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Avatar universal

New Drugs. New Treatment Decisions.

Recently, someone at another discussion group asked me how I thought the newer protease inhibitors like Vertex should affect our current treatment decisions. Here’s an edited version of my answer.
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That's an excellent topic for discussion!

"To treat or not to treat" has always been a controversial issue.

Nowhere is it more controversial than genotype 1's with no or minimal liver damage, i.e. stage 0 or 1.

In this group, doctors are split. Some advocate treatment, the idea being you have a better chance for SVR if you hit the virus early in the cycle, when you're younger, healthier, and when the liver has little or no scarring.

Others advocate a "watchful waiting" approach with regular lipid monitoring and follow-up biopsy in 3-5 years. The idea here being why expose yourself to the side effects of these powerful drugs when your liver is still in decent shape.

In this debate, I tend to favor watchful waiting, although I respect anyone who decides to treat as long as they're making an informed decsion, weighing the pro's and con's. The only right answer is the one that's right for you.

That said, the new protease inhibitors in trials -- like Vertex --  seem to be shifting the "treat or not to treat" paradigm in this select population toward "not to treat".  Because even if we're off with the project 3-5 year release date,  this group still has time to wait.

PART II WILL SHORTLY FOLLOW...

53 Responses
Avatar universal
PART ii

Less clear is the treatment approach with genotype 2's and geno 1's with signficant liver damage, i.e. stage 3 or 4.

Geno 2's with the current drugs, now have an overall 80 per cent chance of being non-detectible with only 24-weeks of treatment. And some select groups are showing similar success with only 12 weeks. For these reasons, many geno 2's are advised to treat now, even with no or minimal liver damage. This makes sense.

As to geno 1's at stage 3 or 4, the question is how long can they afford to wait? Because no one can guarantee these new drugs will pan out in time, treating now with current drugs is still a viable and often the best option. Keep in mind there was a similar excitement about BILN 2061 a few years ago that didn't pan out. So nothing is guaranteed.

Beyond "to treat or not to treat" an equally important issue is how will these upcoming drugs affect non-responders, relapsers and the tx decisions they have to make.

Recently, I spoke to a leading heptologist/researcher and asked what he's doing with relapsers these days. To my suprise he said he's not re-treating most of them with current drugs. The reason -- the promise of the upcoming protease inhibitors like Vertex

We all hope the new protease inhibitors will be the big breakthrough. Our entire community certainly deserves this.

But at this point we still have to be cautiously optimistic and carefully weigh how we factor these new drugs into our tx decision, but make no doubt about it, they certainly are a factor to consider.

And because new developments are happening so fast, the decision that makes sense today, may change tomorrow. One way or another.

-- Jim
Avatar universal
you basically summed up my line of thinking on it. Granted, I don't feel great, with chronic myofascial issues/muscle issues, which makes it seem far, far away. However, I have been following the course of this drug since I found out about it 4 years ago-meaning more than half the wait has passed, including the first trials in humans. I am 1B, got it from a blood transfusion 21 years ago, when I was a kid.
80575 tn?1207132364
I'm a 1b with 0-1 scarring.  After 36 weeks of tx I was stopped because of a viral breakthrough.

With all the buzz about VX-950, NM283, SCH-6, etc. I might have waited to tx. Right now I'm watching the news on all the  protease inhibators and would consider a clinical trial.  Does anyone out there have information about which drug to choose?  NM283 is being developed by a smaller company but with the backing of big pharma.  VX-950....I read yesterday that it's company committed to a bunch of leased space to accommodate their research needs.  My doc at IU Med. Center is high on SCH-6 but it's not even in a Phase I trial yet.....how do you choose?

After seven months off of PEG+RBV, I still catch myself in foggy moments and my neck and shoulder ache all the time...like arthritis and it began while on tx.  I've heard DDose comment about the same.

Mike
Avatar universal
I believe the current trials, at least with Vertex, are only open to treatment naive folks but maybe more current info is at http://www.clinicaltrials.gov/

Depending how you feel physically, you might want to wait a bit considering your minimal liver damage. Also, and I'm not 100 per cent sure on this -- I think for at least the next year or so these drugs will be combined with peg interferon and/or riba. Down the road a bit they will be tested by themselves.

-- Jim
Avatar universal
My first post was written before Part II came on. I did want to address BILN 2061, and I should mention I have talked to Boehringer Ingleheim in the past. They are NOT a publicly traded company, and apparently keep secrets better than some CIA agents. They would not tell me their plans for that drug, or about what they were planning in the future. Of course, there are no SEC filings to read for that either.
For those who might not know, BILN 2061 was a drug that eliminated the virus in vitro very quickly. Cardiac toxicity became the problem, and I believe the problem was in monkeys. Due to that issue, the program was suspended.
What Vertex did was they monitored EKG's and other heart functioning tests during their IB and there were no changes, problems, or abnormalities reported. Even though BILN didn't make it, I do belive it helped the others as to what to look for, etc. Was it Einstein who said that he who never failed, never accomplished anything?

Forbes did an article on this drug last January, before the last trial was completed.

http://www.forbes.com/business/2005/01/24/cz_sg_0124soapbox_inl.html
The thing I found interesting was that since the drug blocks an enzyme that is exclusive to the virus, and not the human body, there shouldn't be a side effect problem-UNLESS it is not broken down by the liver well-which was apparently the problem with BILN's drug. VX-950 has not had that problem.

Schering Plough is working on a small molecule PI as well, but there is very limited data on it, and they are behind VRTX by at least a year, or at least 1 phase. It remains to be seen if they can even match, let alone exceed the data out on 950 yet. Yes, I do own VRTX's stock from 9.18, from 5/04, based on a lot of the above.
Avatar universal
Thanks jmjm - fascinating reading.

As a 1a/1b Grade 2 Stage 2 I've decided to opt for treatment asap.  

But...I was wondering last night (being a/b and reading perhaps overall tx response is lower) what else was coming down the pike.  Explainning in this thread what else is being cooked up is just what I was wondering.  



Avatar universal
I'm a bit confused, maybe you can help...

When they say these new drugs will be available in 3-5 years does that mean they will be available only in trials or as a regular routine of treatment options...and will interferon and riba still be a part of the cocktail in the 3-5 years?

As you know, I still have not decided to treat or not to treat (biopsy will play a big role in decision)...Hearing all the stuff on these drugs coming along with less side effects really interest me, however, keeping my age in mind (54) do I have the luxury of wating it out, and what will the "less side effects" mean?  i.e anemia...

Your input would be appreciated....

Thanks Beth
Avatar universal
Something to keep in mind if you are a non-genotype 1

Protease inhibitors are small molecule drugs, VX-950 specifically targets geno 1b protease. Notice that all participants in the VX-950 trials were geno 1.

An earlier protease inhibitor BLN 2061, which also targeted geno 1 has been halted due to serious cardiac concerns, but data indicates that non-genotype 1's did not have as good a response.
VX-950 may not have the same drop off in non-genotype 1's, but that won't be known until tests on non-genotype 1's are conducted.

http://www.hivandhepatitis.com/2004icr/hepdart_2003/docs/011404_a.html
Avatar universal
VX-950 should be on the market as an approved drug in 3 years, if all goes according to plan, and so far, they are at, or ahead of schedule. Interferon will at the very least be additive, at best, synergistic. They are doing studies on it with and without interferon. They still feel there is good potential for this as a monotherapy, and I think Phase IB data does support that, without a doubt.
They just had a webcast of a presentation this morning, where they reiterated their views: IND (Investigational New Drug Application, which is filed with the FDA to support further clinical trials) will be filed soon, Phase IB to start soon (interferon and 950) Phase II to start this year and to be completed next year, with SVR data, Phase III in 2007, and an NDA filing BY (their words) 2008. An NDA is a New Drug Application, which is filed by a company to the FDA when they submit their drug for approval. In normal cases, a decision is made in 12 months or less. In this case, since it is considered an unmet medical need, the review will be a "priority", which means an answer in 6 months or less.

That is how the mid-late 2008 timeline for the drug to be approved is arrived at.
Avatar universal
I think I may have an answer as to the non geno-1 issue. NS3/4 is the enzyme that blocks the virus from the immune system, and I believe that to be the case (I could be wrong) in all genotypes. BILN did NOT target NS3/4, VX-950 does. 950 "uncoats" the virus (which is protected by NS3/4) and allows the immune system to now be able to identify it and kill it. The drug has a half life about equal to the half life of the virus, which is critical.
I have a call into VRTX (who has not been good at returning them) and I will ask them about that.
Avatar universal
all we need is to see what the SVR rates are per genotype and we can compare the effectiveness against current protocols. So far all I see is the clearance rate.
Avatar universal
Your questions are good ones.

"couldn't think of a nickname" lays out one projected timetable, although I've heard the drugs could come to market sooner if fast-tracked for certain patient populations.

So, yes, the drug currently is in trials and currently being tested with and without inteferon. What they will end up with of course will depend on the trials.

As far as whether you should treat or not treat, this is a very personal question of which I tried to offer some guidelines in my first post. Once you get your biopsy back you'll have more information.

As far as having "less sides" -- yes, that's the word.

-- Jim
Avatar universal
Good topic Jim. Thanks. frank
Avatar universal
Concerning the continuation of interferon in future treatment soups, I believe that if the goal is virus elimination, interferon + riba + inhibitor <i>x</i> will be the cocktail. We have as a general model treatment for HIV. Before anyone jumps my butt, please note the use of the word <i>general</i>. Uh, I believe it was protease inhibitors that turned the corner for HIV treatment. They were not a cure, but increased life spans and maintained better levels of general health longer. What is probably similar is that various inhibitors aren't likely to be a cure in and of themselves for hepC, but, as a sledgehammer to knock it to the ground and interferon/riba as the bullet to the head, so to speak.
Avatar universal
Recollection a little foggy, but I do remember reading about the similarities and difcferences between the use of protease inhibitors between HIV and Hep C. If I remember correctly, they differentiated between the two types of viruses and I believe the conclusion was that the protease inhibitors could actually eradicate the virus, not just knock it down as with HIV.

Intially, yes, it will probably be cocktailed with peg and riba, but this is as much an FDA requirement as anything else. The longer term goal is to use it either as mono-therapy or what many guess would be another type of cocktail but without inteferon or ribavirin. Exciting stuff!

-- Jim
Avatar universal
There are critical differences between HIV and HCV that are important as far as "cures". First, HIV is a retrovirus that integrates into the DNA (I belive, I am not an expert here). There are hidden reservoirs of HIV which is why it hasn't been cured-yet (I'll elaborate later). HCV is an RNA virus with no hidden reservoirs and many in here have been "cured", even if that definition means different things to different people. Many scientists will tell you that the cocktail approach to HCV will become a thing of the past. Targeting the NS3/4 enzyme is a breakthrough that many believe (including myself) will transform treatments just like the cocktail approach to HIV did-In other words, the cocktail approach is the best approach for HIV, but will be the least effective FUTURE approach for HCV. Remember, 950 did what combo treatment couldn't do, and faster. In 14 days, 950 alone had a 4.4 log drop, whereas in 28 days, current therapy averages a 2.4 log drop. That is 100 times more potent in half the time. That tells me that the cocktail approach may not be needed. Granted, many may choose interferon to go with it, because that would probably be like killing a gnat with a sledgehammer.

My family doc told me a few years ago that PI's would transform HCV therapy and better things were coming, and he said there could be real cures. He did not know about 950 though until I told him about it.

My note on HIV: Recently, I was viewing the drudgereport, and saw a headline about a possible cure for HIV, so I read it as it intrigued me. In England, there were 4 people with HIV that were given standard treatment, but they added an anti-convulsive drug and another compound to it. 3 of the 4 completed the trial, and those 3 had an average 75% reduction in "hidden" virus. The reason why they did this test, was, that apparently HIV hides in a certain cell that the anti-convulsive drug is active against. That drug brought out the hidden virus so the haart could kill it. Expanded trials are underway, but it was seen as a significant breakthrough.

Avatar universal
Very good discussion you started. I think a lot of good questions are being asked, and a lot of good info is being distributed.
Avatar universal
Thanks Jim for your info, this was a valuable thread for me...

After I receive the results of my biopsy I am hoping to come to you and cuteus for your personal opinions...You both seem to have a weath of knowledge on this virus and cuteus you are female and although you're younger than me we seem to have some pre exisisting conditions in common as well as genotype and you made it, you're my inspiration...

Thanks again to you both...Beth
Avatar universal
it is ultimately up to you, even if mild damage, to decide how badly you want hcv out of your life. I firmly believe that if drs intervene promptly against anemia and prevent oxygen deprivation damage, there will be less long term effects, and less people quitting tx. It is not fun ot tx, but what a reward it is after it is all over, and you can say; I WAS hcv positive.


here are some techno stuff about viruses:
http://vir.sgmjournals.org/cgi/content/full/81/7/1631
http://cmr.asm.org/cgi/content/full/11/4/614
for those who have the inclination to understand the ins and outs of hep c and others.
Avatar universal
thanks cuteus, I will check it out
Avatar universal
Hey C

What do you mean treat against oxygen deprevation and anemia?

This sounds like something I need to know (we) for the future if it will help us stay in tx and help with the sx!

:)
Avatar universal
I am not very good at explaining technical stuff, but hemoglobin is how the cells transport the life giving oxygen to all the organs. Less red cells=less hgb= oxygen deprivation, which can't be a good thing, right? Riba destroys red cells at a rapid rate.
check this article on the importance of treating anemia, sponsored by the makers of Procrit of course, but interesting to know;
http://www.mydna.com/resources/news/200407/news_20040715_bbanemia.html
Avatar universal
Thank you I get it. I am printing this out so that WHEN my doctor thinks I am being egotistical and know more than HE he will have reasons to LISTEN to me.

I do not believe doctors are NOT fallible...and I want to be armed and prepared.  I want to get better...much more than he wants me to get better if you know what I mean.

Thanks for the link.
Avatar universal
I have a feeling Cuteus' is out binging on Champagne celebrating her SVR so I'll jump in. :)

One of her points has to do with agressively treating anemia on treatment.

To oversimply, anemia is when your hemoglobin drops to ten or below, or when you have more than a two-point drop from your pre-tx level in less than a couple of weeks.

So, let's say your hemoglobin now is 13. If it drops to 11 after two weeks or so on treatment, you may start feeling very fatigued, dizzy when you stand up, even out of breath. It's anemia caused by the ribavirin.

What you want to do is first make sure your doctor does a hemoglobin test at least every other week during the first 12 weeks of treatment. I had mine done weekly. That way you will know what is going on.

If you do develop anemia, the solution is to treat it with weekly injections of a drug called Procrit. It's really a miracle worker and in most cases will get your hemoglobin up to par within 2-4 weeks. Unfortunately, many docs are too slow on the draw and people suffer the symptons of anemia needlessly, or worse -- they have to reduce their ribavirin dose or even go off treatmen.

Vigilant monitoring of your hemoglobin level and early intervention with Procrit is what you want. This is something I recommend to everyone to discuss with their doctors prior to being treated.

-- Jim

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