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5/2/2016
1
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
Slide 3 of 47
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)
Slide 4 of 47
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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Slide 5 of 47
Slide 6 of 47
HIV infection is associated with excess cardiovascular disease risk
8%
92% 1. True
2. False
Slide 7 of 47
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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Slide 8 of 47
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
Slide 9 of 47
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
Slide 11 of 47
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.
Slide 13 of 47
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.
Slide 16 of 47
• 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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Slide 17 of 47
Uncontrolled HIV Replication is Bad
Baker JV and Duprez D. Curr Opin HIV AIDS. 2010; 5: 511-516.
Slide 18 of 47
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.
Slide 22 of 47
AtherosclerosisThe Role of Circulating Monocytes
Moore KJ, Sheedy, Fisher. Nat Rev Immun. 2013. 12: 709-21.
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Slide 23 of 47
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.
Slide 24 of 47
• Oxidized LDL is
elevated in HIV
infection
Zidar et al. JAIDS 2015.
HIV, Oxidized LDL and Monocytes
• OxLDL correlates
with • sCD14
• Inflammatory
monocytes
Slide 26 of 47
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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Slide 27 of 47
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
Slide 28 of 47
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
Slide 29 of 47
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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Slide 31 of 47
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
Slide 32 of 47
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
Slide 33 of 47
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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Slide 34 of 47
Relationship between cumulative LDL-C exposure and age
Horton et al. J. Lipid Res. 2009;50:S172-S177
Slide 35 of 47
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
Slide 36 of 47
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
5/2/2016
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Slide 37 of 47
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
Slide 38 of 47
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.
Slide 39 of 47
(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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Slide 40 of 47
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.
Slide 41 of 47
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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Slide 43 of 47
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
Slide 46 of 47
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
Slide 47 of 47
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.
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