X Congreso de la Sociedad de Medicina Interna de Aragón, Navarra, La Rioja y País Vasco.

1. Riesgo Cardiovascular en el paciente VIH DR. JAVIER PINILLA MORAZA MEDICINA INTERNA HOSPITAL SAN PEDRO

3. Copyright ©2008 American Heart Association Rosamond, W. et al. Circulation 2008;117:e25-e146 CVD and other major causes of death: total, <85 years of age, and 85 years of age. Deaths among both sexes, United States, 2004. Source: NCHS and NHLBI.

7. CV disease Patient Antiretroviral drugs HIV (and other infections) Drug consumption Tobacco Alcohol Cocaine Other? There are reasons to consider that the risk of CV disease may be increased in HIV-infected patients Metabolic abnormalities Dyslipidemia Insulin resistance / DM Body fat changes Lipoatrophy Lipoaccumulation Degree of immunedeficiency PIs Dyslipidemia Insulin resistance ? Body fat changes? Other? NRTIs Dyslipidemia? Insulin resistance? Body fat changes? Other? HIV, HCV, HBV?, other? Dyslipidemia Systemic inflammation Inmune activation Vascular infection

9. Risk factors for CHDin patients treated for HIVcompared with the general population. Clin Infect Dis. 2003 Jul 15;37(2):292-8.

12. SMART: Higher Risk of Opportunistic Disease or Death With Tx Interruption Favors CT ► ► Favors TI Hazard Ratio (TI/CT) (95% CI) 2.6 1.8 3.6 0.1 1 10 4.0 1.2 P < .001 *Among those on ART at BL El-Sadr WM, et al. N Engl J Med 2006; 355:2283-2296 6.6 Endpoint Opportunistic infection or death (OI/death) OI (nonserious) OI (serious) Death from any cause OI/death by BL VL * ≤ 400 copies/mL > 400 copies/mL

14. 0 % with a Major CVD Event Years from Randomization 2752 0.5 1306 1.5 713 2.5 379 3.5 10 5 10 15 20 DC VS 2720 1292 696 377 10 DC VS No. at Risk 31 48 All major CVD events 14 22 Coronary artery disease requiring surgery for invasive procedure 3 8 Non-fatal stroke 5 11 Non-fatal silent MI 12 12 Non-fatal clinical MI 4 7 Death from CVD VS DC 0 1 2 3 4 SMART Study Phillips A, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007 ART discontinuation increases the risk of CV disease relative to standard, continuous ART SMART Study

15. Grunfeld C, et al. CROI 2009. Oral presentation 114

16. The FRAM Study Grunfeld C, et al. CROI 2009. Oral presentation 114

17. The FRAM Study Grunfeld C, et al. CROI 2009. Oral presentation 114

18. The FRAM Study Grunfeld C, et al. CROI 2009. Oral presentation 114

24. Tasa relativa ajustada/año de IP : 1.15 (1.06, 1.25) Tasa relativa ajustada/año de NNRTI : 0.94 (0.74, 1.19) Número de IAMs por 1.000 pacientes por año (IC 95%) Años de exposición a IP o NNRTI 0 2 4 6 8 10 >6 5–6 2–3 3–4 4–5 0 1–2 <1 La exposición a IP se ha asociado con un riesgo aumentado de infarto de miocardio Friis-Møller N et al, N Engl J Med 2007. Estudio D:A:D

25. *Adjusted for conventional risk factors (sex, cohort, HIV transmission group, ethnicity, age, BMI, family history of CVD, smoking, previous CVD events, lipids, diabetes, and hypertension). † Unadjusted model. Relative Rate of MI* (95% CI) 0.72 (0.52–0.99); P =0.05* 1.58 (1.43–1.75); P <0.001 † 1.26 (1.19–1.35); P <0.001* 1.10 (1.01–1.18); P =0.002 * 1.00 (0.93–1.09); P =0.92* Total cholesterol (per mmol/L) Triglycerides (per log 2 mmol/L higher) HDL cholesterol (per mmol/L) PI exposure (per additional year) NNRTI exposure (per additional year) 1 10 0.1 Friis-Moller N et al. N Engl J Med. 2007 Contribution of dyslipidemia to MI risk

26. Ajustado para sexo, edad, cohorte, año, ECV previa, H a familiar de ECV, tabaco, índice de masa corporal, y la otra clase de 3 er fármaco Exposición a NNRTI (por cada año) 0.9 1.0 1.1 1.2 1.3 0.9 1.0 1.1 1.2 1.3 Tasa relativa de IAM (IC 95%) TR 1,00 TR 1,10 TR 1,05 TR 1,16 Exposición a IP (por cada año) Parte (pero no todo) del RCV atribuido a IP puede explicarse por los lípidos Friis-Møller N et al, N Engl J Med 2007. Sin embargo, no se ajustó para exposición a NRTI. NRTI’s timidínicos tienen un impacto en sensibilidad a insulina y en lípidos. Uso de NRTI’s timidínicos pudo ser diferente en pacientes expuestos a IP vs NNRTI.

27. IDV NFV LPV/r SAQ NVP EFV #PYFU: 68,469 56,529 37,136 44,657 61,855 58,946 #MI: 298 197 150 221 228 221 LPV/r e IDV fueron los IPs asociados con mayor riesgo de IAM en el análisis del D:A:D J Lundgren & D:A:D Study Group et al CROI 2009 LB abstr 44. Pis/NNRTIs y riesgo de IAM: exposición acumulada a cada fámaco RR por año IC95% *Prueba aproximada de heterogeneidad: P=0,02 PI* NNRTI 1,2 1,13 1,1 1 0,9

29. 0 2 4 6 8 1 0 A b a c a v i r S p a r i n g R e g i m e n A b a c a v i r C o n t a i n i n g R e g i m e n P = 0 . 0 1 Endothelium- dependent FMD (%) After adjustment for age, gender, traditional risk factors, HIV-specific factors, and baseline brachial artery diameter, current abacavir use was independently associated with lower FMD (p=0.02) Cross-sectional study No data on antiretrovirals other than ABC and other epidemiological characteristics Hsue P et al, CROI 2009 abstract 723 ABC use associated with  endothelial function among patients on ART with HIV suppression

30. 13 [23]% .v. 1 [4]% P = 0.009 30 [25]% .v. 18 [18]% P = 0.032 12 [19]% .v. 5 [2]% P = 0.06 31 [20]% .v. 21 [17]% P = 0.043 Satchell C et al, CROI 2009 abstract 151LB Cross-sectional study No data on antiretrovirals other than ABC and other epidemiological characteristics 25% patients had detectable viral load Significance lost when adjusted for HIV RNA for ADP and epinephrine ABC use associated with  platelet reactivity

31. No Association of Myocardial Infarction with ABC Use: An FDA Meta-analysis. 18th CROI2011; Abstrac 808

34. Cardiovascular Disease and HIV infection: Pathogenesis

38. Law MG, et al. 11th CROI. 2004. Abstract 737. Duration of HAART (years) MI per 1000 PYFU 0 1 2 3 4 5 6 7 8 < 1 1-2 2-3 3-4 4+ 0 Observed Predicted Risk of myocardial infarction in HIV-infected patients can be estimated with the Framingham score DAD Study Law MG et al. HIV Med 2006; 7: 218-230

42. P = .81 Lichtenstein K et al. CROI 2006. Abstract 735. 0 5 10 15 20 25 30 35 % pts on anti-hypertensive or anti-lipemic agents MI incidence per 1000 pt-yrs, by year Incidence of MI per 1000 PYFU 0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2004 2005 2003 0.5 1.0 Effect HR adj 95% CI P-value LLAs 0.34 0.14–0.85 0.021 Age >40 y 2.38 0.88–6.43 0.087 Diabetes 2.45 0.99–6.05 0.052 Smoking 2.22 0.98–5.05 0.057 HOPS Cohort The incidence of myocardial infarction can be satisfactorily modified with intervention

43. Assess CVD risk in next 10 years (Framingham score) Advise on diet and lifestyle in all patients Consider ART modification if CVD risk ≥20% Identify key modifiable risk factors Smoking Blood pressure Coagulation Glucose Li pids Drug treatment if: SBP ≥140 or DBP ≥90 mmHg (especially if 10 year CVD risk ≥20%) Drug treatment if: Established CVD or age ≥50 and 10 year CVD risk ≥20% Confirm DM and drug treatment if: HBA1c ≥6.5% Drug treatment if: Established CVD or T2DM or TC:HDL ratio >6 or 10 year CVD risk ≥20% Target DM or Non-DM; CVD or no CVD: CKD+prot: <130/<80 <140/<90 Target HBA1c <6.5% Target Optimal Standard TC 4 5 (155) (190) LDL 2 3 (80) (115) Target – N/A Treat with acetylsalicylic acid 75-150 mg/d 2009 EACS guidelines on non-infectious co-morbidities in HIV: Prevention of CVD To be released at EACS, Köln 2009.

45. Clin Infect Dis. 2011 Feb 1;52(3):387-95. Epub 2010 Dec 28. Comparative Effectiveness and Toxicity of Statins Among HIV-Infected Patients. Singh S , Willig JH , Mugavero MJ , Crane PK , Harrington RD , Knopp RH , Kosel BW , Saag MS , Kitahata MM , Crane HM . A retrospective cohort study of patients starting their initial statin medications at 2 large HIV clinics (N = 700). The primary observation : change in lipid levels during statin therapy. Secondary observations : individualized National Cholesterol Education Program (NCEP) goals for low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) levels were reached, and toxicity rates. RESULTS: Atorvastatin (N = 303), pravastatin (N = 280), and rosuvastatin (N = 95). One year after starting a statin therapy, patients who received atorvastatin or rosuvastatin had significantly greater decreases in total cholesterol, LDL-C, and non-HDL-C than patients on pravastatin. The likelihood of reaching NCEP goals for LDL-C levels was higher with the use of rosuvastatin (OR 2.1; P = .03) and atorvastatin (odds ratio [OR], 2.1; P = .001) compared with that of pravastatin. The likelihood of reaching NCEP goals for non-HDL-C levels was higher for rosuvastatin (OR 2.3; P = .045) but not atorvastatin (OR, 1.5; P = .1) compared with pravastatin. Toxicity rates were similar for all 3 statins CONCLUSIONS: Atorvastatin and rosuvastatin are preferable to pravastatin for treatment of HIV-infected patients with dyslipidemia, due to greater declines in total cholesterol, LDL-C, and non-HDL-C, with similar lower toxicity rates.

47. MUCHAS GRACIAS