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Author Topic: Update on TMC-125  (Read 3569 times)

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Offline gerry

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Update on TMC-125
« on: November 27, 2006, 02:03:16 PM »
It seems that this second-generation NNRTI will not work in the setting of pre-existing resistance to NRTIs when it is not combined with other active drugs.  :(

"Patients with four or more NRTI mutations at baseline had little or no virologic response to TMC125

Even in patients with just one NRTI mutation at baseline there was a trend towards a viral load rebound apparent by week 12.

An increasing number of NNRTI mutations was associated with a smaller viral load reduction and faster viral rebound.

The study findings suggest that TMC125 may not be approprate as a second-line drug in settings where patients have high levels of nucleoside analogue resistance, and where the drug cannot be combined with nucleoside analogues to which the patient is sensitive, as well as new drug classes such as chemokine antagonists or integrase inhibitors."

Link to article

« Last Edit: November 28, 2006, 09:58:04 PM by gerry »

Offline Moffie65

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Re: Not so good news with TMC-125
« Reply #1 on: November 27, 2006, 02:18:19 PM »

Thank you Gerry, but I must say this is not terribly stellar news for old farts like me who have a large resistance profile.

The Bible contains 6 admonishments to homosexuals,
and 362 to heterosexuals.
This doesn't mean that God doesn't love heterosexuals,
It's just that they need more supervision.
Lynn Lavne

Offline gerry

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Re: Not so good news with TMC-125
« Reply #2 on: November 27, 2006, 02:35:05 PM »
You are not alone with this disappointing news, Tim.  The good news is Merck's integrase inhibitor MK-0518 is also now available on expanded access and is already in Phase III trial stage.  It has pretty impressive results so far with highly resistant virus.

MK-0518

Offline allanq

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Re: Not so good news with TMC-125
« Reply #3 on: November 27, 2006, 03:18:13 PM »
I didn't know that resistance in one class of drugs (NRTI's) can cause resistance to a drug in a different class (NNRTI's).

Thanks for the info.

Allan
Top (Breakfast): Prezista, Norvir, Isentress, Zoloft (2), Glyburide (2), Aspirin
Bottom right (Dinner): Prezista, Norvir, Isentress
Bottom left (Bedtime): Sustiva, Trazodone (2), Lipitor, Septra (no longer taking this)
Center: Alprazolam (Xanax)
Not shown: various vitamins & supplements

Offline gerry

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Re: Not so good news with TMC-125
« Reply #4 on: November 27, 2006, 03:42:03 PM »
I think what the study showed was you cannot rely on TMC-125 if it is being combined with nukes and there is evidence of some resistance to the nukes.  It does not mean that the nuke resistance causes resistance to TMC-125 as well.  The failure may have been due to development of resistance to TMC-125 when combined with nukes with questionable activity against the virus. 

I think it is saying as well that it still has utility, based on earlier studies, by combining it with other drugs that are active against the virus, such as boosted PIs and Fuzeon, in situations in which baseline NRTI/NNRTI resistant mutations already exist. 

Offline RAB

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Re: Not so good news with TMC-125
« Reply #5 on: November 27, 2006, 04:55:03 PM »
Gerry

Interesting news. 

I was hoping to use this drug as part of my next regimen, but perhaps now that won't be possible.  Any thoughts?  I'll see my doctor next week and will ask him too.

I should point out I have 10 mutations to the NRTI class.

Currently I am on Fuzeon, 2PIs (uncertain of mutations to this class), and 2 NRTI (Viread and Epivir).  I've been on this regimen for 3 years next month.  It has proven to be very very durable and effective.

Just got my most recent labs back last Friday:

CD4 879

%  17%

VL  <50

Like Moffie, I'm an "old fart", but I'm very pleased with where I'm at right now, all things considered.

I would like to get off the Fuzeon, for one reason only, the injection site reactions (beyond that Fuzeon is a very good drug with very few side effects in my experience). 

RAB




Offline blondbeauty

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Re: Not so good news with TMC-125
« Reply #6 on: November 27, 2006, 05:17:01 PM »
Resistance...if it wasn┤t for that it would be a really manageable disease.
The only member in these forums approved by WINBA: World International Nail and Beauty Association.
Epstein Barr +; CMV +; Toxoplasmosis +; HIV-1 +.
Counts when starting treatment:
V.L.:80.200 copies. CD4: 25%=503
Started Sustiva-Truvada 14/August/2006
Last V.L.count (Oct 2013): Undetectable
Last CD4 count (OCT 2013): 52%= 933

Offline gerry

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Re: Not so good news with TMC-125
« Reply #7 on: November 27, 2006, 08:41:35 PM »
This is what Dr. Gallant had to say about this study and its interpretation from the Hopkin's website:

"...don't overinterpet the data on NRTI resistance and etravirine (TMC125). The reason that it didn't work as well in patients with NRTI resistance was because they didn't have enough active drugs in their background regimen, not because the NRTI mutations were causing etravirine resistance. I'd certainly feel comfortable using it in someone with multiple NRTI mutations and a K103N (NNRTI) mutation, as long as I was combining it with other active agents, such as an active PI, integrase inhibitor, or Fuzeon..."

I hope this clarifies the situation.

Offline J.R.E.

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Re: Not so good news with TMC-125
« Reply #8 on: November 27, 2006, 08:54:22 PM »
Gerry,


Thanks for that info....



Ray
Current Meds ; Viramune, Epzicom, 40mg of simvastatin, 12.5mg of Hydrochlorothiazide.
Metoprolol tartrate 25mg



http://forums.poz.com/index.php?topic=40802.0

http://forums.poz.com/index.php?topic=45159.0

http://forums.poz.com/index.php?topic=39722.msg495621;topicseen#msg495621

http://forums.poz.com/index.php?topic=46806.0

http://forums.poz.com/index.php?topic=39414.msg491701#msg491701


 In October of 2003, My t-cell count was 16, Viral load was over 500,000, Percentage at that time was 5%. I started my first  HAART regimen  on October 24th,03.

 As of 6/4/14,  t-cells are at 423, Viral load <40

 Current % is at 13% 

  
 62 years young.

Offline Life

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Re: Not so good news with TMC-125
« Reply #9 on: November 27, 2006, 09:22:42 PM »
"When one door closes, three others open."  I wish this statement would hold true in all of our "cases".

Offline HIVworker

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Re: Not so good news with TMC-125
« Reply #10 on: November 27, 2006, 10:47:50 PM »
It's good and bad news, that much is true. However, I am confident that this new drug paves the way to new NNRTIs that are effective against existing resistance.

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline jntmax39

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Re: Not so good news with TMC-125
« Reply #11 on: November 28, 2006, 08:58:35 PM »
I'm sorry but the whole thing confuses me. I don't understand about all of that,I don't even know what my meds are called as far as nukes and pi and all that stuff,I only know what my meds are called by my script wich is sustiva and truvada.
Can someone explain were I can understand please. I try to read the lessons but I seem to get more confused and quite francly It scares me.
THANK YOU

Offline gerry

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Re: Update on TMC-125
« Reply #12 on: November 28, 2006, 10:38:04 PM »
I edited my original post to make it more accurate.  This link also gives a better picture of what the study was all about.

JNT:

You don't need to worry about this.  If you have not viewed the presentation posted by Matt on this thread, I suggest that you do because it gives you a clear understanding of drug resistance.

A great chunk of drug development research in HIV is being devoted to figuring out what agents to use for people who have developed resistance to the antiretrovirals they are using or cross resistance to antiretrovirals they have not used but are in the same class (a phenomenon called cross-resistance).  For instance, with the Sustiva you are taking, which is an NNRTI, it takes only one mutation to make the virus resistant to it.  What's more, if it is the mutation called K103N that happens, then the virus also gets (cross-) resistant to Viramune and Rescriptor, the other 2 NNRTIs that are currently used.  This is what's referred to as having a "low genetic barrier" to resistance: when it takes only one mutation to make the virus resistant to the drug or drug class.  This is different, for instance, for several of the PIs (especially those that can be boosted with Norvir) in which it takes several resistant mutations to emerge before the virus becomes fully resistant to the PI drug.

TMC-125 is a second generation NNRTI that was designed to have a higher genetic barrier to resistance (somewhat similar characteristic to current PIs).  And this fact is true: it takes several NNRTI mutations to make the virus fully resistant to TMC-125.  If one only has a K103N mutation which renders the other NNRTI's Sustiva, Viramune and Rescriptor basically useless, one can still use TMC-125.

The study was basically assessing if people who have failed an NRTI + first generation NNRTI combo can be switched to NRTI/TMC-125.  Unfortunately, a lot of the people who did this switch only had a temporary response, after which the combo failed to control the viral load.  What was found was a lot of these patients had multiple NRTI and NNRTI mutations to begin with, so in reality, simply relying on TMC-125 to keep the virus in check was perhaps doomed to fail to begin with.  That was because there was no other more active drug in the mix.  The investigators did not anticipate that they would be dealing with subjects with relatively high numbers of NRTI and NNRTI mutations.

I think the take home message here is if someone is on a first generation NNRTI (combined with NRTIs) and there is evidence that the combo is failing, this needs to be addressed expeditiously to avoid developing multiple NNRTI mutations (in addition to NRTI mutations) that will affect the usefulness of newer generation NNRTIs.  And this is something that was already anticipated while this drug was being developed.  It also highlights the usefulness of guiding treatment after initial failure with resistance tests to help choose the drug combinations that would most likely work. 

Offline jntmax39

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Re: Update on TMC-125
« Reply #13 on: November 29, 2006, 11:41:38 PM »
GERRY
THANK YOU SO MUCH FOR TAKING THE TIME TO EXPLAIN THIS TO ME.I UNDERSTAND A LITTLE BIT BETTER ABOUT THIS.

Offline gerry

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Re: Update on TMC-125
« Reply #14 on: December 17, 2006, 02:45:19 AM »
This is in response to Rich's questions in another thread:

Actually, I am confused by their conclusions. Are you/they saying that TMC-125 didn't do well because the OBT didn't control viremia and didn't help the new NNRTI? But the PI did because they didn't have any PI resistance?

Yes.  In this particular study, that's why TMC-125 did not do well.  They were hoping that they could simply use TMC-125 to substitute for the previous NNRTIs used in NNRTI/NRTI experienced patients and still pair it up with 2 NRTIs.  What they did not anticipate was that a lot of subjects had multiple NNRTI mutations (23.7% of patients receiving TMC125 had 1 NNRTI mutation; 40.7% had 2 mutations; 23.7% haf 3 NNRTI mutations; 5.1% had 4 NNRTI mutations) which also correlated with multiple NRTI mutations.  This limited the activity of TMC-125, and since the 2 NRTIs paired up with it are also compromised by the TAMS and M184V, then the entire regimen failed.  This was not the case with the boosted PI group because the patients were PI-naive.  But even if the PI-group seemed to have done better, it was unknown how long beyond 16 weeks that response in the PI-group could have been sustained, because the study was stopped at 16 weeks.  Would the PI group have had a rebound as well had they been followed longer because the background NRTI was also not optimized?  Perhaps, but we don't know for sure or for how long or even if it's eventually going to fail because the study was stopped prematurely.  (This is essentially where lagunaguy's situation is, except that his current boosted PI regimen paired up with 2 NRTIs in the setting of M184V and multiple TAMS has succeeded in suppressing the virus for over a year.  And this is not unheard of because there are documented cases in which boosted PI even when used as monotherapy could work in some people.)

I think this study emphasizes the importance of guiding future treatment after failure with resistance tests.  Most studies of treatment-experienced patients use optimized background therapy added to the new drug.  This was not the case here (and is not possible in many resource-limited settings where a big part of the study was conducted).  The hope was that if this had worked, TMC-125 would have been a good go-to drug after first line regimens in resource-poor settings (which happens to be generally NNRTI + 2 NRTIs) fail.  But this proves that this is not a viable option.

There were various reasons why there were a lot more NNRTI and NRTI resistant mutations found on the study patients than what would have been expected in early treatment failure using conventional NNRTI/NRTI combo cited in the Aidsmap article including:  "the lack of drug options due to cost for patients in those countries, leading to extended periods on failing regimens, together with the lack of viral load monitoring that would warn clinicians when it was necessary to switch patients from a failing regimen.  The baseline analysis also found that more than a third of patients in the study were recycling at least one nucleoside analogue used in the past in the hope that it would have some benefit second time around. Around ten per cent were recycling two nucleoside analogues."

 
« Last Edit: December 17, 2006, 03:29:52 AM by gerry »

Offline newt

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Re: Update on TMC-125
« Reply #15 on: December 17, 2006, 04:39:07 AM »
Two reports from i-Base:

Etravirine (TMC-125) available on named patient programme in the UK

Etravirine (TMC-125) associated with -1 log viral load reduction at 48-weeks results in treatment experienced patients

The first study contains the important information that MK-0518 (the new integrase inhibitor) should not be used with TMC-125 until results of an interaction study have been completed. Both drugs are metabolised through a shared glucuronidation pathway.

The second essentially repeats info already noted by fellow poster. More depressing than the resistance thingies is that 4 in 10 TMC-125 users reported grade 3/4 side effects (ie serious) compared to about 2 in q0 in the control group (but this includes from other drugs in the combo).

- matt
"The object is to be a well patient, not a good patient"

Offline Cliff

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Re: Update on TMC-125
« Reply #16 on: December 17, 2006, 06:45:13 AM »
Is this Tibotec's drug?  The one they hyped up as being a flexible molecule....resistant to resistance?

Offline HIVworker

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Re: Update on TMC-125
« Reply #17 on: December 17, 2006, 10:08:12 AM »
OK, I guess my point in the other thread is that given the trial, TMC-125 was really in monotherapy and was compared to PIs - and in this setting it didn't appear to work.

Let me explain why I care, I'm trying to understand the reason. As I work in industry, I am skating on thin ice. I'm not knocking the compound, I'm trying to understand why it didn't work in a setting it should have done. I should probably take my reading and thoughts elsewhere. I just chimed in on the conversation because TM125 was suggested with other drugs to replace a failing regime and I didn't know whether that was the right thing to do until someone figures out the best way to use it, rather than suggest it without data that suggests it works in that background.

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline gerry

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Re: Update on TMC-125
« Reply #18 on: December 17, 2006, 11:35:40 AM »
Rich:

I don't question that you care because I know you do.  However, you need to take a moment and take into consideration the context in which the suggestion was made instead of just firing away the way you did.  There are more professional ways of asking for a clarification.  I never suggested that TMC-125 was the magic answer to his resistance problems.  Your line of questioning made it appear that I was.  What I was trying to explain to him was that he probably would have more options now for other drugs to use even if he completely lost the current NRTI and NNRTI, compared to say 4 years ago when I tried to answer a similar question for another poster and the only other option back then was T-20, which was being used sub-optimally by many patients as their last remaining active drug, unable to combine it with any other active drug in a combo.  That was because that's all they had left.  I wasn't hyping up the drug.  I was trying to explain its potential utility in his particular situation.  That's all I'm saying.

Gerry

Offline gerry

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Re: Update on TMC-125
« Reply #19 on: December 17, 2006, 11:38:17 AM »
Matt:

Thanks for pointing out the side effects and lack of info on interactions.

Cliff:

Yes, unfortunately, this is it.  For now, at least.

Offline HIVworker

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Re: Update on TMC-125
« Reply #20 on: December 17, 2006, 12:33:06 PM »
Firing off? Is that what I am doing if I question logic? I must remember that one for meetings. I think you are translating 'firing off' for clarification. Glad we sorted that out, at least. Let's not get offended by all of this. Maybe you could point out where I was being unprofessional, just for my continued education....

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline gerry

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Re: Update on TMC-125
« Reply #21 on: December 17, 2006, 01:51:30 PM »
Ok.  Let's not have a diva moment over this.  I'm sorry I took a shot at your professionalism.  That was uncalled for.  And I wasn't offended.  It just got a little tiresome for me to explain several times in various ways what I was trying to say and still feel like I'm not getting through.  I'm just gonna have to leave it at that.  And don't worry, I have no intention of advising people to get on the TMC-125 expanded access program without first knowing how to use it and without getting expert advise from more reliable sources.  That was never my intention.  Again, there was a context as to why I even mentioned it in the other thread.  Let's not lose sight of that.  And let's not beat it to the pulp.  Moving on...

Offline HIVworker

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Re: Update on TMC-125
« Reply #22 on: December 17, 2006, 05:36:16 PM »
I think that's the problem Gerry. It's an internet forum. You and I were both on at the same time. It would have been easier to discuss it on the phone. I think what went on was merely rapid posting from both of us because we were both online. It's the problem with internet forums. People can read intent where there isn't any - which is why I put that skating on thin ice comment too.

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline newt

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Re: Update on TMC-125
« Reply #23 on: December 18, 2006, 05:03:20 PM »
From the latest HIV Treatment Bulletin:

8th International Congress on Drug Therapy in HIV Infection


Explanation for failure of TMC-125 (etravirine) in TMC227 study

Simon Collins, HIV i-Base



[..left out the bit on nos an methods etc, so the results...]

Pooled data from all sites showed that an initial viral load response of -1.3 logs at week 8 in the NNRTI arm (compared to >2 log reductions in the PI group) was not sustained to week 12.

In Thailand the rebound occurred before week 4, and occurred after week 8 in South Africa and after week 12 in Argentina and Spain. For patients reaching week 12, only 57% of the TMC-125 groups compared to 91% in the PI group achieved at least -1.0 log viral load decline.

The baseline resistance profiles of patients in the NNRTI arm were slightly more advanced compared to the PI group, but the significant differences in response was probably more related to the fragility or an unsupported NNRTI, comparedto boosted PI regimens which even shows reasonable success rates when used as monotherapy in several small trials, especially in PI-na´ve patients. Although TMC-125 retains activity against NNRTI-resistant virus, it is clearly as vulnerable to rapid resistance when used as virtual monotherapy as existing drugs in this class.

At baseline, the median number of NNRTI mutations was 2 (range 0-4) and median fold change (FC) to TMC125 was 2.0. The median number of NRTI mutations was 1 (range 0-7). However 9% and 12% of subjects in TMC125 and control groups, respectively, did not receive two sensitive NRTIs. Only patients with less than 2 TAMS/M184V maintained viral suppression.

Patients with higher NNRTI and RTI-associated resistance had higher FC to TMC-125. Thai patients had more extensive RTI and NNRTI resistance, and this correlated with a higher FC phenotypic resistance to TMC-125 (5.6 vs </=2.0 in other countries). Increased resistance to RTIs tended to increase with increased NNRTI mutations.

In a multivariate analysis, increased numbers of NRTI and NNRTI mutations, use of inactive NRTIs, and higher TMC125 FC were all independently associated with virologic failure.

comment [author's not mine]

The failure of TMC-125 in this study seems to be convincingly explained by extensive RTI and NNRTI resistance, and recycling of RTIs. It also showed that accumulating NNRTI mutations can compromise chance of benefiting from pipeline NNRTIs.

This is particularly important in countries using NNRTI-based first line regimens where there is limited or no access to viral load monitoring, where patients are treated until clinical failure. Unfortunately, this the exactly the setting that would benefit most from a second generation NNRTI.



Guess this will be online on the i-Base website in a day or two

- matt
"The object is to be a well patient, not a good patient"

 


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