August 14, 2006
David Wohl, M.D., talks with Todd Brown, M.D., about research Brown presented at AIDS 2006 regarding body fat changes in people with HIV. Dr. Brown is an assistant professor of medicine at Johns Hopkins School of Medicine; his research focuses on metabolic and skeletal problems in HIV-positive people.
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|To view poster, click here (PDF).|
What happens after prolonged therapy is another question. What happens to HIV-infected patients on therapy, compared to HIV-negative patients is yet another question. In the Multicenter AIDS Cohort Study (MACS), one of the benefits and the advantages of [this study] is [that] we have a well characterized HIV-negative control group that we can use to compare longitudinal changes in body comps. There are a couple of limitations in the MACS [however]. The first is that we only began collecting body composition measurements in 1999. And most of the men in the MACS have been involved since at least 1991, some since '84. So they have been infected a long time. Since it started in '99, most of them began therapy when effective therapy was available, in '97. So we had a little bit of a truncated effect. But what we see at '99 is that, between the [HIV] positives and the [HIV] negatives, there are very profound differences between the positives and the negatives in body circumference. So they have smaller waist circumference, smaller arm circumference, smaller thigh circumference, smaller waist circumference, decreased BMI [body mass index].
These are HIV-positive men, many of whom are on therapy, but not all of whom are on therapy?
Not all of them -- it's only a handful of people who aren't on therapy. It's the people [who] along the way, stop therapy, start therapy, for whatever reason. But most of the people stay on relatively continuous therapy. The analysis that we have here is trying to figure out -- looking at longitudinal body changes in body composition over time -- [we are] trying to dissect the various contributing factors. So we would have, for each of the outcomes -- BMI, circumferences of the waist, hip, thigh and arm -- we're looking at cumulative exposure to PIs [protease inhibitors], cumulative exposure to NRTIs and cumulative exposure to NNRTIs. We're also looking at the effect of time and the effect of HIV status. Then, just an interaction variable; looking to see if HIV status changes how these anthropometrics change over time. We also control for age and nadir CD4+ cell count.
Right. What we see is that in these graphs that you're showing us on your poster, that both the HIV-negative group and the HIV-positive group tend to increase their waist circumference over time. That could be a normal part of aging, especially in the HIV-negative group. But the rate in the HIV-positive group seems to be higher.
It increases faster, right.
Increases faster. Even though [the HIV-positive group] starts and remains lower, as far as waist circumference, compared to the HIV-negative group. So, it seems like, looking at your poster and other data that are presented here, and before, that we do see a general increase in waist circumference. Now, I know Adrian Dobs and yourself presented other data yesterday, looking at waist circumference, and also waist-to-hip ratio, and the elements of that. One thing I was struck by is, it did seem to indicate that when you're comparing smaller numbers of HIV-positive and HIV-negative people, that waist circumference -- when you measure it absolutely -- wasn't that different between the HIV positives and the HIV negatives, when compared directly. But hip circumference was, and that people with HIV were losing hip, maybe making the belly look a little bit more pronounced. Or the perception that I have a bigger belly was really, my hips are shrinking.
Yes. Right. I think that's a really important point in that -- most of the action does happen at the waist -- but what happens at the belly is another thing entirely. You know, I think that most of us agree that we've all seen lipohypertrophy. We have seen buffalo humps. We have seen big bellies crop up seemingly out of nowhere. So we know it's a real phenomenon. But we also see, in HIV-negative folks, increases in belly. So, I think that study that Adrian presented yesterday was a cross section, using sophisticated measurements like CT and DEXA.
I think it's really important to look at the changes over time, to really figure out what's going on. You know, it could be that the return-to-health phenomenon that you see with antiretroviral initiation continues. It's the thymidine analogs, in particular, that are decreasing the fat mass in the extremities, and probably subcutaneously in the belly, too. Whether or not you have sort of a catch-up in the HIV-positive group on therapy is unclear.
I guess my concern also is that one thing is the waist is increasing and maybe you will equalize with the HIV-negative group. HIV-positive and -negative men, over time, may find themselves, as they enter the golden years, with the same sized waist. But what you're also pointing out is that the limbs are likely -- in HIV-positive men exposed to thymidine analogs -- to maybe do the opposite. I mean, if we had another plot that looked at limbs, we might see divergent lines.
Well, we do. Here, you see: this is the interaction term between year from baseline and HIV status. For thigh, actually, there's a trend towards an increased rate in the HIV-affected agents.
An increased rate of ... ?
Increased thigh circumference over time.
Oh, an increase in thigh circumference over time.
But you have to keep in mind that here, I'm trying to adjust for the effect of antiretroviral therapy.
Right. So when you adjust for the effect of antiretroviral therapy, which is the one thing that might be causing it, you're going to take that off the table. If we took a step back and included it, my feeling, and in the data that we're seeing, I think you'd agree, is that it's likely the HIV-positive men are losing limb fat over time.
Right. In fact, this is a paper -- this is the precursor to this paper that's being published in JAIDS this year -- looking at HIV-infected men on HAART and HIV-negative men longitudinally, and not trying to get at antiretroviral therapy. There are a couple of interesting things. There's actually no effect in the HIV-positive group and an increase in the HIV-negative group.
For limb ...
For limb fat, right.
So it's lower than the HIV-negatives, but there's probably some stabilization of the loss that occurred before observations maybe started.
Exactly. Exactly. But the waist circumference, when you don't take into consideration the effect of antiretrovirals, increase[s] at the exact same rate. So, you know, it's sort of interesting. They start at different points, so there's about a four-centimeter difference in the waist circumference. But they follow the exact same ...
It's a really important point. Because I think people totally miss it, that when you compare HIV-positive [people] and HIV-negatives, which you are uniquely able to do in MACS -- I mean, there's only a couple other places that can do that; maybe just only one other place that can do that -- but that people with HIV have smaller waists than HIV-negative people. That's, again, reeducating people. The perception is the opposite. But I think it's important that we make it clear that, in general, when you look at aggregate groups of people, HIV-positive people have smaller waists.
Right. We don't know because we are getting measurements from '99.
We don't know about pre-therapy.
Right. We don't know that. But all the data that we see shows that before therapy, HIV-positive men and women are even smaller.
Yes. When you look at the metabolic syndrome, and you look at any anthropometric measure, those go up after therapy. So they're starting out pretty small to begin with, and then these increases occur.
When you look at the comparison in MACS in the mid-80s. It's a little bit tricky. I was going to say in the mid-80s, for example. But there, you have people who were really sick, not on any effective antiretrovirals.
Right. Confounding things, too.
So it's a really difficult thing to tease apart.
Well, this has been helpful. And I think that people who listen to this will get a better understanding of sort of the relative difference between HIV-positive and -negative [people] which, again, MACS -- it's restricted to men -- but what MACS is really uniquely able to do. I think this really helps us understand how big a problem that we're seeing. That there are increases in waist circumference that are occurring in people with HIV. There are decreases in limb circumference and fat. But relative to HIV-negative people, probably what we're seeing is smaller waists overall, and not Crix belly in everyone who comes along on HIV therapy. But over time we are seeing trends that maybe HIV-positive people will start to catch up with the HIV-negatives, certainly as far as [the] waist goes.
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