May 17-18 2012, Sarajevo Organized by: Udruženje Partnerstvo za zdravlje

Cardiopulmonary involvement in HIV infection

Nicola Petrosillo

National Institute for Infectious Diseases

“L. Spallanzani”, Roma

•In the context of declining rates of HIV- related morbidity and mortality, proportions of HIV-infected patients affecting by chronic conditions, including cardiovascular (CV) disease, and deaths attributable to these conditions, have increased.

•In comparison with the general population, HIV-infected patients are at increased risk of CV diseases, including acute myocardial infarction (AMI) and advanced subclinical vascular disease.

Background

Pre-HAART

• Pericarditis and pericardial effusion

• Myocarditis and dilated cardiomiopathy

• Endocarditis (IV drug users)

• Cardiac involvement in AIDS-related tumors

HAART

• Pulmonary arterial hypertension (better diagnosed)

• Systemic arterial hypertension (more prevalent with age)

• CV ischemic disease

Changing spectrum of CV disease in HIV-infected patients

Khunnawat C et al. Am J Cardiol 2008;102:635–642

Most common cardiovascular problems

Pre-HAART

• Pericarditis and pericardial effusion

• Myocarditis and dilated cardiomiopathy

• Endocarditis (IV drug users)

• Cardiac involvement in AIDS-related tumors

HAART

• Pulmonary arterial hypertension (better diagnosed)

• Systemic arterial hypertension (more prevalent with age)

• CV ischemic disease

Changing spectrum of CV disease in HIV-infected patients

Khunnawat C et al. Am J Cardiol 2008;102:635–642

Most common cardiovascular problems

• P.A. 40 mm, right P.A. 22, P.A. 40 mm, right P.A. 22, left P.A. 14 mmleft P.A. 14 mm

• Right VentricleRight Ventricle• Major axis 90 mmMajor axis 90 mm• Minor axis 43 mmMinor axis 43 mm• ED volume 88 mlED volume 88 ml• ES volume 62 mlES volume 62 ml• EF: 30 % (n.v. 40-60%)EF: 30 % (n.v. 40-60%)

Feb 5, 2007

PAP 41

TPR 15

CI 1,7

WT 470

Feb 13, 2008

PAP 37

TPR 5,6

CI 2,5

WT 576

• P.A. 35 mm, right P.A. 20, P.A. 35 mm, right P.A. 20, left P.A. 15 mmleft P.A. 15 mm

• Right VentricleRight Ventricle• Major axis 78 mmMajor axis 78 mm• Minor axis 43 mmMinor axis 43 mm• ED volume 87 mlED volume 87 ml• ES volume 46 mlES volume 46 ml• EF: 46 % (n.v. 40-60%)EF: 46 % (n.v. 40-60%)

Cardiac NMR at the beginning ofsildenafil therapy and 1 year later

Simonneau G et al. J Am Coll Cardiol 2009; 54: S43-45

Clinical Classification of Pulmonary Hypertension (Dana Point)

HIV associated pulmonary arterial hypertension

-Higher prevalence than in general population

-(0.5% versus 0.02%)

Prevalence in HIV population

0.5% (6/1200) Speich, Chest 1991 0.4% (47/11894) Zuber, CID 2004

0.5% (66/13400) Opravil, AIDS 2008

0.5% (35/7648) Sitbon, Am J Respir Crit Care Med 2008

0.4% (19/5000) Cicalini, AIDS 2008

Petrosillo N Cicalini S. PVRI Review 2009; 1: 173-9

AIDS Res Hum Retroviruses 2012; 28

HIVHIV

HIV proteins

HIV proteins

Inflammatory mediators

Inflammatory mediators

AngiogenesisProliferation

Apoptosis

AngiogenesisProliferation

Apoptosis

PAH

Lung vascular cells

Lung vascular cells

PAH-specific therapy (prostacyclins, ET-1-receptor antagonists, PDE-5

inhibitors, Ca-channel blockers, etc.

Antiretrovirals

Antiretrovirals

Prevention

?

?

?

?

Figure 3. Conceptual frame of PAH as a complication of HIV infection. The hypothetical events contributing to HRPAH are indicated with arrows. Therapeutic interventions are shown by block arrows. Areas that warrant further research to enlighten molecular mechanisms and potentially unraveling future therapeutic targets are indicated by triangles.

Pre-HAART

• Pericarditis and pericardial effusion

• Myocarditis and dilated cardiomiopathy

• Endocarditis (IV drug users)

• Cardiac involvement in AIDS-related tumors

HAART

• Pulmonary arterial hypertension (better diagnosed)

• Systemic arterial hypertension (more prevalent with age)

• CV ischemic disease

Changing spectrum of CV disease in HIV-infected patients

Khunnawat C et al. Am J Cardiol 2008;102:635–642

Most common cardiovascular problems

• Is CV risk higher among HIV-positive individuals than in the general population?

• If yes, why?

1) Traditional risk factors

2) Role of ARV medication

3) HIV itself

4) Persistent inflammatory state

5) Comorbidities

1) Traditional risk factors

2) Role of ARV medication

3) HIV itself

4) Persistent inflammatory state

5) Comorbidities

•How to assess CV risk?•How to manage it?•How to prevent it?

•How to assess CV risk?•How to manage it?•How to prevent it?

Is CV risk higher among HIV-positive individuals than in the general population?

MI rates in HIV vs non HIV-patientsMI rates in HIV vs non HIV-patients

Higher prevalence of hypertension, diabetes and dyslipidemia (no data on smoking rate)Higher prevalence of hypertension, diabetes and dyslipidemia (no data on smoking rate)

Triant, J Clin Endocrin Metab 2007N=3.851 N=1.044.589

IMA (ICD-9)

Currier, Circulation 2008

Lo, AIDS 2010

N= 32N= 32 N= 78N= 78

6.5% stenosi >70%6.5% stenosi >70%

Why it is higher?

Grunfeld, Circulation 2008Grunfeld, Circulation 2008

1) Traditional risk factors

2) Role of ARV medication

3) HIV itself

4) Persistent inflammatory state

5) Comorbidities

1) Traditional risk factors

2) Role of ARV medication

3) HIV itself

4) Persistent inflammatory state

5) Comorbidities

Age

Aging in HIV population is increasing

Coronary aging in HIV-infected patientsCoronary aging in HIV-infected patients

Methods: observational cross-sectional study in 400 HIV patients receiving ART.

•All pts underwent coronary artery calcium (CAC) screening using computed tomography.

•Coronary age (CA) was calculated based on CAC score.

Findings: increased CA was observed in 40.5% of patients with an average increase of 15 (range 1-43) years compared to their chronological age.

Methods: observational cross-sectional study in 400 HIV patients receiving ART.

•All pts underwent coronary artery calcium (CAC) screening using computed tomography.

•Coronary age (CA) was calculated based on CAC score.

Findings: increased CA was observed in 40.5% of patients with an average increase of 15 (range 1-43) years compared to their chronological age.

Guaraldi, ICAR 2009; CID 2009Guaraldi, ICAR 2009; CID 2009

Cardiovascular risk factors in the D:A:D study population at baseline

Friis-Moller AIDS 2003

Smoking

a p<0.0001Triant, J Clin Endocrin Metab 2007

• Hypertension, diabetes, dyslipidemia

1) Traditional factors2) Role of ARV medication

WHY CV risk is increased

Retrospectives studies Does ART increase the risk?

Kaiser Permanente Registry, Klein JAIDS 2002 No

VA Database, Bozzette NEJM 2003; JAIDS 2008 No

French Hospital Database, Mary Krause AIDS 2003 Yes

California Medicaid, Currier JAIDS 2003 Yes

Danish National Hospital Registry, Obel CID 2007 Yes

Los Angeles County Cohort, Vaughn AIDS Care 2007 Yes

Prospective observational studies

HOPS cohort, Homberg Lancet 2002 Yes

HIV Insight/HOPS, Hoeje HIV Med 2005 Yes

DAD Study cohortNEJM 2003; NEJM 2007; Lancet 2008; JID 2010

Yes

Randomized controlled trial

SMART trial, Phillips Antivir Ther 2008 No

Antiretroviral therapy and risk of myocardial infarction

RR = 1.16 per exposure year (95% CI 1.09 -1.23)

Incidence 3.65/1000 p/y

The D:A:D StudyThe D:A:D Study

NEJM 2003, NEJM 2007NEJM 2003, NEJM 2007

NEJM 2007NEJM 2007

SMART: studio prospettico, randomizzato. end-point primario: infezioni opportunistiche, morte. end-point secondario: malattie CV

El Sadr, N Engl J Med 2006

Van Leuven, Curr Opinion HIV AIDS 2007

“It is not just antiretroviral therapy that hurts the heart!”“It is not just antiretroviral therapy that hurts the heart!”

Prevention of CV risk in HIV

• Avoid smoking (campaign, education. Tailored programs, etc.)

• Prevent traditional risk factors

• Avoid ARV medication with high impact on metabolic disorders

• Treat HIV infection

• Treat metabolic disorders

• Support physical activities