5 y 0 learning objectives 0 slide 7 of 37 overall mortality … risk prediction and hiv slide 20 of...

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Slide 3 of 37

Learning Objectives

After attending this presentation, participants will

be able to:

Recognize important cardiovascular risk factors in HIV infection.

Access cardiovascular risk score programs for clinical use.

Describe the appropriate use of statin therapy in the setting of HIV disease.

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Slide 7 of 37

Overall Mortality and Causes of Death

Smit C, et al. AIDS. 2006;20:741-749.

Overall Mortality*

0

20

40

60

80

Pro

po

rtio

n (

%)

Years Since Seroconversion*

0 5 10 15

Pre-HAART

HAART

Causes of Death†

De

ath

s (

%)

Pre-HAART (n=1424)

HAART (n=514)

*N=7680 seroconverters from 22 cohorts, of whom 1938 died (26%; 1424 pre-HAART and 514 during

HAART).

†No change in the following causes of death: AIDS-related malignancy, other infections, organ

failure, and unknown causes.

0

5

10

15

20

25

30

35

OIs NotSpecified

Hepatitis/Liver

Malig-nancy

CVD/DM

AIDS-Related Non-AIDS-Related

31.7%

19.3%

10.0%

2.5%3.2%

9.9%

2.5%

4.9%

1.3%

4.3%

6.5% 6.4%

Malig-nancy

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Washington, DC: May 13, 2015 1

of 37

AgingChronic HIV

Infection

Impact on Non-AIDS Comorbidities

Decreased Physical Functioning

Insulin Resistance

DyslipidemiaInflammation &Fibrosis

END-ORGAN DISEASE

ART ToxicityGenetics

Obesity, Exercise, Diet, Smoking

HCV and other Co-infections

Warriner AH et al.ID Clin N Am. 2014

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Slide 10 of 37

Incident rate ratio for acute MI by age

30-39 40-49 50-59 60-69 70-79

2.2 1.3 1.8 1.5 1.5

Impact of HIV on risk comparable to traditional risk factors including HTN, DM and hyperlipidemia.

Models adjusted for recognized risk factors

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of 37Houston, we have a CVD problem.• CVD Mortality (729)

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

– CVD mortality 54% ↑increase (HR 1.54) (713%)• Decreasing in gen population

– Rate if VL suppressed: 3.9/1000pt yr

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

• Smoking in the MACS Cohort (743)– 1005 MSM (621 HIV+); Median age 53-55; 82% VL < 50 – Smoking associated with numerous parameters by CAC and coronary CT angiography

• Kidney disease in D:A:D (742) – 34,793 subjects; median 6.3 yrs F/U– 1033 persons 1251 CVD events

Hannah DB et al. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 729. Kelly SG et al. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 743. Ryom L et al. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 742.

eGFR % of Cohort

% of CVD Events

>90 70% 47%

>30 - <90 29.8% 52%

<30 0.2% 1%

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Slide 12 of 37

Two Approaches to Assessing CVD Risk

ACC/AHA Guidelines NLA Recommendations

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Slide 13 of 37Many Similarities • 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 statin 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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of 37

Differences

• ACC/AHA

– Used data from RCT with CVD outcomes and meta-analyses of RCT.

• Only highest level of evidence on statin was used.

• NLA (NCEP Guidelines)

– Included RCT, meta-analyses of RCT, selected post-hoc analyses from RCT, genetic, metabolic, and mechanistic studies.

• Broader approach consistent with previous NCEP recommendations and international guidelines.

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Slide 15 of 37ACC/AHA Statin Benefit Groups• Known ASCVD (Atherosclerotic Cardiovascular Disease)

• Primary elevation in LDL cholesterol > 190 mg/dL

• Age 40-75 with either– Diabetes and LDL cholesterol > 70mg/dL

– 10-year ASCVD Risk Score > 7.5%

• Perspective on statins– Do not recommend dose titration to achieve a pre-specified lipid

level

– Do not recommend non-statin therapies

• Limited ASCVD risk reduction

• Potential for adverse events > benefits

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Slide 16 of 37

ACC/AHA ASCVD Risk Calculator

Please use “Launch Web Version” to calculate ASCVD Risk Score

The calculator to calculate the 10-year ASCVD is located at the following website:http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/PreventionGuidelines_UCM_457698_SubHomePage.jsp

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of 37NLA Recommendations

• Start with risk assessment and patient-provider discussion

• Lifestyle modification is first step

• Judicious use of moderate- to high-dose statins is associated with optimal CVD risk reduction

– Statin therapy is the most potent and evidence-based approach to reducing ASCVD events

– “Lower is better” for atherogenic lipoproteins

• Consider addition of non-statin therapy when statin therapy inadequate

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Slide 18 of 37

NLA Stepwise Approach

• Identify ASCVD risk category

• If very high risk begin with moderate- or high-intensity statin.–Goal LDL <70mg/dL or non-HDL <100mg/dL

• If not high risk, consider statin therapy based on risk factors–Goal LDL <100mg/dL or non-HDL <130mg/dL

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Slide 19 of 37

NLA Criteria for Statin Therapy

Jacobson TA e al. J Clin Lipidol. 2014;8(5):473-88.

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of 37CVD Risk Prediction and HIV• NA-ACCORD

– 25,094 ppts, 271 primary MIs, 219 secondary MIs– CVD RF: age, male, HTN, DM, low HDL, CKD, statin use– HIV RF: lower CD4, detectable viremia, H/O AIDS

• From the HOPS – 2392 participants, 204 CV events – 4 risk equations tested that included age, sex, SBP, smoking, T Chol, with some

including other factors such as type of ART– All 4 underestimate CVD Risk: E/O ratio: 0.75-0.85

• Framingham and ACC/AHA CVD Risk Equations – 2270 subjects: 38% female; 35% HTN; 20% DM; 38% smokers– Median CD4 508; VL<50: 68%– Both equations underestimate risk; particularly bad if risk > 5% for 5-yr prediction

Drozd DR et al. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 748.Lichtenstein K et al. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 747.Triant V et al. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 751.

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Slide 21 of 37Residual CVD Risk Even With Suppressed HIV Viremia

• Atherosclerosis is an inflammatory process

– Endothelial smooth muscle disruption

– Macrophage activation and infiltration

– Oxidized lipid accumulation

– Plaque formation

• Vascular inflammation is greater with HIV infection

– Increased metabolically active macrophages

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

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

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Slide 22 of 37

Despite ARTInflammatory Biomarkers Remain Elevated

Neuhaus JID 2010; Nixon and Landay, Curr Opin HIV/AIDS 2010

-While ART partially reduces some biomarker levels, they may still remain elevated compared with healthy non–HIV-infected individuals.

-Furthermore, inflammatory markers are more strongly associated with end-organ disease and mortality than in HIV-negative populations.

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of 37

STATINS as “Wonder Drugs”?

Blocking HMG-CoA

Reductase ↓ Mevalonate

Decreased precursor for

Cholesterol

&

Geranyl/farensyl

pyrophosphate

THUS

SUBSEQUENTLY

Signaling proteins

-do not undergo requisite

post-translational

modification

-cannot embed in lipid

rafts in membranes

(prerequisite for their biologic

function)

AND VOILA

Greenwood. Nature Rev Immun. 2006; 6:358-70.

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Slide 24 of 37

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.

Greenwood and Mason. Trends in Immunology. 2007; 28:87-98. Mach F. Circulation. 2004; 109:II-15-17.

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Slide 25 of 37

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

McComsey GA et al. CROI 2014

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of 37

sC

D1

4 R

ela

tive

Ch

an

ge

fro

m W

ee

k 0

(%

)

480

p=0.0056

24

p=0.002

480 24

p=0.0049p=0.0366

CD

14

dim

CD

16

+ T

F+

Re

lati

ve

Ch

an

ge

fro

m W

ee

k 0

(%

)

Visit Week from Randomization Visit Week from Randomization

-Rosuvastatin durably reduced sCD14.

-Rosuvastatin significantly reduced inflammatory monocyte population.

Rosuvastatin and Monocytes


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Slide 27 of 37

Visit Week from Randomization

480 24

p=0.0009

p=0.9293

CD

4+

CD

38

+D

R+

Re

lati

ve

Ch

an

ge

fro

m W

ee

k 0

(%

)

Visit Week from Randomization

480 24

p=0.0035

p=0.5091

CD

8+

CD

38

+D

R+

Re

lati

ve

Ch

an

ge

fro

m W

ee

k 0

(%

)

-Rosuvastatin durably reduced T cell activation.

Longer exposure required to detect the effect on circulating T cells.

Rosuvastatin and T cell Activation


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Slide 28 of 37

0

25

50

75

100

125

150

175

+

-

+

+

+

+

+

+

+

-

+

-

****

CD4 T-cells

% o

f S

EB

pro

life

rati

on

Statin

MA

0

25

50

75

100

125

150

175

+

-

+

+

+

+

+

+

+

-

+

-

**

**

CD8 T-cells

Pravastatin

Atorvastatin

Rosuvastatin

Not All Statins are Equal

Overton et al. AIDS 2014.

-Rosuvastatin and Atorvastatin, but not Pravastatin reduce T cell proliferation.

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of 37

Lo J et al. Lancet HIV. 2015;2:e52-e63. Lo J et al. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 136.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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Slide 30 of 37

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

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

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

• Reduce events even among non-HIV 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

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Slide 31 of 37Need 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 to date in small studies, there are no data from large RCTs in HIV investigating tolerability, AEs and efficacy

• How will statins uniquely work in HIV

– LDL lowering

– Effects on inflammatory pathways

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of 37Randomized Trial to Prevent Vascular Events

in HIV REPRIEVE (A5332)

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.

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Slide 33 of 37

Summary• Despite ART, low-grade inflammation persists.

–Soluble inflammatory biomarkers

–T cell activation and senescence

– Inflammatory monocytes

• Interventions to reduce inflammation are needed to reduce morbidity and mortality.

• Statins have robust anti-inflammatory properties that may serve this role effectively.

–Need to assess in an RCT.

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Slide 37 of 37

Acknowledgements

• UAB CFAR– Anju Bansal– Greer Burkholder– Paul Goepfert– Sarah Sterrett– Alan Zajac– Andy Westfall– Shannon Kahan– Mike Saag

• Shared ideas/data– Grace McComsey– Nick Funderburg– Janet Lo

• REPRIEVE Study Team– Steve Grinspoon– Pam Douglas– Udo Hoffmann– Heather Ribaudo– Carl Fichtenbaum– Judy Aberg– Markella Zanni– Katie Fitch– Barbara Bastow

• Mentors– Kevin Yarasheski– Pablo Tebas

Funding: NIH funded CNICS (R24 AI067039); UAB CFAR (P30 AI027767); REPRIEVE (R01 HL123336-01).

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5 y 0 learning objectives 0 slide 7 of 37 overall mortality … risk prediction and hiv slide 20 of...

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