S.Collins HIV i-Base UK-CAB November 2005 UK-CAB November 2005 Feedback from 7th Lipodystrophy...

S.Collins HIV i-Base

UK-CAB November 2005

UK-CABNovember 2005

Feedback from 7th Lipodystrophy Workshop

13-16 November, Dublin



• 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



• 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



• 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)



• 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



PVS placebo p

Chol AUC 0-16 week - 0.6 -0.4 0.8Chol AUC 4-16 week - 0.82 -0.34 0.04Total fat kg + 1.03 -0.09 0.01

Limb fat kg + 0.72 +0.19 0.04

% IAF - 2.9 0.08 0.7

(Mallon et al. Abs 23)

Pravastatin



• 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)



• 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



baseline %∆wk24 %∆wk48

Total-C 6.5 -0.6 -0.12 *

HDL-C 0.9 +0.08 +0.13 *

TG 5.6 -0.8 -0.5 *

Non-HDL-C 5.4 -2.0 -1.7 ** P <0.01

(Dubé et al. Abs 12)

Niacin ER



• 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



• 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



• 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?



NVP brown fat gene expression

Brown fat cellWhite fat cell



• 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



Incremental risk of heart disease

x 1.5 x 2.3x 3.5

x 3.9

x 5.9

x 2.7

x 1.7

Smoking

HypertensionDyslipideamia

S.Collins HIV i-Base UK-CAB November 2005 UK-CAB November 2005 Feedback from 7th Lipodystrophy...

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