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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 Progress September 8 th , 2011. This Grand Rounds is accredited for CME by the Yale School of Medicine.

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Hiv infection and cardiovascular diseases matthew s freiberg md msc

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 Progress

September 8th, 2011


Disclosure accreditation

  • This Grand Rounds is accredited for CME by the Yale School of Medicine.

  • If you wish to receive credit for your participation,

  • you must:

    • sign in

DISCLOSURE & ACCREDITATION


Disclosure accreditation1

DISCLOSURE & ACCREDITATION

Acknowledgement is made on behalf of the Department that:

~ There is no commercial support for this Grand Rounds.

Confirmation is also made that today’s lecture and faculty disclosure have been peer reviewed and:

~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

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/


By 2015 what percentage of hiv infected people living in the u s will be 50 years of age or older1

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/


Hiv infection and cardiovascular diseases matthew s freiberg md msc

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/


Hiv infection and cardiovascular diseases matthew s freiberg md msc

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/


Hiv infection and cardiovascular diseases matthew s freiberg md msc

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/


Hiv infection and cardiovascular diseases matthew s freiberg md msc

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

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.


Hiv infection and cardiovascular diseases matthew s freiberg md msc

The SMART Study

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

Conservation or viral suppression

Participants were followed for 16 months

Primary end points was opportunistic disease

or death from any cause (n=167)

Secondary endpoints were major CVD, renal,

or hepatic disease (n=104 of which 79 were CVD)


Hiv infection and cardiovascular diseases matthew s freiberg md msc

The SMART Study

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


Important questions

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

Is HIV as an independent risk factor for AMI


Prior studies suggesting hiv is associated with a significant ami risk

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


Hiv infection and cardiovascular diseases matthew s freiberg md msc

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


Hiv infection and cardiovascular diseases matthew s freiberg md msc

Freiberg et al. CROI. Boston, 2011


Hiv infection and cardiovascular diseases matthew s freiberg md msc

Freiberg et al. CROI. Boston, 2011


Hiv and the risk of ami in subpopulations

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)

Freiberg et al. CROI. Boston, 2011


Hiv and hcv co infection and the risk of incident chd

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

Freiberg et al. Circ CardiovascularQualityand Outcomes, in press


Hcv arv and the risk of ami among hiv infected men

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

‡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


Does hiv infection increase the risk of other cardiovascular diseases

Does HIV infection increase the risk of other cardiovascular diseases?


Hiv infection and cardiovascular diseases matthew s freiberg md msc

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.

2

Ovbiagele et al. Neurology 2011


Alcohol abuse or dependence hiv and the risk of incident ischemic stroke

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

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


Which of the following is not true about hiv and failure

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


Which of the following is not true about hiv and failure1

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

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

HIV and the Risk of Heart Failure by viral load status

Butt et al. Archives of Internal Medicine, 2011


Echocardiographic parameters by hiv status

Echocardiographic Parameters by HIV Status

Hsue et al. Circ Heart Failure 2010


Hiv infection is associated with diastolic dysfunction

HIV infection is associated with diastolic dysfunction

Hsue et al. Circ Heart Failure 2010


If hiv does increase the risk of cvd what is the mechanism do arvs play a role

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


Conceptual model for hiv and vascular risk

Conceptual Model for HIV and Vascular Risk

Baker et al. European Heart Journal 2011


Chronic hiv infection and microbial translocation

Chronic HIV infection and microbial translocation

Brenchley et al. Nature Medicine 2006


Microbial translocation and mortality among hiv infected people

Microbial translocation and mortality among HIV infected people*

*No adjustment for liver disease or alcohol

Sandler et al. JID. 2011


Biomarkers associated with fatal and non fatal cvd from the smart study

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


Hiv infection and cardiovascular diseases matthew s freiberg md msc

Biomarkers associated

with CVD risk among

those chronically infected

with HIV

2

Ford et al. AIDS 2010


Hiv infection and cardiovascular diseases matthew s freiberg md msc

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

2

Baker et al. JAIDS 2011


Hiv infection and cardiovascular diseases matthew s freiberg md msc

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.

2

Baker et al. JAIDS 2011


Hiv infection and cardiovascular diseases matthew s freiberg md msc

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

ARV Therapy and Levels of Inflammatory Biomarkers

Baker et al. CROI. Boston, 2011


Do non traditional risk factors play a role

Do non-traditional risk factors play a role?


The role of alcohol hepatitis c and hiv and the risk of ami

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

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

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

pg/ml

ng/ml

ug/ml

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

Freiberg et al. ISBRA Conference. Paris, 2010


Fib4 score and levels of scd14 il 6 and d dimer

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

Freiberg et al. ISBRA Conference. Paris, 2010


The association between hiv and hcv viral load and biomarkers in the hiv live study

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

Samet et al. ISBRA Conference. Paris, 2010


Correlation between d dimer scd14 il 6 biomarkers in the vacs

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

* All associations are significant p<0.001


So what might you predict next

So, what might you predict next….


Hiv infection and cardiovascular diseases matthew s freiberg md msc

Characteristics of SMART, CARDIA, and MESA Study Participants.

Neuhaus J et al. J Infect Dis. 2010.


Hiv infection and cardiovascular diseases matthew s freiberg md msc

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

Neuhaus J et al. J Infect Dis. 2010.


Hiv infection and cardiovascular diseases matthew s freiberg md msc

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

Neuhaus J et al. J Infect Dis. 2010.


Hiv infection and cardiovascular diseases matthew s freiberg md msc

The association between biomarkers and HIV status in the VACS

HIV +

HIV -

D-dimer sCD14 IL-6


Does the framingham risk score apply to those with hiv infection

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


Does the framingham risk score apply to those with hiv infection1

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 infection and cardiovascular diseases matthew s freiberg md msc

Freiberg et al. CROI. Boston, 2011


Additional framingham risk score data

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

Predicting MI with the Framingham risk equation

Law et al. HIV Med 2006


Important questions1

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?


Acknowledgements

Acknowledgements

  • Veteran 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


Hiv infection and cardiovascular diseases matthew s freiberg md msc

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.

2

Calmy et al. AIDS 2009.


Hiv infection and cardiovascular diseases matthew s freiberg md msc

Correlation of Lipid Measures with Human Immunodeficiency Virus (HIV) RNA and Biomarkers among HIV-Infected Participants.

Baker J et al. J Infect Dis. 2010.


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