Fat redistribution on ARVs: dogma versus data
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1 Fat redistribution on ARVs: dogma versus data Gary Maartens Division of Clinical Pharmacology UNIVERSITY OF CAPE TOWN IYUNIVESITHI YASEKAPA UNIVERSITEIT VAN KAAPSTAD
2 Half of what we are going to teach you is wrong, and half of it is right. Our problem is that we don t know which half is which. GP Berry, Dean Harvard Medical School
3 Lipohypertrophy fat accumulation
4 Lipoatrophy fat loss
5 Fat redistribution Seen progressively more commonly with duration on ART Fat loss & fat accumulation may occur together or separately Term lipodystrophy not clinically useful Assessed subjectively or on imaging (DEXA, CT, MRI)
6 Fat redistribution patterns Fat loss: Subcutaneous fat everywhere Most noticed face, buttocks, limbs Fat accumulation Subcutaneous & visceral fat Buffalo hump Breasts
7 Lipodystrophy questions What is the pathogenesis? Are fat changes linked to specific ARVs? Does switching ARVs help?
8 Lipoatrophy - pathogenesis Biopsy of affected adipose tissue: Mitochondrial depletion Infiltration with macrophages Pro-inflammatory cytokines apoptosis Associated with NRTIs that are most toxic to mitochondria (d4t, ddi, AZT) JID 2009;200:252 CID 2010; 51:591
9 Lipoatrophy genetic predisposition JID 2008;197:858 JAIDS 2009;51:111
10 Fat loss: RCTs of NRTIs Arms TDF vs 96 weeks: total limb fat 7.9 kg vs 5.0 kg (P.001) TDF vs 48 weeks: total limb fat 8.9 kg vs 6.9 kg (P.03) JAMA 2004;:292:191 JAIDS 2007;44:139 NEJM 2006;354:251
11 Fat loss: NRTIs ACTG5142 (fat loss >20% limbs from baseline) ACTG5142 AIDS 2009;23:1109
12 Fat loss limbs >20% from baseline RCT: LPV/r vs EFV (+2 NRTIs) vs LPV/r + EFV ACTG5142 AIDS 2009;23:1109
13 Increase in limb fat after switching d4t/azt AIDS 2006;20:2043
14 Fat loss - summary Pathogenesis is mitochondrial depletion and inflammation genetic component Caused by NRTIs that are toxic to mitochondria PIs less associated than NNRTIs (?due to PI s anti-apoptotic properties) Switch to less toxic NRTIs results in very slow improvement CPT 2007;82:248
15 Which ARVs cause fat accumulation? Protease inhibitors implicated in initial studies
16 Metabolic sub-study FIRST trial: PI or NNRTI + 2NRTIs; or PI+NNRTI Anthropometry & bio-impedance used to measure fat redistribution 70% of PIs unboosted NNRTIs 63% EFV 37% NVP NRTIs about 50% AZT, 40% d4t J Acquir Immune Defic Syndr 2007;44:
17 FIRST study regional fat No significant difference by strategy
18 Body fat EFV vs LPV with AZT+3TC (LPV alone if VL suppressed on 3 consecutive months) JID 2008;198:234
19 Fat accumulation: LPV/r vs EFV (+2 NRTIs) vs LPV/r + EFV Trunk fat increased from a median of 8.2 kg (IQR ) at entry to 10.4 kg (IQR ) at week 96. There were no significant differences at weeks 48 or 96 by randomized treatment or NRTI selection ACTG5142 AIDS 2009;23:1109
20 What about raltegravir & atazanavir?
21 JAIDS 2010;55:39
22 RCT ATV vs EFV (+AZT + 3TC) VAT visceral adipose tissue SAT subcutaneous adipose tissue TAT total adipose tissue CID 2006;42:273
23 ATV/r vs EFV ACTG5224S Metabolic sub-study of RCT: TDF+FTC vs ABC+3TC (no difference in fat changes) ATV/r vs EFV Subcutaneous limb & abdominal fat gain greater with ATV/r No difference in increases in visceral fat McComsey CROI 2011
24 ATV/r vs ATV (d4t + 3TC) 40 %change from baseline ATV/r ATV -20 VAT wk48 TAT wk48 Limb wk48 VAT wk96 TAT wk96 Limb wk96 20% limb fat 96 wk: ATV/r 29% vs ATV 49% P<0.05 CID 2009;48:1323
25 Switch boosted PI to ATV/r ReAL study: On boosted PI regimen; n=200 VL <400 waist >90cm Randomised to continue vs switch to ATV/r No change in fat distribution on DEXA or fat gain at week 48 & 96 Moyle 17th IAC
26 Switch boosted PI to raltegravir Sub-study of SPIRAL RCT switch to RAL or stay on PI/r All VL suppressed at baseline N=73 (39 switch RAL, 34 stay on PI/r) No differences were seen between treatment groups in the DXA scan regarding body fat after 48 weeks Curran CROI 2011
27 Switching ARVs for fat accumulation we do not recommend switching antiretrovirals to combat lipohypertrophy substitution of HIV medications to reduce regional fat accumulation cannot be advocated JAIDS 2008;49(S2):S93 Curr Opin Infect Dis 2011;24:43
28 Effect of ART on pro-inflammatory cytokines causing wasting JAIDS 2009;52:493
29 Fat accumulation - summary All ART regimens, even ARVs with minimal metabolic effects, cause fat gain No regimen switch effective Is fat accumulation a consequence of treating HIV, which reduces immune activation?
30 Epidemiology of fat redistribution by HIV status FRAM studies HIV pos (on ART about 5 years at baseline) vs controls (from CARDIA cohort) Fat measured by MRI baseline & 5 years Ages well matched, ethnicity reasonable match, HIV+ men mostly MSM (unknown in CARDIA) AIDS 2010;24:1717
31 Fat distribution HIV+ vs control: women
32 Fat distribution HIV+ vs control: men Buffalo hump
33 Change in fat - legs Control HIV+
34 Change in fat - visceral Control HIV+
35 FRAM 1 & 2 studies: summary Subcutaneous fat loss more common in HIV+ HIV+ patients with fat loss at baseline worsened over time Visceral fat accumulation over time no difference by HIV status Fat accumulation similar in women irrespective of HIV status, but lower in HIV+ men than control men (?MSM factor)
36 MACS change in waist circumference MSM AIDS 2007;21:1731
37 Loss of subcutaneous fat (from some NRTIs) together with fat accumulation (due to ageing & lifestyle) results in unusual appearance
38 Adjusted ORs for presence of coronary artery calcium Lipoatrophy alone 3.82 (95% CI: 1.11, 13.1) Fat accumulation alone 7.65 (95% CI: 1.71, 37.17) Mixed lipodystrophy 4.36 (95% CI: 1.26, 15.01)
39 Lipodystrophy and mortality FRAM study Lipoatrophy not associated with mortality Visceral fat accumulation increased population attributable risk of mortality by 6.5% Scherzer CROI 2011
40 Visceral fat & mortality HIV- Kuk Obesity 2006;14:
41
42 Efavirenz and didanosine treatment are associated with the emergence of gynaecomastia. An underlying hypoandrogenism seems to contribute to the emergence of this disorder in these patients.
43
44 Conclusions Fat loss pathogenesis well understood Fat loss improves on switching to NRTIs that are less toxic to mitochondria Fat gain not linked to any ARV & not increased compared with controls Switching ARVs does not improve fat gain Check vascular risk factors with fat gain
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