Copenhagen, Denmark- Two anti-HIV drugs—abacavir (Ziagen, GlaxoSmithKline) and didanosine (Videx, Bristol-Myers Squibb)—appear to be associated with an increased risk of MI, a new study suggests [1].

The study, published online in the Lancet on April 2, 2008, found no link between the most commonly used HIV drugs—zidovudine, stavudine, or lamivudine—and MI rates but suggested that recent (although not cumulative) use of abacavir was associated with almost a doubling of risk for MI, and didanosine showed an increase of around 50%.

The authors, led by Dr Jens Lundgren (University of Copenhagen, Denmark), note that most people with HIV infection will take a combination of drugs for the rest of their lives. Previous studies have suggested that HIV therapy may increase cardiovascular events, and Lundgren et al analyzed data from the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study, a prospective observational cohort of 33 347 HIV-infected patients, to investigate MI rates with cumulative, recent, and past use of various HIV drugs. Adjustments were made for cardiovascular risk factors that were unlikely to be affected by antiretroviral therapy, including individuals' cardiovascular risk profile. They found that recent use of abacavir or didanosine was associated with an increased rate of MI compared with patients with no recent use of these drugs.

MI rates were not significantly increased in those who stopped these drugs more than six months previously compared with those who had never received these drugs. After adjustment for predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir remained associated with increased rates of MI.

The authors note that, if anything, they had expected that stavudine and zidovudine may be associated with increased rates of MI, as these drugs cause dyslipidemia and increased insulin resistance. But in contrast to their expectations, they did not see increased MI rates with these two drugs. The finding that abacavir and didanosine were linked to increased rates of MI was unexpected, because neither drug is thought to have substantial effects on metabolic factors, they say.

"The increased rate of MI in those exposed to abacavir and didanosine was evident while patients were actually receiving the drugs as well as shortly after stopping them but seemed to decrease within a few months after their cessation," they add.

They point out that the DAD study is an observational study and, as such, is not designed to definitively establish whether any associations are causal. But the effect of increased MI rates with abacavir and didanosine remained after various analyses to control for potential confounding factors, and a randomized trial to establish a causal relation between abacavir or didanosine and MI would need at least 5000 patients per arm followed for two years and is unlikely to be feasible.

They note that possible pathogenic mechanisms by which abacavir and didanosine affect the risk of coronary heart disease are as yet unknown, but the effect does not seem to be mediated through changes in metabolic risk factors. The finding that the effect could be reversed on cessation of the drug supports a more rapidly acting underlying mechanism, which could involve vascular inflammation, they add. They further point out that abacavir has been shown to induce cardiomyopathy in mice and rats and is metabolized intracellularly to carbovir, which has the potential to be cytotoxic.

Noting that abacavir is at present frequently used as part of antiretroviral therapy regimens, while didanosine is used to a lesser extent, they say their findings pose a clinical dilemma as to whether to recommend their discontinuation. If discontinuation is considered, the possible risks and benefits of continued use should be assessed in each individual patient and should take into account their underlying risk of MI and the availability of other treatment options, bearing in mind that most other HIV drugs have the potential for long-term toxicity, including metabolic, hemotoxic, renal, or bone-related adverse effects.

Also published simultaneously in the Lancet is a letter from GlaxoSmithKline (GSK), the manufacturer of abacavir, which reports its own analysis of 54 pooled studies, which did not suggest an increased risk of MI with the drug [2]. But the company adds that it "takes the DAD finding seriously and is committed to understanding these data more fully and to communicating openly with treating physicians and regulatory agencies globally."

In a Comment article [3], Drs James Stein (University of Wisconsin School of Medicine and Public Health, Madison) and Judith S Currier (University of California, Los Angeles David Geffen School of Medicine), say that although findings from observational studies should not generally lead to changes in clinical practice, "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 DAD cohort), one additional MI would be expected for every 11 treated with abacavir or every 20 treated with didanosine for five 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 GSK's analysis is not powered to detect meaningful differences, as it was based on only 18 MIs, and "the limitations of summaries of pooled data for uncommon events in studies not designed to detect them are well-known."