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Lipodystrophy 20 years
David Cooper October 2017
AIDS 1998(>2000 citations)
Lipodystrophy syndrome: early report
HIV-associated lipodystrophy syndrome 20 years
One or two syndromes?
Lipoatrophy
Fat accumulation
Cardiovascular disease
Management of cardiovascular disease
Future interventions
One or Two Syndromes?HIV-associated lipodystrophy syndrome 20 years
Wide variation in range 10-80%differences in definitions and methodologydifferences in host factors
geographyagegeneticslifestyle factorsspecific ART useduration of treatment
Lipodystrophy: prevalence
Lipoatrophy and fat accumulation are different processes
One or Two Syndromes?HIV-associated lipodystrophy syndrome 20 years
HIV lipodystrophy case definition study group, Lancet 2003
Lipodystrophy: an objective case definition
One or Two Syndromes?HIV-associated lipodystrophy syndrome 20 years
SyndromeNo. (%) of men
(n=306)No. (%) of women
(n=144) P
Fat atrophy 117 (38.2) 37 (25.7) 0.009Fat deposition 123 (40.1) 77 (53.1) 0.009Mixed 44 (14.4) 19 (13.2) 0.74
NHL study: prevalence and risk factors
Nutrition for Healthy Living Study Jacobson et al, CID 2005
Fat atrophy• triceps skinfold• hip circumference• HIV disease severity• continuous duration of ART• any stavudine use
Fat deposition• female sex• triceps skinfold• percentage of body fat• TG level
Independent determinants of new fat atrophy and fat deposition
One or Two Syndromes?HIV-associated lipodystrophy syndrome 20 years
FRAM: no association of peripheral lipoatrophy with central lipohypertrophy
FRAM, JAIDS 2005
% with peripheral lipoatrophy
0102030405060708090
100
Central Lipohypertrophy Central Lipoatrophy
OR = 0.7CI = 0.47- 1.1P = 0.10
OR = 18.9CI = 5.7 – 63P < 0.001
yesno
One or Two Syndromes?HIV-associated lipodystrophy syndrome 20 years
parameter time change in limb fat mass (kg)week 72 – week 0
change in VAT(cm2)
week 72 – week 0
beta (95% CI) P beta (95% CI) P
ART
on study d4T/AZT
≥ 6 months -0.57 (-1.03, -0.10) 0.017 - -
Body composition
limb fat mass baseline 0.37 (0.26, 0.48) < 0.0001 -4.07 (-7.34, -0.79) 0.016
VAT (cm2)baseline 0.004 (0.001, 0.01) 0.023 -0.16 (-0.25, -0.07) 0.001
change at wk 72 0.02 (0.01, 0.02) < 0.0001 - -
MITOX, ROSEY: change in limb fat and VAT with ART
Wand et al, J Clin Trials 2011
HIV-associated lipodystrophy syndrome 20 years
One or two syndromes?
Lipoatrophy
Fat accumulation
Cardiovascular disease
Management of cardiovascular disease
Future interventions
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
Lipoatrophy: clinical features
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
Visual inspection and physical exam
Patient self-report
Pinchable fat on abdomen
Limb circumference and skin fold thickness
CT, MRI or DEXA scanning
Staging scales for facial lipoatrophy
Lipodystrophy case definition
Metabolic abnormalities
Lipoatrophy: diagnosis and evaluation
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
SVH clinic cohort: changes in body composition after HAART
% ∆ from baseline (median)
Mallon et al, AIDS 2003
central abdominal fat
lean mass
limb fat
weeks after HAART
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
Gilead 903: total limb fat
TDF + 3TC + EFV n= 128 115d4T + 3TC + EFV n= 134 117
kilograms
weeks
Gallant et al, IAC 2004
TFV+3TC+EFV
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
Lipoatrophy: subcutaneous fat biopsy
AZT
CD68 control
d4T
normal
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
SAMA-1: adipose tissue gene expression with NRTI’s
p=0.02med % chg+83
[137]
p=0.01med % chg+25
[116]
p=0.01med % 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
baselineweek 2
Cyt bCOX3COX1
PGC1 NRF-1 mtTFA
p=0.002
Mallon et al, JID 2005
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
Type of adipose tissue disturbance
Implicated antiretroviral agents
Impaired adipogenesis, adipocyte differentiation or function
LPV/r, RTV, EFV, RPV, d4T
pre-adipocyte autophagy and apoptosis
ATV
Impairment of lipid and/or glucose metabolism
ATV/r, LPV/r, RTV, DRV/r, NNRTIs, EFV, NRTIs
Impairment of mitochondrial function
ATV, ATV/r, SQV, LPV/r, RTV, NRTIs
pro-inflammatory ATV/r, LPV/r, RTV, EFV, RPV
prelamin A accumulation protease inhibitors
Adipocytes: effects of specific antiretroviral drugs
Erlandson and Lake; Curr HIV/AIDS Rep 2016
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
0
10
20
30
40
48 96
ACTG5142: lipoatrophy
0
10
20
30
40
50
48 96
%
lipoatrophy
EFV 188 171LPV 191 166LPV/r-EFV 197 173
d4T 93 84AZT 133 117TDF 153 136
weeks on study
Haubrich et al, AIDS 2009
P values at week 96EFV vs LPV/r 0.003EFV vs LPV/r-EFV <0.001LPV vs LPV/r-EFV 0.023
P values at week 96d4T vs AZT 0.003d4T vs TDF <0.001AZT vs TDF 0.023
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
Metabolic derangements
Distress of physical changes in appearance
especially facial lipoatrophy
Disclosure of HIV status
Impact on adherence
Quality of life with restricted neck movement or
breast enlargement
Lipoatrophy: rationale for treatment
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
Switching antiretroviralsswitching the NRTI backboneswitching the third drug
Surgical approachestemporary fillers
poly-L-lactic acid fillercalcium hydroxylapatite
permanent fillersautologous fat transplantation
Thiazolidinediones
Lipoatrophy: treatment
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 24 48 72 108
MITOX-ABCRAVE-ABCRAVE-TDFTARHEELA5215Sd4T4030-TDF
d4T/AZT switch for lipoatrophy: cross study comparisons
Carr et al, JAMA 2002; Martin et al, AIDS 2004; McComsey et al, CID 2004 Moyle et al, AIDS 2006; Milinkovic et al, CROI 2005; Murphy et al, CROI 2005
week
change from
baseline (kg)
on-treatment analysis
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
FLASH: Poly-L-lactic acid for facial lipoatrophy
mean change in FSTV
(cm3)
Carey et al, HIV Med 2009
LipoatrophyHIV-associated lipodystrophy syndrome 20 years
Treatment
Model of changein limb fat mass
Model of 10% increase in limb fat from baseline
Estimate 95% CI P OR 95% CI P
Pioglitazone 0.35 (0.11,0.58) 0.004 2.28 (1.07,4.88) 0.03
Rosiglitazone 0.05 (-0.10, 0.21) 0.48 1.11 (0.72, 1.72) 0.63
Placebo (ref) - - - 1.00
Thiazolidinediones: GEE regression models
Meta-analysis of 6 placebo-controlled trialsof TZD’s for HIV lipoatrophy
Raboud et al, HIV Clin Trials 2010
HIV-associated lipodystrophy syndrome 20 years
Lipoatrophy
Fat accumulation
Cardiovascular disease
Management of cardiovascular disease
Future interventions
One or two syndromes
Fat Accumulation
HIV-associated lipodystrophy syndrome 20 years
Lipohypertrophy: clinical features
Fat Accumulation
HIV-associated lipodystrophy syndrome 20 years
Lipohypertrophy: diagnosis and evaluationVisual inspection and physical exam
Check pinchable fat
Measurement of waist circumference
(>102cm for men and >88cm for women is abnormal)
Waist:hip ratio and BMI less accurate
Stable BMI with increasing waist circumference suggests concomitant lipoatrophy
CT or MRI (not routine)
DEXA measures trunk fat not recommended
Fat Accumulation
HIV-associated lipodystrophy syndrome 20 years
Lipohypertrophy: risk factors
ART but which class?
Switching class does not improve FA
Increasing age, female sex, elevated baseline TG,
higher body fat %
FRAM shows no difference between HIV positives and
HIV negatives
Fat Accumulation
HIV-associated lipodystrophy syndrome 20 years
Women with lipohypertrophy: switch from PI/NNRTI to RAL
n=37 week 0-48 changes pooled 24-week changes
P P
SAT (cm2) -17.8 0.57 0.8 0.59
VAT (cm2) -11.7 0.68 -4.4 0.51
chol (mg/dL) -14 0.01 -17 <0.0001
LDL chol (mg/dL) -2.0 0.16 -9.1 <0.01
HDL chol (mg/dL) -4.0 0.25 -2.6 0.03
TG (mg/dL) -1.0 0.32 -18 <0.01
Lake et al, OFID 2015
Median changes in adipose tissue and lab values
Fat Accumulation
HIV-associated lipodystrophy syndrome 20 years
ARDENT ACTG A5260S: changes in body compositionwith PI or IntSTI initiation
McComsey et al, CID 2016
% change
from baseline
baseline week96
baseline week96
baseline week96
baseline week96
Limb fat change SAT change Trunk fat change VAT change
ATV/rRALDRV/r
P= NSfor all comparisons
Fat Accumulation
HIV-associated lipodystrophy syndrome 20 years
Lipohypertrophy: treatment
Diet and exercise
Metformin
Tesamorelin
Surgical approaches
Fat Accumulation
HIV-associated lipodystrophy syndrome 20 years
Exercise training: reduced trunk fat at 16 weeks
n=10 Baseline Final P value
Strength – leg press (kg) 220 250 0.02
Strength – chest press (kg) 31 37 0.005
Body fat (kg) 16.0 14.4 0.04
Trunk fat (kg) 8.6 7.5 0.03
Roubenoff et al; AIDS 1999
Fat Accumulation
HIV-associated lipodystrophy syndrome 20 years
Metformin: treatment of HIV lipodystrophy
n=25Baseline mean change at 3 mo P
Pbo Met Pbo Met
Weight (kg) 80.8 82.4 1.1 -1.3 0.005
Waist circumference (cm) 97 98 1.1 -1.1 0.02
VAT (cm2) 156 177 12 -11 0.08
SAT (cm2) 153 162 12 -7 0.08
Hadigan et al, JAMA 2000
Fat Accumulation
HIV-associated lipodystrophy syndrome 20 years
Tesamorelin: change in VAT from baseline to 26 wks
Falutz et al NEJM 2007
visceral adipose tissue
%
Tesamorelin n=273Placebo n=137
change in value
cm2
baseline value cm2
P < 0.001
Fat Accumulation
HIV-associated lipodystrophy syndrome 20 years
What happened to the lipodystrophy syndrome?
Fat Accumulation
HIV-associated lipodystrophy syndrome 20 years
What happened to the lipodystrophy syndrome?
Thymidine analogue N(t)RTIs stopped being used
NNRTIs and PIs were replaced with InSTIs as anchor drugs
SMART study showed that HIV was pro-inflammatory and
pro-coagulopathic
DAD study emphasised effects of N(t)RTIs, NNRTIs and PIs
on comorbidities
HIV-associated lipodystrophy syndrome 20 years
Lipoatrophy
Fat accumulation
Cardiovascular disease
Management of cardiovascular disease
Future interventions
One or two syndromes
Cardiovascular Disease
HIV-associated lipodystrophy syndrome 20 years
VA Cohort Study: rates of AMI by HIV status and age
Age group, yr
40-49 50-59 60-69
n= 21,866 19,805 4209
uninfected
AMI rates per 1000 py 1.5 2.2 3.3
HIV infected
AMI rates per 1000 py 2.0 3.9 5.0
Incidence RR 1.34 1.80 1.53
Freiberg et al; JAMA Intern Med 2013
Cardiovascular Disease
HIV-associated lipodystrophy syndrome 20 years
SMART: event ratesevent DC group VS group HR (DC/VS)
[95% CI]P-
value
n rate n rateprimary endpoint: OD or death
120 3.3 47 1.3 2.6 [1.9, 3.7] <0.001
death 55 1.5 30 0.8 1.8 [1.2, 2.9] 0.007
serious OD 13 0.4 2 0.1 6.6 [1.5, 29] 0.01
non-serious OD 63 1.7 18 0.5 3.6 [2.1, 6.1] <0.001
major CVD, renal and hepatic events
65 1.8 39 1.1 1.7[1.1, 2.5] 0.009
grade 4 events 173 5.0 148 4.2 1.2 [0.9, 1.5] 0.13
grade 4 event or death 205 5.9 164 4.7 1.3 [1.03,1.6] 0.03
El-Sadr et al, NEJM 2007
Cardiovascular Disease
HIV-associated lipodystrophy syndrome 20 years
SMART: baseline biomarkers and all cause mortality
unadjusted adjusted
marker OR (4th/1st) P-value OR (4th/1st) P-value
hs-CRP 2.0 0.05 2.8 0.03
amyloid A 2.2 0.07 2.6 0.09
amyloid P 0.7 0.39 1.1 0.84
IL-6 8.3 < 0.0001 11.8 < 0.0001
D- dimer 12.4 < 0.0001 26.5 < 0.0001
F1.2 1.0 0.92 1.2 0.66
Insight Mtg Tlk 2/6/2008
Cardiovascular Disease
HIV-associated lipodystrophy syndrome 20 years
0
5
10
15
20
25 all causedeath
non-AIDS/
violent/accidental
death
AIDS NADMCVD
14 21 35 87 6 16 23 72 15 26 24 36 13 21 33 54 10 19 28 42No events
Crud
e in
cide
nce
rate
spe
r 1,0
00 P
YFU
(95%
CI)
IL-6
START: crude incidence rates of clinical endpoints across biomarker quartiles
crude incidence rates per
1,000 PYFU
(95% CI)
+
˟1st quartile
2nd quartile
3rd quartile
4th quartile
Events n=
Cardiovascular Disease
HIV-associated lipodystrophy syndrome 20 years
DAD: risk of MI by exposure to PIs and NNRTIs
The DAD Study Group; NEJM 2007
adjustedrelative
rate
PIsNNRTIs
Cardiovascular Disease
HIV-associated lipodystrophy syndrome 20 years
DAD: rates of MI by recent use of abacavir
DAD Lancet 2008
rate per 1000
patient years
0
5
10
15
20
25
30
35
events 325 192 60 42 79 33 100 68 86 49patient years 126581 31331 57628 14754 13372 4300 6293 2095 49288 10182
overall low moderate high not known
no recent abacavirrecent abacavir
Cardiovascular Disease
HIV-associated lipodystrophy syndrome 20 years
DAD: cardiovascular risk factors and rate of MI
variable relative rate 95% CIExposure to PI (per additional yr) 1.16 1.10-1.23Exposure to NNRTI (per additional yr) 1.05 0.98-1.13Age (per additional 5 yr) 1.39 1.31-1.46Male sex 1.91 1.28-2.86FH of CAD 1.56 1.10-2.23Smoking 2.83 2.04-3.93Previous cardiovascular event 4.30 3.06-6.03
The DAD Study Group; NEJM 2007
Diabetes, hypertension, total and decreased HDL cholesterolwere also risk factors in second adjusted model
Cardiovascular Disease
HIV-associated lipodystrophy syndrome 20 years
Impact of HIV on inflammation, coagulation, and health
Deeks et al, Immunity 2013
Initiators of inflammation
Other risk factors
Microbial translocation
Liver fibrosis or dysfunction
Innate immunity
Cardiovascular disease
Hypercoagulation
Age-associated diseases
tissue factor expression
alteredcoagulome
HIV-associated lipodystrophy syndrome 20 years
Lipoatrophy
Fat accumulation
Cardiovascular disease
Management of cardiovascular disease
Future interventions
One or two syndromes
Management of CVR
HIV-associated lipodystrophy syndrome 20 years
Cardiovascular risk: calculation
Framingham risk score
AHA/ACC pooled cohort equations CV risk calculator (PCE)
Friis-Moller et al, Eur J Prev Cardiol 2016
DAD model
includes age, gender, BP, smoking, FH, DM, TC, HDL, CD4, cumulative exposure to PIs and NRTIs, current use of ABC
predicted risk more accurately than Framingham
Management of CVR
HIV-associated lipodystrophy syndrome 20 years
Management principles in HIV-infected persons
Same risk reduction strategies as general population
aspirin, statin, BP control, management of DM
Screen for DM and dyslipidaemia at baseline and every 3 to 6 and 6 to 12 months respectively
Use InSTI and avoid ABC in treatment naïve with increased cardiovascular risk
Switch PI to InSTI has modest benefit on dyslipidaemia in treatment experienced
atorvastatin, pitavastatin and rosuvastatin are statins of choice for dyslipidaemia on ART
HIV-associated lipodystrophy syndrome 20 years
Lipoatrophy
Fat accumulation
Cardiovascular disease
Management of cardiovascular disease
Future interventions
One or two syndromes
Future Intervention
HIV-associated lipodystrophy syndrome 20 years
HIV trials: targeting inflammation and/or end-organ disease risk
Lipid lowering
BP lowering
other risk-factor modification
anti-inflammatory
anti-coagulants
Blocking microbial translocation
anti-viral
anti-fibrotic
Future Intervention
HIV-associated lipodystrophy syndrome 20 years
REPRIEVE: trial design (n=6500)
http://reprievetrial.org/overview/
Screening and consent (asymptomatic HIV-infected persons with no history of CVD)
Randomisation
Mechanistic study primary(coronary plaque, vascular inflammation,
or immune activation)
Secondary end points(individual components of primary end point; all-cause death; incidence or progression
of non-calcified plaque; high-risk plaque; inflammatory, immunologic or metabolic biomarkers; predictors of statin effect; and non-AIDS-related comorbidities)
Composite primary end point(CVD-related death, myocardial infarction, unstable angina,
stroke, and arterial revascularization)
Placebo Pitavastatin 4mg daily
Future Intervention
HIV-associated lipodystrophy syndrome 20 years
Polypills: projected risks of ischaemic heart disease (IHD) and stroke after 2 yr of treatment at age 55-64
Wald and Law, BMJ 2003
% reduction in risk (95% CI)Risk factor Agent Reduction in
risk factorIHD event stroke
LDL cholesterol statin 1.8 mmol/l reduction in LDL cholesterol
61 (51 to 71) 17 (9 to 25)
Blood pressure 3 classes of drug at half dose
11 mm Hg diastolic
46 (39 to53) 63 (55 to 70)
Serum homocysteine
folic acid(0.8 mg/day)
3mmol/l 16 (11 to 20) 24 (15 to 33)
Platelet function aspirin(75 mg/day)
not quantified 32 (23 to 40) 16 (7 to 25)
Combined effect all 88 (84 to 91) 80 (71 to 87)
Future Intervention
HIV-associated lipodystrophy syndrome 20 years
PolypillsFixed-dose combination therapy in a single pill to improve prevention and control of atherosclerosis
Combinations of aspirin, ACE/ARB and statin, generally low-dose, sometimes with β-blocker or CCB
Similar concept to fixed-dose combinations for malaria, TB and HIV
Concept without widespread availability and limited experience
Given increased cardiovascular risk in HIV, should the polypill be tested in HIV-infected persons?
Huffman et al, Lancet 2017
Future Intervention
HIV-associated lipodystrophy syndrome 20 years
HIV-comorbidities: development of clinical trial agendaPrinciple: select agent to move to phase 3 with best evidence of relevant biomarker effect
Design limitations
small sample size limiting safety assessment
low power to detect differences in key biomarkers
inability to compare drugs
different target populations
Solution: adaptive phase 2 trial design with rigid criteria for taking best agent to phase 3
Future Intervention
HIV-associated lipodystrophy syndrome 20 years
-70
-60
-50
-40
-30
-20
-10
0
10
% change
from baseline (median)
hsCRP
months
placebo
canakinumab 50mg
canakinumab 150mgcanakinumab 300mg
Ridker ESC 2017
CANTOS: Dose-dependent effects on inflammatory biomarkers and lipids (48 months)
All doses SC q 3 months No effect on LDL-Chol, HDL-Chol or TG
Future Intervention
HIV-associated lipodystrophy syndrome 20 years
CANTOS: primary clinical outcome effects on MACE/MACE+Canakinumab SC q 3 months
placebo(n=3347)
50 mg(n=2170)
150 mg(n=2284)
300 mg(n=2263)
P-trend
Primary endpointIR (per 100 person years)HR95%CIP
4.51.0
(referent)(referent)
4.10.93
0.80-1.070.30
3.90.85
0.74-0.980.021*
3.90.86
0.75-0.990.031
0.020
Secondary endpointIR (per 100 person years)HR95%CIP
5.11.00
(referent)(referent)
4.60.90
0.78-1.030.11
4.30.83
0.73-0.950.005*
4.30.83
0.72-0.940.004
0.003
* Statistically significant, adjusted for multiplicity, in accordance with the pre-specifiedclosed-testing procedures
Ridker ESC 2017
Future Intervention
HIV-associated lipodystrophy syndrome 20 years
CANTOS: additional outcomes (per 100 pt yrs of exposure)Canakinumab SC q 3 months
Adverse Event Placebo(n=3347)
50 mg(n=2170)
150 mg(n=2284)
300 mg(n=2263) P-trend
Any SAE 12.0 11.4 11.7 12.3 0.43Leukopenia 0.24 0.30 0.37 0.52 0.002Any infection 2.86 3.03 3.13 3.25 0.12
fatal infection 0.18 0.31 0.28 0.34 0.09/0.02*Injection site reaction 0.23 0.27 0.28 0.30 0.49Any malignancy 1.88 1.85 1.69 1.72 0.31
fatal malignancy 0.64 0.55 0.50 0.31 0.0007Arthritis 3.32 2.15 2.17 2.47 0.002Osteoarthritis 1.67 1.21 1.12 1.30 0.04Gout 0.80 0.43 0.35 0.37 0.0001ALT > 3x normal 1.4 1.9 1.9 2.0 0.19Bilirubin > 2x normal 0.8 1.0 0.7 0.7 0.34
* P-value for combined canakinumab doses vs placebo Ridker ESC 2017
Future Intervention
HIV-associated lipodystrophy syndrome 20 years
Grivennikov, Greten, Karin. Cell 2010
Immunity, Inflammation, and Cancer
Therapy-induced inflammation
Tumour associated inflammation
Chronic inflammation
InfectionAutoimmunity
Inflammationcaused by
environmental and dietary exposure
Tumour re-emergenceResistance to therapy
Antigen presentationCancer cell killing
Tumour growth/survivalGenomic instability
AngiogenesisImmunosuppression
MetastasisCancer cell killing
MutationsGenomic instabilityTumour promotion
Angiogenesis
MutationsGenomic instabilityTumour promotion
AngiogenesisTUMOUR
DEVELOPMENT