currier, js. iac mexico city, 8/06/08 hiv-related complications: the contributions of virus, host...
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Currier, JS. IAC Mexico City, 8/06/08
HIV-related complications:The contributions of virus, host and
ART
Judith S. Currier, M.D.University of California, Los Angeles
USA
Currier, JS. IAC Mexico City, 8/06/08
HIV Related Complications
Currier, JS. IAC Mexico City, 8/06/08
HIV Associated Complications
HOST VIRUS
ART
Understand the pathogenesis of these events and the relative contributions of these factors will help us develop strategies for prevention and treatment
Currier, JS. IAC Mexico City, 8/06/08
Spectrum of HIV-Related Clinical Events The SMART examined 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
This 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
Currier, JS. IAC Mexico City, 8/06/08
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
Clinical Outcomes Better for Immediate vs Delayed ART in Patients with CD4 >350:
Subset of SMART Study not on ART at Entry
JID 2008;197 (April15) 1133-44
=Immediate=Defer
Untreated HIV was associated development of these Non-AIDS events
Currier, JS. IAC Mexico City, 8/06/08
Focus of this talk
Role of host, virus and ART Clinical Events/Complications
– Using atherosclerosis as an example
Currier, JS. IAC Mexico City, 8/06/08
Focus of this talk
Role of host, virus and ART in Non AIDS Defining Events
– Atherosclerosis
– Renal Disease
– Hepatic Events
– Lipodystrophy
Currier, JS. IAC Mexico City, 8/06/08
Role of Other Host Factors
Smoking
Family History CHD
Diabetes
Hypertension
Currier, JS. IAC Mexico City, 8/06/08
Are Contributions from Traditional Risk Factors the Same in HIV?
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
Risk Factor Unit Iloeje, HIV Med 2005
Friis-Moller N et al. DAD NEJM 2003
HIV – Studies(# 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)
Currier, JS. IAC Mexico City, 8/06/08
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
Currier, JS. IAC Mexico City, 8/06/08
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
Currier, JS. IAC Mexico City, 8/06/08
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
Currier, JS. IAC Mexico City, 8/06/08
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)
Currier, JS. IAC Mexico City, 8/06/08
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)
Currier, JS. IAC Mexico City, 8/06/08
Effects of ART
Lipids effects of ART
Clinical Event Data
Currier, JS. IAC Mexico City, 8/06/08
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
RTG TDF/FTC No chg
Currier, JS. IAC Mexico City, 8/06/08
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
Currier, JS. IAC Mexico City, 8/06/08
Study # Events
Type of Event
PI effect Type of 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
Currier, JS. IAC Mexico City, 8/06/08
Study # Events
Type of Event
PI effect Type of 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 2008
PI effect appears to be cumulative, and partially mediated by lipid changes
Currier, JS. IAC Mexico City, 8/06/08
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 is cumulative, mechanism unknown, possible link to inflammation ?
GSK Meta-analysis, RCT- no association
SMART study- see Late Breaker THAB0305,
Currier, JS. IAC Mexico City, 8/06/08
Smoking
HypertensionDiabetes Genetics
Endothelial
Function
Altered Lipid
Effects
Inflammation
Immune Activation
HIV Replication
ART Effects
Macrophage
recruitment
Insulin
Resistance HIV
Summary of HIV, Host and ART Effects
Currier, JS. IAC Mexico City, 8/06/08
Where Does this Leave Us? 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
Currier, JS. IAC Mexico City, 8/06/08
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, renal and hepatic events
Currier, JS. IAC Mexico City, 8/06/08
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
Jens D. Lundgren, James Stein, Andrew Carr