HIV JO Slide Template

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Update on Cardiovascular Complications
Judith S. Currier, MD Professor of
MedicineUniversity of California Los Angeles
The International AIDS SocietyUSA
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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)
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HIV Related Complications
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Cardiovascular Complications Atherosclerosis

• Epidemiology of CVD in HIV
• Host Factors
• Role of HIV
• Role of ART

5
Non AIDS Events Contributor to Morbidity and
Mortality

• Causes of Death among 68,669 HIV-infected in New
  York City
• Non-HIVrelated deaths increased from 19.8 to
  26.3 between 1999 and 2006
• Due to CVD, substance abuse and non-AIDSdefining
  cancers
• Among individuals 55 years, CVD leading cause
  of death

Overall deaths
HIV-related deaths
Non-HIVrelated deaths
Cardiovascular-related deaths
900
Cancer-related deaths
800
Substance abuserelated deaths
700
600
500
400
Age-Adjusted Mortalityper 10,000 Persons With
AIDS
300
200
100
30
20
10
1999
2000
2003
2004
2001
2002
Sackoff JE, et al. Ann Intern Med.
2006145397-406.
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Risk of MI HIV compared to HIV (-)
LUNDGREN AHA Meeting June 28th, 2007
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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 lt
  .0001) and MI (P lt .002) vs HIV-uninfected men

Rates adjusted to 1990 US population, 5-year age
groups.
Klein D, et al. CROI 2007. Abstract 807.
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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
HIV infected
90
77.68
HIV uninfected
60
Rates per 1000 Person-Yrs
43.63
36.47
33.39
24.47
30
18.74
14.78
10.13
7.56
4.65
3.34
0.88
0
35-44
45-54
55-64
65-74
75-84
18-34
Age Group (Yrs)
Triant VA, et al. J Clin Endocrin Metab.
2007922506-2512.( Slide adapted from Tebas-
Clinical Care Options)
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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
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HOST FACTORS
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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

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Are Contributions from Traditional Risk to MI
Risk the Same in HIV?
Adapted from, Currier JS, Lundgren JD et al.
Circulation 2008118198-210. Sabin CA, Worm S.
Curr Opin HIV AIDS 20082214-219
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Role of Other Host Factors

• Smoking
• Family History CHD
• Diabetes
• Hypertension

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Prevalence of Traditional Cardiac Risk Factors
in the DAD 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
80
60
51.5
Percentage of Cohort With Risk Factor at Baseline
40
33.8
22.2
20
11.4
8.5
3.5
2.5
1.4
0
Family Historyof CHD
PreviousHistory of CHD
CurrentSmoking
BMIgt 30
HTN
Diabetes
? TotalCholesterol
? TG
Friis-Møller N, et al. AIDS. 2003171179-1193.
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Framingham Score and MI Risk in HIV-Infected
Patients
Observed and Predicted MI Rates According to ART
Exposure (DAD Study)
8
7
Observed rates
6
5
Best estimate of predicted rates
4
Rates per 1000 Person-Yrs
3
2
1
0
lt 1
1-2
2-3
3-4
gt 4
None
Duration of cART Exposure (Yrs)
Law MG, et al. HIV Med. 20067218-230.
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ROLE OF HIV
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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 gt 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
35522832296
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Clinical Outcomes Better for Immediate vs Delayed
ART in Patients with CD4 gt350Subset of SMART
Study not on ART at Entry
Immediate
Defer
? Untreated HIV was associated development of
these Non-AIDS events
JID 2008197 (April15) 1133-44
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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 20081721100-11
• 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 20064_at_365

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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 200819979-86).
• 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

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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)

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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 2006202275-83)
• 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)

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Effects of ART

• Lipids effects of ART
• Clinical Event Data

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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
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ART and Lipids in Naïve Patients (Adapted From
Eckhardt and Glesby, Curr Opin HIV/AIDS, 2008)
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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

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Adapted from Currier J, Lundgren JD et al.
Circulation, July 2008
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PI effect appears to be cumulative, and partially
mediated by lipid changes
Adapted from Currier J, Lundgren JD et al.
Circulation 2008
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NRTIs and MI Risk

• Hypothesis- thymidine analogues associated with
  more lipid changes and expected to see
  contribution to MI risk
• DAD Study (Lancet, 2008 3711417-28)
• 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?

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Observational Analysis of SMART Study to
Confirm/Refute DAD 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 (n19)
• 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.
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SMART Current Use of ABC but Not ddI Associated
With Increased CV Risk
Favors Other
Favors ABC/ddl
1.8
ABC (no ddI)
CVD, major (n 70)
ddI (/- ABC)
4.3
MI (n 19)
1.9
CVD, expandeddefinition (n 112)
2.7
CVD, minor(n 58)
10
0.1
1

• 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.
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Inflammatory Biomarkers at BL and on Treatment
With ABC

• SMART1
• 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
• HEAT2
• IL-6 and high-sensitivity C-reactive protein
  decreased from BL at Week 48 and 96 in patients
  receiving ABC/3TC and TDF/FTC

1. Lundgren J, et al. IAC 2008. Abstract
THAB0305. 2. Smith KY, et al. IAC 2008. Abstract
LBPE1138.
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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.
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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-up1
• 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)

• Of 119 CV events in HOPS cohort, no association
  with ABC use2

1. Cutrell A, et al. IAC 2008. Abstract
WEAB0106. 2. Lichtenstein K, et al. IAC 2008.
Abstract THPE0236.
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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

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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?

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Summary of HIV, Host and ART Effects
HIV Replication
ART Effects
Immune Activation
Inflammation
Altered Lipid Effects
Endothelial Function
Macrophage recruitment
Insulin Resistance
HIV
Atherosclerosis
Smoking Hypertension
Diabetes
Genetics
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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

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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

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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