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IAS 2007: Sydney, Australia; July 22-25

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The Body Covers: The 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention
Sixty to 65% of Treatment-Experienced Patients on a Regimen With Darunavir + Etravirine Undetectable at 24 Weeks: An Interview With Anthony Mills, M.D.

July 25, 2007

Anthony Mills, M.D.
Listen (3.5MB, 8.5 min.)
Dr. Mills, could you talk me through the DUET1,2 slides?

Absolutely. The DUET was a study that we started just over a year ago now, and the whole purpose of the study was to provide two new fully functional agents for patients who were highly treatment experienced. In the past, we had never been able to provide more than one investigational agent in the same trial. As we know, sequential monotherapy doesn't really work for patients. What would happen is, people who really needed new drugs would get on new drugs, and then they would just grow resistant. They would get another new drug and grow resistant to that.

We were very excited about the possibility of actually putting two new drugs in, maybe recycling some others and providing a suppressive regimen for patients that was going to be durable and sustained. That's actually what we found.

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Slides by Anthony Mills, M.D.; reprinted with permission. Click here to download the complete slide presentation.
 
Click to enlarge
 
Click to enlarge
Slides by Anthony Mills, M.D.; reprinted with permission. Click here to download the complete slide presentation.
 
Click to enlarge
Slide by Anthony Mills, M.D.; reprinted with permission. Click here to download the complete slide presentation.
When we started the study, both the agents, TMC 114 and TMC 125 [etravirine], were investigational. About four or five months into the study, Prezista (darunavir, TMC 114) got FDA approved. So then there was only one investigational agent. But that was the whole point of the DUET: the union of these two agents that we knew worked really well together, and didn't have a lot of drug-drug interactions, and had good additive synergy, as far as fighting the HIV.

At the time that we enrolled, these were the very sickest patients in our practices. I sent out e-mails to my colleagues in Southern California, and everybody referred me, it seems, to their one sickest patient. One of the things to remember about the study is that these were absolutely the most ill patients that were out there at the time.

The patients came into the study, and everybody in the study got TMC 114, [also known as] Prezista and darunavir. Then patients were randomized, 50/50, to either get TMC 125 or placebo. The investigators then chose an optimized baseline regimen to go along with the darunavir.

What we found was much like in the POWER studies that were released last year3: Patients who got placebo and darunavir actually did very well. We had 45 percent of the people in this trial actually go undetectable on the placebo arm.

But what was really exciting was when we used the combination of the two agents, and added TMC 125 to the regimen, then we got much closer to 60 to 65 percent of the patients undetectable. That's undetectable, less than 50 copies. In the past, when we were doing trials on treatment-experienced patients, we were happy to just get a 1-log drop in viral load. Then some very brave trials would look for less than 400 assay for treatment-experienced patients.

This is the first time that a trial actually set as its primary endpoint undetectable, less than 50 copies. We achieved that in the vast majority of patients.

Is the lesson that treatment-experienced patients need two active agents as a regimen, or is the lesson that these agents are particularly powerful?

I think both of those things are true. We have known all along that patients who have a broad, three-class drug resistance need more than one agent to really put together a suppressive regimen, and that sometimes we'll get transient effectiveness from a single agent. But the virus is very, very smart, and it grows resistant.

So the data here really substantiates what we know already: People do better if they have more active agents. But it also showed a unique intrinsic synergy between these two agents. I think it will be very exciting to see, over the upcoming years, as we do more studies with both of these agents, how they will interact with some of the other novel compounds. We know right now is that these two particular agents seem to work extremely well together and are very, very effective.

How does the 60 percent number compare with other studies of salvage patients? It used to be that 30 percent was considered a success.

Yes, 30 percent was a great success, and that 30 percent frequently was a 1-log drop in viral load, or undetectable, less than 400 copies. The great thing about this is that this was a 60 percent undetectable, less than 50 copies, that was present at 24 weeks.

We're just starting to analyze the 48-week data, but our sense is that that's probably going to be preserved, or maybe even improved over the 48 weeks. Sixty percent, in this patient population, was really unheard of. The vast majority of these patients that were in my practice, that I took care of, had never been undetectable in their whole life, on any previous combination. To get 60 percent of those people undetectable for the very first time is really incredible.

Was that sustained?

It's been sustained so far, yes. Like I said, we're just starting to analyze the 48-week data. I had several patients in my practice who had not fully suppressed yet at 24 weeks, but who did go on to fully suppress after that. This wouldn't be unexpected. This was highly treatment-resistant virus, and especially if patients had high viral loads, sometimes we won't see optimal efficacy at 24 weeks.

What were the side effects?

That was really the great surprise about the study. The drugs, both of them, were so incredibly well tolerated. It was impossible for me to tell as an investigator, because we were blinded to which patients were on placebo and which ones were on TMC 125.

The amazing thing was that all of them came in on complex regimens, all came in with lots and lots of tolerability complaints about whatever regimen they were on at the time.

When we put them on the DUET study and followed up with them subsequent to that, very, very rarely did they have any complaints about any adverse side effects. In fact, I got funny e-mails from patients that said, "Oh, my gosh. For the first time in 10 years, I'm constipated." So that's a good thing to have, if you're on a protease inhibitor.

How many patients were in the trial?

There were 1,200 patients in the entire DUET-1 and -2. There were about 600 patients in each trial. They were really identical trials, just held at different sites all over the world.

Were the results identical between them?

The results were very, very similar, and very, very consistent between the two studies. The undetectable, less than 50 copies, was about 60 percent, very consistent. The placebo arm in both studies was right about 45 percent, again, which is very consistent with the POWER data.

There were a couple of places where things differed a little bit. In DUET-1, there was a statistically significant increase in the CD4 count at 24 weeks, which we didn't see in DUET-2. But again, it may just be that we're still not seeing the full effectiveness of the combination. Or it may also just be that the TMC 114 alone, the darunavir alone, is so good at increasing the CD4 count that we're not going to see a huge difference by adding other agents.

Do you think this study is going to change practice?

I think absolutely this study is going to change practice. It's changed the way that all of us who were active investigators in the study have practiced. Now that the data is out there, and people see how synergistic these two agents work together, I think it's really going to change the way people deal with treatment-experienced patients.

Well, thank you very much.


References

  1. Mills A, Cahn P, Grinsztejn B, et al, on behalf of the DUET-1 study group. DUET-1: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 612 treatment-experienced HIV-1 infected patients. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS204-1.
    View slides: Download PowerPoint

  2. Katlama C, Campbell T, Clotet B, et al, on behalf of the DUET-2 study group. DUET-2: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 591 treatment-experienced HIV-1 infected patients. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS204-2.

  3. Molina JM, Cohen C, Katlama C, et al. TMC114/r in treatment-experienced HIV patients in POWER 3: 24-week efficacy and safety analysis. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0060.
    View poster: Download PDF



  
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