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Practical Management Strategies for Cardiovascular Risk in HIV

Practical Management Strategies for Cardiovascular Risk in HIV. Pablo Tebas, MD Associate Professor of Medicine University of Pennsylvania Philadelphia, Pennsylvania. Pretreatment Assessment for Metabolic Complications in HIV. 1. Identify Presence of CHD MI Unstable/stable angina

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Practical Management Strategies for Cardiovascular Risk in HIV

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  1. Practical Management Strategies for Cardiovascular Risk in HIV Pablo Tebas, MD Associate Professor of Medicine University of Pennsylvania Philadelphia, Pennsylvania

  2. Pretreatment Assessment for Metabolic Complications in HIV 1.Identify Presence of CHD • MI • Unstable/stable angina • Previous coronary procedures • Myocardial ischemia 2.Identify Presence of CHD Equivalents • Peripheral artery disease • Abdominal aortic aneurysm • Coronary artery disease • Diabetes 3.Medical History • Hypertension • Cigarette smoking • Family history of CHD • Low HDL • Perform fasting plasma glucose and lipid measurements* Calculate 10-year CV risk *Measurements should be performed yearly after HAART initiation and more frequently if dyslipidemia, glucose intolerance, or diabetes develops. NCEP ATP III final report. Circulation. 2002;106:3143-3421.

  3. Framingham Risk Score Used to Estimate 10-Year Cardiovascular Risk • Developed for use in general population • Thought to be reasonable predictor in HIV-infected population • However, does not include HIV-specific factors • Immune status • Increased inflammatory markers • Insulin resistance Age: Sex: Total cholesterol: HDL cholesterol: Smoker: Systolic blood pressure: Are you currently on any medication to treat high blood pressure? Female Male Yes No Yes No National Cholesterol Education Program. Available at: http://hin.nhlbi.nih.gov/atpiii/calculator.asp. Accessed March 10, 2008.

  4. Lipids Management: Are the LDL cholesterol targets recommended for the general population also appropriate for patients with HIV?

  5. NCEP ATP III Lipid Goals *Or baseline LDL < 100 mg/dL (< 2.59 mmol/L). NCEP ATP III final report. Circulation. 2002;106:3143-3421. Grundy SM, et al. Circulation. 2004;110:227-239.

  6. Lipid Goals For HIV-Infected Patients • NCEP lipid goals intended for general population likely appropriate for HIV-infected patients • Lipid goals established to reduce cardiovascular risk • Contrary to previous findings, data from D:A:D cohort suggest Framingham risk equation may overestimate risk of cardiovascular events in HIV-infected patients • D:A:D equation more accurately predicted CHD outcomes in HIV-infected population • Incorporates PI exposure as well as conventional CHD risk parameters Friis-Moller N, et al. CROI 2007. Abstract 808.

  7. Lipids Management: What are the preferred management approaches for patients with HAART-associated hyperlipidemia? Specifically, what factors should be considered in deciding whether to switch antiretroviral agents, use lipid-lowering therapy, or both?

  8. Managing Dyslipidemia: PI Switch vs Lipid-Lowering Therapy • When switching antiretroviral therapy • Maintenance of virologic suppression is paramount • Any switch carries some risk of loss of virologic suppression • Lipid-lowering agents • May avoid risks associated with switch but at the price of polypharmacy • More commonly used in US; European guidelines suggest lipid-lowering therapy only after dietary modification and switch strategies Carr A, et al. AIDS. 2001;15:1811-1822. Moyle G, et al. AIDS. 2001;15:1503-1508.Miller J, et al. AIDS. 2002;16:2195-2200. Doser N, et al. AIDS. 2002;16:1982-1983.Aberg JA, et al. AIDS Res Hum Retroviruses. 2005;21:757-767. Calza L, et al. AIDS. 2005;19:1051-1058.

  9. NEFA: Change in TC After Switch From PI to ABC, EFV, or NVP NVP EFV ABC 35 30 29 27 30 25 24 25 21 17 21 Patients With Fasting Cholesterol ≥ 240 mg/dL (6.22 mmol/L) (%) 20 15 12 12 10 7 6 5 0 0 1 2 3 Years Martinez E, et al. CROI 2006. Abstract 521.

  10. GS903E: Change in Lipids After Switch From d4T to TDF (Week 144) TG TC 120 102 100 80 59 Mean Change in Fasting Lipids (mg/dL) 60 * * 41 38 40 20 0 Baseline (Time of Switch) Year 3 N = 85 *P < .001 for comparison with time of switch. Madruga JVR, et al. ICAAC 2007. Abstract H-364.

  11. -1 -3 -3 -5 P = NS -12 -15 P = NS P < .0001 SWAN: Change in Lipids After Switch From Comparator PI to ATV (Week 48) Switch to ATV* (n = 278) Continue PI (n = 141) TG TC LDL HDL Non-HDL 15 9 10 5 0 -3 -5 Mean Change From Baseline to Week 48 (%) -10 -15 -20 -18 -25 P < .0001 -30 -35 -33 -40 P < .0001 *Unboosted ATV, except ATV/RTV used in patients also receiving TDF. Gatell JM, et al. EACS 2005. Abstract PS1/1.

  12. ATAZIP: Switch From LPV/RTV to ATV/RTV • Randomized trial of patients on LPV/RTV > 6 months randomized to continue LPV/RTV 400/100 mg BID (n = 127) or switch to ATV/RTV 300/100 mg QD (n = 121) 20 TG TC LDL HDL 0 -20 Change at Week 48 (mg/dL) P < .0001 Switch to ATV -40 Continue LPV/RTV P < .0001 -60 Mallolas J, et al. IAS 2007. Abstract WEPEB117LB.

  13. Lipid-Lowering Therapy vs Switching PI 12-month, open-label study of 130 patients; 60% male; mean age: 39 years Stable on first HAART regimen randomized to PI  EFV (n = 34) PI  NVP (n = 29) Add bezafibrate (n = 31) Add pravastatin (n = 36) Pravastatin or bezafibrate significantly more effective in management of hyperlipidemia than switching ART to an NNRTI Calza L, et al. AIDS. 2005;19:1051-1058.

  14. Lipids Management: What is the optimal approach to managing a patient with elevated TG but otherwise normal lipids during boosted PI–based therapy?

  15. Strategies for Managing Hypertriglyceridemia • Initial intervention: dietary modifications • Consider antiretroviral switch options • If TG > 500-1000 mg/mL (> 5.65-11.30 mmol/L) and antiretroviral switch not possible, consider fibrates • Gemfibrozil 600 mg BID or fenofibrate 200 mg QD associated with 20% to 50% decrease in TG in general population • If hypertriglyceridemia remains uncontrolled • Fish oil (up to 6 g/day) or niacin (0.5 to 2g twice-dialy) can be added • Niacin associated with flushing and increased insulin resistance NCEP ATP III final report. Circulation. 2002;106:3143-3421.

  16. Dietary Prevention of Dyslipidemia Randomized trial of NCEP diet in adults initiating ART (N = 90) 95% on ZDV/3TC 75% on EFV 15- to 30-minute session with a dietician every 3 months Other outcomes Reduced fat, calorie intake Reduced BMI Increased dietary fiber intake 220 Diet Control 200 180 TC (mg/dL) 160 140 120 100 0 6 12 240 220 200 180 160 140 TG (mg/dL) 120 100 80 60 40 0 6 12 Months Lazzaretti F, et al. IAS 2007. Abstract WEAB303.

  17. Lipids Management: What drug-drug interactions are important for HIV patients when choosing lipid-lowering therapy? Which statins can be used safely in patients receiving PIs?

  18. Lipid-Lowering Agents and PIs:Drug-Drug Interactions Fibrates Fluvastatin Pravastatin* Ezetimibe Fish oil Low interaction potential Statin + fibrate Atorvastatin Rosuvastatin Niacin Use cautiously Lovastatin Simvastatin Contraindicated *AUC ↑↑↑ with DRV. Aptivus [package insert]; 2005. Carr RA, et al. ICAAC 2000. Abstract 1644. Fitchenbaum CJ, et al. AIDS. 2002;16:569-577. Gerber JG, et al. CROI 2004. Abstract 603. Gerber J, et al. IAS 2003. Abstract 870. Hsue PH, et al. Antimicrob Agents Chemother. 2001;45:3445-3450. Lexiva [package insert]; 2007. Prezista [package insert]; 2006. Reyataz [package insert]; 2007.

  19. Lipids Management: What should be the management approach for the patient with high cardiovascular risk who does not reach LDL goals after treatment with statins?

  20. Additional Therapy When LDL Goals Are Not Reached With Statins

  21. Fenofibrate vs Pravastatin in HIV-Infected Subjects: ACTG 5087 • HIV infected and on ARV > 6 months (n = 174) • LDL > 130 mg/dL (> 3.37 mmol/L) and TG > 200 mg/dL (> 2.26 mmol/L) • Randomized to • Fenofibrate 200 mg QD • Pravastatin 40 mg QD • Addition of other drug at Week 12 if lipid goal not achieved • Goal: NCEP composite LDL, HDL, TG targets • 4 (7%) on fenofibrate + pravastatin achieved composite NCEP goal • 2 (3%) on pravastatin + fenofibrate achieved composite NCEP goal • Sequencing fenofibrate then pravastatin resulted in greater absolute and % TG ↓ Aberg J, et al. AIDS Res Human Retrovirus. 2005;21:757-767.

  22. Ezetimibe for Lipid Management • Open-label, 24-week study of 19 patients with LDL  130 mg/dL ( 3.37 mmol/L) receiving ezetimibe 10 mg/day, pravastatin 20 mg/day, and current antiretrovirals[1] • Significant ↓ in TC and LDL and significant ↑ in HDL at Week 24* • No adverse events noted 250 P = .011 Baseline 200 Week 24 P = .005 150 Lipid Levels (mg/dL) 100 P = .004 50 0 TC LDL HDL TG *Subsequent study found that ezetimibe decreased LDL levels by 12% but had no effect on HDL or TG. 1. Negredo E, et al. AIDS. 2006;20:2159-2164. 2. Wohl D, et al. CROI 2007. Abstract 39.

  23. Treatment of Hypertriglyceridemia With Fish Oil • Randomized, controlled trial of high-dose fish oil vs paraffin oil • N = 122 patients with hypertriglyceridemia > 2 g/L on HAART • Mean baseline TG: 4.5 g/L • Significant efficacy at Week 8 • 10 patients with TG > 10 g/L given open-label fish oil: 44% ↓ in TG after 8 weeks • No change in LDL De Truchis P, et al. CROI 2005. Abstract 39.

  24. Metabolic Syndrome and Diabetes:How is “metabolic syndrome” defined in HIV-infected patients and what is the relevance to this population?

  25. Definition of Metabolic Syndrome • According to the NCEP ATP III, individuals with ≥ 3 of the following have the metabolic syndrome • Abdominal obesity (waist circumference > 102 cm for men; > 88 cm for women) • TG ≥ 150 mg/dL (≥ 1.70 mmol/L) • HDL < 40 mg/dL (< 1.04 mmol/L) for men, < 50 mg/dL (< 1.30 mmol/L) for women • Blood pressure ≥ 130/≥ 85 mm Hg • Fasting glucose ≥ 110 mg/dL (≥ 5.55 mmol/L) NCEP ATP III final report. Circulation. 2002;106:3143-3421.

  26. Metabolic Syndrome in HIV-Infected vs HIV-Uninfected Patients • Conflicting data on whether metabolic syndrome more prevalent in HIV-infected patients and whether associated with antiretroviral therapy • May also reflect background regional variations in risk 1. Mondy K, et al. Clin Infect Dis. 2007;44:726-734. 2. Sobieszczyk ME, et al. IAS 2006. Abstract WEPE0147. 3. Jerico C, et al. Diabetes Care. 2005;28:132-137.

  27. Metabolic Syndrome and Diabetes:Are the targets for diabetes management forthe general population also appropriate forpatients on antiretroviral therapy?

  28. Targets For Diabetes Management • No evidence that targets for HIV-infected population should differ from HIV-uninfected population American Diabetes Association. Diabetes Care. 2008;31:S12-S54.

  29. Rosiglitazone vs Metformin in HIV-Infected Patients • 39 HIV-infected men with lipodystrophy randomized to rosiglitazone 8 mg/day or metformin 2 g/day for 26 weeks • Both drugs increased insulin sensitivity • Metformin associated with fat loss, rosiglitazone with SAT gain van Wijk JP, et al. ICAAC 2005. Abstract H-339.van Wijk JP, et al. Ann Intern Med. 2005;143:337-346.

  30. Cautions When Using Insulin-Sensitizing Agents • Patients beginning insulin-sensitizing agents should be monitored closely due to risk of adverse events • Patients with aminotransferase levels > 2.5 x ULN should avoid glitazones • Risk of hepatotoxicity • Patients with elevated serum creatinine levels should avoid metformin • Risk of lactic acidemia AACTG Metabolic Guides. Available at: http://aactg.s-3.com/metabolic/diabetes.pdf. Accessed March 10, 2008.

  31. Lifestyle Issues:Are dietary and exercise advice designed to reduce cardiovascular risk in the general population also appropriate for patients with HIV?

  32. Dietary Intervention to Reduce CVD Risk in HIV-Infected Individuals • 51 HIV-infected patients (45 male and 6 female) receiving PI therapy[1] • High levels of dietary protein (mainly from animal sources) correlated with elevated TC (P < .01), elevated TG(P < .01), and reduced HDL (P < .001) • Diets high in fiber, particularly soluble fiber, associated with higher HDL levels and reduced fat deposition in HIV-infected patients[2] • Randomized study of omega-3 fatty acids in patients receiving HAART[3] • Patients assigned to receive omega-3 fatty acids plus dietary and exercise counseling vs dietary and exercise counseling alone • Mean 25.0% decline vs 2.8% increase in fasting TG, respectively after 4 weeks • However, decrease in TG associated with significant increase in LDL cholesterol 1. Shah M, et al. HIV Med. 2005;6:291-298. 2. Hendricks KM, et al. Am J Clin Nutr. 2003;78:790-795. 3. Wohl DA, et al. Clin Infect Dis. 2005;41:1498-1504.

  33. Exercise Intervention to Reduce CVD Risk in HIV-Infected Individuals • Metformin alone vs metformin with exercise training in 25 HIV-infected patients • Metformin plus exercise led to significantly improved cardiovascular parameters vs metformin alone • Waist-to-hip ratios decreased (P = .026) • Resting systolic blood pressures decreased (P = .012) • Resting diastolic blood pressures decreased (P = .001) • Changes in fasting insulin and insulin AUC more significant with metformin and exercise vs metformin alone (P < .05) Driscoll SD, et al. AIDS. 2004;18:465-473.

  34. Lifestyle Issues:What are the most effective strategies to support patients who want to quit smoking?

  35. Effective Smoking Cessation Strategies • DHHS guidelines on smoking cessation recommend pharmacotherapy for all patients attempting to quit smoking except those with medical contraindications • Approved pharmacotherapies: sustained-release bupropion, varenicline, nicotine gum, inhaler, nasal spray, and patch • More intensive intervention strategies significantly more effective than less intensive ones • Counseling sessions lasting > 3 minutes and > 10 minutes were 1.3-fold and 2.3-fold, respectively, more likely to result in abstinence vs < 3 minutes • 8 sessions were 2.3-fold more likely to result in abstinence vs 0-1 sessions • Treatment by various clinician types, individualized counseling, and multiple intervention strategies associated with successful outcomes Fiore MC. Respir Care. 2000;45:1200-1262.

  36. Lifestyle Issues:Are there data on interactions between antiretrovirals and drugs that help with smoking cessation (eg, varenicline tartrate and bupropion)?

  37. Interactions Between Antiretrovirals and Smoking Cessation Drugs • Varenicline • No reported drug interactions with antiretroviral agents since it undergoes minimal metabolism, with 92% being excreted unchanged in the urine • Bupropion • Metabolized in liver by various CYP450 enzymes, predominantly CYP2B6 • LPV/RTV and bupropion coadministration resulted in significantly decreased exposures and plasma concentrations of bupropion and hydroxybupropion[1] • Administration of ritonavir alone—most potent CYP3A4 inhibitor—may slow buproprion metabolism[2] • Patients receiving boosted PIs should be monitored carefully for bupropion lack of efficacy and adverse effects 1. Hogeland GW, et al. Clin Pharmacol Ther. 2007;81:69-75. 2. Hesse LM, et al. Drug Metab Dispos. 2001;29:100-102

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