December 6, 2010
Myles Helfand: Let's get into the risk factors for cardiovascular disease. You mentioned at the very beginning, Dr. Lundgren, that the waters are still a bit muddied in that area, as far as precisely what you can attribute to causing an increased cardiovascular disease risk in people with HIV. And it also sounds like, if we're talking about this disease manifesting itself in any number of different types of complications, that we could be looking at a myriad of different risk factors.
Jens Lundgren: That's how cardiovascular disease develops. I would say that, although there's still debate, I think it is pretty consistent from the data, at least that I've seen. The major risk factors are age and gender -- both well-known and pretty irreversible risk factors. And among the modifiable risk factors: diabetes, hypertension and dyslipidemia. Well-known, traditional cardiovascular risk factors are really driving this.
In young HIV-infected persons, the risk of cardiovascular disease is very low. The problem is in -- and therefore the [solution], certainly in terms of prevention, needs to absolutely focus on -- people in the older age range, particularly if they have any of the traditional cardiovascular risk factors. And I, of course, in that instance forgot to mention smoking.
Marshall Glesby: Absolutely. Smoking is a key risk factor. I think the data are pretty consistent that the prevalence of smoking tends to be greater in HIV-infected clinical settings than in other settings.
Jens Lundgren: It's very, very difficult for people to quit. There have been all sorts of attempts in intervention trials to reduce smoking via the application of medical interventions. At least, that's the data I've seen from Europe. I'm interested to see what your perspective is, Marshall. But at least in the European setting, I think it has been really, really difficult to actively intervene from the medical side.
It seems like -- at least, the perspective I'm getting is that -- we need to make sure that people understand the harmful effects, and continue to put that message across that it's really up to you [the patient] to make a decision on whether you want to quit or not. But it is helpful to do.
Marshall Glesby: Absolutely. It's, I think, a challenge for anyone, whether they have HIV or not, obviously, to quit smoking. And I think as clinicians we need to be better about trying to help our patients quit. I think it's easier to write a prescription for a statin and address a lipid problem than it is to deal with a behavioral thing like smoking.
Myles Helfand: To what extent, then, would you feel that increased cardiovascular risk in people with HIV -- particularly as they age -- is due to aging versus, to use smoking as an example, the fact that a person has just been smoking for a long time, and the risk increases? How does that factor in with known or theorized HIV-related, or antiretroviral-related, heart disease risks?
Jens Lundgren: I can try to respond to that from the data that I'm aware of. Let's assume that you have a person that, over the next 10 years, has a 10% risk of developing coronary heart disease. So, if you studied 10 persons, one of them will develop coronary heart disease. This one: that's because of his age and let's say he has a little bit of diabetes, etc., etc.
Let's now assume that person has been smoking. Then whatever risk that he had would be multiplied by around 150%. So, from a 10% risk, he would increase to a 20 to 25% risk. That's what you get, on top of everything else, if you're smoking. If this person quits smoking, that doesn't necessarily mean that his risk goes back to 10%, because it takes some time for the harm from smoking to vanish. But if he actually does that, data that we have accumulated, as well as data from the background population, would argue that, say, after five to seven years, his risk will go back to 10%. So the heart forgives you for smoking.
But it's important that people start to do this at a fairly young age, in cardiovascular terms -- when they at least turn 40 -- because that's where the underlying risk starts to increase, and that's where you get the most [benefit], in terms of prevention from quitting smoking, before you turn 45 and 50, where the risk really starts to kick up.
Myles Helfand: All right. Let's focus on that older population, then, particularly in light of the fact that the larger proportion of people living with HIV are 40 or older, and becoming older as time goes on.
We know, for young people, the main thing is to avoid or ameliorate all of the traditional risk factors that can put a person at risk for cardiovascular disease. If your patient is 40 or older, what do you do as an HIV clinician? What is your approach to the assortment of risk factors? How do you factor in something like, for instance, senescence? We've slowly, but increasingly over the past few years, seen signs that suggest that HIV infection itself is somehow accelerating certain aspects of the aging process.
Marshall Glesby: First of all, I'd like to object to your cutoff of age 40 as older.
Myles Helfand: [Laughs.] In my defense, I was only doing so because Dr. Lundgren had mentioned it a minute earlier. I by no means would say 40 is a cutoff.
Marshall Glesby: OK, there you go. The issue of senescence: It's interesting academically, and I think there is a lot of active investigation, trying to sort out the potential roles of immune activation and premature senescence, in terms of the pathogenesis of various complications that we see in people with HIV, including coronary heart disease.
In terms of what we can practically do in a clinical setting at this point: I think we don't really know. There are studies that are planned, or perhaps ongoing, that are looking at different approaches to reduce inflammation and immune activation, and looking at surrogate measures of atherosclerosis and other potential end organ complications.
One issue that has emerged in recent years since the SMART study is concern about uncontrolled HIV. I think probably most of the people listening to this are aware of the SMART study, which randomized people to continuous versus intermittent antiretroviral therapy, based on their CD4 counts. The intermittent arm had an excess of cardiovascular events. A lot of that has been attributed to inflammation related to uncontrolled HIV viremia or bursts of HIV replication. And there have been some nice biomarker studies, which I think Dr. Lundgren has been involved with, that have looked at markers of coagulation and inflammation and associated them with mortality, for example.
So I think controlling HIV is probably an important thing. And the START study, looking at when the optimal time to initiate antiretroviral therapy may be, will hopefully provide important data in this regard.
Jens Lundgren: The SMART study was an interesting study, also to further understand the development of cardiovascular disease and HIV. But obviously it was an interruption study. You're comparing people on treatment that either continued therapy or interrupted therapy. The study was interrupted fairly soon after it was started, given the fact that there was an overwhelming difference in clinical outcome that favored the continued antiviral therapy arm.
Therefore, we've been struggling when we have been analyzing the SMART study, to have a sufficient endpoint to actually look at each of the components by themselves. In, for example, cardiovascular disease, we really didn't have enough endpoint to have a robust finding on that.
What it clearly shows is that you shouldn't interrupt therapy. But whether actually providing antiviral therapy, per se, is a strategy to reduce cardiovascular disease? As Marshall was saying: that's really the study that needs to show this.
We did another publication that came out in the Journal of AIDS recently, looking at biomarkers in the small group of patients in SMART that were not on therapy when they were enrolled, and where we essentially have a sort of miniature of the SMART study; namely, that if they were randomized to the so-called DC [drug conservation] arm, the interruption arm, essentially they just stayed off therapy. And those who were randomized to the VS [virological suppression] arm, they initiated therapy.
It was interesting. It's around 450 patients, but at least in that subset of patients, over a six-month period thereafter, we couldn't find a difference in these inflammatory markers. Again, this is too small of a cohort to really make a generalized statement from. But that was interesting.
So, at least in my picture, it's a very interesting, it's a very compelling, hypothesis. But we really need to nail this before we can say something that can, at least in my opinion, guide, in a robust way, the clinical management.
Myles Helfand: In the meantime, besides the potential HIV-related factor, we have the seminal D:A:D study -- which, of course, you've been intimately involved with, Dr. Lundgren. It investigated the potential tie between cardiovascular risk and specific antiretrovirals or antiretroviral classes.
Jens Lundgren: That's true. That has been an interesting exercise. You can say that the problem with the D:A:D study is that it's not a randomized trial, and therefore whatever we can observe in that study will be mere associations, which may or may not be causal. That's unfortunately the nature of the beast, because we haven't done the large-scale randomized trials to elucidate this.
Of course, when you look at D:A:D data and other data from observational studies, you need to be very cautious around how you interpret them. But at least the data from D:A:D, which have been supported by numerous other observational studies, have suggested that protease inhibitors, at least some drugs in the protease inhibitor class, are associated with an excess risk of cardiovascular disease. I think that's at least pretty consistent in the literature, that that's a problem.
The other observation that has been generated from the D:A:D study data was this highly unexpected association with abacavir [Ziagen]. Although I should emphasize that this signal -- again, we can't really say it was because of abacavir -- but at least the signal was confined to people at high underlying risk, and therefore really not something that is of relevance in people in which the underlying risk is relatively low. But in people with a high underlying risk, we did see a rather striking high rate of coronary heart disease in those on abacavir, as opposed to those who were not. It appeared to be reversible for those who stopped it, at least. Their risk had dropped down to whatever underlying risk that they had because of other factors.
Recently, there's been the suggestion that perhaps the explanation for this is that the drop leads to platelet hyperreactivity: The platelets become more sticky, which, by itself, doesn't cause coronary heart disease. But if you have extensive plaque formation in your coronary arteries, then if your platelet stickiness increases, your propensity to develop clinical symptoms from that will likely increase. And that is at least a potential mechanism.
But again, I would like to emphasize that this is really only relevant for people who have a high underlying risk, and for whom they already have existing subclinical atherosclerotic processes. There's a lot of debate about this, and a lot of controversy, and a lot of different opinions around it, which I think just signals that the research community is trying to deal with the signal, like any other safety signal, and trying to sort it out.
Myles Helfand: In the case of the protease inhibitors, could you put that risk in a little bit of context?
Jens Lundgren: Compared to the abacavir signal, which appeared to be, at least epidemiologically, a rapid turn-on, rapid turn-off signal, it seems like the protease inhibitor signal is more gradual. So the longer you've been on the drug, the greater the problem becomes. So there is that time factor, which was not true for the abacavir signal.
The other thing, again, is that these are expressed in relative terms. Therefore, if your underlying risk is very low, then, for example, doubling your risk because you're on a protease inhibitor really doesn't change your risk materially.
On the other hand, if your underlying risk is fairly substantial -- for example, if you have multiple traditional risk factors and you're getting older -- then it starts to be more clinically relevant to deal with.
Of course, the two ways to deal with it, if I can just complete that, is that you can either consider using another [antiretroviral] drug, or you can start to be more aggressive in your management of traditional cardiovascular risk factors. At least theoretically, both of those should be effective.
Marshall Glesby: I agree completely with what Jens just said. I think we have to be perhaps a little bit cautious just impugning all protease inhibitors. I know that there have been some analyses from D:A:D looking at specific drugs, and probably as more person-years of observation accrue, there may be better power to look at them. But we do know that there can be differences in the class, in terms of effects on insulin sensitivity and lipids. And that may not be all that's driving these associations if they are causal between myocardial infarction and the use of this class of drugs. I think we have a lot to learn, still, about nuances within the class, and what drugs may be worse than others.
Jens Lundgren: Absolutely. We don't, at least in D:A:D, have enough power, as you said, to really claim whether this is a class effect, or whether it's just some individual drugs that drive it. And really the only way to deal with that is to allow for more person-years to accumulate -- which is now happening, but it will probably take another year before we'll have enough data.
One of the drugs that we have been asked about quite a lot is atazanavir [Reyataz]. But that will take at least another year before we'll have enough data to look into that.
No comments have been made.