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The XVII International AIDS Conference (AIDS 2008)

New SMART Study Analysis Appears to Confirm Link Between Abacavir and Myocardial Infarction Risk

An Interview With Jens Lundgren, M.D.

August 1, 2008

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Arguably, the most anticipated research presentation of the XVII International AIDS Conference (AIDS 2008) was conducted by Jens Lundgren, M.D., Chief Physician and Director of the Copenhagen HIV Programme, where the D:A:D cohort is based. In February 2008, D:A:D study results were presented that suggested an association between abacavir (ABC, Ziagen) use and an increased risk of myocardial infarction (MI), particularly in patients with high baseline MI risk. In an attempt to confirm these findings, Dr. Lundgren and colleagues conducted an analysis of data from the SMART study, the largest HIV treatment-related clinical trial ever conducted. In this interview, conducted by Gerald Pierone, Jr., M.D., which took place before Dr. Lundgren presented his data at AIDS 2008 on Aug. 7, Dr. Lundgren summarizes the findings and significance of this new SMART analysis.

To read our previous interview with Jens Lundrgen, click here.

Jens Lundgren, M.D.
Jens Lundgren, M.D.
Thank you for being here, Dr. Lundgren.

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You are so welcome.

Can you tell us a little bit about your study and what your data showed?

We wanted to see whether we could reproduce the findings that we saw recently in the D:A:D study, in terms of whether certain antiretroviral drugs are associated with an excess risk of cardiovascular disease.1 And indeed, in a separate data set, we were able to reproduce the findings that we had in D:A:D, suggesting that there is an association between abacavir and an increased risk of cardiovascular disease.2

Can you comment on the potential mechanism for the association with abacavir? Did you do any specific studies to look at this?

We already had established in the D:A:D study that this association, if it was real, was likely not due to the fact that abacavir is directly influencing the underlying atherosclerosis, but rather that the drug would increase a propensity for already existing atherosclerosis to manifest itself clinically as a myocardial infarction.

In the SMART study what we tried to pursue was whether the drug is associated with any altered levels of biomarkers, and we had access in SMART to six different biomarkers that mimic inflammation and coagulation. For two of the biomarkers that reflect inflammation, namely, interleukin-6 and high-sensitivity CRP [C-reactive protein], they were higher in patients who were using abacavir, as opposed to patients who were using other drugs. That suggests that the drug has a proinflammatory potential, although we clearly need to do more research to further establish such a link.

Since your original data was presented, a typical comment I have been hearing from people is, "Well, I take care of a thousand patients and I have not seen an association with abacavir." Tell me about type II error and the fallacy of a statement like that.

That's an important comment, and I appreciate the question because I think we need to all understand that if we want to examine these potential relatively rare events, we need to look at very large data sets in order to have enough power to really separate out what are associations, real associations, and whether a situation with a lack of association is just due to the fact that you are studying too few patients. In the instance that you are mentioning here, in a clinic, myocardial infarction, cardiovascular disease is, luckily, still a relatively rare event in HIV patients, due to the fact that many HIV patients are relatively young, in cardiovascular terms.

In the background population, most of the cardiovascular disease we see is happening in patients in their 50s and 60s, and few HIV patients are still in that age range. Clearly, as people survive longer -- luckily because of antiretroviral treatment -- we will see more cardiovascular disease, just due to the fact that the HIV population is aging.

I think people may not have seen this if they were to just reflect back on their own patients, but really, you need a large group of patients to establish these associations.

Along those lines, pharma companies have whole divisions that deal with media and public relations to help mitigate potential bad news about their medications. Have you witnessed any examples of unfair characterization of the D:A:D data?

I think that it would be for others to make up their own minds about that. I'm very focused on making sure that people understand our results, and that's why I'm having this interview with you to communicate our results. There have been all sorts of angles made to our data, but I don't want to really go into that.

That's away from the science.

I'm trying to stay -- what do you call it in the U.S. -- stay focused on the ball?

Right. Keep the eye on the ball.

There we go.

To your knowledge, are there any other observational data sets? Are any of the large observational groups trying to either verify or refute the findings of D:A:D?

As I understand it, my French colleagues are looking into a case control study within France. I'm assuming that there may be other study groups around the world that are looking into this, as well. Of course, the issue here will be whether there are enough endpoints in those studies to really have the ability to confirm or refute the findings that we had. I think that will be a challenge.

It was interesting that I happened to receive an e-mail from Medscape, talking about the Glaxo retrospective look back at their data3 showing that they did not find an association with abacavir. But when you look at the confidence intervals of their data set, clearly it's underpowered to really show a significant difference. I think it really underscores what you're saying.

I think that's probably right.

Do you think, with the information at hand, that this is enough for clinicians to start changing their prescribing behaviors and patterns?

The D:A:D study group already, in February, when we released our own data, released a position statement stating that we felt that this data was sufficiently concerning that, for patients with a high underlying risk on abacavir, it may be prudent to consider other drug options if such other drug options exist and would be considered more safe.4 So this would be in patients with high underlying risk, based on the data I've seen so far.

The editorial in Lancet that accompanied our paper essentially was in agreement with that position, and I think that position is still valid.5 I think that's probably what we should continue to do.

For most patients, namely, all those patients who are luckily at low risk for cardiovascular disease, this is not really something that I would say is clinically concerning. But for patients with high underlying risk -- and the way to calculate that, as you know, is to do a Framingham risk calculation in individual patients -- it may be prudent to consider other options. But we all know that antiretroviral treatment is a lifesaver. So don't go out here and play with this. Be very careful in your consideration and make sure that whatever options you consider switching to indeed are considered more safe in your particular situation. Of course, that depends on your treatment history and resistance, and all sorts of different things.

I think the good news is that now, with all the new medications, there are certainly options for people who do need or want to switch off a medication like abacavir, or protease inhibitors, for that matter, as well.

I think we're privileged at the moment, but of course we need to protect all our drugs, because we will need them, at least in a population of patients; I think we'll need all of them to keep continuous benefit of antiretroviral treatment in the future.

OK, thank you very much for your time. We look forward to the next installment of the D:A:D data base, maybe next year, looking at protease inhibitors.

We'll do that. Thank you.

This transcript has been lightly edited for clarity.


References

  1. D:A:D Study Group, Sabin CA, Worm SW, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. April 26, 2008;371(9622):1417-1426.
  2. Lundgren J, Neuhaus J, Babiker A, et al, and the SMART/INSIGHT and D:A:D Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the SMART study. In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City, Mexico. Abstract THAB0305.
  3. Cutrell A, Brothers C, Yeo J, Hernandez J, Lapierre D. Abacavir and the potential risk of myocardial infarction. Lancet. April 26, 2008;371(9622):1413.
  4. The D:A:D Steering Committee. Position statement on recent use of abacavir and didanosine, but not of thymidine analogues, is associated with risk of myocardial infarction. Copenhagen HIV Programme. February 4, 2008.
  5. Stein JH, Currier JS. Risk of myocardial infarction and nucleoside analogues. Lancet. April 26, 2008;371(9622):1391-1392.


This article was provided by TheBodyPRO.com. It is a part of the publication The XVII International AIDS Conference.
 



Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.
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