HIV and Cardiovascular Disease: Practical … and Cardiovascular Disease: Practical Management Strategies . ... Slide courtesy JS Currier . ... failure to account for confounding from

Brad Cutrell, MD

Assistant Professor

VA North Texas Healthcare System, Dallas, TX

University of Texas Southwestern, Dallas, TX

HIV and Cardiovascular Disease:

Practical Management Strategies

I have no relevant financial

disclosures or conflicts of interest and

will not be discussing non-FDA

approved drug uses.

Learning Objectives

By the end of this presentation, participants will be able to:

Explain contribution of traditional risk factors and ART to incidence of CVD in HIV

Describe two pathogenic mechanisms that lead to increased CVD in HIV

Apply JNC 8 guidelines to the management of hypertension

List four specific patient groups with an indication for statin therapy based on currentACC/AHA cholesterol guidelines

Outline

Summary Overviews

– CVD Epidemiology in HIV

– CVD Pathogenesis in HIV

– CVD Risk Prediction in HIV

Atherosclerotic CVD Primary and Secondary Prevention in HIV: Clinical Management Strategies

Topics Not Covered

Other Manifestations of Cardiac Disease

– Pericardial Disease

– Heart failure and Cardiomyopathy

– Arrhythmias and Sudden Cardiac Death

– Pulmonary HTN

Acute Management of ACS

CVD EPIDEMIOLOGY IN HIV

Causes of Death in French HIV

National Survey, 2005

Lewden C, et al. JAIDS. 2008;48:590-8.

Median CD4 cont

2000 2005

Underlying cause of death in HIV-infected adults: Overall distribution in 2000

(n = 964) and 2005 (n = 1042), and most recent CD4 cell count by cause;

Mortalite´ 2000 and 2005 surveys, France.

HIV-related CVD – Significant Mortality

1,876 deaths among 39,727 patients

Non-AIDS related deaths accounted for 50.5%

~16% were due to CVD

13 HIV Cohorts

1996-2006

CVD

15.7%

Non-AIDS

infection

16.3%

Non-AIDS

Malignancy

23.5%

Violence,

Substance

abuse

15.4%

Liver-related

14.1%

Other

9.0% Respiratory

3.1%

Renal

3%

Antiretroviral Therapy Cohort Collaboration. Clin Infect Dis. 2010;50:1387-1396

Slide courtesy JS Currier

CVD Incidence Rates in HIV

Increased CVD incidence in HIV-infected patients compared to uninfected controls1-3

– RR for MI and clinical CVD events: 1.5 - 2.0

– Significant even after controlling for traditional risk factors

– RR more pronounced in younger age groups

– Absolute risk remains low in most cohorts due to youth

Data limited by small event numbers and incomplete capture of other cardiac risk factors

1. Currier J, et al. JAIDS. 2003; 33:506-512. 2. Triant V, et al. J Clin Endocrinol Metab. 2007; 92:2506-12.

3. Klein D, et al. JAIDS. 2002; 30:471-77.

CVD Incidence Rates in HIV Summary of MI Rates and RR Across Studies1-3

Cohort HIV + Pts/CVD

Events

HIV + Event

Rate (per

1000 pt yrs)

HIV – Event

Rate (per

1000 pt yrs)

HR or RR of

CVD event:

HIV+/HIV-

Kaiser 5000 / 162 3.7 2.2 1.68

MGH 3851 / 189 11.13 6.98 1.75

MediCal 28512 / 294 4.12 3.32 1.24

FHDH 74958 / 360 1.24 NR 1.5

DAD II 23437 / 345 3.6 N/A N/A

VA 36766 / 1207 8.1 N/A N/A

VACS 82549/ 871 5.0* 3.3* 1.48#

1. Currier J, et al. Circulation. 2008: 118:e29-e35. 3. Freiberg MS, et al. JAMA Intern Med. 2013; 173;614-622.

2. Lang S, et al. AIDS. 2010; 24:1228.

MGH, Massachusetts General Hospital; MediCal, California Medicaid Database; FHDH, French Hospital Database on HIV;

DAD, Data Collection on Adverse Events of Anti-HIV Drugs Study Group; VA, Veterans Affairs; VACS, VA Aging Cohort

Study; N/A, not available; NR, not reported; * Event rate for ages 60-69, # RR for entire cohort

Paradigms of HIV-CVD Interplay

HIV AND ART

TRADITIONAL

RISK

FACTORS

CVD

TRADITIONAL

RISK

FACTORS

CVD HIV AND ART

HIV AND ART

TRADITIONAL

RISK

FACTORS

CVD

HYPOTHESIS #1:

MARKER OF RISK

FACTORS

HYPOTHESIS #2:

WORSENS RISK

FACTORS

HYPOTHESIS #3:

INDEPENDENT

EFFECT BEYOND

RISK FACTORS

CVD Risk Factors

TRADITIONAL CVD RISK

FACTORS

Age

Gender

Genetics (Race/Family History)

HTN

Dyslipidemia

Smoking

Diabetes/Insulin Resistance

Obesity/Sedentary Lifestyle

Modifiable risk factors in

bold.

• Higher prevalence of many

traditional CVD risk factors in

HIV-infected pts compared to

non-infected pts1-2

• Relative contribution to CVD

risk appears to be similar to

general population3

• Increased CVD risk appears

to persist despite adjustment

for these risk factors

1. Saves M, et al. Clin Infect Dis. 2003; 37:292.

2. Kaplan RC, et al. Clin Infect Dis. 2007; 45:1074.

3. Currier J, et al. Circulation. 2008: 118:e29-e35.

Comparison of Risk Factor

Prevalence: HIV vs. non-HIV

RISK FACTOR APROCO VS. WHO

MONICA1

(Data for men 34-44 yo)

WIHS/MACS COHORTS2

(Data for men only shown)

HIV-POS HIV-NEG HIV-POS HIV-NEG

Smoking 56.6% 32.7% 35% 28%

HTN 5.2% 12.8% 33% 34%

Diabetes 2% 3% 16% 11%

Elevated TC 59.6% 60.8% NR NR

Elevated TG 32.3% 13.5% 10% 2%

Low HDL 44.9% 23.1% 43% 21%

Statistically significant differences in bold

1. Saves M, et al. Clin Infect Dis. 2003; 37:292. 2. Kaplan RC, et al. Clin Infect Dis. 2007; 45:1074.

CVD Risk Factors

TRADITIONAL CVD RISK

FACTORS

Age

Gender

Genetics (Race/Family History)

HTN

Dyslipidemia

Smoking

Diabetes/Insulin Resistance

Obesity/Sedentary Lifestyle

NON-TRADITIONAL CVD RISK

FACTORS

Direct effects of HIV infection

- Chronic inflammation

- Endothelial dysfxn / Hypercoaguability

- Immune deficiency/senescence

ART (in general or specific agents)

Lipodystrophy syndrome

HCV co-infection

Renal disease, albuminuria

Other factors …

• Residual excess risk has led to investigation of novel/nontraditional risk factors.

HAART and the Heart

Association between ART exposure and increased CV events in most studies (except early large VA study) 1-3

Exposure to older protease inhibitors (e.g. lopinavir-ritonavir) most consistent association of risk, likely mediated by lipids; limited data but less concern with newer PIs1-2

Some but not all studies show association with recent use of abacavir; failure to account for confounding from CKD possible explanation4-5

ART interruption associated with higher rates of CV events in SMART study compared to continuous arm (1.3/100 py vs. 0.8/100 py) 6

1. DAD:Friis-Moller N, et al. N Engl J Med. 2007; 356:1723.

2. Mary-Krause M, et al. AIDS. 2003; 17:2479.

3. Bozzette SA, et al. N Engl J Med. 2003; 348:702.

4. DAD :Sabin CA, et al. Lancet. 2008; 371:1417.

5. Bedimo RJ, et al. Clin Infect Dis. 2011; 53:84.

6. SMART Study: El-Sadr WM, et al. N Engl J Med. 2006;

355:2283.

CVD Epidemiology Summary

Increased relative risk of CVD events in HIV-infected patients compared to uninfected patients

Higher prevalence of traditional CVD risk factors (such as smoking) partially explains increased risk

Select ART (primarily older PIs) are associated with increased risk, likely from worsening traditional risk factors

Benefits of HAART and CVD risk associated with treatment interruption outweigh CVD risks of treatment

CVD PATHOGENESIS IN HIV

Pathogenesis of CVD in HIV

Boccara F, et al. JACC 2013; 61:511-23.

We will briefly discuss:

• Chronic inflammation

and immune activation

• Abnormal lipid

metabolism

Deeks, SG et al. NEJM

2012; 367:1246-54.

Role of Chronic Inflammation

clinicaloptions.com/hiv

The Challenges of Managing the Aging HIV-Infected Patient

Chronic Inflammation Persists in the

Setting of Treated HIV Infection

T-cell activation higher in treated HIV vs controls[1]

Lipopolysaccharide higher in treated HIV vs controls[2]

Tissue factor elevated in treated HIV vs controls[3]

1. Hunt PW, et al. J Infect Dis. 2003;187:1534-1543. 2. Brenchley JM, et al. Nat Med. 2006;12:1365-

1371. 3. Funderburg NT, et al. Blood. 2010;115:161-167.

% C

D38+

HL

AD

R+

C

D8+

T C

ells

80

60

40

20

0 HIV +

Untreated (n = 82)

HIV + ART

(n = 65)

HIV - (n = 132)



Low CD4+ Count Associated With CVD

Nadir CD4+ cell count ≤ 200 cells/mm³ independently associated with carotid IMT[1,2]

Proximal CD4+ cell count during therapy associated with incident CVD and AMI[3]

Kaiser study: higher risk of CHD seen only in treated HIV+ pts with either recent or lowest CD4+ cell count ≤ 200 cells/mm3[4]

Nadir CD4+ cell count < 350 cells/mm3 independently associated with worsened arterial stiffness and endothelial function[5,6]

Will there be a CV benefit in earlier initiation of antiretroviral therapy?

1. Hsue PY, et al. Circulation. 2004;109:1603-1608. 2. Triant VA, et al. J Acquir Immune Defic Syndr.

2010;55:615-619. 3. Lichtenstein KA, et al. Clin Infect Dis. 2010;51:435-447. 4. Klein D, et al. CROI 2011.

Abstract 810. 5. Ho JE, et al. AIDS. 2010;24:1897-1905. 6. Ho E, et al. AIDS. 2012;26:1115-1120.

Lipid Parameters in HIV Patients

Compared to Uninfected Controls

Group TG TC LDL HDL Comments

HIV +, ART naïve ↑ ↓ ↓ ↓ Small, dense LDL

particles

HIV +, PI-based

ART

↑↑ ↔ / ↑ ↔ / ↑ ↓ More apoB lipoproteins

(VLDL/LDL)

Rose H, et al. Atherosclerosis 2008; 199:79-86.

• HIV-infected patients have “pro-atherogenic” lipid profile at baseline

• ART, esp. older PIs, increase TG and “normalize” LDL and TC while

HDL remains low

Disordered HDL Metabolism

Rose H, et al. Atherosclerosis. 2008 July; 199: 79-86.

HIV-induced LCAT and CETP activity shunts cholesterol into

apoB lipoproteins (and thus extrahepatic tissue)

CVD RISK PREDICTION IN HIV

CVD Risk Prediction

Goal is to match the intensity of CV risk factor modification to the predicted

risk of CVD?

Framingham Risk Score

http://hp2010.nhlbihin.net/atpiii/calculator.asp

Accessed January 21,2013.

• Was used for general

population to determine

lipid targets

• Appeared to

underestimate risk in

HIV pts (based on

D:A:D cohort and

others)

• Doesn’t include HIV-

specific risk factors

(CD4, ART exposure)





Clinical Impact of New Data From ICAAC, IDWeek, and EACS 2013

D:A:D Updated Models of Global CVD

Risk/Comparison With Framingham

Retrospective analysis of 32,663 HIV+ persons from 20 countries in Europe and Australia with

– No CVD disease at entry to study, and

– Data on CVD risk factors

1010 CVD events in 186,364.5 PY → overall rate of 5.42/1000 PY (95% CI: 5.09-5.76)

– Includes MI (n = 493); stroke (n = 295); angioplasty (n = 129); bypass (n = 44); other CVD death (n = 36); carotid endarterectomy (n = 13)

– 2 D:A:D models used (1 including exposure to certain ARV agents) and compared with Framingham model

Friis-Møller N, et al. EACS 2013. Abstract PS1/3.



D:A:D Hazard Ratios for Risk of CVD

Events Using 3 Models

*If treated. Friis-Møller N, et al. EACS 2013. Abstract PS1/3. Reproduced with permission.

Risk Factor Unit D:A:D

+ ARVs

D:A:D

- ARVs

Framingham

(Males Only)

Age Linear 22.0 24.0 21.4

Sex M/F 1.37 1.41 N/A

Diabetes Y/N 1.96 2.08 1.78

Smoking Current

Former

2.25

1.24

2.26

1.27

1.92

TC

HDL-C Linear

2.58

0.61

2.98

0.59

3.08

0.39

Systolic BP Linear 4.59 4.56 6.91

7.38*

Family hx CVD Y/N 1.37 1.39

CD4+ cell count 2-fold higher 0.89 0.89

ABC, current Y/N 1.47

PI, cumulative Yrs 1.05

NRTI, cumulative Yrs 1.03



D:A:D Summary of Key Conclusions

Classic CVD risk factors important in HIV+ pts

Framingham appears to underestimate risk compared with D:A:D models

Risk related to current use of ABC lower than previous estimates

– HR: 1.47 vs no current ABC use

Framingham model

D:A:D reduced model

D:A:D full model

Observed Kaplan-Meier

5-Yr CVD Risk by Age and Diabetes Status

Es

tim

ate

d 5

-Yr

Ris

k, %

12

10

8

6

4

2

0

Friis-Møller N, et al. EACS 2013. Abstract PS1/3. Reproduced with permission.

http://www.cphiv.dk/TOOLS/tabid/437/

Default.aspx

CVD PREVENTION IN THE HIV

CLINIC

CVD Primary Prevention

To prevent CVD, first provider has to CONSIDER THE PATIENT AT RISK!

HIV guidelines generally follow those for general public with special consideration of drug-drug interactions and metabolic effects of ART

Suggested Approaches:

– Have Systematic Approach to assessing CV risk factors

– Design workflow to make it “easy” to follow guidelines

– Understand and maximize non-physician resources

– Consider dedicated “Metabolic” visit (in stable pts)

– Evaluate your practice as part of QI process

2013 HIV Primary Care Guidelines

Aberg J, et al. CID 2014; 38(1):1-34.

Clinical Inertia in CVD Prevention

Retrospective study of 90 pts in UAB HIV clinic not at LDL goal showed 44% of patients failed to have appropriate intervention over 12-month span1

– Women and pts in highest CVD risk category most likely affected by inertia, higher absolute LDL less likely

Same clinic reported study of 397 patients qualifying for ASA for primary prevention based on USPSTF guidelines, found that only 66 (17%) patients received therapy2

– OR of receipt of ASA doubled for each additional CVD risk factor

Conclusions: Clinical inertia major issue in CVD prevention in HIV clinic and clinicians tend to rely on clinical impression rather than practice guidelines

1. Willig JH, et al. Clin Infect Dis. 2008; 46:1315.

2. Burkholder GA, et al. Clin Infect Dis. 2012; 55:1550.

ABCs of CVD Prevention Aspirin

Blood pressure

Cholesterol

Diet

Exercise

Fumes (smoking)

Glucose (DM/insulin resistance)

HAART

Maximize

non-MD

resources

Utilize

pharmacist and

specialist

expertise in

complex cases

Management: Aspirin

USPSTF recommend ASA for primary prevention:

– Men 45-79 with net benefit for preventing MI

– Women 55-79 with net benefit for preventing stroke

– Younger pts: Not recommended; Age > 80: insufficient evidence

– Net benefit considers risk of GIB (NSAIDs 3-4x; prior ulcer or GIB 2-3x)

– Use dose 81 mg daily

USPSTF Aspirin for Primary Prevention of Cardiovascular Disease Guidelines, 2009.

Recent CV Guideline Changes

Updated Guidelines in late 2013:

– JNC 8: Hypertension

– ACC/AHA Management of Blood Cholesterol

– ACC/AHA Lifestyle Management

– ACC/AHA Cardiovascular Risk Assessment

– ACC/AHA Management of Obesity

Intended to apply RCT evidence to specific clinical research questions, NOT comprehensive guidelines

Controversial from outset of publication (HTN and Chol)

Management: Blood Pressure

Definition of HTN and prehypertension not addressed

Key Changes from JNC-7:

– Goal BP: < 140/90 (age 18-60), < 150/90 (age ≥ 60)

– Goal BP in diabetes/CKD: < 140/90 regardless of age

– Recommended drug classes: thiazide diuretics, ACE-I, ARB or CCB (except in AA and pts with CKD)

– 3 drug treatment titration strategies suggested

JNC 8 Guidelines for Mgmt of HTN. JAMA. Published online 12/18/13.



HTN Examples

Example Patient BP Target BP Drugs to Use

65 yo WM, BP 142/85

50 yo AAF, BP 148/95

63 yo AAM, BP 149/84, Cr

0.9, + microalbuminuria

72 yo WF, BP 138/85, on

ACE-I/HCTZ combo

* CKD defined as eGFR < 60 mL/min if age < 70 or microalbuminuria


65 yo WM, BP 142/85 < 150/90 Lifestyle mgmt, no meds

at this time

50 yo AAF, BP 148/95

63 yo AAM, BP 149/84, Cr


72 yo WF, BP 138/85, on

ACE-I/HCTZ combo



at this time

50 yo AAF, BP 148/95 < 140/90 Thiazide or CCB

63 yo AAM, BP 149/84, Cr


72 yo WF, BP 138/85, on

ACE-I/HCTZ combo



at this time


63 yo AAM, BP 149/84, Cr


< 140/90 ACE-I or ARB

72 yo WF, BP 138/85, on

ACE-I/HCTZ combo



at this time


63 yo AAM, BP 149/84, Cr


< 140/90 ACE-I or ARB

72 yo WF, BP 138/85, on

ACE-I/HCTZ combo

< 150/90 No change; continue if

tolerating without AEs

Changes to Come..

SPRINT trial

– RCT of 9300 non-diabetics with increased CVD risk pts

– Goal SBP < 120 or < 140

– Strongly favors goal SBP < 120

Revision of BP guidelines likely due out this fall

N Engl J Med 2015;373:2103-16.

Management: Cholesterol

Key Changes from New Lipid Guidelines:

– Highlights 4 groups most likely to benefit from statins

– Focus on statin intensity, NOT treatment to specific LDL or non-HDL targets

– New Pooled Risk Equation to predict 10-year ASCVD risk

– No “routine role” for non-statin therapy

– Emphasis on “patient-centered” approach with discussion of individual risk/benefits of therapy

ACC/AHA Guidelines for Mgmt of Blood Cholesterol. Stone NJ, et al. JACC. 2013

4 ASCVD Statin Benefit Groups

4 Patient Groups which benefit from statins:

– Clinical ASCVD (includes CAD, CVA/TIA, PVD)

– LDL≥ 190 mg/dL

– Diabetes age 40-75 with LDL 70-189 mg/dL

– 10-year ASCVD est. risk ≥ 7.5% with LDL 70-189 mg/dL

For NYHA II-IV heart failure and hemodialysis pts, no recommendation made due to lack of evidence proving efficacy in these populations


New ASCVD Risk Equation

CVD/CHD Prevention Guidelines: Key

Differences

ATP-III Lipid Guideline (2004)

AHA/ACC Guideline (2013)

Risk Prediction

Framingham Risk Score (FRH*) CHD 10-year risk

-Limitations: -White race -no Diabetes mellitus (DM)

Pooled cohort equations (PCE) CVD 10-year risk

- Includes: - AA race - DM

Lipid-Lowering Therapy / Statins for:

LDL target, determined by: - # of risk factors - 10-year FRH risk score

- CHD or CHD equivalent

-Clinical ASCVD

-LDL > 190

-DM (LDL > 70)

-PCE > 7.5% (LDL > 70)

* 2004 Framingham Score for CHD, not “general” Framingham Score for CVD (2008)

Defining Statin Intensity

Defined by average % reduction in LDL seen in RCTs

Must take into account HIV drug interactions

High-Intensity Statins Moderate-Intensity

Statins

Lower LDL by ≥ 50% Lower LDL by 30-50%

Atorvastatin 40-80 mg/d

Rosuvastatin 20-40 mg/d

Pravastatin 40-80 mg/d

Simvastatin 20-40 mg/d

Atorvastatin 10-20 mg/d

Rosuvastatin 5-10 mg/d

In HIV, start low and slowly titrate!


Drug Interactions: Lipid-lowering

Agents and PI-based ART

*AUC ↑↑↑ with DRV.

Fibrates

Fluvastatin

Pravastatin*

Ezetimibe

Fish oil

Use cautiously Statin + fibrate

Atorvastatin

Rosuvastatin

Niacin

Lovastatin

Simvastatin Contraindicated

Low interaction potential

Aptivus [package insert]; 2005. Carr RA, et al. ICAAC 2000. Abstract 1644.

Fitchenbaum CJ, et al. AIDS. 2002;16:569-577. Gerber JG, et al. CROI 2004.

Abstract 603. Gerber J, et al. IAS 2003. Abstract 870. Hsue PH, et al. Antimicrob

Agents Chemother. 2001;45:3445-3450. Lexiva [package insert]; 2007. Prezista

[package insert]; 2006. Reyataz [package insert]; 2007.


Management Algorithm


Management Algorithm

Recommended Follow-Up


• Repeat lipid

panel 4-12

weeks after

starting or

changing statin

• Repeat lipids to

monitor

adherence and

therapeutic

response, NOT

to target specific

LDL

Do these guidelines apply to HIV

patients?

“Clinician judgment is especially important for several patient groups for whom the RCT evidence is insufficient for guiding clinical recommendations. These patient groups

include … those with serious comorbidities and increased ASCVD risk (e.g., individuals

with HIV, etc.)”


PCE Risk

Group N=

Average

FRH score

(95% C.I.)

AMI

incidence rate

(95% C.I.)

Average

PCE score

(95% C.I.)

CVD

incidence rate

(95% C.I.)

<5% 5,575 2.6 (2.5-2.6) 2.6 (2.1-3.4) 2.6 (2.6-2.7) 5 (4.2-6.0)

5-7.5% 2,539 6.9 (6.8-7.1) 4.7 (3.5-6.3) 6.2 (6.2-6.2) 10.0 (8.2-

12.1)

7.5-10% 1,861 9.7 (9.5-9.9) 6.0 (4.3-8.4) 8.7 (8.7-8.7) 11.6 (9.2-

14.7)

>10% 5,089 15.9 (15.7-

16.1) 9.5 ( 8.1-11.1)

17.6 (17.3-

17.8) 17.1 (15.2-

19.1)

Which Risk Prediction Score is Best?

Predicted and Observed AMI/CVD Incidence Rates by

FRH/PCE score

Slide courtesy Dr. Henning Drechsler

patients CVD

events AMI

events

PCE<7.5% FRH<10%

7,383 263 122

PCE<7.5% FRH≥10%

731 27 13

PCE≥7.5% FRH<10%

1,511 95 48

PCE≥7.5% FRH≥10%

5,439 416 219

Which Risk Prediction Score is Best?

Time to event analysis

Slide courtesy Dr. Henning Drechsler

Statin Therapy in HIV:

Other Benefits?

ALLRT cohort (3601 subjects) evaluated statin use and non-accidental death or non-AIDS defining complications1

– Adjusted HR for death 0.81 [.53-1.24], for non-AIDS malignancy 0.43 [.19-.94]

Hopkins cohort of 1538 virologically-suppressed pts2

– HR for death of 0.33 [0.14-0.76] associated with statin use in multivariate analysis controlling for demographic and clinical factors

VA HIV cohort from 1995-2009 including > 25k patients and 6435 deaths3

– Significant reduction in all-cause mortality per year of cumulative statin exposure

– Any statin: HR 0.95 [0.93-0.98]; Potent statin: HR 0.86 [0.81-0.93]

1. Overton ET, et al. CID 2013; 56:1471-1479; 2. Moore RD, et al. PLoS One 2011;

3. Drechsler H, et al. CROI 2013 Abstract 765.

Carr A, et al. AIDS. 2001;15:1811-1822. Moyle G, et al. AIDS. 2001;15:1503-1508. Miller J, et al. AIDS. 2002;16:2195-2200.

Doser N, et al. AIDS. 2002;16:1982-1983. Aberg JA, et al. AIDS Res Hum Retroviruses. 2005;21:757-767. Calza L, et al.

AIDS. 2005;19:1051-1058.

PI Switch vs. Lipid-Lowering Rx

Metabolic Parameter PI Switch Statin Fibrate

TC -10% to -30% -11% to -45% 0% to -5%

HDL 0% to +3% 0% to +6% 0% to +17%

TG -10% to -25% 0% to -25% -20% to -45%

Insulin sensitivity Variable No change No change

When switching antiretroviral therapy

– Maintenance of virologic suppression is paramount

– Any switch carries some risk of loss of virologic suppression

Lipid-lowering agents

– May avoid risks associated with switch but at the price of polypharmacy

– More commonly used in US; European guidelines suggest lipid-lowering

therapy only after dietary modification and switch strategies

Cholesterol Conclusions (Tentative)

Follow guidelines for pts with clinical ASCVD, LDL > 190 mg/dL, and diabetics

Consider “individualized” risk/benefit ratio of statin Rx in others (with predicted 10-year ASCVD risk as only one component)

Start lower dose statin and slowly titrate to achieve % LDL reduction goals (rather than a specific LDL)

Reserve non-statin therapy for statin intolerance or ↑↑ triglycerides

Consider more “lipid-friendly” ART if viral suppression possible

Need validation of risk calculators in HIV patients and RCT data on statins in HIV patients w/o clinical ASCVD (REPRIEVE trial)

Diet

Group Recommendations Evidence

Strength

↑ LDL Consume “heart-healthy” dietary pattern (DASH diet,

AHA diet, USDA Food Pattern)

I. A

Consume 5-6% of daily calories from saturated fat I. A

Limit calories from saturated and trans fat I. A

↑ BP

Consume “heart-healthy” dietary pattern (DASH diet,

AHA diet, USDA Food Pattern)

I. A

Limit Na+ intake to < 2.4 gm/d (preferably < 1.5 gm/d) IIa. B

Combine DASH diet with lower Na+ intake I. A

Eckel RH, et al. 2013 AHA/ACC Lifestyle Management Guidelines

Exercise

Group Recommendations Evidence

Strength

↑ LDL Engage in aerobic exercise 3-4 sessions/wk, average

duration 40 minutes/session, moderate to vigorous

intensity

IIa. A

↑ BP

Engage in aerobic exercise 3-4 sessions/wk, average

duration 40 minutes/session, moderate to vigorous

intensity

IIa. A

Eckel RH, et al. 2013 AHA/ACC Lifestyle Management Guidelines

SMOKING CESSATION

Smoking cessation has GREATEST impact (≈ 50%) on CVD risk reduction of any single intervention

DHHS guidelines recommend pharmacotherapy for all patients except those with medical contraindications

– Approved agents: Nicotine patch, gum, inhaler, nasal spray, bupropion and varenicline

– No drug interactions with varenicline; caution with bupropion and boosted PIs

More intensive counseling interventions with better results in HIV+ patients, particularly when initiated by MD

Vidrine DJ, et al. AIDS. 2006; 20:253.

Insulin Resistance / Diabetes

Definitions of Diabetes: 2013 ADA Guidelines

– HbA1c ≥ 6.5%* or

– Fasting plasma glucose (FPG) ≥ 126 mg/dL* or

– Plasma glucose ≥ 200 mg/dL after 2 hrs during OGTT* or

– Random plasma glucose ≥ 200 mg/dL with symptoms

* Should be confirmed on repeat testing

Screening Frequency:

– Prior to and 1-3 months after starting HAART

– FPG or HbA1c in all patients every 6-12 months

Aberg J, et al. CID 2014; 38(1):1-34.



HbA1c Underestimates Glycemia in HIV-

Infected Persons

HIV (n = 100)

Control (n = 200)

Glu

co

se (

mg

/dL

)

Kim PS, et al. Diabetes Care. 2009;32:1591-1593.

450

400

350

300

250

200

150

100

50

0 4 5 6 7 8 9 10 11 12 13 14

HbA1c (%)

Prospective cross-sectional study of 100 HIV-infected adults with type 2 diabetes (77%) or fasting hyperglycemia (23%)



Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.

Step 1: Monotherapy

Step 2: Dual therapy

Step 3: Combination

therapy

Step 4: Complex insulin

strategies

Insulin (multiple daily doses)

Insulin (usually basal)

GLP-1 receptor agonist

DPP-4 inhibitors

Thiazol- idinediones

Sulfonylurea

Healthy eating, weight control, increased physical activity

Metformin

TZD

TZD TZD

TZD

DPP-4-i DPP-4-i DPP-4-i

GLP-1-RA GLP-1-RA GLP-1-RA

Insulin Insulin

Insulin Insulin

SU SU SU

+ + + + +

+ + + + +

or

or

or

or

or

or

or

or

or

or

or

or



HbA1c Goal for the Prevention of Diabetes

Complications

< 7% Individualization is key:

Tighter control (HbA1c 6.0% to 6.5%): younger, healthier

Looser control (HbA1c 7.5% to 8.0%+): older, hypoglycemia prone, comorbidities

Should HbA1c goal be lower in HIV-positive patient if it underestimates glycemia?

Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.

HAART: CVD CONSIDERATIONS Guidelines for Starting HAART:

– DHHS: all patients regardless of CD4 count (varying evidence strength)

– IAS-USA: specifically mention high CV risk as an indication for HAART

Primary focus is choosing a regimen which will achieve virologic suppression

In patients with CV risk factors, consideration given to:

– More metabolically-favorable PIs: ATV/r and DRV/r

– If no renal disease, may favor TDF-FTC > ABC

– NNRTI- or INSTI-containing regimens also reasonable

– For treatment-experienced, can consider switch strategy if virologic suppression achievable

DHHS HIV Treatment Guidelines 2013; IAS-USA HIV Treatment Guidelines 2012

METABOLIC PROFILE OF ART

Lundgren JD, et al. HIV Medicine. 2008; 9:72-81.

INSTI

RAL

EVG

DTG

Conclusions

CVD is prevalent among HIV patients with significant morbidity and mortality

Pathogenesis of CVD in HIV is multifactorial including chronic inflammation/immune activation and abnormal lipid metabolism

Consistent delivery of CVD prevention strategies require a systematic, multi-disciplinary approach

Applicability of CVD guideline changes to HIV patients is unclear

Improved CV risk prediction and validated guidelines specific for HIV patients are urgently needed

The End

Mortality Trends in HIV

Introduction of HAART in 1996 led to dramatic reductions in AIDS-related morbidity and mortality1

Non-AIDS related causes of morbidity and mortality of increasing importance, with 3 dominant players2

– Cardiovascular Disease (CVD)

– Chronic liver disease, primarily from viral hepatitis

– Non-AIDS defining malignancies

1. Pallela FJ, et al. N Engl J Med. 1998; 338:853.

2. Neuhaus J, et al. AIDS. 2010; 24:697.

Initial Screening for Metabolic

Complications

HISTORY PE LABS

• Hx of CHD, CVA, PVD,

DM2, HTN, HLD

• FHx of premature CVD

(male < 55, female <65)

• Menopausal status in

women

• Smoking status

• Diet and exercise hx

• Substance abuse

(EtOH, IVDU)

• Medications with

metabolic AEs

• Blood Pressure

• BMI, Height, Weight

• Waist Circumference

• Signs of lipodystrophy

• Signs of cardiac dz or

PAD

• Fasting glucose

• Fasting lipid profile

• Serum Cr (eGFR)

• Consider reflex TSH,

HCV Ab, micro-

albuminuria (if CKD)

Adapted from Dube MP, et al. Clin Infect Dis. 2003; 37:614.

COMMUNICATING CVD RISK TO

PATIENTS

http://www.heartagecalculator.com

• FRS 10-year predicted risk may be

difficult for patients to conceptualize

• “Heart age” calculates the age of a

reference patient with ideal risk profile

that shares same risk as the patient

•Endorsed by British Heart Federation

as tool to communicate risk to patients

• Bristol HIV cohort study found HIV+

patients had significantly higher heart

age than actual age, with deviation

greatest in smokers and older patients

• May be a useful tool for

communicating risk to HIV+ patients

Davies T, et al. JIAS. 2012; 15:18152.



CV Risk Persists in Treated HIV Infection;

Inflammation Predictive of This Risk

ART-treated/virologically suppressed HIV-infected patients have greater carotid IMT vs controls[1,2]

– hsCRP strongly associated with IMT in bifurcation region[2]

HIV-infected patients with well-controlled disease have greater arterial inflammation (using FDG-PET)

– Associated with sCD163 but not CRP or D-dimer[3]

1. Hsue PY, et al. AIDS. 2009;23:1059-1067. 2. Hsue PY, et al. J Am Heart Assoc. 2012;1:pii: jah3-

e000422. 3. Subramanian S, et al. JAMA. 2012;308:379-386.

Meta-Analysis of MI Risk in HIV

vs. non-HIV Patients

HIV – no ART

RR 1.61 (1.43-1.81)

p<0.001

HIV – on ART

RR 2.0 (1.7-2.37)

P<0.001

Islam, FM, et al. HIV Medicine; 2012; 13:453-68.

Documents

HIV and Cardiovascular Disease: Practical … and Cardiovascular Disease: Practical Management Strategies . ... Slide courtesy JS Currier . ... failure to account for confounding from