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ICAAC 2007 Summaries: Pablo Tebas, M.D.

By Bonnie Goldman With Questions and Comments from Trevor Hawkins, M.D.

September 20, 2007

Listen (3.9MB MP3, 7.5 min.)
Hi. My name is Pablo Tebas. I work at the University of Pennsylvania, in Philadelphia. I am going to talk a little bit about the study that we did in collaboration in the AIDS Clinical Trial Unit (ACTU). It's a study looking at antiretroviral treatment interruption and its effects on lipids and immune activation on cardiovascular risk.

The reason we did the study is because an important study called the SMART study1, that tested two different strategies for managing HIV infection. One strategy was to continue antiretroviral therapy, and go for an undetectable viral load for as long as possible. The other one was called treatment-sparing arm, basically trying to maintain high CD4 cell count, but using as this as little as possible antiretroviral therapy.

One of the very surprising results in this study was that, in the patients that interrupted therapy [there was an] unexpectedly high and increased incidence in cardiovascular events. That didn't make a lot of sense, because their cholesterol and lipid fractions were going down. At that point, we generated several hypotheses [regarding] why this was happening. But that was an unexpected result of that study.

So, we decided to look at a study that we did in the ACTG, looking at treatment interruption, and to see what happened with two things: with lipids and with immune activation. What we saw, in a study of 47 patients that stopped therapy after having well-controlled viral replication, is that the lipid levels went down very quickly, the cholesterol levels increased around 15 percent, the LDL cholesterol decreased 15 percent. Thus, the bad cholesterol went down. So, in theory, that's good for your heart. But the bad news is that the HDL cholesterol -- which is the good cholesterol -- the one that protects you from cardiovascular disease, also went down.

The net effect, when you discontinue therapy is, you have a decrease in the bad cholesterol, but also a decrease in the good cholesterol. So in the end, it's a washout. You really don't get a big benefit by stopping therapy in your lipids. The glucose and the insulin didn't change, and that was not a big surprise. The thing that we saw was that after treatment interruption, not surprisingly, there is a dramatic increase in immune activation. We look at that, looking at two markers, CD38 and HLDR+, which are markers on CD8 cells of immune activation. Also, we look in plasma at two more necrosis factors, too. And both parameters went up very quickly immediately after treatment interruption.

So what happens when you interrupt treatment is that your lipids really don't change much your cardiovascular risk. Your good cholesterol goes down, and your bad cholesterol goes down. At the end it is a washout. But your immune activation goes up dramatically, and that's a situation that can increase, at the end, your cardiovascular risk. And this study might help explain why, in the SMART study, in a 5,000 patient study, at the end what they saw was an increase in cardiovascular events, and not a decrease...which is what they were expecting. And that's basically the bottom line of our study, and why we did it.

So, another reason not to do a treatment interruption.

I think the study explains why the treatment interruption doesn't work in patients, and why you get an increase in cardiovascular events. Maybe in the future we will be able to control immune activation, but until we are able to do that, I don't think treatment interruption is a good idea.

Is there any understanding about why the immune activation happens?

Well, it's driven by viral replication. So when the virus replicates, any viral diseases, ongoing viral replication drives immune activation is a way the organism fights against the infection. It's difficult to control, but it's well known that immune activation can be deleterious. In many infections, it's worse, the response, the immunologic response, than the infection itself.

Trevor Hawkins: Do we know that these immune markers are, in themselves, related to cardiovascular disease? Or do we just know that they are generally sort of inflammatory?

Yes. C-reactive protein and other markers are more classically associated in epidemiological studies. But these markers correlate well with other non-markers.

Trevor Hawkins: Do they correlate with C-reactive protein?

We have not looked at C-reactive protein. We have frozen samples, and I suspect a review of the paper will ask for that. But money is tight, and we will do it if they ask us. But I think there are well known markers of immune activation. Most immunologists use HLA-DR CD38, and TNF receptor as classic markers of immune activation. So, I think they are good markers for that.

Trevor Hawkins: Yes. Immune activation, obviously, is a fairly broad thing. There's immune activation and there's pro-inflammatory, and then there's inflammation in the coronary arteries. It makes sense, but I don't know whether we've actually sort of...

Yeah. We don't have all the... I think what happens in this thing is that you go from a situation that you have a parthenogenic state, with high lipids, high cholesterol, with people on treatment, low immune activation...and you flip it. You basically go to not that much change in lipids, because your HDL goes down. If you have developed a plaque in that situation, it creates an instability, and increases your cardiovascular risk.

It's like having... I mean, people with MI's...they get MI's when they have an infection, they get MI's when they are in a situation of stress or inflammation. So that's what I think.

Trevor Hawkins: It makes sense. It makes absolute sense.

Yeah. It's curious that we didn't think about this when the SMART trial was being designed.

Trevor Hawkins: I had to list my top 15 ICAAC posters and I put this one number one.

Really? Oh, thank you.

Trevor Hawkins: Because I actually think this is really where we're going. This, with SMART, and all the other stuff, that says treat everyone. Don't wait. What's the point of waiting till 350? It's all kind of theoretical. Let's just treat everybody.

Economics is tough. Economics is tough. But you have a good point, in that maybe this cannot... Unless we can control that, immune activation. The risk of not being on treatment; the price you pay is too high.

Trevor Hawkins: So we give everyone cyclosporine until they have reached...

Cyclosporine. We have tried that, and it didn't work, either. Maybe something will do it. I mean, some immune therapy. Because, I mean, if not, the goal is... I mean, what we're telling the patient: "You're going to have to take these medicines for the next 50 years." We need to find other ways. Antiretroviral treatment is so efficacious, that it's difficult to think that we're going to find something else that is going to be able to control that. Here, we are ten years in HIV treatment and 24 approved antiretrovirals, and only one immunomodulator -- thalidomide for the ulcers in the mouth. And it doesn't work that well, either.

Thank you.

Footnotes

  1. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. November 30, 2006;355(22):2283-2296.

To view this study abstract, click here.

To view the poster, click here.




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