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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
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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,

Dec 18, 2015

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Page 1: 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,

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

Page 2: 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,

Currier, JS. IAC Mexico City, 8/06/08

HIV Related Complications

Page 3: 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,

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

Page 4: 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,

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

Page 5: 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,

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

Page 6: 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,

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

Page 7: 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,

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

Page 8: 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,

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

Page 9: 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,

Currier, JS. IAC Mexico City, 8/06/08

Role of Other Host Factors

Smoking

Family History CHD

Diabetes

Hypertension

Page 10: 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,

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)

Page 11: 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,

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

Page 12: 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,

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

Page 13: 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,

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

Page 14: 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,

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)

Page 15: 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,

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)

Page 16: 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,

Currier, JS. IAC Mexico City, 8/06/08

Effects of ART

Lipids effects of ART

Clinical Event Data

Page 17: 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,

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

Page 18: 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,

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

Page 19: 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,

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

Page 20: 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,

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

Page 21: 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,

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,

Page 22: 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,

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

Page 23: 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,

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

Page 24: 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,

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

Page 25: 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,

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