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Does HIV treatment increase the risk for cardiovascular disease? If so, are some treatments riskier than others? This update from the DAD study — the largest cohort investigation of the adverse effects of antiretroviral therapy — suggests a possible role for PIs in cardiovascular disease.
Among 23,437 HIV-infected patients, most of whom were treated in Europe, 345 developed myocardial infarction (MI) during 94,469 person-years of observation. Overall, in a multivariate model, potent combination antiretroviral therapy increased the risk for MI by 16% per year of exposure, compared with no treatment (relative risk, 1.16; 95% confidence interval, 1.09–1.23); PI exposure carried the same relative risk. By contrast, NNRTI therapy did not significantly increase the rate of MI (RR, 1.05; 95% CI, 0.98–1.13). After additional adjustment for serum lipid levels, the effect of PIs on MI risk was reduced but not eliminated (RR, 1.10; 95% CI, 1.04–1.18). Follow-up was insufficient to allow for investigation of individual agents within drug classes. Established risk factors for cardiovascular disease were associated with higher rates of MI than was exposure to combination antiretroviral therapy, with adjusted relative risks of 1.4 for each 5-year increase in age, 1.9 for male sex, 2.8 for current smoking, and 4.3 for history of prior cardiovascular disease. Notably, 61% of all study participants were either current or former smokers.
The DAD Study Group. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007 Apr 26; 356:1723-35.
Stein JH. Cardiovascular risks of antiretroviral therapy. N Engl J Med 2007 Apr 26; 356:1773-5.
Hughes MD and Williams PL. Challenges in using observational studies to evaluate adverse effects of treatment. N Engl J Med 2007 Apr 26; 356:1705-7.
Comment
As the rate of HIV-related opportunistic infections and malignancies has fallen, the risk for non–HIV-related events, such as cardiovascular disease, has become increasingly important to HIV clinicians and patients. In fact, this large, well-designed study is the third one published on this topic in the New England Journal of Medicine since 2003 (348:702 and 349:1993). Although these findings certainly point to HIV treatment — and PI use in particular — as risk factors for MI, we as clinicians must not infer that a “silent epidemic” of cardiovascular disease exists that somehow negates the hugely beneficial effect of HIV treatment overall. As nicely summarized by editorialists, the overall effect of antiretroviral therapy on MI risk was quite small. Furthermore, using observational studies to ascribe adverse events to particular treatments has known limitations, most notably an inability to avoid confounding, because study participants are not randomized and, hence, could differ in some critical way that influences outcome. Finally, the surprising results from the SMART study, showing an increase in cardiovascular events related to treatment interruption (ACC Nov 29 2006), suggest that the most dangerous clinical state for the overall health of our patients is being off treatment entirely — and, of course, smoking cigarettes!