March 30, 2010
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To help us get a better sense of where the clinical winds are now blowing, I'm pleased to have on the phone one of the top clinician-researchers in the field of HIV- and antiretroviral-related complications: Pablo Tebas, an associate professor of medicine at the University of Pennsylvania School of Medicine and principal investigator in the Adult AIDS Clinical Trials Unit at the University of Pennsylvania. Dr. Tebas, thank you so much for joining us.
Pablo Tebas: You're welcome.
Myles Helfand: I suppose we should begin with what has become one of the real hot-button issues: the issue of inflammation. What has CROI told us that will hopefully allow us to wrap our heads around what this is, what it does, and what we can do about it?
|Pablo Tebas, M.D.|
Definitely, inflammation has been one of the hottest, if not the hottest, topics related to HIV in the last couple of years. We know for a fact that patients with HIV, when they are not being treated, they have high levels of inflammation that are associated with high-level viremia. And when we treat them with antiretroviral therapy, those levels of inflammation decrease. But we know, too, that they don't become completely normal.
This residual inflammation -- we can call it that -- has been associated with a myriad of complications of HIV. Some people have said it's responsible for the lack of increase in CD4 cells in some patients. Some people have said it's responsible for accelerated progression of atherosclerosis in some individuals, for accelerated bone loss, for a lack of response to vaccines, for the increased incidence of cancers in patients with HIV.
So there has been a lot of focus on trying to understand why these patients have residual levels of inflammation that are not completely corrected with antiretroviral treatment, and what kinds of long-term complications are associated with this residual inflammation.
Myles Helfand: What kind of research did CROI provide that shed some new light on the subject?
Pablo Tebas: There were a lot of presentations from the UCSF [University of California, San Francisco] group -- from Priscilla Hsue, and also Steven Deeks and Peter Hunt, and other members of the UCSF group. Their focus has been, in patients treated with antiretroviral therapy, the role that this residual inflammation plays in the progression of atherosclerosis.
They looked at this issue in many different ways. They did ultrasounds of the carotids, and looked at the progression of atherosclerosis in the carotids. They looked at the elasticity of the blood vessels in response to this residual inflammation. They looked at the effects of starting [antiretroviral therapy] earlier versus later, and what the effects are on these surrogate markers of atherosclerosis.
I think the general theme of their studies is that patients with HIV infection, in spite of having good control of antiretroviral replication, have these increased levels of inflammation. And those levels are associated with a more rapid progression of atherosclerosis as measured by these different surrogate markers. However, there have not been a lot of studies presented from that group on what to do about it.
There was a study that looked at the effects of valganciclovir [Valcyte], which is a treatment for cytomegalovirus -- because there was a previous study from the same group showing that a lot of the immune responses of patients with well-controlled HIV [also apply to] cytomegalovirus. So the hypothesis was that if you control cytomegalovirus replication, you would decrease the level of inflammation. They did a study in which they gave valganciclovir to patients with well-controlled HIV. And, really, they didn't see a lot of difference in the residual levels of inflammation.
They have also tried to intensify HIV treatment, adding a drug like raltegravir [RAL, Isentress] in patients with well-controlled virus. They didn't see a lot of changes on residual inflammation.
The story is a little bit different if you add a CCR5 antagonist, like maraviroc [MVC, Selzentry, Celsentri]. If you add maraviroc, you decrease the residual levels of inflammation. The study was [led by Timothy] Wilkin. It was a study from ACTG [AIDS Clinical Trials Group] showing that if you add maraviroc to [the antiretroviral regimens of] patients with well-controlled HIV, the inflammation goes down. But we don't know what the long-term effect is of that decreased level of inflammation. Would it benefit the patients with regard to cardiovascular outcomes, or CD4 outcomes, or bone outcomes? That is the kind of thing that we still don't know. If we intervene, to try to reduce these residual levels of inflammation, do we make a difference in the clinical outcome of the patients? I think that's going to be an area of intensive research in the next few years.
Myles Helfand: How sure are we, even at this point, that inflammation itself over the long term does result in actual clinical events that seriously impact the health and potentially threaten the lives of HIV-infected patients?
Pablo Tebas: We don't know from the HIV. We know that antiretroviral therapy works very well, and decreases morbidity and mortality in patients with HIV infection. We don't know what price we pay for having this low-level inflammation.
If we look at other fields like cardiology or geriatrics, inflammation has been associated with outcomes. If you look at the cardiovascular literature, in people with C-reactive protein -- which is a similar marker of inflammation -- people with higher C-reactive proteins have a higher risk of developing cardiovascular events. For decades now, we've known that atherosclerosis has a strong inflammatory component, [responsible] for both the progression and the risk of rupture of atheromatous plaques. The cardiovascular events associated with that are triggered by inflammation.
There was a study published a couple of years ago in the New England Journal of Medicine, the JUPITER study, that I think is probably like a proof-of-concept of the type of interventions that we are going to be using in patients with HIV infection. In that study, patients with normal lipids -- so, they have cholesterol that was in the normal range -- but that had high levels of inflammation, as measured by C-reactive protein, were randomized to receive a statin -- simvastatin [Zocor] -- or not. There was a decrease in the incidence of cardiovascular events [among those who received a statin].
So I think many groups around the globe are thinking about trying to add something to patients with HIV, something simple to take, probably like a statin, to see if that makes a difference in the long run for cardiovascular outcomes and other outcomes.
Myles Helfand: How related is that to inflammation, per se? We saw some data presented at CROI from the everlasting D:A:D study about the impact of triglycerides on MI [myocardial infarction] risk. How does that tie in with, or compare to, the impact of inflammation on potential cardiovascular risk?
Pablo Tebas: I think both are part of, or contributors to, the increased cardiovascular risk that we see in patients with HIV -- the alterations in the lipids that are seen associated with some drugs that we use for the treatment of HIV, and also the residual inflammation. The data from the D:A:D in this particular CROI, the question they tried to answer is: Does hypertriglyceridemia -- which is a risk factor for cardiovascular events, though not as powerful of one as cholesterol -- predict the risk of cardiovascular events in patients with HIV? And the answer is probably yes; it predicts. But it's much less powerful than cholesterol in predicting cardiovascular events.
I think the conclusion for a clinician from that trial is that if you have to focus on something to try to decrease the cardiovascular risk of the patient that is in front of you, you'd better focus on lowering the total cholesterol, and try to reach LDL [low-density lipoprotein] goals. You will get more benefit if you follow that approach than if you try to chase the triglyceride levels.
I usually worry about triglycerides when they are over 500, or over 1,000, because they increase the risk of pancreatitis. But most of my patients have triglycerides in the 200 to 300 range, and I usually don't worry too much about that. I recommend diet, basically, and for some people maybe adding fish oil. But I don't worry too much about that if the LDL cholesterol goals are within range, and if the patient is not a smoker. I try to focus on other cardiovascular risk factors, rather than in the triglycerides.
Myles Helfand: That seems to get to the heart of what D:A:D has essentially been all about over the past few years: Sure, there does appear to be some kind of relationship between cardiovascular risk and certain antiretrovirals. It's just that the overall risk of these kinds of things is still lower, right, than something like smoking, or BMI [body mass index], or having a family history of cardiovascular disease -- that kind of thing?
Pablo Tebas: Yes. I think the traditional risk factors play a stronger role than some of the treatment-related factors. We shouldn't forget that HIV by itself is a very strong predictor of cardiovascular risk. An old paper from the New England Journal of Medicine showed that when we started highly active antiretroviral therapy, the risk of cardiovascular events went down dramatically. We tend to forget about that, because we focus a lot on the lipid abnormalities associated with some of the HIV treatments. But that was a study that was done more than a decade ago, and it was a very strong result.
Then the SMART study was presented, showing that when you stop antiretroviral therapy, in fact, you see an increase in cardiovascular events. I think that reminded us of the benefits of therapy in reducing cardiovascular events, and the risk of having uncontrolled viremia. Remember, the SMART study randomized people to viral load-driven therapy versus CD4-driven therapy in which you would start and stop therapy based on your CD4 cell count. It was developed in part as a response to the perceived increased risk of cardiovascular events associated with treatment. It was a strategy to try to minimize total drug exposure, and it didn't work out. Because I think HIV is a more important risk factor than anything that you get from the treatment.
Myles Helfand: So is there a possibility that we're making more of inflammation than it actually is? Given that, as you said, antiretroviral therapy -- when it's effective, when it really suppresses the virus well -- significantly reduces inflammation risk? I mean, it's still there, but it's not necessarily as great. Is inflammation really worth the amount of time and attention that we're currently paying trying to figure out how to measure it, how to find markers that can actually gauge it, and figure out what to do about it?
Pablo Tebas: Well, some of it. I think inflammation has been a little bit of the flavor of the last year or two. I think eventually we will put it in adequate perspective.
I think treatment of HIV reduces inflammation remarkably. There is residual inflammation that we don't know why it's happening. There is some residual inflammation -- not in everybody; some patients have residual levels of inflammation. And if we understand that -- why it's happening -- and we develop interventions to deal with it, we will probably learn something that will probably not only benefit HIV-positive patients, but will benefit other people that have these inflammatory conditions that have been associated with cardiovascular events.
I think eventually that this is the way we will look at this: Treatment benefits patients. We should treat people earlier, so we don't let them go with very, very high levels of inflammation associated with high levels of HIV viremia. And then, when the viremia goes down, and the inflammation goes down, well, we will have to develop interventions to deal with this residual level of inflammation. And I think that will be it.
Yes, I think there has been an emphasis, maybe too much emphasis, on this. But it's an interesting thing. And we can learn a lot about this disease process, and other diseases. I think that's why there is so much scientific interest in this area.
Myles Helfand: The potential ramifications of this significant outpouring of scientific interest, though, is that a lot of HIV-infected people are reading about this research and are getting a sense that there's a lot going on in the area of inflammation, that it's potentially a big deal. So, as a practicing clinician, what do you tell an HIV-infected person who comes to you; who maybe has been living with HIV for five, 10, 15, 20 years; and who is on treatment and may be doing OK, but is really concerned about all of this research that is coming out saying that inflammation is a problem, and it doesn't seem to be going away, even when you're on really good treatment?
Pablo Tebas: Well, I try to put this into perspective with the patient. I think the best interventions to reduce inflammation are relatively simple: eat healthy; exercise; if you have cardiovascular risk, maybe take a lot of aspirin; if you smoke, definitely try to quit smoking; and if your lipids are a little bit high because of HIV or its treatment, then do an intervention like a statin. I think that, at this point, this sounds like the most prudent recommendation. If all my patients were able to quit smoking and stay that way, they would definitely decrease their levels of inflammation to a reasonable level, and I don't think they would have a dramatic increase in their cardiovascular risk.
In fact, there is some data that suggest that the risk of MIs in patients with HIV that are well controlled, and are taking these new medicines that aren't associated with lipid problems, and are being monitored and getting statins and quitting smoking -- you are basically going to have, down the road, the same risk as anybody else for cardiovascular events.
Drink a little bit of red wine at night and enjoy life. That's what I try to tell them.
No comments have been made.
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