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HIV-Lipodystrophy: Guidelines Development

HIV-Lipodystrophy: Guidelines Development. Donald Kotler, MD Professor of Medicine Columbia University College of Physicians and Surgeons St. Luke’s-Roosevelt Hospital Center New York, NY. HIV-Associated Lipodystrophy. Hyperlipidemia. Insulin resistance. Fat accumulation. Fat atrophy.

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HIV-Lipodystrophy: Guidelines Development

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  1. Kotler_MDS218_final

  2. Kotler_MDS218_final HIV-Lipodystrophy:Guidelines Development Donald Kotler, MD Professor of Medicine Columbia University College of Physicians and Surgeons St. Luke’s-Roosevelt Hospital Center New York, NY

  3. Kotler_MDS218_final HIV-Associated Lipodystrophy Hyperlipidemia Insulin resistance Fat accumulation Fat atrophy

  4. Kotler_MDS218_final Lipodystrophy • Are lipodystrophy and metabolic disorders a single syndrome or multiple, overlapping syndromes? • Are these conditions caused by ART, host factors, HIV disease, or a combination of factors?

  5. Kotler_MDS218_final Guidelines: Rationale • Response to need for cost effective approach to diagnosis and management • Clinical and public health (epidemiologic) needs • Guidelines will need periodic revision

  6. Kotler_MDS218_final Aims: Guidelines • Glucose metabolism • Lipid metabolism • Body composition • Cardiovascular risk • Lactic acidemia • Osteopenia

  7. Kotler_MDS218_final Glucose Metabolism • Pre-HAART data • Phenotype • Effect of PI in healthy volunteers • Effects of fat accumulation • Effects of fat depletion • Recommendations • Future directions

  8. Kotler_MDS218_final Fasting Glucose vs OGTT FastingIntolerance Fasting Diabetes 2-hour Intolerance 2-hour Diabetes 110, <126 126 140, <200 200 1 (3%) 0 9 (30%) 0 Engelson. 13th IAC; 2000; Durban. Abstract ThPpB 1437.

  9. Kotler_MDS218_final Effect of Indinavir Upon Glucose Metabolism • Design: prospective, open-label • Patients: 10 healthy volunteers • Treatment: IDV 800 mg TID x 1 mo • Measurements: insulin resistance, lipids, body composition • Findings: insulin resistance rose while lipids and body composition did not change Noor. 2nd Workshop on Lipodystrophy.

  10. Kotler_MDS218_final VAT and Insulin Sensitivity 10 r = –.050P <.0001 8 6 Insulin Sensitivity(10-4 - min-1/(U-1 mL) 4 2 0 0 250 300 100 150 200 50 VAT (cm2)

  11. Kotler_MDS218_final Lipoatrophy and Insulin Resistance • Design: prospective, cross-sectional • Subjects: 15 HIV+ with LD, 14 HIV+ without LD, 12 controls • Measurements: insulin resistance, body composition, soluble TNF receptors • Findings: insulin resistance was reduced more in muscle than in fat, and was associated with lipoatrophy and increased sTNFR2 levels Mynarcik. JAIDS 2000;25:312.

  12. Kotler_MDS218_final Clinical Fasting glucose Investigational Fasting insulin C-peptide HOMA Oral glucose tolerance test HgbA1C (diabetes only) Consensus:Insulin Resistance

  13. Kotler_MDS218_final Metformin in HIV-Lipodystrophy • Randomized, controlled trial • Metformin at 500 mg BID • Treatment associated with decreased insulin AUC during OGTT (P = .01) • Treatment associated with weight loss(P = .005), decreased blood pressure(P = .009) • Trend towards decreased VAT • Metformin decreased TPA and PAI-1 Hadigan. JAMA 2000;284:472.

  14. Kotler_MDS218_final Rosiglitazone in Lipodystrophy • Insulin resistance is common • Insulin resistance is drug-related • Insulin resistance precedes fat redistribution • Insulin resistance is related to microvascular disease in other circumstances • Thiazolidinediones decrease insulin resistance

  15. Kotler_MDS218_final Fat Metabolism • Pre-HAART data • Phenotype • Effect of PI in healthy volunteers • Effects of other ARVs • Genetic susceptibilities • Recommendations

  16. Kotler_MDS218_final Fat Metabolism:Pre-HAART Data • Elevated fasting triglycerides • Association with elevated de novo synthesis • Associated with decreased clearance • Association with serum alpha interferon • Decreased HDL, LDL, VLDL chol, and apo B • Increased prevalence of LDL-B • Apoprotein E2 associated with higher triglycerides • Triglycerides fell with AZT therapy

  17. Kotler_MDS218_final Effect of RTVUpon Serum Lipids • Design: double-blind, placebo-controlled • Patients: 21 healthy volunteers • Treatment: RTV for 2 weeks • Findings: RTV treatment led to rises in triglycerides, VLDL chol, LDL chol, apo B, and Lp (a) Purnell. AIDS 2000;14:51.

  18. Kotler_MDS218_final Evaluation: Dyslipidemia • Fasting lipid profile • 8 hr, preferably >12 hr • TGs, total and HDL chol, calculated LDL • Calculated LDL is inaccurate if TGs >400 • Evaluate prior to therapy • Repeat 3 to 6 months • Repeat 1 to 2 months if baseline TGs are elevated • Screen for other risk factors Adult ACTG Cardiovascular Disease Focus Group, 5/25/00.

  19. Kotler_MDS218_final NCEP Guidelines:Treatment Initiation Treatment Decisions Based on LDL-Cholesterol Level* Initiation Level LDL GoalPatient Category (mg/dL) (mg/dL) Dietary Therapy Without CHD and <2 risk factors 160 <160 Without CHD and  2 risk factors 130 <130 With CHD >100 100Drug Treatment Without CHD and <2 risk factors 190 <160 Without CHD and  2 risk factors >130 100 *LDL = low-density lipoprotein; CHD, coronary heart disease.

  20. Kotler_MDS218_final Treatment of Hyperlipidemia • Potential for drug-drug interactions between statins/fibrates and antvirals • Atorvastatin, simvastatin, lovastatin, benzafibrate, ciprofibrate, fenofibrate, and gemfibrozil are metabolized primarily by CYP3A4 • Cerivastatin and fluvastatin are metabolized by CYP2C8 and CYP2C9, respectively • Pravastatin is not primarily metabolized by CYP isoenzymes

  21. Kotler_MDS218_final Body Fat Redistribution • Definitions • Prevalence • Associations • Measurements • Recommendations • Future directions

  22. Kotler_MDS218_final Body Fat Distribution • Refers to the 3-dimensional localization of adipose tissue depots within the body • Various depots affect metabolism differently • Compartment size affected by many factors • Health consequences • Associations with hyperlipidemia, insulin resistance, atherosclerosis • Association with absolute, not relative,fat contents

  23. Kotler_MDS218_final Prevalence of Fat Redistribution Prevalence Estimate* Reference n/N % Method(s) Boix et al 1998 5/272 2 SR/CR Shaw et al 1998 12/961 13 PE Dong et al 1999 21/116 18 SR/PE Veny et al 1998 35/158 22 PE Lichtenstein et al 2000 529/1077 49 CR Miller et al 2000 723/1350 51 SR/PE Carr et al 1998 74/116 64 SR/PE Carr et al 1999 95/113 84 SR/PE *Prevalenceestimates are forcombined lipohypertrophy and lipoatrophy. Abbreviations: SR – self-report; PE – physical examination; CR – chart review. Boix. 12th World AIDS Congress, 1998. Abstract 12398. Shaw. J STD & AIDS 1998;9:595-599. Dong.J Acquir Immune Def Syndr Hum Retrovirol 1999;21:107-113. Veny. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy 1998. Abstract I-92. Lichtenstein. 7th Congress on Retroviruses and Opportunistic Infections 2000. Abstract 23. Carr. AIDS 1998;12:F51-F58. Carr. Lancet 1999;353:2093-2099.

  24. Kotler_MDS218_final Regional Measurements • Cross-sectional imaging • CT, MRI • Whole body and single slice • Regional DXA • Anthropometry • Regional BIA • Ultrasound

  25. Kotler_MDS218_final Abdominal MRI Scans VAT VAT SAT SAT Control Subject Increased VAT

  26. Kotler_MDS218_final DXA and Fat Distribution • Most appendicular fat is SAT • Change in appendicular fat = change in SAT • Trunk fat is comprised of SAT and VAT • Mild improvement over anthropometrics in non-HIV conditions • Comparison to anthropometrics in HIV infection not reported

  27. Kotler_MDS218_final Changes in Trunk Fat vs VAT 8 y = 0.4564x –0.2556R2= 0.7153 6 4 2 Change in VAT (Liters) 0 –10 –8 –6 –4 –2 0 2 4 6 8 10 –2 –4 –6 –8 Change in Trunk Fat (kg)

  28. Kotler_MDS218_final Difference vs Average of Predicted and Measured VAT 3 2 Mean + 2SD = 1.57 1 Difference Between Measured andPredicted VAT (Liters) Mean = 0.058 0 –6 –4 –2 0 2 4 6 –1 Mean –2SD = –1.43 –2 –3 Average of Measured and Predicted VAT (Liters)

  29. Kotler_MDS218_final Changes in Limb Fat vs SAT 10 8 y = 1.7514x + 0.13R2 = 0.6978 6 4 2 Change in SAT (Liters) 0 –5 –4 –3 –2 –1 0 1 2 3 4 5 –2 –4 –6 –8 –10 Change in Limb Fat (kg)

  30. Kotler_MDS218_final Difference vs Average ofPredicted and Measured SAT 4 Mean + 2SD = 3.17 3 2 1 Difference Between Measured andPredicted SAT (Liters) Mean = 0.016 0 –10 –8 –6 –4 –2 0 2 4 6 8 10 –1 –2 Mean –2SD = –3.0 –3 –4 Average of measured and predicted SAT (liters)

  31. Kotler_MDS218_final Waist vs Hip (Male Controls) 1600 y = 0.8577x + 166.09R2= 0.8086 1400 1200 1000 WC (mm) 800 600 400 200 200 400 600 800 1000 1200 1400 1600 CIC (mm)

  32. Kotler_MDS218_final Clinical Significance + – Coronary arterydisease 0.938 ± 0.051 0.925 ± 0.054 CVA 0.958 ± 0.051 0.925 ± 0.054 All cause deaths 0.935 ± 0.053 0.925 ± 0.053 Larsson. BMJ 1984.

  33. Kotler_MDS218_final Anthropometric Analyses • WHR predicts adverse consequences in epidemiologic studies • WHR lacks sensitivity and specificity compared to CT or MRI, also in HIV • Waist circumference and sagittal diameter are better predictors of VAT by single-slice CT in non-HIV • Multivariate techniques

  34. Discriminant Function vsVAT by MRI Kotler_MDS218_final 45 40 35 Female No Lipo DF Female Lipo 30 25 20 0 5 10 VAT vol (L) DF = 0.043*WC-0.70*WHR

  35. Kotler_MDS218_final Clinical Waist circumference Investigational Single-cut CT Single-cut MRI DEXA Ultrasound BIA (not useful) Evaluation: Visceral Fat

  36. Kotler_MDS218_final Effect of Discontinuing d4T • 9-month follow-up • Increased SAT • No change in VAT • Results imply that lipoatrophy is reversible Saint-Marc. 7th CROI; 2000; San Francisco. Abstract 52.

  37. Kotler_MDS218_final Lipodystrophy:Effect of Exercise • Design: prospective, open label • 10 men with truncal obesity • 16-week exercise program • Results: significant decrease in total body and truncal fat, no significant change in weight, lean mass, or bone density nor adverse effects Roubenoff. AIDS 1999;13:1373.

  38. Kotler_MDS218_final Week Baseline 12 24 36 48 60 8 6 4 VAT (Liters) 2 0 rhGH dose 6 mg 0 2 mg

  39. Kotler_MDS218_final Risk: Benefit Analysis ofCAD* and HAART Average calculated increase in CHD events = 0.14% per year  Mortality rates in HIV-infected patients by 50% in the US Risks Benefits *CHD = coronary heart disease. Adapted from Grunfeld. 6th CROI; 1999; Chicago. Palella. NEJM 1998;338:853.

  40. Kotler_MDS218_final Clinical Classic risk factors Investigational Carotid doppler Stress echo Noninvasive coronary artery assessment Novel metabolic parameters Evaluation: Cardiovascular Risk

  41. Kotler_MDS218_final Lactic Acidosis • Liver dysfunction as opposed to lipodystrophy • Non-specific symptoms, may be fatal • Reversal with cessation of NRTI therapy • Mild elevations are common • Utility of screening lactate is questionable • 5 mmol/L with symptoms or 10 mmol/L, irrespective of symptoms, is significant • Need care in sample collection • Routine monitoring not recommended

  42. Kotler_MDS218_final Osteopenia/Osteonecrosis • Previous studies had documented avascular necrosis of the femoral head • May be asymptomatic • Studies show demineralization in a range that may become clinically significant • Not likely related to PI therapy • NRTI therapy may affect bone mineral • Routine screening is not recommended

  43. Kotler_MDS218_final

  44. Kotler_MDS218_final For more HIV-related resources, please visit www.hivguidelines.org

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