Direct-acting Drugs Danoprevir plus RG7128 Suppress HCV without Interferon

[Bill1954]

While this still hasn’t been ‘SVR proven’, the preliminary 5 log-10 reduction at 14 days looks very interesting; more in the article from the hivandhepatitis site:

“SUMMARY: Results from the INFORM-1 trial, which evaluated 2 experimental agents that target different steps of the hepatitis C virus (HCV) lifecycle, showed that a combination of direct-acting drugs can suppress viral replication without interferon or ribavirin. As described in the October 14, 2010 advance online edition of The Lancet, the HCV protease inhibitor danoprevir (RG7227 or ITMN-191) plus the polymerase inhibitor RG7128 reduced HCV RNA by about 5 logs in both treatment-naive and previously treated patients, and caused no serious side effects in this 14-day study.”

http://www.hivandhepatitis.com/hep_c/news/2010/1022_2010_a.html

--Bill

[dointime]

"The great thing about PI-resistant mutations is that they're less fit than wild type. They never get a chance to improve their game because the available replicative space is always taken up by the gung-ho wild-type virus. In the presence of the PI all of a sudden they're the only ones left and viral evolution being what it is, they will learn  quickly how to optimize for survival. Not good for the patient. Breeding bugs that are both fit and resistant to NS3/4A Pis pretty much excludes using any PI of that type in a future tx. On the other hand if you quit early enough, wild-type should bounce back and you can count on the PI to at least eliminate the wild-type again in another attempt."

This is not exactly my understanding of resistant mutations.  I think that resistant mutations are already optimized for survival in the presence of a PI.  The mutation is how the virus escapes being latched on to by the PI.  I don't think that mutations become more fit given more time.  To become more fit they would have to revert back to wild type which is the optimum state for the virus, and they do that slowly when the PI is removed, no matter how long or short a time the PI was used.  

I do agree that if the PI does not get you to UND within a short time - I would say 4 - 8 weeks - then it is probably useless after that and pointless to carry on poisoning yourself with it.

dointime  

[willing]

>Also, I'm thinking if I do the PI/Soc when it's available that I'll quit in > 2 months unless I'm UND with a >1 PCR. What do you think of this >approach. I'm only considering it because I think the 25% that won't >succeed are those that have a new mutant strain, and if the PI
> and Riba at peak levels aren't wiping it out completely by then,
>they never will.
>What are your thoughts on this??

First, good luck with your surgery today. The approach above makes good sense to me. If you have a minute check out the arithmetic in the comment on Trin's thread:
http://www.medhelp.org/posts/Hepatitis-C/A-couple-of-good-links-regarding-Telaprevir-and-Boceprevir/show/1382103
(you'll need the table at the bottom of abstract 216 from the boce "respond-2" aasld presentation and additional data from the second of the two links Trin gave).

The tx is messing with my head in a big way, so it's quite possible, there's a mistake, but if not the conclusion is that if 4w lead in and 8w of soc+boce don't get you to UND it may be time to think about plan B.

The great thing about PI-resistant mutations is that they're less fit than wild type. They never get a chance to improve their game because the available replicative space is always taken up by the gung-ho wild-type virus. In the presence of the PI all of a sudden they're the only ones left and viral evolution being what it is, they will learn  quickly how to optimize for survival. Not good for the patient. Breeding bugs that are both fit and resistant to NS3/4A Pis pretty much excludes using any PI of that type in a future tx. On the other hand if you quit early enough, wild-type should bounce back and you can count on the PI to at least eliminate the wild-type again in another attempt.

BTW, relying on your Dr. to make  these sort of decisions for you may not be so wise. From the advert for Pockros's Debrief talk  (to be included in the '10  "best of the liver talks " summary)

"To aid medical professionals in learning this new information, an enduring document will be made available for reference a few short months following the meeting, both online and in print. “We cannot make true AASLD guidelines,” Dr. Pockros elaborates, “until the drugs are labeled by the FDA. However, we can provide a set of rules to follow for anyone treating patients with hepatitis C.” The slides of the Hepatitis Debrief will be available as part of the Best of The Liver Meeting®.

“All hepatologists don’t know about these antivirals yet,” Dr. Pockros expounds. “These rules are new and our knowledge in special populations such as HIV-coinfected patients and decompensated cirrhosis patients is lacking. This program will benefit anyone who is seeing patients in the next year, hepatologists and non-hepatologists alike.” Attendees will walk away from this half-hour presentation with up-to-date information they may use in treating hepatitis C patients in 2011."

So that half hour of training will likely be a large part of  the background that goes into Dr. recommendations about how to use DAAs in '11. No one has a clue yet. And if there's one thing that's sure, it's that we'll be thinking about all this  more than they will.

[IMstacie]

I posted part of an article on the other side about how it seems that HCV is becoming the virus of choice for the big pharma firms as well as some small ones.  They are competing, in a race!! There have been a lot of articles in Bloomberg, Marketwatch, etc.  The big pharmas see it as a profitable endeavor with a market that is forecasted to more than double by 2015.  Whatever the reason, it will help the victims.

"10/29/2010-A number of pharma firms including Merck (NYSE:MRK), Johnson & Johnson (NYSE:JNJ) and Bristol-Myers Squibb (NYSE:BMY) are in a heated race to come up with newer more affective treatments for hepatitis C.  The global market is forecasted to more than double by 2015 to $9 billion.  Large pharma firms are hitting it hard to find other avenues of growth".

[Bali05]

where do you get <1 PCR ?

[merryBe]

thank you for the great explaination. It's making more sense now.  You are probably right, the Pharms may not lock arms, but then again there have been some aquisitions lately that may have benefit to us, of late.

I'm thinking they can't be too far from at least having maintainance drugs as well, it's just doesn't seem right that they'd continue to resist that approach.
After all, the average HIV person has a VL under 100....and we have 1 million on average. If we were maintained at 50 or 100, then then need for transplants might all but disappear.
Do you think there will be any efforts in this direction?
I'm just kind of blown away that they did this for aids, and yet have no intention of doing it for HCV because of fear of "super strains"....shouldn't they worry with HIV as well?

I mean, obviously the VL that sticks around with HIV is composed of the drug resistant virons, and they could go airborne anytime, in which case the whole planet will be affected, and yet they now medicate all 30 million HIV people and think nothing of it.

So why is there no movement towards this with HCV??? Not that I'd want that to cross to mucosa either, but it seems unjust that the medical community decides one group should be spared while another should just die the death.

Also, I'm thinking if I do the PI/Soc when it's available that I'll quit in 2 months unless I'm UND with a >1 PCR.
What do you think of this approach. I'm only considering it because I think the 25% that won't succeed are those that have a new mutant strain, and if the PI and Riba at peak levels aren't wiping it out completely by then, they never will.
What are your thoughts on this??

[dointime]

"  So even among ifn-challenged null responders two DAAs aren't enough, which is consistent with the prediction from Rong et al. A three DAA combo (NS5B, NS5A and NS3) may reach the threshold  - and of course this is not being tested. On a practical level it may not matter. If even the weak ifn-response typical of null-responders is enough - that's all that matters!"

But will it be enough?  That is my new million dollar question.

dointime