September 14, 2009
There's nothing like hearing the results of studies directly from those who actually conducted the research. In this interview, you'll meet one of these impressive HIV researchers and read his explanation of a study he presented at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2009).
My name's Nick Funderburg. I work with Case Western Reserve University in Cleveland, Ohio. My poster is titled "Differential Effects of Maraviroc (MVC) and Efavirenz (EFV) on Markers of Immune Activation (IA) and Inflammation and Their Association With CD4 Cell Rises: A Subanalysis of the MERIT Study."1
Nick Funderburg, M.D.
As has been previously shown, maraviroc [MVC, Selzentry, Celsentri] seems to increase CD4 cells from baseline better than efavirenz [EFV, Sustiva, Stocrin]. We wanted to know if that was due to changes in immune activation and inflammation. We looked at a number of different markers: CD38 expression on T cells, CRP [C-reactive protein], D-dimers, IL-6 [interleukin-6]. D-dimers and IL-6 have been shown to be important in the SMART study for all-cause mortality in HIV-infected patients.2 We also looked at TNF [tumor necrosis factor] receptor 1 and 2 and neopterin.
They're all known markers of immune activation and inflammation. What we found was that patients that were given maraviroc had earlier decreases in levels of CD38 expression on CD4 cells and levels of D-dimers.
Basically, super-imposable decreases in the levels of CD38 on CD8 cells and TNF receptor 1, 2 and neopterin. We also saw that patients that were given maraviroc had steady levels of CRP, where as patients that were given efavirenz had slight increases.
IL-6 levels actually decreased a little more quickly with efavirenz than with maraviroc. Then, we tried to correlate some of these markers of immune activation with the increases seen in CD4 level. We found that there were significant correlations with the levels of CD38 on the T cells and increases in CD4 cells. But we didn't find a significant correlation with levels of IL-6, D-dimers or CRP.
I think there are some trends to suggest that maraviroc decreases levels of immune activation maybe a little bit earlier than efavirenz. This may be playing a role in the increases in CD4-cell levels that you can measure. But there's also a possibility that by blocking CCR5 with maraviroc you may be promoting different migration patterns of the cells.
Basically, you may be able to measure more cells in the blood because they're not migrating into the peripheral tissue. I think some more work needs to be done to sort those two hypotheses out, but there are definitely some trends towards maraviroc having an effect on inflammatory markers.
What I thought was interesting here is that it confirms what the SMART study noted about all these markers. Have other studies demonstrated the decrease in these kinds of markers once therapy has started?
I'm not really sure if there've been any recent publications. The SMART study came out about a year ago or so, looking at D-dimers and IL-6 and finding that there were definitely correlations with adverse events. I think there's probably going to be a lot of interest in comparing different drug regimens to see if IL-6 and D-dimer levels can be modulated by different treatments.
Is this considered a significantly different decrease in D-dimer concentration, using maraviroc?
No, it's not necessarily significantly different in the maraviroc arm, compared to the efavirenz arm. But it does seem to occur earlier with maraviroc than it does with efavirenz. Then at week 48, you end up at basically the same place. Right now, it's hard to say if decreasing D-dimer levels earlier will have a significant clinical outcome. But I would think that anytime you can decrease inflammatory markers or clotting markers like D-dimers, it's probably a good thing to do it early rather than later.
So in this study you saw the difference at 12 weeks?
Yes, at 12 weeks you can see a pretty nice decrease in the levels in the maraviroc arm versus the efavirenz arm.
What's the most frequently asked question regarding your poster?
They want to know what the real conclusions are. Can you say that maraviroc is blocking immune activation better than efavirenz? Is that the cause of the increase in the CD4 cells? I think right now there's some suggestion that that could be occurring, but we can't say for sure whether that's the real reason.
Just intriguing data right now.
Yes. Intriguing data. More questions, I guess now, than answers. But that's always exciting.
This transcript has been lightly edited for clarity.