Dyslipidemia and Insulin Resistance in Pediatric HIV

1
Dyslipidemia and Insulin Resistance in Pediatric
HIV Infection Implications for Cardiovascular
Health

• George K. Siberry, MD, MPH
• Pediatric Maternal AIDS (PAMA) Branch
• Eunice Kennedy Shriver National Institute of
  Child Health and Human Development
• NIH, Bethesda, MD
• MAY 2011

2
Disclosure of Financial Relationships

• This speaker has no significant financial
  relationships with commercial entities to
  disclose.

This slide set has been peer-reviewed to ensure
that there areno conflicts of interest
represented in the presentation.
3
Objectives

• Understand the frequency, risk factors and
  proposed underlying mechanisms of dyslipidemia
  and insulin resistance (IR) in HIV-infected
  children receiving HAART.
• Appreciate the relationship between dyslipidemia,
  IR and cardivascular risk
• Review cardiovascular risk assessment and
  monitoring in HIV-infected children youth.
• Understand available therapeutic interventions
  for dyslipidemia and IR in HIV-infected
  adolescents.

4
Definitions

• Dyslipidemia Elevated total cholesterol, LDL
  and/or Triglycerides (TG) Low HDL
• Insulin Resistance (IR) insulin levels higher
  than expected for glucose levels
• Spectrum IR -gt hyperglycemia -gt DM
• HOMA-IR homeostasis model assessment of IR
• fasting glucose (mmol/L) x fasting insulin
  (µU/ml)/22.5
• Metabolic Syndrome abdominal obesity,
  dyslipidemia, impaired glucose regulation, and
  high blood pressure Li Ped2011
• Lack of consensus pediatric definition
• NCEP(pediatric) 3 of (1) waist circ 90thile
  (2) TG 110 (3) HDLlt40 (4) DBP
  /SBP90thile(5) FPG 100
• Lipodystrophy abnormal fat distribution
• Peripheral lipoatrophy central lipohypertrophy

5
Established Risk Factors for CHD in Adults
Wilson Circulation 1998

• Framingham Study
• Generate 10-year Risk Score
• Limited to 20 yrs old
• RISK FACTORS
• Older Age
• High BP
• Smoking
• Diabetes
• Elevated LDL
• Low HDL
• Male sex (not pictured)
• OTHER
• Obesity (central)

6
2-hr OGTT
Fasting Glucose
HEALTHY ADULTS (Finland) Qiao EurHeartJ 2002
Coronary Heart Disease
CV Mortality
7
Hyperinsulinemia Independent Risk Factor for
Ischemic Heart Disease (IHD) in Adults Despres
NEJM 1996
gt 150mg/dL
gt119mg/dL

• 2103 Canadian men, 1985
• 114 IHD cases in 5 year follow-up
• Nested case-control.
• DM excluded.
• Matched on smoking, EtOH, BMI
• Specimens after 12-hr fast

gt 6.0
8
Endothelial Function

• Endothelium Monocellular layer lining entire
  vascular system
• Regulation of vascular tone
• NO, Endothelin, Other vasoactive substances
• Anti-thrombosis (prostacyclins)
• Anti-inflammatory (Developmental endothelial
  locus-1)
• Anti-proliferative (NO, prostaglandin I2)
• Endothelial dysfunction associated with CV risk
  factorsand improves with mgmt of CV risk factors

9
INTERACTION of CVD RISK FACTORS and ENDOTHELIAL
DYSFUNCTION
Butt et al. Curr Pharm Des 2010
10
? MI Risk in HIV Adults Currier JAIDS 2008
11
Role of Traditional CVD Risk Factors in Adults
with HIV Infection Currier JAIDS 2008

• Effects of risk factors in HIV adults similar
  to those in HIV-uninfected
• High rate of some risk factors (eg, smoking) in
  HIV infection
• Traditional risk factors contribute significantly
  to CVD risk in HIV

12
Endothelial Dysfunction Markers Improve with
HAART (Adults) Kristofferson 2009
Plt0.05 vs. controls Plt0.01 vs. controls
Plt0.001 vs. controls
Plt0.01 and Plt0.001 vs. the HIV-infected
treatment-naive group

• HIV effect ? ED biomarker levels pre ART
• ART effect Most endothelial dysfunction
  biomarkers improve with HAART
• hsCRP ART improves but not to normal

13
Role of Antiretroviral Agents in ? MI RiskData
Collection on Adverse Events of Anti-HIV Drugs
(DAD) Study

• 580 MIs with gt178K P-Y. HIV Adults
• NO associated ? MI Risk
• TDF, ZDV, d4T, 3TC
• NVP, EFV
• NFV, SQV
• Significantly ? MI Risk
• Abacavir (recent) RR 1.70
• Didanosine (recent) RR 1.41
• Indinavir RR 1.12 (1.08, adj. for lipids)
• Lopinavir/rtv RR 1.13 (1.09, adj. for lipids)

14
Higher CV Risk with Treatment Interruption
Phillips AIDS2008 SMART

• SMART randomized adults suppressed on ART to
  continuous vs CD4 guided ART
• Hazard Ratio 1.57 for major CVD events
• Interruption associated with altered lipid
  profile
• Total and LDL cholesterol reduced
• HDL reduced
• Interruption associated with inflammatory markers
  (IL-6, hsCRP, D-dimer) Kuller 2008

15
Factors That Potentially Influence Cardiovascular
Risk in HIV Patients Currier JAIDS 2008
16
Which of the following statements is NOT true
about HIV infection and CVD Risk?

• HIV infection increases CVD risk
• HIV treatment with HAART eliminates
  HIV-attributable excess CVD risk
• HIV treatment with HAART reduces but doesnt
  necessarily normalize endothelial dysfunction
• Certain antiretroviral drugs may increase CVD
  risk more than others
• Evidence from Adults

17
Reference Ranges for Children

• 1TC, LDL Elevated TCgt200mg/dL, LDLgt130mg/dL
• 1HDL High Risk lt40 mg/dL (lt50 female)
• 1Triglyceride gt150-200 mg/dL elevated
• Plasma Glucose gt100mg/dL impaired gt126 mg/dL
  DM
• HOMA-IR gt2.5IR prepubertal gt4IR pubertal
• BMI 85-95ile Overweight gt95ile Obese
• Blood Pressure gt90ile at risk gt95ile
  (repeatedly) hypertension
• Varies with Age, Sex, Pubertal stage,
  Fasting state, Height 1Inconsistent by study

18
OverviewHIV-Infected Children

• Metabolic disorders reported in HIV-infected
  children on antiretroviral therapy
• Lipodystrophy reported in 6-47
• Hyperlipidemia reported in 13-67
• Insulin resistance 0-13, with hyper-insulinemia
  reported in 60
• Puberty is time when children are most likely to
  develop metabolic complications.

Courtesy Lynne Mofenson
Krause JC et al. J Ped Endo Met
200922345-51 Aldrovandi G et al. AIDS
200923661-72 Tassiopoulos K et al. JAIDS. 2008
47607-14 Rosso R et al. Euro J Endo
2007157655-9 Vigano A et al. Antivir Ther.
200712297-302 Ene L et al. Eur J Pediatr.
200716613-21
Ergun-Longmire B et al. Endocr Prac.
200612514-21 Dzwonek AB et al. JAIDS.
200643121-3 Carter RJ et al. JAIDS.
200641453-60 Farley J et al. JAIDS.
200538480-7 Beregszaszi M et al. JAIDS.
200540161-8 European Paediatric Lipdystrophy
Group. AIDS. 2004181443-1451
19
Lipodystrophy associated with dyslipidemia and
IR VERKAUSKIENE Ped Res 2006
Courtesy of Professor Gabriel Anabwani, BIPAI
Botswana (FEB-2010)
20
Results Prevalence of metabolic outcomes
Prevalence of Metabolic OutcomesAlam NE et al,
Euro Ped HIV Lipodys Study. XVIII IAS, Vienna,
July 2010 Abs
Hypertriglyceridemia
24 (95 CI 20, 29)
Hyper-cholesterolemia
13 (95 CI 9, 16)
67
28
16
1
Courtesy Lynne Mofenson
Glucose intolerance
1 (95 CI 0, 2)
4
21
Dyslipidemia Risk Factors in HIV-Infected Children

• Hypercholesterolemia reported in 13-47 and
  hypertriglyceridemia in 15-67 of HIV infected
  children. Associated factors
• PI use (particularly ritonavir) or d4T use
• Undetectable RNA, higher CD4 count
• BMI gt90ile,
• Presence of lipodystrophy
• Young age puberty (studies differ)

Courtesy Lynne Mofenson
Beregszaszi M et al. JAIDS. 200540161-8 Europ
ean Paediatric Lipdystrophy Group. AIDS.
2004181443-1451 McComsey G et al. Pediatrics.
2003111e275-81 Cheseaux JJ et al. JAIDS
200230288-93
Tassiopoulos K et al. JAIDS. 2008 Vigano A et al.
Antivir Ther. 200712297-302 Carter RJ, et al.
JAIDS. 200641453-60 Farley J et al. JAIDS.
200538480-7
22
Development of Hypercholesterolemia is More
Frequent in Children on PI-Based HAART
Tassiopoulos K et al. JAIDS 2008
Cholesterol gt220 Entry 13 of 2123
children Follow-up additional 13 (median f/u
50.4 mos) Incidence 3.4/100 pt-yr
NO ART Incidence 1.3/100 pt/yr
HAART, no PI Incidence 1.4/100 pt/yr
ART but not HAART Incidence 2.8/100 pt-yr
HAART including PI Incidence 4.1/100 pt-yr
Courtesy Lynne Mofenson
23
P1045 PI Use Significantly Associated with
Lipid Abnormalities in HIV-Infected
ChildrenAldrovandi G et al. AIDS 200923661-72
Courtesy Lynne Mofenson
24
Use of PI, Lower Viral Load, Younger Age, and
Good Adherence Associated with Development of
Hypercholesterolemia Tassiopoulos K et al.
JAIDS 2008
Courtesy Lynne Mofenson
25
Insulin Resistance Frequency and Risk Factors in
Perinatal HIV Vigano 2009 Beregszaszi 2005

• 37 HIV-infected children followed 4 yrs
• Regimens associated with insulin resistance d4T-
  3TC - (RTV or IDV)
• Lower risk of IR d4T-3TC-NFV and TDF-3TC-EFV
• Increased risk with puberty
• 130 HIV-infected children followed 2 years
• IR baseline 13 -gt 26 at 2 yrs
• Risk factors PI use, puberty

26
Possible Mechanisms for ART Effect on
Dyslipidemia/IR

• PI direct action on glucose movement thru
  glucose transporter-4 Murata JBiolChem2000
• Thymidine analog NRTI mitochondrial toxicitiy
  Vigano 2009
• Increase in BMI (indirect effect)
• Direct ARV effect on endothelium Wang 2009
• Impaired endothelium-mediated vasorelaxation(rtv,a
  bc,3tc,ddi,idv,zdv)
• ?endothelial nitric oxide synthase
  (zdv,3tc,abc,rtv,idv)

27
Choose the child MOST likely to have dyslipidemia
and/or IR

• 1) 5yo, on nevirapine, zidovudine, lamivudine,
  with BMI 97ile
• 2) 8yo, on lopinavir/r, lamivudine, stavudine,
  with BMI 95ile
• 3) 12yo, on atazanavir (unboosted), lamivudine,
  abacavir, BMI 75ile
• 4) 16yo, on efavirenz, tenofovir, emtricitabine,
  with BMI 95ile

28
Why Do These Findings Matter In Children?

• Myocardial infarctions not occurring in
  perinatally HIV-infected youth
• Strokes are rare in HAART era
• Risk factor link to CVD outcomes is for adults
• Male, Age, SBP (and hypertension treatment),
  Total and HDL cholesterol, smoking, DM
• Framingham risk score 20 yrs old
• Reducing risk factors reduces CVD risk
• Perhaps dyslipidemia and IR in youth means
  little for risk of cardiovascular events later in
  life?

29
Pediatric Metabolic Syndrome Predicts Adult CVD
25 Years Later Morrison Pediatrics 2007
PediatricMetabolic Syndrome -TGgt110 BMIgt90ile
BPgt90ile FPGgt110 HDLlt50 (?)/40 (?)
30
Cardiovascular Risk Assessment in Healthy
Children Youth

• CV events rare in children but
• Atherosclerosis begins in childhood Berenson
  Bogalusa NEJM 1998
• CV risk factors associated with atherosclerosis
  in youth
• Berenson Bogalusa NEJM 1998. PDAJ JAMA 1990
• CV Risk factors in childhood persist into
  adulthood
• Weber JChrDis 1983. Mahoney AnnNYAcadSci 1991.
  Porkka AmJEpi 1994.
• High BMI in childhood associated with increased
  CV risk in adulthood Baker NEJM 2007
• Obesity, glucose intolerance, and hypertension in
  childhood associated with premature death Franks
  NEJM 2010
• So cardiovascular risk factors matter in
  childhood and cardiovascular disease has onset
  early in life

31
Pathobiological Determinants of Atherosclerosis
in Youth
PDAY Score -15 to 34 yo - Athero lesions at
autopsy -CA ?Odds by 18 per point McMahan
AIM2005
32

• Intermediate Outcomes Between Dyslipidemia/IR (or
  other risk factors) and CV Events?
• For children?

33
Non-Invasive Assessments

• Serum markers (inflammation, coagulation,
  myocardial)
• hsCRP, IL6, D-dimer, vWF, ProBNP, Troponin,
  Endothelin, Adhesion molecules (VCAM-1,
  E-selectin, ICAM-1), soluble thrombomodulin
• ECHO structural and functional measurements
• Carotid Intima Media Thickness (CIMT)
• Flow mediated dilatation (FMD)
• Endothelium in large artery responds to changes
  in blood flow (release BP cuff after 4 minutes)
  with relaxation of smooth muscle cells.
• Arterial stiffness
• Cardiac Positron Emission Tomography (PET)
• assess coronary flow reserve (CFR) and coronary
  endothelial function
• Cardiac MRI Estimates coronary blood flow/flow
  reserve without radiation
• CT Coronary Artery Calcifications (CAC) CAC
  atherosclerosis
• Stress-induced cardiovascular reactivity (SBP gt
  DBP) associated with CIMT in youth Roemmich
  Athero2011

34
ECHO Functional Measures Stanton 2009

• EF ejection fraction
• Strain (e) deformation
• ? Length 100 / Initial Length (2-D Long axis)
• Can be measured on existing ECHOs
• Impaired Global Longitudinal Strain (gt -12) and
  EF equally predictive of all-cause mortality
  after adjusting for age, hypertension and
  diabetes (non HIV adults)

35
ECHO Abnormalities Common in HIV-Infected Adults
in HAART Era Mondy CID 2011
Predictors of Echocardiographic Abnormalities

• 656 HIV Adults. 2004-2006. 73 on HAART.

36
Estimated Effect of HAART on Cardiac Dysfunction
(Children) Patel K et al. XVIII IAS Conf,
Vienna, July 2010 Abs.
Courtesy Lynne Mofenson
37
Predictors of Cardiac Dysfunction among Children
Who Started HAART Patel K et al. XVIII IAS
Conf, Vienna, July 2010.
Courtesy Lynne Mofenson
38
HIV Risk factor for abnormal cardiac strain (by
ECHO) in children Sims Antivir Therap 2010

• 28 7-32 yrs old, perinatal/early HIV infection
• 28 age-, sex-matched controls
• All asymptomatic (cardiac)
• ECHOs on all
• EF and FS normal in both groups
• HIV Significantly impaired strain, strain rate,
  and higher LV mass index

39
Carotid intimal media thickness (CIMT)

• Associated with vascular events in adults Lorenz
  Circ 2007
• ? evidence that CIMT in children predicts
  vascular events Davis Circ 2001 Lorenz Stroke
  2006
• CV risk factors, including PDAY score, in
  children predict abnormal CIMT
• In later adulthood Raitakari JAMA2003 McMahan
  AmJCard2007
• In youth Shah Ped2011
• 15-year change in CV risk/PDAY from adolescence
  predicts adult CIMT McMahan 2007

40
CIMT
41
Structural and Functional Vasculature Changes in
HIV-Infected Children Charakida M et al.
Circulation 2005112103-9
Courtesy Lynne Mofenson

• Carotid intima-media thickness (IMT)
• Increased in HIV-infected vs control uninfected
  children (plt0.001).
• Increases with age in HIV-infected but not
  uninfected children.
• In infected children, PI treatment associated
  with increased carotid IMT.
• Suggests both HIV antiretroviral drugs play
  role.

• HIV

p0.04
p0.01
PI treated
Non-PI treated
Untreated
42
Cardiac MR
Courtesy Rohan Hazra
Example of coronary irregularities on cardiac MRI
(A) and corresponding finding on Coronary CTA (B)
(red arrows). There is low signal intensity
lesion in the left main coronary artery, which is
confirmed as a non-calcified plaque seen on the
CTA (B). (C) Example of normal right coronary
artery on cardiac MRI showing smooth edges of the
coronary arteries.
43
Coronary Artery Abnormalities Mikhail PIDJ 2011

• 27 HIV-infected 13-29yo (mean 19), All ARV
• 93 perinatally infected, 70 undetectable VL
• 18 history of smoking
• 7 past (but no current) cardiac history
• ?TC 7.4, ?TG 26, ?HDL 37
• CAA in 14 (52)
• 13 with lt25 lumenal narrowing
• 1 with 25-50 lumenal narrowing
• Only independent predictor smoking
• By comparison, 9.3 prevalence of CAC in healthy
  18-30 year-olds (Yan JAMA 2006)

44
Evidence of early or ?risk of CVD in HIV-infected
children on HAART includes the following EXCEPT

• Increased carotid artery intimal thickness
• Coronary artery calcifications
• Coronary artery abnormalities
• Abnormal cardiac strain
• Increased myocardial infarction incidence

45
Screening Recommendations US DHHS Pediatric ARV
Treatment Guidelines

• Adolescents
• Fasting lipid panel and plasma glucose (PG)
• Starting or changing ART, then 3-6 mos later,
  then every 6-12 mos
• Children without additional risk factors
• Lipid profile and PG
• Starting or changing ART, then every 6-12 mos
• (Non-fasting OK, but confirm with fasting
  specimen if elevated TG, LDL, or PG )
• Children with risk factors or abnormal baseline
• Fasting lipid panel and PG
• Starting or changing ART, then every 6 mos

46
Treatment- General

• As for HIV-uninfected children
• Increase Exercise Eat Healthier Pediatrics 2007
• Nutrition eval/diet education total fatlt30 of
  calories, sat. fatlt10 of calories,
  cholesterollt300 mg/d, avoid trans fats
• Ensure healthy BMI (lt85-95 percentile)
• Ensure SBP and DBP lt90-95 ile
• Avoid tobacco use and passive exposure
• Review whole drug profile
• Ex 2nd generation antipsychotics Correll JAMA
  2009
• Weight gain (aripiprazole, olanzapine,
  quetiapine, risperidone)
• Lipid changes ? Tchol, ?TG, ?nonHDL chol
• olanzapine, quetiapine risperidone only TG
• Insulin resistance and Metabolic syndrome
• quetiapine, olanzapine

47
Proven Benefits of Lifestyle Changes NEJM
2002246(6)393
Healthy Adults Lifestyle Intervention -Weight
loss -Low-calorie, Low-fat diet -150minutes/week
exercise
48
Treatment ARV switch

• Pediatric studied
• PI -gt EFV improved Tchol, LDL, TG McComsey 2003
• d4T/PI -gt TDF/EFV improved lipid profile Vigano
  2005
• PI -gt NVP improved Tchol, HDL Gonzalez 2006
• Avoid lipid-unfriendly
• PI, esp. RTV, IDV, LPVr
• d4T
• Choose lipid-friendly.
• NNRTI (esp. NVP) ATV
• TDF
• ATV or PI-sparing may reduce IR
• Limited ped data Vigano Clin Drug Invest 2009

49
Pharmacologic Treatment Different in HIV
context?

• Current guidelines stratify definitions and
  treatment indications for children based on
  presence of absence of underlying conditions
  Pediatrics 2007 AAP
• More aggressive treatment for conditions
  associated with accelerated atherosclerosis
• familial hyperchol DM (1 and 2) Renal insuff
  cardiac transplant Kawasaki disease chronic
  inflammatory disease congenital heart disease
  post childhood cancer survivors.
• Debate about whether HIV-infected should be
  condition that warrants more aggressive approach
  than for healthy children

50
Pharmacologic Treatment- Elevated Cholesterol
Vigano 2010, AAP 2007, AAP 2008, Ped ARV GL

• No specific guidelines for ped HIV
• LDLgt130 ?gt160? gt190? (HIVCV risk factor?)
• Consider statins
• Children 8 yo already on modified diet
• LDLgt160 or, if higher risk, LDL 130mg/dL
• Children lt8yo, on diet, LDLgt500
• Ped label Pravastatin(8yo), Atorvastatin (10y)
• Beware drug interactions
• PI/r Avoid Lova, Simvastatin ?atorvastatin
• NNRTI ?most statins prn lipid response
• IMPAACT P1063 (atorvastatin)

51
Pharmacologic Treatment- Elevated Cholesterol
Vigano 2010
Pravastatin 8 yo Atorvastatin 10 yo
52
Pharmacologic Treatment Elevated TG

• No clear guidelines in ped HIV context
• Prompt intervention for TG gt500 mg/dL
• Alter ART regimen, if possible
• Consult Pediatric Lipid Specialist
• First line in adults Fibrates
• Not approved for children
• Only in consultation with pediatric lipid
  specialist
• Fish oil
• Niacin (?HDL, ?TG)
• Not approved for children
• Not routinely recommended because poorly
  tolerated

53
Pharmacologic Treatment Insulin Resistance

• No clear guidelines in ped HIV context
• For type-2 diabetes mellitus
• Oral hypoglycemic
• Metformin- approved gt10 yrs old
• Reduce IR and BMI in nonHIV with IR
• Thiazolidineones not approved in children
• Otherwise, insulin therapy

54
Consider the following patient

• 10 year-old perinatally HIV-infected boy
• Well controlled on LPVr-3TC-d4T
• BMI 97ile, SBP gt90ile, DBP lt90ile
• Non-fasting labs
• Tchol 210, LDL 170, HDL 50, TG 200
• Glucose 115
• Risperidone for behavioral disorder

55
Choose the best management option for the
following patient

• 10 yo boy, LPVr-3TC-d4T, Risperidone
• BMI 97ile, SBP gt90ile, DBP lt90ile
• Non-fasting labs Tchol 250, LDL 160, HDL 50, TG
  200 Glu 115

• Initiate atorvastatin, niacin, and metformin
• Counsel on modified diet and exercise
• Repeat labs in fasting state
• Discontinue all antiretroviral treatment
  temporarily
• Discontinue risperidone

56
The best option is

• Initiate atorvastatin, niacin, and metformin
• Counsel on modified diet and exercise
• Repeat labs in fasting state
• Discontinue all antiretroviral treatment
  temporarily
• Discontinue risperidone

57
Appropriate Elements of Management May Include
the Following EXCEPT

• 10 yo boy, LPVr-3TC-d4T, Risperidone
• BMI 97ile, SBP gt90ile, DBP lt90ile
• FASTING labs Tchol 230, LDL 150, HDL 50, TG 150
  Glu 105

• Counsel on modified diet and exercise
• Find alternative to risperidone in behavioral
  management
• Replace stavudine with abacavir
• Replace lopinavir/r with atazanavir
• Initiate pravastatin

58
The best option is

• Counsel on modified diet and exercise
• Find alternative to risperidone in behavioral
  management
• Replace stavudine with abacavir
• Replace lopinavir/r with atazanavir
• Initiate pravastatin

59
With updated information below, what would be
your next management step?

• 6 months of intensive diet and exercise
  modification
• d4T-gt ABC. No change in LPV/r due to too much
  past resistance. Risperidone discontinued.
• BMI 85ile, SBP lt90ile, DBP lt90ile
• FASTING labs repeated Tchol 205, LDL 130, HDL
  50, TG 125 Glu 90

• Discontinue modified diet and exercise since
  ineffective
• Initiate simvastatin
• Change LPV/r to ATV despite documented resistance
• Initiate niacin
• Continue current management and re-evaluate in 6
  mos

60
The best option is

• Discontinue modified diet and exercise since
  ineffective
• Initiate simvastatin
• Change LPV/r to ATV despite documented resistance
• Initiate niacin
• Continue current management and re-evaluate in 6
  mos

61
Acknowledgements

• Lynne Mofenson
• Rohan Hazra
• Grace McComsey