Background

The long-term cardiovascular effects of HIV infection and HIV therapy are incompletely understood. Certain antiretroviral medications, and HIV itself, have been associated with dyslipidemia, hyperinsulinemia, morphologic changes, and increased inflammatory markers, which may accelerate the development of cardiovascular disease. Identifying and defining the cardiovascular risk posed by HIV infection and its therapies has become a vital area of research.

Relationship between Prolonged Exposure to ART and Myocardial Infarction

Abstract: Relationship between Prolonged Exposure to Combination ART and Myocardial Infarction: Effect of Sex, Age, and Lipid Changes. Wafaa El-Sadr, P Reiss, S De Wit, A D'Arminio Monforte, R Thiebaut, L Morfeldt, R Weber, C Pradier, G Calvo, M Law, O Kirk, C Sabin, N Friis-MØller, J Lundgren, and On behalf of the D:A:D Study Group. Abstract 42.

Description: The D:A:D Study is an ongoing observational cohort study that evaluates the risk of myocardial infarction (MI) in 23,000 HIV-infected patients. Preliminary data presented previously showed an association between exposure to combination antiretroviral therapy (ART) and MI.(1) The present analysis includes data collected through early 2004 and represents nearly 77,000 patient-years of follow-up.

Patients were exposed to combination ART for a mean of 4.5 years. Combination ART was defined as regimens containing a nonnucleoside reverse transcriptase inhibitor (NNRTI) and/or a protease inhibitor (PI), plus nucleoside analogues (NRTIs). At baseline, 18% of patients had not received ART, 82% had received NRTIs, 35% had received NNRTIs, and 69% had received PIs. Subjects had a mean CD4 count of 418 cells/µL; 26% had AIDS.

Results: During the study period, 277 patients experienced a first MI. The risk of MI was lowest in those not exposed to combination ART and rose steadily with increasing time of exposure, from 1.39/1,000 patient-years in ART-naive subjects to 6.07/1,000 patient-years for those exposed >=6 years (relative risk 4.38 compared with no exposure [p = .0001]). In multivariate analysis, there was a 1.17-fold increased risk of MI per additional year of exposure to combination ART. This additional risk was found in various subgroups, including both men and women, younger and older individuals, and those who had not received ART before study entry. The incidence of MI also was associated with traditional cardiac risk factors, such as male sex, smoking, and hyperlipidemia. Lipodystrophy did not affect the risk of MI. Analysis of the effect of lipid abnormalities on MI revealed that dyslipidemia did not account for all of the association between ART and MI. Thus, exposure to ART was an independent risk factor for MI, with cardiovascular risk increasing with duration of ART.

Risk for Myocradial Infarction Increases with Duration of Exposure to ARVs

Abstract:Changes Over Time in the Use of Antiretroviral Therapy and Risk Factors for Cardiovascular Disease in the D:A:D Study. Caroline Sabin, L Morfeldt, N Friis-Moller, M Rickenbach, P Reiss, A d'Arminio Monforte, C Pradier, O Kirk, G Calvo, M Law, P Mercie, W El-Sadr, S De Wit, J Lundgren, and The D:A:D Study Group. Abstract 866.

Description: In a related presentation on the D:A:D cohort, the study team examined changes in cardiovascular risk factors during the follow-up period and found that the proportion of patients with > =2 traditional cardiovascular risk factors increased between 2000 and 2003, from 34.6% to 42.4%. During this time, lipid levels were unchanged, though the proportion of patients taking lipid-lowering therapy increased (from 4% to 8%). A modest decrease in the percentage of patients receiving PI therapy (and an increase in patients receiving NNRTIs) was observed. Although the proportion of patients with risk factors for MI remained substantial throughout the study period, the risk of MI, after adjustment for cardiovascular risk factors, decreased somewhat over time (rate ratio 2003/2004 compared with 1999/2000: 0.64 [p=.002]).

Comment: The D:A:D study continues to substantiate its initial observation that ARV therapy increases the risk of MI, and that MI risk increases linearly with duration of exposure to ARVs. It is hoped that data accumulated over additional years of study follow-up will clarify the contributions of specific ARV medications or ARV classes to ischemic heart disease, as well as the interaction of HIV infection, ARV medications, and traditional cardiovascular risk factors.

As the cohort is followed over time, it also may be possible to observe the effect on cardiovascular outcomes of risk factors that may increase in the population over time (eg, age, lipid disorders, duration of ARV therapy) and, on the other hand, of interventions intended to reduce cardiovascular risk (eg, lipid-lowering therapy, smoking cessation, selection of ARV medications).

It is important to note again that the absolute increased risk of MI attributable to ARV therapy remains low, while the overall health benefits of ARV therapy are substantial. In addition, classical risk factors such as tobacco use and hyperlipidemia substantially contribute to cardiovascular disease in HIV-positive patients and should be addressed by care providers.

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