Metabolic Complications of HIV Infection and Antiretroviral Therapy (ART)

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 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 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. 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

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

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

7. 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

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 lactate pyruvate 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 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

13. 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

14. 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 gamma2 • 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

15. 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)

16. 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.

17. 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.

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? • Do not resume ART – continue to monitor • Resume ART with efavirenz + lopinavir/ritonavir • Resume ART with TDF + 3TC + efavirenz • Resume prior ART regimen, supplemented with L-carnitine • 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/ritonavir1 • 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.

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? • Do not resume ART – continue to monitor • Resume ART with efavirenz + lopinavir/ritonavir • Resume ART with TDF + 3TC + efavirenz • Resume prior ART regimen, supplemented with L-carnitine • 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? • 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/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 Breast enlargement Central adiposity Peripheral lipoatrophy

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 Results for concordant self-report & exam % of patients p < 0.05 for all 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. 10th CROI, Boston, 2003. Abstract 736.

32. Lipohypertrophy Risk Factors Pathophysiology Interventions

33. 0 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) p = NS p <0.001 % of patients Zolopa A et al. 10th CROI, Boston 2003, Abstract 734.

35. 0 Lipohypertrophy: Pathophysiology

36. 0 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.

37. 0 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. 0 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. 0 Metformin Therapy for Lipohypertrophy? • N = 26 patients on ART 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.

40. 0 Lipohypertrophy: Treatment Options • Diet/exercise • Switching protease inhibitors out of ART regimen: inconsistent results • Diabetes agents? • Plastic surgery?

41. 0 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.

42. 0 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

43. 0 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

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46. 0 What intervention would you recommend for her condition? • Discontinue lopinavir/ritonavir, substitute atazanavir or an NNRTI • Discontinue d4T, substitute abacavir or tenofovir • Initiate rosiglitazone therapy • Plastic surgery: facial injections • None of these interventions is likely to help

47. 0 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. 0 ? Etiology of Lipoatrophy: Evidence of Mitochondrial Toxicity in Adipocytes These are your mitochondria on ARVs These are your mitochondria J Acquir Immune Defic Syndr 2002 February 1;29(2):117-121

49. 0 Lipoatrophy: Treatment Options • Switching d4T out of regimen: evidence for slow reversal of lipoatrophy

50. 0 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 regimen1 • 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-up2 • Similar findings from other studies3,4,5 Mean change in limb fat mass (intention-to-treat analysis) 4. JAIDS 2003;33:22-8. 5. JAIDS 2003;33:29-33. 1. JAMA 2002;288(2): 207-15. 2. AIDS 2004;18:1029-36. 3. CID 2004;38:263-270.