virions lived forever, I could see the game changing, but the half-life of a hepatitis virion is 1 day...


So much for the watch and wait... All the time wasted sitting on the side lines. The treatment of choice is STILL Interferon and Ribavirion.

Get er done and get it over with life is too short waiting for a pipe dream. If i had waited I would be three years behind from where i'm at not.


jep

[spectda]

I guess they are saying that the mutations that get by the PIs will be harder to treat then the ones created by just interferon and riba. I thought the mutations usually die off, am I wrong?
It makes me a bit leery of the boce trial I am about to start, but I still feel it's my best chance with 1a, f2.5 and g3. There's no 100% yet so we do our best to get close and hope we are one of the lucky ones!

[Trish77]

Mike, this is old news and the resistance issue with Telaprevir is known information.  It does not impact SVR rates on the first time treating with Telaprevir.  What it does is mutate the virons to be resistant to Telaprevir and possibly other PI's that attack the same molecular structure.  Therefore, the challenge is to those treating a 2nd time with Telaprevir.  Good thing Telaprevir has excellent SVR rates first time around with SOC.  Other good news is that there are other PI's that are capable of dealing with and attacking the virons that are mutated by Telaprevir as they have a different mechanism.

See this thread posted by Mr. Liver:

http://www.medhelp.org/posts/Hepatitis-C/Protease-resistance-explained-/show/1111476

That's my understanding of it and if incorrect, I'm sure and I hope that willing or Mr. Liver, etc will jump to correct the parts where I might be a little off.

So this is not new information or dire information.  Simply something to be aware of when treating with Telaprevir that if you are one of the few who does not SVR with Telaprevir, you will need to use a different drug on the 2nd go-round.  Which is sort of the way it goes with SOC too ... you change the way you do things the 2nd time around.

So not a show-stopper in the slightest there.

Trish

[copyman]

I agree with Trinity. This has been known from the early Telap trials. I knew going into the Telaprevir trial that if I didn't clear I had no other options until the polys could be added to the cocktail. They actually did gene sequencing, etc during the Telaprevir study I was in. I think this was what they were checking for.

I still think the benefit outweighs the risk

[Willy50]

I will echo what a few have already mentioned.  I think that it it's possible that the stock may have dipped today in reaction to the 1000 point dip in the market today.

When the compound was first tested, back when it was called VX-950 it was tested in mono-therapy.  I'm guessing this was back in 2005 or 2006 at the latest.  They knew about the resistance issue even before they proved it in that mono-therapy trial.  I believe it was known before and proven in vitro testing.

The deal is, that yes, there is a resistance issue.  Yup, it's a biggun if and when you attempt to treat with mono-therapy.  However..... the drug is not intended to be used as mono-therapy, and the resistant variants that develop, for the most part are taken care of by SOC.  If and when they add yet another drug, such as VX-222 it is going to further bring down the viral load with increased speed and coverage.

Nothing perfect by itself, but as a team there will be stunning results.

In short, I don't think that the market drop today pertains to resistance.  Further, nothing new here and it doesn't affect the SVR rate that we will see w/ triple therapy or with dual acting antivirals in general.

Absolutely, resistance will be a factor with those who fail, but the best results so far have been in the 80-85% range for geno 1 naives.  It is entirely possible that pre-dosing, adding adjuncts like Vit D or alinia could bring it up further still.

IMHO,

Willy

[Trinity4]

Of course I'm speaking for myself but having done 72 wks of SOC and failed I stepped back and looked at my options.   Infergen with MAYBE a 10 - 15 percent chance of SVR and hell that goes with it.  Then there was another round of SOC, checking for IR, pre-dosing riba, upping the riba dosage and even changing the brand of interferon.  In my mind what kept playing over and over is I would basically be doing the same thing but expecting different results without any statistics that show a better chance of SVR.
I know there are risks with the PI's but at least the chance of SVR is much higher even for relapsers so to me that's where the benefit outweighs the risk.  
Like copyman, if I don't clear with triple therapy I'll know it wasn't because of IR or inadequate riba dosage because I'll have eliminated those factors and I'll wait for the polys.  Despite the odds of developing a resistance to the protease inhibitors when the possibility of crossing over to cirrhosis is staring you in the face the PI's are looking very sexy to me and I have to keep hoping the triple therapy will be my ticket home.

Trin

[mike716]

All of the points made here are well taken, but the issue is not whether triple therapy is better than SOC alone, but whether the FDA is going to approve the PIs. The recently-released information (it came out two days ago, not today, you market-watchers) confirming and expanding on the effect of Telaprevir to cause the rapid growth of viral escape mutants is more weight on the negative side of the FDA scales. Like everyone else, I certainly hope the PIs are approved. They are my best shot, too. But it's best to be realistic and not take approval for granted.

The article by the research/gov insider I quoted a month or two ago, saying that the gov had not made up its mind yet on PI approval, was based on this very fear: the growth and propagation of escape mutants. Let's face facts: HCV is still being transmitted by injection-drug users, some of whom are volunteering in PI trials. The danger of the propagation of escape mutants is real. The same thing has happened with TB: hospitalized TB patients given antibiotics have been the culture medium for the creation and propagation of a TB mutation resistant to all known antiobiotics that has become a new disease that is untreatable. The USG as well as international committees dealing with epidemics are sensitive to this issue.

I trust and pray that the PIs will be approved. But taking it for granted is foolish. It's also counterproductive, because it is the concentration on the PIs as a solution for geno 1s that is sidetracking research funding for other potential cures like therapeutic vaccines, immune system boosters, and even CAMs.

I'm sorry if I upset everyone with this article. But I don't think it is a moot point.

Mike

[RobertBeWell]

Can someone explain what is the point I'm missing here?

The presence of these "mutants" have nothing to do with the presence or absence of this drug, right? They are a simple product of "glitches" in a replication process that happens, according to this article, one trillion times in a 24 hour period.

The way this thread reads, it seems that we're creating a frankenstein virus or something.

The mutants will die off, just like a "normal" copy of the virus. So whats the problem?

What am I missing?

[Trish77]

The mutants may or may not die off.  If the virus is completely eradicated, yes.  If not, then the mutants will be Telaprevir-resistant.  That means if one has to go through treatment a second time, it would have to with a different PI than Telaprevir the second time around and one that attacks differently than Telaprevir does.  I believe both Telaprevir and Boceprevir attack in the same way but don't quote me on that.

Trish

[Trish77]

Mike,

You focus on the downside of the PI's and while it does exist in the resistance profile, it has been known for some time.  What you ignore is the extreme upside and that's the huge increase in SVR when using a PI and also the potential for shortened treatment duration from 48 weeks to 24 weeks.  In my opinion, this greatly outweighs the resistance issues of a PI.  If indeed it's 20% chance of mutation but 80% or higher chance of a cure AND at potentially half the treatment time....which way would you go?  Now some who can afford to wait might want to hang in there for some of the other PI's coming along and go for a quadruple therapy and hit this with REALLY big guns.  But really, you've got a greatly accelerated chance at a cure with Telaprevir.   Your way of putting it is like saying people die in car accidents so therefore we won't allow cars on the road anymore.  

It hasn't been much different on SOC, Mike.  We've been doing SOC up until now at less than 50% chance of a cure knowing that if treatment fails the first time, we're not going the same route the next time because you have to go at it differently.  

Alot of drugs coming along and I like this brief synopsis of where things are going posted in Cory's thread:

http://pubs.acs.org/cen/coverstory/88/8818cover.html

Researchers expect three waves of small-molecule drug approvals, each of which will improve HCV treatment. First, telaprevir and boceprevir are likely to be approved next year as add-ons to the current treatment regimen. The second wave, in three to five years, will bring second-generation protease blockers, a crop of polymerase inhibitors, and new classes of compounds such as Bristol-Myers Squibb’s NS5A inhibitor and Debiopharm’s cyclophilin inhibitor. Finally, researchers hope that in the next five to 10 years they will reach the ultimate goal—enough data to convince doctors and the Food & Drug Administration that the virus can be quieted with combinations of small molecules alone.
-----------------------------------------------------------------------------------------------------------------------

Telaprevir and Boceprevir aren't the cure-all but they are a great next step from what we have now and hardly a reason to feel despair.  I'll be surprised as hell if the FDA turns down approval on the basis you suggest they will.  I hardly doubt any of these companies would be putting their drugs all the way to Phase III and Phase IV trials if they didn't have a hope in hell of approval.  Not buying your version of it, Mike.  The evidence doesn't back it up.

Trish

[copyman]

The study center I was at had doctors attend meetings with FDA & Vertex. They assured me that this drug WILL be approved in 2011.

This mutent / resistance thing has been around since Telaprevir was being tested in labs early on. Vertex would not have moved forward spending millions of dollars if they thought it would be a problem with the FDA approval.

The FDA cannot ignore the words "NO VIRUS DETECTED" on 80-85% of people ttreating !

[Trish77]

The article at the link copied from Cory's thread and noted above is an excellent read.  There is alot of "buzz" among the medical community over the drugs in the pipeline the next while.    It's certainly come a long ways from the days of mono therapy.  Anyone reading that article would have much to be hopeful about, I think.  Hope is a good thing.

Trish

[nygirl7]

Good posts Trish in fact I can't add anything except Mike please don't be a negative Nelly.  Everyone knows that ALL trial drugs may / may not be released soon / ever.  It's one of the reasons many have treated with regular SOC and gotten it done with. For those who have treated but relapsed it is their golden ticket out of this hell.

Many drugs have come and gone before but these are special and appear as if they ARE going to make it.

There is no reason to beleive that these drugs won't be approved - it is really a matter of WHEN. These are phase III and IV not phase I or even 2. None of this is new information they have known all these details since 2005 when I joined this forum. The SVR rates have NOT changed and are much higher than current SOC - with a shorter time period. Why would anyone NOT want and 85% chance of succes if they had failed previously or not?

[susan400]

And who knows, the FDA may just end up making them do more trials on it before it's released, like a broader scale trial w/more people?  Sign me up for the Boceprevir please??!!!

Susan400

[T246]

I agree with robertbewell and suggest you RE- read what he and others have said.  Your points and the nEws you passed is very old news.

Nothing personal,but I FIND IT INTERESTING THAT YOU ARE DINGING THIS DRUG SHORTLY AFTER YOU GOT PUSHED OUT OF THE TRIAL.

Projection, transference is a common reaction to frustration.

I hope you do well.
Thanks

[banarep]

I have to agree with most others here.  Just checked my study docs and this was all laid out in them.  This is old news.  I wonder why it and who is releasing it now.

[Willy50]

Just to buffer what Mike posted about.....

Yes, the resistance issues have been known for some time.  On the other hand, the early protease inhibitors were incredibly potent and presented a prospect of increasing the cure rate and shortening the TX time.  Of course they were going to get the green light.

Now that there are other types of TX becoming viable as forms of TX, it may be possible that the resistance issue could become of greater importance.  I still have about the same view of other drugs, but I also assume that there are others who may take a longer view.

This may sound far fetched, but if you were to look at a way to make this into a thriller movie plot you would have the deadly disease that mutates into a more virulent or tougher to treat form.  

In essence, if there were IVDU participants in the PI trials that didn't clear, they could go back and spread the new and resistant form of HCV.  I think that epidemiologists look for the crucial time where a disease mutates, or is able to change in meaningful and more dangerous ways.  Like the swine or avian flu, that can jump from a species to humans.  Unless I am mistaken didn't HIV have a similar start?  It came out of the blue and got a serious toe hold before anyone knew what it was?

I believe that the question that Mike poses or the article provided was that some groups are now starting to evaluate the longer term threats, not only the positives, but potential negatives of introducing PI's (and the virtually guaranteed resistant virii they can produce) into the general population.

I just thought that I would validate Mikes post and explain some of the ramifications of the concern over resistance issues.  For the most part I believe however, that the drugs, along with their attendant imperfections will be combined into a potent cocktail which will ultimately cure the very large percentage of us, leaving perhaps only the very few people who cannot be cured or those who keep reinfecting themselves and others thru IVDU.

best,
Willy

[mike716]

Thanks, Willy, for the clear exposition of these issues. I believe you are right vis-a-vis HIV, too.

I'm not going to get into it with the people baiting me here, but I've been thinking a lot about all this lately and have come up with a few questions:

- To what extent are the members of this forum representative of the much larger worldwide community of HCV infectees?

- How many new infectees are there now from intravenous drug use, mass innoculation, dental and medical procedures, and other means of transmission?

- Is it possible to be objective about the rest of humanity when one is ill? (That is, would I [we] forego the use of an effective drug if it was shown that it will eventually result in the propagation of a new, resistant viral subspecies that is easily transmitted and highly virulent?)

Regarding question three, if we say "Yes, I am objective and am thinking about humanity as well as myself", then how come we are still participating like mad in the consumer society, buying tons of junk we don't need, even though we know that manufacturing all that junk is destroying the planet?

What about question two? Is our thinking about the HCV epidemic based on the assumption that there is no more transmission of the virus, that it has been stopped, or nearly so? Is it a valid assumption? And even if it were valid as regards the U.S. and Europe, doesn't the fact of globalization and easy worldwide migration make this almost a moot point, since a new, resistant, more-easily-transmitted, more virulent HCV subspecies WILL be reintroduced to the U.S. and Western Europe sooner or later from wherever it gets started, if that happens?

As to question one, that's something I've been wondering about for a long time. Most of the people who contribute to this forum are highly litterate and intelligent. But is that true of the majority of HCV infectees worldwide? If not, who is making decisions for them? And how are their decisions going to affect us?

Mike

[Trish77]

Mike,

Speaking for myself, my own comments are not meant to bait you.  They are an exact representation of my opinion and I never set out to post anything in an attempt to "bait" anyone.  Some people like to do that, other people like to read that into posts but I don't think any of the posts in this thread were made to "bait" you.  When I read Willy's comment I thought "Well...that's not what Mike is talking about..." and now reading your response to it, I see that you ARE talking about creating a superstrain of HCV that then gets transmitted to others and makes HCV even harder to get rid of in the rest of the population.  

Is that your contention and that of your original post?  I'm going to assume yes ..  and on that assumption say then I missed that entirely. If what you were actually pointing at was the broader implications and not the personal ones only, then I missed that.  I was looking at it as you were saying it would make it harder for that individual to clear their own virus.   The personal implications of resistance with Telaprevir ARE well known and the overwhelming positive aspects are overriding.  Your posts often focus on the bit of negative and overlook the overwhelming amount of positive and that's what I saw in your original post so responded back with the positive aspect on a personal level for treating with Telaprevir.  

As for the possibility of creating a strain of HCV that gets passed around to others...hm.  I've never seen that discussed and it's an interesting discussion point.  One for another post than this one as it will make this even longer than the subsequent post might turn out to be if I answer your questions. :)

Trish

[copyman]

lets not make this sound like a horror flick where a mutent virus will attack the world. you cant expect someone who has HCV and wants to treat with the PI's to think about humanity. that is just plain silly. they should think only about curing themselves of HCV, and PI's give them the best chance to do that !!!
Bottom line is the FDA will approve PI's late this year or early 2011 because it offers CURE to millions worldwide.

[Trish77]

Mike, I have to say that your post on second read and understanding what you're driving at really gave me pause to think.  I've been reading various things to gain a perspective on this.  I really enjoy those kinds of things.  I also apologize for calling you Chicken Little - I did think you were saying "the sky is falling!" and you're saying we really need to think about what we're doing here and if we're making a bigger problem than we're solving by using the PI's.  I think your question is at least worth discussing if even to come to the conclusion that the risk is minimal.  It's a good question and a meaty one to consider.  I like a good chew. :)

I looked at superbugs and how they develop.  They're antibiotics for bacterial infections and not viruses but still, they develop by people not finishing the antibiotic and therefore not killing off all the bacteria, thereby leaving some to remain and develop resistance to the antibiotic.  Then other people get that same mutated infection and the antibiotics no longer work.

To apply that to the HCV situation ... the transmission vector for Telaprevir-mutated Hep C virions would be someone who has been treated then passing that along to someone else.

How possible is that in reality?   If it's someone treating with Telaprevir, they're already very HCV-aware, not typically an IVDU.  It could happen but it's not likely.  This could happen more readily in other parts of the world where sterilization procedures and management of the blood supply are much more behind other parts of the world.  You mention the way people move around the globe these days and in Canada, immigration is actually one of the causes of newly-diagnosed HCV infections - people immigrating from those parts of the world where HCV is more prevalent due to less stringent practices.   How likely is it that those persons will have had Telaprevir and relapsed/non-responded and then passed it on to someone else?  Interesting question yet again and perhaps, yes, worth keeping in mind when Telaprevir does hit the mainstream and becomes widely available.  

I think the risk of this is incredibly low in North America and that we'd be more at risk from carriers in other countries.  

The key is to knock out the virus first time as much as possible.  Telaprevir gets pretty close on that.  Further to that and because they've noticed the resistance issue, trials continue combining Telaprevir with VX-222 for example.  A one-two+two(Soc) knockout punch so to speak.  

Interesting.

I don't think it's a concern enough to keep Telaprevir off the market when the issue is known and smart of Vertex to be looking for the drug that makes the right powerful combo to knock this thing out of the park the first time as much as possible.

Right now we've got a majority of the world's population at Geno 1, 2 and 3.  Treatments for Geno 1 are less than 50% successful and treatment at 48 weeks.  Telaprevir and Boceprevir raises that considerably and potentially reduces treatment to 48 weeks.

In the big picture, I tend to think that Vertex and and the other PI makers will do as they're already doing and look for the combo drug required to companion with their PI.  We already do have other PI's and drugs that combat the strain that Telaprevir can create a resistance to.  It's certainly worth being aware of and considering, however in light of the dismal success rate and lengthy treatment time for Geno 1's, I highly doubt that the FDA will keep the PI's off the market but rather be mindful of the resistance issues and the drug companies will be continue trialling, as they already are, to find the magic combo drug.

On a personal level, if I took a PI and relapsed or non-responded and was aware of the mutant capability, I doubt I'd do anything different than I normally would anyway and that's follow safe practices so that I don't infect anyone else.  If I'm doing that, then I"m not risking anyone else.  The risk is my own when doing Telaprevir.  So personally, yes, I would go ahead and take Telaprevir being confident that I'm not putting anyone at risk other than myself.  

I'll leave it at that even though there's more I could say on this.  I think you're going to generate an interesting discussion on this one and I look forward (I think :) to the various inputs from people on this.  


Trish

[Willy50]

I think that it is kind of tough for laymen to try to talk about things that to some extent are not known by the liverheads.

It may not be safe to reduce this to analogy or comparison.  I think of something like TB that was within reach of being totally eradicated, but has now come back....... mutated and with some resistant forms that are showing resistance to our best attempts to treat.

To a large extent, HCV is largely a self limiting disease.  I have it and it is not likely that I will pass it.  If untreated, my virus may die with me and not infect others.  In the case of IVDU however, the virus can be spread quite easily.  If one were to have a resistant form of HCV, it too could be spread. (in the real world however, these new resistant strains may not be as hardy as the default strains)

Frankly, I believe that the new forms of TX will remove so much of the infection from the population that most of us will look at the problem as *solved*.  

Epidemiologists or microbiologists with a longer view may take a look at what type of virus may be created when we start helping channel the direction in which a virus is left to mutate.  It kind of echos what protocols are being used with the use of antibiotics nowadays.  Which drug do we chose and in what circumstances?  What followup form of TX should/must be followed when protocol A fails, when protocol B fails?

What may look like a *solution* in the near term, may not necessarily turn out to be one in the long term.

Micheal Crichton novel, anyone?

best,
Willy

[WriteItDown]

This is just the natural progression with fighting off many diseases.  Humans create a drug; the disease becomes somewhat resistant; humans create a newer drug.  And on it goes.

Are we representative of the world population of HCV patients here?  Probably not.  We all have computers, we all are literate, most of us have opportunities to treat, and we have the free time to post on here.  I'm guessing that puts us squarely in the much more fortunate camp.

As for your unrelated question regarding consumer society, yeah, we should buy less stuff.  I try to and I'm sure many other people do as well.

[Trish77]

"potentially reduces treatment to 48 weeks."

should say "potentially reduces treatment to 24 weeks" of course...

[adamben101]

Also, as far as I've seen, Telaprevir is the only PI so far to shorten treatment to 24 weeks.  Boceprevir is still a 48 week treatment.  Please correct me if I'm wrong.

[spectda]

well said!

[spectda]

I think that;s correct regarding treatment for 1a and 1b , although I think people with the less hard to treat genotypes can be treated for  24 weeks with standard treatment.

[GSDgirl]

I am /was geno 2B, treated for 24 weeks and cleared.  There are some 2B's that don't clear the first time, not sure why tho.

Denise

[Marcia2202]

I guess it is because they are in the 20% who don't clear.  I know it sounds like a smarta§§ comment, but it isn't supposed to be. :-)

We don't really know why some people clear and others don't.

[mike716]

You wrote:

"I guess it is because they are in the 20% who don't clear.  I know it sounds like a smarta§§ comment, but it isn't supposed to be."

I think it's called a "tautology", Marcy. Otherwise known as "circular reasoning". Don't worry about it, though. It's common practice.

The Boceprevir trial that I didn't get into is collecting blood from participants so as to investigate genetic differences that affect response to therapy. I believe there is a lot of this research going on and headway is being made there.

My own opinion about why some people clear and others don't is that it depends on whether or not you've been fudging on your taxes. But my data is not all in yet.

Mike

[merryBe]

tautology as opposed to tauntology  : )

so by fudging you mean if I'm three years behing then I'm gonna get fudged for having made some...but if it's a legal fudge recipe does the same apply???

I really don't want 3 more years of chemo cause I fudged ya know!!!

ps, if you think that's scary read up on ritonivir....resistance galore AND a but.t load of sides that'll choke a horse....of course they are thinking of adding it to all treatment plans...but the chances of ODing on your other drugs or the chemo are astronomically greater when adding this...intestinal bleeding, you name it...

funny how there are 100 promising reviews for every blip that states the down sides with all this stuff.

mb

[merryBe]

mike, I think the thing everyone is missing is maybe WHY the resistance might be more.

hint...study the numbers for the teleprevir vs boceprevir trials. where is the main differentiation and why. It's the boceprevir lead-ins, where lead-ins were used boceprevir had substantial advantages.

Conclusion, one has to boost the immune system and get riba levels to optimal levels before adding the PI in order to boost it's effect and lessen resistance, that said there will be some, as there has been with Riba/INF.
I still think it's ludacrous to suggest we add no new drugs until all resistance can be eliminated since that will condemn millions that could be cured to horrible deaths, but I do understand the concerns. What baffles me is why only 20 dollars is being spent per hcv patient on research while almost 3000 is spent per AIDS patient per year on research. Since hepatitis is the real world wide epidemic, far more vast than AIDs, shouldn't the research dollars be going towards solutions BEFORE half the planet becomes infected???

personally, if I were running the world, I'd try to use electroporation therapy to deliver riba sooner...a one two punch in under a week would be ideal, would give less room for adaptation...although it's hard to say if the human body could adjust to that or whether folks would be flying out the windows.

Robert...
.your VL is 500,000 in a 1/4 teaspoons of blood...there are 3 teasonns in each tablespoon, 16 tablespoons per cup, 4 cups per quart and 5 quarts of blood....meaning you have 3x16x4x5x500,000....do the math...480 billion virons is what you carry and they adapt everyday. the majority of hcv patients carry 1 mil and up per ml so they all carry a trillion or more copies.

Retroviruses have been observed mutating as often as every 20 minutes...nothing new there..they still treat AIDS patients with a plethora of antivirals knowing all this, that they could create a super strain....
if the powers that be decide to withhold similar adjuncts to hepatitis patients, I hope the world will see it for what it is.

[mike716]

My opinion is that the direction of research has been skewed by collusion (read "corruption") between the pharmas and the government agencies that are funding/approving new drugs. Instead of revamping already-exisiting antivirals like nterferon and Ribavirin, they should be concentraing on therapeutic vaccines and antifibrotics, IMHO.

The "choice" between not doing SOC and ending up cirrhotic, or treating with SOC (with or without a PI) and ending up clearing or maybe not clearing the virus, but with a series of awful side effects that maybe ruin the rest of your virus-free life (if you clear), is not a reasonable choice.

Pharma and the gov went with what they had, probably trying to capitalize (make more profits) without too much new and costly research. That's how I see it, anyway. I mean, where are the news reports on vaccines and antifibrotics? Everything concentrated on SOC and additions to SOC. Nothing else is discussed or funded.

Mike

[GrandOak]

Mutating resistance to third party drugs has been a known throughout the trials.   So no surprises there.  It's the primary reason why many later trials focused on using only during the new meds at beginning weeks of TX.

No reports on mutations becoming resistant to Interferon or Riba that I've ever heard about.

New drugs are aimed at disrupting the reproduction mechanism, which given the virues nack for mutating to avoid natural immune system attacks it is not surprising it would mutate to compensate for the blocks the new meds attempt to throw at it.

[IAmTheWalrus]

There are a lot of really good points made in this thread. I hope that the development of the new (NS5A, etc.) will continue and may eventually solve the problem that Mike brings up. In the meantime, we should be treating with the best we can. Certainly the increased SVR rates of Telaprevir and Boceprevir justify the approval and use of in conjunction with SOC. The comments of Trish and others cover this topic well.

While development of PI resistant strains of Hep C becoming widespread is theoretically plausible, I don't think there is very good evidence that this is likely to happen. Can we really compare transmission of these mutant strains with transmission of bacterial infections? I am thinking that the transmission vectors here are going to put a damper on this spread. In any case, in the absence of some more concrete evidenced of creating a super-Hep C strain, it is best to continue treating with them and hope for future developments to continue to improve effectiveness.

I would be sadly shocked if the FDA turns down Telaprevir considering the lives that would be saved by its use. I understand that the FDA has no objection to the humanitarian use of Telap and Bocep for genotype 1 SOC failures, but that Vertex and Schering have not applied for the approval. This does not sound like the FDA will withhold approval for concern of super-bug resistance.

Feel free to jump in if I am mistaken in this.

Brent

[IAmTheWalrus]

Oops! I meant Merck, not Schering in the previous post. Sorry!

[mike716]

Hi, Brent? How's it going?

You wrote:

} Can we really compare transmission of these mutant strains with
} transmission of bacterial infections? I am thinking that the transmission
} vectors here are going to put a damper on this spread.

I think the same biological "rules" apply to both. The danger is that both the transmissibility and virulence of the microbe will increase. It has been shown that this does occur when demographics (population concentration, and therefore increased transmission) favors the virus, as seems to have occurred with HIV. Pressuring the microbe with drugs may also have this effect, as the microbe develops better transmission and higher virulence in order to survive and offset the attack on it. The main danger is to the continued effectiveness of the specific drugs being used as therapy, but there may also be a residual effect on future infectees. This is the history of resistant TB, and perhaps also of the recent flu epidemics.

As you say, it may not occur. But the approach being taken to HCV - attacking it genetically - is the one most likely to have undesirable consecuences. A vaccine or other method of increasing the body's immune response, or meds that stop the fibrosis of hepatic tissue, would be safer.

} I understand that the FDA has no objection to the humanitarian use of Telap and Bocep for genotype 1 SOC
} failures, but that Vertex and Schering have not applied for the approval.

Not sure what you mean by this. Why would the PIs need special approval for second-time Tx?

Mike

Mike

[WriteItDown]

Something that improves the body's immune response -- that's interferon. I think one key point you have to keep in mind here is that it's extremely hard to find cures for complex viral diseases like HCV. So, while it is a problem that the protease inhibitors create resistant strains, the benefits of these drugs (high cure rate) outweighs the risk.

[Rockerforlife]

The goods news far out weighs the bad news,80% cured rates for Bocep is nothing to snezze at,.

[TeeTom]

All I can say is I have hepc type 1a the worst one. I have been in a roche trial with the PI that they are testing. At the begining my viral load was over 5mil, at week 10 I was delcared UND and been there for 6 weeks now.

My point is, There are other drugs besides Tela that have also had good results

Teetom

[Diane12855]

I thought the whole reason for the Ribaviron is to stop the virus from replicating. If it is doing its job, then the chance of mutations goes WAY down... right? I know I'm a newbe and haven't read all of the articles everybody else has read... but I have read all the documentation that comes with my meds. Since this part wasn't taken into account in the article, it kind of looks to me like they were WANTING to be able to say it doesn't work.

[mike716]

Please, let's try to get one thing straight: There's no question here about whether SOC+PI works. It works. The only question is about the consequences of large numbers of infectees taking this combination, in particular if 20% of them still do not eliminate the virus and henceforth can spread a drug-resistant virus, perhaps a virus with higher transmission and virulence (I say "perhaps" only).

What this thread is about is moral responsability. Perhaps the threat of producing resistant strains that can cause a renewed epidemic is too small to weight the scales. But the question is real. It's a question of primary importance today. Put in other terms, it's this: Do I do what is best for me, even at an unacceptable cost to the human species? Or do I sacrifice my individual well-being, happiness, health, even life, in order to preserve the human species? This question, the "business" of health care is ignoring.

Don't forget, I don't say SOC+PI is implicated in this way. I don't have enough facts. No one does, yet. That's the problem with making genetic attacks on viruses. We don't know for sure what the consequences are.

This is a question that every MD must ask before prescribing antibiotics for a bacterial infection, and it's a valid question as regards SOC+PIs. It is a question that big pharma and its government henchmen never consider, or discard as not being their concern. But in a sense it is the only important question today. Not whether to take SOC+PIs, but whether to accept responsability for others.

I, for one, will probably end up taking SOC+PI if my condition worsens and there is no other approved medication. But I don't believe that it is a solution to the problem, and I think it has been blown way out of proportion for purely financial gain, with little consideration of the long-term consequences.

To my mind, SOC+PI is a stop-gap until something different and better is found. But that is not the way this is being handled by the authorities.

Mike

[Trish77]

"To my mind, SOC+PI is a stop-gap until something different and better is found. But that is not the way this is being handled by the authorities."

I think it is being handled as simply the next best thing to SOC and not the next and last best thing.  They continue to trial drugs that may even replace SOC and Vertex is already trialling a companion drug with Telaprevir.  So I don't really see any evidence of anyone being complacent about this current crop of Phase III / Phase IV PI's as being as good as it gets.  I think the quest will continue to come up with something that gives near 100% cure rates and reduces treatment time along with the quest for something that gets rid of the nasty interferon.

I think the chance of spreading a mutant HCV is very minimal, far less than the risk of producing a superbug from antibiotics which are far more prevalent and the illnesses they're used for far more prevalent as well.

[mike716]

All current epidemic viruses are mutations that have increased in virulence (ability to cause mortality in the infected body) as their difficulty in transmission has been lessened by transfusion, intravenous blood factor use, and intravenous drug use.

Microbes are evolving all the time, as are all forms of life. Their speed of mutation depends in great part on environmental pressures. In a stable host environment, microbes co-exist in and with the host species. There exists what's called endemic immunity. Few die from the microbe. But when the host environment changes, the microbe adapts. If transmission is made easier for the microbe, it can increase its virulence without lessening its frequency in the host population. If it is attacked - by another microbe (inter-parisitic competition), by pharmaceuticals that affect its genetics, etc. - it evolves to evade the threat.

There is no "stable" microbial genome without a "stable" host environment. Attacking a microbe's genetics is a destabilization of the microbe-host relationship. The microbe will evolve.

Epidemiology must concern itself with the dynamic situation. If it does not, it plays into the strategy of the microbe.

Mike

[WriteItDown]

I think that anyone who has treated for HCV certainly knows enough so as not to run the risk of infecting others.  Remember, this is a blood-borne disease that is not so easily transmitted. Of course, there will always be mistakes, but my feeling is that the risk of spreading viral mutations is quite low.

[nygirl7]

Hansmiami this is a serious trial you should look into as it's gotten well past its test stages.................it's working wonders for people who failed other attempts.

[HectorSF]

Referring to the original article by Rob Waters, is a health reporter for Bloomberg News.

I think that other posters have shown that most if not all of the information in the article has been know for many years regarding drug resistance and PIs. This was something that was learned my years ago when treatments for HIV were being developed. The idea of the drug "cocktail" which is what I think the author was trying to infer (VX-222) is an important concept and is why treatment with Telaprevir is combined with peg-interferon and ribaviron at the present time. In the future PIs should as Telaprevir will be combined with other antivirals as HIV medicine is. The peg-interferon and ribaviron parts of the HCV cocktail are used to eliminate the viral mutants that remain after Telaprevir eliminates the main HCV virus which is the most robust "fittest" of all the viruses and is the majority of the virus population. The main HCV virus or "wild virus" as it is called is what returns if UND is not achieved or the rebounds during treatment or there is a relapse after treatment. No SVR.

Main points about HCV viral mutants and variations:

Definitions:
“Wild type” is the dominate virus
“Mutants” mutations of the parent “wild type” virus

* (First and foremost) Mutants are there all the time in every person with chronic HCV. HCV mutates more rapidly then HIV. HCV has a high rate of replication with approximately one trillion particles produced each day in an infected individual. Due to lack of proofreading by the HCV RNA polymerase, HCV also has an exceptionally high mutation rate, a factor that may help it elude the host's immune response.
* Mutants were first uncovered by Vertex using their “Population sequencing” model – hundred of PCR tests per time point yielding the entire sample of virus population.
*       Vertex showed that the use of Telaprevir knocks down the main HCV virus “wild virus” 3-5 logs, this allowed the viewing of the mutants. The mutations are the majority of the virus that remain if a patient viral load plateaus or rebounds. I.E. Treatment does not eliminate the virus.
* RVR is a predictor of SRV because if the main or “wild virus” is driving down to zero quickly (within 4 weeks), no “parents” (wild viruses) exits to create the mutants.
* Peg-interferon and ribavirin role in the cocktail is to eliminate the remaining mutants.

I believe this clinical and modeling data is important in the understanding the HCV virus and as such and will help to lead to future improvements in treatments for all HCV sufferers. Antivirals are the biggest step in improvement of % of SVR since the peg-interferon/ribavirin combo.

Bottom Line:
59 Percent of Patients Overall Achieved SVR with Telaprevir-Based Regimens in Study 107 after not achieving SVR with at Least One Prior Course of Treatment for Hepatitis C Virus Infection.
56% of prior treatment null responder patients achieved SVR with a 48-week telaprevir-based regimen
97% of prior treatment relapsers
55% of prior treatment partial responders achieved SVR with 24-week or 48-week telaprevir-based regimens

Cheers!
HectorSF

[Trish77]

We'll have to agree to disagree, Mike.  I think the risk of creating an undefeatable resistant mutant strain of HCV that takes over the world is quite low.  If you really thought this was an issue, you wouldn't be doing the PI's and yet you plan to and you consider yourself in a high-risk category with regards to probability of success.  So you of all people, if you choose and suggest we should be looking at this from a moral perspective, would be a perfect candidate for not doing a PI in the scenario you paint.  As it is, I wouldn't let any of this discourage anyone from doing a PI.  I would simply put the factors in place that would contribute to the best possible chances for success - those things that help maintain adherence to therapy for the duration and deal with any factors that might reduce effectiveness of the drugs while on treatment - which isn't a whole lot different than the prep for SOC alone.  Add a PI to the mix and chances for success increase considerably.  

[mike716]

My point was not about individual decisions to treat, not even my own, but about the direction of research and funding.

[Trish77]

Previously:  "The only question is about the consequences of large numbers of infectees taking this combination, in particular if 20% of them still do not eliminate the virus and henceforth can spread a drug-resistant virus, perhaps a virus with higher transmission and virulence (I say "perhaps" only). "

Currently:  "My point was not about individual decisions to treat, not even my own, but about the direction of research and funding. "

Well you've gone from "the only question" to a whole other point now to research and funding. You're kind of all over the place as long as you have something to rant about it seems. It was your "only question" that I was responding to.  You can't be all that concerned if you're willing to take a PI and contribute to this potential spread of a drug-resistant virus.

I'm not trying to pick on you, Mike, really I'm not.  You're just so inconsistent.  Railing away at Big Pharma and the nasty conspiracy one minute and then getting checked out for participation in a drug trial the next.  Talking about our moral obligations towards the greater global Hep C community in not contributing to a potential PI-resistant strain of Hep C and then declaring you'll probably take a PI.   Like a case of do what I say but not what I do.  

[spectda]

20 percent is the amount of people that don't respond to the treatment supposedly, From what I understand only a portion of those people create dominant mutations that don't eventually die off. I may have misunderstood of course.

[mike716]

I'm getting kinda tired of all this baiting, but I'll make a last attempt at stating my case. Sure, if SOC+PI is the only thing available, of course I'm gonna do it. What choice have I got? But my points are that there should be somethhing better available and that it shouldn't be something that's gonna maybe cause a worse epidemic down the line. Is that so hard to understand? It's no contradiction, as far as I can see.

But I guess anything I (or anyone else?) says that doesn't toe the conformist line is a no-no, huh?

Okay, I'll just shut up and do as I'm told (not).

Mike

[Trish77]

You're not being baited in the slightest.  You're simply being disagreed with.  Is THAT so hard to understand?  Anyone who doesn't agree with you is a conformist sheep?  Geez, Mike.  Your logic simply doesn't stack up and I don't see the same level of risk as you do any more than I see the worldwide conspiracy against heppers that you do.  It has nothing to do with conforming or non-conforming.  Impossible really to discuss this coherently when you're going to treat those who disagree with you as ignoramuses for doing so. So..yeah...that might as well be the last thing said on it.

[merryBe]

I think the bru-ha-ha over super strains is greatly exaggerated.

It's true, it is possible, of that we can be sure.

However it's also true that species have enormous adaptive potential and highly complex immune systems.

When you stop to think about it, mass extinctions are almost exclusively the result of the catestrophic events of the planet, floods, asteroids, etc.. The adapative nature of out immune systems and those of the smallest one cells creatures, allows us to write new code to our DNA as fast as any retrovirus can rewrite it's own.

I know it sounds absurd, but really, it's as if you have two software programmers sitting side by side...one writes a fatal bug, the other one writes the fix for it. As long as the QA guy does his job (code is viable) the patch will work.
When you get down to the molecular level that's what has always taken place, cells adapt, evolve if you will, by seeing where a weakness lies and rewriting a line of code.

It's rather impossible for us to comprehend the complexity of all this, as each little strand of DNA contains 3 billion lines of code....our cells all have it, and the virus does as well. Bottom line is the human being has been effectively fighting unseen enemies of immense complexity for a very long time, and we will continue to do so.

I think the benefit of wiping out viruses far outweighs the risks. Many of the deadliest diseases on the planet arrise from them.
Just as we once began the attack on the bacterium of the planet, and have wiped out many microbes that used to kill millions, it's high time we attacked the viral world, and we may find this world holds the keys to why cancers form as well. Causes of cancers are still poorly understood, but many are now known to have have a viral or parasitic component.

If we were to stick to the gloom and disaster theologies of what might go wrong we would still be dealing with polio, small pox, leprosy and a whole host of other scourges we no longer have to face.
I think Pasteur was on the right track, and a return to fear will never produce better long term outcomes.

[Rockerforlife]

Mike,take er easy man,I understand what your saying aboiut the mutation problem,but before this even does happen,this planet is going to hell anyway

[mike716]

Thanks for the comic relief, Rocker. I needed it .

Mike

[merryBe]

Do not let yourself be tainted with a barren skepticism. (Pasteur)

There's a lot of reason to suspect that down the road therapies will be far more effective and less toxic. Every week I see some news on what sugars, and fats and proteins all do to this virus...and which herbs interrupt transcription or some other phase of viral replication. That's the good news.

The other issue is that at your stage you really don't have that much time. The same thing Trish and I are facing is where you also are at. For my money the attempt to halt things would be to embrace the triple therapy horns and all...if not to go the preventative route full bore.
Personally I'm planning on doing both.  The real issue here is time....
beyond that, preventative add up, but could buy one time to wait...maybe, but I think they need to be taken seriously and at correct dosages to really do that.

Check your messages.

[gypsyjoey]

In the spirit of Keep it Simple Stupid (K.I.S.S.)

I treated twice previously with Interferon & Riba without success.

I treated for 7-months with Telapravir added to those drugs and am still clear 10-months post treatment.

That is all I have to know.

Joey

[mike716]

What telaprevir trial were you in?

[mike716]

Since in my last blood test my hep enzymes were down to normal range, I'm in a denial phase at the moment. It's sorta like the manic phase of a manic-depressive complex: I can feel the return of fear and loathing  as I get into position for the the second round of the biopsy-or-not-to-biopsy derby approaching.

M.