Marshall J. Glesby, MD, PhDProfessor of Medicine, Healthcare

Policy and ResearchWeill Cornell College of Medicine

New York, New York

Cardiovascular Complications of HIV and Its Treatment

FORMATTED: 11/06/15

New Orleans, Louisiana: December 15-17, 2015

Slide 2 of 42

FM Islam, J Wu, J Jansson and DP Wilson. HIV Med. 2012;13:453-68.

Relative Risk of CVD Among People Living with HIV: A systematic review and meta-

analysis

HIV+ vs. HIV-

HIV+ exposed to ART vs. HIV-

(a)Study Relative risk (95% CI) Weight

Obel (2007) 1.39 (0.81, 2.39) 4.72

Triant (2007) 1.75 (1.51, 2.03) 46.62

Lang (2010) 1.50 (1.30, 1.73) 48.67

Overall (I-squared = 18.4%, p = 0.294) 1.61 (1.43, 1.81) 100.00

Obel (2007) 2.12 (1.62, 2.77) 32.95

Benito (2002) 2.40 (1.69, 3.41) 20.54

Klein (2007) 1.78 (1.43, 2.22) 46.51

Overall (I-squared = 13.2%, p = 0.316) 2.00 (1.70, 2.37) 100.00

(b)Study Relative risk (95% CI) Weight

0.1 1 10

0.1 1 10

Slide 3 of 42

Causes of Death

Malignancy

CV event

Hepatic

Pancreatitis

ESRD

Non-AIDS Events Are More Common Than AIDS Events

1 Data Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study Group. AIDS. 2010;24:1537-48;2 Mocroft A, et al. J Acquir Immune Defic Syndr. 2010;55:262-70.

Clinical Events in EuroSIDA2

ADINon-ADI

n = 12,844

1,025 ADIs*

1,058 non-AIDS events

D:A:D1

Renal 1%

Lactic acidosis/pancreatitis 1%

Bacterial infection 7%

Non-natural 9%

Other/unknown 13%

AIDS-related32%

Liver-related

14%

Non-AIDS cancers12%

CVD-related 11%

*ADIs: AIDS-defining illnesses; ** ESRD: end-stage renal disease.

**

Slide 4 of 42

Tenofovir x 12 weeks

n=8

PlaceboX 12 weeks

n=9

Washout periodX 4 weeks

PlaceboX 12 weeks

TenofovirX 12 weeks

Randomization

Does TDF lower lipids? ACTG A5206: Design• HIV RNA

<400 on stable cART

• TG 150-1000 or non-HDL-C 100-250 mg/dL

Tungsiripat M et al, AIDS 2010;24:1781-4.

Slide 5 of 42

-40-35-30-25-20-15-10

-505

Totalchol

Non-HDL-C

LDL-C HDL-C TG

Tenofovir Placebo

% c

hang

e

P 0.01 0.02 0.04 0.93 0.81

Data from: Tungsiripat M et al, AIDS 2010;24:1781-4.

N = 17

Slide 6 of 42

Stable and Unstable Plaque

Adapted from Heart Center Online http://www.heartcenteronline.com

Multidetector CT can detect features of unstable/ vulnerable plaque

Slide 7 of 42

HIV+ Pts More Likely to Have Plaque with High Risk Features

Multidetector Spiral Coronary CT Angiography

Low at

tenua

tion p

laque

Pos re

modele

d plaq

ue

Spotty

calci

ficati

on

At leas

t one

3-fea

ture p

laque

0102030405060

HIV- (n=101)HIV+ (n=41)

P = 0.02

P = 0.05

P = 0.69

P = 0.02

Matched on major CVD risk factors.Median age 45, 48

sCD163 associated among HIV+ Zanni MV et al, AIDS 2013;27:1263-72

Slide 8 of 42

ATP III vs 2013 ACC/AHA Guidelines in 150 HIV-infected Patients with Cardiac CT Data

05

101520253035

2004 ATP III 2013 ACC/AHA

P = 0.005 P = 0.04

% fo

r who

m s

tatin

s re

com

men

ded

P = 0.01 P = 0.01

Zanni MV, AIDS 2014;28:2061-70

Effects of Untreated HIV: SMART Study

HIV-infected patients with

CD4+ cell count > 350 cells/mm3

(N = 5472—84% on cART)

Viral Suppression ArmHAART continuously administered

(n = 2752)

Drug Conservation (Treatment Interruption) ArmTreatment stopped when CD4+ cell count

> 350 cells/mm3; restarted when CD4+ cell count < 250 cells/mm3

(n = 2720)

El-Sadr WM, et al. N Engl J Med. 2006;355:2283-2296.

Slide 30 of 42

SMART Study and CV Events

El-Sadr WM, et al. N Engl J Med. 2006;355:2283-2296. Phillips A, et al. Antiviral Ther 2008;13:177-187

Events DC VS RH(DC/VS) 95% CI p-value

Clinical MI, silent MI, CAD requiring invasive procedure or surgery, CVD death

48 31 1.57 1.00–2.46 0.05

+ Peripheral vascular disease, CHF, CAD requiring medication 76 52 1.49 1.04–2.11 0.03

+ Unobserved death from unknown cause 84 54 1.58 1.12–2.22 0.009

Conclusion• Discontinuation strategy associated with higher risk

of CV disease

Slide 31 of 42

DC Patients on cART at Baseline with HIV RNA < 400 (n = 132)

-0.4-0.3-0.2-0.1

00.10.20.30.4

IL-6 HDLp

ΔIL

-6 (p

g/m

l)

ΔH

DLp

(μm

ol/L

)

≤ 400 401 10,000 > 50,000 -10,000 -50,000

Month 1 HIV-RNA (copies/ml)

P = 0.0003 for trend

P < 0.0001 for trend

Duprez DA et al, Atherosclerosis 2009;207:524-9

Slide 32 of 42

Slide 12 of 42Cascade of Events Due to Chronic Immune Activation and Inflammation

Chronic Inflammation

Atherosclerosis, Osteoporosis, Neurocognitive

Degeneration, Frailty, Metabolic Syndrome, etc

Low-level Viral Replication

Secretion of Pro-inflammatory Cytokines

Immune Activation/Senescence

Microbial translocation

Loss of gut CD4s

Viral Co-Infections(CMV, KSHV, HCV, HBV)

Adapted from: Martin DE, Abstract 8023, XVIII International AIDS Conference, Vienna, Austria 20 July 2010

Slide 13 of 42

Copyright © 2012 American Medical Association. All rights reserved.

From: Arterial Inflammation in Patients With HIVSubramanian S et al, JAMA. 2012;308(4):379-386. doi:10.1001/jama.2012.6698

There is increased aortic PET-FDG uptake (red coloration) in a participant infected with HIV compared with a non-HIV FRS-matched control participant. Neither participant had known heart disease. For each participant, the FRS was low with a score of 2 and calcium was not present on the cardiac CT scan. Neither participant was receiving a statin.

FDP accumulates in metabolically active macrophages infiltrating affected vessels

Slide 14 of 42

Target : Background Ratio(n = 27/group)

0

0.5

1

1.5

2

2.5

HIV-infected FRS-Matched Known Atherosclerosis

Mean age: 51.6 54.3 68.9

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

sCD163 correlated with TBR among HIV+r= 0.44; p = 0.03

Slide 15 of 42

Statins May Have Favorable Effects on Coronary Artery Plaque in HIV-Infected Patients

Lo J, Lancet HIV 2015;2:e52-63

• 40 pts with subclinical coronary atherosclerosis and aortic inflammation by PET imaging with LDL-C < 130 mg/dL randomized to atorvastatin 20 mg 40 mg or placebo x 12 m

• No significant effect of atorvastatin on arterial inflammation (unusable data on 19)

• Atorvastatin reduced non-calcified plaque volume and high-risk plaque features

Slide 16 of 42

Intervention

Clinical Primary Endpoint

TimeScreening

AndConsent

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

AndConsent

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)

reprievetrial.org

Slide 17 of 42

RCT of Pitavastatin vs Pravastatin % Change in Lipids at Week 52

TC LDL-C HDL-C TG

-35

-30

-25

-20

-15

-10

-5

0

5

10

15

Pitavastatin 4 mg (n=98)

Pravastatin 40 mg (n=90)

P = 0.009 P < 0.001 P = 0.20 P = 0.09

HIV+, LDL 130-220 and TG < 400 after 4 week washout/dietary stabilization

Sponseller CA, CROI 2014, 751LB

Slide 18 of 42

HIV-infected Population controls HIV-infected Population controls0

10

20

30

40

50

60

70

80

Danish Study: ~3 of 4 of MIs in HIV-Infected Individuals Associated with Ever Smoking vs ~1 of 4 in Matched Controls

% of MIs that could be prevented if everyone had same risk as never smokers

% of MIs that could be prevented if everyone had same risk as previous smokers

Rasmussen LD, Cin Infect Dis 2015;60:1415-23

Slide 19 of 42

Summary• Risk stratification tools for the general population are

generally not validated in HIV-infected patients–Reasonable to use Framingham or Pooled Cohort

Equations–Consider counting HIV as a risk factor as per NLA

• Inflammation and immune activation are likely important contributors to atherosclerosis

• Are statins indicated more broadly? –A large clinical endpoint trial (REPRIEVE) is underway