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Risk Factors for Myocardial Infarction in HIV-Positive Patients

Posted on: Friday, 11 February 2005, 03:00 CST

Summary: We describe the clinical characteristics of 12 HIV- infected patients who suffered from myocardial infarction (MI) in our clinical cohort. They were compared with a control group matched (1:2) for factors related to cardiovascular risk (age, gender, smoking habit, risk factor for HIV acquisition, hypertension, family history for relevant cardiovascular events, and body mass index) by conditional (fixed-effect) logistic regression analysis. Among patients with MI, 6/12 had never used protease inhibitors (PIs) or were antiretroviral therapy nave. The only variables marginally associated with MI were nadir CD4+ T-cell count <50/mm^sup 3^ (odds ratio (OR): 7.2; 95% confidence interval (CI) 0.81-64.2; P: 0.077) and zenith >100,000 HIV RNA copies/mL (OR: 7; 95% CI 0.81-60.2; P: 0.076) at univariate analysis. Moreover, the use of PIs did not result in being associated with the risk of MI. Ourdata show that in HIV-infected patients, PI use does not seem to have any negative impact on MI while the possible impact of advanced HIV infection itself needs further investigations.

Keywords: infarction, HIV, antiretroviral therapy, protease inhibitor, risk factors

Introduction

Highly active antiretroviral therapy (HAART) including protease inhibitors (Pis) has determined a dramatic decrease of opportunistic infections and has prolonged the survival of HIV-infected patients in industrialized countries. However, several adverse effects of HAART are being observed in clinical practice such as hyperlipidaemia, glucose intolerance or diabetes mellitus, lipodystrophy, etc.1,2 While some side-effects are trivial and short- lived, others may be life threatening. Importantly, metabolic abnormalities that occur after HAART resemble the X-syndrome, which is correlated with cardiovascular risk in HIV-negative subjects.3

Although several case reports have linked cardiovascular diseases with PI utilization,4 evidence from autopsy studies performed before the PI era had already demonstrated the presence of atherosclerotic lesions, even in paediatric AIDS patients and in the absence of traditional risk factors.5,6 In particular, it is not yet conclusively documented whether HIV by itself, the use of PIs, or concomitant risk factors is the main factor responsible for increased cardiovascular risk in HIV-infected patients.

The objective of this retrospective study is to assess factors associated with the risk of myocardial infarction (MI) in our cohort. With this objective in mind, a case-controlled study was conducted, comparing clinical and epidemiological characteristics of these patients with a control group closely matched for factors that can independently affect cardiovascular risk, in order to explore whether HIV-related factors may also have an impact.

Materials and methods

Patients and characteristics

Data from HIV-infected patients followed at the Institute of Infectious and Tropical Diseases of the University of Brescia (Italy) were recorded on a central electronic database.7 Overall, 3482 HIV-infected patients were registered from the beginning of the HIV epidemic. These patients were asked to return for laboratory and clinical controls at least every 3-4 months. At each visit, any event that occurred in the patient's clinical history since the last visit was recorded.

After reviewing the database, 12 HIV-infected patients with proven MI were identified.8 For all of them, several variables were collected at the time of MI as follows: gender, age, risk factor for HIV acquisition, family history for relevant cardiovascular events, a documented history of hypertension (diastolic blood pressure ≥90mmHg), current or previous smoking habit, body mass index (BMI), total cholesterolaemia, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterolaemia (when available), triglyceridaemia, diabetes mellitus, current and previous exposure to antiretrovirals (drugs and length of exposure), CD4+ T-cell count and its ever lowest value (nadir), HIV plasma viral load (pVL; assayed by the branched DNA method, Quantiplex 3.0 Chiron) and its ever highest value (zenith), Framingham score and hepatitis C virus antibody (HCV Ab) test. Viro-immunological efficacy of HAART and antiretroviral drug prescription were also assessed from MI.

Table 1 Characteristics of 12 patients with MI

Case-controlled study

To explore predictive factors that may have had an impact on the risk of MI, a case-controlled study was conducted. Patients with MI were identified and exactly matched at a 1:2 ratio with controls randomly selected from our cohort for the following variables: age, gender, smoking habit, risk factor for HIV acquisition, history of hypertension, family history for relevant cardiovascular events, BMI, and history of confirmed hyperlipidaemia (i.e. values above the range of normality applied by our laboratory: total cholesterolaemia >250mg/dL or triglyceridaemia >200mg/dL). A complete followup was collected for control patients from the first contact to our centre up to the most recent observation. Univariate conditional (fixed- effect) logistic regression analysis was performed. Multivariable analysis was not performed due to small patient number. However, the calculated statistical power was >80%.9 Statistical analysis was performed using STATA software, version 7.0 (Stata Corporation, College Station, TX, USA). P < 0.05 was considered to indicate statistically conventional significance.

Results

Case descriptions of patients with MI

In our database, 12 patients who suffered from MI were identified (Table 1). Three of them (25%) were females and their mean age ( standard deviation [SD]) at the diagnosis of MI was 42 8 years. Four had acquired HIV infection through the sexual route. Of note, 6/ 12 (50%) had never used PIs in the treatment history, three of them being completely nave for antiretrovirals at the time of MI. Among patients with MI, two died from immediate MI complications. In one patient, severe abdominal aorta occlusion and incomplete occlusion of brachial arteries due to atherosclerotic plaques were diagnosed several months after MI, but symptoms (leg tenderness and pain) were referred 18 months before. The remaining patients were followed up for a median of 47 months (range: 9-108) from MI and no cardiovascular events were recorded despite the application of PI containing HAART in all but one for a median of 20 months (range: 0- 70).

Case-controlled study

Matching between cases and controls was conducted as previously described, considering the following variables: age, gender, smoking habit, risk factor for HIV acquisition, history of hypertension, family history for relevant cardiovascular events and BMI (Table 2). The other variables recorded were not significantly different between cases and controls. However, the following variables appeared to be clustered between cases and controls, although not at a conventional statistically significant value: nadir of CD4 + T- cell count <50/mm^sup 3^ (41.7% in cases versus 12.5% in controls; odds ratio (OR): 7.2; 95% confidence interval (CI) 0.81-64.2; P: 0.077) and zenith pVL >100,000 copies/mL (81.8% in cases versus 50% in controls; OR: 7; 95% CI 0.81-60.2; P: 0.076). At multivariate analysis, none of the variables that were analysed resulted in being associated with the risk of MI.

Discussion

The occurrence of MI in HIV-positive patients is of major concern as morbidity and mortality due to this disease can compromise benefits deriving from HAART; however, it is still unclear whether PI use by itself could favour the occurrence of MI in HIV-positive persons. There is a well-described association between Pi-based HAART and hypertension, hyperlipidaemia, and/or glucose intolerance; and reports of premature MI have been described in young HIV- infected persons with dismetabolic syndrome receiving potent antiretroviral therapy.4,10

Table 2 Distribution of variables among cases and controls

However, observational studies from various cohorts have yielded conflicting results. Data from the HOP study have demonstrated that the use of PIs is moderately associated with increased incidence of MI." Similarly, a large observational cohort (the DAD study12) has found that PI use is associated with a 27% relative increase in the rate of MI per year of exposure over the first 7 years of its use in a population in which primary or secondary preventive intervention to reduce associated risks for these events was not systematically applied. It should also be considered that >35,000 person-years of follow-up had been necessary to demonstrate an increase in the rate of MI during HAART in such a population, suggesting that absolute risk deriving from HAART is low and perhaps preventable by primary or secondary intervention to reduce associated risk factors (such as smoking habits, sedentariness, hyperlipidaemia, etc.). Moreover, data from the Kaiser Permanent study13 failed to show any increased incidence of coronary events in patients receiving PIs, evidence that was recently confirmed by the Veteran Affair study.14

Most of these studies are limited as very few adverse ischaemic events are recorded, patients are exposed to PIs for a limited amount of time, and data regarding medication adherence and traditional cardiovascular risk factors and individual durati\on of HIV infection are almost neglected. Another limitation of current literature data is intrinsically linked to the design of the cohort studies in which HIV-negative control was lacking. Therefore, even large cohorts like DAD or HOP were unable to assess the influence of HIV infection itself on the occurrence of cardiovascular diseases simply because the length of PI exposure, duration of HIV infection, and amount of exposure to concomitant risk factors (age, smoking, hyperlipidaemia, coinfections, occurrence of menopause, etc.) are all time dependent and, then, co-linearity of variables cannot be excluded a priori in these studies.

In the present study, we have tried to minimize most of the above- mentioned limitations through a close matching for known cardiovascular risk factors between cases and controls. With this objective in mind, we were able to explore whether factors related to HIV infection itself could be implicated in the occurrence of MI.

One interesting finding from our study is that 50% of patients who suffered from MI were nave for PIs, three of them being nave for any antiretroviral drug. Moreover, most of those patients who recovered from MI continued on PI containing HAART and none of them had recurrent ischaemic cardiovascular events over a mean of two- year follow-up. Also, our case-control study did not prove the definitive impact of PIs on the risk of MI. Rather, it demonstrates the complexity of this matter because correlation with surrogate markers of advanced HIV infection such as nadir CD4+ T-cell count and zenith in the pVL has been found. Similar findings related to nadir CD4+ T-cell count have been reported by David et al.15 for the risk of ischaemic cardiovascular diseases and by Hsue et al.16 as far as differences in carotid artery intima-media thickness have been studied.

Interpretations of these results are far from straightforward, and several explanations can be posed. Firstly, it could be that HIV itself exerts a role in the pathogenesis of MI.5,6 In this regard, studies that consider the actual duration of HIV infection as covariate are clearly advisable. A second explanation could be that the degree of immunosuppression related to HIV infection may promote a pathogenetic role of concomitant infectious agents characterized by endothelial tropism such as cytomegalovirus.16 In this regard, it can be hypothesized that HAART could even be beneficial if immunosuppression is controlled, which may control opportunistic infections with tropism for the endothelium. Finally, the correlation found with markers indicative of HIV progression could reflect an increased exposure to non-infectious risk factors for cardiovascular events (such as age, smoking habits, hyperlipidaemia, etc.) due to co-linearity of variables and, therefore, this correlation could be interpreted simply as an epiphenomenon. The existence of concomitant risk factors that may predict cardiovascular complications independently of PI exposure has been demonstrated by the DAD study, in which also age, male gender, smoking habit (ever), hyperlipidaemia, and hypertension had an impact. These results underline the importance of interventions aimed at reducing associated risk factors for cardiovascular events in the population of HIVinfected patients, regardless of the possible direct impact of PIs on the risk of MI. Finally, conventional cardiovascular risk equations using data from the DAD study have suggested that the increase in the relative risk of MI as a result of antiretroviral therapy (ARV) may be as high as three- fold in a worst-case scenario.17 However, the absolute risk is modest with a best estimate of three-year risk less than or equal to 1% in all groups of patients (untreated, on ARV and ARV ceased), and the absolute risk is outweighed by the benefits of ARV reducing AIDS events and death in most patients.18

Long-term follow-up and more systematic data analyses, are necessary for a reliable estimate of the cardiovascular risk associated with HIV infection by itself and/or with the effect of antiretroviral treatment. This should be performed in the context of prospective and controlled cohort trials with a known and properly assessed duration of HIV infection and with a control group of HIV- negative patients.

References

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2 Mallon PW, Carr A, Cooper DA. HIV-associated lipodystrophy: description, pathogenesis and molecular pathways. Curr Diabetic Rep 2002;2:116-24

3 Reaven G, Segal K, Hanptman J, et ni. Effect of orlistat assisted weight loss in decreasing coronary heart disease risk in patients with syndrome X. Am J Cardiol 2001;87:827-31

4 Passalaris JD, Sepkowitz KA, Glesby MJ. Coronary artery and human immunodeficiency virus infection. Clin Infect Dis 2000;31:787- 97

5 Paton P, Tabib A, Loire R, et al. Coronary artery lesions and human immunodeficiency virus infection. Res Viral 1993;144:225-31

6 Joshi VV, Pawel B, Connor E, et al. Arteriopathy in children with acquired immune deficiency syndrome. Pedintr Pnthol 1987;7:261- 75

7 Carosi G, Castelli F, Suter F, et al. Antiviral potency of HAART regimens and clinical success are not study coupled in real life conditions: evidence from the MASTER-1 study. HIV Clin Trials 2001;25:399-407

8 WHO MONICA Project. MONICA Manual, Part IV: Event Registration Available at: [www.ktl.fi/publications/ monica/manual/index.htm] (accessed 22 September 2002)

9 Dupont WD. Power calculations for matched case-control studies. Biometrics 1988;44:1157-68

10 Henry K, Melroe H, Huebsch J, et al. Severe premature coronary artery disease with protease inhibitors. Lancet 1998;351:1328

11 Holmberg SD, Moorman AC, Williamson JM, et al. Protease inhibitors and cardiovascular outcomes in patients with HIV-I. Lancet 2002;360:1747-8

12 Friis-Moller N, Weber R, D'Arminio Monforte A, et al. Exposure to HAART is associated with an increased risk of myocardial infarction. 10th Conference on Retroviruses and Opportunistic Infections, 10-14 February 2003, Boston. (Abstract number 130 [ses 26])

13 Klein D, Hurley L. Hospitalizations for coronary heart disease and myocardial infarction among HIV+ patients in the HAART era. Ninth Conference on Retroviruses and Opportunistic Infections, 24- 28 February 2002, Seattle, WA. (Abstract number 696-T [ses 91])

14 Bozzette SA, Ake CF, Tarn HK, et al. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med 2003;348:702-10

15 David MH, Hornung R, Fichtenbaum CJ. Ischemic cardiovascular disease in persons with human immunodeficiency virus infection. Clin Inf Dis 2002;34:98-102

16 Hsue P, Lo J, Franklin A, Bolger AF, Decks S, Walters D. Increased atherosclerotic progression in patients with HIV: the role of traditional and immunologie risk factors. Wth Conference on Retroviruses and Opportunistic Infections, 10-14 February, 2003, Boston. (Abstract number 139Ib [ses 26])

17 Smiela M, Gnarpe J, Lonn E, et al. Multiple infections and subsequent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation 2003;107:251-7

18 Law M, Friis-Moller N, Weber R, et al. Modelling the 3-years risk of myocardial infaction among participants in the Data Collection on Adverse Events of Anti-HIV Drug (DAD) Study. HIV Med 2003;4:1-10

(Accepted 8 September 2003)

E Quiros-Roldan MD PhD, C Torti MD, C Tinelli MD, F Moretti MD, B Zanini MD, V Tirelli MD, A Pan MD, S Casari MD and G Carosi

Department of Infectious and Tropical Diseases, Pzle Spedali Civili 1, Brescia 25123; Biostatistics Unit, IRCCS Policlinico S Matteo, Pavia, Italy

Correspondence to: Dr Eugenia Quiros-Roldan

Email: kaeniaquiros@hotmail.com

Copyright Royal Society of Medicine Press Ltd. Jan 2005

Source: International Journal of STD & AIDS

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