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Steven K. Grinspoon, MDProfessor of Medicine

Harvard Medical School

Boston, Massachusetts

Statin Use and Cardiovascular

Disease in HIV

FLOWED: 04/18/16

Los Angeles, California: April 25, 2016

Slide 2 of 36

Statin Use and Cardiovascular Disease in HIV

Steven Grinspoon, M.D.

Professor of Medicine

Harvard Medical School

IAS–USA

April 25, 2016

Slide 3 of 36

Financial Relationships With Commercial Entities

Dr Grinspoon has served as a consultant to

Navidea Biopharmaceuticals, Theratechnologies,

Merck & Co, Inc, and Gilead Sciences, Inc. He has

received grants and research support to his

institution from Gilead Sciences, Inc, Kowa

Pharmaceuticals, and Theratechnologies.

(Updated 04/25/16)

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Slide 4 of 36

Learning Objectives

After attending this presentation, participants will

be able to:

Describe the current epidemiology of cardiovascular disease (CVD) in HIV

Describe the unique pathophysiology of CVD in HIV

Describe the potential utility and limitations of statin use to prevent CVD in HIV

Slide 5 of 36

Most Epidemiological Studies Suggest

that Rates of CVD in HIV are:

6%

50%

38%

6% 1. Equal to that seen in non HIV

2. 10% higher

3. 50-100% higher

4. 200% higher

Slide 6 of 36

Current Status of CVD Prevention in HIV

• Even as rates of death and mortality related to HIV

have decreased with use of more potent ART,

CVD rates, remain increased among HIV patients

and are a leading cause of morbidity and mortality

• There is limited understanding of the mechanisms

and treatment strategies for CVD in HIV

• No large scale primary CVD prevention strategy

has been tested in HIV

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CVD Risk in HIV-Infected Patients is Beyond

That Predicted by Traditional Risk Factors

0

0.5

1

1.5

2

2.5

Eff

ec

t S

ize

of

MI

or

CH

Din

HIV

vs

. n

on

HIV

In the VACS cohort, the

HR of MI was 1.48 in HIV

vs. non-HIV veterans

after adjusting for FRS,

comorbidities, and

substance use (95% CI

1.27-1.72).

(Freiberg, 2013)

Slide 8 of 36

Which of the Following is Not a Common

Feature of Coronary Plaque in HIV Patients?

74%

7%

19% 1. Eccentric high risk fatty plaque lesions

2. Inflamed plaque

3. Heavily calcified plaque

Slide 9 of 36

Increased Traditional Risk Factors Account for

Only a Portion of CVD Risk in HIVA

RR 1.75

P<0.0001

0

2

4

6

8

10

12

HIV Non-HIV

Even

ts P

er

1000 P

Ys

• DM, HTN, and dyslipidemia, though increased, accounted for 25% of excess risk

• Newer studies suggest importance of genetics, inflammation and immune dysfunction,

as non traditional risk factors

Triant JCEM 2007, Rotger Clin Infect Dis. 2013

Dyslipidemia

Hypertension

Diabetes

HIV+ non-HIV+

0 5 10 15 20 25

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HIV Infection

CD4+ T

cells

Microbial translocation

Viral reactivation (CMV) and co-infection (HCV)

Chronic activation of T cells and monocytes

Acute MI

Persistent viral infection

Endothelial cell activation

HIV: a State of Immune Activation and

Suppression

Adapted from Hsue JID 2012

Slide 11 of 36

Immune Activation Relates to Novel

Atherosclerotic Phenotype in HIV

• In the general population, MI does not typically result

from gradual expansion of subclinical coronary plaque,

but rather from rupture of vulnerable high risk plaque in

75% of cases

• Recent studies in HIV+ patients without known CVD

demonstrate that atherosclerotic plaques are indeed:

– Inflamed

– Non-calcified, high risk morphology features (vulnerable)

– Associated with immune activation markers

Slide 12 of 36

Increased Arterial Inflammation in HIV

Subramanian JAMA 2012

HIV FRS -Matched

Controls

Aort

ic T

BR

by P

ET

p = 0.0003 p = 0.0003

1.0

1.5

2.0

2.5

3.0Control HIV

CVD

Controls

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Arterial Inflammation Linked to Immune Activation in HIV

Ao

rtic

(T

BR

)

Natural Log of sCD163 (ng/ml)

ρ=0.53; P-value<0.03

5.5 6.0 6.5 7.0 7.5 8.0 8.51.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

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Inflamed High Risk Plaque Identified by FDG

Composed of Activated Macrophages

Rudd Circulation 2002

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Increased Rates of Atherosclerosis in HIV by

Coronary CT Angiography

Control HIV P value

Presence of plaque 34% 59% 0.02

Mean plaque volume (µl) 85 173 0.02

Agatson Score 0 (0, 9.9) 0 (0,17.9) 0.29

Segments with plaque 1.2 2.2 0.03

Non-calcified segments 0.46±0.98 0.99±1.57 <0.05

Calcified segments 0.29±0.81 0.26±0.77 0.87

Any stenosis > 70% 0% 6.5% 0.06

Lo AIDS 2010; Post Annals 2014

• Young HIV-infected men and matched controls

• Baseline FRS, FH CHD, and smoking rates similar

• Similar data observed from the MACS cohort

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% o

f su

bje

cts

wit

h h

igh

ris

k m

orp

ho

log

y p

laq

ue

LOW ATTENUATION

PLAQUE (LAP)

POSITIVELY REMODELED

(PR) PLAQUE

Mean minimal attenuation

< 40 Hounsefield Units

Plaque segment /

reference segment > 1.05

RC

A

RC

A

Increased High Risk Morphology

Plaque in HIV Patients

Naghavi Circ 2003, Schoenhanger Circ 2000 &JACC 2001; Zanni AIDS 2013

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Persistent Viral Replication Microbial Translocation

T-cell activation Monocyte Activation

A New Paradigm for Atherogenesis in HIV

↑ High Risk Plaque ↑ Inflammation

RCA

Slide 18 of 36

Current Challenges in Preventing and

Treating CHD in HIV

• Understanding the optimal timing and use of ART to

maximize effects on immune function and minimize

metabolic effects

• Identifying patients with disease: current risk identification

strategies are not adequate

• Developing a safe and effective strategy for primary

prevention, especially for those not identified by current

algorithms, but with substantial subclinical disease

• Developing an intervention that addresses both traditional

and immune-related risk factors

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SMART and START- Effects on CVD

• SMART- Randomized trial of continuous vs.

intermittent ART guided by CD4 count (begun when

<250 and stopped when >350). Stringent viral

suppression reduced AIDS and CVD events.

• START- Randomized trial of immediate vs. delayed

ART in naïve HIV patients with CD4 > 500 (vs.

initiation at CD4 < vs. 350). Earlier initiation reduced

AIDS events but not CVD events.SMART NEJM 2006; START NEJM 2015

Slide 20 of 36

Statins Have the Unique Potential to Work

in HIV Because:

94%

3%

3%

0% 1. They reduce triglycerides

2. They improve glucose simultaneously with lipids

3. They lower LDL

4. They lower LDL and may have anti-inflammatory effects

Slide 21 of 36

Potential Interventions For CVD in HIV

•Traditional Risk Modification Strategies

- Antihypertensive

- Antidiabetic

-ASA

-Statins

•Immune/Inflammatory Modulators

-ART

-CCR5 Antagonists

- IL Antagonists

- Methotrexate

- Statins

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Statin Effects on CVD in non HIV Population

• In a meta-analysis of 26 studies

with 170,000 patients, statins were

shown to reduce events by 22% per

39 mg/dL lowering in LDL

CTT Lancet 2010

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2013 ACC/AHA Statin Guidelines

Stone Circulation 2013

•Unclear how these guidelines

pertain to HIV Patients

•Need for a discussion between

patients and providers

•Need for more data

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Many HIV Patients with High-Risk Plaque would not

Receive Recommendation for Statin by 2013 Guidelines:

CHD risk underestimated by traditional risk scores

Zanni AIDS 2014

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Statins Reduce Vascular Events in Non HIV

Patients with Low LDL and Increased CRP

Events/100p-y:Placebo: 1.36 Rosuva: 0.77HR 0.56

• LDL was reduced 47 mg/dL, and should have resulted in a HR of 0.73 based

on LDL lowering alone, according to CTTC meta-analysis.

• Instead JUPITER showed a HR of 0.56, greater than expected based on

LDL lowering alone

Ridker N Engl J Med 2008; CTTC Lancet 2010

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Statins Address Both Traditional and Immune

Risk Factors in HIVLDL Lowering:

Dampening of Immune Activation:• Decrease monocyte activation reflected in decreased circulating levels of

sCD14 and the macrophage-derived phospholipase Lp-PLA2

Silverberg Ann Int Med 2009, McComsey CROI 2013, Funderburg JAIDS ePUB

• Statins lower LDL by similar amounts in patients with and without HIV: (HIV-

infected: -26.2%; HIV-uninfected: -26.9%)

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Statins are Generally Safe and Well-Tolerated

in HIV

• Despite immune suppressant effects, no adverse effects on viral

replication (Moncunill AIDS 2005, Negredo AIDS 2006)

• Absolute rates of grade 3 or 4 adverse effects on liver and muscle –

low (Silverberg Ann Int Med 2009)

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Newer Statins May Not Increase Glucose and

Not Interact with PIs

Drug PI

Interaction

Effects on

Glucose

LDL Lowering and Dose

Pravastatin (40 mg/d) - - -33 mg/dL, -25%

Atorvastatin (20 to 40 mg/d) + +/- -38 mg/dL, -29%

Rosuvastatin (10 mg/d) + + -28 mg/dL -28%

Pitavastatin (4 mg/d)* - - -48 mg/dL, -28%

Sponseller CROI 2014, Aberg Endo 2013, Eckard JID 2014, Stone JACC 2013

*Among dyslipidemic patients with high starting cholesterol levels.

Pitavastatin metabolized primarily by glucoronidation. Minimally metabolized by CYP3A.

No known interactions with antiretroviral therapy no dose limitations. Included in 2013

ACC/AHA guidelines as a recommended moderate dose statin.

Slide 29 of 36

Statin Effects on Coronary Artery

Plaque in HIV

Lo CROI 2015, Lancet HIV 2015

p = .009 p < .0001 p = .005

Placebo Atorvastatin

-50

-30

-10

10

30

50

70

90

110

Pe

rce

nt

Ch

an

ge

in

N

on

ca

lcif

ied

Pla

qu

e

-80

-60

-40

-20

0

20

40

Ab

so

lute

Ch

an

ge

in

D

ire

ct

LD

L (

mg

/dL

)

Placebo Atorvastatin -100

-80

-60

-40

-20

0

20

Ch

an

ge

in

Lp

-PL

A2

(ng

/mL

)

Placebo Atorvastatin

p = .009 p < .0001 p = .005

Decreasing non-calcified plaque in proximal left anterior descending (LAD)

coronary artery in patient on atorvastatin for 12 months.

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Need for a Large RCT to Inform Clinical Practice

• HIV patients with low traditional risk scores are at increased risk

for CVD with subclinical plaque and inflammation

• It is unknown if statins will prevent CVD and should be

recommended for the HIV population

• Though largely well tolerated in small studies, there are no data

from large RCTs in HIV investigating efficacy and tolerability

• How will statins uniquely work in HIV?

– LDL lowering

– Effects on inflammatory pathways

30

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100+ Sites Across US, Thailand and Canada

Opened April 2015

www.reprievetrial.org

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REPRIEVE Schema

Intervention

Screeningand

Consent

Pitavastatin Placebo

RandomizationR

Mechanistic Study

Mechanistic

Primary Endpoint Coronary plaque, vascular

Inflammation, immune activation

Asymptomatic HIV patients with no history of CVD and ASCVD < 10%

Primary

Endpoint

Clinical

CVD Death MI Unstable Angina TIA & Stroke Arterial Revasc PAD

N=800, 2 yrs

N=6500, avg. 4-5 yrs

3 visits/year

Lifestyle Advice

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Endpoints• Time to first Major Adverse Cardiovascular Event (MI,

Stroke, Angina, Revascularization, PAD, CVD death)

• Secondary Endpoints

– AIDS events

– Non AIDS events (liver, kidney, DM)

– Relationship of immune function and LDL to MACE

response

– Safety

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Objectives:

• To determine:

– Effects on high risk

coronary plaque

– Effects on immune

function in relationship

to plaque

Mechanistic Substudy

• Green + Red: Non-

calcified Plaque Volume:

115 mm3

• Red: Low Attenuation

Plaque Volume: 28 mm3

Slide 35 of 36

Novelty

• First major CVD prevention trial in HIV

• Largest study to date focused on HIV-related CVD;

will inform standard of care

• Represents a new paradigm of long-term prevention

trial for chronic co-morbidities

• Partnership between NHLBI, NIAID and Office of

AIDS Research to fund an important HIV study

Slide 36 of 36

Conclusions and Future Directions

• Traditional and non traditional risk factors contribute to

increased CVD risk in HIV, which manifests as inflamed,

noncalcified high risk plaque in association with immune

activation

• Modulation of traditional and nontraditional risks is

necessary to prevent CVD in HIV

• Statins may be an effective strategy to prevent CVD in HIV

and should be tested in large trials to determine optimal

practice patterns