NEW YORK -- April 1, 2008 -- A study that appears in the April 2, 2008, online edition of The Lancet suggests that there may be long-term safety issues with the use of the antiretroviral drugs abacavir and didanosine. Both medications were found to be associated with an increased risk of myocardial infarction (MI).
Previous studies have examined the long-term effects of combination drugs from the nucleoside reverse transcriptase inhibitor (NRTI) class used to treat patients with HIV infection, especially with regard to cardiovascular (CV) outcomes. However, attention has mainly focused on protease inhibitors and their potential effect on a patient's increased risk of MI.
Professor Jens D. Lundgren, Rigshospitalet, University of Copenhagen, Denmark, and colleagues used data from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study (N = 33,347) to investigate the development of MI and the cumulative, recent (currently or within the preceding 6 months), and past use of zidovudine, didanosine, stavudine, lamivudine, and abacavir.
Adjustments were made for CV risk factors that were not likely to be affected by antiretroviral therapy such as CV risk profile. No associations were found between the rate of MI and cumulative or recent use of the most commonly used NRTIs -- zidovudine, stavudine, or lamivudine.
Over the course of 157,912 person-years, the researchers found that 517 patients developed MI.
However, recent -- but not cumulative -- use of abacavir or didanosine was associated with an increased rate of MI. Abavacir nearly doubled the risk of MI, and the use of didanosine showed a 50% increased risk. Study participants who discontinued use of these medications 6 months or more previously were at no more increased risk of MI than participants who had never used them.
After adjusting for predicted 10-year risk of coronary heart disease, the study authors also found that recent use of both didanosine and abacavir remained associated with increased rates of MI.
The investigators suggested that underlying biological mechanisms that lead to a CV inflammatory response may be responsible for the increased incidence of MI, but they noted that more research is needed.
Professor Lungren commented, "Abacavir is, at present, frequently used as part of antiretroviral therapy regimens, while didanosine is used to a lesser extent. Our findings pose a clinical dilemma: should clinicians simply increase their vigilance of possible risk of [MI] without making changes to abacavir or didanosine use while waiting for further evidence to accrue, or should all or some patients who are receiving these drugs be advised to consider discontinuing their use?
"If the decision is made to consider discontinuation of either drug," he continued, "then a full assessment of the possible risks and benefits of their continued use should be undertaken. Such an assessment must be individualised for each patient and should take into account their underlying risk of [MI], the availability of other treatment options after taking into account their history of past treatment and HIV resistance testing, and the safety profile of alternative HIV medication."
Also published simultaneously is a Correspondence letter from GlaxoSmithKline, the manufacturers of abacavir. They highlight how their own analysis of 54 pooled studies did not suggest an increased risk of heart attack from abacavir. A spokesperson from GSK comments: "...we did not find a result consistent with that of D:A:D. ... GSK takes the D:A:D finding seriously and is committed to understanding these data more fully and to communicating openly with treating physicians and regulatory agencies globally."
In a linked Comment, James H. Stein (University of Wisconsin School of Medicine and Public Health) and Judith S. Currier (University of California David Geffen School of Medicine) discuss the clinical implications of the study results and the response from GlaxoSmithKline. They state: "In general, findings from observational studies should not lead to changes in clinical practice, especially without confirmation. In this case, however, the magnitude of the increased risk of myocardial infarction among the subset of individuals at high risk of coronary heart disease cannot be ignored. ... In these individuals (about 6% of the D:A:D cohort), 1 additional myocardial infarction would be expected for every 11 treated with abacavir, or every 20 treated with didanosine for 5 years. On the basis of this risk, alternatives to abacavir and didanosine in high-risk patients should be considered; ... however, the decision to switch antiretroviral therapy must be made cautiously."
They comment that the analysis by GlaxoSmithKline "is not powered to detect meaningful differences: it was based on only 18 myocardial infarctions, and the limitations of summaries of pooled data for uncommon events in studies not designed to detect them are well known. Because coronary events were not adjudicated formally in these antiretroviral therapy efficacy studies, interpretation of the rates of 'coronary artery disorders' is difficult. Available data on coronary heart disease from clinical trials, such as those included in the Cutrell report, should be submitted for peer review so their design and analyses can be described in detail and their conclusions fully interpreted".
SOURCE: The Lancet, April 2, 2008
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