News Release

Study suggests antiretroviral HIV drug linked to increased risk of heart attack

Peer-Reviewed Publication

The Lancet_DELETED

Doubts over the long-term safety of the HIV nucleoside reverse transcriptase inhibitor abacavir are raised in a research Article published Online and in an upcoming issue of The Lancet. Abacavir and the less commonly used antiretroviral drug didanosine were found to be associated with an increased risk of myocardial infarction (heart attack).

The success of HIV antiretroviral therapy means that most people with HIV infection will take a combination of drugs (usually a protease inhibitor and a nucleoside reverse transcriptase inhibitor [NRTI]) for the rest of their lives. Previous studies have sought to investigate the long-term effects of these drug classes, especially with regard to cardiovascular outcomes. Attention has focused mainly on protease inhibitors and their potential effect on increased risk of heart attack.

Jens D Lundgren (Rigshospitalet and University of Copenhagen, Denmark) and colleagues used data from the D:A:D study to investigate cumulative, recent (currently or within the preceding 6 months), and past use of the NRTIs zidovudine, didanosine, stavudine, lamivudine, and abacavir, and the development of heart attack in 33 347 patients. Adjustments were made for cardiovascular risk factors that were unlikely to be affected by antiretroviral therapy, including individuals’ cardiovascular risk profile.

No associations were found between the rate of heart attack and cumulative or recent use of the most commonly used NRTIs zidovudine, stavudine, or lamivudine. However, recent—but not cumulative—use of abacavir or didanosine was associated with an increased rate of heart attack: almost a doubling of risk for abacavir, and around a 50% increased risk for didanosine. Individuals who had stopped using these drugs six months or more previously were at no more increased risk of heart attack than people who had never used these drugs.

The investigators suggest that underlying biological mechanisms leading to a cardiovascular inflammatory response could be responsible for the increased incidence of heart attack from abacavir and didanosine, although more research is needed in this area.

Professor Lundgren comments: “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 myocardial infarction 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, 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 myocardial infarction, 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 (GSK), 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. Dr Didier Lapierre 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), USA, discuss the clinical implications of the study results, and GSKs response. 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), one 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 GSKs “analysis 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”.

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Professor Jens D Lundgren, Centre for Viral Diseases/KMA, Rigshospitalet & Copenhagen HIV Programme; http://www.cphiv.dk, University of Copenhagen, Faculty of Health Sciences The Panum Institute/Building 21.1 Blegdamsvej 3B 2200 Copenhagen N, Denmark. T) +45 35 45 57 57; (mobile) +45 40 87 93 03; jdl@cphiv.dk

Correspondence Dr Didier Lapierre, c/o GlaxoSmithKline Press Office. T) +44 (0) 20 8047 5502 (Phil Thomson, Gwenan White, or Alice Hunt).

Comment Dr James H Stein, Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. T) +1 608-262-6343; jhs@medicine.wisc.edu

pressoffice@lancet.com
Please mention The Lancet as the source of this material
Issued by Tony Kirby, Press Officer, The Lancet


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