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Riesgo Cardiovascular en Paciente VIH

I Congreso GESIDA Conferencia Especial GSK Madrid, 22 Octubre 2009. Riesgo Cardiovascular en Paciente VIH. Esteban Martínez Servicio de Infecciones Hospital Clínic Universidad de Barcelona España.

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Riesgo Cardiovascular en Paciente VIH

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  1. I Congreso GESIDA Conferencia Especial GSK Madrid, 22 Octubre 2009 Riesgo CardiovascularenPaciente VIH Esteban Martínez Servicio de Infecciones Hospital Clínic Universidad de Barcelona España

  2. There are reasons to consider that the risk of CV disease may be increased in HIV-infected patients Aging Drug consumption Tobacco Alcohol Cocaine Other? Metabolic abnormalities Dyslipidemia Insulin resistance / DM Body fat changes Lipoatrophy Lipoaccumulation Degree of immunedeficiency Patient CV disease Antiretroviral drugs HIV (and other infections) Other? 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

  3. D:A:D Study: Low and stable incidence of myocardial infarction in HIV-infected patients D:A:D Study 5 4 3 Incidence of MI (per 1000 PYFU) 2 1 0 2003 2007 2008 2009 No. MI 126 345 517 580 PYFU 36199 94969 157912 178835 NEJM 2003; NEJM 2007; Lancet 2008; CROI 2009

  4. Contribution of the PATIENT

  5. Increased risk of CV disease in HIV+ persons relative to HIV- ones: impact of traditional factors • Approximately 2-fold higher incidence of CAD / MI • Higher prevalence of other types of CV disease in HIV+ vs HIV-: • Peripheral arterial disease 1, 2 • Increased cIMT 3-5 In these studies, higher prevalence of traditional CV risk factors (smoking, HT, DM, and dyslipidemia) in HIV+ relative to HIV- 1. Palacios R et al. AIDS Res Human Retrovir 2008; 2. Periard D et al. Clin Infect Dis 2008; 3. Hsue PY et al. Circulation 2004; 4. Mercie P et al. HIV Medicine 2005; 5. Lekakis J et al. Clin Sci 2008; 6. Lorenz MW et al. Atherosclerosis 2008

  6. No differences in CV disease between HIV+ and HIV- when prevalence of traditional CV factors is similar

  7. HIV+ patients with myocardial infarction have higher prevalence of traditional CV risk factors Lundgren, J & DAD Study Group et al CROI 2009 abstract 44LB; Lang et al, CROI 2009, abstract 43LB

  8. Several studies suggest lower CD4 cell counts associated with higher rates of non-AIDS events Cardiovascular disease Non-AIDS cancer Liver Disease Renal disease Causes of morbidity/mortality: • SMART • D:A:D • CASCADE* • FIRST • VACS† • SMART • FIRST • VACS • SMART • D:A:D • CASCADE • FIRST • D:A:D • CASCADE • FIRST • Aquitaine Studies suggesting association with lower CD4+ count: Goulet JL, et al. Clin Infect Dis 2007; Weber R, et al. 12th CROI; CASCADE Collaboration, AIDS 2006; Baker JV, et al. AIDS 2008; Weber R, et al. Arch Intern Med 2006; Bruyand M, et al. 15th CROI; El Sadr WM, et al. N Engl J Med 2006 * Cardiovascular disease or type 2 diabetes; † Vascular disease

  9. From a purely CV perspective, it is better to administer ART than not to administer it

  10. Contribution of the VIRUS

  11. A relative HDL-cholesterol deficit is characteristic of HIV infection MACS study Pre-seroconversion 250 220 Pre-HAART 201 200 Post-HAART 171 Plasma concentration (mg/dL) 150 129 122 100 100 51 40 39 50 0 Total cholesterol LDL-chol HDL-chol Total cholesterol / HDLc ratio increased Riddler SA, et al. JAMA 2003; 289: 2978-82.

  12. HDL-cholesterol modulates CV risk associated with LDL-cholesterol Framingham study 3.0 2.0 Coronary disease risk 1.0 25 45 HDL-chol, mg/dL 0.0 65 100 160 220 85 LDL-chol, mg/dL Gordon T, et al.Am J Med 1977;62:707–14; *3rd Report of the NCEP Expert Panel Kannel WB. Am Heart J 1985;110:1100-1107.

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

  14. SMART Study: the higher the viral load rebound the higher the HDL-c decrease DC Patients on ART at Baseline with HIV RNA ≤ 400 copies /mL: HDL Decline at 1 Year According to HIV RNA Level at 1 Year P < 0.001 for trend HDL Decline (mg/dl) ≤ 400 401-10,000 10,001-50,000 >50,000 HIV RNA at 1 Year N = 239 148 158 164 Neaton J. Personal communication

  15. 6 SMART Study: Inflammation and coagulation markers asscociated with risk of CVD/death 5 4 3 2 1 N=499 stored baseline plasma samples P=0.003 P=0.002 P=0.06 2.8 2.8 Odd ratio (95% CI) CV disease/death 2 0 IL-6 D-dimer Amyloid P P-values are for adjusted odds ratios for the 4th vs 1st quartile of each biomarker at baseline, estimated using logistic regression Kuller L, et al. CROI 2008. Abstract 139.

  16. Contribution of the THERAPY

  17. PI use linked to Mi in some initial cohort studies, but there were some potential biases HOPS cohort: Low, but increasing incidence of MI associated with • Hypertension • Smoking • Male gender • Age > 50 years • Dyslipidaemia • Diabetes • Use of PI 3.5 3.0 2.5 2.0 Incidence (Per 1000 PYFU) 1.5 1.0 0.5 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 • Potentialconfounding and biases: • Competingrisks of non-HIV diseasesduetoincreasedsurvival • “Use of PI” wasequivalentto “optimal ART” (vs suboptiomal ART) Holmberg SD, et al. Lancet. 2002;360:1747-1748

  18. Higher risk of MI with PI exposure (but not with NNRTI exposure) D:A:D study Adjusted relative rate/year of PI: 1.15 (1.06, 1.25) Adjusted relative rate/year of NNRTI: 0.94 (0.74, 1.19) 10 8 6 Number of MIs per 1000 PYFU (IC 95%) 4 2 0 0 <1 1–2 2–3 3–4 4–5 5–6 >6 Years of exposure to PI or NNRTI Friis-Møller, et al. N Engl J Med. 2007;326:1723-1735

  19. NNRTI-containing ART increases HDL-cholesterol more than PI-containing ART FIRST study NRTI: d4T or AZT en >75% PI: NFV, IDV (ritonavir boosting included) NNRTI: EFV, NVP Shlay JC et al. J Acquir Immune Defic Syndr 2007; 44: 506-517

  20. Not all lipid changes with ART are necessarily ART-related HIV-Negative 2, 3, 4 HIV-Infected 1 P <.001 5 P =.06 P <.05 4 LDL is a “Return-to-Normality” effect not a drug effect LDL Cholesterol mmol/L 3 2 1 0 5 P <.01 P <.01 4 3 TG is a drug-specific effect P <.007 Triglycerides mmol/L 2 1 0 RTV IDV NFV RTV IDV LPV/r In each bar pair, the light color indicates baseline values and the darker color indicated values after receiving ART. 1. Periard et al. Circulation. 1999; 2. Purnell et al. AIDS. 2000; 3. Noor et al. AIDS. 2001; 4. Lee et al. AIDS. 2004

  21. PIs increase triglycerides and their effect depends on RTV boosting dose FPV/r2003 FPV/r1002 FPV1 (ABC+3TC) (TDF+FTC) (ABC+3TC) Naive patients Better than NFV = ATV/r = LPV/r 70 60 50 Median lipid change at week 48(mg/dL) 40 30 20 10 0 Triglycerides -10 1. Nadler JP et al. 44th ICAAC 2004. Poster H-156 (NEAT Study) 2. Smith K et al. 46th ICAAC 2006; San Francisco. Abstract H-1670a (ALERT Study) 3. Eron J et al. XVI International AIDS Conference 2006; Abstract THLB0205 (KLEAN Study)

  22. Contribution of dyslipidemia to MI risk 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* HDL cholesterol (per mmol/L) Triglycerides (per log2 mmol/L higher) Total cholesterol (per mmol/L) PI exposure (per additional year) NNRTI exposure (per additional year) 1 10 0.1 Relative Rate of MI* (95% CI) *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. Friis-Moller N et al. N Engl J Med. 2007

  23. Part (but not all) of CV risk attributable to PI can be explained by lipids RR 1.16 Exposure to PI (per year) RR 1.10 RR 1.05 Exposure to NNRTI (por year) RR 1.00 0.9 0.9 1.0 1.0 1.1 1.1 1.2 1.2 1.3 1.3 Relative rate of MI (95% CI) Adjusted for sex, age, cohort, year, prior CVD, family CVD , smoking, body mass index, and the other 3rd drug Friis-Møller N et al. N Engl J Med 2007

  24. Traditional factors explain little on CV risk associated with IDV and LPV/r in DAD study Primary model Dislipidemia Increased blood pressure Diabetes mellitus Lipodystrophy Glucose All above Lopinavir/r Indinavir + lipid-lowering and antihypertensive medication 0.9 1 1.1 1.3 1.4 RR of IAM (95%CI) Lundgren JD et al., CROI 2009. Abst 44LB

  25. Ritonavir boosting does not modify the risk associated with individual PIs in DAD study # PYFU: 44, 657 Saquinavir (global) 24,727 Saquinavir + rtv 26,145 Saquinavir - rtv 68,469 Indinavir (global) 22,186 Indinavir + rtv 57,961 Indinavir - rtv 0.9 1 1.1 1.2 1.3 1.4 RR of IAM (95%CI) Lundgren JD et al., CROI 2009. Abst 44LB

  26. PI use different over time; patients treated with same PI also differ over time Datos del Hospital Clínic, Barcelona 2008

  27. Higher risk of myocardial infarction with recent ABC or ddI use? Stratified by recent* didanosine use Stratified by recent* abacavir use 35 30 25 20 15 10 5 0 35 30 25 20 15 10 5 0 No recent didanosine Recent didanosine No recent abacavir Recent abacavir Rate (per 1000 PY) Rate (per 1000 PY) Overall Low Moderate High Not known Overall Low Moderate High Not known Predicted 10-year CHD risk Predicted 10-year CHD risk D:A:D study Rates of MI for Recent or No Recent Use of different NRTIs Zidovudine Stavudine Lamivudine Didanosine Abacavir Recent use No recent use Recent use No recent use Recent use No recent use Recent use No recent use Recent use No recent use MI events 214 303 134 383 377 140 124 393 192 325 4.5(3.7, 5.3) 3.0(2.7, 3.3) 6.1(5.3, 7.0) 2.6(2.3, 2.9) Event rate (95% CI)/1000 person-years 3.4(3.0, 3.9) 3.2(2.8, 3.5) 3.7 (3.1, 4.4) 3.1(2.8, 3.5) 3.7 (3.3, 4.1) 2.5(2.1, 2.9) Rates of MI for Recent Use of Didanosine and of Abacavir by Predicted 10-year Coronary Heart Disease (CHD) Risk Recent = still using or stopped within last 6 months Sabin C et al., CROI 2008; #957c.

  28. DAD and French Hospital Database Studies: discrepancies among results Increase in the risk of MI by individual antiretroviral drugs and families * Recent exposure means current exposure or stopped in the previous 6 months 1. DAD NEJM 2007; 2. DAD Lancet 2008; 3. DAD CROI 2009; 4. FHDB CROI 2009

  29. Higher biomarkers with ABC (no ddl) at entry in SMART study do not mean causality Median (IQR) levels in ”Others NRTIs” 2.3 (1.0-5.3) 2.2 (1.4-3.7) 3.6 (1.9-6.8) 65 (51-86) 0.3 (0.2-0.5) 0.4 (0.3-0.5) (µg/L) (µg/mL) (pg/mL) (mg/mL) (nmol/L) (µg/mL) * *: p=0.02 **: p=0.07 For all others:p>0.1 % adjusted difference using ”ABC (no ddI)”versus using ”other NRTIs” * ** n=791 * For known CVD risk factors, CD4 count, HIV-RNA, hepatitis status, and use of NNRTIs and PI 72% < 400 copies/mL ART was not randomized Lundgren J et al XVII IAC, Mexico, 2008 & AIDS 2008

  30. ABC use associated with endothelial function among patients on ART with HIV suppression Cross-sectionalstudy No data onantiretroviralsotherthan ABC and otherepidemiologicalcharacteristics P = 0 . 0 1 1 0 8 6 dependent FMD (%) Endothelium- 4 2 0 A b a c a v i r A b a c a v i r S p a r i n g C o n t a i n i n g R e g i m e n R e g i m e n 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) Hsue P et al, CROI 2009 abstract 723

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

  32. A re-analysis of the FHDH Study has not found a MI signal for NRTIs, including ABC This is different from D:A:D Without D:A:D, we would have found no association Adjusted for hypertension, smoking, family history of premature CAD, use of cocaine and/or IV drug use, plasma HIV-1 RNA level, CD4/CD8 cells ratio, exposure to emtricitabine, atazanavir, ritonavir and tipranavir Costagliola. IAS 2009. MOAB201

  33. Relative to TDF/FTC, ABC/3TC does not promote mechanisms known to be involved in MI BICOMBO Sub-study: patients with sustained viral suppression, clinical stability, and no prior CVD • Patients switching to ABC/3TC (n = 46) or TDF/FTC (n = 34) • Markers of inflammation, endothelial dysfunction, insulin resistance, and hypercoagulability compared at BL and Wk 48 • None of these markers were significantly different between arms at Wk 48 ABC/3TCTDF/FTC P = .12 20 P = .33 15.4 12.6 15 P = .69 P = .96 P = .13 P = .84 P = .52 8.4 8.8 10 7.8 P = .59 6.6 5.9 5.2 Median Change From BL at Wk 48 (%) 5.1 P = .73 4.0 4.6 5 P = .26 0.1 0.05 0.1 0 -0.4 -2.0 -2.5 -2.2 -2.8 -5 -3.9 ICAM-1 MCP-1 D-dimer Selectin-P Insulin OPG Selectin-E VCAM-1 Adiponectin hsCRP Martinez et al. IAS 2009. MOAB203

  34. Theassociationbetween ABC and MI maybebiasedbychronickidneydisease Veterans Cohort Study • HR: Unadjusted HR of AMI for each PY of exposure to each one of the categories • Most recent estimated GFR (by MDRD method; carried forward) . • Age, hypercholesterolemia, HTN, type 2 DM, and tobacco use. Bedimo R et al. IAS 2009. MOAB202

  35. NRTI use different over time; patients treated with same NRTI also differ over time Datos del Hospital Clínic, Barcelona 2008

  36. Management

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

  38. The incidence of myocardial infarction can be satisfactorily modified with intervention HOPS Cohort MI incidence per 1000 pt-yrs, by year 4.5 35 4.0 30 3.5 25 3.0 % pts on anti-hypertensive or anti-lipemic agents 20 2.5 Incidence of MI per 1000 PYFU 2.0 15 1.5 10 1.0 5 0.5 0 0 2003 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2004 2005 Effect HRadj 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 P = .81 Lichtenstein K et al. CROI 2006. Abstract 735.

  39. 2009 EACS guidelines on non-infectious co-morbidities in HIV: Prevention of CVD 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 Lipids 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 – N/A Treat with acetylsalicylic acid 75-150 mg/d Target HBA1c <6.5% Target Optimal Standard TC 4 5 (155) (190) LDL 2 3 (80) (115) To be released at EACS, Köln 2009.

  40. Conclusions • Higher risk of CVD in HIV + than HIV – persons: • Rationale for CVD prevention in clinical practice • Traditional risk factors account for a substantial portion of CV risk in HIV + persons: • Rationale for early and aggressive intervention • Uncontrolled HIV and other concurrent co-infections further increase the risk for CV disease: • Rationale for early and continuous ART and for HCV and other co-infections • Individual ARVs and classes associated with increased risk of CV disease through mechanisms not yet completely understood: • Contribution of ART lower than traditional factors & uncontrolled infection. • Rationale for choosing ART in patients with high CV risk (≥20%): • PI’s associated with MI at least through lipid impact • Controversial role of ABC: it may be a marker of increased CV disease, but causative role not demonstrated and potential mechanism not clear

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