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E. Turner Overton, MDAssociate Professor of Medicine

University of Alabama at BirminghamBirmingham, Alabama

Statins, Rainwater, and Pure Grain Alcohol:

Cardiovascular Disease Management in 2016

FINAL: 04/06/16

Washington, DC: April 15, 2016

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Financial Relationships With Commercial Entities

Dr Overton has received research funding

through the University of Alabama Birmingham

School of Medicine from AbbVie, Bristol-Meyers

Squibb, Gilead Sciences, Inc, Merck & Co, Inc,

and ViiV Healthcare. (Updated 04/15/16)

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Learning Objectives

After attending this presentation, participants will

be able to:

Describe HIV pathogenesis in the setting of viral suppression

Demonstrate how end organ disease is unique in the setting of HIV disease.

– Cardiovascular Disease as an example.

Recognize the potential for statins to prevent non-AIDS events and the need for additional data.

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HIV infection is associated with excess cardiovascular disease risk

8%

92% 1. True

2. False

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Starting ART reduces the risk of CV disease to the level reported in HIV negative persons.

37%

47%

16% 1. True

2. False

3. It depends…

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The primary goal of statin therapy is:

0%

71%

1%

28% 1. To lower LDL cholesterol

2. To lower HDL cholesterol

3. To prevent cardiovascular disease events

4. To improve exercise performance

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Atherosclerosis: An Inflammatory Process

• An atherosclerotic lesion develops as focal thickening of the inner layers of the artery– Vascular endothelial cells– Smooth muscle cells– Immune cells

• T lymphocytes, macrophages, & neutrophils

• Plaque formation is triggered by– Arterial wall injury– Lipoprotein deposition– Endothelial activation– Pro-inflammatory molecules

Libby et al JACC; 2016, 9: 1091-1103

Early Atherogenesis Advancing Atheroma

• Recruitment of inflammatory monocytes • Macrophage replication• Foam cell formation

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Improving Survival

Lohse N et al. Ann Intern Med. 2007

Population controls

HIV: 2000-2005Current ART

HIV: 1997-1999Early ART

HIV: 1995-1996Pre-ART

But Still Below General Population

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Slide 12 of 47Schouten et al. CID 2014.

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CVD Mortality Higher in HIV-positive, even with Suppressed HIV Virus.

Hanna et al. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 729.Freiberg et al. JAMA Intern Med. 2013 Apr 22;173(8):614-22.

• 145,009 HIV+ subjects reported 2001-2012• 71% male, median age 49 yrs

– CVD mortality 54% ↑increase (713%)

• Decreasing in gen population

• aHR 1.54 (95% CI: 1.47-1.62)

– Adjusted for age, sex, race/ethnicity, location, and year

– Rate if VL > 400cp/mL: 7.7/1000pt yr

– Rate if VL suppressed: 3.9/1000pt yr

– General population: 3.2/1000pt yr

Impact of HIV on risk comparable

to traditional risk factors including

HTN, DM and hyperlipidemia.

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• Many pathogenic stimuli induce a similarinflammatory response.

• Interleukins• Tumor Necrosis Factor• TGF-beta

• With removal of the stimulus, healing ensues.

• Inflammation decreases• Healing occurs

• When the stimulus persists• Pathogenic responses occur

• Fibrosis• Tissue destruction • Altered function• Progressive Disease

The Inflammation Hypothesis

Forrester and Libby. American Journal of Cardiology; 2007, 5: 732–738END ORGAN DISEASE

Persistent HIV Infection

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Uncontrolled HIV Replication is Bad

Baker JV and Duprez D. Curr Opin HIV AIDS. 2010; 5: 511-516.

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Residual CV Disease Risk With Suppressed Viremia• Vascular inflammation is greater with HIV infection

– Increased metabolically active macrophages

– Greater non-calcified, metabolically active, rupture-prone plaque

Yarasheski et al. J Inflammation. 2012. Zanni et al. AIDS. 2013.

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AtherosclerosisThe Role of Circulating Monocytes

Moore KJ, Sheedy, Fisher. Nat Rev Immun. 2013. 12: 709-21.

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Proportions of monocyte subsets are altered in HIV-1

Funderburg N T et al. Blood 2012;120:4599-4608

-Monocyte populations are altered with HIV infection

-Decreased classic monocytes (CD14++CD16-)

-Increased CD16+ monocytes (elevated inflammation)

-While HAART and virologic control shift monocyte populations towards normal, they remain altered compared with healthy non-HIV infected individuals.

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• Oxidized LDL is

elevated in HIV

infection

Zidar et al. JAIDS 2015.

HIV, Oxidized LDL and Monocytes

• OxLDL correlates

with • sCD14

• Inflammatory

monocytes

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How is HIV Unique?

Boccara F, et al. J Am Coll Cardiol. 2013;61:511-523

Unique Features of HIV:• Depletion of key regulatory T cell

populations• Changes in gut mucosal integrity• Excess bacterial translocation• Promotion of systemic

inflammation

• Lymphocyte activation• Monocyte activation• Elevated circulating inflammatory

biomarkers• Neutrophil activation• Hypercoagulable state• Pro-atherogenic lipid profile

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How to Beat Inflammation• Treat early!• Continue ART.

– Maintain undetectable viremia

• Stop smoking• Maintain normal weight• If overweight, lose at least 5-10% of body weight• Exercise• Have a healthy diet• Cut down on alcohol, avoid drugs

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Are we START-ing ART early enough?

The INSIGHT START Study Group. N Engl J Med 2015;373:795-807.

Endpoint Immediate Initiation

DeferredInitiation

Total events 42 96

AIDS-related events

14 50

Non-AIDS event 28 46

CVD 12 14

Malignancy 9 18

Liver or renal 1 2

Death (other) 6 12

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CD4+ T cells in the Colonic Mucosa in Early HIV Infection

Schuetz A et al. PLoS Pathogen; 2014.

Acute/Early HIV Cohort

a) CD4 cells in the sigmoid colon mucosa decrease with longer time till diagnosis

b) CD4 cells correlated with colonic HIV RNA

c) CD4 cells correlated with plasma HIV RNA

d) Increased HIV-infected cells with later HIV stage

e) Decreased CD4 T cells (brown) and increased macrophages (red) with later stages of HIV infection.

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Potential Interventions Beyond Suppressive ART

• Smoking cessation• Key lifestyle factors

– Diet– Exercise

• ART Switch• Lipid lowering therapy, aka statins• Address other traditional factors

– HTN– DM/Insulin resistance

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Approach to Lipid Lowering (Statin) Therapy

• Lipid screening for primary prevention at 5 year intervals

• Lifestyle therapy is the recommended first step

• CVD risk reduction is the goal of lipid lowering therapy

• Moderate- or high-intensity statins therapy is recommended

• Patient-provider discussion is central to decisions on drug treatment

• Repeat lipid assessment is suggested to monitor adherence

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HIV Specific Lipid Issues

Lipid alterations after ART treatment

• ↑triglycerides

• ↑total cholesterol

• ↑ VLDL cholesterol

• ↑ LDL cholesterol – Often < 160mg/dL

– Small, dense LDL particles

• ↑ HDL cholesterol – But still below normal levels

Challenges for various statin therapies

• Drug-drug interactions*

• Insulin resistance

• Side effects

• Pill burden

Adapted from Dubé MP. Lipid Management, DOI 10.1007/978-3-319-11161-2_14

Oxidized lipid particles remain elevated!!!!

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Relationship between cumulative LDL-C exposure and age

Horton et al. J. Lipid Res. 2009;50:S172-S177

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KEY RECOMMENDATIONS• Clinicians should be aware that HIV-infected patients are at increased risk for ASCVD.

• Risk is independent of major established risk factors.• A fasting lipid panel should be obtained in all newly identified HIV-infected patients.• For primary prevention, HIV infection may be counted as an additional risk factor for risk

stratification.• Statin therapy is first-line therapy for elevated LDL-C and non-HDL-C.

• Drug-drug interactions must be considered.• Atorvastatin, rosuvastatin, and pitavastatin are preferred agents.

High risk condition and residual risk:HIV-infected persons

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Suggested Statins in the Setting of ARTRitonavir or Cobicistat Containing Regimens

High Intensity Statin Moderate Intensity Statin Low Intensity Statin

Atorvastatin 20mg Atorvastatin 10mg Pravastatin 10-20mg

Rosuvastatin 10-20mg Rosuvastatin 5mg Fluvastatin 10-20mg

Pravastatin 40-80mg* Pitavastatin 1mg

Pitavastatin 1mg

Simvastatin and lovastatin are contraindicated for patients receiving a PI or cobicistat.*With darunavir, reduce pravastatin to 20-40mg.

NNRTI, Raltegravir, or Dolutegravir Containing Regimens

High Intensity Statin Moderate Intensity Statin Low Intensity Statin

Atorvastatin 40-80mg Atorvastatin 10-20mg Pravastatin 10-20mg

Rosuvastatin 20mg Rosuvastatin 10mg Fluvastatin 20-40mg

Pravastatin 40-80mg Pitavastatin 1mg

Pitavastatin 2-4mg Lovastatin 20mg

Lovastatin 40mg Simvastatin 10mg

Simvastatin 20-40mg

Adapted from Dubé MP. Lipid Management, DOI 10.1007/978-3-319-11161-2_14

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Endpoints

Co-Primary CVD: FMD

Bone: % change in hip & lumbar spine BMD

Secondary IMT and CAC

Systemic & vascular inflammation

Lymphocyte & monocyte activation

Insulin resistance

Body composition

SATURN-HIV Design

Week 0 Week 48 Week 96

RosuvastatinN=72

PlaceboN=75

Inclusion

•HIV-1 & ≥18 years

•On ART >6mo & HIV-1 RNA ≤1000 cps/ml

• Fasting LDL-C≤130mg/dl

•Heightened immune activation (CD8+CD38+DR+ ≥19% or hsCRP ≥2μg/ml)

•No CVD or diabetes

•No fragility fractures

•No immunomodulatory, bone tx, or hypolipemics

Stratified by:•PI vs not•Osteopenia vs not•CAC vs not

Longenecker et al. HIV Med 2013

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sC

D14 R

ela

tiv

e C

han

ge

fro

m W

eek 0

(%

)

480

p=0.0056

24

p=0.002

480 24

p=0.0049

p=0.0366

CD

14

dim

CD

16+

TF

+

Rela

tiv

e C

han

ge fro

m W

eek 0

(%

)

Markers of Monocyte Activation

Funderburg NT et al. CID. 2014; 58: 588-95.

Visit Week from Randomization

480 24

p=0.0009

p=0.9293

CD

4+

CD

38+

DR

+

Rela

tiv

e C

han

ge fro

m W

eek 0

(%

)

Visit Week from Randomization480 24

p=0.0035

p=0.5091

CD

8+

CD

38+

DR

+R

ela

tiv

e C

han

ge fro

m W

eek 0

(%

) Markers of T Cell Activation

-Rosuvastatin durably reduced sCD14.

-Rosuvastatin significantly reduced inflammatory monocyte population.

-Rosuvastatin durably reduced T cell activation.

Longer exposure required to detect the effect on T cells.

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(C)

% c

han

ge f

rom

baselin

e

-60

-50

-40

-30

-20

-10

0

10

20

30

40

80

* *

CD4 T-cells CD8 T-cells

Prav Ator Prav Ator

HLADR+

CD38+

CD38+HLADR+

-60-50-40-30-20-1001020304050607080

(D)

* *

CD4 T-cells CD8 T-cells

Prav Ator Prav Ator

TIM3+

PD1+

TIM3+PD1+

Not All Statins are EqualAtorvastatin decreases markers of T-cell activation and senescence

-Atorvastatin but not Pravastatin reduced T cell activation.

Decreased CD38, HLA-DR, and dual positive cells.

-Atorvastatin significantly reduced T cell senescent markers.

Decreased TIM3 and PD1 expression.Overton et al. AIDS 2014.

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Lo J et al. Lancet HIV. 2015;2:e52-e63. Longenecker CT et al. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 137.

Statins Reverse Atherosclerosis!• Atorvastatin: Reduction in Coronary Artery Plaque Volume by

coronary CT angiography (CCTA). – Coronary plaque in

• 53% of the HIV group (also ↑rupture-prone noncalcified plaque)• 35% of the HIV-negative group

– Regression with Atorvastatin beyond expected with LDL lowering alone

• Rosuvastatin: Stabilization of CIMT– Daily rosuvastatin stopped progression of CIMT– Also decreased monocyte and lymphocyte activation, decreased NT-

proBNP and Lp-PLA2– Factors predicted a bigger drop in cIMT:

• higher baseline cIMT, IL-6 (an inflammation marker), and percentage of patrolling monocytes (CD14dimCD16 cells).

Baseline

Month 12

Images courtesy of Dr. Janet Lo.

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Statins: Ideal Strategy to Reduce Non-AIDS and Vascular Events in HIV

• Traditional effects to lower LDL, effective to lower LDL (-26%), with few AEs (myositis 1.9%) in HIV Silverberg Annals 2009

• Pleiotropic effects to reduce monocyte activation, chemo-attraction and vascular inflammation Funderburg CID 2013, Eckard JID 2014

• Reduce events even among nonHIV patients with low LDL but increased inflammation Jupiter NEJM 2008

• Use is low among HIV patients (19.6% in ACTG), clinicians awaiting results from RCTs ACTG survey

Slide 42 of 47Yusuf S et al. NEJM 2016.

• Multicenter, double blind, placebo controlled trial with 2X2 factorial design• Rosuvastatin versus placebo• Candesartan/HCTZ versus placebo

• 12,705 participants with intermediate CVD risk• Composite endpoint of

• Death from CVD causes• Nonfatal MI• Nonfatal stroke• Heart Failure• Revascularization

The Heart Outcomes Prevention Evaluation (HOPE)-3 Trial

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Lipid lowering effect and Primary endpoint

• Significant decrease in LDL cholesterol• ↓ 33.7 mg/dL

• Significant reduction in primary outcome• 6.5% placebo recipients• 4.3% combined therapy group

• Trend towards decreased events in rosuvastatin versus candesartan/HCTZ arm

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Intervention

Clinical

Primary Endpoint

TimeScreening

And

Consent

Asymptomatic HIV+ patients with no history of CVD

Pitavastatin 4mg/dayPlacebo

MICV Death Unstable Angina Arterial Revasc

Secondary

Endpoints

Individual components of primary endpoint

All Cause Death

RandomizationR

Incidence/Progression of noncalcified plaque; High-risk plaque

Mechanistic

Study

Inflammatory, immunological, metabolic biomarkers

Mechanistic

Primary Endpoint

Coronary plaque, vascular inflammation, immune activation

Stroke

Predictors of statin effects

Statin safety and non AIDS comorbidities: DM, Infections, Cancer

All cause death

Figure 4. Schematic overview of REPRIEVE trial design.

Intervention

Clinical

Primary Endpoint

TimeScreening

And

Consent

Asymptomatic HIV+ patients with no history of CVD

Pitavastatin 4mg/dayPlacebo

MICV Death Unstable Angina Arterial Revasc

Secondary

Endpoints

Individual components of primary endpoint

All Cause Death

RandomizationR

Incidence/Progression of noncalcified plaque; High-risk plaque

Mechanistic

Study

Inflammatory, immunological, metabolic biomarkers

Mechanistic

Primary Endpoint

Coronary plaque, vascular inflammation, immune activation

Stroke

Predictors of statin effects

Statin safety and non AIDS comorbidities: DM, Infections, Cancer

All cause death

Figure 4. Schematic overview of REPRIEVE trial design.

6 year

F/u

(n=6500)

(n=800)

Funded by NHLBI and NIAID. Supported by KOWA Pharmaceuticals and Gilead.

Statins have emerged as potential modulators of the process of inflammation, particularly in diseases that are immune-related or diseases where aberrant activation of T cells plays an important role.

Primary Clinical Hypothesis (A5332)• Statin therapy will prevent

atherosclerotic cardiovascular disease (ASCVD) events in HIV-infected persons on antiretroviral therapy (ART) in whom traditional CVD risk is not significantly increased.

ACTG A5332

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Conclusions• HIV and its therapy contribute to cardiac risk along with the traditional host factors

• Controlling viral replication partially reduces CVD risk.

• Early ART may significantly mitigate HIV-associated CVD risk.

• No reliable inflammatory markers to predict risk.

• Currently available risk scores fail to accurately estimate CVD risk in the setting of HIV infection.

• Smoking cessation, dietary and exercise interventions are effective.

• Statins may be of benefit in addition to lipid lowering effects.

• HOWEVER, more data are needed to inform use in traditional low risk populations.