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 - PowerPoint PPT PresentationTRANSCRIPT
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