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D Neaton and the INSIGHT SMART ESPRIT Study Groups and SILCAAT Scientific CommitteeAnna D Nordell Matthew McKenna Aacutelvaro H Borges Daniel Duprez Jacqueline Neuhaus James

of Inflammation and CoagulationSeverity of Cardiovascular Disease Outcomes Among Patients With HIV Is Related to Markers

Online ISSN 2047-9980Dallas TX 75231 is published by the American Heart Association 7272 Greenville Avenue Journal of the American Heart AssociationThe

doi 101161JAHA11400084420143e000844 originally published May 28 2014 J Am Heart Assoc

httpjahaahajournalsorgcontent33e000844World Wide Web at

The online version of this article along with updated information and services is located on the

for more informationhttpjahaahajournalsorgAccess publication Visit the Journal at

is an online only Open Journal of the Amer ican Heart AssociationSubscriptions Permissions and Reprints The

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Severity of Cardiovascular Disease Outcomes Among Patients WithHIV Is Related to Markers of In1047298ammation and CoagulationAnna D Nordell BA Matthew McKenna BA Alvaro H Borges MD MSc Daniel Duprez MD PhD Jacqueline Neuhaus MS

James D Neaton PhD for the INSIGHT SMART ESPRIT Study Groups and SILCAAT Scienti1047297c Committee

Background- mdash In the general population raised levels of in1047298ammatory markers are stronger predictors of fatal than nonfatal

cardiovascular disease (CVD) events People with HIV have elevated levels of interleukin-6 (IL-6) high-sensitivity C-reactive protein

(hsCRP) and D-dimer HIV-induced activation of in1047298ammatory and coagulation pathways may be responsible for their greater risk of

CVD Whether the enhanced in1047298ammation and coagulation associated with HIV is associated with more fatal CVD events has not

been investigated

Methods and Results- mdash Biomarkers were measured at baseline for 9764 patients with HIV and no history of CVD Of these

patients we focus on the 288 that experienced either a fatal (n=74) or nonfatal (n=214) CVD event over a median of 5 years Odds

ratios (ORs) (fatal versus nonfatal CVD) (95 con1047297dence intervals [CIs]) associated with a doubling of IL-6 D-dimer hsCRP and a

1-unit increase in an IL-6 and D-dimer score measured a median of 26 years before the event were 139 (107 to 179) 140

(110 to 178) 109 (093 to 128) and 151 (115 to 197) respectively Of the 214 patients with nonfatal CVD 23 died during

follow-up Hazard ratios (95 CI) for all-cause mortality were 172 (128 to 231) 173 (127 to 236) 144 (115 to 180) and 188

(139 to 255) respectively for IL-6 D-dimer hsCRP and the IL-6 and D-dimer score

Conclusions- mdash Higher IL-6 and D-dimer levels re1047298ecting enhanced in1047298ammation and coagulation associated with HIV are

associated with a greater risk of fatal CVD and a greater risk of death after a nonfatal CVD event

Clinical Trial Registration- mdash URL httpwwwclinicaltrialgov Unique identi1047297er SMART NCT00027352 ESPRIT NCT00004978

SILCAAT NCT00013611 ( J Am Heart Assoc 20143e000844 doi 101161JAHA114000844)

Key Words cardiovascular disease bull in1047298ammation

O

ver 15 years ago an association between enhanced

in1047298ammation as demonstrated by higher plasma levelsof C-reactive protein (CRP) and risk of coronary heart disease

(CHD) in middle-aged men without previous cardiovascular

disease (CVD) was reported using data from the Multiple Risk

Factor Intervention Trial (MRFIT)1

In MRFIT CRP was stronglyrelated to CHD mortality but was not related to nonfatal

myocardial infarction (MI) Importantly most of the CHD

deaths occurred more than 10 years after the CRP measure-

ment This MRFIT observation that markers of in1047298ammation

are stronger predictors of fatal as compared to nonfatal CHD

events has been con1047297rmed in other studies2 ndash 4

Reasons for

this 1047297nding include the possibility that patients with higher

in1047298ammatory markers may have different underlying vascular

disease It has been speculated that patients with greater

levels of in1047298ammation might be more likely to experience fatal

arrhythmias that result in sudden death or have greater levels

of in1047298ammation in unstable plaques1 ndash 3 It is also possible that

low-grade in1047298ammation results in activation of the coagulation

system increasing the likelihood of fatal outcomes subse-

quent to plaque rupture4

Other reasons include a greater

presence of other CVD risk factors among those with higher

in1047298ammatory biomarker levels that increased risk of death or

the presence of other nonvascular conditions that are

associated with chronic in1047298ammation and that lead to an

increased risk of fatal events

From the Division of Biostatistics School of Public Health University of

Minnesota Minneapolis MN (ADN MM JN JDN) Department of

Infectious Diseases Rigshospitalet and Copenhagen HIV Programme University

of Copenhagen Copenhagen Denmark (AHB) Cardiovascular Division

University of Minnesota Minneapolis MN (DD)

Accompanying Table S1 is available at httpjahaahajournalsorgcontent

33e000844supplDC1

A list of all INSIGHT SMART ESPRIT Study Groups and the SILCAAT Scienti 1047297c

Committee participants is provided in Data S1 available at httpjahaahajournalsorgcontent33e000844supplDC1

Correspondence to James D Neaton PhD Division of Biostatistics 2221

University Ave SE Room 200 Minneapolis MN 55414 E-mail jimccbrumn

edu

Received January 28 2014 accepted April 23 2014

ordf 2014 The Authors Published on behalf of the American Heart Association

Inc by Wiley Blackwell This is an open access article under the terms of the

Creative Commons Attribution-NonCommercial License which permits use

distribution and reproduction in any medium provided the original work is

properly cited and is not used for commercial purposes

DOI 101161JAHA114000844 Journal of the American Heart Association 1

ORIGINAL RESEARCH

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Patients with HIV may contribute to our understanding of

these 1047297ndings in the general population They are in a

sustained in1047298ammatory state even when taking suppressive

antiretroviral therapy (ART)5 Reasons for this in1047298ammatory

state and the associated chronic state of immune activation

have been reviewed67 Some key 1047297ndings concerning HIV

in1047298ammation and CVD which we and others have described

are (1) compared to age- and gender-matched people in the

general population interleukin-6 (IL-6) high-sensitivity CRP

(hsCRP) and D-dimer are elevated5 (2) patients with HIV

appear to be at an increased risk of CVD compared to

individuals without HIV8 ndash 12 and (3) IL-6 hsCRP and D-dimer

measured several years beforehand are associated with all-

cause mortality and fatal or nonfatal CVD113 The results in

the reports by Kuller and Duprez which utilized stored plasma

specimens from the Strategies for Management of Antiretro-

viral Therapy (SMART) trial1415 also suggested that though

the associations of these biomarkers with fatal or non-fatal

CVD was similar to associations reported in general popula-

tion studies the association with all-cause mortality wasstronger than for CVD even though the deaths in SMART

were attributed to a number of different causes

Collectively these 1047297ndings led us to formulate 2 hypoth-

eses (1) HIV-positive patients with higher levels of IL-6

hsCRP and D-dimer measured several years before the CVD

event are more likely to experience a fatal as compared to a

nonfatal CVD event and (2) mortality after nonfatal CVD

events is higher among HIV-positive patients with higher as

compared to lower levels of IL-6 hsCRP and D-dimer also

measured several years before the nonfatal event To

investigate these hypotheses we used data from SMART

and 2 other large international clinical trials of HIVtreatments

Methods

Study Populations

This investigation included patients from 3 large international

HIV treatment trials conducted by the International Network

for Strategic Initiatives in Global HIV Trials the SMART

trial1415 the Evaluation of Subcutaneous Proleukin in a

Randomized International Trial (ESPRIT)1617

and the Subcu-

taneous Recombinant Human Interleukin-2 in HIV-Infected

Patients with Low CD4+

Counts under Active Antiretroviral

Therapy (SILCAAT) trial17 These trials were carried out in 33

25 and 11 countries respectively The SMART study

compared continuous ART with intermittent ART among HIV-

positive patients with a CD4+ cell count of more than 350

cellsmm3

ESPRIT and SILCAAT compared IL-2 plus ART

versus ART alone among HIV-positive patients with CD4+

counts of 300 cellsmm3

or more and with CD4+

counts of 50

to 299 cellsmm3 respectively All studies were approved by

an institutional review committee and patients were included

only after giving informed consent

Biomarker Measurements

IL-6 hsCRP and D-dimer were measured at baseline before

randomization in each trial using stored plasma for patients

who provided written consent For patients in SMART these

biomarkers were measured at the Laboratory for Clinical

Biochemistry Research at the University of Vermont (Burling-

ton) In the ESPRIT and SILCAAT trials laboratory measure-

ments were performed by SAIC-Frederick (Frederick MD) All

samples in both laboratories were analyzed blinded to

treatment group and CVD event status IL-6 was measured

by the same method at each laboratory (Chemiluminescent

Sandwich ELISA RampD Sytems Minneapolis MN) D-dimer

levels were measured by ELISA on the Sta-R analyzer Liatest

D-DI (Diagnostic Stago Parsippany NJ) for patients in SMART

and on a VIDAS instrument (bioM

erieux Inc Durham NC) forpatients in ESPRIT and SILCAAT hsCRP was measured by

ELISA by both laboratories For SMART a NBTMII nephelom-

eter N Antiserum to Human CRP (Siemens Diagnostics

Deer1047297eld IL) was used For ESPRIT and SILCAAT an RampD

Systems ELISA assay was used Twenty samples were

independently analyzed at each laboratory for these biomar-

ker levels Table S1 summarizes the measurements made at

each laboratory Lower limits of detection (LLOD) for IL-6

hsCRP and D-dimer were 016 pgmL 016 lgmL and

001 lgmL for SMART In ESPRIT and SILCAAT LLOD were

0156 pgmL 0078 lgmL and 0045 lgmL

Baseline and Follow-up Measurements

In all 3 studies the following baseline measurements were

obtained before randomization age sex race body mass

index (BMI) CD4+ cell count HIV-RNA duration of ART and

previous AIDS clinical event In SMART and ESPRIT additional

baseline measurements were made including hepatitis BC

coinfection diabetes and use of blood pressure and lipid-

lowering medication For patients in SMART smoking status

was assessed and blood lipids were measured During follow-

up HIV RNA levels and CD4+

cell counts were recorded every

4 months in each study

Events

CVD events considered were deaths attributed to CVD

unwitnessed deaths that were not attributed to suicide drug

abuse or violence nonfatal MI nonfatal stroke and coronary

artery disease (CAD) requiring surgery In SMART and ESPRIT

documentation of CVD events that was provided by the

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clinical sites were reviewed by an endpoint review committee

using prespeci1047297ed criteria18 Criteria for acute MI followed the

universal de1047297nition of MI19 CAD requiring surgery required

a procedure report hospital discharge summary or other

medical record from the hospitalization during which the

procedure was performed (coronary artery bypass graft

coronary artery stent implant coronary artherectomy or

percutaneous transluminal angioplasty) For strokes 5 criteria

were considered (1) acute onset with clinically compatible

course including unequivocal objective 1047297ndings of a localizing

neurological de1047297cit (2) computed tomography (CT) or mag-

netic resonance imaging (MRI) compatible with diagnosis of

stroke and current neurologic signs and symptoms (3) stroke

diagnosed as cause of death at autopsy (4) positive lumbar

puncture compatible with subarachnoid hemorrhage and

(5) death certi1047297cate or death note from medical record listing

stroke as the cause of death A participant was considered to

have experienced a stroke if the 1047297rst and second criteria were

met the third criterion was met the 1047297rst and fourth criteria

were met or the 1047297rst and 1047297fth criteria were met In SILCAATCVD events reported as serious adverse events were coded

according to the Medical Dictionary for Regulatory Activities

(MedRA version 120) The following Standardized MedRA

Query codes were used for nonfatal stroke (20000082)

nonfatal MI (20000047) and CAD requiring surgery

(10068176 10052086 10057787 or 10063025) In all 3

studies cause of death was coded using documentation of

the death provided by the clinical sites using the Coding of

Death in HIV system20

In addressing our 1047297rst hypothesis we de1047297ned fatal CVD

events as (1) deaths attributable to CVD or unwitnessed

deaths for patients that did not experience a nonfatal MI orstroke before their death and (2) deaths within 28 days after

a nonfatal MI stroke or CAD Patients who experienced MI

stroke or CAD events and survived at least 28 days were

de1047297ned as having nonfatal CVD events

For our second hypothesis we considered any patient with

an MI stroke or CAD event who survived at least 28 days

For this group of patients we assessed subsequent risk of all-

cause mortality

Statistical Analyses

Logistic regression including indicators for study the patient

was enrolled in (SMART ESPRIT SILCAAT) was used to study

the association of each biomarker with fatal CVD In addition

to considering each biomarker individually we also consid-

ered a combined IL-6 and D-dimer score used for predicting

all-cause mortality among HIV patients with a suppressed viral

load Because of their independent association with all-cause

mortality the IL-6 and D-dimer score was created in order to

account for the contribution of both markers in a single

combined measure This score was determined using the

control arms of SMART ESPRIT and SILCAAT (144 deaths)

and was adjusted for age gender and study IL-6 and D-dimer

were log2 transformed The regression coef1047297cients from this

Cox model for IL-6 and D-dimer were then used to create the

IL-6 and D-dimer score21

In this investigation the biomarkers were log2 transformed

because their distributions were right-skewed With this

approach a 1 log2 higher level of a biomarker corresponds

to a doubling of the marker Results are also cited for tertiles

of each biomarker which were de1047297ned using all of the

patients in the 3 studies that experienced a fatal or nonfatal

CVD event Other covariates measured in each study that

were considered potential confounding factors were time

between biomarker measurement and the event age gender

race baseline BMI HIV RNA level baseline CD4+ cell count

and earlier AIDS event at study entry We also considered the

interaction between time between biomarker measurement

and the event with the log-transformed biomarker In

sensitivity analyses we adjusted for hepatitis BC coinfec-tion diabetes and use of blood pressure and lipid-lowering

medication (SMART and ESPRIT) and then added smoking and

the ratio of total cholesterol to high-density lipoprotein (HDL)

cholesterol (SMART only) We also carried out separate

analyses for patients in the control arms of the 3 studies

These patients were to receive continuous ART with a goal of

suppressing HIV-RNA levels during follow-up This is the

recommended standard of care for patients with HIV22

Cumulative mortality after a nonfatal CVD event was

estimated using the Kaplan-Meier method Cox models that

included study indicators were used to study factors related

to mortality for the 214 patients who experienced a nonfatalCVD event Models included the same covariates as the

logistic model as well as CD4+

cell counts and HIV-RNA levels

both proximal to the nonfatal event Hazard ratios (HRs) and

95 con1047297dence intervals (CIs) are cited The proportional

hazards assumption was tested by including an interaction

term between each biomarker and log-transformed follow-up

time

All analyses were performed using SAS statistical software

(version 92 SAS Institute Inc Cary NC) P lt005 was

considered signi1047297cant

Results

Among the 11 278 patients randomized in these trials (5472

SMART 4111 ESPRIT and 1695 SILCAAT) 10 001 (89) had

IL-6 hsCRP and D-dimer measured on stored baseline plasma

samples for consenting patients (5017 SMART 3570 ESPRIT

and 1414 SILCAAT) Of these 9764 (98) did not report a

history of CVD at study entry (Figure) Over a median

(interquartile range IQR) follow-up of 50 (23 71) years 74

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of these 9764 patients developed fatal CVD for 68 of these

patients the CVD event reported was death (36 resulting from

CVD and 32 unwitnessed deaths) for 6 additional patients

death occurred within 28 days ofa nonfatal CVD event (3after a

stroke and 3 after an MI) Two hundred and fourteen patients

experienced an MI stroke or CAD event and survived at least

28 days (102 MIs 43 strokes and 69 CADs requiring surgery)

Thus 26 of CVD events (74 of 288) were fatal The median

(IQR) time from biomarker measurement at baseline to the

event was 26 (11 47) for fatal and non-fatal CVD events

Comparison of Fatal and Nonfatal CVD Events

Baseline characteristics for patients according to the develop-

ment of a CVD event during follow-up and its severity are

summarized in Table 1 In these univariate analyses IL-6

D-dimer and the IL-6 and D-dimer score were signi1047297cantly

greaterfor those patients who experienced a fatal as compared

to a nonfatal CVD event hsCRP levels were also higher for

those with fatal events as compared to nonfatal events but the

difference was not signi1047297cant (P =026) Consistent with a

previous report13

levels of all 3 of the biomarkers were higher

for patients who developed CVD as compared to those who did

not Difference in biomarker levels for those with and without a

CVD event and bythe severity ofthe CVD event wasconsistent

across all 3 studies (Table 2) In regression models we

considered the interaction of study with each biomarker and

none were signi1047297cant (P gt040 for all) In the summary below

we pool the results for the 3 studies

When considered as continuous log2-transformed mea-

surements higher levels of IL-6 D-dimer and the IL-6 and D-

dimer score were associated with greater odds of a fatal CVDevent (Table 3) This was evident in uni- and multivariate

analyses When tertiles were considered signi1047297cant differ-

ences between the third and 1047297rst tertiles were found for IL-6

D-dimer and the IL-6 and D-dimer score The risk gradient as

judged by the odds ratio (OR) for a doubling of the biomarker

and based on the tertile analysis tended to be strongest for

D-dimer and the IL-6 and D-dimer score and weakest for

hsCRP Interactions of each biomarker and time between

10001 patients with

biomarker measurements

9764 patients with no

history of CVD at entry

288 patients with a CVD

event during follow-up

8766 patients with no

CVD during follow-up

710 patients with no contact

in the 12 months before

study closure (unknown

CVD status)

Exclusions455 SMART

541 ESPRIT

281 SILCAAT

Exclusions202 SMART

35 ESPRIT

0 SILCAAT

214 non-fatal

events

74 fatal events

68 CVD

deaths

6 deaths within 28 days of

non-fatal event

23 deaths 191

survivors

11 278 HIV + Patients5472 SMART

4111 ESPRIT

1695 SILCAAT

Figure Flow diagram of patients included in analyses CVD indicates cardiovascular disease ESPRIT

Evaluation of Subcutaneous Proleukin in a Randomized International Trial SILCAAT Subcutaneous

Recombinant Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active

Antiretroviral Therapy SMART Strategies for Management of Antiretroviral Therapy

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biomarker measurement and the event were also considered

and none were signi1047297cant Sensitivity analyses were per-

formed excluding the unwitnessed deaths and results were

similar to those in Table 3 For example univariate ORs (95

CI) associated with a doubling of IL-6 D-dimer hsCRP and

the IL-6 and D-dimer score were 141 (103 to 192) 136

(101 to 182) 113 (092 to 137) and 150 (108 to 207)

respectively

Considering the 206 patients (54 fatal and 152 nonfatal

events) in SMART and ESPRIT that had measurements

recorded at baseline we adjusted for 4 additional covariates

diabetes hepatitis BC coinfection and use of blood pressure

and lipid-lowering medication Adjusted ORs were similar to

those shown in Table 3 for IL-6 D-dimer hsCRP and IL and

D-dimer score ORs (95 CIs) were 133 (95 CI 095 to

186) 143 (95 CI 102 to 200) 118 (95 CI 095 to

147) and 149 (95 CI 103 to 215) respectively

For the 115 patients (31 fatal and 84 nonfatal events) in

SMART for whom we could also adjust for smoking and total

HDL cholesterol adjusted ORs were 110 (95 CI 072 to

167) 139 (95 CI 090 to 215) 125 (95 CI 091 to

170) and 122 (95 CI 078 to 193) for IL-6 D-dimer

hsCRP and the IL-6 and D-dimer score respectively

In SMART the OR associated with a doubling of IL-6 was

lower than in analyses based on all 3 studies or based on

SMART and ESPRIT For all 5017 patients in SMART median

Table 1 Baseline Characteristics for HIV-Positive Patients Who Experienced CVD Events According to Severity

No Event Fatal CVDdagger

Nonfatal CVDDagger

P Valuesect

Baseline characteristics n 9476 74 214

Age (y) median (IQR) 42 (36 to 48) 48 (41 to 54) 49 (42 to 54) 076

Sex ( female) 22 14 8 021

Race ( black) 19 23 16 020

BMI (kgm2) median (IQR) 243 (221 to 270) 240 (221 to 270) 243 (221 to 271) 058

CD4+ cell count (cellsmm3) median (IQR) 487 (367 to 669) 409 (331 to 644) 469 (356 to 633) 063

HIV-RNA lt500 copiesmL 77 74 77 064

Earlier AIDS event 26 39 29 010

IL-6 (pgmL) median (IQR) 18 (12 to 28) 31 (19 to 45) 23 (15 to 35) 001||

highest tertile (lt188) 20 45 28

middle tertile (188le9lt314) 27 31 36

lowest tertile (ge314) 52 24 36 002 para

D-dimer (lgmL) median (IQR) 024 (015 to 037) 035 (024 to 061) 027 (017 to 045) 0006||

highest tertile (lt022) 21 45 29

middle tertile (022le9lt

041) 31 32 34 lowest tertile (ge041) 47 23 37 003 para

hsCRP (lgmL) median (IQR) 16 (07 to 36) 31 (11 to 75) 22 (11 to 56) 026||

highest tertile (lt155) 21 39 31

middle tertile (155le9lt417) 29 32 34

lowest tertile (ge417) 50 28 35 049 para

IL-6 and D-dimer score median (IQR) 002 (060 to 061) 085 (020 to 136) 030 (020 to 089) 0003

highest tertile (lt104) 19 51 27

middle tertile (104le9lt175) 28 26 36

lowest tertile (ge175) 53 23 37 0001 para

BMI indicates body mass index CVD cardiovascular disease hsCRP high-sensitivity C-reactive protein IQR interquartile rangeNo event measurements noted for completenessdagger

Deaths attributed to CVD and unwitnessed deaths not resulting from violence suicide or drug abuse that were not proceeded by a nonfatal event or deaths within 28 days of the nonfatal

CVD eventDagger

Nonfatal myocardial infarction coronary artery disease requiring surgery or nonfatal stroke for participants that survived at least 28 dayssect

From a univariate logistic model comparing fatal and nonfatal CVD events (n=288)||

P values reported based on log2-transformed biomarker measurement para

P value based on 2 df chi-square test

Tertiles were de1047297ned using all of the patients in the 3 studies that experienced a fatal or nonfatal CVD event

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T a b l e

2

C h a r a c t e r i s t i c s o f

S M A R T

E S P R I T a n d S I L C A A T P a t i e n t s W i t h a n d W i t h o u t F a t a l N o n f a t a l C V D

E v e n t s

S M A R T

E S P R I T

S I L C A A T

N o

E v e n t

F a t a l C V D

N o n f a t a l C

V D

N o E v e n t

F a t a l C V D

N o n - F a t a l C V D

N o E v e n t

F a t a l C V D

N o n - F a t a l C V D

B a s e l i n e c h a r a c t e r i s t i c s

n

4 6 9

7

3 2

8 6

3 4 1 8

2 6

9 1

1 3 6 1

1 6

3 7

A g e ( y ) m e d i a n ( I Q R )

4 3

( 3 7 t o 5 0 )

5 0 ( 4 7 t o 5 4 )

5 0 ( 4 3 t o

5 5 )

4 0 ( 3 5 t o 4 6 )

4 4 ( 3 8 t o 5 1 )

4 8 ( 4 1 t o 5 4 )

4 0 ( 3 6 t o 4 7 )

4 9 ( 4 3 t o

5 8 )

4 7 ( 4 1 t o 5 4 )

S e x (

f e m a l e )

2 7

2 2

1 5

1 8

4

4

1 6

1 3

3

R a c e (

b l a c k )

2 9

4 1

3 4

9

8

4

9

1 3

5

B M I ( k g m 2 ) m e d i a n

( I Q R )

2 5

0 ( 2 2 5

t o

2 8 1

)

2 4 0

( 2 1 8

t o

3 0 1

)

2 5 7

( 2 2 3

t o

2 8 4

)

2 3 7

( 2 1 9

t o

2 5 9

)

2 4 4

( 2 3 1

t o

2 5 8

)

2 3 9

( 2 2 0

t o

2 6 0

)

2 3 8

( 2 1 7

t o

2 6 1

)

2 3 0

( 2 1 3

t o

2 6 9

)

2 3 5

( 2 2 1

t o

2 6 1

)

B P - l o w e r i n g d r u g u s e

1 7

4 7

3 7

5

0

1 0

N A

N A

N A

L i p i d - l o w e r i n g d r u g u s e

1 4

1 3

3 3

1 0

1 3

2 0

N A

N A

N A

H e p a t i t i s B o r C

c o i n f e c t e d

1 7

3 1

1 4

2 2

2 9

1 5

N A

N A

N A

C D 4 +

c e l l c o u n t ( c e l l s

m m

3 ) m e d i a n ( I Q R )

5 9 8

( 4 6 7 t o

7 9 4 )

6 4 9 ( 4 4 2 t o

8 7 4 )

5 9 3 ( 4 5 0

t o

8 3 8 )

4 5 3 ( 3 6 8 t o

5 8 1 )

3 9 9 ( 3 4 1 t o

5 1 6 )

4 7 0 ( 3 8 6 t o

5 8 2 )

2 0 2 ( 1 5 0 t o

2 5 5 )

2 0 0 ( 1 4 4 t o

2 6 9 )

1 8 8 ( 1 3 1 t o

2 4 9 )

A R T

8 4

8 1

8 7

1 0 0

1 0 0

1 0 0

1 0 0

1 0 0

1 0 0

T i m e s i n c e f i r s t A R T

( y )

m e d i a n ( I Q R )

6 ( 4 t o 8 )

7 ( 5 t o 9 )

6 ( 4 t o 8

)

4 ( 2 t o 6 )

5 ( 2 t o 6 )

6 ( 4 t o 8 )

4 ( 2 t o 8 )

3 ( 1 t o 6 )

5 ( 3 t o 8 )

B a s e l i n e H I V - R N A lt 5 0 0

c o p i e s m L

7 2

7 2

7 2

8 1

6 9

8 1

8 2

8 8

7 8

E a r l i e r A I D S e v e n t

2 4

4 1

3 4

2 7

5 8

2 3

3 2

6

3 2

D i a b e t e s

6

1 3

2 1

2

8

6

N A

N A

N A

S m o k e r

4 1

5 3

5 2

N A

N A

N A

N A

N A

N A

T o t a l H D L c h o l e s t e r o l

( m m o l L ) m e d i a n ( I Q R )

4 6

( 3 6

t o 5 9

)

4 1

( 3 1

t o 5 5

)

6 1

( 4 2

t o

8 1

)

N A

N A

N A

N A

N A

N A

I L - 6

( p g m L ) m e d i a n

( I Q R )

1 7

( 1 1

t o 2 9

)

4 1

( 2 0

t o 6 5

)

2 6

( 1 8

t o

4 5

)

1 9

( 1 3

t o

2 7

)

2 7

( 2 1

t o

3 2

)

2 2

( 1 5

t o

3 1

)

1 8

0 ( 1 2

0 t o

2 7

0 )

2 5

( 1 6

t o

3 6

)

1 9

( 1 5

t o 2 9

)

D - d i m e r ( l g m L )

m e d i a n ( I Q R )

0 2

0 ( 0 1

3 t o

0 3

7 )

0 3

7 ( 0 2

1 t o

0 7

2 )

0 2

7 ( 0 1

5 t o

0 4

9 )

0 2

6 ( 0 1

9 t o

0 3

7 )

0 3

3 ( 0 2

5 t o

0 4

8 )

0 2

8 ( 0 1

9 t o

0 4

2 )

0 2

5 ( 0 1

7 t o

0 3

6 )

0 4

2 ( 0 3 0

t o

0 7

0 )

0 2

7 ( 0 1

8 t o

0 4

2 )

h s C R P

( l g m L ) m e d i a n

( I Q R )

1 7

( 0 7

t o 4 0

)

5 9

( 1 3

t o 8 9

)

2 6

( 1 4

t o

6 7

)

1 5

( 0 7

t o

3 2

)

2 4

( 1 0

t o

3 7

)

1 7

( 1 0

t o

4 2

)

1 4

( 0 6

t o

3 3

)

3 5

( 2 3

t o

5 0

)

2 3

( 1 0

t o 4 6

)

I L - 6 a n d D - d i m e r s c o r e

m e d i a n ( I Q R )

0

1 2 ( 0 8

1 t o

0 6

4 )

1 1

7 ( 0 1

6 t o

1 9

5 )

0 5

1 ( 0

0 8 t o

1 1

4 )

0 0

9 ( 0 3

9 t o

0 5

9 )

0 5

6 ( 0 2

9 t o

0 9

2 )

0 1

8 ( 0 2

1 t o

0 7

8 )

0 0

3 ( 0 5

3

t o 0 5

1 )

0 6

1 ( 0 2 2 t o

1 1

9 )

0 0 1

5 ( 0 2

5 t o

0 5

6 )

A R T i n d i c a t e s a n t i r e t r o v i r a l t h e r a p y B P

b l o o d p r e s s u r e B M I b o d y m a s s i n d e x C V D c a r d i o v a s c u l a r d i s e a s e E S P R I T

E v a l u a t i o n o f S u b c u t a n e o u s P r o l e u k i n

i n a R a n d o m i z e d I n t e r n a t i o n a l T r i a l H D L

h i g

h - d e n s i t y l i p o p r o t e i n h s C R P

h i g h -

s e n s i t i v i t y C - r e a c t i v e p r o t e i n S I L C A A T

S u b c u t a n e o u s R e c o m b i n a n t H u m a n I n t e r l e u k i n - 2 i n H I V - I n f e c t e d P a t i e n t s w i t h L o w

C D 4 +

C o u n t s u n d e r A c

t i v e A n t i r e t r o v i r a l T h e r a p y S M A R T

S t r a t e g i e s f o r M a n

a g e m e n t o f A n t i r e t r o v i r a l T h e r a p y

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(IQR) levels of IL-6 for smokers and nonsmokers were 198

(119 to 323) and 165 (105 to 286) respectively (P lt0001

for difference) To investigate whether the adjustment for

smoking led to the lower OR for SMART we compared

unadjusted and smoking adjusted ORs for SMART partici-pants In the unadjusted model the OR associated with a

doubling of IL-6 was 129 (95 CI 093 to 180) in the model

adjusting for smoking the OR was 130 (95 CI 093 to

181)

There were 134 patients in the control arms of the 3

studies that experienced a CVD event (32 fatal and 102

nonfatal) ORs were similar to those cited for all patients in

Table 3 but CIs were wider as a result of the smaller number

of events Adjusted ORs (fatalnonfatal events) were 162

(95 CI 096 to 274) 140 (95 CI 088 to 225) 111 (95

CI 082 to 151) and 189 (95 CI 105 to 341) for IL-6

D-dimer hsCRP and the IL-6 and D-dimer score respectivelyInteraction P values for treatmentcontrol and each biomar-

ker were all gt059

Biomarker Association With Mortality After a

Nonfatal CVD Event

Among the 214 patients who had a nonfatal CVD event there

were 23 deaths (107) Cumulative mortality 6 and

12 months after the nonfatal event for these patients all of

whom survived at least 28 days was 29 and 40

respectively

In univariate analyses higher levels of each of the

biomarkers were associated with an increased risk of death(Table 4) HRs were reduced with covariate adjustment yet

remained signi1047297cant for all 4 biomarkers There was no

evidence that the proportional hazards assumption did not

hold for each biomarker (interaction P values all gt073)

Discussion

Based on our previous work and studies in the general

population we formulated 2 related hypotheses on the

association of in1047298ammatory and coagulation markers and the

severity of future CVD events in HIV-positive patients In

analyses that adjusted for HIV- and CVD-related factors we

found that among HIV-positive patients who developed CVD

(1) those with higher levels of IL-6 D-dimer and an IL-6 and

D-dimer score but not hsCRP measured several years earlier

were signi1047297cantly more likely to have a fatal CVD event and

(2) the risk of death after an MI stroke or CAD event was

signi1047297cantly increased among HIV-positive patients with

higher baseline levels of IL-6 hsCRP and an IL-6 and D-dimer

score but not D-dimer In this latter analysis the biomarkers

Table 3 Unadjusted and Covariate Adjusted Odds Ratios for Fatal CVDdagger

(Versus Nonfatal CVDDagger

) According to Tertile and

Associated With a Doubling of Each Biomarker or 1-Unit Increase of IL-6 and D-Dimer Score

Biomarker

Lowest Tertile M iddle Tertile Highest Tertile

OR Associated With Doubling of

Biomarker

OR OR 95 CI P Value OR 95 CI P Value Omnibus P Valuesect

OR 95 CI P Value

IL-6 pgmL

Univariate 10 132 (066 to 264) 044 246 (125 to 487) 001 002 139 (107 to 179) 001

Adjusted 10 141 (069 to 288) 034 262 (126 to 546) 001 002 141 (107 to 186) 001

D-dimer (lgmL)

Univariate 10 163 (080 to 333) 018 247 (125 to 485) 0009 003 140 (110 to 178) 0007

Adjusted 10 174 (080 to 375) 016 270 (127 to 575) 001 005 145 (110 to 192) 0008

hsCRP (lgmL)

Univariate 10 117 (060 to 229) 065 149 (077 to 288) 024 049 109 (093 to 128) 031

Adjusted 10 117 (059 to 233) 065 155 (078 to 310) 021 039 110 (093 to 130) 029

IL-6 and D-dimer

score

Univariate 10 115 (056 to 238) 071 307 (157 to 600) 0001 0001 151 (115 to 197) 0003

Adjusted 10 120 (057 to 254) 064 367 (174 to 772) lt0001 lt0001 158 (117 to 213) 0003

hsCRP indicates high-sensitivity C-reactive protein OR odds ratio

Covariates include study indicators log-transformed time to event age gender race body mass index HIV-RNA baseline CD4 + cell count and earlier AIDS at baselinedaggerNumber of fatal CVD events=74Dagger

Number of nonfatal CVD events=214sect

Based on 2 df chi-square test

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were measured a median of 26 years before the nonfatal

event To our knowledge the prognostic importance of these

markers for fatal as compared to nonfatal CVD events has

not been studied in the setting of HIV infection

Considering the results based on the 1047297rst hypothesis our

1047297ndings are consistent with studies in the general populationthat show an increased risk of more fatal CVD events for

patients with higher in1047298ammatory markers In MRFIT higher

CRP levels at baseline were signi1047297cantly associated with CHD

death all of which occurred 11 to 17 years after the CRP

measurement (P lt0001) No association (P =078) was found

between baseline CRP and nonfatal MIs which occurred 6 to

7 years after CRP measurement1

In the PROSPER study IL-6

and CRP measured at baseline in over 5000 patients were

both more strongly related to fatal CVD events than nonfatal

CVD events3 Engstreuroom et al measured 5 other in1047298ammation-

sensitive plasma proteins (ISPs) mdash 1047297brinogen orosomucoid

a1-antirypsin haptoglobin and ceruloplasmin mdash

6075 healthymen and found that for men who subsequently developed a

coronary event fatal events were related to the number of

ISPs measured at the baseline examination which was an

average of 129 years before the events2

In addition to IL-6 D-dimer a 1047297brin degradation product

and marker of ongoing coagulation was signi1047297cantly associ-

ated with severity of CVD disease We have previously shown

that D-dimer is elevated among patients with HIV infection5

The signi1047297cant association of baseline D-dimer with severity

of CVD outcomes may re1047298ect activation of coagulation

systems in response to low-grade in1047298ammation associated

with HIV infection It has been shown that HIV replication

alters the composition of extrinsic pathway coagulation

factors23 and this cycle of in1047298ammation and coagulation

resulting from infection may increase the risk of progressive

organ dysfunction and death2425

Higher levels of in1047298ammatory markers and D-dimer for those

with fatal CVD may also re1047298ect greater underlying disease In

cross-sectional studies higher D-dimer levels have been

associated with severity of peripheral atherosclerosis2627

In an overview of 3 studies higher levels of IL-6 measured at

the time of stroke diagnosis were associated with an

increased risk of a poor outcome including death28 and

concluded that IL-6 may be a general marker of disease

severity Although we excluded HIV-positive patients with a

history of CVD recent cross-sectional comparisons ofHIV-positive men and women without a history of CVD with

HIV-negative controls have found differences in vascular

abnormalities29 ndash 31 In 2 studies by the same group those with

HIV were found to have more noncalci1047297ed coronary plaque by

CT angiography2930 Furthermore in one of these studies

correlations between soluble CD163 and increased amount of

noncalci1047297ed plaque suggests that monocyte and macrophage

activation may contribute to formation of vulnerable plaque in

HIV-positive patients30

Thus it is possible that those with

higher in1047298ammatory markers had more vulnerable plaque

than those who did not In another study31

HIV-positive

patients without a history of CVD had more structural andfunctional abnormalities based on cardiac MRI than HIV-

negative patients

Studies in the general population have reported that higher

levels of markers of in1047298ammation measured at the time of an

acute coronary event are related to subsequent mortality but

not to recurrent coronary events32 ndash 34

These observations

may be related to the 1047297ndings of our second hypothesis that

mortality after nonfatal CVD events would be higher among

HIV-positive patients with higher as compared to lower levels

of IL-6 hsCRP and D-dimer For patients in the general

population De Servi et al speculated that the highest

in1047298ammatory markers observed during an acute coronary

syndrome are more likely to be observed among patients who

had high levels before the event35 If HIV patients who are

already in a state of ongoing immune activation with chronic

low-grade in1047298ammation are at increased risk of an exagger-

ated in1047298ammatory response after their CVD event as has

been suggested based on 1047297ndings in the general population3

this could explain the 1047297ndings based on our second hypoth-

esis However we cannot directly address this because

Table 4 Unadjusted and Covariate Adjusted Hazard Ratios for All-Cause Mortality After Nonfatal CVDdagger

(n=214) Events

Associated With a Doubling of Biomarker or 1-Unit Increase in IL-6D-Dimer Score

Biomarker

Median (IQR) Univariate Adjusted

Deaths (n=23) Survivors (n=191) HR 95 CI P Value HR 95 CI P Value

IL-6 pgmL 31 (23 to 62) 22 (15 to 32) 172 (128 to 231) lt0001 185 (125 to 272) 0002

D-dimer lgmL 047 (029 to 059) 027 (017 to 042) 173 (127 to 236) lt0001 176 (117 to 266) 0007

hsCRP lgmL 53 (26 to 75) 20 (10 to 49) 144 (115 to 180) 0001 139 (108 to 178) 001

IL-6 and D-dimer score 094 (037 to 157) 018 (025 to 072) 188 (139 to 255) lt0001 201 (135 to 301) lt0001

CVD indicates cardiovascular disease hsCRP high-sensitivity C-reactive protein HR hazard ratio

Covariates include study indicators log-transformed time to event age gender race body mass index HIV-RNA at baseline and proximal to nonfatal CVD event CD4+ cell count at

baseline and proximal to nonfatal CVD event and earlier AIDS at baselinedaggerNumber of deaths after a nonfatal CVD event=23 including deaths attributed to CVD and unwitnessed deaths not resulting from violence suicide or drug abuse

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biomarkers were not measured at the time of the nonfatal

CVD event

There are several limitations to our 1047297ndings Cause of

death was uncertain for many of the deaths However

because sudden cardiac deaths account for most cardiac and

many non-AIDS deaths among HIV-positive individuals36 we

found it reasonable to consider unwitnessed deaths not

attributable to suicide drug abuse or violence as fatal CVD

In addition we showed in a sensitivity analysis that results

did not differ when unwitnessed deaths were excluded from

the logistic models Another limitation was that important

CVD risk factors at baseline were not fully assessed and could

only be partially adjusted for ORs were reduced when only

SMART patients for whom smoking and blood lipids were

measured at baseline were considered Although IL-6 levels

were higher among smokers than nonsmokers in SMART the

percentages of patients with fatal and nonfatal events who

smoked were similar (Table 2) and ORs from unadjusted and

smoking-adjusted models were also similar suggesting that

smoking was not an important confounding factor in studyingseverity of CVD events We also did not measure the

biomarkers in the time period immediately before events

occurred or at the time of the event Correlations among

measurements taken more remotely with those proximal to

the event may be informative Finally power for both

hypotheses was limited particularly for the analyses

restricted to the subgroup of patients who participated in

SMART as well as for the patients in the control arms of the 3

studies and as a consequence CIs are wide for those

analyses Strengths include the central measurement of the

biomarkers excellent follow-up and the uniqueness of this

investigation in HIV-positive patients

Conclusion

In conclusion we sought to assess the prognostic value of

in1047298ammatory and coagulation markers for fatal outcomes

among patients with HIV who experience CVD events We

found that activated in1047298ammatory and coagulation pathways

as demonstrated by higher IL-6 and D-dimer plasma levels

are associated with a greater risk of fatal as compared to

nonfatal CVD and a greater risk of death after a nonfatal CVD

event These 1047297

ndings suggest that chronic in1047298

ammation andactivated coagulation associated with HIV leads to a poor

outcome when a CVD event occurs

Acknowledgments

The authors acknowledge the SMART ESPRIT and SILCAAT patients

See N Engl J Med 20063552283-2296 for the complete list of

SMART investigators and N Engl J Med 20093611548-1559 for the

complete list of ESPRIT and SILCAAT investigators

Sources of Funding

This study was funded by the National Institutes of Health

(Grant No U01AI46957 and U01AI068641 [ESPRIT and

SMART] U01AI042170 and U01AI46362 [SMART]) SILCAAT

was supported by grants from Chiron and Novartis The

funding sources had no role in data collection data analysis

or decisions to publish the results

Disclosures

None

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coronary heart disease in the MRFIT nested case-control study Am J Epidemiol 1996144537 ndash 547

2 Engstreuroom G Hedblad B Stavenow L Tyden P Lind P Janzon L Lindgeuroarde FFatality of future coronary events is related to in1047298ammation-sensitive plasmaproteins a population-based prospective cohort study Circulation200411027 ndash 31

3 Sattar N Murrary HM Welsh P Blauw GJ Buckley BM Cobbe S de Craen AJMLowe GD Jukema JW Macfarlane PW Murphy MB Stott DJ Westendorp RGJShepherd J Ford I Packard CJ for the Prospective Study of Pravastatin in theElderly at Risk (PROSPER) Study Group Are markers of in1047298ammation morestrongly associated with risk for fatal than for non-fatal vascular events PLoSMed 20096e1000099

4 van Wijk DF Boekholdt SM Wareham NJ Ahmadi-Abhari S Kastelein JJ StroesES Khaw KT C-reactive protein fatal and nonfatal coronary artery diseasestroke and peripheral artery disease in the prospective EPIC-Norfolk cohortstudy Arterioscler Thromb Vasc Biol 2013332888 ndash 2894

5 Neuhaus J Jacobs DR Baker JV Calmy A Duprez D La Rosa A Kuller LH PettSL Ristola M Ross MJ Shlipak MG Tracy R Neaton JD Markers ofin1047298ammation coagulation and renal function are elevated in adults with HIVinfection J Infect Dis 20102011788 ndash 1795

6 Catalfamo M Le Saout C Lane HC The role of cytokines in the pathogenesisand treatment of HIV infection Cytokine Growth Factor Rev 201223207 ndash 214

7 Deeks SG Tracy R Douek DC Systemic effects of in1047298ammation on health

during chronic hiv infection Immunity 201339633 ndash

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8 Triant VA Lee H Hadigan C Grinspoon SK Increased acute myocardialinfarction rates and cardiovascular risk factors among patients with humanimmunode1047297ciency virus disease J Clin Endocrinol Metab 2007922506 ndash 2512

9 Lang S Mary-Krause M Cotte L Gilquin J Partisani M Simon A Boccara FBingham A Costagliola D Increased risk of myocardial infarction in HIV-infected patients in France relative to the general population AIDS2010241228 ndash 1230

10 Obel N Thomsen HF Kronborg G Larsen CS Hildebrandt PR Soslashrensen HTGerstoft J Ischemic heart disease in HIV-infected and HIV-uninfected individ-uals a population-based cohort study Clin Infect Dis 2007441625 ndash 1631

11 Currier JS Taylor A Boyd F Dezii CM Kawabata H Burtcel B Maa JF HodderS Coronary heart disease in HIV-infected individuals J Acquir Immune De1047297 cSyndr 199933506 ndash 512

12 Freiberg MS Chang CCH Kuller LH Skanderson M Lowy E Kraemer KL ButtAA Goetz MB Leaf D Oursler KA Rimland D Barradas MR Brown S Gilbert C

McGinnis K Crothers K Sico J Crane H Warner A Gottlieb S Gottdiener JTracy RP Budoff M Watson C Armah KA Doebler D Bryant K Justice AC HIVinfection and the risk of acute myocardial infarction JAMA Intern Med 20131 ndash 9

13 Duprez DA Neuhaus J Kuller LH Tracy R Belloso W De W ITS Drummond FLane HC Ledergerber B Lundgren J Nixon D Paton NI Prineas RJ Neaton JDfor the INSIGHT SMART Study Group In1047298ammation coagulation andcardiovascular disease in HIV-infected patients PLoS One 2012 7 e44454

14 SMART Study Group CD4+

count-guided interruption of antiretroviral treat-ment N Engl J Med 20063552283 ndash 2296

15 SMART Study Group Risk for opportunistic disease and death after reinitiatingcontinuous antiretroviral therapy in patients with HIV previously receivingepisodic therapy a randomized trial Ann Intern Med 2008149289 ndash 299

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16 Emery S Abrams DI Cooper DA Darbyshire JH Lane HC Lundgren JD Neaton JD the ESPRIT Study Group The evaluation of subcutaneous proleukin (R)(interleukin-2) in a randomized international trial rationale design andmethods of ESPRIT Control Clin Trials 200223198 ndash 220

17 The INSIGHT-ESPRIT Study Group and SILCAAT Scienti1047297c Committee Interleu-kin-2 therapy in patients withHIV infectionNEnglJMed 20093611548 ndash 1559

18 Lifson AR INSIGHT Endpoint Review Committee Writing Group Belloso WHDavey RT Duprez D Gatell JM Hoy JF Krum EA Nelson R Pederson C PerezG Price RW Prineas RJ Rhame FS Sampson JH Worley J for the INSIGHTStudy Group Development of diagnostic criteria for serious non-AIDS eventsin HIV clinical trials HIV Clinical Trials 2010 114 205 ndash 219

19 Thygesen K Alpert JS White HD Universal de1047297nition of myocardial infarction J Am Coll Cardiol 2007502173 ndash 2195

20 Kowalska JD Friis-Moslashller N Kirk O Bannister W Mocroft A Sabin C Reiss PGill J Lewden C Phillips A D-Arminio Monforte A Law M Sterne J DeWit SLundgren JD for the CoDe Working Group the D A D Study Group TheCoding Causes of Death in HIV (CoDe) Project initial results and evaluation ofmethodology Epidemiology 201122516 ndash 523

21 Grund B Baker J Deeks S Wolfson J Wentworth D Cozzi-Lepri A Cohen CPhillips A Lundgren J Neaton J for the INSIGHT SMARTESPRITSILCAATStudy Groups Combined effect of interleukin-6 and D-dimer on the risk ofserious non-AIDS conditions data from 3 prospective cohorts (Abstract 60)In Program and abstracts of the 20th Conference on Retroviruses andOpportunistic Infections Atlanta GA March 2013

22 Panel on Antiretroviral Guidelines for Adults and Adolescents Guidelines for theUse of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Depart-ment of Health and Human Services Available at httpaidsinfonihgovcontent1047297leslvguidelinesadultandadolescentsglpdf Accessed May 15 2014

23 Baker JV Brummel-Ziedins K Neuhaus J Duprez D Cummins N Dalmau DDeHovitz J Lehmann C Sullivan A Woolley I Kuller L Neaton JD Tracy RP HIVreplication alters the composition of extrinsic pathway coagulation factors andincreases thrombin generation J Am Heart Assoc 20132e000264

24 Dellinger RP Cardiovascular management of septic shock Crit Care Med 200331946 ndash 955

25 Levi M van der Poll T Beurouller HR Bidirectional relation between in1047298ammationand coagulation Circulation 20041092698 ndash 2704

26 Lassila R Peltonen S Lepeuroantalo M Saarinen O Kauhanen P Manninen VSeverity of peripheral atherosclerosis is associated with 1047297brinogen and

degradation of cross-linked 1047297brin Arterioscler Thromb Vasc Biol 1993131738 ndash 1742

27 Lee AJ Fowkes FG Lowe GD Rumley A Fibrin D-dimer haemostatic factorsand peripheral arterial disease Thromb Haemost 199574828 ndash 832

28 Whiteley W Jackson C Lewis S Lowe G Rumley A Sandercock P Wardlaw JDennis M Sudlow C In1047298ammatory markers and poor outcome after stroke aprospective cohort study and systematic review of interleukin-6 PLoS Med 20096e1000145

29 Zanni MV Abbara S Lo J Wai B Hark D Marmarelis E Grinspoon SKIncreased coronary atherosclerotic plaque vulnerability by coronary com-puted tomography angiography in HIV-infected men AIDS 2013271263 ndash

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30 Fitch KV Srinivasa S Abbara S Burdo TH Williams KC Eneh P Lo J GrinspoonSK Noncalci1047297ed coronary atherosclerotic plaque and immune activation inHIV-infected women J Infect Dis 20132081737 ndash 1746

31 Holloway CJ Ntusi N Suttie J Mahmod M Wainwright E Clutton G HancockG Beak P Tajar A Piechnik SK Schneider JE Angus B Clarke K Dorrell LNeubauer S Comprehensive cardiac magnetic resonance imaging andspectroscopy reveal a high burden of myocardial disease in HIV patientsCirculation 2013128814 ndash 822

32 Lindahl B Toss H Siegbahn A Venge P Wallentin L Markers of myocardialdamage and in1047298ammation in relation to long-term mortality in unstablecoronary artery disease N Engl J Med 20003431139 ndash 1147

33 James SK Armstrong P Barnathan E Califf R Lindahl B Siegbahn A SimoonsML Topol EJ Venge P Wallentin L Troponin and C-reactive protein havedifferent relations to subsequent mortality and myocardial infarction afteracute coronary syndromea GUSTO-IV substudy J Am Coll Cardiol 200341916 ndash 924

34 Zamani P Schwartz GG Olsson AG Rifai N Bao W Libby P Ganz P Kinlay SIn1047298ammatory biomarkers death and recurrent nonfatal coronary events afteran acute coronary syndrome in the MIRACL study J Am Heart Assoc 20132e003103

35 De Servi S Mariani M Mariani G Mazzone A C-reactive protein increase inunstable coronary disease cause or effect J Am Coll Cardiol 2005461496 ndash 1502

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Severity of Cardiovascular Disease Nordell et al

b t J 1 2014htt j h h j l D l d d f