Viral resistance to 950

I'm new to posting a question so hope I'm doing it right.  I posted back in Sep't. to "Couldn't Think of a Nickname" re: some earlier info. I had heard about the virus quickly developing resistance to 950 in a matter of weeks.  Is this consistent with what you know about this drug?  Also if that's the case, isn't it unlikely that VX 950 would ever be used as a monotherapy?

[Upbeat]

This is old news but may answer your question.

Drug Resistance
The risk of viral resistance is likely to pose a major challenge to the development and clinical use of NS3 serine PIs, as it has with HIV PIs. in vitro studies using HCV replicons have identified mutations conferring drug resistance to BILN 2061 and VX-950. These findings were certainly not unexpected. Indeed, the potential for resistance is virtually guaranteed for compounds targeting the NS3 protease.
However, combinations of PIs could in theory offset the risks of resistance. Indeed, HCV strains containing mutations that rendered the virus resistant to BILN-2061 were still susceptible in vitro to VX-950, and vice versa. Ideally, companies with compounds in or approaching early clinical development -- such as Boehringer Ingelheim, Schering-Plough, and Vertex -- will collaborate on researching combination approaches after initial safety and efficacy has been demonstrated.

But the potential for resistance ultimately means that any PI will initially have to be used with PegIFN.

                                                         Ron

[Liv]

Thanks - guess I wasn't current on the old news.

[couldn't think of a nickname]

The most common resistant strain found was the A156T strain. Even though it was found in some, it was rendered much less fit. It is sensitive to IFN though, which is another reason the trials are the way they are. A combo approach could combat that, as different PI's might have different resistance profiles.

There are HCV drugs being developed to address these issues already, and trail the field by a couple to a few years. In fact, VRTX already has a second generation compound (improved version) being worked on. ITMN has one in phase I I think.

In some cases, it might work as a monotherapy, maybe depending on genotype, vl, or other factors, but we may not know because this compound won't be tested with many monotherapy arms. Might not be worth the time and money right now, also depending on where the next compound is.

The resistance issue applies to probably most antiviral drugs really, and in this case, this is why you have to hit it hard and hit it fast. The virus doesn't want to die, so it tries to adapt to save itself.

[Liv]

Thanks so much.  I appreciate your patience and eloquence in explaining this "old news".

[couldn't think of a nickname]

yqw.

[willows]

I remember a post about NM283 and some viral breakthru at about 8 weeks or something for one of the posters here, but do not remember viral resistance to VX 950.  If someone can remember than post, please direct me to it.  My doc has told me already that from my profile I have developed a resistance to IFN, so I am very interested in the PI's and viral mutation.

My doc has convinced me to delay maintenance to keep the mutation down until the new drugs are available, but if there is mutation against VX950 also, well, I have to rethink the PLAN.  He was gung ho on VX for me in about a year or so, but since I am just beginning to show symptoms of cirhossis, I'm trying to follow VX closely.  Thanks in advance to anyone who may have info about the post regarding VX and viral resistance.  Good day to all!
Willow

[SixtiesSage]

What happend to 950 was that after 2 weeks of MONOTHERAPY, viral breakthrough was noticed. This means that 950 is not good alone, but when used with interferon viral breakthroughs have not been anything significant, and rapid viral reductions have been dramatic.

Every anti-viral or anti-bacterial drug can cause mutations ESPECIALLY if someone starts to take the drug and then quits after a few treatments or so. This gives the stronger virons, that have had a chance to mutate against the drugs to come back with a vengeance. This is why is is important to always finish a course of treatment of anit-virals or bacterials as best as one can.

This is also why 950 has so much hope concerning it. Dramatic and rapid viral reductions are associated with higher levels of SVR at least in current treatments. Data concerning SVR using 950 will be out soon. Because of the fast drop in viral loads, the SVR rate will hopefully be much higher. It has been estimated that geno's 2 and 3 will have near 100% SVR and 2's and 3's will be between 80 and 90%. Lets hope this is on the low end.

[SixtiesSage]

Ooops! On the last line I meant 1's and 4's, instead of 2's and 3's again. I have to admit; its been 5 years since TX and some of the brain fog has not lifted.

[couldn't think of a nickname]

http://www.natap.org/2006/EASL/EASL_09.htm

First, breakthrough was NOT seen at the best dose group, 750 mg 3x per day, which is what is being used. Trough concentration levels need to be over 1000 (micrograms/per kg I think) for the best dosing.

Notice on the link:
1. Wild type virus is the virus we consider normal to HCV. After the majority is killed off, you can identify mutant strains.

2. Mutant strains were shown to have much less fitness, and were impaired. This is why it got replaced by WT virus after dosing.

3. They did not treat long enough for SVR. They used a very sensitive test, <10, but even 5 copies per mililiter is a lot considering how many ml's of blood the body has.

4. we don't know if 950 can work alone. It hasn't been tested long enough. Viral decline slopes suggest it can do it, it might just take longer. Key point: STUDIES HAVE NOT SHOWN IT WON"T WORK AS A MONOTHERAPY. It still could work, but there is no point in testing it that way. It would take too much longer to get to market.

5. Notice how slowly vl returned.