April 25, 2013
What do we know so far about what's to blame for this higher level of MI risk among people with HIV?
There is clearly this conceptual model of immune activation going on in people living with HIV. That immune activation leads to the expression of all these inflammatory chemicals that we have now come to appreciate -- and are even measuring routinely in our clinical research studies, if not sometimes even in clinic.
These inflammatory markers, or chemicals, have been known to have effects on people's risk for cardiovascular disease and the pathogenesis of cardiovascular disease, such that those who live with more inflammation -- whether it be from rheumatoid arthritis or other disease states that are chronic and inflammatory -- have higher rates of problems with their arteries and with atherosclerosis.
So it follows suit that you can imagine -- connect the dots, in a way -- that among people living with HIV, the same sort of thing happens.
There certainly is a component, I think, of the therapies, and what they do. How big a component that is, how big that drop is in the bucket, is up for debate. And different medicines have different activities; how much of that is active or operational, when HIV therapy reduces immune activation by controlling the virus? Is any effect of HIV medicine trumped by what it does to HIV itself? That, again, is debatable -- and it's all relative: If you have a drug that raises your LDL cholesterol, we believe that's going to raise your risk for cardiovascular disease -- even if it does reduce your immune activation -- compared to another drug that reduces your immune activation to the same extent but doesn't increase your LDL. Somebody will potentially have an event due to that LDL increase over time, if you look at enough people.
The thing that's not measured, and that I really am concerned about in some of these cohort studies, is that they're looking at people from a long period in the past -- 10 years or more, sometimes. I wonder whether or not these data will hold up over time.
By that, I mean: If we're looking at people in the D:A:D cohort, or these cohorts from Boston or the U.S. in general, we're looking at people with HIV infection who may have not been treated for five, six, seven, 10 years. These are people who oftentimes were diagnosed and were managed before guidelines became more aggressive, and who lived with HIV replicating in their body, with that immune activation.
How much of the groundwork for coronary artery disease and cardiovascular disease was paved by [studies involving people with] untreated HIV infection for a long time? With earlier treatment -- and with drugs that are not as offensive to lipids and cardiovascular risk -- will we still see this excess when we account for the traditional risk factors?
That's an intriguing question for me. I wonder whether or not some of the data we're seeing now will be relevant even just a decade from now, when we have a different paradigm for treating HIV.
Is the determination of risk really that subjective? Are there objective tools that we can use? How reliable is Framingham for HIV-infected people, for instance?
It looks like Framingham is pretty good. If anything -- like I think the D:A:D folks have been trying to tell us for a while, but we now have better data [to support] -- I think it probably underestimates risk for cardiovascular disease over a 10-year period in people living with HIV.
The way I look at [a person's Framingham score] is: Here's your bare-minimum risk. It's at least this -- or, if not, somewhat higher.
But if you ever play with the Framingham Risk Score -- which is really fun to do; I play with it all the time with my patients. I'll look at it and I'll say, "Well, here's what happens if I lower your LDL. And here's what happens if I raise your HDL. Here's what happens if you stop smoking" -- which, of course, has the biggest influence, and it's dramatic. If you change the things that you think you can change, you can get an incremental sense for what kind of differences you're seeing.
I think these risk assessments are useful. They help people quantify what range they are in. But they're not exact. And I think the D:A:D study from many years ago showed that there was a little bit of an added effect of HIV. I think that probably is the case.
Have you used the Veterans Aging Cohort Study Index?
That's really fascinating, too. And I think that we should be thinking more about it. One thing that may prevent some of us from using it more widely is it's a little complicated. I think there probably is an app for that already. As that kind of thing gets marketed, and becomes as ubiquitous as Framingham Risk and as easy to plug people into, I think it will be useful.
For a lot of my patients that I would probably calculate, I already know that they've got problems. If you already have anemia, which is a big driver of the frailty risk, that counts for a lot in that index. I can tell whether or not you have anemia, and if you have anemia, you have a whole bunch of other stuff going on.
It's less useful for my 50-year-old guy who gave up smoking years ago, who never smoked, and goes to the gym all the time. For me, I probably wouldn't reach for the frailty calculator.
But I do see how it's a useful tool. I think that the people who've developed it have done a really great job of validating it, and I think it should get more attention. I like how they've used it on a population basis that really helps us understand where people get into the danger zone.
Do you feel that inflammation markers are worth testing for in your patients, or does that not really inform the decision that you might otherwise make? Is it more for research purposes?
I very rarely order inflammatory markers on my patients. I usually don't have motivation to do so. I will sometimes do it: I have a patient I'm seeing now on whom I just ordered an hs-CRP -- a C-reactive protein level -- and a D-dimer. She's not on ritonavir; she didn't tolerate it, so I needed to put her on a friendly, effective regimen. She's doing great on abacavir/3TC and unboosted atazanavir, but does have hypertension and some dyslipidemia, and I've worried a little bit about that. So I did check a CRP and a D-dimer on her, to see if there was an increase. Whether or not any increase is related to the abacavir, I can't tell -- unless I stop the abacavir, replace it with something else and see what happens to those inflammatory markers. I'd probably repeat [the marker testing] before I did anything.
But that's a pretty unusual circumstance. Normally, I don't do it. If my person's on tenofovir/FTC and efavirenz, and doing great for years, I'm not going out and ordering a CRP or a D-dimer to check coagulation -- and certainly not an IL-6, or any of these things. I don't do that yet. I think we have to learn more about how to use those things.
You can certainly look at platelet count as a poor man's marker of inflammation. But it's unreliable.
I don't think it's ready for prime time to do an inflammatory panel. I do check lipids; I think those are important to check. I reduce the LDL, to the extent that I can, in people whose LDLs are not anywhere near where they should be.