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HIV Complications Update
Judith S. Currier, MD, MSc
University of California, Los Angeles
Updated Disclosures
• Research Grant to UCLA from Theratechnologies
Incidence in select Opportunistic Infections 2000‐2010: NA‐ACCORD, Adapted from: Buchaz et al. JID 2016
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Legarth, A et al. JAIDS 2016
HIV + 2006‐2014
HIV + 2000‐2005
HIV + 1996‐1999
HIV – 1996‐2004
Subset of Well Controlled HIV
No prior co‐morbiditiesViral load < 500
Still had reduced survival Compared to matched popcontrols
Legarth, A et al. JAIDS 2016
Chronic liver disease
Cognitive disorders
Non-AIDS cancers
Chronic renal disease
OsteoporosisCVD
Frailty
Depression
Diabetes mellitus
COPDSlide P. Reiss
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Long Term Complications of Treated HIV Disease
• Epidemiology of Non AIDS Events
•Pathogenesis• Interventions
True or False
I manage all aspects of care of primary care for the HIV positive patients in my practice?
A. True
B. False
Non‐AIDS Causes of Death 2005‐2015
Adapted from Farahani, M et. al. Int J STD AIDS February 10, 2016 as doi:10.1177/0956462416632428
Meta‐analysis of 19 studies reporting deaths in cohorts on ART
Prevalence of Non‐AIDS Deaths
53% high income settings
34 % developing country settings
18% Sub Saharan African setting
Among Non‐AIDS deaths, CVD, Cancer, Liver disease were most common
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• Modelling study projected HIV population in Netherlands
• By 2030• 28% of HIV‐infected patients > 3 NCD’s
• 54% of HIV‐infected patients will be on medications to treat NCDs
28 29
73
84
0
10
20
30
40
50
60
70
80
90
% Age > 50 % > 1 NCD
2010 2030
Evidence for Increased Risk CHD in HIV
• 2003‐MediCal Claims data, excess risk highest in younger age groups (Currier J et al., JAIDS 2003)
• 2007‐Partners Cohort RR MI 1.75 in HIV+ compared to HIV –
(Triant V et al. JCEM, 2007)
• 2013 VA 50% increased risk of AMI after adjustment for risk factors; also noted for women (Freiberg, M et al JAMA IM 2013; Womak 2014)
Trends in Mortality due to CVD in HIV:US 1999‐2013
Proportionate circulatory mortality in HIV-infected women (left) and men (right) aged 25 years and older, 1999 to 2013.
Adapted from: Feinstein M et al. The American Journal of Cardiology, Volume 117, Issue 2, 2016, 214–220
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Trends in Mortality due to CVD in HIV:US 1999‐2013
Adapted from: Feinstein M et al. The American Journal of Cardiology, Volume 117, Issue 2, 2016, 214–220
Non‐Calcified Coronary Plaque more Common in HIV• UCLA Autopsy Study:
• Higher rate of >75% stenosis in HIV compared to control and unusual patterns of calcification in advanced HIV patients (in internal elastic lamina) (Micheletti, RG et al. Cardiovasc Pathol. 2009 Jan‐Feb;18(1):28‐36.)
• Non‐calcified plaque associated with immune activation in HIV (Fitch KV et al, JID 2013208(11);1737‐46
• MACS Cohort (Post W, et al Ann Int Med 2014)
• HIV+ associated with non‐calcified plaque score (p=0.03), along with HTN, DM, dyslipidemia
Cardiac Function
• Cardiac MRI Studies• High burden of myocardial fibrosis, cardiac steatosis among Asx HIV‐infected individuals 1‐4
• Decreased systolic function in HIV compared to controls
• Increased pericardial fat among HIV‐infected individuals with lipo‐accumulation
• Heart Failure Clinical Studies: HIV increases risk of HF,5,6
• 27,363 HIV+ 55,125 HIV‐ free of CVD, 2003‐12
1.Holloway CJ et al Circulation 2013, 2. Thiara DK et al JID 2015,3.Diaz‐Zamundio M et al J Cardiovasc Magn Reson 2015,4. Chew K CROI 2015. 5. White et al. Circulation 2015,6. Butt et al. Archives of Internal Medicine 2011, 7. Secemsky E et al JACC HF 2015
HIV status Events HF Rates HF Risk*
Heart Failure Preserved Ejection Fraction (EF>=40)
HIV+ 752 2.05 (1.85‐2.27) 1.21 (1.05‐1.40)
HIV‐ 361 1.80 (1.67‐1.83) 1.0
Heart Failure Reduced Ejection Fraction (EF<40)
HIV+ 586 2.11 (1.91‐2.34) 1.58 (1.36‐1.89)
HIV‐ 373 1.40 (1.29‐1.52) 1.0
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HOSTGeneticsLifestyle
Virus/ImmuneSystem
AntiretroviralTherapy (ART)
Understanding the relative contributions of each of these factors to the pathogenesis of specific complications in HIV will help to inform the development of strategies for prevention and treatment
What Contributes to the Risk of Non AIDS Events in HIV?
Deeks SG. 2001. Annu Rev Med, 62:141-55Appay V, et al. J Pathol. 2008;214:231-241
Lederman ML, et al. Adv Immunol. 2013;119:51‐83
Loss of immuno‐reguatory cells
Thymic dysfunction and loss of regenerative potential
Co‐Infections
HIV replication
Loss of gut mucosal integrity and microbial translocation
Defects in T cell regenerative potential
Loss of immuno‐regulatory function
CMV and other copathogen levels
Microbial translocation
Innate Immune Activation
Increased cell turnover and lymphoid fibrosis
Increased TF expression and clotting
CAD/stroke, thrombosis
Immune exhaustion
Malignancy
Cytokine secretion (eg, IL‐6, TNFL)
“Inflam‐Aging(atherosclerosis, osteoporosis)
ART
Inflammatory Lipids
Pathogenesis of Non‐Infectious Complications in Treated HIV Disease
Visceral Adiposity
HIV Infection
Host‐Virus
A single measurement of IL‐6 or D‐dimer predicts Serious Non‐AIDS events (SNA)/mortality over next 10y
Grund, PLoS One, 2016, INSIGHT SMART/ESPRIT/SILCAAT Study Group; Ledwama, PLoS One, 2012
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0 1 2 3 4 5 6 7
Death
AIDS
Non‐AIDS
CVD
Malignancy
Hazard Ratio of Study Endpoints for Plasma Levels of Biomarkers4th/1st Quartile
hs‐CRP D‐Dimer IL‐6
IL‐6 stronger predictor of CVD and malignancy than D‐dimer but C.I overlapIndependent associations of IL‐6 were stronger for non‐AIDS related death and all cause death and similar for CVD and non‐AIDS malignancy
Adapted from Borges, AH, INSIGHT SMART AND ESPRIT Groups, JID 2016:214 (1 August)
Biomarkers IL‐6, d‐Dimer and hs CRP for Clinical Events : SMART and ESPRIT
Biomarkers
• Several studies demonstrate that biomarkers such as IL‐6, sCD14 or the CD4/CD8 ratio may help identify those patients at increased risk for non‐AIDS events
• Prediction models for combinations of these markers are being tested currently
• At present these are not ready for widespread clinical use. It is also not clear that they will identify patients you could not already recognize at being of high risk due to traditional risk factors.
• Stay tuned..
HOSTGeneticsLifestyle
Virus/ImmuneSystem
AntiretroviralTherapy (ART)
What Contributes to the Risk of Non AIDS Events in HIV?
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Contributions of ART to CVD
• The ‘toxicity’ of untreated HIV disease outweighs any excess risk of CVD associated with ART1
• Longer duration of older protease inhibitors (indinavir, lopinavir/r) associated with increased MI risk in observational trials2,3; however no association between ART agents and CT angiographic evidence of plaque4
• Abacavir has been associated with increased relative risk of MI; most consistent findings among patients with other risk factors5‐6; mechanism unclear
• What about other contemporary agents?
1. El Sadr et al (SMART)NEJM. 2006; 355(22):2283–96 2. NEJM 2003 Nov 20;349(21):1993‐2003. 3. DAD N Engl J Med. 2007 Apr 26;356(17):1723‐35 4. AIDS. 2016 Oct23;30(16):2477‐2486. 5.Worm (DAD) J Infect Dis 2010; 201:318–330. 6. Llibre JM, Hill A. Antiviral Res 2016; 132:116–121.
A5260: A Clinical Trial to Assess ART and Complications
A5257: Phase III, prospective, multi‐center, randomized, open‐label trial (N=1809)ART‐naïve, HIV+ subjects ≥18 yr, VL ≥ 1000 c/mL
Randomized 1:1:1 to three NNRTI‐sparing ARV regimensStratified by screening HIV‐1 RNA level (≥ or <100,000 copies/ml),
Framingham 10‐year CHD risk score (<6% vs ≥6% risk), and A5260s participation
Abstract WEAB0106LB
A5260s Substudy (N=328)No known CVD, diabetes mellitus, or use of lipid‐lowering medications
Participants followed for 96 weeks after enrollment of last subject
At baseline and week 96DXA scan (limb fat, trunk fat and lean mass)
CT abdomen (visceral and subcutaneous abdominal fat)
At baselineLeptin, adiponectin, IL‐6, hs‐CRP, D‐dimer, sCD14, sCD163
FTC/TDF + RAL(N=106)
FTC/TDF + ATV/r (N=109)
FTC/TDF + DRV/r(N=113)
Jim Stein, Todd Brown, Grace McComsey, Heather Ribaudo, Carlee Moser, Theo Kelesidis, Michael Dube, Otto Yang
How Does ART Impact Biomarkers ?ACTG 5260s: ATV/r, RAL, DRV/r
• Examined fold change in biomarkers among participants who maintained viral suppression over 96 weeks
• RAL‐ associated with a persistent decline in IL‐6 where as ATV/r and DRV/r were not
• D‐Dimer declined with ATV/r and DRV/r but not RAL
• Measures of T cell activation declined in all groups, monocyte activation was inconsistent
ACTG 5260s Kelesidis et al. CID 2015
RAL
DRV
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Plasma levels of oxidized HDL decrease whereas plasma levels of oxidized LDL increase with initiation of ART in ART naïve HIV infected persons with low cardiovascular risk
Kelesidis et al Antivir Ther. 2016 [in press]
Progression of Carotid Intima Medial Thickness and ART: Slower rate with ATV/r
• CCA and bifurcation: significant CIMT progression within each arm (m/year)• Bilirubin levels > 0.6mg/dl at week 4 and 24 associated with slower rate of progression of IMT.
• Is atazanavir protective against CVD in HIV?
CCA CIMT Carotid Bifurcation CIMT
More on Atazanavir, Bilirubin and MI risk
• Cohort studies have evaluated this association• CNICS cohort: 22,689 people, 568 MI or ischemic stroke (Crane et al; 2016)
• Higher bilirubin levels associated with lower risk of T1 MI and stroke, but also with higher risk for T2MI(those due to oxygen supply demand mismatch such is in sepsis)
• VA study (LaFleur, J et al; 2016)• Lower risk of MI for those on ATV regimen (HR 0.66), no difference in stroke rates
• Atazanavir no longer considered a preferred agent due to higher risk of d/c due to bilirubin
• Might consider in a patient at high CVD risk
Crane H, et al. Abstract 013 Antiviral Therapy 2016;21 Suppl 1:A15; LaFleur, J et al Abstract 016 Antiviral Therapy 2016;21Suppl 1: A18)
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Image Adapted from Environmental Health Perspectives • volume 121 | number 2 | February 2013
“It’s an uncommonly dangerous thing to be left without any padding against the shafts of disease.” ― George Eliot, Middlemarch
The Role of Adipose Tissue
Adipose Tissue
• Major endocrine organ closely associated with the immune system• Fat surrounds lymph nodes
• Adipocytes are prominent in bone marrow and fat depots
• CD4 + T cells in fat have activated memory phenotype
• In obesity fat becomes pro‐inflammatory with influx of CD8+ T cells that secrete IL‐6 and TNF‐alpha, these factors may stimulate HIV replication and or contribute to CVD, insulin resistance, diabetes and dyslipidemia
• Two groups have reported on possible role of adipose tissue as a reservoir of HIV (Couturier AIDS 2015,29:667‐674; Damouche, A. et al Plos Pathog. 11, e1005153)
Body Mass Index kg/m2 Categories
Underweight < 18.5Normal 18.5‐24.9Overweight 25‐29.9Obese 30‐40Morbidly obese > 401998‐2010 n‐14,084 (83% men)
• Median BMI at ART initiation rose from 23.8 to 24.8
• The percentage of HIV group with obesity rose from 9 to 18%
Three years after starting ART
• 22% of those with normal BMI at baseline were overweight
• 18% of those overweight at baseline were obese
Temporal trends in obesity in treated HIV
Koethe, JR et al. (NA‐ACCORD). AIDS Res and Hum Ret, 2016
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Contemporary ART is associated with fat gainMean (97.5% CI) percent change in VAT (ITT): ACTG 5260s
ATV/r 31%RAL 33%DRV/r 29%
McComsey G, et al. CID 2016 doi: 10.1093/cid/ciw017
CT adipose density reflects adipocyte histology. Lake, J. et al A5224s
Change in Waist Circumference on ART at 96 Weeks ACTG 5257 (n= 1,814)
Bhagwat, P et al 18th Int Workshop on Co‐mordities and Adverse Drug Reactions in HIV, Antiviral Therapy2016;21 Suppl 1:A9
Interventions to Reduce Non‐AIDS Events in HIV
• Lifestyle interventions• Smoking cessation
• Smoking may synergize with HIV to increase mortality
• Screen and treat for hypertension, diabetes
• Diet and Exercise (1‐3)
• Earlier ART
1.Lindegaard B, J Clin Edno Metab 2008 2.Troseid M, JAIDS 2014 3.Fitch K AIDS 2012;26:587‐97
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Immediate ART reduces infection related Cancers, Borges G, et al. CID Sept 2016
HIV+ Individuals in Care No Longer Have Elevated MI Risk compared to controls(2010‐2011), Kaiser Cohort
• Cohort to evaluate MI risk from 1996 to 2011 by HIV status
• Adjusted MI rate ratio for HIV status declined over time, reaching 1.0 (95% confidence interval, .7‐1.4) in 2010‐2011 (most recent period)
Klein DB, et al. Clin Infect Dis. 2015;60(8):1278‐1280.
Incidence Rate/100,000 py Rate Ratio (95% CI)
Calendar Year HIV‐positive HIV‐negative Adjusted
1996‐1999 276 136 1.8 (1.3, 2.6)
2000‐2003 324 162 1.7 (1.4, 2.1)
2004‐2007 270 178 1.3 (1.0, 1.6)
2008‐2009 245 167 1.3 (.9, 1.7)
2010‐2011 195 165 1.0 (.7, 1.4)
MI Incidence Rates and Rate Ratios for HIV Status
Progress in Developing Interventions to Target Novel Pathways“Probe” Studies
Anti‐fibrotics?
IL‐7?
HIV ‐1 Infection
Immunodeficiency
Microbi al
Translocation
Viral Reactivation
(eg, CMV)
Innate Immune Activation (MØ/DC)
? T Cell Turnover,
Activation, Lymphoid
Fibrosis
Functional T Cell Defects /
CD4+ Lymphopenia
Infections, Malignancy
Inflammatory Cytokine
Secretion
(eg, IL ‐6, TNF ‐α )
Cardiovascular , Renal, and
Liver Disease ,
Osteo porosis , Frailty,
Cognitive Dysfunction
TLR 7,8
Activation
?Tissue Factor,
Clotting
Thrombosis,
CAD/Stroke
? IDO ‐1 ‐ induced
Tryptophan
Catabolism
T Cell Proliferative
Defects
Th17 depletion
Rifaximin (A5286)Sevelamer (A5296) Chloroquine
(A5258)Novel CMV
Drugs? Other TLR
Inhibitors?
LD‐Methotrexate(A5314)
IDO‐1Inhibitors?
Pro‐biotics(A5350)Pre‐biotics?
IL ‐1 inhibitors Canakinumab
TNF ‐α inh ibitors?
IFN ‐α Inhibitors?
Ruxolitinib(A5336)
Slide credit Peter Hunt
STATINS(A5332)
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Progress in Developing Interventions to Target Novel Pathways“Probe” Studies
Anti‐fibrotics?
IL‐7?
HIV ‐1 Infection
Immunodeficiency
Microbi al
Translocation
Viral Reactivation
(eg, CMV)
Innate Immune Activation (MØ/DC)
? T Cell Turnover,
Activation, Lymphoid
Fibrosis
Functional T Cell Defects /
CD4+ Lymphopenia
Infections, Malignancy
Inflammatory Cytokine
Secretion
(eg, IL ‐6, TNF ‐α )
Cardiovascular , Renal, and
Liver Disease ,
Osteo porosis , Frailty,
Cognitive Dysfunction
TLR 7,8
Activation
?Tissue Factor,
Clotting
Thrombosis,
CAD/Stroke
? IDO ‐1 ‐ induced
Tryptophan
Catabolism
T Cell Proliferative
Defects
Th17 depletion
Novel CMV
Drugs? Other TLR
Inhibitors?
LD‐Methotrexate(A5314)
Pro‐biotics(A5350)Pre‐biotics?
IL ‐1 inhibitors Canakinumab
TNF ‐α inh ibitors?
IFN ‐α Inhibitors?
Ruxolitinib(A5336)
Slide credit Peter Hunt
STATINS(A5332)
IL‐1β inhibition in HIV
• Canakinumab is a monoclonal antibody directed against IL‐1 β, approved for use in a inflammatory diseases including JRA, FMF
• Currently being studied in a trial of 17,200 HIV negative adults with CVD to test whether reducing inflammation decreases future CVD events (CANTOS)
• HIV Pilot study led by Priscilla Hsue• NHLBI funded: Hsue, Deeks, Ridker, Tawakol
• N=100 individuals randomized 2:1 treated with 150mg canakinumab at baseline and at 12 weeks, followed for 36 weeks, measuring arterial inflammation with FDG‐PET
NHLBI R01HL125034
Ruxolitinib
HIV+ on ART Suppressed VL
Arm A RUX+ART (ART not provided by study)
Follow-Up (only ART; ART not provided by study)
2:1
Arm B No Study Treatment; only ART (ART not provided by study)
Study Week
0 1 4 5 12 Study Week
0 12
• Ruxolitinib is an FDA approved Jak2 inhibitor that disrupts the Jak‐STAT pathway.
• This pathway is thought to be up‐regulated in HIV infection and may contribute to the production of pro‐inflammatory cytokines, notably IL‐6 and TNF‐alpha
• This is a proof of concept study with only 5 weeks of drug exposre
• Participants must have CD4 > 350, be suppressed with good renal function and not on boosted PI
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Statin use in HIV: Which statement best reflects your current view1. I follow current AHA/ACC guidance for use of statins without
modification for patients with HIV
2. I prescribe statins to patients with HIV without regard to current guidelines
3. I don’t know what we should be doing about the use of statins in patients with HIV
“RANDOMIZED TRIAL TO PREVENT VASCULAR EVENTS IN HIV”
THE REPRIEVE TRIAL TESTS A STRATEGY TO PREVENT HEART DISEASE IN HIV
REPRIEVE is the first large‐scale randomized clinical trial to test a strategy for preventing heart‐related disease among people living with HIV.
www.reprievetrial.org
Funded by NHLBI and NIAID. Supported by KOWA Pharmaceuticals.
Principal Investigators: Steven Grinspoon, MDPamela S Douglas, MDUdo Hoffmann, MD, MPHHeather Ribaudo, PhD
• Statin clinical endpoint trial in HIV• Statins reduce inflammation• Pitavastatin has no interactions with ART
• Patients with treated HIV who do not meet criteria for statins will be randomized to pivastatin or placebo
• 6500 patients• 100 sites globally
• Mechanistic Substudy to examine CT Angio outcomes
• Substudies on sex differences, renal outcomes and muscle function
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Summary
• Non‐AIDs events are a growing cause of morbidity and mortality in treated HIV in all settings
• Inflammation and the Innate immune activation appear to be contributors; biomarkers may have utility in predicting risk and informing interventions
• Traditional risk factors remain important• Fat gain on ART may represent a “return to health” but obesity is a growing concern
• New interventions to reduce inflammation for patients on ART under evaluation
• Impact of newer ART agents warrants investigation
Thank‐you!
• UCLA CARE Center Team
• Jordan Lake (now at UT Houston)
• Peter Hunt
• Priscilla Hsue
• Peter Reiss
