Early after highly active antiretroviral therapy (HAART) became available for HIV-infected patients, an increased cardiovascular risk was hypothesized on the basis of several case reports , and because of the increased prevalence of an atherogenic biological profile . This trend was confirmed thereafter by large prospective studies [3,4]. Atherosclerosis in HIV-infected patients was also investigated through carotid intima-media thickness (IMT) measured by B-mode ultrasonography. The studies conducted among HAART-treated patients showed an increased IMT, mainly associated with conventional cardiovascular risk factors such as older age, male sex, tobacco use, elevated body mass index (BMI) or total cholesterol [5–8]. Intervention measures were then proposed to aim at reducing the cardiovascular risk of HIV-infected patients, such as a switch of antiretroviral regimen from protease inhibitors (PI) to non-nucleoside reverse transcriptase inhibitors  or the use of lipid-lowering drugs . Therefore, since 2000, national and international guidelines have included recommendations for limiting the metabolic side-effects of HAART . One could expect to observe changing patterns of case management and thus a reduction in the cardiovascular risk in HIV-infected patients. In the present study, we report on the atherosclerosis risk measured through the IMT 36-month changes in relation to the evolution of care practices in a French cohort of HIV-infected patients.
Patients included in the present report were those from the SUPRA Study described elsewhere , with information available at three scheduled visits: month 0 (baseline), month 12 (12 months after) and month 36. Briefly, patients of the Aquitaine Cohort were included successively if they were seen in one of the five participating centres in Bordeaux (France) from September 1999 to April 2000. If the patient agreed to participate in this study, IMT evaluation was performed at the three planned clinic visits. In addition to information routinely collected within the Aquitaine Cohort, more precise data about the cardiovascular risk factors were systematically recorded.
Carotid IMT was measured by B-mode ultrasonography, on the common part of the left and right carotid arteries. IMT calculation was performed semi-automatically by an IMT analysis software (version 5.0) in a ‘Workstation Imaging station’ (IôDP, Paris, France).
A total of 233 patients were included in the study with a median age of 44 years at baseline [interquartile range (IQR) 39; 50], 57 (25%) were women, 138 (59%) were current smokers and 74 (32%) were at the AIDS stage. At month 0, 200 patients (86%) were treated by a combination of at least three antiretroviral drugs, including 127 with a PI-containing regimen; five patients were treated by fibrates, none by statins. During the first 12 months, eight new patients were treated by statins and eight by fibrates, 42 had their antiretroviral regimen changed to stop the PI and 10 patients stopped smoking. A total of 63 patients thus benefited from at least one of these three preventive measures for cardiovascular risk. During the same period, serum triglycerides, LDL and total cholesterol remained stable: P = 0.24, 0.75 and 0.78, respectively (Table 1). Conversely, the median IMT increased from 0.55 to 0.57 mm (P < 0.0001). In the following 24-month period, 52 more patients switched from a PI-containing to a PI-free regimen, 30 new patients were treated with lipid-lowering drugs and 14 stopped smoking, resulting in a 36-month prevalence of 40 patients (17%) treated with fibrates or statins, 141 (60%) with a PI-free antiretroviral regimen and 114 (49%) who did not smoke. During the same 2-year period, there was a significant decrease in total cholesterol (P < 10−4), LDL-cholesterol (P = 0.05) and median IMT from 0.57 to 0.53 mm (P < 10−4). The proportion of patients performing physical activity at least once per week was stable, approximately 30%, throughout follow-up. However, among them, the proportion of those who practised more than once per week tended to increase: 64% at month 0, 69% at month 12 and 72% at month 36. The median BMI at baseline (22.6, IQR 20.6; 24.6) remained stable during follow-up (P = 0.09 and P = 0.14). When analysing the association at the individual level between these interventions aimed at reducing the cardiovascular risk and IMT evolution, the only significant association was with smoking cessation (P = 0.06). Using a linear mixed model for repeated measures taking into account all three interventions, we estimated a decreasing IMT slope between month 12 and month 36 of −0.045 [95% confidence interval (CI) −0.056; −0.033] in those without intervention compared with −0.086 (95% CI −0.13; −0.043) in those who stopped smoking (P = 0.06). However, the significance of this association tended to decrease when adjusting for age, sex, BMI and total cholesterol (P = 0.11). During follow-up, cardiovascular events were documented in two patients: both men, 39 and 51 years old, treated by HAART with PI, both presenting with lipid disorders; one of them smoked 15 pack-years. IMT values were 0.55 and 0.57 mm at the time of coronary angioplasty, which was performed in the context of angina pectoris.
One limitation of this study was the representativeness of the study sample compared with the population of HIV-infected patients in France and other industrialized countries. One might expect that patients’ behaviour and clinical management were better in this group compared with the rest of the Aquitaine cohort, because of early information on the study objectives at the time of enrolment and full access of the attending physician to baseline IMT results and cardiovascular risk assessment. Study participants may thus represent patients to whom special attention was paid for their cardiovascular risk. Also, IMT is a surrogate marker of long-term atherosclerosis and not of acute coronary events. Other factors such as oxidative stress, the inflammatory process and cytokine production are involved in plaque rupture occurring in unstable plaques leading to clinical events. Finally, our results come from a small sample with no randomization of preventative measures. The potential impact of interventions aimed at cardiovascular risk prevention thus need to be confirmed in larger study populations and with clinical outcomes (myocardial infarction, stroke) as in the D:A:D collaboration . Nevertheless, should our results be confirmed, the potential impact of smoking cessation in particular should encourage its active promotion by clinicians providing HIV care.
Sponsorship: This study was partly supported by the French charity ECS ‘Ensemble Contre le Sida’ (9e appel d’offres). ACUSON Inc., Bristol-Myers Squibb, Roche and Glaxo-Welcome (Paris, France) provided additional financial support to the project. The Aquitaine Cohort within which the study was conducted is supported by the French National AIDS Research Agency (ANRS) through the Coordinated Action no. 7 ‘Cohorts’.
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