1. Metabolic Complications of HIV Infection and Antiretroviral Therapy (ART) Christopher Behrens, MD University of Washington

2. Metabolic Complications of HIV Infection and ART Lactic Acidemia Lipodystrophy Dyslipidemia Insulin Resistance Cardiovascular Disease Bone Mineralization Disorders

3. Lactic Acidemia & Lactic Acidosis Definitions Lactic Acidemia: serum lactate level greater than 2.0 mmol/L in conjunction with a normal serum pH –Common in HIV-infected patients on ART –Varying degrees of severity –Often asymptomatic Lactic Acidosis: serum lactate level greater than 2.0 mmol/L in conjunction with a serum pH less than 7.30 –Reflects most serious form of lactic acidemia –Rare but potentially fatal –Common signs & symptoms include lethargy, fatigue, weight loss, nausea, abdominal pain, and dyspnea –Concomitant hepatotoxicity common with hepatomegaly, hepatic steatosis, and even ascites and encephalopathy Schambelan M et al. JAIDS 2002;31:257-75

4. Classification of Lactic Acidemia *Symptoms and signs that suggest lactic acidemia consist of nausea, vomiting, abdominal pain, weight loss, fatigue, myalgias, abdominal distention, abdominal pain, dyspnea, and cardiac dysrhythmias. Source: HIV Web Study (www.hivwebstudy.org); Schambelan M et al. JAIDS 2002;31:257-75

5. Proposed Pathophysiology of Lactic Acidemia NRTI-induced mitochondrial toxicity

6. CELL glucose pyruvatelactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP NRTI-induced mitochondrial toxicity Proposed Pathogenesis MITOCHONDRION Fatty Acids

7. CELL glucose pyruvatelactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP NRTI-induced mitochondrial toxicity Proposed Pathogenesis MITOCHONDRION mtDNA DNA pol γ Fatty Acids

8. CELL glucose pyruvatelactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP MITOCHONDRION mtDNA DNA pol γ Fatty Acids NRTIs NRTI-induced mitochondrial toxicity Proposed Pathogenesis

9. CELL glucose pyruvatelactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP NRTI-induced mitochondrial toxicity Proposed Pathogenesis MITOCHONDRION mtDNA DNA pol γ Fatty Acids NRTIs

10. CELL glucose pyruvatelactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP NRTI-induced mitochondrial toxicity Proposed Pathogenesis MITOCHONDRION mtDNA DNA pol γ Fatty Acids NRTIs

11. CELL glucose pyruvatelactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP NRTI-induced mitochondrial toxicity Proposed Pathogenesis MITOCHONDRION mtDNA DNA pol γ Fatty Acids NRTIs

12. CELL glucose pyruvate lactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP NRTI-induced mitochondrial toxicity Proposed Pathogenesis MITOCHONDRION mtDNA DNA pol γ Fatty Acids NRTIs

13. CELL glucose pyruvate lactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP NRTI-induced mitochondrial toxicity Proposed Pathogenesis MITOCHONDRION mtDNA DNA pol γ Fatty Acids NRTIs

14. NRTIs have different levels of mitochondrial toxicity Rank: ddC/ddI/d4T > 3TC > ZDV > ABC for effects on mitochondrial DNA polymerase gamma 1 Tenofovir has low affinity for mitochondrial polymerase gamma 2 However, cases of severe hyperlactatemia have been reported in association with all NRTIs 3 1. Kakuda TN. Clin Ther 2000 Jun;22(6):685-708 2. Johnson AA et al. J Biol Chem 2001 Nov 2;276(44):40847-57 3. Schambelan M et al. JAIDS 2002;31:257-75

15. Risk Factors for the Development of Lactic Acidemia in Persons Taking NRTIs *Most cases have involved stavudine **Especially with the use of stavudine plus didanosine Source: HIV Web Study (www.hivwebstudy.org)

16. Hyperlactatemia & Lactic Acidosis Measuring Serum Lactate Levels  No vigorous exercise for 24 hours prior  Draw without tourniquet and fist clenching  Use pre-chilled gray top (fluoride-oxalate) tube  Place on ice and promptly send to lab; process within 4 hours  If increased, confirm with repeat measurement  Arterial pH measurement if frank acidosis suspected Schambelan M et al. JAIDS 2002;31:257-75.

17. Recommendations for the Management of Lactic Acidemia Source: HIV Web Study (www.hivwebstudy.org); Carr A. Clin Infect Dis 2003;36 (Suppl 2):S96-100.

18. Case 44 year old male with C3 AIDS, well-controlled on ART regimen of d4T/3TC/efavirenz Develops severe lactic acidosis and is admitted to the ICU Recovers with discontinuation of ART and supportive care, but CD4 count now 290 cells/mm³, HIV viral load 66,000 copies/mL What are your recommendations regarding antiretroviral therapy? 1.Do not resume ART – continue to monitor 2.Resume ART with efavirenz + lopinavir/ritonavir 3.Resume ART with TDF + 3TC + efavirenz 4.Resume prior ART regimen, supplemented with L- carnitine 5.I don’t know; just tell me the answer and get on with the talk

19. Resumption of Antiretroviral Therapy after Lactic Acidosis NRTI-sparing regimen? –Promising early results from trials of efavirenz + lopinavir/ritonavir 1 Addition of mitochondrial-supporting compounds as prophylaxis against recurrent lactic acidosis? –Limited evidence of benefit in hastening recovery of patients with lactic acidosis, but efficacy in preventing the condition has not been established 2-4 Re-initiation of therapy using ‘mitochondria-sparing’ NRTIs (tenofovir, abacavir, 3TC, AZT)? –Reasonably safe in two studies 5,6 1. Allavena C et al. JAIDS 2005;39(3):300-306. 2. Fouty B et al. Lancet. 1998;352:291-2. 3. Lenzo NP et al. AIDS. 1997;11:1294-6. 4. Schramm C et al. Eur J Anaesthesiol. 1999;16:733-5. 5. Lonergan JT et al. AIDS. 2003;17:2495-9. 6. ESS40010 Study Team. JAIDS. 2004;36:935-42.

20. Case 44 year old male with C3 AIDS, well-controlled on ART regimen of d4T/3TC/efavirenz Develops severe lactic acidosis and is admitted to the ICU Recovers with discontinuation of ART and supportive care, but CD4 count now 290 cells/mm³, HIV viral load 66,000 copies/mL What are your recommendations regarding antiretroviral therapy? 1.Do not resume ART – continue to monitor 2.Resume ART with efavirenz + lopinavir/ritonavir 3.Resume ART with TDF + 3TC + efavirenz 4.Resume prior ART regimen, supplemented with L- carnitine 5.I don’t know; just tell me the answer and get on with the talk

21. Lipodystrophy

22. Case 1 41 year old HIV-infected man on PI-based ART presents for routine follow-up Complains of recent weight gain, especially in the abdomen “It’s the protease paunch!”

23. Case 1 continued PMH: –HIV infection x 5 years Well-controlled on ART CD4 nadir = 140 cells/mm³, most recent = 360 No OIs, though radiology studies have suggested HIV encephalopathy –Hypertension Medications : –d4T + 3TC + lopinavir/ritonavir (Kaletra) x 2 years –Enalapril 10mg qd

24. Case 1 continued PE: obese abdomen, otherwise unremarkable

25. What intervention would you recommend? A.Ask his wife to padlock the fridge and get him a treadmill B.Discontinue lopinavir/ritonavir, substitute an NNRTI such as efavirenz or nevirapine C.Start metformin 500mg bid D.Liposuction E.None of the above have been demonstrated to improve HIV-associated visceral fat accumulation

26. HIV/ART Toxicities: Lipodystrophy Constellation of body habitus changes –Fat accumulation (lipohypertrophy): central (esp. visceral) fat, dorso-cervical fat pad (buffalo hump), breasts, lipomata, within muscle & liver –Fat wasting (lipoatrophy): face, extremities, buttocks, and trunk Lack of clear case definition has hampered clinical research: wide variation in reported prevalence Increasing evidence that lipoatrophy and lipohypertrophy are distinct entities, though can occur simultaneously Hyperlipidemia and insulin resistance also variably present

27. Facial lipoatrophy Central adiposity Peripheral lipoatrophy Breast enlargement

28. Dorsocervical Fat Pad

29. FRAM Study: Defining Lipodystrophy Study Outline Aim: compare randomly selected HIV-infected subjects and healthy controls to identify statistically significant differences and any linkages between lipodystrophic body changes Three types of evaluation: –Self-report re: body habitus changes –Clinical evaluation of presence/degree of visible lipoatrophy –Body composition measures including whole-body MRI and DEXA scanning Grunfeld C. XIV International AIDS Conference, 2002, Abstract TuOr158.

30. FRAM: Defining Lipodystrophy N = 565 men 33-45 years old –412 HIV+ w/o OIs in past month –153 HIV-negative controls from CARDIA study Examined fat loss/deposition in peripheral sites (cheeks, face, arms, legs, buttocks) and central sites (waist, abdomen, neck, chest, upper back) Peripheral and central lipoatrophy more common in HIV+ subjects Central lipohypertrophy more common in HIV-negative subjects Lack of concordance between lipoatrophy and lipohypertrophy p < 0.05 for all Results for concordant self-report & exam % of patients Gripshover B et al. 10th CROI, Boston, 2003, Abstract 732.

31. Lipodystrophy in Women: WIHS Women’s Interagency HIV Study (WIHS): prospective, multi-site study of progression of HIV infection in women 1,057 HIV-infected and HIV-uninfected women evaluated every 4 months over an 18-month period beginning in 1999 Over 18 months, mean weight and total body fat increased slightly in HIV-negative women but remained stable in HIV- positive women Incidence of peripheral and central lipoatrophy in HIV- positive women was double that of HIV-negative women Incidence of central lipohypertrophy was similar in HIV- positive vs HIV-negative women Tien PC et al. 10 th CROI, Boston, 2003. Abstract 736.

32. Lipohypertrophy Risk Factors Pathophysiology Interventions

33. Lipohypertrophy: Risk Factors Duration of antiretroviral therapy Use of protease inhibitors Markers of disease severity Age Female gender Lichtenstein KA. JAIDS 2005;39:395-400.

34. Incidence & Size of Buffalo Humps N = 421 HIV(+) men vs 151 matched HIV(-) controls (FRAM cohort) % of patients Zolopa A et al. 10 th CROI, Boston 2003, Abstract 734. p = NSp <0.001

35. Lipohypertrophy: Pathophysiology

36. Lipohypertrophy: Treatment Options Diet/exercise 1-4 1. Jones SP et al. AIDS 2001 Oct 19;15(15):2049-51 2. Roubenoff R et al. Clin Infect Dis 2002 Feb 1;34(3):390-3 3. Roubenoff R et al. AIDS. 1999;13:1373-1375. 4. Thoni GJ et al. Diabetes Metab. 2002;28:397-404.

37. Lipohypertrophy: Treatment Options Diet/exercise Switching protease inhibitors out of ART regimen: inconsistent results Drechsler H, Powderly WG. Clin Infect Dis. 2002;35:1219-1230.

38. Lipohypertrophy: Treatment Options Diet/exercise Switching protease inhibitors out of ART regimen: inconsistent results Diabetes agents? –Patients with lipodystrophy often demonstrate insulin resistance as well

39. N = 26 patients on ART with insulin resistance and fat redistribution Randomized to metformin or placebo for 12 weeks Hadigan C et al. JAMA 2000;284:472-7. p = 0.08 Metformin Therapy for Lipohypertrophy? Mean change in visceral abdominal fat, mm 3

40. Lipohypertrophy: Treatment Options Diet/exercise Switching protease inhibitors out of ART regimen: inconsistent results Diabetes agents? Plastic surgery?

41. Surgical Correction of Buffalo Hump? Liposuction or surgical excision a reasonable option, esp. if pain or functional limitations Only small studies to date Generally well-tolerated with favorable initial results Conflicting data regarding recurrence: one study found a recurrence rate of just 5% (1/18 patients) 1 while another study reported a recurrence rate of 50% (5/10 patients) 2 1. Gervasoni C et al. 10 th CROI, Boston, 2003. Abstract 723. 2. Piliero PJ et al. 10 th CROI, Boston, 2003. Abstract 724.

42. What intervention would you recommend? A.Ask his wife to padlock the fridge and get him a treadmill B.Discontinue lopinavir/ritonavir, substitute an NNRTI such as efavirenz or nevirapine C.Start metformin 500mg bid D.Liposuction E.None of the above have been demonstrated to improve HIV-associated visceral fat accumulation

43. Case 2: Lipoatrophy 43 year old woman with history of PCP now doing well on ART: d4T/3TC/lopinavir/ ritonavir She complains that her cheeks appear sunken and the veins in her arms and legs are more prominent

46. What intervention would you recommend for her condition? A.Discontinue lopinavir/ritonavir, substitute atazanavir or an NNRTI B.Discontinue d4T, substitute abacavir or tenofovir C.Initiate rosiglitazone therapy D.Plastic surgery: facial injections E.None of these interventions is likely to help

47. Lipoatrophy: Risk Factors Antiretroviral therapy –ART, esp. 2 NRTIs plus PI –d4T, esp. when used with ddI –Hierarchy: d4T/ddI/ddC > AZT > TDF/ABC/3TC Prior AIDS diagnosis Lower CD4 nadir Lower body weight before ART Caucasian race Male gender Older age Grinspoon S et al. N Engl J Med 2005;352:48-62. Podzamczer D et al. 11th CROI, 2004, Abstract 716. Lichtenstein KA et al. JAIDS 2003;32:48-56. Joly V et al. AIDS 2002;16:2447-2454. Dube M et al. 4th Int’l Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 2002, abstract 27. Shlay J et al. XV International AIDS Conference, 2004, Abstract ThOrB1360.

48. J Acquir Immune Defic Syndr 2002 February 1;29(2):117-121 ? Etiology of Lipoatrophy: Evidence of Mitochondrial Toxicity in Adipocytes These are your mitochondria These are your mitochondria on ARVs

49. Lipoatrophy: Treatment Options Switching d4T out of regimen: evidence for slow reversal of lipoatrophy

50. Abacavir substitution for patients with subcutaneous lipoatrophy (LA): MITOX 111 patients with subjective LA on stable AZT- or d4T- containing ART randomized to substitute abacavir or continue current regimen 1 Limb fat mass measured by DEXA and by subjective physician assessment Statistically significant increase in limb fat mass by DEXA at 104 weeks of follow-up 2 Similar findings from other studies 3,4,5 1. JAMA 2002;288(2): 207-15. 2. AIDS 2004;18:1029-36. 3. CID 2004;38:263-270. 4. JAIDS 2003;33:22-8. 5. JAIDS 2003;33:29-33. Mean change in limb fat mass (intention-to-treat analysis)

51. Lipoatrophy: Treatment Options Switching d4T out of regimen: evidence for slow reversal of lipoatrophy Diabetes agents? - Rosiglitazone increases subcutaneous fat in type 2 diabetic patients and reverses the block of adipocyte differentiation induced by ART in vitro

52. Rosiglitazone for Lipoatrophy? Discouraging results to date N=108 HIV-1-infected adults with LA on ART randomized to rosiglitazone 4 mg twice daily (n=53) or matching placebo (n=55) for 48 weeks 1 Limb fat increased by 0.14 kg in the rosiglitazone group and 0.18 kg in the placebo group (p=NS) Two other similar studies: –One showed no improvement 2 –One showed modest benefit 3 1. Carr A et al. Lancet. 2004;363:429-438. 2. Sutinen J et al. Antivir Ther 2003;8:199-207. 3. Hadigan C et al. Ann Intern Med 2004;140:786-794. Change in limb fat by DEXA www.clinicaloptions.com

53. Lipoatrophy: Treatment Options Switching d4T out of regimen: evidence for slow reversal of lipoatrophy Diabetes agents? Facial injections? –Intradermal injections of polylactic acid

54. Valantin MA et al. AIDS 2003, 17:2471–2477

55. VEGA: 96 week results Valantin MA et al. AIDS 2003, 17:2471–2477

56. What intervention would you recommend for her condition? A.Discontinue lopinavir/ritonavir, substitute atazanavir or an NNRTI B.Discontinue d4T, substitute abacavir or tenofovir C.Rosiglitazone D.Plastic surgery: facial injections E.None of these interventions are likely to help

57. Dyslipidemia

58. Dyslipidemia: Case continued He returns for followup 3 months later and reports some improvement with increased physical activity You check a fasting lipid panel

59. Case continued Fasting lipid panel Total cholesterol = 320 mg/dL Triglycerides= 870 mg/dL HDL cholesterol = 32 mg/dL LDL cholesterol: could not be calculated

60. What intervention(s) would you recommend to improve his lipid profile? A.Discontinue lopinavir/ritonavir, substitute atazanavir B.Discontinue d4T, substitute tenofovir C.Ask his employer to replace the donuts in the vending machine with granola D.Start simvastatin E.Start gemfibrozil F.Nothing needs to be done; dyslipidemia associated with HIV/ART is not associated with an increase in CAD

61. Decreased levels of HDL & LDL (especially HDL) and elevated triglycerides seen in HIV-infected patients prior to introduction of ART Most protease inhibitors have been associated with marked elevations in triglycerides and LDL but little effect on HDL levels NNRTIs and stavudine also associated with dyslipidemic effects HIV infection and PI-based ART each associated with pro- atherogenic profile dyslipidemia Substantial evidence that PI-based ART increases risk of coronary artery disease (CAD) 2-4 HIV/ART Toxicities: Dyslipidemia 1. Schambelan M et al. JAIDS 2002; 31(3):257-75. 2. 11 th CROI, 2004, Abstract 739. 3. 11th CROI, 2004, Abstract 736. 4. 11 th CROI, 2004, Abstract 737.

62. The DAD Study Group, N Engl J Med 2003;349:1993-2003 Incidence of Myocardial Infarction According to the Duration of Exposure to Combination Antiretroviral Therapy

63. Risk Factors for MI in patients on ART: DAD Use of ART (per additional year)1.26** Age (per additional 5 yrs)1.38 Male Sex1.99 Current or former smoker2.17 Prior history of CAD5.84 Risk FactorRelative Risk of MI* The DAD Study Group, N Engl J Med 2003;349:1993-2003 * Multivariate analysis ** revised to 1.17 on further follow-up

64. Often improves with removal of offending agents from regimen Treatment with fibrates and/or statins often indicated Beware of drug interactions, risk of myositis ART- associated Dyslipidemia: Treatment

65. Switch ART regimen or initiate lipid- lowering pharmacotherapy? Trend of mean plasma triglyceride levels of 130 evaluable patients switched from protease inhibitor to nevirapine (arm A) or efavirenz (B), or treated with pravastatin (C) or bezafibrate (D), at baseline and after 3, 6, 9 and 12 months of follow-up. Calza L et al. AIDS 2005: 19(10), 1051-8.

66. Switch ART regimen or initiate lipid- lowering pharmacotherapy? Trend of mean plasma total cholesterol levels of 130 evaluable patients switched from protease inhibitor to nevirapine (arm A) or efavirenz (B), or treated with pravastatin (C) or bezafibrate (D), at baseline and after 3, 6, 9, and 12 months of follow-up. Calza L et al. AIDS 2005: 19(10), 1051-8.

67. Lipid-Lowering Agents and ARV Therapy: Potentially Dangerous Drug Interactions Agent Pravastatin Atorvastatin Lovastatin Simvastatin Gemfibrozil Fenofibrate Niacin Bile sequestrants No dose adjustment Dose titration Avoid No dose adjustment Associated with insulin resistance Avoid Recommendation Dube MP et al. Clin Infect Dis 2000;31:1216-24.

68. What intervention(s) would you recommend to improve his lipids? A.Discontinue lopinavir/ritonavir, substitute atazanavir B.Discontinue d4T, substitute tenofovir C.Ask his employer to replace the donuts in the vending machine with granola D.Start simvastatin E.Start gemfibrozil F.Nothing needs to be done, as studies have failed to document an increase in CAD in patients on ART

69. Insulin Resistance

70. Insulin Resistance (IR) Defined as condition in which increased levels of insulin are required to exert normal biologic response 1 Typically associated with increased fasting insulin levels, but clinically relevant thresholds of insulin levels have not been defined IR should be suspected in setting of elevated fasting blood glucose levels or impaired glucose tolerance 1. Olefsky JM. Ellenberg & Rifkin’s Diabetes Mellitus (1997):513-52.

71. American Diabetic Association: Prediabetes & Diabetes Pre-diabetes Diabetes mellitus Impaired fasting glucose Impaired glucose tolerance Fasting glucose 100- 125 mg/dL 2-hour post-load glucose 140-199 mg/dL during OGTT Fasting glucose ≥126 mg/dL or 2 hr post- load glucose ≥200mg/dL during OGTT, or symptoms of diabetes with random glucose ≥200mg/dL Adapted from: http://clinicaloptions.com/2004lipo

72. HIV/ART Toxicities: Insulin Resistance Direct mechanism: medication-induced –PIs can have a direct effect on glucose metabolism 1 –Indinavir leads to decreased insulin sensitivity in both HIV-infected and uninfected subjects 2 –Amprenavir may not share this class effect 3 –Efavirenz, but not nevirapine, implicated as well 4 –NRTIs also recently identified as risk factor 5 –Mechanism: inhibition of an insulin-regulated glucose transporter GLUT4 ? 6 Inhibition of peroxisome proliferator-activated receptor gamma? 7,8 1. Dube MP et al. JAIDS 2000;27:130-4. 2. Noor MA et al. AIDS 2001;15:4. 3. Dube MP et al. Antivir Ther 2001;6(4):11. Abst 14. 4. Mehta et al, 9th CROI, 2002, Abstract 679. 5. Brown TT et al. AIDS 2005, 19:1375–1383 6. Murata H et al. J Biol Chem 2000;275:251-4. 7. Caron M et al. Diabetes 2001;50:1378–88 8. Miserez AR et al. AIDS 2002;16:1587–94.

73. HIV/ART Toxicities: Insulin Resistance Indirect mechanism: via changes in body fat composition (lipohypertrophy, lipoatrophy) 1-4 1. Hadigan C et al. Clin Infect Dis 2001;32:130–9. 2. Mynarcik DC et al. J Acquir Immune Defic Syndr 2000;25:312–21. 3. Kosmiski LA et al. AIDS 2001;15:1993–2000. 4. Meininger G et al. Am J Clin Nutr 2002;76:460–5. www.clinicaloptions.com

74. Currier et al, 9th CROI, February 2002, abstract 677-T

75. Insulin resistance is associated with increased risk of CAD in non-HIV infected patients www.clinicaloptions.com Despres JP et al. N Engl J Med. 1996;334:952-957.

76. Insulin Resistance: Treatment Consider avoiding implicated PIs for patients with pre-existing diabetes or significant risk factors Substitution of PI with NNRTIs 1,2 or abacavir 3, if regimen potency can be maintained Treatment of diabetes mellitus: similar to that for HIV-uninfected individuals Screen for and treat insulin resistance? 1. Martinez E et al. AIDS 1999;13:805–10. 2. Martinez E et al. Clin Infect Dis 2000;31:1266–73. 3. Walli RK et al. Eur J Med Res 2001;6:413–21.

77. Bone Mineralization Disorders associated with HIV and/or ART Osteonecrosis Osteopenia

78. Avascular Necrosis of the Femoral Head

79. Higher Prevalence of Osteonecrosis in HIV-Infected Adults Screening MRIs performed on 339 asymptomatic HIV-infected adults and 118 age- and sex-matched HIV-negative controls Osteonecrosis of the femoral head identified in 15 of 339 (4.4%) HIV-infected patients compared to 0/118 controls (p<0.05) Comparison of HIV-infected patients with or without osteonecrosis showed no difference by age, sex, race, risk factor, CD4 cell count, viral load, antiretroviral therapy, blood lipids or CBC. The risk was increased for those who had received corticosteroids, lipid-lowering agents or testosterone. Miller KD et al. Ann Intern Med 2002 Jul 2;137(1):17-25.

80. Other studies of HIV-infected patients have found similar associations with steroid use and hyperlipidemia but not with the use of specific antiretroviral agents 1,2 Implication: consider this diagnosis in HIV- infected patients with shoulder, groin, or hip pain 1. Scribner AN et al. JAIDS 2000;25:19-25. 2. Glesby MJ et al. JID 2001;184:519-23. Higher Prevalence of Osteonecrosis in HIV-Infected Adults

81. StudySamplePrevalence*Risk Factors Carr, 2001 Australia 221 HIV+ men, Wt. 70-75 kg 25%Lactate level low weight Huang, 2001 Boston, MA 41 HIV+ men, BMI 25 18 HIV- men, BMI 25 BMD reduced in HIV+ men w/ high visceral fat Historical low weight; high visceral fat McDermott, 2001 New England 203 HIV+ men, BMI 24 62 HIV+ women, BMI 25 BMC reduced in men on ART ART use and duration Knobel 2001 Spain 58 HIV+ men, 22 HIV+ women, BMI 23 overall 100 HIV- controls, BMI 23 89% in HIV+ 30% in HIV- Weight, BMI Nolan, 2001 Australia 183 HIV+ men BMI 23-24 56% in PI-treated; 49% in PI-naïve Low pre-ART BMI; Indinavir protective Gold, 2002 Australia 110 HIV+ men lean mass 57 kg 55%Age, lean body mass, duration of NRTI use Mondy, 2003 St. Louis, MO 108 HIV+ men, 17 HIV+ women; BMI 25 46%BMI, smoking, wt loss, steroids Arnsten, 2003 New York, NY 200 HIV+ women: BMI 28 205 HIV- women: BMI 32 30% in HIV+ 24% in HIV- Age, race, BMI; PI use >1 year protective Studies on Osteopenia in HIV Adapted from Arnsten JH et al, 10 th CROI, Boston 2003, Abstract 103 * combined prevalence of osteopenia and osteoporosis

82. Alendronate for HIV-associated osteopenia: 48 week results N=31 HIV-infected subjects on ART with lumbar spine BMD t- scores less than -1.0 87% male, 80% Caucasian, 29% smokers, mean age 44 yo; mean BMI 25kg/m2 Median CD4 count 561 cells/mm³; 84% had VL <400 copies/mL Randomized to alendronate 70 mg weekly (n=15) or placebo (n=16) All patients received calcium 1g daily and vit D 400 IU daily No serious adverse events p = 0.005 % change from baseline in BMD Mondy K et al. 10th CROI, Boston, 2003. Abstract 134. p = NS

83. Metabolic Complications of HIV and ART Summary & Conclusions

84. Hyperlactatemia/Lactic Acidosis Potentially fatal syndrome linked to prolonged NRTI use, especially ddI, d4T Signs and symptoms often subtle, nonspecific Venous lactate level useful in diagnosis Discontinuation of ART indicated for symptomatic hyperlactatemia/lactic acidosis Resumption of ART that includes NRTIs is controversial

85. Lipodystrophy Lipoatrophy more common in HIV-infected individuals and has been linked to markers of HIV disease severity and to d4T Switching out the offending agent appears to improve lipoatrophy, but very slowly Buffalo humps may be no more common in HIV- infected patients, but may be larger when they do occur Central fat deposition less common in HIV-infected individuals Diet, exercise are the most effective treatments for central fat accumulation Plastic surgery: short-term benefit; long term - ?

86. Dyslipidemia & ART Many antiretrovirals, especially protease inhibitors, associated with dyslipidemia ART-induced dyslipidemia may contribute to risk of coronary artery disease, though short-term absolute risk appears to be small Discontinuation of dyslipidemia-inducing agents will generally improve lipid profile ART-induced dyslipidemia can be treated with fibrates and/or statins, but response is often sub-optimal and potential drug interactions need to be considered carefully

87. Linked to many protease inhibitors, efavirenz, and possibly some NRTIs Also linked to presence of lipodystrophy Progression to frank diabetes mellitus possible Monitor with fasting glucose values Improvement may or may not be seen with switching out of the offending agents Insulin Resistance

88. HIV & Bone Disease Patients with HIV infection, especially Caucasian men, appear to be at increased risk of osteopenia Etiology not known at this time Role of ART overall and of individual ARV agents is unclear Routine screening not recommended Intervention warranted for modifiable risk factors such as smoking, alcohol, steroid use, hyperlipidemia, wasting, sedentary lifestyle, low calcium intake HIV-infected patients also at increased risk of osteonecrosis Consider diagnosis of osteonecrosis in patients with unexplained shoulder/hip/groin pain

89. The End