D:A:D study shows that PIs rather than NNRTIs drive the previously reported cardiovascular risk of combination antiretroviral therapy

The D:A:D study is a large international observational study of more than 23,400 HIV-infected patients from 11 cohorts in Europe, Australia, and the United States. It was established to look at cardiovascular risks that may be related to combination ARV treatment (cART), and has reported an adjusted RR of 1.16 per year of exposure [95%CI 1.09 to 1.23], equivalent to approximately doubling the risk of myocardial infarction (MI) over five years.

At CROI this year, the researchers were able to present their first results of the effects of drug classes on this risk. By 2005, 345 patients had experienced an MI over 94,469 person-years (3.65/1000 person-years). The risk of MI decreased over calendar time (RR for 2003-2004 vs 1999 0.50 [0.32 to 0.77]), but this was an effect that is removed by adjusting for latest lipid levels (RR for 2003-2004 vs 1999 0.82 [0.49 to 1.37]).

Total exposure to the PI drug class was 72,846 person-years (30,198 person-years in patients with no NNRTI exposure) and to the NNRTI drug class 52,457 person-years (9808 person-years in patients with no PI exposure). MI incidence increased from 1.53/1000 person-years in those not exposed to PI to 6.01/1000 person-years in those exposed for >6 years (RR/year of exposure: 1.17; 1.12 to 1.23). The incidence also increased slightly with NNRTI exposure (RR/year: 1.07; 1.00 to 1.14). After adjustment for the other drug class and other known risk factors for MI, the relative rate per year of PI exposure was 1.16 (1.10 to 1.23, p = 0.0001), while for NNRTI it was 1.05 (0.98 to 1.13, p = 0.17).

Total cholesterol, HDL cholesterol and triglycerides were associated with the risk of MI; adjustment for these reduced the effect of PI and NNRTI exposure to 1.10 [1.03 to 1.17] and 1.01 [0.93 to 1.10], respectively.

Comment

It has taken over six years follow-up in this impressive cohort database, and 345 MI events before the study achieved power to look at individual class effects. Given the variability of individual drugs within classes to impact on lipids, and that most, but not all, of the increased risk is explained by lipid changes, this raised immediate interest in the role of individual drugs.

Because of the historical nature of a cohort the introduction of newer drugs including PIs boosted with low dose RTV is underrepresented in the current analysis. In addition, because of the design of DAD which has a given start point and censors the past treatments of a patient, a bias could be introduced towards patients on PIs (more severe disease, longer time on therapy etc.). However, dyslipidemia in HIV-positive patients should be taken seriously and managed as in the HIV-negative population.

While the absolute annual risk of MI is still low, the lifetime risk accumulates to an effect that is comparable with smoking. Advice to reduce lifestyle-associated risks (diet, exercise and smoking cessation) continues to remain as important as for the general population.

Friis-Moller N, Reiss P, El-Sadr W et al. Exposure to PI and NNRTI and Risk of Myocardial Infarction: Results from the D:A:D Study. 13th Conference on Retroviruses and Opportunistic Infections, 5-8 February 2006, Denver, Colorado. Abstract 144.
http://www.retroconference.org/2006/Abstracts/27347.HTM