Conséquences métaboliques et cardiovasculaires du VIH et de son traitement

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1 Conséquences métaboliques et cardiovasculaires du VIH et de son traitement Colloque VIH et Nutrition Réunion 15/02/2018 Assistance Publique Hôpitaux de Paris Pr Franck Boccara, MD, PhD Cardiologie, INSERM UMRS938 HUEP St Antoine, Sorbonne Universités, Paris, France

2 Epidémiologie

3 Before ART ( ) After ART ( ) Long term exposure to ART and aging DCM/Heart failure % Decreased Impact of aging Systemic HTN NR 20-30% Impact of aging Coronary artery disease NR 2-5% Impact of aging Stroke NR? Impact of aging Atrial fibrillation QT prolongation (sudden death) Peripheral vascular disease NR NR 1%? Impact of aging Impact of new drugs? NR 5% Impact of Tobacco and HVC Pericarditis 11 % Decreased No potential risk Endocarditis %? No potential risk Pulmonary HTN 0.5% 0.5%? VTE-PE NR? Impact of new drugs

4 Morlat P, CROI 2012, Abs. 1130

5 The ANRS EN20 Mortalité 2010 Survey in France 13,6% Hénard S et al. CROI 2013 Atlanta, USA

6 The ANRS EN20 Mortalité 2010 Survey in France 75% Hénard S et al. CROI 2013 Atlanta, USA

7 Est-ce que le risque d IDM dans la population VIH+ est supérieure à celui de la population VIH-?

8 Rates per 1000 Person-Yrs Incidence of Acute Myocardial Infarction (MI) in HIV+ in Boston, USA Acute MI rates determined in 3851 HIV-infected and 1,044,589 HIV-uninfected patients from Overall rates per 1000 person-years higher in HIV-infected vs HIV-uninfected patients: vs HIV + HIV - RR = Age Group (Yrs) Triant VA, et al. J Clin Endocrin Metab. 2007;92:

9 Freiberg MS et al. JAMA Intern Med 2013 HIV veterans had a 50% increased risk of MI as compared to the HIV- veterans, USA patients including 33% HIV+, 97% M, 48% Afro-Am, FRS 6% AMI rates per person-years 871 MI (42% of HIV+) Med FU 5.9 y 25 *1.50 HIV- HIV * *2.19 *1.34 * < * incident rate ratio Age

10 What about France? RR of MI is also increased by 50% in HIV+ population as compared to the general population (FHDH) Men HIV- men HIV+ men SMR Men 1.4 Women Global SMR 1.5 HIV- women HIV+ women SMR women 2.7 Lang S. et al. AIDS 2010;24:

11 Mortalité cardiovasculaire. Etats-Unis Données CDC WONDER database USA Pop gal: 35M certificat de décès HIV Feinstein, MJ et al. Am J Cardiol 2015

12 Diminution de la difference incidence IDM entre VIH+ et VIH- en Californie, USA HIV-positive and HIV-negative subjects contributing personyears (mean 4.8 years/subject) and person-years (mean 5.8 years per subject), respectively. Klein DB et al. CID 2015;60:

13 The Danish cohort 5897 HIV-infected individuals and population controls; median age was 36 8y Absolute risk and relative risk of MI/stroke with age in HIV-infected individuals and controls Relative risk of MI/stroke with calendar years Rasmussen LD et al. Lancet HIV 2015; 2: e288 98

14 Y-a-t-il des FDR spécifiques?

15 Percentage of Cohort With Risk Factor at Baseline Prevalence of Traditional Cardiac Risk Factors at Baseline in the D:A:D Study Large cohort of HIV-infected patients on HAART followed longitudinally (N = 23,468) 18,962 (80.8%) with previous ART exposure; 4506 (19.2%) antiretroviral naive Family History of CHD 1.4 Previous History of CHD Current Smoking BMI HTN Diabetes Total > 30 Cholesterol TG Friis-Møller N, et al. AIDS. 2003;17:

16 Traditional CV risk factors are associated with MI patients :33% HIV+, 97% M, 48% Afro-Am, FRS 6% VETERANS Study Characteristics Relative risk 95% CI Age Controled HTN Uncontroled HTN Diabetes mellitus LDLc > 160mg/dL HDLc < 40mg/dL Triglycerides > 150mg/dL Current smoking HVC infection egfr 30-60ml/mn/1.73m² HIV infection MI (42% HIV+), Median FU 5.9 years Freiberg MS et al. JAMA Intern Med 2013

17 Impact of lipids D:A:D study TC (per mmol/l ) TG (per 2-fold ) HDL (per mmol/l ) RR: 1.31* ( ) RR: 1.26 ( ) RR: 1.58* ( ) RR: 0.65* ( ) RR: 0.72 ( ) Relative Rate of MI (95% CI) *Unadjusted model. Multivariable Poisson model adjusted for age, sex, BMI, HIV risk, cohort, calendar year, race, family history of CVD, smoking, previous CVD event, TC, HDL, hypertension, diabetes. TG did not meet statistical significance in adjusted model. Friis-Møller N, et al. N Engl J Med. 2007;356:

18 Effects of protease inhibitors on Lipid Metabolism in HIV-Infected Individuals Class Drug TG/VLDL LDL HDL RTV LPV/r / TPV/r SQV/r /? IDV/r PI DRV/r / FPV/r ATV/r / NFV? ATV /? IDV * All data are from trials with antiretroviral naïve patients

19 Quels sont les FDR spécifiques d IDM?

20 SMART ART cease is associated with a higher risk of CV events 2 HIV treatment strategies assessed for overall clinical benefit: CT or CD4- guided TI TI associated with significantly greater disease progression or death, compared with CT: RR: 2.5 (95% CI: ; P <.001) Parameter HR (95% CI) Death from any cause Death from major cardiovascular, renal and hepatic events Risk of Complications 0.1 Favors TI Favors CT El-Sadr W, et al. N Engl J Med. 2006;355:

21 Traditional CV risk factors are associated with MI patients :33% HIV+, 97% M, 48% Afro-Am, FRS 6% VETERANS Study Characteristics Relative risk 95% CI Age Controled HTN Uncontroled HTN Diabetes mellitus LDLc > 160mg/dL HDLc < 40mg/dL Triglycerides > 150mg/dL Current smoking HVC infection egfr 30-60ml/mn/1.73m² HIV infection MI (42% HIV+), Median FU 5.9 years Freiberg MS et al. JAMA Intern Med 2013

22 HIV infection, viral load and current CD4 cell count are associated with the risk of MI HIV parameters Relative risk 95% CI HIV infection Viral load > 500 c/ml CD4 cell count < Freiberg MS et al. JAMA Intern Med 2013

23 1. DAD NEJM 2007; 2. DAD Lancet 2008; 3. DAD CROI 2009; 4. FHDH Archives of Int Med 2010 PI (as a family) Increased of MI with some PI and NRTI DAD DAD DAD FHDH % per year (relative to NNRTI) (10% per year, after adjustment for dyslipidemia, hypertension, and DM) % per year (relative to SQV) LPV/r % per year 37% per year IDV % per year Not significant APV/fAPV - - Not significant 52% per year ABC - 90% recent exposure * 60% recent exposure * 7% per year No effect if IVDU and cocaine are excluded ddi - 49% recent exposure * 41% recent exposure * Not significant

24 Boccara F. et al. J Am Coll Cardiol. 2013;61:

25 Quelle prise en charge du RCV?

26 PACS-HIV study. Secondary prevention HIV+ N = year FU HIV+ n = 103 HIV- n = 195 Hazard ratio HR [95% CI] Recurrent ACS 9 6 HR 4.6 [ ] Urgent PCI 7 3 HR 3.0 [ ] 3 year FU Recurrent ACS HR 3.4 [ ]* ACS: acute coronary syndrome, PCI : percutaneous coronary intevention * Data not published ACS Matched age ( 5yrs), gender, type of ACS MACE STEMI, NSTEMI, UA HIV- N = 195 Boccara F. et al. Eur Heart J 2011;32:41-50.

27 Boccara F. et al. Am Heart J. 2017;183: Moindre diminution du LDLc et non-hdlc chez le VIH+ vs VIH- en postsca surtout les 6 premiers mois. LIPIDS-PACS substudy Lipid parameters variation over 36 months LDLc HDLc Non-HDLc TG

28 PACS-HIV study Multivariate analysis of factors associated with increased risk of recurrent ACS at 3 years FU Multivariate analysis Hazard Ratio 95% CI P value HIV+ versus HIV Total cholesterol, mg/dl* LDLc, mg/dl* *time-dependent covariates ESC 2014

29 Lipides et VIH en prévention secondaire. LIPIDS-PACS substudy Distribution of statins prescribed along the 3 year FU Boccara F. et al. Am Heart J. 2017;183:

30 Intéractions importantes entre certaines statines et inhibiteurs de protéases et Cobicistat Drug-Drug Interactions Fibrates Rosuvastatin** Fluvastatin Pravastatin* Ezetimibe Fish oil Low interaction potential Statin + fibrate Atorvastatin** Niacin Use cautiously Lovastatin Simvastatin Contraindicated *AUC with DRV. **AUC Atorva x 5 avec DRV/Cobi et x10 avec ATV/cobi

31 ESC/EAS. Eur Heart J. 2011;32:

32 Who is at cardiovascular risk for ESC/EAS? LDLc < 0.7g/L LDLc < 1g/L LDLc < 1.30g/L ESC Guidelines on CVD prevention 2016

33 Perspectives

34 Randomized Trial to Prevent Vascular Events in HIV REPRIEVE (A5332) Principal Investigators: Steven Grinspoon, MD Pamela S Douglas, MD Udo Hoffmann, MD, MPH Heather Ribaudo, PhD Time Asymptomatic HIV+ patients with no history of CVD Placebo R (n=6500) Pitavastatin 4mg/day Screening And Consent Randomization Intervention 6 year F/u Mechanistic Study (n=800) Coronary plaque, vascular inflammation, immune activation Mechanistic Primary Endpoint CV Death MI Unstable Angina Stroke Arterial Revasc Clinical Primary Endpoint Individual components of primary endpoint All cause death Incidence/Progression of noncalcified plaque; High-risk plaque Inflammatory, immunological, metabolic biomarkers Secondary Endpoints Predictors All Cause of statin Death effects Statin safety and non AIDS comorbidities: DM, Infections, Cancer Figure 4. Schematic overview of REPRIEVE trial design. Funded by NHLBI and NIAID. Supported by KOWA Pharmaceuticals.

35 Conclusions Athérosclérose est maintenant la 1 ère cause de maladie CV chez les patients VIH+ traités (3ème cause de décès) Risque IDM VIH+> VIH- Risque IDM VIH+ ART incluant IP+ > Risque IDM VIH+ ART- Physiopathologie complexe avec des FDR CV traditionnels prédominant (tabac, cocaïne) et des FDR spécifiques: lipodystrophie, inflammation chronique, VIH luimême, activation immune, ART. ART et le contrôle immunovirologique sont les 1ères armes pour lutter contre les maladies CV