Get documents about "Hiv Jo Slide Template - PowerPoint
W
Description
Hiv Jo Slide Template document sample
Document Sample
Slide 1
Update on Cardiovascular
Complications
Judith S. Currier, MD
Professor of Medicine
University of California Los Angeles
The International AIDS Society–USA
Slide 2
Disclosure Information
Dr Currier received research grants to UCLA
from Tibotec, Merck, GlaxoSmithKline and
Theratechnologies and served as a
consultant or received honoraria from Bristol-
Myers Squibb, GlaxoSmithKline, Merck,
Pfizer, and Tibotec. In addition she serves on
a data safety monitoring board for Koronnis
and Achillion Pharmaceuticals. (Updated
09/01/08)
Slide 3
HIV Related Complications
Slide 4
Cardiovascular Complications:
Atherosclerosis
Epidemiology of CVD in HIV
Host Factors
Role of HIV
Role of ART
Slide 5
Non AIDS Events: Contributor to
Morbidity and Mortality
Causes of Death among 68,669
Overall deaths
HIV-infected in New York City HIV-related deaths
Non-HIV–related deaths
per 10,000 Persons With AIDS
Cardiovascular-related deaths
Non-HIV–related deaths 900
Age-Adjusted Mortality
Cancer-related deaths
800 Substance abuse–related deaths
increased from 19.8% to 26.3% 700
600
between 1999 and 2006 500
400
300
– Due to CVD, substance 200
100
abuse and non-AIDS– 30
20
defining cancers 10
1999 2000 2001 2002 2003 2004
– Among individuals ≥ 55
years, CVD leading cause
of death
Sackoff JE, et al. Ann Intern Med. 2006;145:397-406.
Slide 6
Risk of MI: HIV + compared to HIV (-)
Study Size Outcome HIV+ vs HIV- Adj. CV
RF
Klein, JAIDS, 4,159/39,877 CAD adm (6.5 vs 3.8/1000 Partial
’02 PY)
Klein, CROI, 5,000/43000 CAD adm (4.5 vs 2.9/1000 Partial
’07 PY)
Currier, JAIDS,
’03
28,513/3 mill CAD (only in Partial
adm young)
Triant, JCEM,
’07
3,851/1 mill MI adm (75%) Partial
Obel, CID, ’07 3,953/0.4 CAD (39-112%) Partial
mill
adm
LUNDGREN AHA Meeting June 28th, 2007
Slide 7
CHD Incidence Higher in HIV- Infected
Patients compared to HIV-negative
Administrative data on 5000 HIV-infected men followed for 10.5
years compared with 43,000 age-matched HIV-uninfected men
HIV-infected men had higher rates of CHD (P < .0001) and MI
(P < .002) vs HIV-uninfected men
Age-Adjusted Rates* All HIV- HIV-Uninfected
From 1996-2004, Events Infected Comparator
per 1000 Person-Yrs Patients Group
(95% CI)
Hospitalization for CHD 6.1 (4.9-7.3) 2.9 (2.7-3.1)
Hospitalization for MI 3.8 (2.8-4.7) 2.2 (2.0-2.4)
*Rates adjusted to 1990 US population, 5-year age groups.
Klein D, et al. CROI 2007. Abstract 807.
Slide 8
MI Rates Higher in HIV-Infected
Compared to HIV-Uninfected Patients
Administrative Hospital Database : Acute MI rates in 3851
HIV-infected and 1,044,589 HIV-uninfected patients from
1996-2004
– MI rate per 1000 person-years higher in HIV-infected vs HIV-
uninfected patients: 11.13 vs 6.98
120
Rates per 1000 Person-Yrs
HIV infected
90
HIV uninfected 77.68
60
43.63 36.47
33.39
30 24.47
18.74 14.78
4.65 0.88 10.13 3.34 7.56
0
18-34 35-44 45-54 55-64 65-74 75-84
Age Group (Yrs)
Triant VA, et al. J Clin Endocrin Metab. 2007;92:2506-2512.( Slide adapted from Tebas- Clinical Care Options)
Slide 9
What explains higher rates of CVD in HIV?
HOST VIRUS
ART
Understanding the relative contributions of each of these
factors to the pathogenesis of CVD in HIV will help to
inform the development of strategies for prevention and
treatment
Slide 10
HOST FACTORS
Slide 11
Genetic Factors and CHD Risk
Genetic predisposition to CHD and genetic predisposition
to HIV acquisition/progression- could they be linked?
Monocyte Chemoattractant Protein (MCP-1) and CCR2 axis
MCP-1 involved in migration of monocytes into intima
during atherosclerosis plaque formation
MCP-1 Alleles linked to atherosclerosis in HIV- and HIV
+ populations (Alonso-Villaverde C, 2004)
CCR-2 is receptor for MCP-1
Polymorphisms in CCR-2 gene examined for role in
atherosclerosis and also in HIV transmission, no clear
link
Slide 12
Are Contributions from Traditional Risk to
MI Risk the Same in HIV?
Risk Factor Unit Iloeje, HIV Friis-Moller N HIV –
Med 2005 et al. DAD Studies
NEJM 2003 (# studies)
Age Yr inc 9% 6% 6-9% (7)
Sex M vs F NA 110% 110-160% (2)
Diabetes Y vs N 260% 90% 140-252% (3)
Smoking Y vs N 140% 290% 70-290% (3)
HTN Y vs N 30% 80% 80-90% (3)
Adapted from, Currier JS, Lundgren JD et al. Circulation 2008;118:198-210.
Sabin CA, Worm S. Curr Opin HIV AIDS 2008;2:214-219
Slide 13
Role of Other Host Factors
Smoking
Family History CHD
Diabetes
Hypertension
Slide 14
Prevalence of Traditional Cardiac
Risk Factors in the D:A:D Study
Large cohort of HIV-infected patients on HAART followed
longitudinally (N = 23,468)
18,962 (80.8%) with previous ART exposure; 4506 (19.2%)
antiretroviral naive
100
Percentage of Cohort With
Risk Factor at Baseline
80
60
51.5
40 33.8
22.2
20
11.4 8.5
1.4 3.5 2.5
0
Family Previous Current BMI HTN Diabetes Total TG
History History Smoking > 30 Cholesterol
of CHD of CHD
Friis-Møller N, et al. AIDS. 2003;17:1179-1193.
Slide 16
ROLE OF HIV
Slide 17
Spectrum of HIV-Related Clinical
Events
The SMART was designed to examine a strategy of
limiting time on ART with the hopes of reducing the rates
of ART associated complications.
CD4 > 350, 5472 pts randomized to DC or VS groups
Event # Rate DC Rate VS HR
OD/Death 169 3.4 1.3 2.6
CVD/Renal 104 1.8 1.1 1.7
Liver
The study brought into focus the importance of serious non
AIDS Events among patients interrupting ART
El-Sadr WM, Lundgren JD et al NEJM 2006; 355:2283–2296
Slide 19
How HIV infection per se may
contribute to atherosclerosis
HIV demonstrated to infect smooth muscle cells in vitro
and in vivo and increase secretion of monocyte
chemoattractant (CCL-2) Eugenin EA et al Am J Pathol 2008;172:1100-11
Macrophages are host for HIV and these cells play a
pivotal role in atherosclerosis
– HIV impairs ABCA-1 in macrophages, important for reverse
cholesterol transport; this in turn may lead to conversion into foam
cells and initiate placque formation in the vessel wall. Mujawar, Z,
et al PLoS Biol 2006;4:@365
Slide 20
How HIV infection per se may
contribute to atherosclerosis (2)
HIV may also directly impair HDL metabolism-
enhancing transfer of HDL to apoB lipoproteins
(Rose,H, et al Atherosclerosis 2008;199:79-86).
HIV TAT may promote secretion of MCP-1 (Park IW,
Blood, 2001)
Collectively these findings suggest that untreated
HIV could contribute to development of
atherosclerosis; magnitude of the effect is unclear
Slide 21
Inflammation and HIV
CRP is an acute phase reactant that independently
predicts risk of CV events in adults
CRP predicts HIV disease progression and mortality in
untreated women (adj for RNA and CD4) ( Feldman 2003; Drain
2007)
Uncontrolled HIV infection is associated with elevated
levels of markers of inflammation (CRP), levels decline
with treatment but not to normal (Henry, 2002)
– Less is known about how different ART agents impact CRP
during successful treatment of HIV, data on abacavir and
TDF presented at this conference
In SMART Study IL-6 and d-dimer rose after treatment
interruption and baseline levels were associated with all
cause mortality. (Kuller, CROI 2008)
Slide 22
Inflammation, HIV and Markers of
Atherosclerosis
Higher levels of hsCRP not strongly associated with IMT in
several small studies (Ross CROI 2008; Currier 2007; Hsue 2006)
Hsue reported CMV specific T cells responses, but not
hsCRP or immune activation (CD38+ CD4 and CD8)
associated with IMT (AIDS 2006;20:2275-83)
Endothelial function improved during 24 weeks of ART
with no significant change in hsCRP (ACTG 5152s; JACC 2008 in
press)
Pilot study of TNF inhibitor, pentoxifylline 400 mg TID,
showed improvements in endothelial activation marker,
VCAM-1, and in brachial FMD (2% to 8%) over 8 weeks
( Gupta S,CROI 2008)
Slide 23
Effects of ART
Lipids effects of ART
Clinical Event Data
Slide 24
Impact of Lipids on CV Risk in DAD
RR of MI per year of CART 1.17 (1.11-1.24)
• Men 1.14 (1.06-1.24)
• Women 1.38 ( 1.07-1.76)
• After adjustment for lipid levels
• RR MI 1.10 ( 1.01-1.19)
• Part, but not all of the association is
explained by lipids
• Other possible factors:
• Diabetes, insulin resistance, inflammation,
DAD Study NEJM 2007
Slide 25
ART and Lipids in Naïve Patients
(Adapted From Eckhardt and Glesby, Curr Opin HIV/AIDS, 2008)
Drug NRTI T chol LDL HDL TG TC:
HDL
ATV/r TDF/FTC
LPV ABC/3TC
LPV TDF/FTC
FAPV/r ABC/3TC
FAPV/r TDF/FTC NA
DRV/r TDF/FTC
EFV ZDV/3TC NA
EFV TDF/FTC NA
MVC ZDV/3TC NA
RAL TDF/FTC No chg
Slide 26
Association between ART and CVD
Types of Studies
– Randomized Trials
– Prospective Observational Cohorts
– Retrospective Reviews
– Administrative Databases
Challenges
– Different endpoints
– Variable assessment of and control for risk factors
– Limited follow-up in some studies
Slide 27
Study # Type of PI effect Type of
Events Event Study
Coplan,2003 19 MI No RCT
Phillips, 2008 31 CVD Y RCT
Holmberg, 2002 21 CVD Y P Cohort
Iloeje, 2005 127 CVD Y P Cohort
DAD I, 2007 345 MI Y P Cohort
Mary Krause, 2003 66 MI Y Retro
Rickerts, 2000 29 MI ART effect Retro
Klein, 2007 162 CAD adm Y Adm Data
Bozette, 2003 1207 CAD adm No Adm Data
Currier, 2003 1360 CAD adm ART Adm
Adapted from Currier J, Lundgren JD et al. Circulation, July 2008
Slide 28
Study # Type of PI effect Type of
Events Event Study
Coplan,2003 19 MI No RCT
Phillips, 2008 31 CVD Y RCT
Holmberg, 2002 21 CVD Y P Cohort
Iloeje, 2005 127 CVD Y P Cohort
DAD I, 2007 345 MI Y P Cohort
Mary Krause, 2003 66 MI Y Retro
Rickerts, 2000 29 MI ART effect Retro
Klein, 2007 162 CAD adm Y Adm Data
Bozette, 2003 1207 CAD adm No Adm Data
Currier, 2003 1360 CAD adm ART Adm
PI effect appears to be cumulative, and partially mediated by lipid changes
Adapted from Currier J, Lundgren JD et al. Circulation 2008
Slide 29
NRTIs and MI Risk
Hypothesis- thymidine analogues associated with more
lipid changes and expected to see contribution to MI risk
DAD Study (Lancet, 2008 371:1417-28)
– No association between ZDV or d4T and MI risk, incomplete
data on tenofovir to date
– Increased risk associated with recent exposure to ABC (HR
1.9), less so with ddI (HR 1.49)
– Excess risk magnified in those with underlying RF
– Risk decreased after cessation
– Contrasts with PI Risk which appears to be cumulative,
mechanism unknown, possible link to inflammation
– Interaction between PI and NRTI risk – how does updated info
on ABC impact PI associated risk in DAD?
Slide 30
HIV/AIDS Update From Mexico City 2008
Observational Analysis of SMART
Study to Confirm/Refute D:A:D Results
Analysis of SMART participants in 3 post hoc subgroups by NRTI use
– Patients receiving ABC and not ddI
– Patients receiving ddI, with ABC or other NRTIs
– Patients receiving NRTIs other than ABC and ddI
CV endpoints
– MI (n=19)
– Major CVD events: clinical and silent MI, stroke, surgery for CAD, and
CVD death
– Expanded major CVD events: major CVD events plus peripheral vascular
disease, CHF, pharmacotherapy for CAD, and unwitnessed deaths
– Minor CVD events: CHF, peripheral vascular disease, or CAD requiring
pharmacotherapy
Lundgren J, et al. IAC 2008. Abstract THAB0305. clinicaloptions.com/hiv
Slide 31
HIV/AIDS Update From Mexico City 2008
SMART: Current Use of ABC but Not
ddI Associated With Increased CV Risk
Favors ABC/ddl Favors “Other”
1.8 ABC (no ddI)
CVD, major ddI (+/- ABC)
(n = 70) 4.3
MI
(n = 19)
1.9
CVD, expanded
definition (n = 112)
2.7
CVD, minor
(n = 58)
0.1 1 10
•Adjusted HR* (95% CI) of CVD
Increased risk of CVD events with use of ABC driven entirely by patients with
5 CV risk factors at BL (adjusted HR: 3.1)
– No increased risk observed in patients without 5 risk factors, though difference in
risk between patients with vs without these risk factors not statistically significant
Lundgren J, et al. IAC 2008. Abstract THAB0305. clinicaloptions.com/hiv
Slide 32
HIV/AIDS Update From Mexico City 2008
Inflammatory Biomarkers at BL and on
Treatment With ABC
SMART[1]
– BL levels of high-sensitivity C-reactive protein and IL-6 27% (P = .02) and 16%
(P = .02) higher, respectively, for patients receiving ABC without ddI vs those
receiving other NRTIs
HEAT[2]
– IL-6 and high-sensitivity C-reactive protein decreased from BL at Week 48 and 96 in
patients receiving ABC/3TC and TDF/FTC
Inflammatory Study Arm BL, Geometric Week 48, Fold Δ Week 96, Fold Δ
Marker Mean in in Geometric in Geometric
pg/mL Mean vs BL Mean vs BL
IL-6 ABC/3TC 1.91 0.74 0.81
TDF/FTC 1.97 0.77 0.75
High-sensitivity C- ABC/3TC 1.88 0.88 0.95
reactive protein TDF/FTC 1.72 0.80 0.83
1. Lundgren J, et al. IAC 2008. Abstract THAB0305.
2. Smith KY, et al. IAC 2008. Abstract LBPE1138. clinicaloptions.com/hiv
Slide 33
HIV/AIDS Update From Mexico City 2008
Retrospective Analysis of ABC and CV
Risk in Clinical Trials Database
Retrospective analysis of 54 clinical trials (N = 14,683 treatment-naive and -
experienced patients) with 24 weeks of follow-up (1995 - 2006)
– 13 trials randomized adults to ABC vs control
– 33 trials included ABC in background regimen
– 8 trials did not include ABC
Performed MedDRA database query for events coded as “coronary artery
disorders” or “ischemic coronary artery disorders”
– Specific preferred terms: coronary artery atherosclerosis, coronary artery disease,
coronary artery occlusion, acute myocardial infarction, angina pectoris, angina
unstable, myocardial infarction, myocardial ischemia
Fatal cases due to any cause externally reviewed
Incomplete BL data precluded calculation of Framingham risk
Cutrell A, et al. IAC 2008. Abstract WEAB0106. clinicaloptions.com/hiv
Slide 34
HIV/AIDS Update From Mexico City 2008
ABC Not Associated With CV Risk in Clinical Trials
Database, HOPS
No difference in incidence of CV events with ABC exposure in
54-trial analysis with 24-48 weeks of follow-up[1]
– RR of any or acute MI with ABC: 0.863 (95% CI: 0.40-1.86)
– RR of any ischemic CAD or disorder with ABC: 0.593 (95% CI: 0.35-1.01)
ABC-Treated Patients No ABC Treatment
Outcome
(n = 1570) (n = 1692)
Frequency, Rate/1000 Frequency, Rate/1000
% Person-Yrs % Person-Yrs
MI (any or acute) 0.127 2.15 0.355 4.1
Any ischemic CAD or 0.768 7.64
0.318 4.3
disorder
Of 119 CV events in HOPS cohort, no association with ABC
use[2]
1. Cutrell A, et al. IAC 2008. Abstract WEAB0106.
2. Lichtenstein K, et al. IAC 2008. Abstract THPE0236. clinicaloptions.com/hiv
Slide 35
Where does this leave us ?
Two observational studies, with control for known
confounders suggest association with ABC and
MI risk, not confirmed in smaller RCT
– Risk occurs in those patient with other risk factors
– Interaction between PI associated Risk and ABC
risk uncertain
– Limited data with tenofovir to date
Risk needs to be interpreted in context of
treatment and presence of modifiable risk factors
Mechanism to be defined
Slide 36
One Opinion: Individualize
Await further data from ongoing RCT comparing
ABC and TDF in naives ( acknowledging that size
too small to see difference in MI rates)
Patient stable on ABC with 5 risk factors and
options to change- consider switch, if limited
options- continue treatment- successful treatment of
HIV is the priority
Smoking cessation should be a higher priority that
changing NRTI component of ART
Patient stable on ABC without RF- would not modify
Naïve patient starting ART?
Slide 37
Summary of HIV, Host and ART Effects
HIV Replication
ART
Effects
Immune Activation
Inflammation
Altered Lipid
Effects
Endothelial Macrophage Insulin
Function recruitment Resistance
HIV
Smoking
Diabetes Genetics
Hypertension
Slide 38
Summary
ART treatment benefits outweighs risk, delaying therapy
not the answer, impact of earlier treatment under study
Understanding differences between ART agents is critical
when we are considering treatment over decades
Addressing CVD risk factors and tailoring ART regimens
for individual patients pending further data
Important to understand mechanism of ART risk, and the
contributions of HIV
– Prospective assessment of inflammatory markers in cohorts
and controlled trials with patients at comparable stages of
disease is a start
Slide 39
Future Directions
Continue efforts to enhance screening and reduce modifiable
risk factors for CVD, renal and hepatic disease
Examine the role of earlier treatment on non-AIDS events
and morbidity in controlled trials and cohorts
Examine differences between treatment regimens on
markers of inflammation and atherosclerosis, renal and
hepatic disease
Continue to investigate direct effects of HIV on CV ( and
other) events
Slide 40
Acknowledgements
AHA State of the Science Conference : Initiative to Decrease
Cardiovascular Risk and Increase Quality of Care for Patients
Living with HIV, Proceedings Circulation published online June ,
2008
Related docs
Other docs by urh13133
