Cardiovascular Risk in HIV: What Is the Role of Antiretroviral Therapy? David A. Wohl, MD Clinical Associate Professor, Division of Infectious Diseases University of North Carolina at Chapel Hill, School of Medicine Co-Principal Investigator UNC-CH AIDS Clinical Trials Unit (NIH/DAIDS) Co-Director of HIV Services North Carolina Department of Corrections Chapel Hill, North Carolina
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Cardiovascular Risk in HIV: What Is the Role of Antiretroviral Therapy?
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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
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
– 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.
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
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
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