ΛΟΙΜΩΞΗ HIV. Ιγνάτιος Οικονομίδης,MD,FESC Β Πανεπιστημιακή Καρδιολογική

ΛΟΙΜΩΞΗ HIV Ιγνάτιος Οικονομίδης,MD,FESC Β Πανεπιστημιακή Καρδιολογική Κλινική, Νοσοκομείο «Αττικόν»

Infection

Acute Myocardial Infarction p er 100,000 HIV/AIDS discharg es 800 700 600 500 400 300 200 100 0 1994 1995 1996 1997 1998 1999 2000 2001 2002 Source: SPARCS database, NYSDOH

MI and HIV duration Mary-Krause et al, AIDS, 2003

HIV AND CARDIOVASCULAR RISK FACTORS Lipid abnormalities Lipodystrophy Insulin resistance Inflammation Changes in renal function

CAUSES OF METABOLIC ABNORMALITIES Effects of a chronic inflammatory conditions Medication effects Changes in body composition

EFFECTS OF HAART

Lipid abnormalities HDL LDL VLDL OxLDL Small, dense LDL

Lipodystrophy Loss of subcutaneous fat Relative preservation of visceral fat Preservation of dorsocervical fat (buffalo hump) Fat in the breasts

Brown TT et al. Arch Intern Med 2005;165:1179-84

Insulin resistance Drug-induced Increased visceral fat-inflammation Inhibition of mitochondrial function in muscle

HAART EFFECTS Hypertriglyceridemia (40-80%) Hypercholesterolemia (10-50%) Mixed forms (10-40%) Hyperinsulinemia-Insulin resistance (30-40%) Diabetes-Positive OGTT (10-15%) 15%)

EPIDEMIOLOGICAL EVIDENCE FOR CARDIOVASCULAR DISEASE Retrospective cohort studies Clinical databases Prospective HIV cohort studies Randomized clinical trials

Surrogate markers of atherosclerosis 8,00 F=11.7, p<0.01 7,07 0,75 F=4.2, p=0.01 0,64 0,66 6,00 FMD (%) 5,43 IMT (mm) 0,55 0,50 4,00 2,00 2,76 0,25 0,00 HIV CAD NORMAL HIV CAD NORMAL HAART related with increased IMT Lekakis J Ikonomidis I et al, Clin Science,2008

Lekakis J Ikonomidis I et al, Clin Science,2008

Reactive hyperemia Lekakis J Ikonomidis I, Microcirculation 2010

Carotid atherosclerosis: HIV+HAART Study population Features studied Endpoints Lekakis et al. (Clin Sci. 2008) 71 HIV 29 CAD 25 healthy IMT Metabolic parameters Increased IMT was closely related to protease inhibitor related changes of metabolic parameters in HIV infected patients Hsue et al. (AIDS. 2009) 368 HIV 93 healthy 33 HIV controls IMT Infection and immune parameters Chronic inflammation as reflected by elevated CRP levels in all HIV infected patients, may account for early atherosclerosis PERI study (Coron Artery Dis. 2008) 83 HIV 83 healthy IMT Cardiovascular risk factors HIV infection was associated with increased IMT and elevated prevalence of cardiovascular risk factors Lorenz et al. (Atherosclerosis. 2008) 292 HIV 1168 healthy IMT Infection and therapy parameters HIV infection and HAART are independent risk factors for early carotid atherosclerosis. Vascular risk is 4 14% greater and the "vascular age" 4 5 years higher in HIV positive subjects compared to healthy controls Jerico et al. (Stroke. 2006) 68 HIV 68 HIV with CVD risk factors HAART HAART should be considered a strong, independent predictor for the development of subclinical atherosclerosis in HIV infected patients

Endothelial dysfunction: HIV+HAART Charakida et al. (Circulation. 2005) Lekakis et al. (Clin Sci. 2008) Solages et al. (Clin. Infect. Dis. 2006) Flammer et al. (Heart. 2009) Study population 83 HIV children 59 healthy children 71 HIV 29 CAD 25 healthy 75 HIV 223 healthy Features studied FMD HAART Infection parameters FMD Metabolic and disease parameters FMD Metabolic and disease parameters 39 HIV HAART regimens Endpoints HIV infection in childhood is associated with adverse structural and functional vascular changes that are most pronounced in children exposed to PI therapy HAART induced lipid disorders may lead to endothelial dysfunction in HIV patients HAART induced lipid disorders may lead to endothelial dysfunction in HIV patients HAART regimens affect vascular function through a combination of atherogenic lipid profiles and direct detrimental effects on endothelium

HIV and vascular function 10 8 6 4 2 0 HIV (+) without HAART HIV (+) withhaart Hypertensive PWV (m/sec) Lekakis J Ikonomidis I et al Am J Hypertens 2009

Patients naïve to HAART Vlachopoulos et al Artery Res 2009

Vlachopoulos et al Artery Res 2009

N=2789 Seaberg et al Stroke. 2010;41:2163-2170.

Seaberg et al Stroke. 2010;41:2163-2170

Arterial stiffness: HIV INFECTION+HAART Lekakis et al. (Am J Hypertens. 2009) Schillaci et al. (Arterioscer Thromb Vasc Biol. 2005) Van Vonderen et al. (J AIDS. 2009) Schillaci et al. (Hypertension. 2001) Vlachopoulos et al (Artery Res 2009) Study population 56 HIV 28 hypertensives 28 healthy 32HIV 32 healthy 77 HIV 52 healthy 39 HIV 78 healthy 51 adults 35 healthy Features studied PWV Metabolic parameters PWV Infection parameters Arterial stiffness Arterial stiffness Infection PWV,wave reflection HAARTnaïve` Endpoints HIV patients on HAART had similar PWV with hypertensives. Patients on HAART had higher PWV than patients without. HIV infection and age predict higher PWV values HIV infection was associated with increased arterial stiffness HIV infection is an independent risk factor for worse arterial stiffness In the early stages of HIVinfection,decreased wave reflections and similar aortic stiffness, in HAARTnaive patients than controls. Sevastianova et al. (Antivir Ther. 2005) 59 HIV Arterial stiffness HAART The use of PI s predicts abnormal arterial stiffness

MI EXPOSURE TO HAART N=23.437 DAD Study Group. N Engl J Med 2007;356:1723-35

DAD Study Group. N Engl J Med 2007;356:1723-35

DAD Study Group. Lancet 2008; 371: 1417 26

Lower arterial stiffness and Framingham score after switching abacavir to tenofovir in men at high cardiovascular risk. Augmentation index (AI) in 20 men who switched from abacavir to tenofovir. After 4 weeks, reduction of mean AI from 22% by 4% (P = 0.03) Framingham risk score by 2% (P = 0.01), which was driven by lower total cholesterol (0.8 mmol/l; ; P = 0.002). Consistent trends were observed through week 24. Abacavir may impair cardiovascular function by increasing total cholesterol levels. Sinn et al AIDS. 2010 Sep 24;24(15):2403-5

SCREENING FOR CHD IN HIV PATIENTS Pretest likelihood for CHD Stress tests Newer inflammatory markers CRP, Adiponectin Surrogate markers IMT Coronary artery calcium scores

CHD RISK PREDICTION MODELS Framingham equation HIV-specific models

PREVENTION STRATEGIES Cigarette smoking Diabetes mellitus Dyslipidemia Mode of antiretroviral therapy

HYPERLIPIDEMIA TREATMENT IN HIV PATIENTS WITH HAART Elevated LDL or elevated non HDL with TG 200-500 mg/dl Statin (B1) Pravastatin Atorvastatin Fluvastatin Alternatives Fibrate(C1) or Niacin (C3) Triglycerides >500mg/dl Fibrates(B1) Niacin or fish oils (C3)

AIDS. 2006 Nov 28;20(18):2395-8

CONCLUSIONS HIV pts live longer owing to the success of antiretroviral therapy Cardiovascular disease now ranks as a major cause of death in this population Dyslipidemia, insulin resistance, inflammation and changes in body composition are likely to contribute to this These abnormalities are due to HIV infection, related inflammation or toxicities of HAART

CONCLUSIONS(II) Cardiovascular risk evaluation should be performed regularly in those pts Life style modifications should be encouraged Pharmacological treatment of dyslipidemia and diabetes is mandatory Maintaining virological suppression should be the main concern in HIV pts Development of optimized screening, prediction and treatment algorithms for CHD is of utmost importance

PREVENTION STRATEGIES QUESTIONS AND PRIORITIES FOR RESEARCH -Optimal cessation strategy for smoking -Optimal treatment strategy for dyslipidemia -Lifestyle intervention -Optimal antiretroviral therapy

La Pitie Institute, Paris

HIV-positive patients treated with protease inhibitors have vascular changes resembling those observed in atherosclerotic cardiovascular disease. Lekakis J, Tsiodras S, Ikonomidis I, Palios J, Poulakou G, Rallidis L, Antoniadou A, Panagopoulos P, Papadopoulos A, Giamarellou H, Kremastinos DT. Clin Sci (Lond). 2008 Sep;115(6):189-96.

Grinspoon S. Circulation 2009;119:770-772

HIV AND CARDIOVASCULAR RISK FACTORS Lipid abnormalities Lipodystrophy Insulin resistance Inflammation Changes in renal function

HIV AND CARDIOVASCULAR RISK FACTORS Lipid abnormalities Lipodystrophy Insulin resistance Inflammation Changes in renal function

HIV AND CARDIOVASCULAR RISK FACTORS Lipid abnormalities Lipodystrophy Insulin resistance Inflammation Changes in renal function

HIV AND CARDIOVASCULAR RISK FACTORS Lipid abnormalities Lipodystrophy Insulin resistance Inflammation Changes in renal function

Microalbuminuria 5 times more common

Hadigan C et al. Ann Intern Med 2004;140:786-94

HIV AND CARDIOVASCULAR RISK FACTORS QUESTIONS AND PRIORITIES FOR RESEARCH -Better identification of direct and indirect HIV effects on metabolic parameters -HIV-induced proatherosclerotic changes in lipoprotein structure Contribution of dyslipidemia and insulin resistance to cardiovascular disease -Identification of the mechanisms of body composition changes -Individual drug vs class effects

DAD Study Group. N Engl J Med 2007;356:1723-35

EPIDEMIOLOGICAL EVIDENCE QUESTIONS AND PRIORITIES FOR RESEARCH -Importance of appropriate control groups -Relative impact of traditional and nontraditional risk factors -Risk profile of drugs -Determination of the true risk

EFFECTS OF HIV AND THERAPY ON HEART AND VESSELS Left ventricular dysfunction Myocarditis Endothelial dysfunction Pulmonary hypertension Pericardial effusion

EFFECTS OF HIV AND THERAPY ON HEART AND VESSELS Left ventricular dysfunction Myocarditis Endothelial dysfunction Pulmonary hypertension Pericardial effusion

ECG abnormalities in ~60% LV dysfunction by Echo common Data from pre HAART era

EFFECTS OF HIV AND THERAPY ON HEART AND VESSELS Left ventricular dysfunction Myocarditis Endothelial dysfunction Pulmonary hypertension Pericardial effusion

MI EXPOSURE TO HAART DAD Study Group. N Engl J Med 2003;349:1993-2003

AIDS-RELATED ACTIVE LYMPHOCYTIC MYOCARDITIS

HIV-ASSOCIATED DILATED CARDIOMYOPATHY

HIV-ASSOCIATED PERICARDIAL EFFUSION

Myocarditis 50% positive biopsy in the pre-haart era Endothelial dysfunction mildly improves with antiretroviral therapy Pulmonary hypertension in 1/200 pts Pericardial effusion 11% per year

HIV-ASSOCIATED CARDIAC TUMORS

HIV-ASSOCIATED PULMONARY HYPERTENSION

Barbaro G, J Respr Dis, 2004

HIV AND HEART-VESSELS QUESTIONS AND PRIORITIES FOR RESEARCH -Specific drug effects -Biomarkers for vascular and myocardial dysfunction -Development of effective treatment strategies

SCREENING IN HIV PATIENTS QUESTIONS AND PRIORITIES FOR RESEARCH -Identification of optimal screening strategy -Risk stratification algorithm -Sensitivity and specificity of diagnostic tests -Clinical utility of surrogate markers

CHD RISK PREDICTION MODELS QUESTIONS AND PRIORITIES FOR RESEARCH -Choice of end points -Development of an accurate risk prediction model

HIV AND CARDIOVASCULAR RISK FACTORS Lipid abnormalities Lipodystrophy Insulin resistance Inflammation Changes in renal function

HYPERGLYCEMIA THERAPY IN HIV PTS WITH HAART Sulfonylureas Biguanides Thiazolidinediones Insulin therapy