Cardiovascular Risk in HIV: What Is the Role of

Antiretroviral Therapy?David A. Wohl, MD

Clinical Associate Professor, Division of Infectious DiseasesUniversity of North Carolina at Chapel Hill, School of Medicine

Co-Principal InvestigatorUNC-CH AIDS Clinical Trials Unit (NIH/DAIDS)

Co-Director of HIV ServicesNorth Carolina Department of Corrections

Chapel Hill, North Carolina

2

Overview

• HIV-related morbidity and mortality• CVD and risk factors

– Similarities and differences compared with general population

– Review of ongoing cohort studies:insights and limitations

• HAART and CV risk: Are there any differences among ARV agents?

3

HIV-related Morbidity and Mortality

4

EuroSIDA: Reduction in the Incidence of AIDS and Death Since the

Introduction of HAART

Sept

199

6–M

arch

199

7

Sept

199

9–M

arch

200

0

Mar

ch 1

995-

Sept

199

5

Sept

199

5-M

arch

199

6

Mar

ch 1

996-

Sep

t 19

96

Mar

ch 2

000-

Sept

200

0

Sept

200

0-M

arch

200

1

Mar

ch 2

001-

Sept

200

1

Com

bin

ed

AID

S a

nd

death

rate

sSe

pt 1

994

Sept

200

1-on

war

ds

Sept

199

8-M

arch

199

9

Mar

ch 1

997-

Sept

199

7

Sept

199

7-M

arch

199

8

Mar

ch 1

998-

Sept

199

8

Patie

nts

(%)

% patients on HAARTCombined rate of AIDS and death

Morbidity and Mortality Across Europe, Israel, and Argentina ~10,000 Patients

1

10

100

0

20

40

60

80

100

Mar

ch 1

999-

Sept

199

9

Mar

ch 1

995

Mocroft A et al. Lancet. 2003;362:22-29.

5

Immunosuppression Increases the Risk

of Non–HIV-related Death (D:A:D Study)

RR of Death According to Immune Function and Specific Cause

Weber R et al. Presented at: 12th Annual Conference on Retroviruses and Opportunistic Infections; February 24, 2005;Boston, MA. Abstract 595.

• N=23,441– Of these, 82% on ART

• 1248 (5.3%) deaths 2000–2004 (1.6/100 person-years)• Incidence of CV-related mortality (9%) lower than other non–HIV-related deaths,

liver-related mortality (14%), and HIV-related mortality (30%)

Latest CD4+ count (cells/mm3)

100

>500<50 50–99 100–199 200–349

1.0

10

Rela

tive r

isk o

f d

eath

0.1350–499

MalignancyHeart

HIVLiver

6

SMART Study: Uncontrolled HIV Replication Increases the

Risk of CVD• CD4+ guided drug conservation (DC) strategy was associated with

significantly greater disease progression or death compared with continuous viral suppression (VS): RR 2.5 (95% CI: 1.8–3.6; P<.001)

• Includes increased CVD-, liver-, and renal-related deaths and nonfatal CVD events Severe Complications End Point and Components

SubgroupsNo. of Patients

With EventsRelative Risk

95% CI

Severe complications

CVD, liver, renal deaths

Nonfatal CVD events

Nonfatal hepatic events

Nonfatal renal events

114

63

31

7

14

0.1 10VS Better

DC Worse

1.5

1.4

1.4

1.5

2.5

SMART=Strategies for Management of Anti-Retroviral Therapy.El-Sadr W et al. Presented at: 13th Annual Conference on Retroviruses and Opportunistic Infections; February 8, 2006; Denver, CO. Abstract 106LB.

7

HIV-related Morbidityand Mortality: Summary

• HIV+ patients have an increased life expectancy since the introduction of HAART

• The best prospective data show the relative rate of MI in HIV+ population is low and decreasing over time

• From a public health standpoint, MI and other CVD events are a relatively smaller issue in HIV+ patients when compared with overall HIV-related morbidity and mortality

• Most guidelines support maximal viral suppression and increased immune function– Increasing CD4+ T-cell count to levels approaching

uninfected controls may reduce all-cause mortality, as well as HIV-related mortality1

1. Weber R et al. Presented at: 12th Annual Conference on Retroviruses and Opportunistic Infections; February 24, 2005;Boston, MA. Abstract 595.

8

Cardiovascular Diseaseand Risk Factors

Similarities and DifferencesCompared With the General

Population

9

Traditional Factors Are the Biggest Contributor to Coronary Heart Disease

(CHD) in HIV Population

Diabetes

*Metabolic syndrome.CRP=C-reactive protein; IMT=intima-media thickness; Lp(a)=lipoprotein(a).

Lipids*

Family history

Abdominal

obesity*

Hyper-tension*

Cigarette

smoking

Hyper-glycemia

Inactivity, diet

Age

Insulin resistanc

e*

Emerging markers:

Lp(a) CRP, IMT and endothelial

function

Gender

CHD Risk

HIV infection

HAART

?

10

In the General Population, Multiple Traditional Risk Factors Confer Synergistic Increases in

the Risk of MI: INTERHEART Study

Risk factor (adjusted for all others)

Evaluated Factors Associated With MI in 15,000 MI Patients vs 15,000 Case Controls

>90% of total risk can be attributed to these factors. ApoB/A1=apolipoproteins B and A1; DM=diabetes mellitus; HTN=hypertension; Obes=abdominal obesity; PS=psychosocial; RF=risk factors; Smk=smoking.

Yusuf S et al. Lancet. 2004;364:937-952.

Smk(1)

DM(2)

ApoB/A1(4)

1+2+3 All 4 +Obes All RFs1

2

4

8

16

32

64

128

256

512

Od

ds r

ati

o (

99

% C

I)

2.9(2.6–3.2)

2.4(2.1–2.7)

1.9(1.7–2.1)

3.3(2.8–3.8)

13.0(10.7–15.8)

42.3(33.2–54.0)

68.5(53.0–88.6)

182.9(132.6–252.2)

333.7(230.2–483.9)

HTN(3)

+PS

11

*Continuous variable.MV=multivariate; VL=viral load.Lichtenstein K et al. Presented at: 13th Annual Conference on Retroviruses and Opportunistic Infections; February 6, 2006; Denver, CO. Abstract 735.

Overall Incidence of CV Events Is Low in an HIV-infected Population:

HOPS Cohort

Nadir HDL*

MV Logistic Regression Analysis of Risk Factors for CVD(n=1807)

0.97

1.731.95

3.243.31

0.1

1

10

Age >40 Diabetes Hyper-lipidemia

HTN

Ad

juste

d o

dd

s r

ati

o(9

5%

CI)

• >8000 patients followed since 1993 in HIV Outpatient Study (HOPS)• 1807 selected patients from 3/1/96 to 9/30/05 with available baseline and ≥1 cholesterol, TG,

and glucose value recorded (note possible selection bias)• Results: 84 CVD events in 57 patients

– No association found for specific ARV/class, pre-HAART CD4+ cell count, time on HAART, BMI >30, peak VL, peak TC, peak LDL, or peak TG

– Risk of CV events reduced with lipid-lowering agents

P=.004P<.001 P<.001 P=.024 P=.059

12

Risk Factors for CHD inan HIV+ Population

Relative rate of myocardial infarction (95% CI)Multivariable Poisson model

(adjusted for BMI, HIV risk, cohort, calendar year, and race)

RR 2.29 (1.61-3.26)Diabetes mellitus (yes vs no)

RR 1.67 (1.21-2.30)Hypertension (yes vs no)

Better Worse

0.1 0.5 1 5 10

Family history

Previous CVD

Male gender

Age per 5 years older

Smoking

Copenhagen HIV program (D:A:D)Lundgren JD et al. Presented at: 12th Annual Conference on Retroviruses and Opportunistic Infections; February 23, 2005; Boston, MA. Abstract 62.

13

Incidence of Smoking Is Increased AmongHIV-infected Individuals vs the General

Population

• HIV+ men and women (n=223) on PI-based regimens vs 527 HIV- male subjects – HIV+ patients have lower HDL-C and higher TG– Predicted risk of CHD was greater in HIV+ men (RR=1.2) and women (RR=1.6), P<.0001

No difference in TC

Blood glucose

126 mg/dL

P=NS

0

10

20

30

40

50

60

70

P<.0001

Smoking

P<.01

Hypertension

Pati

en

ts (

%)

P<.0001

HDL-C <40 mg/dL

P=NS

LDL-C 160 mg/dL

Savès M et al. Clin Infect Dis. 2003;37:292-298.

APROCO Cohort (HIV+)MONICA sample (HIV–)

14

VA Database: No Evidence of Increased CV Events in 36,766 Veterans With HIV

(1993-2001)

• 8.5-year retrospective assessment of VA databases

• Median exposure: – NRTI: 17 months– PI: 16 months– NNRTI: 9 months

• CV disease and overall mortality

– 1764 CV admissions– 521 CV deaths– 16,731 total deaths

• Marked decline in overall mortality since HAART

• No evidence of increase in CV hospital admissions or CV mortality with HAART

0

0.5

1.0

1.5

2.0

2.5

NoART

0 <2 2–4 >4

Ad

mis

sio

ns p

er

100 p

t-yrs

NRTIs + NNRTIs

NRTIs + PIs

CVD AdmissionsCVD Admissions

ART (years of use)Bozzette SA et al. N Engl J Med. 2003;348:702-710.

15

D:A:D Study: Rates of MI in HIV-infected and HAART-treated

Patients Over Time

RR

(9

5%

CI)

99/00 01 02 03 04/050.25

0.5

1

2

• Incidence of MIs is low: 345 over 94,469 pt-years follow-up (3.7/1000 pt-years) PI exposure associated with risk of MI (RR: 1.17/year of exposure; 95% CI 1.12-1.23)• No evidence of risk of MI with NNRTI exposure, despite fewer years of experience

(RR: 1.07/year of exposure; 95% CI 1.00-1.14)• PI exposure 72,846 pt-yrs; NNRTI exposure 52,457 pt-yrs

D:A:D=Data Collection on Adverse Events of Anti-HIV Drugs.Friis-Møller N et al. Presented at: 13th Annual Conference on Retroviruses and Opportunistic Infections; February 8, 2006; Denver, CO. Abstract 144.

Overall RRModel adjusted for: sex, age, cohort, prior CVD, family CVD history, smoking, BMI, cART exposure

Model adjusted for serum-lipids (total cholesterol, HDL-C, and triglycerides)

16

Studies on CV Risk in HIV-infected and HAART-treated Patients Are

Inconsistent N Study Event ARV Effect Traditional Risk Factors

VA1 36,766 R 1207 CHD No effect with HAART or PI Not evaluated

HOPS2 1807 P 84 CV events

No association found for specific ARVs Age >40 y, diabetes, HTN

D:A:D3 23,490 P 345 MI Greater risk with cART and PI Smoking, age, gender, HTN, DM

Kaiser4 4408 R 86 MI Greater risk for HIV+ vs HIV-Greater risk on PIs Not evaluated

Medi-Cal5 28,513 R NA Greater risk with ART in 18–33 year olds only Not evaluated

French6 34,976 R 49 MI Greater risk with PI vs HIV- Age

Johns Hopkins7 2671 Case

control 43 CHD Greater risk for HIV+ vs HIV- Age, HTN, DM

Frankfurt8 4993 R 29 MI Greater risk with HAART Age >40

SMART9 5472 P 63 CHD Increased risk with intermittent HAART Age

P=prospective; R=retrospective.1. Bozzette SA et al. N Engl J Med. 2003;348:702-710. 2. Lichtenstein K et al. 13th CROI, Denver 2006. Abstract 735.3. Friis-Møller N et al. 13th CROI, Denver 2006. Abstract 144. 4. Klein D et al. 13th CROI, Denver 2006. Abstract 737.5. Currier JS et al. J Acquir Immune Def Syndr. 2003;33:506-512.

6. Mary-Krause M et al. AIDS. 2003;17:2479-2486. 7. Moore RD et al. 10th CROI, Boston 2003. Abstract 132. 8. Rickerts V et al. Eur J Med Res. 2000;5:329-333. 9. El-Sadr W et al. 13th CROI, Denver 2006. Abstract 106LB.

17

Cardiovascular Disease and Risk Factors:

Similarities and Differences Compared

With the General Population

• Traditional risk factors for CV disease, suchas age and smoking, increase CV risk in both HIV+ and HIV– individuals

• HIV disease may confer its own increase in CVD risk

• HAART may contribute to increased CV risk, but the absolute increase due to HAART is low

18

Choosing an Initial Regimen: Tolerability and Toxicity

NRTIs• GI discomfort• Headache• Hypersensitivity reaction• Neuropathy• Pancreatitis• Bone marrow suppression• Lactic acidosis• Lipoatrophy• Dyslipidemia

NNRTIs• Rash• CNS• Hepatitis• Dyslipidemia• Teratogenicity

Protease inhibitors• GI discomfort• Diarrhea• Paresthesia• Hyperbilirubinemia• Dyslipidemia• Lipodystrophy• Nephrolithiasis• Skin/nail changes• Interaction with ARVs• Food interactions

Type and magnitude of lipid variation may vary between classes and agent

19

RTV 100 mg bid or LPV/r (HIV–) 14 days

Metabolic Effects of Low-dose Ritonavir

Parameter BaselineRTV

(100 mg bid)

LPV/r(400/100 mg

bid)

N 20 20 20

Total cholesterol (mg/dL)

166 185* 197*

LDL-C (mg/dL) 97 113* 120*

HDL-C (mg/dL) 53 51† 53

Triglycerides (mg/dL) 79 98* 114‡

*P≤.001; †P=.01; ‡P=.015.Shafran SD et al. HIV Med. 2005;6:421-425.

20

KLEAN study: FPV/r vs LPV/r (+ ABC/3TC):No Differences in Lipid Levels Between

Study Arms

• Open-label, non-inferiority study: 878 ART-naïve, HIV+ patients randomized to FPV + RTV (n=436) 700 mg/100 mg bid or LPV/r (SGC) 400 mg/100 mg bid (n=443)

• Primary end points: proportion of patients achieving HIV-1 RNA <400 c/mL at Week 48 and treatment discontinuations because of an adverse event

0

50

100

150

200

250

TC LDL-C HDL-C TG

Fast

ing

lipid

leve

ls(m

g/dL

)

FPV + RTV at baseline FPV + RTV at Week 48 LPV/r at baseline LPV/r at Week 48

Fasting Lipid Levels at Week 48

KLEAN=Kaletra versus Lexiva with Epivir and Abacavir in ART-Naïve patients; SGC=soft gel capsule.Eron R Jr et al. Lancet. 2006;368:476-482.

21

Fasting Lipid Profiles forBoosted vs Unboosted

Atazanavir

Lipid Percent Changes From Baseline to Week 48

96-week randomized, open label, prospective study of ATV + RTV (300/100 mg) vs

ATV (400 mg), both in combination with 3TC and extended-release d4T (N=200)

Malan N et al. Presented at: 13th Annual Conference on Retroviruses and Opportunistic Infections; February 7, 2006;Denver, CO. Abstract 107LB.

<.01 0.21 0.69P value

TC LDL-C HDL-C TG

15

23

30

26

6

16

29

-3-5

0

5

10

15

20

25

30

35

Mean

ch

an

ge f

rom

baselin

e (

%)

ATV 300 + RTV

ATV 400

<.01

22

Lipid Profiles: Once-daily BoostedFPV/r vs ATV/r + (TDF/FTC)

Smith K et al. Presented at: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, CA. Abstract H-1670a.

160 153116 127

180160

133177

0

50

100

150

200

250

FPV/r ATV/r FPV/r ATV/r

Mg

/dL

Cholesterol Triglycerides

Mg

/dL 95 97

38 38

103

41 45

99

0

50

100

150

FPV/r ATV/r FPV/r ATV/r

LDL HDL

Baseline

Week 24

23

Lipid Profiles:Atazanavir vs Comparator PI

Sension M et al. 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, MA. Poster #858.

8 10

42

11

01020304050

ATV 400 Comparator PI

Total Cholesterol <200 mg/dL

BL Wk 12 BL Wk 12

Pati

en

ts (

%)

50 5268

54

0

25

50

75ATV 400 Comparator PI

HDL ≥40 mg/dL

BL Wk 12 BL Wk 12

Pati

en

ts (

%)

20 24

52

22

0

25

50

75ATV 400 Comparator PI

TG <150 mg/dL

BL Wk 12 BL Wk 12

Pati

en

ts (

%)

814

33

14

01020304050

ATV 400 Comparator PI

LDL-C <130 mg/dL

BL Wk 12 BL Wk 12

Pati

en

ts (

%)

24

• Primary end points– Time to virologic failure– Regimen completion: virologic failure or toxicity-related discontinuation of any regimen component

ACTG 5142: LPV/r vs EFV vs LPV/r + EFV

Antiretroviral-naïve patients*;

VL >2000 copies/mL;any CD4+ cell count

(N =753)

LPV/r SGC 400/100 mg twice daily + 2 NRTIs*

(n=253)

EFV 600 mg once daily + 2 NRTIs*

(n=250)

LPV/r SGC 533/133 mg twice daily + EFV 600 mg once daily

(n=250)

Week 96Stratified for VL ≤ or > 100,000, hepatitis coinfection, and selection of NRTI

Riddler SA et al. 16th International AIDS Conference. August 13-18, 2006. Toronto, Ontario. Abstract THLB204.

*Lamivudine plus either ZDV, d4T XR, or TDF, selected by investigator before randomization.

25

ACTG 5142: 96-Week Tolerability Results

Patients (%)

Lopinavir/r(n=253)

Efavirenz +

Lopinavir/r

(n=250)

Efavirenz

(n=250)

Grade 3/4 adverse event 18 20 19

Grade 3/4 laboratory abnormality 32 45 33

LDL-C >190 mg/dL 3 6 1

Triglycerides >750 mg/dL 3 14 6

AST >5 times ULN 4 5 4

ALT >5 times ULN 3 7 5ACT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal.Riddler SA et al. 16th International AIDS Conference. August 13-18, 2006. Toronto, Ontario. Abstract ThLB204.

26

Lipid Effects of NNRTIs: EFV vs NVP

5†

49†

34*

40

31

-4%

20

43

35

27

-10

0

10

20

30

40

50

60

TC LDL-C HDL-C TG TC:HDL-C

ratio

Mea

n ch

ange

fro

m b

asel

ine

(%)

EFV arm NVP arm

Lipid Changes at Week 48• 2NN study

– Prospective analysisin treatment-naïve patients

• Lipid profiles

• Randomized treatments– Efavirenz (n=289)

– Nevirapine (n=417)

– All patients: 3TC + d4T

*P<.05 and †P<.001 vs NVP arm.

Adapted from van Leth F et al. PLoS Med. 2004;1:64-74.

27

Lipid Changes Differ Among NRTIs

Fasting Total Cholesterol

0

0.5

1.0

1.5

2.0

TG TC LDL-C HDL-C

TDF

d4T

Mean

ch

an

ge f

rom

baselin

e

valu

e (

mm

ol/

L)

P<.001 P<.001

P<.001

P=.003

d4T vs TDF (3TC + EFV)

Arribas JR et al. Presented at: 18th International Conference on Antiviral Research; April 11-14, 2005; Barcelona, Spain;Gallant J et al. N Engl J Med. 2006;354:251-260; Podzamzscer D et al. Presented at: 12th Annual Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, MA. Abstract 587S.

Study week

-10

0

10

20

30

40

0 4 16 24 32 48

Mean

ch

an

ge f

rom

baselin

e

(mg

/dL)

P<.001

21

36

TDF + FTC + (EFV)

Combivir + (EFV)

28

Summary• Dyslipidemia has been reported with PIs,

NNRTIs,and NRTIs

• Ritonavir boosting affects lipid profiles regardless of the PI chosen

• NNRTIs are associated with increases in all lipid parameters

• All NRTIs, when used in combination with other antiretrovirals, are associated with an increasein lipid parameters

• HDL-C increases seen with antiretrovirals may favorably impact cardiovascular risk