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Metabolic Complications of HIV Infection and HAART

Metabolic Complications of HIV Infection and HAART . Christopher Behrens, MD University of Washington. Metabolic Complications of HIV Infection and HAART. Lactic Acidemia Lipodystrophy Dyslipidemia Insulin Resistance Cardiovascular Disease Bone Mineralization Disorders.

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Metabolic Complications of HIV Infection and HAART

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  1. Metabolic Complications of HIV Infection and HAART Christopher Behrens, MD University of Washington

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

  3. Lactic Acidemia & Lactic AcidosisDefinitions • Lactic Acidemia: serum lactate level greater than 2.0 mmol/L in conjunction with a normal serum pH • Common in HIV-infected patients on HAART • 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. 0 NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose MITOCHONDRION lactate pyruvate Acetyl CoA Krebs cycle Fatty Acids NADH FADH2 Oxidative phosphorylation ATP

  5. 0 NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose MITOCHONDRION lactate pyruvate Acetyl CoA Krebs cycle Fatty Acids NADH FADH2 DNA pol γ mtDNA Oxidative phosphorylation ATP

  6. 0 NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose MITOCHONDRION lactate pyruvate Acetyl CoA Krebs cycle Fatty Acids NADH FADH2 NRTIs DNA pol γ mtDNA Oxidative phosphorylation ATP

  7. 0 NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose MITOCHONDRION lactate pyruvate Acetyl CoA Krebs cycle Fatty Acids NADH FADH2 NRTIs DNA pol γ mtDNA Oxidative phosphorylation ATP

  8. 0 NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose MITOCHONDRION lactate pyruvate Acetyl CoA Krebs cycle Fatty Acids NADH FADH2 NRTIs DNA pol γ mtDNA Oxidative phosphorylation ATP

  9. 0 NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose MITOCHONDRION lactate pyruvate Acetyl CoA Krebs cycle Fatty Acids NADH FADH2 NRTIs DNA pol γ mtDNA Oxidative phosphorylation ATP

  10. 0 NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose MITOCHONDRION pyruvate lactate Acetyl CoA Krebs cycle Fatty Acids NADH FADH2 NRTIs DNA pol γ mtDNA Oxidative phosphorylation ATP

  11. 0 NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose MITOCHONDRION lactate pyruvate Acetyl CoA Krebs cycle Fatty Acids NADH FADH2 NRTIs DNA pol γ mtDNA Oxidative phosphorylation ATP

  12. 0 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

  13. 0 NRTIs have different levels of mitochondrial toxicity • rank: ddC/ ddI / d4T > 3TC > ZDV > ABC for effects on mitochondrial DNA polymerase gamma1 • tenofovir has low affinity for mitochondrial polymerase gamma as well2 • However, cases of severe hyperlactatemia have been reported in association with all NRTIs3 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

  14. 0 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)

  15. 0 Hyperlactatemia & Lactic AcidosisMeasuring 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.

  16. 0 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.

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

  18. Resumption of Antiretroviral Therapy after Lactic Acidosis • NRTI-sparing regimen? • Promising early results from trials of efavirenz + ritonavir/lopinavir1 • 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 established2-4 • re-initiation of therapy using ‘mitochondria-sparing’ NRTIs (tenofovir, abacavir, 3TC, AZT)? • reasonably safe in two studies5,6 1. Allavena C et al.JAIDS2005;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.

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

  20. Lipodystrophy

  21. Case 1 • 41 year old HIV+ man on PI-based HAART presents for routine followup • Complains of recent weight gain, especially in the abdomen • “It’s the protease paunch!”

  22. Case 1 • 41 year old HIV+ man on PI-based HAART presents for routine followup • Complains of recent weight gain, especially in the abdomen • “It’s the protease paunch!” HIPAA

  23. Case 1 continued • PMH: • HIV-infected x 5 years • well-controlled on HAART • Nadir CD4 140, most recent 360 • No OIs, though radiology studies have suggested HIV encephalopathy • Hypertension • Medications • d4T+ 3TC + Kaletra (ritonavir/lopinavir) x 2 years • Enalapril 10mg qd

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

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

  26. HIV/HAART Toxicities: Lipodystrophy • Constellation of body habitus changes • Fat accumulation (lipohypertrophy): central (esp.visceral) fat, dorso-cervical fat pads (buffalo humps), 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 breast enlargement central adiposity peripheral lipoatrophy

  28. Lipoatrophy N Engl J Med 2005;352:48-62.

  29. Dorsocervical Fat Pad

  30. FRAM: Defining Lipodystrophy • N = 565 men 33-45 years old • 412 HIV+ w/o OI’s 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 Results for concordant self-report & exam % of patients p < 0.05 for all Gripshover B et al. 10th CROI, Boston, 2003, Abstract 732.

  31. Risk Factors for Lipoatrophy and Lipohypertrophy Percentage of studies showing statistically significant associations between risk factors and either lipoatrophy (LA) (9 studies) or lipohypertrophy (LH) (8 studies) using multivariate analysis. Lichtenstein KA. JAIDS 2005;39:395-400.

  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 Percentage of studies showing statistically significant associations between risk factors and lipohypertrophy (LH) (8 studies) using multivariate analysis. Lichtenstein KA. JAIDS 2005;39:395-400.

  34. Lipohypertrophy: Pathophysiology • dysregulation of 11-beta-hydroxysteroid dehydrogenase? • Dysregulation of adipocyte differentiation and/or function? • ????

  35. Lipohypertrophy: Treatment Options • diet/exercise1-4 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.

  36. Lipohypertrophy: Treatment Options • diet/exercise • Switching Protease Inhibitors out of HAART regimen: inconsistent results Drechsler H, Powderly WG. Clin Infect Dis. 2002;35:1219-1230.

  37. Lipohypertrophy: Treatment Options • diet/exercise • Switching Protease Inhibitors out of HAART regimen: inconsistent results • Diabetes Agents? • Patients with lipodystrophy often demonstrate insulin resistance as well

  38. Metformin Therapy for Lipohypertrophy? • N = 26 patients on antiretroviral therapy with insulin resistance and fat redistribution • randomized to metformin or placebo for 12 weeks Mean change in visceral abdominal fat, mm3 p = 0.08 Hadigan C et al. JAMA 2000;284:472-7.

  39. Lipohypertrophy: Treatment Options • diet/exercise • Switching Protease Inhibitors out of HAART regimen: inconsistent results • Diabetes Agents? • Plastic Surgery?

  40. Surgical Correction ofBuffalo 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. 10th CROI, Boston, 2003. Abstract 723. 2. Piliero PJ et al. 10th CROI, Boston, 2003. Abstract 724.

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

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

  43. What intervention would you recommend for her condition? • Discontinue Kaletra, substitute atazanavir or an NNRTI • Discontinue d4T, substitute abacavir or tenofovir • Initiate rosiglitazone therapy • Plastic surgery: facial injections • None of these interventions are likely to help

  44. Lipoatrophy Risk Factors Pathophysiology Interventions

  45. Lipoatrophy: Risk Factors • Antiretroviral Therapy • HAART, esp. 2 NRTIs plus PI • d4T, esp. when used with ddI • Hierarchy: d4T/ddI/ddC > AZT > TDF/ABC/3TC • Older age • Lower body weight before therapy • Prior AIDS diagnosis • Lower CD4 nadir • Caucasian race • Male gender? 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.

  46. ? Etiology of Lipoatrophy: Evidence of Mitochondrial Toxicity in Adipocytes J Acquir Immune Defic Syndr 2002 February 1;29(2):117-121

  47. HIV infection may independently contribute to mitochondrial toxicity mtDNA:nDNA ratio Non-HIV Infected (n = 24) HIV Infected, naïve to antiretrovirals (n = 47) HIV Infected, with mitochondrial toxicity, before stopping ARVs (n = 8) HIV Infected, with mitochondrial toxicity, after stopping ARVs (n = 7) N Engl J Med 2002; 346:811-820, Mar 14, 2002.

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

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