42 Relationship between Prolonged Exposure to Combination ART and Myocardial Infarction: Effect of Sex, Age, and Lipid Changes Wafaa El-Sadr*1, P Reiss2, S De Wit3, A D'Arminio Monforte4, R Thiébaut5, L Morfeldt6, R Weber7, C Pradier8, G Calvo9, M Law10, O Kirk11, C Sabin12, N Friis-Møller13, J Lundgren13, and On behalf of the D:A:D Study Group 1Community Prgms for Clin Res on AIDS, Harlem Hosp, Columbia Univ, New York, NY, USA ; 2HIV Monitoring Fndn, Academic Med Ctr, Univ of Amsterdam, The Netherlands; 3St-Pierre Cohort, Ctr Hosp Univ St-Pierre, Brussels, Belgium; 4L Sacco Hosp, Univ of Milan, Italy; 5Aquitaine Cohort, Bordeaux Univ Hosp, INSERM U593, France; 6HIVUS, Karolinska Hosp, Stockholm, Sweden; 7Zurich Univ Hosp, Switzerland; 8Ctr Hosp Univ Nice, Hosp de l'Archet, France; 9BASS, Autonomous Univ of Barcelona, Spain; 10Australian HIV Observational Database, Natl Ctr in HIV Epidemiology and Clin Res, Sydney, Australia; 11EuroSIDA, Copenhagen HIV Prgm, Hvidovre Univ Hosp, Denmark; 12Royal Free and Univ Coll, London, UK; and 13Copenhagen HIV Prgm, Hvidovre Univ Hosp, Denmark

Background:  Prior data from the D:A:D Study suggest association of combined ART exposure with an increased risk of myocardial infarction. We investigated if the linear trend previously reported continues with further combined ART exposure, whether it is modified by age or sex, and possible mechanisms for this relationship.

Methods:  Observational study of 23,441 HIV-infected patients (24% women) from 11 cohorts from Europe, Australia, and the United States were followed to February 2004 to determine the incidence rates of first prospective myocardial infarction (per 1000 person-years), and relative rates of factors associated with myocardial infarction from Poisson regression models are reported.

Results:  By 2004, the mean exposure time to combined ART was 4.46 years. Over 76,577 patient-years, 277 patients experienced a first myocardial infarction. The myocardial infarction incidence increased from 1.39/1000 patient-years in those not exposed to combined ART, to 2.53/1000 patient-years in those exposed for < 1 year, to 6.07/1000 patient-years in those exposed for ≥ 6 years (RR compared to no exposure:  4.38 [95% CI 2.39 to 8.04], p = 0.0001). After adjustment for other potential risk factors, there was a 1.17-fold [1.11 to 1.24] increased risk of myocardial infarction per additional year of combined ART exposure. Similar results were found after inclusion of repeat myocardial infarctions (1.18 [1.09 to 1.28]), inclusion of only definite myocardial infarction (58.5% of myocardial infarctions) (1.22 [1.11 to 1.35]), and restricting the analysis to naïve patients (n = 4161) at entry (1.39 [0.93 to 2.08]). Although the rate of myocardial infarction was higher in men than women (2.04 [1.30 to 3.21]), the RR associated with combined ART was similar in men (1.14 [1.06 to 1.24]) and women (1.38 [1.07 to 1.76], p value for interaction 0.51). The relationship was similar in younger and older patients (men > 45 and women > 55 years; p value for interaction 0.41). Including time-updated levels of serum total cholesterol (RR 1.15 [1.06 to 1.25] per mmol/L), HDL cholesterol (0.60 [0.42 to 0.88] per mmol/L), and triglycerides (1.64 [0.98 to 2.74] per log₂) in the same model, reduced the association of additional year of combined ART with myocardial infarction to 1.10 [1.01 to 1.19]. Adjustment for lipid-lowering medication did not further affect the association between combined ART exposure and myocardial infarction. Lipodystrophy was not associated with the risk of myocardial infarction (RR 0.99 [0.75 to 1.30]).

Conclusions:  These findings suggest that while the overall absolute risk of myocardial infarction remains modest, the risk continues to increase with longer exposure to combined ART over the first 7 years of use. The relative increase in risk appears similar in men and women, and in older and younger subjects. Dyslipidemia explained part but not all of the association of combined ART with risk of myocardial infarction.

Keywords: adverse effects; myocardial infarction; cardiovascular disease