Increased risk of myocardial infarction associated with duration of protease inhibitor treatment

Several large studies have addressed the concern that antiretroviral therapy could increase the risk of cardiovascular disease, and a useful analysis and summary (including the AIDS article reviewed here) was published earlier this year by the Forum for Collaborative Research and is now available online [1].

Results from the largest of these studies to date, the DAD study with almost 24,000 patients and 36,000 patient years follow-up, showed a small but significant increased risk associated with each year of antiretroviral treatment. Although the absolute risk is still very low for most HIV-positive patients, this finding is most relevant to those who already have traditional high risk factors, and the importance of lifestyle modifications such as smoking cessation, diet and exercise is as important as it is for HIV-negative individuals. Full results from this study have just been published, together with an editorial comment in New England Journal of Medicine [2].

Data in the FHDH includes all HIV-positive patients who have provided consent from a network of 68 French University Hospitals. Data has been collected prospectively since 1992 with a follow-up form completed at least every six months, and by 1999 more than 73,000 patients were included with a median follow-up of 32 months.

Entry to the study started from January 1996, when PI therapy was just becoming widely available in France, and patients with a previous history of MI were excluded. Women were not included in the analysis because the very low number of cardiovascular events (n=6) recorded in the database for this period would not sufficiently power the final results.

MI was diagnosed in 60 men, including 49 cases in men using PI treatment. In the Cox model, exposure to PI was associated with a higher risk of MI [relative hazard (RH), 2.56; 95%CI, 1.03-6.34]. The expected incidence in the French general male population (FGMP) was 10.8/10,000 PY. The standardised morbidity ratio relative to the FGMP was 0.8 (95% CI, 0.5-1.3) for men exposed to PI for < 18 months (G1), 1.5 (95% CI, 0.8-2.5) for men exposed for 18-29 months (G2) and 2.9 (95% CI, 1.5-5.0) for men exposed for > 30 months (G3). With G1 as reference, the standardised morbidity ratio was 1.9 (95% CI, 1.0-3.1) for G2 and 3.6 (95% CI, 1.8-6.2) for G3.

In the multivariate analysis, initial CD4 cell counts, exposure to NRTI and exposure to NNRTI did not influence the risk of MI. MI was more likely in older patients and those exposed to PI. The risk of MI increased by 42% per 10-year age increment, and more than twofold in patients exposed to PI.

In an editorial comment in the same journal Peter Reiss emphasised that this increased risk, while important to follow closely, remained very low compared to the clear benefit provided by combination therapy. He also reaffirmed the importance of lifestyle changes to modify known cardiovascular risks and “cautious use of lipid lowering and anti-diabetic agents according to available guidelines”. [4]

Focusing on absolute rather than relative risk was also one of the summary recommendations from the Forum for Collaborative Research report cited earlier, which also recommended always including patients with MI risk factors including previous history of MI.