1. S.Collins HIV i-Base UK-CAB November 2005 UK-CAB November 2005 Feedback from 7th Lipodystrophy Workshop 13-16 November, Dublin

2. S.Collins HIV i-Base UK-CAB November 2005 Treatments: uridine, pravastatin, facial fat after switch, Niacin ER, buttock implants, Other: monitoring access programmes, Polypill, NVP and brown fat, heart disease Mechanisms: are fat loss and fat accumulation caused by a single process; nevirapine and brown fat Q&As throughout please Overview

3. S.Collins HIV i-Base UK-CAB November 2005 Uridine - for people on AZT or d4T Pravastatin - showed fat return Niacin ER - no reduction in VAT Switch - RAVE analysis showed return of facial fat Buttock implants - first reports - not a simple process Treatments/Interventions

4. S.Collins HIV i-Base UK-CAB November 2005 Randomised trial: 36g, 3x day for first 10 days of each month, for 3 months @ ~£60/month 20 people on d4T- or AZT-regimens randomised to NucleomaxX or placebo Limb fat, total fat and intra-abdominal fat all inc. vs placebo and baseline (~400-1600g) HDL fell (1.24 to 1.15mmol/). No effect on TG, lactates and insulin resistance (Sutinen et al. Abs 7) Study 2: 16 pts, 36gTID every other day for 16 wks - no∆ mtDNA in fat or PBMC, only pt and doc survey (MacComsey et al. Abs 82) Uridine (NucleomaxX)

5. S.Collins HIV i-Base UK-CAB November 2005 33 men on stable PI; TC>6.5 (median =7.6) 4 week dietary advice: randomised to PVS (40mg/day) or placebo for 16 weeks No change AUC cholesterol from baseline Modest changes from week 4 Total fat and limb fat both increase and % IAF decreased (Malon et al. Abs 23) Pravastatin

6. S.Collins HIV i-Base UK-CAB November 2005 PVSplacebop Chol AUC 0-16 week - 0.6-0.40.8 Chol AUC 4-16 week - 0.82-0.340.04 Total fat kg+ 1.03-0.090.01 Limb fat kg+ 0.72+0.190.04 % IAF- 2.90.080.7 (Mallon et al. Abs 23) Pravastatin

7. S.Collins HIV i-Base UK-CAB November 2005 Sub-study (n=47) from UK RAVE study: switch from AZT or d4T to TDF (n=23) or ABC (n=24) 39/47 with facial LA at baseline; no reported benefit from pts in either arm Mean volume difference (3D scan) at wk 48 was +2539mm3 (both cheeks) and +0.36kg (limb fat change, DEXA) Correlation between increases in cheek and limb; no differences between TDF and ABC (Benn et al. Abs 8) Switch (RAVE)

8. S.Collins HIV i-Base UK-CAB November 2005 48-wk multi-centre open label study in 33 men with TG >200mg/dl (67% white) 500mg titrations every 4-6 weeks up to target 2000mg/day (n=23 reached 2000mg/day; 8 reached 1500mg/day) No reduction seen in VAT (not in abstract) Caution careful monitoring for glucose regulation and liver (Dubé et al. Abs 12) Niacin ER

9. S.Collins HIV i-Base UK-CAB November 2005 baseline%∆wk24%∆wk48 Total-C6.5-0.6-0.12 * HDL-C0.9+0.08+0.13 * TG5.6-0.8-0.5 * Non-HDL-C5.4-2.0-1.7 * * P <0.01 (Dubé et al. Abs 12) Niacin ER

10. S.Collins HIV i-Base UK-CAB November 2005 Spanish plastic surgery dept Rarely reported at Lipo Workshops Report on 7 women Used silicone implants, placed inside muscle Satisfied by results but no with contrast to thin legs MRI scans for safety - will require replacement (Fontdevila et al. Abs 41) Buttock implants

11. S.Collins HIV i-Base UK-CAB November 2005

12. Monitoring access programmes www.hivforum.org Monitoring side effects: harm vs safety Polypill - INSIGHT group (ld aspirin, lisinopril (ACE inhibitor to lower BP), hydrochlorithiazide (diuretic), pravastatin (cholesterol lowering). nevirapine and brown fat Risk of cardiovascular disease Other

13. S.Collins HIV i-Base UK-CAB November 2005 Reversal of fat loss also increased intra-abdominal fat (IAF - also known as VAT = visceral adipose tissue) Analysed lipoatrophy studies: MITOX (and ROSEY) - male, 72 weeks, symptomatic lipoatrophy, DEXA If limb fat increased, VAT tended to increase. If VAT decreased, limb fat tended to decrease. Different risk factors (Wand et al. Abs 3) Single mechanism?

14. S.Collins HIV i-Base UK-CAB November 2005

15. NVP brown fat gene expression Brown fat cellWhite fat cell

16. S.Collins HIV i-Base UK-CAB November 2005 Biopsies from lipoma from HIV- and HIV+ +/- HAART In vitro study of brown pre-adipocytes in culture exposed to individual ARVs Gene expression related to brown fat was then measured in cultures and biopsies Gene for preferentially expressing brown fat partially determined in lipoma, and markers (UCP- 1) were activated by d4T and nevirapine (and suppressed by efavirenz, nelfinavir, saquinavir) NVP brown fat gene expression

17. S.Collins HIV i-Base UK-CAB November 2005 Incremental risk of heart disease x 1.5 x 2.3 x 3.5 x 3.9 x 5.9 x 2.7 x 1.7 Smoking Hypertension Dyslipideamia