1. Lipodystrophy Impact of HIV 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 David A Cooper National Centre in HIV Epidemiology and Clinical Research The University of New South Wales Sydney, Australia David A Cooper National Centre in HIV Epidemiology and Clinical Research The University of New South Wales Sydney, Australia Lipodystrophy and metabolic disorders in HIV disease

2. Lipodystrophy 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Lipoatrophy

3. Lipodystrophy 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Fat accumulation

4. Lipodystrophy 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 increased levels of IL-6 and TNF-  in adipose tissue correlate with 1  adipose tissue apoptosis adipocytes and preadipocytes undergo apoptosis 2  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 fat 3,4 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 Cytokines and tissue inflammation in lipoatrophy

5. Lipodystrophy 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Impact of HIV disease Effects of RTIs Effects of PIs Clinical studies in naïve patients Switch studies Intervention Summary

6. Lipodystrophy 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Impact of HIV disease Effects of RTIs Effects of PIs Clinical studies in naïve patients Switch studies Intervention Summary

7. Lipodystrophy Impact of HIV 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 subgroupspatient events relative risk (95% CI) total114 CVD, liver or renal death 31 non-fatal CVD63 non-fatal liver14 non-fatal renal7 favours VS ► ► favours DC 1.5 1.4 2.5 1.4 El-Sadr, Neaton et al, CROI 2006 ► SMART: effect of ART discontinuation

8. Lipodystrophy Impact of HIV 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 SMART: baseline biomarkers and all cause mortality unadjustedadjusted markerOR (4 th /1 st )P-valueOR (4 th /1 st )P-value hs-CRP2.00.052.80.03 amyloid A2.20.072.60.09 amyloid P0.70.391.10.84 IL-68.3<0.000111.8<0.0001 D- dimer12.4<0.000126.5<0.0001 F1.21.00.921.20.66 Insight Mtg Tlk 2/6/2008

9. Lipodystrophy Impact of HIV 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 RR 11.81.92.33.1 3.23.14.4 RR per year of cART overall 1.17 (previously 1.26) men1.14 women 1.38 incidence of MI per 1000 py exposure to HAART (years) 0 2 4 6 8 none 10 < 11-22-33-44-55-6> 6 all subjects DAD: ART effect El-Sadr et al, CROI 2005 other independent risk factors: increasing age, male, smoking, prior CVD, family history smoking rate fell from 52% to 45% between 2000 and 2003

10. Lipodystrophy 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Impact of HIV disease Effects of RTIs Effects of PIs Clinical studies in naïve patients Switch studies Intervention Summary

11. Lipodystrophy Effect of RTIs 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Potential consequences of mitochondrial dysfunction lipodystrophy neuropathies hepatic steatosis myopathy pancreatitis lactic acidosis metabolic disease (LD, IR,  TGs) ART cytokines HIV DNA polymerase-  uncoupling transport oxidative stress apoptosis phosphorylation proteolytic processing glycosylation

12. Lipodystrophy Effect of RTIs 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 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 Effects of NRTIs on adipocytes in vitro 2nd Lipo workshop, Toronto 2000 Domingo et al, AIDS 1999

13. Lipodystrophy Effect of RTIs 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Changes in adipose tissue gene expression with NRTI exposure p=0.02 med % chg +83 [137] p=0.01 med % chg +25 [116] p=0.01 med % chg +42 [131] med % chg -63 [77] p=0.001 med % chg -88 [54] p=0.005 med % chg -60 [62] (gene : β actin) x 1000 gene : β actin baseline week 2 Cyt b COX3 COX1 PGC1 NRF-1 mtTFA p=0.002 Mallon et al, CROI 2004

14. Lipodystrophy Effect of RTIs 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 DAD: recent exposure to ABC and ddI may increase the risk of MI Sabin et al, CROI 2008 *recent = still using or stopped within last 6 months **similar to model 2 ZDV ddI d4T 3TC ABC 0.5 0.75 1 1.25 1.5 1.75 2 2.25 RR=1.40, p=0.005 RR=1.63, p=0.0001 adjusted** relative rate (95% CI) CHD (MI, CV deaths, invasive procedures) n=693 Relationship of recent* use of NRTIs and risk of CHD

15. Lipodystrophy Effect of RTIs 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 NNRTIs and mitochondria In vitro El Hadri et al, J Biol Chem. 2004 SREBP-1c -+ D2 100 80 20 0 60 40 * 100 80 20 60 40 † † † PPAR-  EFV day of Culture -+ D4 -+ D7 *P<.05 †P<.001 mRNA levels (% of control) mRNA levels (% of control)

16. Lipodystrophy Effect of RTIs 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Impact of HIV disease Effects of RTIs Effects of PIs Clinical studies in naïve patients Switch studies Intervention Summary

17. Lipodystrophy Effect of PIs 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Effect of PIs on adipocytes in vitro decreased expression of PPARγ, SREBP-1c, C/EBP- α, and leptin mRNA 1-3 inhibition of glucose uptake 1,4 insulin resistance 3,5 increased lipolysis; decreased expression of CD36 (fatty acid transporter) 1 inhibition of adipogenesis impaired preadipocyte protein synthesis 3,6 impaired adipocyte differentiation 2,4,6,7 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. Lipodystrophy Effect of PIs 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Effects of PIs on adipocyte lipid and glucose metabolism controlIDV day 0 day 6 similar results with PPAR-γ SREBP-1 control IDV 3T3 rat preadipocytes

19. Lipodystrophy Effect of PIs 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 <1% - 24% percent change relative to placebo insulin-stimulated glucose disposal rate per unit of insulin (mg/Kg/min per  IU/mL) + 4% - 34% glycogen storage rate (mg/Kg/min) LPV/r (n=20) ATV (n=20) P=N.S. P=0.006 P=0.008 P=NS Effect of ATV and LPV/r on insulin sensitivity Noor et al, CROI 2004

20. Lipodystrophy Effect of PIs 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 RTV 100mg bid or r/LPV (HIV-) x 14 days Shafran et al, HIV Med 2005 p ≤0.01 change from baseline 14 days RxbaselineRTVLPV/r n=20 total cholesterol (mmol/l) 4.34.85.1 LDL cholesterol (mmol/l) 2.512.933.11 HDL cholesterol (mmol/l) 1.391.321.38 triglycerides (mmol/l)0.871.111.29 Effect of RTV 100mg bd and LPV/r on lipids in HIV -ves p <0.05 RTV vs LPV/r at day 14

21. Lipodystrophy Effect of PIs 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 PI-induced glucose and lipid disturbances PI-induced glucose and lipid disturbances insulin resistanceGLUT4GLUT1 decreased fat storage in adipocytes impaired glucose uptake and utilisation in muscle and adipocytes increased hepatic lipid and VLDL production and secretion hyperlipidemia lipodystrophy suppressed adipogenesis TG synthesis, apoB, VLDL HIV - PIs lipodystrophy

22. Lipodystrophy 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Impact of HIV disease Effects of RTIs Effects of PIs Clinical studies in naïve patients Switch studies Intervention Summary

23. Lipodystrophy Clinical studies in naïve patients 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Changes in body composition following HAART %  from baseline (median) Mallon et al, AIDS 2002 central abdominal fat lean mass limb fat weeks after HAART

24. Lipodystrophy Clinical studies in naïve patients 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Gilead 903: total limb fat TDF + 3TC + EFV128115 d4T + 3TC + EFV134117 kilograms weeks Gallant et al, IAC 2004

25. Lipodystrophy Clinical studies in naïve patients 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 ACTG 5142: incidence of lipoatrophy at week 96 by subgroup patients Haubrich R et al. 14th CROI. 2007; Los Angeles, Calif. Abstract 38. n=414363736750

26. Lipodystrophy Clinical studies in naïve patients 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 ACTG 5142: lipid changes HDL cholesterolnon-HDL cholesterol 8 9 16 26 22 43 change in lipid levels (mg/dL) total cholesteroltriglycerides 32 33 57 46 19 62 0 15 30 45 60 75 p>0.5 p<0.001 p=0.006 p<0.001 p<0.03 p<0.001 p=0.3 EFV + NRTIs LPV/r + NRTIs LPV/r + EFV no difference in use of lipid-lowering Tx between LPV/r and EFV Haubrich et al, CROI 2007

27. Lipodystrophy Clinical studies in naïve patients 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 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. Lipodystrophy Clinical studies in naïve patients 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Raltegravir 004: lipid effects vs EFV mean change from baseline, mg/dL (mmol/L) RAL* 100-600 mg bid (n = 160) EFV 600 mg qd (n = 38) P value total:HDL ratio -0.59-0.47.52 cholesterol -2.3 (-.06)+20.7 (+.53)<.001 LDL-C -7.5 (-.19)+3.0 (+.08).016 triglycerides -1.0 (-.01)+49.5 (+.56).068 *all raltegravir dose groups combined. Markowitz et al IAS 2007

29. Lipodystrophy Clinical studies in naïve patients 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 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 Summary

30. Lipodystrophy 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Impact of HIV disease Effects of RTIs Effects of PIs Clinical studies in naïve patients Switch studies Intervention Summary

31. Lipodystrophy Switch studies 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 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 d4T/AZT switching for lipoatrophy: cross study comparisons week BUT... return to normal is +3kg to 5kg in 5-10 years? change from baseline (kg) on-treatment analysis

32. Lipodystrophy Switch studies 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 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. Lipodystrophy 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Impact of HIV disease Effects of RTIs Effects of PIs Clinical studies in naïve patients Switch studies Intervention Summary

34. Lipodystrophy Interventions 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 If lipid lowering drugs are necessary STATIN serum LDL cholesterol above threshold, or triglycerides 2- 5 mmol/L with elevated non- HDL cholesterol: STATIN (pravastatin or atorvastatin) serum triglycerides FIBRATE >5 mmol/L: FIBRATE (gemfibrozil or fenofibrate) or Approach to lipid disorders and cardiovascular risk Dubé et al, CID 2003

35. Lipodystrophy Interventions 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 study population HIV+ adults with LDL-C > 4 mmol/l and TG > 2.2 mmol/l Aberg et al, ARHR 2005 fenofibrate (n = 60) pravastatin (n = 63) achieved goal (%)NCEP7%3% LDL13%14% HDL67%56% TG60%44% median change (%)LDL-5%-8% HDL17%6% TG-45%-25% non-HDL-21%-16% Effect of lipid-lowering drugs

36. Lipodystrophy Interventions 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 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 insulin resistance improved4/4 total cholesterol increased4/4X triglyceridesincreased4/4X limb fatno change3/4 83 patient years? increased1/4 7 patient years?

37. Lipodystrophy Interventions 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 cm 2 baselineweek 13week 26 tesamorelin placebo -15.2% +5% 145 150 155 160 165 170 175 180 185 -12.1% +3% ** P < 0.001 vs placebo ** Tesamorelin: visceral fat accumulation

38. Lipodystrophy Interventions 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Wohl et al, Clin Infect Dis 2006 Investigational pharmacologic therapies interventionlipids insulin resistance central adiposity lipoatrophy rGHworse reducedworse tesamorelinbetterno changereduced— metforminbetter reducedworse

39. Lipodystrophy Interventions 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Estimating benefits and risks patient: 39 year old male, HIV+ clinical findings CVD risks CDC Bsmoker no IDUcholesterol 5.6 mmol/l pre-ART: CD4+ 220 HIV-RNA 120,000 HDL-C 1.0 mmol/l NRTI-PI ART: HIV-RNA NDBP 125/75 CD4+ 380 after 6 monthsno diabetes (OGTT) LD+

40. Lipodystrophy Interventions 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Estimating benefits and risks estimated 10-year CVD risk (Framingham) no intervention10% fibrate10% statin (chol 4.1, HDL 1.0) 7% PI switch to ATV / NVP / EFV6% stops smoking2% stops smoking and PI switch1% 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. Lipodystrophy 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 Impact of HIV disease Effects of RTIs Effects of PIs Clinical studies in naïve patients Switch studies Intervention Summary

42. Lipodystrophy 第 22 回日本ｴｲｽﾞ学会教育セッション 2008.11.27 prevent 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.