April 27, 2014
A major study published recently in the Annals of Internal Medicine has reinvigorated discussion about the link between cardiovascular disease and HIV. Not that the debate over the complex interplay between HIV and heart health had been dissipating -- if anything, it's one of the hottest areas of HIV research, dovetailing with issues ranging from inflammation to senescence.
What sets this new research apart, however, is its scope and sheer gravitas: It's a solidly constructed, cross-sectional investigation of roughly a thousand participants in the storied Multicenter AIDS Cohort Study (MACS) conducted by Wendy Post, M.D., of the Johns Hopkins University School of Medicine, and colleagues. What's also notable about this new research is the way in which its findings were quickly misinterpreted.
To drill down into the data and tease out the real clinical implications, our research editor Warren Tong spoke by phone with David Wohl, M.D., an associate professor of medicine at the University of North Carolina School of Medicine and the co-director of HIV services at the North Carolina Department of Corrections.
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To summarize this research: They went through the MACS cohort and pulled about a thousand individuals, 600 HIV infected, 383 uninfected; and they found a higher risk of coronary artery disease in the patients living with HIV, as opposed to those who were not.
Some of the headlines have been characterizing the new study as showing that there's more heart disease in people living with HIV than people without -- and in this case, when we're talking about "people," we're talking about male people, not female people. Because the MACS cohort is just men.
I think we have to be careful, because what they're looking for is plaque. Plaque in the coronary arteries is atherosclerosis. It is not good for you. But many of us have plaque. About three-quarters of the men in the MACS cohort -- these are HIV-positive men and HIV-negative men, all men who have sex with men [MSM] -- about three-quarters had plaque. So, plaque is not abnormal, if you think about it as part of the normal aging process.
We all get plaque eventually. It doesn't necessarily mean that these people had, quote-unquote, heart disease.
The thing that they did do that, I think, makes this study really important and unique is that they looked for the different types of plaque. Previously we've had studies that have been pretty small -- rigorously done, but small. This study was rigorously done and had a lot of people. I think there are some big take-home messages from this study because of those advantages, compared to other studies that have been done.
Can you go over the different types of plaque that they were looking for?
There are concerns about plaque in general. But we've talked a lot in the past about calcified plaque. Those are plaques that are harder. There's calcium in them. Calcium, as we know, is a mineral that's in our bones. When we do CT scans and look for calcium in the heart, we can see those plaques light up. That's done not-uncommonly in the general population; you get these CT calcium scores. They've been used for a while to add more information about the propensity for people to have a heart attack, above and beyond what we can get with the EKG or even a stress test.
But there are other types of plaque that don't show up so well. These are uncalcified, or noncalcified, plaques. These are softer. They are considered more vulnerable to rupture. And when they rupture, they send debris downward -- just like a frozen river [that] starts to thaw. Some of that ice is going to go downstream, and if you start getting it into the small tributaries, they can block flow. That's what's going to happen in the heart. When we block flow, the muscle dies -- in this case, heart muscle.
What they were able to do [in this study] is look at calcified plaque, uncalcified or noncalcified plaque, and mixed plaque, based upon how it looked on the imaging studies. A subgroup of people actually did have calcium scores done from the larger group, and they compared them between the HIV-positive and HIV-negative people.
Some big take-homes: One is, even in this population of gay men living in major metropolitan areas in the United States, there were differences between the HIV-positive and HIV-negative men, just in their general characteristics. Some people generally think that the MACS cohort is homogeneous. It isn't.
Even in this cohort that's refined, if you will, to a certain group of people, being HIV positive carried with it additional risk factors for cardiovascular disease that had to be adjusted for. So it's not like you just enroll men who have sex with men in these areas, and the HIV-positive and HIV-negative men are going to be the same. Being HIV positive is often associated with other risk factors of cardiovascular disease: lifestyle risk factors.
That's one thing that I think is important. It's better; it's closer than in a lot of other studies. But there are still differences that had to be adjusted for. Which is fascinating to me, because I do think people with HIV generally have had different types of lives -- not everybody, but oftentimes -- compared to HIV-negative people.
Going to the data itself: After adjusting for those factors, what we saw was that you were more likely to have uncalcified plaque, which we said may be more vulnerable to rupture, if you're HIV positive. It's about one-and-a-half times the risk of having vulnerable plaque, if you're HIV positive versus HIV negative.
But there were other factors that, when you start adjusting for cardiovascular risk in demographics, became less significant -- borderline significant, is what they said -- and that's with calcified plaque, or plaque overall. There's clearly a signal.
Fascinating to me, however, was that when we looked at where the plaque occurred, as far as the age spectrum, what we saw was a really interesting pattern: For the HIV-negative men, over time, they started to get more and more calcified plaque, and less of the noncalcified plaque; whereas, for HIV-positive men, the calcification was less likely to occur later on in age, but the vulnerable, noncalcified increased.
There were differences that you can see throughout the age spectrum, but they were really more profound in people 65 and older, HIV positive versus HIV negative. I think that probably drove a lot of the statistical difference between the groups.
Putting that into more simple words, what it means is that the difference that was seen between HIV-positive men and HIV-negative men, as far as these noncalcified, vulnerable plaques, was more profound in men who are 65 and above, and was driven largely by the decrease in vulnerable plaques that we saw in the HIV negatives, while we saw an increase in the HIV positives. And when we have one group that's going down and one group that's going up, that leads to a bigger chance of finding a significant difference than if one group stayed stable and the other one changed.
For patients who are growing older with HIV, is this something that they should be worried about? Or is the risk not as significant as the headlines might make them seem?
I think that the risk has to be put into perspective. Again, plaques were pretty common here. There were a lot of lifestyle factors that were accounted for, but they couldn't account for everything. We don't know that the HIV-positive men are bearing increased burden of these vulnerable plaques strictly because they're HIV positive. There's a signal for that, but, you know -- cocaine use wasn't looked at [for instance]. I don't know what cocaine does to creating vulnerable plaques versus calcified plaques.
There are other things that are very hard to measure. That's been my mantra, almost to the point of annoyance: You can't correct for a lot of these other things because they're not measured, and we don't know what the effects are.
Is there an effect of HIV itself? There may be a co-inflammation thing that may tie into this. But it wasn't such a huge, profound difference. The difference was seen in much older men more than middle-aged and younger men. I think there's more that has to be done. It's certainly important.
What can men do? You said "worry." That's the one thing they shouldn't do. And I worry about studies like this, that contribute to worry. You can only change the things you can change, and you can't change the things you can't change. So, change the things you can change.
What can you change? Many of the people who are listening to this are already doing it. They're exercising. They don't smoke. They don't smoke marijuana -- again, not measured in this study. They don't do cocaine. They eat fairly healthy diets. Those are the types of things any of us have to do. I have to believe that that helps ameliorate some of the excess risk that may -- capital M-A-Y -- be related to living with HIV.
There are studies that, at the HIV conference we went to just about a month ago, showed that exercise does seem to be beneficial. I don't think that this [MACS data] would change me from doing anything else that I do when I talk to patients about living a healthy lifestyle. You can't get rid of the HIV right now, and until we do, there's nothing else I think you can do than just the normal things that we all have to do to try to prevent ourselves from having any plaque in our heart, let alone vulnerable plaque.
What about the two results that they found with lower CD4 counts and people who have been on treatment longer being associated with the higher risk?
Associations with low CD4 cell count and being on therapy longer: Those are also markers for being older and living with HIV a longer period of time, and being infected longer ago. Again, it's hard to tease those out from the effects of: If you're 25 years old, you haven't been alive long enough to be someone who's had HIV for 30 years. But if you're 68 years old, you certainly could be someone who's been living with [HIV that long].
So: It's a marker for age; it's a marker for drug exposure; it's a marker for being around [during a time when more people] were doing crack cocaine, or doing powder cocaine, or living a hard life. I'm talking in general terms, because we're talking about a large dataset here. I think we have to be careful about some of these associations.
It does play into this idea that low CD4 cell count and prolonged HIV infection increase exposure to inflammation over a longer period of time. Inflammation has been associated with atherosclerotic disease and other end-organ diseases. If you drink the Kool-Aid on this, you may say that there is this Axis of Evil of immune activation, of inflammation, and then end-organ disease.
I think that's part of it. I just don't understand completely how big a part of it. This study, again, helps us understand that there are differences between HIV positive and HIV negative [in terms of plaque], but I am impressed by how the difference is modest. It wasn't like you're at 3, 4, 5, 10 times the risk of these bad plaques if you were HIV positive. But I do think it's important to pay attention to this and try to find out pathologically what's going on here.
As a provider, what would you say to a patient who is already on the fence about starting treatment, sees a study like this, and decides not to start treatment as early as he or she should?
I think people who are infected and don't want to start treatment are crazy, unless they have a fantastically good reason not to start therapy -- like, it's going to cost them $1,500 a month. And then it becomes my problem, because I have to figure out how to get them their medicines. But there's no reason.
The only [other] reason I could see that you don't start medicine is you're an elite controller, your viral load is undetectable and your T-cell count is 900. Then we can have the conversation. As you get closer and closer to that, I understand more of your ambivalence. If you have a T-cell count that's 1,000 and your viral load is 500, I could still maybe be talked into having a debate about it.
But I am a strong believer that if you're infected, you should be on therapy; that the benefits of therapy outweigh the risks; and that, again, the problems that we see with ongoing HIV replication and end organs are not a good thing. We should treat it. If I was infected and I had a CD4 cell count of 1,000 and a viral load of 30,000, I would start on HIV medicine.
For providers, how do they continue to monitor this, or make sure that the risk is not as high?
I think we don't do anything different right now. I don't think that the authors would suggest we do anything different right now, clinically. You hear that a lot in studies, and that's because you have to be careful, because you don't want to extrapolate too far.
Right here and now, there are several things I'd do. I'd risk-stratify, as far as cardiovascular disease. I'd change the things that can be changed, and the things that can't be changed, we have to figure out more about. Do we try to use anti-inflammatories? Do we try to use statins? Do we give more aspirin than we should? Those are the types of things that are being studied. But they're not innocuous.
Right now, I'd do the usual stuff. For the majority of my patients, there are levers I can pull that work that have nothing to do with how much CRP they have, or IL-6 -- these are inflammatory markers. It has to do with cutting down on their smoking. It has to do with losing weight. It has to do with eating less french fries, and cookies, and soft drinks.
There are some people who are great [about these things]. These are the people that I feel for, who -- they're doing everything right. Their cholesterol is good. They may be on a statin. They exercise. They look great. And they're like, "Do I carry excess risk because of my HIV infection?" For those people, I hand-wring. I'm not sure. The data suggests: somewhat. You're doing everything you can to reduce your risk.
But, look: We all carry different risks, right? Because of our genetics. If you carry a gene that protects you against heart disease, but I carry a gene that gives me a propensity to heart disease -- like, my dad's had stents placed in his heart. If I carry that gene, we're starting already with an uneven playing field. That happens all the time in life. Maybe HIV is like that gene; it gives you another hit, another risk. It may be one that we can't change -- just like we can't change our genes.
Again: We're trying to figure out what we can change, what we can't change. There's a lot of work being done. The vast majority of risk reduction is happening right now. We should just keep doing that and not go crazy.
Some of my patients get really excited that they carry this excess risk, and [they fear] they're basically going to spontaneously combust. We have to cool our jets. That's not going to happen. That's not what's happening. Very, very few people actually go on and get heart attacks who are HIV positive. The D:A:D cohort presented really nice, updated data. And when you look at the number of people who've been followed in that cohort in Europe, and the time that they've been followed, and the number of actual heart attacks they've been able to document: It is such a small, small number.
So, relative risk may go up, but absolute risk remains low. We're taking a rare event and making it somewhat less rare. But it's still a rare event.
How do these results impact the people who weren't included: younger people with HIV, or women?
That's a great question. I think younger people have natural protection, so we don't worry as much. I'm sure cardiologists would say, "Well, wait a second; the groundwork for some of these plaques and stuff like that happens early on, so those people are not exempt from practicing healthy lifestyles." You do damage early on, it's hard to reverse it; or it may be irreversible. So we want to keep a healthy lifestyle from an early age.
For women, the story may be different. Women are very hard to compare when you talk about HIV positive and HIV negative, because there's a bunch of factors. Most women with HIV are African American, or women of color. When you start looking at HIV negatives, controls: If they're more white, you've got to adjust for that. With color and race come a bunch of different confounders that we have to adjust for. I could go long into that, whether they be lifestyle, or community, or living with stress. There's a whole body of literature that could be brought into that.
Even so, there are some data that really do suggest women may be more at risk for cardiovascular disease with HIV, compared to HIV-negative women. Again, those studies are really hard to do. We're trying to get a better handle on it. But women have to pay attention to this, too -- maybe even more so than men, is what some of the data seem to be suggesting.
If there's anything you want to add, or any other takeaways that you wanted to include, please feel free.
I think this is a great topic. I think this is a really good study. It gets us incrementally closer to where we want to be to understand this. It was really well done, and it's important. But I think even the investigators would say there are caveats here. We have to understand more about this. I'd just caution my patients not to overinterpret these data just yet.
OK. I hope everyone keeps that in mind. Thank you very much.
This transcript has been lightly edited for clarity.
Warren Tong is the research editor for TheBody.com and TheBodyPRO.com.
Follow Warren on Twitter: @WarrenAtTheBody.