The Body Covers: The 47th Interscience Conference on Antimicrobial Agents and Chemotherapy
ICAAC 2007 Highlights: An Interview With Trevor Hawkins, M.D.
September 19, 2007
Dr. Hawkins, what did you think were the biggest, most important HIV presentations of the conference?
Probably the most talked about presentation has got to be ARTEMIS,1 just because it's another shot in this sort of salvo of attack on lopinavir [generic name: lopinavir/ritonavir; brand name: Kaletra; also known as LPV/r] as the giant PI [protease inhibitor] in the field. And this time it hit home. I think the trouble with TITAN,2,3 which was in experienced patients [and presented] in Sydney, was that there was a lot of background noise (i.e., there was a lot of preexisting resistance to lopinavir), which muddied the waters. So, even though in TITAN darunavir [brand name: Prezista; also known as TMC114] did better, you couldn't walk away saying, well, it did better in patients with resistant virus.
These patients in ARTEMIS were [treatment] naive. They had no background noise at all. Not only was darunavir not inferior on every level, it was superior in patients with [a viral load] greater than 100,000. It had less diarrhea, and a better lipid profile with regard to triglycerides. It did better. There's no way around it. It did better than lopinavir. So that's cool for darunavir, and I think it was significant.
For myself, I thought that some of the data on the entry inhibitors, CCR5 inhibitors, was intriguing -- intriguing not only clinically, but also as a possible insight into pathogenesis.
There were a number of presentations [on CCR5 inhibitors]. There was the 48-week MOTIVATE 14 data we saw yesterday, as a late breaker. Nothing remarkable in terms of the data, except that it was durable. The 24-week response we saw previously5 was durable at 48 weeks, and it's a pretty good response. Remember, they didn't use darunavir in the background, and very little tipranavir [brand name: Aptivus; also known as TPV]. So, it was pretty good in very [treatment-]experienced patients. I did those studies in the clinic.
We saw a new drug from Progenics called PRO 140, which is an IV [intravenous] CCR5 inhibitor, which also had quite a good dose response.6
That's preclinical, right?
That's preclinical. That's very early, yes. But I think it looked like it had a good dose response curve, with better responses with the higher doses. Everyone with a 5 mg/kg dose had a greater than 1-log drop. So it looks like it's consistent.
But I think a really intriguing point of all this is that everybody who failed in all of the CCR5 inhibitors had a good CD4 response. Now, the CD4 response was less if they failed with X4 virus, dual/mixed. Nevertheless, it was still better than the placebo arm in MOTIVATE,4 whether they failed with X4 or R5, or whether the placebo failed with X4 or R5. What is driving that? The answer is, we don't know.
But to make a rather conceptual leap, there was a session on pathogenesis earlier (the first day of the conference) and there was a presentation on monkey virus. They were SIV [simian immunodeficiency virus] monkeys. SIV causes disease in rhesus macaques. It doesn't cause disease in sooty mangabeys. What's the difference between sooty mangabeys and rhesus macaques? Immune activation. You see a lot of immune activation in macaques, and none in sooty mangabeys. What drives immune activation? Well, there are probably a number of things. But one of the intriguing things was, the sooty mangabeys had 33% lower expression of CCR5 receptors.
I'm making a big leap here. But do CCR5 inhibitors block immune activation, therefore allowing for a better CD4 response? And might that be of use in using R5 inhibitors in the future? A positive side, rather than the rather scary bit about what's going to happen down the road: Would that in fact improve, or give us a way of using R5 inhibitors that we hadn't previously thought of? So I think that was intriguing.
What do you think the clinical implications are of all of this?
I don't know what the clinical implications are. I think R5 inhibitors will still be used predominantly in salvage. However, since we know how to suppress virus, and that's one way of reducing immune activation, do we then treat everybody? I think that's where I'm at right now -- test everyone, treat everyone -- or can we delay treatment by reducing immune activation?
We saw some data here on the use of IL-2 [generic name: aldesleukin; brand name: Proleukin; also known as interleukin-2]7 to delay treatment start. I don't know how likely that is to catch on; there are a lot of side effects [with IL-2 use]. But what about pre-treatment with R5 inhibition, since it doesn't generate a lot of mutations that cause cross-resistance to any other? And could we pre-treat, and delay start of treatment that way, by reducing immune activation? It didn't work with cyclosporine [brand name: Neoral, Sandimmune, Gengral], but maybe it will work with this.
Some other data that was there: I think it's ACTG 5211 [actual study was ACTG 5102]8 study. Pablo Tebas presented a study looking at patients who stopped therapy and were going to restart when they hit 350. What they saw in those patients who stopped therapy was that, yes, their cholesterol and triglycerides went down, but the HDL [high-density lipoprotein] went down, as well. So the total cholesterol/HDL ratio didn't change. Insulin and glucose stayed the same. People saw a very quick increase in the amount of immune activation, as measured by CD38, HLA-DR, and so on.
Again, we're making a bit of a jump, but that was a possible explanation for the SMART9 data, where people in the treatment interruption arm got more cardiovascular events, more renal events, more hepatic events. Maybe this is due to immune activation that causes the release of proinflammatory cytokines and an increase in inflammation in blood vessels.
So I think that's another very important key issue: really looking at how to fine-tune treatment and prevent downstream harm to our patients.
Dr. Hawkins, thank you so much.
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