hiv infection and cardiovascular diseases matthew s. freiberg, md, msc university of pittsburgh...

HIV infection and cardiovascular diseases

Matthew S. Freiberg, MD, MSc

University of Pittsburgh School of Medicine and Graduate School of Public Health

Yale GIM Research in ProgressSeptember 8th, 2011

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Acknowledgement is made on behalf of the Department that:

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~There are no conflicts of interest.

By 2015, what percentage of HIV infected people living in the U.S. will be 50 years of age or older

15%

25%

35%

50%

http://www.cdc.gov/hiv/resources/factsheets/

At the end of 2006, African Americans accounted for what percentage of all new HIV infection diagnoses

15%

35%

45%

50%

http://www.cdc.gov/hiv/topics/aa/

In 2006, the rate of new HIV infection for black women was nearly __ times as high as that of white women and nearly __ times that of Hispanic/Latina women.

3 and 2

5 and 3

10 and 3

15 and 4

http://www.cdc.gov/hiv/topics/aa/

Background

HIV infection is associated with– Increased coronary calcium1

– Progression of carotid IMT2

– Endothelial dysfunction as measured by FMD3

Antiretroviral therapy (ARV) is associated with AMI risk in observational studies4

Intermittent ARV, however, is associated with a greater risk of AMI than continuous ARV for viral suppression5

1. Lai et al. Archives of Internal Medicine 2005; 2. Hsue et al. Circulation 2004; 3. Solages et al. CID 2006; 4. DAD study group. NEJM 2007; 5. SMART study group. NEJM 2006.

11

The SMART Study

The Strategies for Management of ART (SMART) study is a RCT of 5472 HIV+ Participants who were assigned either to drugConservation or viral suppression

Participants were followed for 16 months

Primary end points was opportunistic diseaseor death from any cause (n=167)

Secondary endpoints were major CVD, renal,or hepatic disease (n=104 of which 79 were CVD)

12

The SMART Study

The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:2283-2296

Important Questions

Is HIV infection an independent risk factor for AMI?

Does HIV infection increase the risk of other cardiovascular diseases?

If HIV does increase the risk of CVD what is the mechanism? Do ARVs play a role?

Do non-traditional risk factors play a role?

If so, does the Framingham risk score apply to those with HIV infection?

Is HIV as an independent risk factor for AMI

Prior studies suggesting HIV is associated with a significant AMI risk

Triant et al.1

– AMI rate ratio=1.75 (95% CI=1.51-2.02, p<0.001)

Klein et al.2

– AMI rate ratio=1.4 (95% CI=1.3-1.7, p<0.001)

Obel et al.3

– IHD hospitalization RR=2.12 (95% CI=1.62-2.76)

Currier et al.4

– CHD RR=2.16 (95% CI=1.81-2.58) for men 25-34– CHD RR=1.53 (95% CI=1.10-2.13) for women 25-34

1. Triant et al. J Clin Endo Metab 2007; 2. Klein et al. CROI. Boston, 2011; 3. Odell et al. CID. 2007 4. Currier et al. JAIDS 2003

Veterans Aging Cohort Study Virtual Cohort and Ischemic Heart Disease Quality Enhance Research Initiative

Cohort of HIV+ and 1:2 matched age, gender, race/ethnicity, and clinical site matched Veterans

All participants alive in 2003 eligible and free of baseline CVD (n=84,832, 33% HIV+)

All AMI outcomes clinically confirmed by IHD QUERI

Validated smoking data, blood pressure and lipid measurements were used

Baseline characteristics of cohort

Characteristics, n (%)

HIV+ n=28,134

HIV- n=56698

Age, years (mean ± SD) 48.5±9.5 49.1±9.3 Men (%) Race/ethnicity African American White Hispanic

97.3 47.5 38.0 7.1

97.3 47.4 38.1 7.8

CHD risk factors Hypertension 22.1 32.5 Diabetes 14.3 21.2 Hypercholesterolemia 33.2 38.8 Current Smoker Other risk factors

60.2 54.0

Hepatitis C infection 35.1 15.8 EGFR<30ml/min/1.73m2 1.4 0.5 BMI ≥ 30 (kg/m2) 13.8 37.7 Hx of Substance Use Cocaine abuse or dependence 11.3 7.3 Alcohol abuse or dependence 14.1 13.4 Laboratory Analysis Median CD4 count 352 Median HIV-1 RNA 1070

Freiberg et al. CROI. Boston, 2011

HIV status and the risk of AMI

Risk Factors HR for AMI with 95% CI

HIV infection 1.95 (1.60-2.38) Age (10 yrs) 1.43 (1.28-1.57) Female gender 0.35 (0.11-1.09) Race/ethnicity African American Hispanic Other

0.79 (0.64-0.97) 1.51 (1.12-2.04) 0.43 (0.23-0.81)

Hypertension 1.58 (1.29-1.94) Diabetes 2.08 (1.70-2.55) Hyperlipidemia 1.34 (1.10-1.64) Current Smoking 1.98 (1.52-2.57) HCV infection 1.06 (0.85-1.33) EGFR<30 ml/min/1.73m2 4.28 (2.72-6.72) BMI ≥ 30kg/m2 0.91 (0.73-1.14) History of cocaine abuse or dependence

1.40 (0.96-2.05)

History of alcohol abuse or dependence

0.76 (0.54-1.06)


HIV and the risk of AMI in subpopulations

Among never smokers (HR=2.82, 95% CI=1.60-2.38)

Among those not on Statin therapy (HR=1.88, 95% CI=1.51-2.34)

Among those without hepatitis C, renal disease, or obesity (HR=1.82, 95% CI=1.37-2.40)


HIV and HCV Co-infection and the Risk of Incident CHD

* Incidence rates are age and race/ethnicity adjusted per 1000 person-years Model 1 adjusted for age, race/ethnicity, education, BMI, traditional CHD risk factors, and substance use Model 2 adjusted for all in model 1 plus competing risk of death

Mortality

Rates

Adj. CHD

Rates*

HR for CHD

95% CI

Model 1

HR for CHD

95% CI

Model 2

HIV+HCV+

HIV+HCV-

HIV-HCV+

HIV-HCV-

6.11 (5.91-6.31)

3.92 (3.78-4.07)

2.08 (2.02-2.15)

1.29 (1.26-1.31)

6.24 (6.05-6.43)

3.99 (3.85-4.13)

3.01 (2.92-3.09)

3.26 (3.20-3.31)

2.01 (1.28-3.21)

1.42 (0.97-2.06)

0.97 (0.54-1.73)

1.0

2.45 (1.83-3.27)

1.90 (1.52-2.37)

1.15 (0.77-1.71)

1.0

Freiberg et al. Circ Cardiovascular Quality and Outcomes, in press

HCV, ARV, and the risk of AMI among HIV infected men

Duration of ART

HR for CHD with 95% CI‡

Recent ART

HR for CHD with 95% CI‡

death is

censored

death is a

competing risk

death is

censored

death is a

competing risk

HCV+HIV+ 2.13

(1.12-4.05)

1.60

(1.03-2.48)

2.05

(1.09-3.82)

1.57

(1.02-2.40)

HIV+HCV- 1.0 1.0 1.0 1.0

‡Models adjusted for age, race/ethnicity, education, BMI, traditional CHD risk factors, and substance use Class of ARV (either duration or recent use), HIV viral load, CD4 count, and adjustment for death as a Censoring event or a competing risk

Freiberg et al. Circ Cardiovascular Quality and Outcomes, in press

2

Increasing incidence of ischemic stroke in patients with HIV

Figure 1 Trends in stroke hospitalization by type among persons with a diagnosis of HIV in the United States population 1997-2006(A) Ischemic stroke: trend p value p value = 0.27. (C) Intracerebral hemorrhage: trend p value = 0.88.

Ovbiagele et al. Neurology 2011

Alcohol Abuse or Dependence, HIV, and the Risk of Incident Ischemic Stroke

Incidence rates are age and race/ethnicity adjusted per 1000 person-years

Model adjusted for age, race/ethnicity, education, CVD risk factors, hepatitis C; and DX of cocaine abuse or dependence

Stroke

events

N (%)

Adjusted Stroke

Incidence Rate*

HR for Stroke

with 95% CI

HIV+ and alcohol DX (n=818)

HIV+ and no alcohol DX (n=1584)

HIV- and alcohol DX (n=1995)

HIV- and no alcohol DX (n=4112)

25 (3.1%)

33 (2.1%)

45 (2.3%)

57 (1.4%)

5.36 (5.16-5.70)

3.71 (3.50-3.93)

3.49 (3.38-3.61)

2.14 (2.07-2.21)

2.51 (1.42-4.46)

1.95 (1.24-3.05)

1.68 (1.07-2.65)

1.0

Freiberg et al. Research Society on Alcoholism Conference, San Antonio, 2010

Which of the following is NOT true about HIV and failure

HIV is associated with a nearly two fold increased risk of heart failure

Ongoing HIV viral replication may play a role

HIV is not associated with heart failure after adjusting for CHD, ischemic cardiomyopathy, and hazardous alcohol consumption

HIV and the Risk of Heart Failure

Butt et al. Archives of Internal Medicine, 2011

HIV and the Risk of Heart Failure by viral load status

Butt et al. Archives of Internal Medicine, 2011

Echocardiographic

Parameters by HIV Status

Hsue et al. Circ Heart Failure 2010

HIV infection is associated with diastolic dysfunction

Hsue et al. Circ Heart Failure 2010

Conceptual Model for HIV and Vascular Risk

Baker et al. European Heart Journal 2011

Chronic HIV infection and microbial translocation

Brenchley et al. Nature Medicine 2006

Microbial translocation and mortality among HIV infected people*

Sandler et al. JID. 2011

*No adjustment for liver disease or alcohol

Biomarkers associated with Fatal and Non-Fatal CVD from the SMART Study

Hs CRP HR=1.6 (95% CI=0.8-3.1) p=0.20

IL-6 HR=2.8 (95% CI=1.4-5.5) p=0.003

Amyloid A HR=1.6 (95% CI=0.9-2.9) p=0.12

Amyloid P HR=2.8 (95% CI=1.4-5.3) p=0.002

D-dimer HR=2.0 (95% CI=1.0-3.9) p=0.06

Kuller et al. CROI. Boston, 2008

2

Biomarkers associated with CVD risk amongthose chronically infectedwith HIV

Ford et al. AIDS 2010

2

ART Use, Viral Suppression, and CD4 Change Over Follow-Up

Baker et al. JAIDS 2011

2

Median levels of hsCRP (A), IL-6 (B), and D-dimer (C) are presented for VS and DC groups at each visit. Error bars represent the interquartile range (IQR).

*P values represent the difference between treatment groups in the change from baseline (on loge scale) and are adjusted for baseline biomarker level.

Baker et al. JAIDS 2011

Average change to 1 month in the DC versus VS group in total, large, medium and small HDL-p (μmol/L) by treatment group among HIV infected people.

Duprez et al. Atherosclerosis 2009

ARV Therapy and Levels of Inflammatory Biomarkers

Baker et al. CROI. Boston, 2011

The role of alcohol, hepatitis C, and HIV and the risk of AMI

Freiberg and Kraemer. Alcohol Research and Health. 2010

Current Alcohol Consumption and HIV VL and Levels of sCD14, IL-6, D-dimer, and Fib4 Score

Current drinking category

HIV VL

sCD14 ng/ml

IL-6 pg/ml

D-dimer ug/ml

Fib4 score

Non-hazardous 75 (50, 485) 1709 (1410, 2060) 1.78 (1.25, 2.73) 0.23 (0.15, 0.39) 1.27 (0.93, 1.79)

Hazardous 400 (75, 4380) 1734 (1485, 2071) 2.17 (1.49, 3.64) 0.25 (0.13, 0.42) 1.32 (0.98, 1.97)

Abuse or dependence diagnosis

406 (75, 10702) 1740 (1514, 2110) 2.42 (1.61, 3.59) 0.29 (0.18, 0.59) 1.51 (1.07, 2.49)

P value 0.0001 0.18 0.0001 0.004 P=0.0005

HIV VL

sCD14 ng/ml

IL-6 pg/ml

D-dimer ug/ml

Fib4 score

1st Tertile 1676 (1414, 2074) 1.96 (1.30, 3.11) 0.22 (0.13, 0.37) 1.33 (0.98, 1.98)

2nd Tertile 1717 (1503, 2070) 2.02 (1.42, 3.43) 0.26 (0.16, 0.45) 1.33 (0.97, 1.97)

3rd Tertile 1878 (1579, 2265) 2.43 (1.66, 4.28) 0.38 (0.22, 0.71) 1.50 (1.08, 2.22)

P Value 0.0001 0.0001 0.0001 P=0.004

All values are median (25th,75th percentiles)

Freiberg et al. ISBRA Conference. Paris, 2010

HCV Status and Levels of sCD14, IL-6, D-dimer, and FIB4 Score

1600

1650

1700

1750

1800

1850

sCD14

HCV infected

HCV uninfected

0

0.5

1

1.5

2

2.5

IL-6

HCV infected

HCV uninfected

0.23

0.24

0.25

0.26

0.27

0.28

D-dimer

HCV infected

HCV uninfected

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

FIB4

HCV infected

HCV uninfected

Median values for all biomarkers, p values ≤ 0.001 for all

ng

/ml

pg

/ml

ug

/ml


FIB4 Score and Levels of sCD14, IL-6, and D-dimer

Fib4 Score sCD14 ng/ml

IL-6 pg/ml

D-dimer ug/ml

<1.45 1651 (1408, 2007) 1.83 (1.24, 2.81) 0.22 (0.13, 0.39)

1.45-3.25 1822 (1547, 2177) 2.16 (1.55, 3.76) 0.29 (0.18, 0.54)

>3.25 1929 (1586, 2378) 3.35 (2.37, 5.19) 0.37 (0.21, 0.66)

P value P=0.0001 P=0.0001 P=0.0001


The association between HIV and HCV viral load and biomarkers in the HIV LIVE Study

Viral Load (VL)

Biomarker Category

HIV+ HCV+ N=127

HIV+ HCV-N=122

HIV- HCV+ N=53

HIV- HCV-N=59

P value

Percentage of participants with >75th percentile of Biomarker

IL-6 32.3 16.0 42.5 12.5 <0.01

CRP 21.3 26.8 25.6 24.0 0.81

Cystatin C 40.7 17.0 23.3 12.0 <0.01

SSA 26.2 22.2 19.5 26.1 0.78

TNF alpha 35.2 22.3 20.9 6.0 <0.01

MCP-1 23.2 26.8 23.4 18.0 0.67

IL-10 37.0 23.2 25.6 6.0 <0.01

INF gamma 11.1 16.1 18.6 12.0 0.56

Samet et al. ISBRA Conference. Paris, 2010

Correlation between D-dimer, sCD14, IL-6 biomarkers in the VACS*

Biomarker Spearman Rank Coefficients D-dimer sCD14 IL-6 D-dimer -- 0.24 0.40 sCD14 0.24 -- 0.45 IL-6 0.40 0.45 --

* All associations are significant p<0.001

So, what might you predict next….

Characteristics of SMART, CARDIA, and MESA Study Participants.

Neuhaus J et al. J Infect Dis. 2010.

Median Levels and Interquartile Ranges (IQRs) of Biomarkers for SMART, CARDIA, and MESA Study

Participants.


Biomarkers Levels in SMART Study Participants Receiving Antiretroviral Therapy (ART) Who Had an HIV

RNA Level ≤400 Copies/mL and Percentage Differences in Levels Versus CARDIA and MESA Study Participants


00.

40.

81.

21.

6 22.

42.

80

5

10

15

20

25

30

35

00.

40.

81.

21.

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42.

80

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150

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1950

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HIV +

HIV -

HIV Variable N Median 25th 75th 1st 99th Min MaxPos DD 1526 0.26 0.15 0.49 0.01 3.24 0.01 20

sCD14 1528 1718 1447 2086 875 3624 198 5000IL6 1524 2.08 1.42 3.38 0.48 19 0.48 210

Neg DD 831 0.30 0.21 0.53 0.06 3.54 0.03 20sCD14 834 1733 1480 2051 977 3300 660 3314IL6 826 1.785 1.16 3.16 0.42 32.66 0.42 379.31

D-dimer sCD14 IL-6

The association between biomarkers and HIV status in the VACS

Does the Framingham risk score apply to those with HIV infection?

Yes but it probably overestimates the risk

Yes but it probably underestimates the risk

No, because middle aged Caucasians from Framingham, Massachusetts cannot generalize to an HIV population

I have no idea

HIV status and the risk of AMI

Risk Factors HR for AMI with 95% CI

HIV infection 1.95 (1.60-2.38) Age (10 yrs) 1.43 (1.28-1.57) Female gender 0.35 (0.11-1.09) Race/ethnicity African American Hispanic Other

0.79 (0.64-0.97) 1.51 (1.12-2.04) 0.43 (0.23-0.81)

Hypertension 1.58 (1.29-1.94) Diabetes 2.08 (1.70-2.55) Hyperlipidemia 1.34 (1.10-1.64) Current Smoking 1.98 (1.52-2.57) HCV infection 1.06 (0.85-1.33) EGFR<30 ml/min/1.73m2 4.28 (2.72-6.72) BMI ≥ 30kg/m2 0.91 (0.73-1.14) History of cocaine abuse or dependence

1.40 (0.96-2.05)

History of alcohol abuse or dependence

0.76 (0.54-1.06)


Additional Framingham Risk Score Data

Median Baseline Framingham Risk score– HIV+ 6.0– uninfected 6.0

HIV infected Veterans have an increased risk of AMI ( HR=1.95, 95% CI=1.60-2.38)

This risk persisted among never smokers

This risk persisted among those without HCV, renal disease, or obesity

Predicting MI with the Framingham risk equation

Law et al. HIV Med 2006

Important Questions

Is HIV infection an independent risk factor for AMI?




If so, does the Framingham risk score apply to those with HIV infection?

AcknowledgementsVeteran Aging Cohort Study (VACS) Participants

Mentors– Amy Justice, MD, PHD– Lewis Kuller, MD, Dr.PH

Project Officers– Cheryl McDonald, MD, NHLBI– Kendal Bryant, PhD, NIAAA

NHLBI HL095136-03; 03S1; 03S2

NIAAA AA0159136-06S1

Project Coordinators: Carol Rogina and Glory Koerbel

Collaborators: – Jason Baker MD, MPH, University of Minnesota– Russ Tracy, PhD, University of Vermont– Jeffrey Samet, MD, MA, MPH, Boston University

2

Cardiovascular and metabolic markers before and after a median of 8 months of combination antiretroviral therapy and their correlation with HIV-RNA before combination antiretroviral therapy.

Calmy et al. AIDS 2009.

Correlation of Lipid Measures with Human Immunodeficiency Virus (HIV) RNA and Biomarkers

among HIV-Infected Participants.

Baker J et al. J Infect Dis. 2010.

hiv infection and cardiovascular diseases matthew s. freiberg, md, msc university of pittsburgh...

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