An Interview With David Alain Wohl, M.D.
Managing Cardiovascular Risk
Where does this leave us, then, practically speaking, in terms of what to do with the confusing array of data? From the standpoint of any clinician who is treating an HIV-infected patient today and may be concerned about their cardiovascular risk, how should they be approaching this?
Well, I think there is data you can look at and say, "Here is excess risk." Like I said, it's pretty clear that we're seeing this consistently from study to study. There's greater risk for cardiovascular disease among people living with HIV, even when you correct for the bad stuff -- smoking, whatever.
When you don't correct for that -- which we don't; in real life, we don't say, "Hmm, you know, since you're a smoker, I'm going to discount that." We count that. People with HIV unadjusted for these factors have a lot of cardiovascular disease, and much of that is driven by lifestyle stuff. Your smoking is a big deal; that really matters a lot. Uncontrolled blood pressure. Obesity.
When you look at U.S. cohort studies like the groups have done repeatedly that have been published, they match on a whole bunch of different things. But do they match on region? Because I happen to know that in the region that I live in, in the South, there is a higher prevalence of obesity and diabetes compared to other places. I bet that translates into the HIV population, too. If you have more people living in the South with HIV and they are more represented in some of these cohorts, let's say -- and I'm not saying that's the case -- does that mean we have an imbalance, just because of geography, and how the geographic considerations factor in?
It's hard to tease out, but what I will say is people with HIV do have an increased risk of cardiovascular disease that's evident to anyone who is looking. A lot of that is driven by the behaviors, the lifestyle, of people living with HIV. Take that away, though, and you're still left with something.
For us, that means figuring out: If immune activation paves the way for cardiovascular disease, let's reduce immune activation to the extent that we can. The number one way to remove immune activation from the equation is to treat HIV, because the immune system won't be activated to respond to HIV if the HIV level is so low. So: treating earlier; treating more effectively; engaging people in care; keeping them on therapy; no breaks in therapy, no holidays; using therapies that are as innocuous as possible for cardiovascular health, and we're getting more and more and more of those; and, for people who have innate cardiovascular risk, due to genetics or whatever, treating that aggressively.
There was a really nice simulation that was done by the D:A:D cohort, where over-40 people had an increased risk compared to all these cohorts. They manipulated the data to say, "What happens if you drop blood pressure? What happens if you drop cholesterol? What happens if you make people who are smokers stop smoking?" While most things had incremental benefits, stopping smoking was huge.
It's easy to get up on your soapbox and complain about smoking, but so many people in our population living with HIV smoke that it's worth doing that. It sounds somewhat hackneyed and redundant, but it is a really big deal.
We could talk about how many angels dance on the head of a pin, in terms of one antiretroviral versus another; but probably, the biggest bang for the buck will be just doing the stuff that we do outside of HIV to reduce cardiovascular risk -- these lifestyle changes -- which are really hard to do in a lot of our patients, but will make a big difference.
If you can't do that, or if there's still some remnant of risk due to some immune factors, maybe there's something else you could do. Many people are studying anti-inflammatories, whether it be traditional aspirin -- which is underutilized, by the way, in people living with HIV; study after study shows that we are not as present in thinking about aspirin as an intervention as we should be for people living with HIV.
We do great with statins. But there may be other things that we can do to reduce immune activation and inflammation beyond that that people are studying, when you've done everything else.
Why are we good with statins, but not aspirin?
I think statins have become pretty easy to use. And I think we've gotten great data about how to use them with HIV therapy. I think the guidelines are very clear about when to apply statins or lipid-lowering therapy.
I think the aspirin data have been more confusing for clinicians: who should be on them, who should not be on them, the risks involved. Most of us are really good at keeping up with things that we're told about that are clear and concise. When there's murkiness, things start to see some falling off.
I think what we need to do is start thinking more and more about traditional methods for reducing coronary artery disease, including using aspirin; using statins; implementing effective, evidence-based interventions to get people to change their habits that are bad, whether that be smoking -- and there are methods and there are pharmaceutical aids that help, as well -- or getting people into gear to eat well and exercise.
Again, these are tough things, even without HIV. But when you have a population that's at increased risk, it becomes really important to apply those in a way that's going to work.
I want to come back to antiretroviral therapy for a second. Do you feel that the choice of drugs is not a really important part of the conversation?
I think the choice of drugs is less a part of the conversation than many people make it out to be.
A decade ago, this was a huge thing. A decade ago, this was all we were talking about, when the first D:A:D results were coming out.
I think that's right; the D:A:D results implicating abacavir and ddI were concerning. Overall, even before that, results showed that people exposed to HIV therapy had an increased risk of myocardial infarction and cardiovascular disease over time. [However,] I think it's a little messy, and it involves people who have been treated and then went for a long period of time without treatment -- a whole mess of different therapies, including older therapies.
Most of our therapies raise LDL a little bit. Most of our therapies increase triglycerides. The increase in HDL that some of our therapies give us: We don't know whether or not that's as meaningful as HDL that rises from exercise. Not all HDL is created equally. So there is probably an effect of being on therapy that's a little hard to quantify and tease out, but is there.
The abacavir question still is really controversial. I think that abacavir, for the great majority of people who will take it, will not do them any harm. The question is in someone who already has risk factors: Is that the drug that you should use? When there are alternatives, most people are turning to the alternatives. And when there's not -- well, then you need to use it and just be aware; maybe try to compensate by being aggressive about other risk factors.
Remember -- and this is an important point -- there's absolute risk and relative risk. The relative risk [of MI] is increased. That means that, compared to people not on the drug, you have an increased risk that may be several fold higher, or whatever: 1.17, or 1.2, or 1.5.
But the absolute risk -- how many people out of a thousand are going to get it? -- is pretty low. The vast majority of people are not going to have this outcome. Even among people who have risk factors, not all of them are going to get a heart attack. So, I think that we have to be realistic.
There's a taint of abacavir right now that hasn't been completely dispelled by the data that's accumulated since then. We don't really have a great pathogenic mechanism, although there are some papers that purport to describe some stuff. But there are other papers that don't show the same thing, and some that don't even get published because there are negative results. We don't really have a full answer.
I think that, for most patients, it's a fine drug to use if you cannot use tenofovir -- and there are still people who can't use tenofovir, so I don't hesitate to put them on abacavir, if it means that's what I've got to get their virus under control. Because that's the number one thing: getting their virus under control. The worst thing you could do is not have their virus under control.
We just focused a lot on abacavir, but I want to make sure that we don't ignore the other drugs. If we look across the armamentarium of currently recommended drugs in the U.S. DHHS guidelines, are we not really looking at any particular noteworthy cardiovascular risk there?
No: I think Norvir is a problem, too. I think that we have to boost our protease inhibitors with Norvir is problematic. I think we know that Norvir has its own inherent issues, as far as cardiovascular risk -- and for lipid increases. It would be nice not to have that.
With cobicistat, we don't get much improvement, although we see lower triglyceride increases -- most notably, smaller triglyceride increases than we see with ritonavir in the head-to-head study that looked at it with atazanavir. That will be nice.
Efavirenz doesn't have that much of a benefit, as far as lipids go, compared to the boosted protease inhibitors. There are myths that it does; it doesn't. It leads to very similar sorts of lipid profiles, so I don't think you could get a benefit there.
Raltegravir is really innocuous when it comes to lipids, and it looks like it shouldn't cause anything. But there's baggage with it being a twice-a-day drug.
With dolutegravir, will that become another factor? It could. That may be more heart-safe, especially if we use it with tenofovir and FTC. It's going to be co-formulated with abacavir and 3TC, so that may be tantalizing for some people -- but then you have to deal with the abacavir issue.
I think we should be thoughtful about our medicines, vis-à-vis cardiovascular risk. That makes a lot of sense. But that is, to me, secondary or tertiary to dealing with the big-ticket items that we've talked a lot about.
To tie it back into what you had said very early in this conversation: It's also about being well aware of what your local epidemic is like, what the cardiovascular risk factors are among the population of people that you're treating. There are so many of these potentially regional, potentially socioeconomic associations with particular risk factors that are really worth paying attention to, and really worth addressing with your patient, even though some of those topics might be a little bit uncomfortable; and then being able to properly assess and try to do something about it.
Absolutely. I wish that we had more that we can offer our patients. I am really, really, really good at writing antiretroviral prescriptions. I am really, really, really not as good at recommending what would be a winning nutritional program for a patient who comes in with obesity, hypertension and diabetes, or pre-diabetes.
We need to have more of a streamlined, accessible, clinically useful approach to that.
Do we need a cardiovascular risk version of the U.S. DHHS guidelines panel? Do we need a panel that specifically covers this?
I think it would be great. The thing we need to do, though, is understand that even outside of HIV there's a lot of controversy here. Just go to your local bookstore and you'd find all these incredible diets. Someone's on a paleo diet, where they're munching down a lot of fat; and you have other people who are vegans; and you have other people who are doing the Mediterranean diet -- which, to me, naturally just seems to make a lot of sense, and a recent New England Journal of Medicine article showed that it seems to be very effective.
But diet is very cultural. Diet is very ingrained. There's a lot of psychological investment in your diet. It's very hard to change. But I do believe that dietary changes can help.
As I kind of intimated, it's not only just reducing the ingestion of these foods that can lead to promotion of atherosclerosis; there may be other effects on the microbiome, on the flora, that exist within us that change as well, that may also have benefits -- again, with inflammation and with atherosclerosis.
We're just in the infancy of understanding that part of it. But trust me: We are all going to be hearing a lot more about that, in ways that are only starting to get out now.
But there are some interventions that I think we're going to have to look at that may be beneficial to our patients, and may not be magic bullets, but may augment those types of things we're talking about, as far as lifestyle.
We'll explore those issues in more detail in the future, but for this discussion, I think we need to leave it there. Thank you so much, Dr. Wohl.
This transcript has been edited for clarity, grammar and length.
Visit our HIV Management Today home page for more episodes in this series.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
Follow Myles on Twitter: @MylesatTheBody.
Copyright © 2013 Remedy Health Media, LLC. All rights reserved.