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Risk Factors for Coronary Heart Disease in Patients Treated for Human Immunodeficiency Virus Infection Compared with the General Population
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- "Our results suggest a limited increase in the risk of CHD in HIV-1infected patients, compared with the general population"
Clinical Infectious Diseases 2003;37:292-298
Marianne Saves 1, Genevieve Chene 1, Pierre Ducimetiere,2 Catherine Leport,3 Gwena‘l Le Moal,4 Philippe Amouyel,5 Dominique Arveiler,6 Jean-Bernard Ruidavets,7 Jacques Reynes,8 Annie Bingham,2 and FranŤois Raffi,9 for the French WHO MONICA Project and the APROCO (ANRS EP11) Study Group
1INSERM U593 (ex U330), Universite Victor Segalen Bordeaux 2, Bordeaux, 2INSERM U258, Villejuif, 3Laboratoire de Recherche en Pathologie Infectieuse, Faculte X, Bichat, Paris, 4Service de Maladies Infectieuses, CHU Jean Bernard La Miletrie, Poitiers, 5INSERM U508, Institut Pasteur, Lille, 6Laboratoire d'Epidemiologie et de Sante Publique, Faculte de Medecine, Strasbourg, 7INSERM U558, Departement d'Epidemiologie, Universite Paul SabatierToulouse Purpan, Toulouse, 8Service de Maladies Infectieuses, Hopital Gui de Chauliac, Montpellier, and 9Service de Maladies Infectieuses, Hotel-Dieu, Nantes, France
"..results from long-term observational studies on the risk of CHD in treated HIV-1infected patients have not yet been published, the estimation of a predicted risk of CHD and the relative contribution of risk factors could prove useful for the clinical management of these patients..Compared with persons in the general population of the same age, HIV-1infected patients who receive PIs have a particular atherogenic profile: they are thin; they have elevated triglyceride levels and low HDL cholesterol levels, without an increase in the LDL cholesterol level; and they are frequently smokers. This profile yielded a moderately, albeit significantly, higher predicted risk of CHD for HIV-1infected, PI-treated patients, compared with the general population, and smoking strongly contributed to this higher risk... At the initiation of PI-based therapy, 35% of the patients had already been exposed to other antiretrovirals... When the metabolic complications substudy started, the median CD4+ cell count was 451 cells/mm3 (range, 131451 cells/mm3), and the median HIV-1 RNA level was 2.3 log10 copies/mL..... The relative contribution of antiretroviral therapy, chronic inflammation due to the ongoing viral infection, and their interaction is very difficult to identify...risk assessment for cardiovascular disease should be a part of routine HIV care. This should include not only laboratory abnormalities but also assessment of smoking habits, exercise activity, and family history of cardiovascular disease. Interventions to address modifiable risk factors should be implemented and evaluated"
SUMMARY
The distribution of risk factors for cardiovascular disease in patients aged 35-44 years who were treated for human immunodeficiency virus type 1 (HIV-1) infection was compared with that for a population-based cohort. HIV-1infected men treated with a protease inhibitor containing regimen (n = 223), compared with HIV-1uninfected men (n = 527), were characterized by a lower prevalence of hypertension, a lower mean high-density lipoprotein cholesterol level, a higher prevalence of smoking, a higher mean waist-to-hip ratio, and a higher mean triglyceride level (patients often had prior ART experience). No difference was found for total plasma or low-density cholesterol levels, nor for the prevalence of diabetes. Similar trends were observed among female subjects. The predicted risk of coronary heart disease was greater among HIV-1infected men, 20% greater compared to HIV negayives, (relative risk [RR], 1.20) and women, 59% greater compared to HIV negative, (RR, 1.59; P < 10-6 for both), compared with the HIV-1uninfected cohort. HOWEVER, the estimated attributable risks due to smoking were 65% and 29% for HIV-1infected men and women, respectively. Because most HIV-1infected people will ultimately need antiretroviral therapy, risk factors for cardiovascular disease should be determined at the initiation of treatment, and interventions should be considered for all patients who have them.
BACKGROUND
With the widespread use of protease inhibitors (PIs), preliminary data have suggested that an increased incidence of coronary heart disease (CHD) occurs among HIV-1infected patients. Indeed, abnormalities that may contribute to an increased risk of CHD, such as hyperlipidemia, insulin resistance, and fat redistribution, are frequently found after the initiation of a HAART regimen. However, these risk factors for CHD may be attributed to receipt of antiretroviral therapy, to HIV-1 infection, or to both. To date, few comparisons of patients treated for HIV-1 infection with people of the same age from the general population have been conducted. Moreover, while results from long-term observational studies on the risk of CHD in treated HIV-1infected patients have not yet been published, the estimation of a predicted risk of CHD and the relative contribution of risk factors could prove useful for the clinical management of these patients. Therefore, we used data from a cohort of HIV-1infected patients who initiated a PI-containing regimen and data from the French World Health Organization study monitoring trends and determinants of cardiovascular disease (WHO-MONICA) Project to compare the distribution of risk factors for CHD and to calculate a predicted risk for CHD.
METHODS
From May 1997 through June 1998, the Antiproteases Cohorte (APROCO; ANRS Study EP11) enrolled patients to study the progression of HIV-1 infection after the initiation of a PI-containing antiretroviral regimen (baseline). Overall, 1172 HIV-1infected adults were enrolled at 47 French AIDS centers and were observed every 4 months. From December 1998 through July 1999, we performed a nested cross-sectional study that aimed to describe clinical and laboratory metabolic complications (MC), including risk factors for CHD; this specific study will be referred as "the APROCO metabolic complications (APROCO-MC) substudy." During this period, patients underwent a follow-up visit at 12 or 20 months after the initiation of the PI-based regimen.
The sample of comparison consisted of subjects included in the WHO-MONICA Project in France and has been described elsewhere. In brief, during the period of 19951997, a cross-sectional, age- and sex-stratified random sample of subjects aged 3564 years was selected from the French general population. For the present study, we restricted the analysis to the subjects aged 3544 years, the stratum most represented in the APROCO-MC sample (45% of subjects).
Subjects who had smoked during the 12 months before inclusion in the APROCO-MC sample and current smokers in the MONICA sample were classified as smokers. Systolic and diastolic blood pressures were determined using a sphygmomanometer, with the subject in the sitting position after 5 min at rest. Blood glucose, serum triglyceride, and total and high-density lipoprotein (HDL) cholesterol levels were measured after a 12-h overnight fast. Low-density lipoprotein (LDL) cholesterol levels were calculated using the Friedwald equation.
The 5-year relative risk (RR) of CHD in the APROCO versus MONICA populations was assessed using the risk of occurrence of CHD as a function of risk factors estimated from 2 different observational studies involving general populations. For the sake of robustness, the first estimation was derived from the French cohort of the PRIME Study, which was composed of 7500 men aged 5059 years who had been recruited in 19911993 and observed for 5 years. In this cohort, the individual risk was estimated by a logistic function of a linear combination R of smoking, systolic blood pressure, and total and HDL cholesterol levels (The PRIME Study Group, unpublished data). For this estimate, the RR for the 2 populations (the APROCO cohort vs. the MONICA cohort) was approximated by the exponential of the difference between the mean value of R in the 2 populations. The attributable risk due to only smoking differences was estimated as the ratio (RRS-1)/(RR-1), with RRS being the RR for CHD, keeping only smoking as a risk factor in R. The second estimation was computed using the Framingham data. The mean value of the linear combination R for specific risk factors (smoking, systolic blood pressure, ratio of total cholesterol to HDL cholesterol level, and blood glucose level of >1.40 g/L) was calculated for a hypothetical 40-year-old subject observed for 5 years. Because there was no information on left ventricular hypertrophy for either population, this characteristic was not taken into account. The absolute 5-year risk for this hypothetical subject in each population was computed as 1-exp(-exp R) (Weibull model), and their ratio provided an estimate of the RR for the 2 populations (the APROCO cohort vs. the MONICA cohort).
The distribution of risk factors for CHD was compared between both cohorts using analysis of variance for continuous variables and logistic regression for dichotomous variables. All analyses were adjusted for body mass index (BMI). Data were analyzed using SAS software, version 6.12 (SAS Institute).
RESULTS
The APROCO-MC substudy comprised 614 patients. Two hundred seventy-four of the patients were 3544 years old; of these, 223 (81%) were men. At the initiation of PI-based therapy, 35% of the patients had already been exposed to other antiretrovirals. When the metabolic complications substudy started, the median CD4+ cell count was 451 cells/mm3 (range, 131451 cells/mm3), and the median HIV-1 RNA level was 2.3 log10 copies/mL (range, 1.3-5.7 log10 copies/mL). Overall, the median total duration of antiretroviral therapy was 26 months (range, 10-127 months), including use of PI-based regimens (mean duration, 13 months; range, 122 months). At baseline, 20% of patients started receiving saquinavir, 27% started receiving ritonavir, 49% started receiving indinavir, and 46% started receiving nelfinavir. At the visit for the metabolic complications substudy, 19% of patients had received saquinavir, 27% had received ritonavir, 49% had received indinavir, and 46% had received nelfinavir. With regard to nucleoside analogues, 34% of the patients had received zidovudine, 38% had received didanosine, 68% had received lamivudine, and 76% had received stavudine.
Among the 1038 subjects of the same age as those in the MONICA sample, 527 (51%) were men. The median BMI was lower in HIV-1infected men than it was in men in the MONICA sample (P < 10-6). However, among HIV-1infected men, the prevalence of smoking, the mean waist-to-hip ratio, and the mean triglyceride level were significantly higher, whereas the mean HDL cholesterol level was lower, even after further adjustment for smoking status (data not shown). The prevalence of arterial hypertension remained lower among HIV-1infected men. The mean total cholesterol level, the mean LDL cholesterol level, and the prevalence of diabetes among men did not differ between the 2 samples. In HIV-1infected women, the same trends were observed. However, the mean plasma total cholesterol level for HIV-1infected women was higher than that observed in the MONICA sample.
With use of the PRIME model, the 5-year RR for CHD (for HIV-1infected vs. HIV-1uninfected persons) was found to be 1.20 for men and 1.59 for women (P < 10-6 for both). The estimated attributable risk due to smoking was 65% for men and 29% for women. With use of the Anderson equation, the RR was found to be 1.39 for men and 2.17 for women (P < 10-6 for both).
The same analyses were performed for men aged 4554 years (86 subjects in the APROCO-MC cohort and 611 subjects in the MONICA sample). Results showed similar trends, with a higher risk of CHD of 22% (PRIME model) for the HIV-1infected population.
DISCUSSION
Compared with persons in the general population of the same age, HIV-1infected patients who receive PIs have a particular atherogenic profile: they are thin; they have elevated triglyceride levels and low HDL cholesterol levels, without an increase in the LDL cholesterol level; and they are frequently smokers. This profile yielded a moderately, albeit significantly, higher predicted risk of CHD for HIV-1infected, PI-treated patients, compared with the general population, and smoking strongly contributed to this higher risk.
In most cases of cardiovascular complications reported in patients receiving a PI-containing regimen, at least 1 known risk factor could be identified. Smoking is a common behavior among HIV-1infected subjects. Increases in plasma total cholesterol levels are probably related to PI use. In fact, before they began receiving PIs, HIV-1infected patients had decreased plasma total cholesterol levels. While receiving PI therapy, an increase in the total and LDL cholesterol levels is also common, whereas HDL levels are heterogeneous. Nevertheless, HDL cholesterol levels remain significantly lower in HIV-1infected patients receiving PI therapy than in HIV-1uninfected control subjects. Hypertriglyceridemia is a common abnormality seen in HIV-1infected patients; although it was observed long before the era of PI therapy , it has been observed more frequently among patients receiving PI therapy . Our BMI and waist-to-hip ratio data are similar to those from other studies of patients receiving PI therapy . The higher waist-to-hip ratios seen among HIV-1infected patients was mainly associated with their lower hip circumferences. Finally, as was shown in a study by Klein et al., the prevalence of arterial hypertension was lower in our HIV-1infected population, compared with the general population, and the prevalence of diabetes was not elevated. However, most of the glucose abnormalities were detected in these patients with use of an oral glucose tolerance test, which was not available in the MONICA study.
We calculated an estimated risk function instead of an observed incidence, which would require a longer follow-up period. Until the results of ongoing prospective studies on the incidence of CHD are available, this approach is still interesting. Whether this atypical atherogenic profile had a different impact on the observed risk of CHD among HIV-1infected patients, compared with the general population, remains unknown.
In our study, the duration of PI treatment for HIV-1infected patients was short. We can anticipate a higher risk after a longer duration of treatment, as has been noted in the French hospital database and the multicenter D:A:D study . Although Bozzette et al. did not report an increase in the risk of cardiovascular disease among HIV-1infected patients over time, they acknowledged that a longer observation period was required to observe the development of cardiovascular disease.
Our results suggest a limited increase in the risk of CHD in HIV-1infected patients, compared with the general population, as was reported by Klein et al. The cross-sectional design of our study should discourage persons from making conclusions about the potential impact of PI use on the risk of CHD, in the absence of an assessment made at the initiation of PI therapy and without comparison with a reference group of HIV-1infected patients who have not been exposed to PIs. The relative contribution of antiretroviral therapy, chronic inflammation due to the ongoing viral infection, and their interaction is very difficult to identify. Nevertheless, our results suggest that smoking makes a major contribution to the risk of CHD in HIV-1infected patients, particularly men, independent of other risk factors that are or are not linked to use of Pis.
In conclusion, risk assessment for cardiovascular disease should be a part of routine HIV care. This should include not only laboratory abnormalities but also assessment of smoking habits, exercise activity, and family history of cardiovascular disease. Interventions to address modifiable risk factors should be implemented and evaluated.
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