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Metabolic Complications of HAART

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Increasing age or BMI and minority race greatest risk factors among all veterans ... Duvivier et al (AIDS 2009, 23:817-24): lumbar spine BMD over 48 weeks decreased ... – PowerPoint PPT presentation

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Title: Metabolic Complications of HAART


1
Metabolic Complications of HAART
  • Asilomar Faculty Development Conference
  • 15 September 2009
  • Ronald Wilcox MD FAAP
  • rwilco_at_lsuhsc.edu

2
Program Developed by the Delta AETC
Principal Investigator/Program Director Ronald
D. Wilcox MD FAAP
3
ROUND ONE
Sugar
Da Lipid Dilemma
Too Much, Too Little
Brittle Bones
DM Part Deux
100
100
100
100
100
200
200
200
200
200
300
300
300
300
300
400
400
400
400
400
500
500
500
500
500
4
100 Class of anti-retrovirals most commonly
associated with causing insulin resistance
5
Insulin Resistance in HIV Most common thought
protease inhibitors Best way to measure insulin
resistance is hyper-insulinemic euglycemic
clamp Ex 1 dose of indinavir ? 30 decrease in
insulin sensitivity in HIV- subjects Mechanisms
1. Reduction of glucose uptake in adipocytes by
altering adipogenic proteins 2. Halving of
GLUT4 translocation by noncompetitive reversible
binding
100
6
200 Pneumocystis jiroveci treatment that is a
pancreatic beta cell toxin
7
200
Pentamidine Second line therapy for severe
PcP Dosed at 4 mg/kg IV daily Shown to initially
stimulate beta cells of the pancreas ? cell death
possibly Should obtain accuchecks q6 hours while
on this therapy to monitor for hypoglycemia and
hyperglycemia with ketoacidosis
8
300 In a rat model, Zhang et al (2009)
demonstrated an increased incidence of apoptosis
in this type of cells triggered by exposure to
protease inhibitors
9
1. fa/fa rats - exposed to PIs for 7 weeks ?
found increased apoptosis of the beta cells of
the pancreas. 2. Exposed insulinoma cells and
human pancreatic cells in vitro to 48-96 hours of
RTV, LPV, ATV, or TPV ? Greater cell death and
reduced insulin-secretory capability. Exposure to
the PIs led to activation of mitochondria-associat
ed caspase-9, promoting release of cytochrome c
leading to cell death.
300
10
400 Initial results of WIHS study in regards to
effects of PIs on DM incidence AND Two races
identified as having highest risk for DM
development by the Swiss HIV Cohort Study
11
DM in HIV Women (WIHS) and Swiss HIV Co-hort
Study
400
  • WIHS
  • Initial cohort study
  • 2.8 incidence in PI-receiving women
  • 1.2 those who had not received cART
  • 1.4 in controls - higher overweight incidence in
    HIV- women 33 vs 23
  • Later review
  • No difference between the HIV and HIV- women
  • NRTI Exposure gt 3 years risk to 2.6 fold
  • Swiss HIV cohort study
  • Asian ethnicity 4.9 fold risk
  • Black ethnicity 2.2 fold risk

12
500 When comparing cART-receiving HIV persons to
HIV-uninfected persons, Brown et al in Arch Int
Med in 2005 reported this amount increase in
relative risk of development of DM (expressed as
fold change)
13
Incidence of DM
500
  • Pre-HAART Rare in HIV persons
  • As HIV patients BMIs have increased, so has the
    incidence of DM
  • One study reported diabetes incidence in PI
    recipients with lipodystrophy of 2 that rose to
    7 after 14 months (0.5 in HIV- controls)
  • Brown et al
  • Prospective study over 4 years
  • 10 of HIV cART recipients developed DM whereas
    only 3 of HIV- men did.
  • After adjusting for age and BMI, there was a
    4-fold increase in relative risk

14
100 Co-infection common in those with HIV that
increases the likelihood of DM development
15
Risk Factors for DM in HIV
100
  • Butt A et al. AIDS 2009 23(10) 1227-34
  • 3227 HIV and 3240 HIV- VA patients
  • HIV persons more likely to be younger, HCV Ab
    , black males, with a lower BMI
  • Increasing age or BMI and minority race greatest
    risk factors among all veterans
  • HCV co-infection and use of nRTIs and NNRTIs (but
    not PIs) were associated with a higher risk of DM
    in HIV
  • Increasing alcohol use and hx of drug use
    negative predictors of DM
  • Compared to non-drinkers, HIV persons who drank
    31-60 drinks per month had an OR of 0.40

16
200 nRTI associated with increased insulin
resistance
17
IR and nRTIs
200
  • Stavudine
  • Increased truncal fat
  • Reduced peripheral fat
  • Increased plasma insulin levels
  • Effects only partially reversible
  • Lipoatrophy ? decreased secretion of 2 important
    adipokines leptin and adiponectin (which are
    both involved in glucose metabolism)

18
300 Recommended first line therapy for insulin
resistance in HIV
19
Therapeutic options for IR in HIV
300
  • Metformin first choice therapy
  • Significantly decreases plasma insulin, BMI, and
    diastolic BP
  • No increased incidence in lactic acidosis
  • Use cautiously in those with lipoatrophy
  • Cannot use in those with impaired renal function
    (Cr gt 1.4)
  • Glitazone sisters (Pio and Rosi) effectiveness in
    HIV ltlt HIV- although have been shown to increase
    subQ fat in HIV-
  • Sulfonylureas low dose when given with
    ritonavir due to increased levels
  • Therapy overall is same insulin use lower in
    those diagnosed with DM after their HIV diagnosis

20
400 As evaluated at the CORE Center, the
discrepancies seen in meeting ADA goals between
HIV men and women for each of the following
parameters HbA1C Lipid levels Aspirin use
21
Meeting of ADA Goals in HIV
400
  • Adeyami et al. CID 2009 49 799-802
  • 216 HIV patients of CORE Center evaluated
  • ADA Goals
  • HbA1C lt 7.0
  • BP lt 130/80
  • Total cholesterol lt 200
  • LDL lt 100
  • TG lt 150
  • HDL gt 40 in men, gt 50 in women
  • Aspirin use in all

22
Meeting of ADA Goals in HIV
400
  • DM diagnosed a mean of 3 years after HIV
    diagnosis
  • Women at 47, men at 52 (p.001)
  • Women had higher BMI (30.9 vs 27.3,plt.001)
  • Patients with undetectable VL more likely to meet
    HDL goal but less likely to meet TC or LDL goals
  • BP goals met in 56 of clients but less likely if
    on HAART

23
100 nRTI most commonly associated with osteopenia
in studies
24
Tenofovir and Bone Loss
100
  • Inhibits mineralization of new bone, demonstrated
    in assays of the hip and spine
  • Associated with renal phosphate wasting
  • Appears to be worsened if vitamin 25(OH) D levels
    are low ? increased PTH ? bone resorption
  • Some authors have proposed that all patients on
    tenofovir should receive calcium and vitamin D
    supplementation

25
200
Effects of the Protease Inhibitor class and
Zidovudine on bone mineral density
26
Zidovudine and PIs
200
  • Protease inhibitors as a class increased
    incidence of osteopenia and osteoporosis
  • Zidovudine shown to induce osteoclastogenesis ?
    increased bone resorption
  • Some studies suggest any HAART therapy may
    increase bone loss (next slide) although most
    suggest less NNRTI involvement
  • Duvivier et al (AIDS 2009, 23817-24) lumbar
    spine BMD over 48 weeks decreased 4.9 in
    patients on LPV/r or IND/r versus 1.5 loss in
    those on NNRTI-based regimen BUT was equal loss
    in hip assay

27
NNRTIs vs PIs and Bone Loss
200
  • Brown Todd et al. JAIDS 2009 Aug 15 51(5)
    554-560
  • 155tx-naïve patients randomized 12 to receive
    EFV or LPV/r with ZDV/3TC for 96 weeks
  • LPV/r arm if had VL lt 50 three times in weeks
    24-48, ZDV/3TC was discontinued (89 by week 32)
  • Lower baseline total BMD assoc with lower weight,
    non-black race, and lower baseline HIV RNA levels
  • At week 24 LPV/r arm 0.7 decrease in BMD
    versus 0.6 in EFV arm.
  • At week 96 LPV/r arm (90 monotherapy for
    average of 68 weeks) 2.5 decrease versus 2.3
    decrease in EFV/ZDV/3TC arm
  • Authors conclusion No difference in tx type

28
300 Proportion of treatment-naïve HIV-infected
persons with osteoporosis or osteopenia
29
Tx-Naïve Patients
300
  • Many studies? 1/3 of treatment-naïve HIV persons
    have osteopenia or osteoporosis
  • Thought to be due to chronic inflammation from
    HIV infection which may have direct effects on
    osteoclast activity
  • Control of viral load has shown a reversal of
    this effect in some studies

30
400 Component of the HIV virus associated with
increasing osteoclast activity
31
gp120
400
  • Given to HIV- persons at levels similar to
    someone with untreated HIV infection (Modarresi
    et al, Amer J Path 2009)
  • Induced expression of the osteoclast
    differentiation factor RANKL in CD4 t-cells ?
    increased bone resorption
  • Some studies have shown a decrease in HIV viral
    loads lead to an increase in bone density
  • Viral Protein Vpr also reported to have this
    association

32
500 Once yearly injectable treatment for
osteoporosis recently shown by Huang et al to be
safe and effective in HIV patients (AIDS 2009)
33
Zoledronate
500
  • 27 HIV men, 3 HIV women
  • Excluded people with recent dental problems
  • Median T-scores of lumbar spine -1.7 and hip -1.4
  • Median CD4 count 461 and 93 with VL lt400
  • Bone density measured absolutely and as
    sex-adjusted T-scores significantly improved in
    tx group
  • Increase of 3.7 4.1 in lumbar spine
  • Increase of 3.2 2.2 in hips
  • Bone resorption markers decreased over study
  • C-terminal telopeptides and cross-linked
    N-telopeptides of type I collagen
  • One patient developed uveitis

34
100 Two nRTIs most strongly associated with
lipoatrophy
35
Lipoatrophy
100
  • Most commonly involves
  • Face
  • Appendices
  • Buttocks
  • Strongest association with d4T gt AZT use
    (thymidine analogues)
  • Thought to be due to inhibition of mitochondrial
    gamma-DNA polymerase ? reduction of mitochondrial
    DNA

36
200 Highest non-medication related risk factor
for development of lipo-atrophy as shown by the
HOPS co-hort
37
Risk factors for Lipoatrophy
200
  • HOPS Study
  • Evaluated patients at two time points 21 months
    apart
  • Advanced immunodeficiency
  • CD4 lt 100 at Survey 2 time (OR 4.2)
  • Higher HIV viral load
  • Older age
  • White race (OR 5.2)
  • Low BMI lt 24 (OR 2.4)
  • Longer duration of HIV

38
300 Effects of obesity on CD3, CD4, and CD8
counts in HIV-infected patients as demonstrated
by Adeyemi et al at the CORE Center (Metab Clin
Exp 2009 58 1285-7)
39
Obesity and Inflammation
300
  • Current estimates 20-30 of HIV persons in US
    obese
  • Obesity increases via adipocytes substances with
    pro-inflammatory or immune-modulating functions
  • Leptin, adiponectin, CRP, IL-6, TNF-alpha
  • In non-HIV-infected obese persons higher CD3,
    CD4, and CD8 levels ? improved levels after
    gastric bypass surgery
  • Looked at 216 patients on HAART with VL lt 50 for
    at least 6 months
  • As BMI increased, so did CD3, CD8, and total
    lymphocyte counts but CD4 not significantly
    increased

CD4
CD3
CD8
TLC
40
400 Growth hormone releasing hormone that has
been shown by Falutz et al to decrease visceral
fat deposition (NEJM 2007)
41
Treatment of Lipodystrophy
400
  • Thiazolidinediones and metformin inconsisent
    effects on visceral fat
  • Metformin ? lipoatrophy
  • Testosterone dec total subQ fat but not
    visceral
  • rhGH ? fat-oxidizing and lipolytic properties ?
  • non-sustaining loss visceral fat and decrease in
    BP and TG but increases lipoatrophy
  • Tesamorelin (GHRH)
  • decreased visceral fat by 15 with increased subQ
    fat, decreased TG, and increased HDL
  • Expensive and requires parenteral administration
  • Liposuction or surgery
  • Lifestyle changes

42
500 Gold standard test for the study of fat
composition and distribution in children (per
Alves et al in the Brazilian J of ID 2008)
43
Evaluation of Lipodystrophy in Pediatric
Populations
500
  • Pre-pubertal children have milder lipodystrophy
    than pubertal
  • Lipohypertrophy most common manifestation
    (12-20) followed by mixed (5-9) followed by
    lipoatrophy (4-8)
  • DEXA scan best way to study fat composition and
    distribution in children
  • CT and MRI used to evaluate visceral fat
  • Clinical evaluation most common though to avoid
    use of sedating agents

44
100 HIV-infected patients on HAART respond
(better, the same, or worse) to anti-lipid
therapy compared to HIV-negative people
45
Response to Lipid Therapy
100
  • Protease inhibitors, efavirenz, and stavudine
    have been shown to increase levels of cholesterol
    and triglycerides
  • Elevated cholesterol levels in at least 25 of
    people on HAART
  • ACTG A5087 12 week study
  • Fenofibrate 9 LDL, 66 HDL, 48 TG NCEP goals
    met
  • Pravastatin 36 LDL, 49 HDL, 18 TG

46
Response to Lipid Therapy
  • French Agence Nationale de Recherche sur le SIDA
    (ANRS 126)
  • rosuvastatin 10 mg/d vs. pravastatin 40 mg/day
    (n42 each arm)
  • Results
  • LDL changes 37 R vs 19 P (plt0.001)
  • HDL changes no difference between arms
  • Overall it has been found that responses to
    anti-lipid therapy in HIV-infected persons is
    suboptimal compared to HIV-negative groups

47
200 HIV medication shown to decrease levels of
statins
48
Lowered statin levels
200
  • Broken down by the CYP3A4 system
  • Efavirenz acts as an inducer of CYP3A4 so expect
    lower levels of statins
  • Elvitegravir also causes some induction of this
    enzyme

49
300 Co-infection associated with lower
cholesterol levels than HIV mono-infected
patients
50
HCV and Hyperlipidemia
300
  • Liver is involved with cholesterol metabolism a
    severely diseased liver may be associated with
    low cholesterol levels
  • Brazilian study by Almeida of 110 HIV patients
  • Baseline total cholesterol
  • HCV 141.7 33.2
  • HCV- 156.6 37.4
  • Follow-up 14 months
  • HCV 157.3 31.8
  • HCV- 183.0 38.5
  • No effect seen on triglyceride levels by HCV

51
400 Pravastatin usage is not recommended with
this protease inhibitor
52
Statins and HAART
400
  • Broken down by CYP3A4 so levels increased when
    given with PIs, especially ritonavir
  • Simvastatin AUC levels incr. 30-fold with rtv/sqv
  • Generally should avoid simvastatin, lovastatin,
    and fluvastatin with PIs
  • Atorvastatin and rosuvastatin can be started at
    low dose
  • Pravastatin can be used with all except DARUNAVIR
  • Concerns about possible rhabdomyolysis

53
500 Effects on levels of HAART for each of the
following Fibrates Bile sequestrants Fish
Oil Niacin
54
Hypertriglyceride treatment
500
  • First line therapy recommended Fibric acid
    derivatives
  • Gemfibrozil
  • Fenofibrate
  • Second line Fish oil or niacin
  • Bile sequestrants contra-indicated due to
    concerns about absorption of HAART

55
Hypertriglyceride treatment
500
  • Gemfibrozil
  • 16 week study of diet change versus gemfibrozil
    diet change
  • Median fasting TG at baseline 496
  • Week 4 to week 16 change in TG levels
  • Diet alone 31 mg/dl
  • Diet gemfibrozil - 108 mg/dl
  • No significant drug interactions with HAART known
    for fibrates, fish oil, or niacin

56
Hypertriglyceride treatment
500
  • Fish oil
  • Anti-inflammatory properties reduces
    atherogenesis
  • DeTruchis et al
  • 8 week study placebo vs fish oil TID
  • Median fasting TG at baseline 450
  • 25 decrease TG levels fish oil vs 1 placebo
  • ACTG A5186
  • Baseline fasting TG of 667
  • Fish oil 1.5 gm BID 46 decrease
  • Fenofibrate 160 mg daily 58 decrease
  • Combined if did not reach goal 65.5 reduction

57
  • 3 of 5 diagnostic criteria for the metabolic
    syndrome (including actual numbers)

58
Metabolic Syndrome
  • Requires 3 of the following
  • Abdominal obesity (waist circumference gt 102 cm
    for men and gt 88 cm for women)
  • Triglyceride levels gt 150
  • HDL less than 40 for men and 50 for women
  • BP gt 130/85 mm Hg
  • Fasting glucose gt 110 mg/dL

59
Metabolic Syndrome and Subclinical
Atherosclerosis in Patients Infected with HIV
  • Mangili et al. CID 2007 44 1368-74
  • Patients (314) with metabolic syndrome
  • More likely to have common carotid intima
    thickening gt 0.8 mm (17 vs 7, p.009)
  • Equally likely to have internal carotid intima
    thickening gt 1.0 (20 vs 13, p.15)
  • Positive coronary artery calcium scoring on high
    resolution CT (80 vs 47, plt.0001)
  • Bottom Line Metabolic Syndrome more likely in
    HIV patients so need to screen for
    atherosclerosis of carotids and coronary arteries
    if present

60
Credits Questions Ronald D. Wilcox Slide
Layout Steve Styron (Tulane Medical Center)
Ronald D. Wilcox (Delta AETC)
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