HIV drugs and heart attacks: what’s the real story?

The ‘Data Collection on Adverse Events of Anti-HIV Drugs’ study (a large study known as D:A:D, which is monitoring the effects of HIV drugs) continues to find that if you are currently taking, or have recently taken, either abacavir (Ziagen – also in Kivexa and Trizivir) or ddI (didanosine, Videx) you’re respectively 70% and 30% more likely to have a heart attack.¹

This risk is raised regardless of other conditions that might cause heart attacks like cholesterol, diabetes and high blood pressure. The risk was raised even in the three-quarters of patients who weren’t at high risk of a heart attack – and a quarter of heart attacks were in this low-risk majority.

However it’s important to note that these increases arerelative to your current risk of having a heart attack and if you’re at low risk, low risk plus 70% still means quite low risk. Heart attacks were still quite uncommon; in the eight years now covered by the study, there were 580 heart attacks in over 33,000 patients, or one per 308 patients per year.

D:A:D also reported an 8 to 9% increase in heart attack risk for every year spent taking the protease inhibitor (PI) drugs lopinavir/ritonavir (Kaletra) and indinavir (Crixivan – whether or not it was taken with ritonavir). For the first time, D:A:D also reported a similar cumulative risk with abacavir too: the risk of heart attacks increased by 7% for each year of exposure.

The reason for distinguishing between current and cumulative exposure is that it distinguishes between a rise in a health risk that increases as soon as a patient starts taking a drug, but stops when they stop, and a chronic side-effect which may only become apparent after several years, and may persist after the drug is stopped.

For instance, this would imply that with abacavir, when you started the drug your risk of a heart attack would rise by 70% compared to non-abacavir users; after two years it would be 84% higher; and if you then stopped taking it and switched to a drug with a neutral effect it would remain raised, relative to people who had never taken abacavir, by 14%.

No increased heart attack risk was found with any other HIV drug studied, including tenofovir (Viread: also in Truvada and Atripla), though in this case only three years’ data have been collected so far, resulting in a wide margin of uncertainty. D:A:D hasn’t yet been able to evaluate the risk for the newer PIs like atazanavir and darunavir, or other new classes.

But we’re clear about abacavir at least? Not necessarily. Since these findings were initially presented at the Conference on Retroviruses and Opportunistic Infections (CROI) last February,² a nearly-as-large US study of army veterans failed to find a link between abacavir and heart attack: current use only raised the risk by 17%, rather than 70%, and this could have been due to chance.³

Why the difference? The D:A:D researchers tell readers that their findings “cannot be assumed to reflect causal associations and must be interpreted cautiously because of the potential for unmeasured confounding”.

The weakness of cohort studies is that a so-called ‘confounder’ - an unrecorded or unlooked-for characteristic of the patients - might have caused the effect seen. Because studies like D:A:D are so big, they can only select a very limited range of things they want to find out about patients. They can miss something crucial.  

In the case of the US veterans’ study, the researchers think they may have found their confounder in the shape of kidney disease. Because this may be exacerbated by tenofovir use, the argument goes, patients with it are more likely to be prescribed abacavir instead…and HIV patients with kidney disease were four times more likely to have a heart attack. More recently a French study found the same association.⁴

The D:A:D study does not collect kidney disease data (or hasn’t done so far). [Please see correction below.] But there was very little difference between patients on tenofovir and ones on abacavir in terms of the cardiovascular risk data they did collect, such as blood pressure and cholesterol levels.

One theory is that the studies that show an association between abacavir and heart attacks largely feature patients who were already on HIV drugs, while ones that show no association featured patients new to treatment. Having untreated HIV infection raises the risk of a heart attack at least as much as abacavir does. The argument is that any increase in risk due to abacavir was counterbalanced by the decrease in risk due to bringing HIV viral load under control.⁵

So the question over abacavir and heart attacks remains unsettled. Until the question is settled – and it will be if studies like D:A:D accumulate enough data – all that guidelines like those published by the British HIV Association can say is that “Patients currently on abacavir-containing regimens should be carefully reviewed to see whether other options are available”.⁶

Correction

We printed a correction to this article in the March edition of HIV Treatment Update. It read:

"In last month's Upfront on HIV drugs and cardiovascular disease, we stated that the D:A:D study did not collect data on kidney disease. In fact D:A:D has been collecting data on creatinine levels, a marker of kidney disease, since 2006 and in a letter to The Lancet 18 months ago, the researchers wrote that adjusting for kidney disease made no difference to the association between abacavir and heart attacks."⁷