David A Cooper National Centre in HIV Epidemiology and Clinical Research

1. Lipodystrophy and metabolic disorders in HIV disease David A Cooper National Centre in HIV Epidemiology and Clinical Research The University of New South Wales Sydney, Australia

2. Lipoatrophy

3. Fat accumulation

4. Cytokines and tissue inflammation in lipoatrophy • increased levels of IL-6 and TNF- in adipose tissue correlate with1 •  adipose tissue apoptosis • adipocytes and preadipocytes undergo apoptosis2 •  adipose tissue fibrosis • adipocytes and preadipocytes are dying and are replaced • repair process fills in the space by laying down collagen •  adipose vascularity •  macrophage infiltration of adipose tissue • increased levels of IL-18 correlate with  limb fat3,4 1. Cervera, et al. Antivir Ther. 2004; 2. McComsey, et al. Antiviral Therapy: 2006 3. Lindegaard, et al. AIDS. 2004. 4. Lindegaard et al. J Acquir Immun Defic Syndr. 2004;36

5. Impact of HIV disease • Effects of RTIs • Effects of PIs • Clinical studies in naïve patients • Switch studies • Intervention • Summary

6. Impact of HIV disease • Effects of RTIs • Effects of PIs • Clinical studies in naïve patients • Switch studies • Intervention • Summary

7. 1.5 1.4 1.5 1.4 2.5 SMART: effect of ART discontinuation ► ► favours VS ► favours DC El-Sadr, Neatonet al, CROI 2006

8. SMART: baseline biomarkers and all cause mortality Insight Mtg Tlk 2/6/2008

9. 10 all subjects 8 6 4 2 0 none < 1 1-2 2-3 3-4 4-5 5-6 > 6 DAD: ART effect RR 1 1.8 1.9 2.3 3.1 3.2 3.1 4.4 RR per year of cART overall 1.17 (previously 1.26) men 1.14 women 1.38 incidence of MI per 1000 py exposure to HAART (years) • other independent risk factors: increasing age, male, smoking, prior CVD, family history • smoking rate fell from 52% to 45% between 2000 and 2003 El-Sadr et al, CROI 2005

10. Impact of HIV disease • Effects of RTIs • Effects of PIs • Clinical studies in naïve patients • Switch studies • Intervention • Summary

11. ART cytokines HIV HIV Potential consequences of mitochondrial dysfunction • metabolic disease • (LD, IR,  TGs) • DNA polymerase-g • uncoupling • transport • oxidative stress • apoptosis • phosphorylation • proteolytic processing • glycosylation • lipodystrophy • neuropathies • hepatic steatosis • myopathy • pancreatitis • lactic acidosis

12. Effects of NRTIs on adipocytes in vitro • cause adipocyte toxicity and exhibit synergistic toxicity with PIs(no NNRTI data) • alter expression of oxidative phosphorylation genes • lead to reduced mtDNA (without mtDNA mutations) in adipocytes from lipoatrophic patients • subcutaneous adipocyte apoptosis and focal lipogranulomata in patients receiving NRTI-PI 2nd Lipo workshop, Toronto 2000 Domingo et al, AIDS 1999

13. med % chg -63 [77] med % chg -88 [54] med % chg -60 [62] p=0.005 p=0.001 p=0.01 p=0.01 med % chg +42 [131] med % chg +25 [116] med % chg +83 [137] p=0.02 Changes in adipose tissue gene expression with NRTI exposure p=0.002 gene : β actin COX3 Cyt b COX1 (gene : β actin) x 1000 mtTFA NRF-1 PGC1 Mallon et al, CROI 2004

14. DAD: recent exposure to ABC and ddI may increase the risk of MI Relationship of recent* use of NRTIs and risk of CHD CHD (MI, CV deaths, invasive procedures) n=693 ZDV ddI d4T 3TC ABC RR=1.40, p=0.005 RR=1.63, p=0.0001 0.5 0.75 1 1.25 1.5 1.75 2 2.25 adjusted** relative rate (95% CI) *recent = still using or stopped within last 6 months **similar to model 2 Sabin et al, CROI 2008

15. 100 80 60 40 † † † 20 100 * 80 60 40 20 0 NNRTIs and mitochondria In vitro mRNA levels (% of control) SREBP-1c mRNA levels (% of control) PPAR- - + D2 - + D4 - + D7 EFV day of Culture *P<.05 †P<.001 El Hadri et al, J Biol Chem. 2004

16. Impact of HIV disease • Effects of RTIs • Effects of PIs • Clinical studies in naïve patients • Switch studies • Intervention • Summary

17. Effect of PIs on adipocytes in vitro • decreased expression of PPARγ, SREBP-1c, C/EBP-α, and leptin mRNA1-3 • inhibition of glucose uptake1,4 • insulin resistance3,5 • increased lipolysis; decreased expression of CD36 (fatty acid transporter)1 • inhibition of adipogenesis • impaired preadipocyte protein synthesis3,6 • impaired adipocyte differentiation2,4,6,7 1. Kannisto et al, AIDS 2003 2. Bastard et al, Lancet 2002 3. Caron et al, Diabetes 2001 4. Janneh et al, AVT 2003 5. Cianflone et al, AVT 2006 6 Roche et al AIDS 2002 7. Vernochet et al, AIDS 2003

18. Effects of PIs on adipocyte lipid and glucose metabolism control IDV SREBP-1 day 0 similar results with PPAR-γ day 6 control IDV 3T3 rat preadipocytes

19. Effect of ATV and LPV/r on insulin sensitivity glycogen storage rate (mg/Kg/min) insulin-stimulated glucose disposal rate per unit of insulin (mg/Kg/min per IU/mL) percent change relative to placebo P=N.S. + 4% <1% P=NS - 24% - 34% P=0.008 P=0.006 LPV/r (n=20) ATV (n=20) Noor et al, CROI 2004

20. Effect of RTV 100mg bd and LPV/r on lipids in HIV -ves RTV 100mg bid or r/LPV (HIV-) x 14 days p ≤0.01 change from baseline p <0.05 RTV vs LPV/r at day 14 Shafran et al, HIV Med 2005

21. TG synthesis, apoB , VLDL GLUT4 GLUT1 PI-induced glucose and lipid disturbances hyperlipidemia increased hepatic lipid and VLDL production and secretion insulin resistance lipodystrophy lipodystrophy HIV - PIs suppressed adipogenesis impaired glucose uptake and utilisation in muscle and adipocytes decreased fat storage in adipocytes

22. Impact of HIV disease • Effects of RTIs • Effects of PIs • Clinical studies in naïve patients • Switch studies • Intervention • Summary

23. Changes in body composition following HAART central abdominal fat %  from baseline (median) lean mass limb fat weeks after HAART Mallon et al, AIDS 2002

24. Gilead 903: total limb fat kilograms weeks TDF + 3TC + EFV 128 115 d4T + 3TC + EFV 134 117 Gallant et al, IAC 2004

25. ACTG 5142:incidence of lipoatrophy at week 96 by subgroup patients Haubrich R et al. 14th CROI. 2007; Los Angeles, Calif. Abstract 38.

26. no difference in use of lipid-lowering Tx between LPV/r and EFV 62 57 46 43 33 32 26 22 19 16 9 8 ACTG 5142: lipid changes p<0.03 LPV/r + NRTIs EFV + NRTIs p<0.001 75 p<0.001 LPV/r + EFV p<0.001 p<0.001 60 change in lipid levels (mg/dL) p=0.006 p<0.001 p>0.5 45 p<0.001 p=0.3 p<0.001 30 p=0.3 15 0 HDL cholesterol non-HDL cholesterol total cholesterol triglycerides Haubrich et al, CROI 2007

27. Possible explanations for observed changes in limb fat between EFV and LPV/r • EFV contributes to lipoatrophy? • LPV/r protects against lipoatrophy? • differential weight gain between groups (dietary effect?) • other?

28. Raltegravir 004: lipid effects vs EFV *all raltegravir dose groups combined. Markowitz et al IAS 2007

29. Summary • gains in limb and trunk fat are observed with all ART within the first ~6 months of therapy • potentially related to viral control and return to health • peripheral fat loss and trunk fat gain do not necessarily occur together • the strongest association with limb fat loss is observed with NRTIs, particularly thymidine analogs • different PIs show different effects on limb fat • NFV makes it worse • ATV has no effect • boosted PIs may increase limb fat mass • trunk fat increases with initiation of all ART, but the exact causes remain unknown • most studies don’t look at visceral fat

30. Impact of HIV disease • Effects of RTIs • Effects of PIs • Clinical studies in naïve patients • Switch studies • Intervention • Summary

31. d4T/AZT switching for lipoatrophy: cross study comparisons on-treatment analysis change from baseline (kg) week BUT... return to normal is +3kg to 5kg in 5-10 years? Carr et al, JAMA 2002; Martin et al, AIDS 2004; McComsey et al, CID 2004 Moyle et al, CROI 2005; Milinkovic et al, CROI 2005; Murphy et al, CROI 2005

32. Conclusions • ARV selection can influence the risk of developing lipoatrophy • among NRTIs, TDF is associated with less limb fat loss than thymidine-containing regimens. Switch studies suggest ABC also has a limited impact on body fat • among PIs, emerging data do not support a class effect on the development of lipoatrophy; switching from a PI provides no additional benefit or protection against LD • NRTIs accompanying PIs or NNRTIs can influence the risk of lipoatrophy • both PIs and EFV produce increases in abdominal fat • recent large clinical trials suggest that among preferred first-line regimens, LPV/r is associated with less lipoatrophy than EFV

33. Impact of HIV disease • Effects of RTIs • Effects of PIs • Clinical studies in naïve patients • Switch studies • Intervention • Summary

34. Approach to lipid disorders and cardiovascular risk If lipid lowering drugs are necessary or serum LDL cholesterol above threshold, or triglycerides 2-5 mmol/L with elevated non-HDL cholesterol: STATIN (pravastatin or atorvastatin) serum triglycerides >5 mmol/L: FIBRATE (gemfibrozil or fenofibrate) Dubé et al, CID 2003

35. Effect of lipid-lowering drugs study population HIV+ adults with LDL-C > 4 mmol/l and TG > 2.2 mmol/l Aberg et al, ARHR 2005

36. Rosiglitazone:randomised trials outcomes Sutinen et al, Antiviral Ther 2003; Carr et al, Lancet 2004 Hadigan et al, Ann Intern Med 2004; Cavalcanti et al, CROI 2005

37. 185 180 175 170 165 160 155 150 145 Tesamorelin: visceral fat accumulation +3% +5% placebo cm2 ** -12.1% ** -15.2% tesamorelin baseline week 13 week 26 ** P < 0.001 vs placebo

38. Investigational pharmacologic therapies Wohl et al, Clin Infect Dis 2006

39. Estimating benefits and risks

40. Estimating benefits and risks • unknown risks are • 10-year risk of AIDS or death • at 3 years: on HAART 2.4%, off ART 6.1% • risks of PI switch / statin

41. Impact of HIV disease • Effects of RTIs • Effects of PIs • Clinical studies in naïve patients • Switch studies • Intervention • Summary

42. We should focus more on trying to prevent these metabolic complications, as well as their potential atherogenic consequences in patients starting treatment for the first time.