hiv, dyslipidemia, and cvd risk · 2012-11-20 · hiv, dyslipidemia, and cvd risk sergio fazio, md,...

HIV, Dyslipidemia, and CVD Risk

Sergio Fazio, MD, PhD

Cornelius Vanderbilt Chair of Cardiovascular Medicine

Professor of Medicine, Pathology, Immunology and Microbiology

Chief, Section of CVD Preventio

Vanderbilt University Medical Center

Nashville, Tennessee

One Case

54-yo man with HIV, diabetes, HTN, and dyslipidemia

No CHD, no family history of CHD, no smoking

HIV: controlled onAtripla 600/200/300 and Isentress 400 mg twice

a day

HTN: controlled on HCTZ/ACE-I

T2D: poorly controlled on metformin 1000 plus glipizide 4

(HbA1c 9.3%)

LDL 83 mg/dl, on pravastatin 40 mg

TG 1770 mg/dl on fenofibrate 160 and fish oil supplement 2 g

Also on aspirin 81 mg

One Case

Stress test normal, CAC zero

Amylase and lipase normal

AST 114, ALT 151

Dietary instructions

Omega 3 supplement to 4g

Metformin to 2000 mg

Glipizide to 10 mg

At 3-month follow up, patient has lost 10 pounds

TG 330 mg/dl (LDL 94 mg/dl)

HbA1c 6.3%

AST 60, ALT 75

Another Case

64-yo man with HIV, diabetes, CAD (stent in LAD 8 years prior),

and dyslipidemia

HIV: controlled on Truvada 200/300 mg, Isentress 400 mg twice a

day, Intelence 100 mg Tab 2 tablets twice a day for 120 days

T2D: poorly controlled on glipizide 5 (HbA1c 9.0%)

Lipids: LDL 97 mg/dl, TG 75 mg/dl, HDL 38 (rosuvastatin 10 mg)

AST 34, ALT 62

Another Case



Glipizide to 10 mg


LDL 29 mg/dl

HbA1c 6.3%

AST 30, ALT 32

Another Case



Glipizide to 10 mg


LDL 29 mg/dl

HbA1c 6.3%

AST 30, ALT 32

TG 260, HDL 26

CVD Risk Factors with HIV Infection

Traditional risk factors

Age

Dyslipidemia

Hypertension

Higher smoking rates

Impaired glucose tolerance

Insulin resistance

Nontraditional risk factors

Subcutaneous fat loss

Visceral fat gain

Inflammation, CRP increases

Direct effects of the virus on the vasculature, increased CIMT

Effects of ARV drugs, lipodystrophy

Grinspoon et al. Circulation 2008;118(2):198-210.

HIV and Dyslipidemia

Untreated patients with HIV infection commonly show

Increased TC

Decreased LDL-C

Decreased HDL-C

Increased TG

Patients treated with ARV medications commonly show

Increased TC

Increased LDL-C

Decreased HDL-C

Increased TG

1. Feeney, Mallon. Open Cardiovasc Med J 2011;5:49-63.

2. Grinspoon et al. Circulation 2008;118(2):198-210.

3. United States Department of Veterans Affairs. http://www.hiv.va.gov/provider/manual-primary-

care/dyslipidemia.asp#S2X.

HIV and CHD Risk

Increased rates of CHD in HIV-infected patients on anti-

retrovirals

HIV-positive patients in the Kaiser-Permanente cohort

(N = 20,081) had significantly increased CHD risk

(p<.001) over HIV-negative control group

(N = 215,158)

DAD, a large, prospective, multicohort study

(N = 23,468) showed association between ARV therapy

and risk of MI

1. Feeney, Mallon. Open Cardiovasc Med J 2011;5:49-63.

2. Klein et al. Circulation 2012;125:A060.

3. Friis-Møller et al. New Engl J Med 2003; 349(21):1993-2003.

HAART and CVD Risk: Results

from the DAD Study

The highest prevalence of dyslipidemia was seen in regimens

containing drugs from both the PI and NNRTI classes,

suggesting a possible additive effect of combinations of drugs

from these drug classes

Dyslipidemia was most strongly correlated with current use of

ARV regimens, rather than a history of previous drug

regimens

There was a strong association between elevated total

cholesterol level and higher CD4+ cell counts, which was

present within each treatment category (PI, NNRTI,

NNRTI+PI) except the ARV-therapy-naïve group

Friis-Møller et al. AIDS 2003;17(8):1179-1193.

Abnormal Lipid Parameters in HIV Patients

Abnormalities in lipid parameters can be due

to

HIV

HIV Medications

Other Medications

Other Diseases

Other Factors

Genetic predisposition

Can Triglycerides Cause

Atherosclerosis?

Association between TG and CHD in populations is weaker than that between LDL and CHD

Trials with TG-lowering drugs have not produced definitive evidence

Severe hyperTG does not commonly cause CVD

TG accumulation is not a hallmark of atherosclerosis

Foam-cell Formation:

Cholesterol entry

Li and Glass. Nat Med 2002

Lipid Profile in Patients With Premature

Coronary Artery Disease

*P<0.005 as compared with control. †P<0.05 as compared with control.

Genest JJ Jr, et al. Circulation. 1992;85:2025-2033.

Men Women

Control

CAD

†

†

134

110

57

152

219

47

0

50

100

150

200

250

Pla

sm

a L

ipid

Co

nce

ntr

ati

on

, m

g/d

L

LDL-C TG HDL-C

*

*

138 141

45

139

177

35

LDL-C TG HDL-C 0

20

40

60

80

100

120

140

160

180

200

Pla

sm

a L

ipid

Co

ncen

trati

on

(m

g/d

L)

Recommended NCEP cutoff points

TG Levels and CHD Risk:

Meta-analysis of 29 Studies

N=262,525.

*Individuals in top versus bottom third of usual log-TG values, adjusted for at least age, sex, smoking status, lipid concentrations, and (in most studies) blood pressure.

Sarwar N, et al. Circulation. 2007;115:450-458.

≥10 years 5902

<10 years 4256

Adjusted for HDL

Yes 4469

No 5689

Groups CHD Cases

Overall CHD Risk Ratio*

Decreased

Risk

CHD Risk Ratio* (95% CI)

1.72 (95% CI, 1.56-1.90)

2 1 Increased

Risk

Sex

Male 7728

Female 1994

Nonfasting 2674

Fasting 7484 Fasting Status

Kuopio Study: Metabolic Syndrome and Mortality

Yes Metabolic Syndrome: No

CVD Mortality

0 2 4 6 8 10 12

0

5

10

15

20

RR (95% CI), 3.55 (1.96-6.43)

Follow-up, y

All-Cause Mortality

0 2 4 6 8 10 12

0

5

10

15

20 RR (95% CI), 2.43 (1.64-3.61)

Follow-up, y

RR = relative risk.

Lakka HM, et al. JAMA. 2002;288:2709-2716.

CV Risk Assessment

Advanced lipid testing

hsCRP and Lp-PLA2

cIMT

CAC

Long-Term Prognosis Associated with Absolute

Coronary Calcification and CAC Progression

n= 25,257

Budoff M, et al. J Am Coll Cardiol.

2007;49(18):1860-70. Epub 2007 Apr 20.

Follow-up (years)

Surv

ival P

roba

bilit

y

0.50

0.75

1.00

Non-Progressors

0 5 10 15 20

Progressors

Budoff M and Raggi P, submitted for pubblication

Lifestyle Changes

Diet (calories, nutrients, alcohol, supplements)

Weight management

Exercise

Smoking cessation

Central Adiposity in HIV is Associated with

Increased 5-year Mortality

Scherzer R, et al. AIDS. 2011; 25(11):1405-1414.

reference

1.77 (1.03, 3.03) P = 0.039

2.12 (1.13, 3.98) P = 0.019

Tertile 1

Tertile 2

Tertile 3

VAT: {

Odds ratio (95% CI)

0.10 1.00 10.00

Effects of a 6-month Lifestyle

Modification Program in HIV Pts

P = 0.008

mm

Hg

Systolic Blood Pressure

-20

-15

-10

-5

0

5

10

-4

-3

-2

-1

0

1

2

3

P = 0.022

cm

Waist Circumference

Control Lifestyle

Fitch KV, et al. AIDS. 2006;20(14):1843-1850.

Lipid-lowering Management Strategies

Lifestyle changes

Statins (plus ezetimibe

Fibrates

Omega 3 supplementation

Niacin

LaRosa JC et al. N Engl J Med. 2005;352.

0

30

5

10

15

20

25

Statin

Placebo

HPS

CARE

LIPID

HPS

CARE

LIPID

4S

4S

LDL cholesterol (mg/dL)

0 210 190 170 150 130 110 90 70

TNT (80 mg)

TNT (10 mg)

Event

(%)

Benefits of Intensive LDL-C Lowering

Coadministration of Statins with Protease Inhibitors

Statins Protease Inhibitors Drug-Drug Interaction Dosing Recommendation

Rosuvastatin Darunavir; Saquinavir,

Fosamprenavir,

Lopinavir,

Tipranavir

Atazanavir

Atazanavir + Ritonavir

Lopinavir + Ritonavir

Possible increase in rosuvastatin concentration

Inc. Rosuv. AUC 213% & Cmax by 6-fold

Inc. Rosuv. AUC 3-fold & Cmax 7-fold

Inc. Rosuv. AUC 2-fold & Cmax 5-fold

Start 5 mg; Use lowest possible

dose

Limit dose to 10 mg

Limit dose to 10 mg

Limit dose to 10 mg

Atorvastatin All Protease Inhibitors

Nelfinavir

Fosamprenavir+/-Ritonavir

Darunavir or Saquinqvir +

Tipranavir+ Ritonavir

Telaprevir

Increase atorvastatin concentration

Ritonavir

Use lowest possible dose

Limit dose to 40 mg

Limit dose to 20mg

Limit dose to 20 mg

AVOID

AVOID

Pravastatin Darunavir

Lopinavir+/-Ritonavir

Saquinavir

Darunavir/Ritonavir

Increases prava-concentration

Increases pravastatin -concentration

May decrease prava-concentration (~50%)

Inc. pravastatin AUC 81% & Cmax 63%

Use lowest possible dose

No dose adjustment (FDA)

No dose adjustment (FDA)

Pitavastatin Atazanavir

Atazanavir+ Ritonavir

Darunavir+Ritanavir

Lopinavir+Ritonavir

31%increase in pitavastatin AUC

20-26% decrease in pitavastatin AUC.

20-26% decrease in pitavastatin AUC

No dosage adjustements.

Simvastatin

or Lovastatin

All Protease Inhibitors inc.

Boceprevir or Telaprevir

Significant increases in simvastatin

or lovastatin concentrations

ALL Contraindicated

Kiser JJ, et al. J Acquir Immune Defic Syndr.. 2008;47(5):570-8. Busti AJ, et al. J Cardiovasc Pharmacol.

2008;51(6):605-10; U.S. FDA Update. 3/1/12.

Time After Dose Administration (Hours)

0 4 8 12 16 20 24

Pla

sm

a C

on

ce

ntr

ati

on

(n

g/m

L)

0

10

20

30

40

50

60

Pitavastatin

Pitavastatin + Lopinavir/Ritonavir

Pitavastatin and Lopinavir/Ritonavir PK Study Pitavastatin Plasma PK Profile

• 1Mean plasma Concentration vs time profile of pitavastatin administered and measured alone vs coadministered with lopinavir/ritonavir

• Lopinavir/Ritonavir 800mg/200mg, Pitavastatin 4mg

• Pharmacokinetics data obtained from 23 healthy subjects that completed the study

• ng/mL=nanograms per milliliter; PK=pharmacokinetic

Change in AUC0-T ↓ 20%

Change in Cmax ↓ 4%

2

5

Morgan RE et al. J Acquir Immune Defic Syndr. 2012;Mar 5 [In press].

LIVALO [package insert]. Montgomery, AL: Kowa Pharmaceuticals America, Inc. / Indianapolis, IN: Eli Lilly and Company; 2012.

LIV-MT-0372, PS78181.

Pitavastatin and Lopinavir/Ritonavir PK Study Lopinavir Plasma PK Profile

2

6


0 2 4 6 8 10 12

Pla

sm

a C

on

ce

ntr

ati

on

(n

g/m

L)

6000

8000

10000

12000

14000

16000

Lopinavir

Pitavastatin + Lopinavir/Ritonavir





LIV-MT-0372, PS78181





Pitavastatin and Lopinavir/Ritonavir PK Study Ritonavir Plasma PK Profile

2

7


0 2 4 6 8 10 12

Pla

sm

a C

on

ce

ntr

ati

on

(n

g/m

L)

0

200

400

600

800

1000

1200

Ritonavir

Pitavastatin +Lopinavir/Ritonavir





LIV-MT-0372, PS78181





Pitavastatin and Darunavir/Ritonavir PK Study Pitavastatin Plasma PK Profile1

• 1Mean plasma Concentration vs time profile of pitavastatin administered and measured alone vs coadministered with darunavir/ritonavir

• Darunavir/Ritonavir 800mg/100mg, Pitavastatin 4mg





Data on file:04/26/2012:

LIVALO [package insert]. Montgomery, AL: Kowa Pharmaceuticals America, Inc. / Indianapolis, IN: Eli Lilly and Company; 2012. LIV-MT-0372, PS78181

6

Pitavastatin and Darunavir/Ritonavir PK Study Darunavir Plasma PK Profile1

2

9

Change in AUC0-T ↑ 3%

Change in Cmax ↑ 6%





Data on file: 04/26/2012


Pitavastatin and Darunavir/Ritonavir PK Study Ritonavir Plasma PK Profile1

3

0

Change in AUC0-T ↑ 8%

Change in Cmax ↑ 2%





Data on file: 04/26/2012:


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753589/figure/F1/

Lipid-lowering Management Strategies: Fish Oils and Fibrates

Fish oils

• Known to decrease triglycerides in HIV-infected patients1

• Well tolerated and have few side effects1

• Cardiovascular benefit is unclear1

Fibrates

• Appear to have no pharmacologic interactions with ARVs1

• Reduce triglycerides by 40%-50% in HIV-infected patients; are well tolerated1

• Most clinical studies report that 1%-40% of patients achieved a target of TG ≤200 mg/dL1

• Less effective than statins for reducing LDL-C2

• Cardiovascular benefit is unclear1

1. Feeney, Mallon. Open Cardiovasc Med J 2011;5:49-63. 2. Dube, Fenton. Clin Infect Dis 2003;36(Suppl 2):S79-S83.

• HIV=human immunodeficiency virus; ARVs=antiretrovirals; TG=triglyceride; LDL-C=low-density lipoprotein cholesterol

Lipid Changes on Atorvastatin

in the TNT Study

TNT Investigators (2005) N Engl J Med

Days After Month 1 Visit

Eve

nt R

ate

, %

PROVE IT-TIMI 22 Trial Subanalysis:

Relationship Between LDL-C, TG, and CHD

HR: 0.81

CI: 0.68, 0.96

P=.015

LDL ≥70 HR: 0.73

CI: 0.62, 0.87

P<.001

TG ≥150

TG <150 LDL <70

Days After Month 1 Visit

Eve

nt R

ate

, %

Estimates of Death, MI, and Recurrent ACS

Between 30 days and 2 years of Follow-Up

According to Achieved LDL-C <70 mg/dL According to Achieved TG <150 mg/dL

19% 27%

HR: hazard ratio

Miller M, et al. J Am Coll Cardiol. 2008;51:724-730.

Subanalysis of the PROVE IT-TIMI 22 study in 4162 patients hospitalized for ACS and

randomized to atorvastatin 80 mg or pravastatin 40 mg, with follow-up through 2 years.

Fibrate Efficacy Overview: CHD Risk Reduced 35%

in Patients with Dyslipidemia

Overview of fibrate efficacy in clinical trials

CHD events significantly reduced in patients with dyslipidemia

HHSa VA-HITb BIPc FIELDd ACCORDe

P=0.02

P=0.002

P=0.006

P=0.02

P=0.16

P=0.005

P=0.32

P=0.055

aHelsinki Heart Study, TG 204 mg/dl HDL-C <42 mg/dl; bThe Veterans Affairs Cooperative Studies Program High Density

Lipoprotein Cholesterol Intervention Trial, TG>180; cBezafibrate Infarction Prevention, TG>200; dFibrate Intervention and Event

Lowering in Diabetes, TG>204; HDL-C<40;eAction to Control Cardiovascular Risk in Diabetes, TG>204; HDL-C<34.

Elam JC. Curr Opin Lipidol. 2011;22 (7):55-61.

Saito Y et al. Atherosclerosis. 2008;200:135-40.

35

Patient Subgroup – TG >150mg/dL

and HDL <40mg/dL: JELIS

Lipid-lowering Management Strategies: Niacin

Increases HDL-C

Commonly causes flushing

Can cause insulin resistance

Affects glycemic control in patients with diabetes

Should be used with caution in HIV patients who exhibit insulin resistance or lipodystrophy

Short-term use of niacin has shown to improve endothelial function in HIV-infected patients with low HDL-C

Lo. Curr Opin Endocrinal Diabetes Obes 2011;18(2):144-147.

• HDL-C=high-density lipoprotein cholesterol; HIV=human immunodeficiency virus

AIM HIGH: No Measurable Effects of Niacin Added to Simvastatin

3414 Subjects with CAD

Simvastatin alone or with ezetimibe ± ER niacin

On niacin TG 120 mg/dL, HDL 44 mg/dL, LDL 65 mg/dL

Controls TG 152 mg/dL, HDL 38 mg/dL, LDL 67 mg/dL

282 subjects on niacin had primary endpoint (16.4%)

274 controls had primary endpoint (16.2%)

NEJM, 2011; 365: 2255-2267

1o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or

cerebrovascular revascularization

Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.

AIM-HIGH—Results

Conclusions

The dyslipidemia of HIV patients may have different causes and proper diagnosis will help management

CV risk assessment as in other patient types

Lifestyle changes (weight loss) very effective in adjusting glucose and TG/HDL levels

Statins to be used according to FDA restrictions

Fibrates, niacins, and omega 3 fats have not provided definitive evidence of CV benefits yet

hiv, dyslipidemia, and cvd risk · 2012-11-20 · hiv, dyslipidemia, and cvd risk sergio fazio, md,...

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