March 31st, 2008

FDA Investigating Safety of Abacavir and Didanosine — Old News or New?

The FDA has issued one of its new “early communications” indicating that it has opened an investigation into the safety of abacavir and didanosine based on analyses showing higher rates of myocardial infarction with these drugs than with other NRTIs in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study.

The pace of our field is sometimes remarkably fast: Immersed in HIV care or research or policy, we think of this as old news — after all, it was presented over a month ago at the Retrovirus Conference. These D:A:D results linking abacavir and ddI to increased MI risk have already been the subject of extensive discussions in clinics, conference rooms, and meetings. But I have to remind myself that no, it’s not old news at all — the full paper has not yet been published, although it will be soon — and that we still need some time to process the data, and to consider the questions raised by the findings. Is this a causal relationship, or just an association? Why has it not been seen in other studies? What is the mechanism? Would it still be the case with HLA-B*5701 screening? Why is the risk not cumulative? When will we be seeing data on tenofovir? (I suspect soon, given when tenofovir was approved.) What do abacavir and ddI have in common that would cause this? What should we be doing with our patients on abacavir who are doing well? I confess my answer to all of these questions is the same: I just don’t know.

D:A:D is an extremely important study that has already provided enormous insight into HIV treatment. But as the D:A:D investigators no doubt would agree, there are limitations to ascribing toxicities to treatment based on observational data. So I guess I’m proposing that as of today (March 31, 2008) we view these results as suggestive, and hypothesis-generating, rather than defining standard of care right now.


The D:A:D data have now been published in the Lancet. There is also an accompanying editorial here (subscription required).

3 Responses to “FDA Investigating Safety of Abacavir and Didanosine — Old News or New?”

  1. Daniela Nikolova says:

    Is there link between higher rate of myocardial infarction-effect of ABC and ddI and the metabolic disorders of ART, or is it a specific effect of these nukes?

  2. Paul Sax says:

    In DAD, the effects of ABC and ddI are not mediated through their influence on lipids — even when adjusting for lipids (and other risk factors), the effect remained (see Figure 2 in the paper). The authors speculate in the discussion section that it may have something to do with increasing vascular inflammation, which might also explain why the effect went away once the drugs were stopped.


  3. John says:

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HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

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