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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

DISCLOSURE & ACCREDITATION


Disclosure accreditation1
DISCLOSURE & ACCREDITATION of Medicine.

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/


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/


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/


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 nearly __ times as high as that of white women and nearly __ times that of Hispanic/Latina women.

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.


The SMART Study nearly __ times as high as that of white women and nearly __ times that of Hispanic/Latina women.

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)


The SMART Study nearly __ times as high as that of white women and nearly __ times that of Hispanic/Latina women.

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


Important questions
Important Questions nearly __ times as high as that of white women and nearly __ times that of Hispanic/Latina women.

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 nearly __ times as high as that of white women and nearly __ times that of Hispanic/Latina women.


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


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


Freiberg et al. CROI. Boston, 2011 Heart Disease Quality Enhance Research Initiative


Freiberg et al. CROI. Boston, 2011 Heart Disease Quality Enhance Research Initiative


Hiv and the risk of ami in subpopulations
HIV and the risk of AMI in subpopulations Heart Disease Quality Enhance Research Initiative

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 Heart Disease Quality Enhance Research Initiative

* 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 Heart Disease Quality Enhance Research Initiative

‡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



Increasing incidence of ischemic stroke in patients with HIV diseases?

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 Ischemic Stroke

  • 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 Ischemic Stroke

  • 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 Ischemic Stroke

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 Ischemic Stroke

Butt et al. Archives of Internal Medicine, 2011


Echocardiographic parameters by hiv status
Echocardiographic Ischemic StrokeParameters by HIV Status

Hsue et al. Circ Heart Failure 2010


Hiv infection is associated with diastolic dysfunction
HIV infection is associated with diastolic dysfunction Ischemic Stroke

Hsue et al. Circ Heart Failure 2010



Conceptual model for hiv and vascular risk
Conceptual Model for HIV and Vascular Risk Do ARVs play a role?

Baker et al. European Heart Journal 2011


Chronic hiv infection and microbial translocation
Chronic HIV infection and microbial translocation Do ARVs play a role?

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


Biomarkers associated SMART Study

with CVD risk among

those chronically infected

with HIV

2

Ford et al. AIDS 2010


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

2

Baker et al. JAIDS 2011


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


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 total, large, medium and small HDL-p (μmol/L) by treatment group among HIV infected people.

Baker et al. CROI. Boston, 2011


Do non traditional risk factors play a role
Do non-traditional risk factors play a role? total, large, medium and small HDL-p (μmol/L) by treatment group among HIV infected people.


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 Score

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



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.

Neuhaus J et al. J Infect Dis. 2010.


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.



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



Additional framingham risk score data
Additional Framingham Risk Score Data infection?

  • 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 infection?

Law et al. HIV Med 2006


Important questions1
Important Questions infection?

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 infection?

  • 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


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.


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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