Measures of Morbidity. Morbidity and Mortality Weekly Reports.
HIV, Co-morbidity and Ageing - fgcasal.orgfgcasal.org/VIH_SIDA_V/VIH_SIDA_V_Peter_Reiss.pdf · HIV,...
Transcript of HIV, Co-morbidity and Ageing - fgcasal.orgfgcasal.org/VIH_SIDA_V/VIH_SIDA_V_Peter_Reiss.pdf · HIV,...
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HIV, Co-morbidity and Ageing
“A good head and a good heart are always a
formidable combination”
Peter Reiss Director HIV Monitoring Foundation Professor of Medicine Division of Infectious Diseases & Department of Global Health Amsterdam Institute for Global Health and Development Academic Medical Center, University of Amsterdam
V Encuentro de Salud Pública 8 October 2015, Madrid, Spain
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Disclosures Dr. Reiss reports having received:
Unrestricted investigator-initiated grant support
through his institution from Gilead Sciences,
Janssen Pharmaceutica NV., Merck&Co, Bristol-
Myers Squibb, ViiV Healthcare and Boehringer-
Ingelheim
Honoraria through his institution from Gilead
Sciences and Janssen Pharmaceutica NV. for
scientific advisory board and data safety monitoring
committee participation
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Changing Age Structure of Population with HIV
in Care in The Netherlands
42% older than 50 yrs; 14% older than 60 yrs
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As expected co-morbidity burden & use of
co-medication in HIV increases with ageing
0
20
40
60
80
100
Four or morecomorbidities
Three comorbidities
Two comorbidities
One comorbidity
% o
f p
art
icip
ants
<50 years 50-64 years 65+ years
Agegroups
No comorbidity
Comedications
Comorbidities
n=5761 n=2233 n=450
0
20
40
60
80
100
Four or morecomedications
Three comedications
Two comedications
One comedication
% o
f p
art
icip
ants
No comedication
Swiss
CohortStudy
H I VSwiss
CohortStudy
H I V
Hasse B. et al. Clin Infect Dis 2011 53;1130-1139
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Modelling the Changing Age-structure
of PLWHIV in the Netherlands • Median age will increase from 43.9 years in 2010 to 56.6 years in
2030
• Proportion of HIV-patients aged ≥ 60 will increase from 8% to 39%
and aged ≥ 70 years from 8% to 12%
Smit M, et al, on behalf of the ATHENA observational cohort; Lancet Infect Dis 2015
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Deeks SG, et al. BMJ 2009; 338:a3172
Many chronic diseases of ageing have been shown to be more common in those with HIV, even after adjustment for ART use and traditional (lifestyle-related) risk factors
Chronic liver
disease
Neurocognitive decline
Non-Aids cancers
Chronic kidney disease
Osteoporosis &
Fragility fractures
Cardiovascular
disease
Frailty Diabetes mellitus
COPD
Do HIV-positive persons age faster than HIV-uninfected persons?
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Chronic disease drivers (known and suspected) acting in concert in HIV
ART
Toxicity
Host
Clinical
Chronic
Co-morbidity HIV
Persistent
Immune Dysregulation
& Inflammation
in treated
HIV disease
Deeks SG, et al. BMJ 2009; 338:a3172
AGEING
Lifestyle (smoking etc)
Genetic
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Are these age-related chronic conditions
just Accentuated or also Accelerated?
Accentuated & Accelerated risk
Condition occurs more often and
at younger age among those with
HIV than among
HIV-uninfected comparators
Accentuated risk
Condition occurs at the same
age but more often in those
with HIV than among
HIV-uninfected comparators
Shiels MS. Age at Cancer Diagnosis among persons with AIDS in the US. Ann Intern Med 2010
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• Prevalence and incidence of
age-associated non-communicable comorbidities (AANCC)
and their risk factors in persons ≥45 yrs
• Started October 2010
• Participants:
HIV-1-infected: from the HIV outpatient clinic at the
Academic Medical Center (Amsterdam)
HIV-1-uninfected: from the Amsterdam Public Health Service
sexual health clinic, and the ongoing
Amsterdam Cohort Studies on HIV/AIDS
Comorbidity and Ageing with HIV A prospective comparative cohort study
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Populations’ Age Structure
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HIV neg
(n=524)
HIV pos
(n=540) p-value
Age (years) 52.1 (47.9-58.3) 52.9 (48.3-59.6) 0.20
Male gender 85.1% 88.1% 0.15
Dutch 81.3% 72.2% <0.001
MSM 69.7% 73.9% 0.125
Time since HIV-1 diagnosis (yrs) 12.1 (6.2-17.1)
Mean CD4 count at enrollment (cells/mm3) 565 (435-745)
Nadir CD4 count (cells/mm3) 180 (78-260)
Viral load > 200 at or within 4 mos prior to
enrolment among cART-treated participants 1.5%
Prior clinical AIDS 31.3%
On cART
95.7%
• 79.1% started Rx-naive
• 20.9% started ART-exp.
Years since ART was first initiated (yrs) 10.4 (4.4-14.5)
Duration of viral load < 200 (since last > 200
) (yrs) 5.8 (2.4 – 10.2)
Known cumulative duration CD4 < 200(mos) 0.8 (0.0 – 9.6)
Data presented as median (IQR) or percentage as appropriate.
P-value represents Wilcoxon Rank Sum or Chi2 as appropriate
Demographic and HIV characteristics
Schouten J et al. Clin Infect Dis. 2014
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Comorbidity risk factors
HIV neg
(n=524)
HIV pos
(n=540) p-value
Smoking status
currently / ever (%)
24.6 / 38.9%
32.0 / 35.0%
0.007 /
0.23
Smoking (packyears, smokers only) 15.0 (4.5-28.8) 22.2 (7.8-36.8) <0.001
Severe alcohol use 7.3% 4.8% 0.098
Daily to monthly use of:
cannabis
cocaine
ecstasy
11.6%
2.9%
8.6%
13.5%
3.7%
4.3%
0.356
0.442
0.004
BMI (kg/m2) 24.5 (22.8-27.0) 24.2 (22.3-26.6) 0.019
Blood pressure systolic (mmHg) 133 (125-143) 135 (126-147) 0.006
Blood pressure diastolic (mmHg) 79 (72-85) 81 (75-89) <0.001
Data presented as median (IQR) or percentage as appropriate.
P-value represents Wilcoxon Rank Sum or Chi2 as appropriate Schouten J et al. Clin Infect Dis. 2014
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Age-associated Noncommunicable
Comorbidity Prevalence
HIV neg
(n=524)
HIV pos
(n=540) p-value
≥1 AANCC* (%) 61.8% 69.4% 0.009
Number of AANCC (mean (SD)) 1.0 (0.95) 1.3 (1.14) <0.001
Schouten J et al. Clin Infect Dis. 2014
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Comorbidity in relation to age
Schouten J et al. Clin Infect Dis. 2014
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Osteopenia/osteoporosis in 3 bone locations
K. Kooij et al, J Infect Dis, 2014
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Hypertension
Prevalence of hypertension
0
20
40
60
80
100
Pre
vale
nce
of
hype
rte
nsio
n (
%)
HIV-infected HIV-uninfected
Antihypertensives + / HT +
Antihypertensives + / HT -
Antihypertensives - / HT +
Normotension
Hypertension, measured Hypertension, treated
55% 69%
22%
17%
23% 14%
R. Van Zoest et al 16th Int Wkshp on Comorb and ADR in HIV, Philadelphia, October 2014
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More frailty and pre-frailty at any age in HIV+ participants
HIV- HIV+ HIV- HIV+ HIV- HIV+ HIV- HIV+ HIV- HIV+
K.Kooij et al 8th Netherlands Conference on HIV Pathogenesis, Epidemiology, Prevention and Treatment, Amsterdam, November 2014
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All frailty factors more prevalent in HIV+ participants
K.Kooij et al 8th Netherlands Conference on HIV Pathogenesis, Epidemiology, Prevention and Treatment, Amsterdam, November 2014
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Neurocognitive impairment
AIDS. 2015 Mar 13;29(5):547-57
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Comorbidity in relation to age
Schouten J et al. Clin Infect Dis. 2014
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baseline 2-years
% %
Comorbidity Burden After 2 Year Follow-up 436 HIV-pos en 437 HIV-neg
mean # comorbidities 1,23 (baseline) 1,26 (follow-up) mean # comorbidities 0,84 (baseline) 0,84 (follow-up)
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Risk Factors Associated with Comorbidity
Nr of
AANCC
Hypertension CVD Low
BMD
Frailty
Recognized
risk factors
+ + + + +
HIV +
(- once
time spent
with low
low CD4
accounted
for)
+
( WHR;
both waist&
hip circumf. )
+
+
(
body
weight)
+
( (history of)low
BMI)
ART
duration
- - - - -
Specific ART
exposure
+/- (RTV) Prior d4T +(RTV) +(RTV) +/- (PI)
AANCC: Age Associated NonCommunicable Comorbidity
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Chronic disease drivers, known and suspected
Deeks SG, et al. BMJ 2009; 338:a3172
AGING
ART
Toxicity
Host
Clinical
Chronic
Co-morbidity HIV
Persistent
Immune Dysregulation
& Inflammation
in treated
HIV disease
Lifestyle (smoking etc)
Genetic
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HIV-infected individuals who are ART-naïve with
CD4+ count > 500 cells/mm3
Immediate ART Group
Initiate ART immediately
following randomization
N=2,326
Deferred ART Group
Defer ART until the CD4+ count
declines to < 350 cells/mm3 or
AIDS develops
N=2,359
Primary composite endpoint, target = 213
• Serious AIDS or death from AIDS
• Serious Non-AIDS Events and death not attributable to AIDS o CVD, ESRD, decompensated liver disease, & non-AIDS defining cancers
Early ART is associated with less inflammation during ART
Will this result in benefit?
Strategic Timing of AntiRetroviral Treatment (START) Study
Slide courtesy of Steve Deeks
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Strategic Timing of AntiRetroviral Treatment
(START) Study
No. of
Participants
Type of event Imm.
ART
Def.
ART
Serious AIDS 14 50
Serious non-AIDS 29 47
Total* 42 96
* One participant in each group had both a Serious AIDS
and a Serious Non-AIDS Event
26 Lundgren et al, IAS 2015, Vancouver July 2015
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Chronic disease drivers, known and suspected
Deeks SG, et al. BMJ 2009; 338:a3172
AGING
ART
Toxicity
Host
Clinical
Chronic
Co-morbidity HIV
Persistent
Immune Dysregulation
& Inflammation
in treated
HIV disease
Lifestyle (smoking etc)
Genetic
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“Well treated HIV-infected individuals may lose more life years
through smoking than through HIV.
Excess mortality associated with smoking increases markedly with
age. Therefore, increases in smoking-related mortality can be
expected as the treated HIV-infected population ages. Interventions
for smoking cessation should be prioritized.”
The Host and Lifestyle:the importance of smoking
Helleberg M et al. Clin Infect Dis. 2013;56:727-734 Helleberg et al. AIDS 2015
ARTCohort Collaboration
ARTCohort Collaboration
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Chronic disease drivers, known and suspected
Deeks SG, et al. BMJ 2009; 338:a3172
AGING
ART
Toxicity
Host
Clinical
Chronic
Co-morbidity HIV
Persistent
Immune Dysregulation
& Inflammation
in treated
HIV disease
Lifestyle (smoking etc)
Genetic
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ART has clearly become less toxic, but…
Reasons for modifying treatment within 3 years of starting cART
it remains amongst the most common reasons for modifying treatment
http://www.hiv-monitoring.nl/english/research/monitoringrapporten/
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ARV toxicities may accentuate the clinical expression of certain co-morbidities Some examples:
Some PI’s
ABC (?)
TDF ATV/r,LPV/r,(DRV/r?)
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GS-US-292-0109 Switch to E/C/F/TAF in Virologically Suppressed Adults
All patients
– HIV-1 RNA <50 copies/mL for ≥96 weeks on stable TDF-based regimen
– Estimated GFR >50 mL/min
E/C/F/TAF = EVG 150 mg, COBI 150 mg, FTC 200 mg, TAF 10 mg
E/C/F/TDF = EVG 150 mg, COBI 150 mg, FTC 200 mg, TDF 300 mg
*Boosted by RTV or COBI
35
Primary Endpoint
HIV-1 RNA <50 c/mL
Week 0
Switch to E/C/F/TAF
Continue TDF-Based
Regimen
96 48
Virologically
Suppressed
Adults
E/C/F/TDF
(n=459)
EFV/FTC/TDF
(n=376)
Boosted* ATV + FTC/TDF
(n=601)
Randomized (2:1), active-controlled,
open-label study
n=959
n=477
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1,79
-0,28
-3
-2
-1
0
1
2
3
4
Baseline Week 24 Week 48
GS-US-292-0109 DXA Scan Results: Spine BMD
Regardless of prior treatment regimen, differences between arms were statistically significant
More than 2% difference between the arms at Week 48 36
Me
dia
n %
Ch
an
ge
in
BM
D (
Q1
, Q
3)
E/C/F/TAF
TDF-Based Regimen
Change From Baseline to Week 48 All Participants (N=1,369)
p <0.001
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1,37
-0,26
-2
-1
0
1
2
3
Baseline Week 24 Week 48
GS-US-292-0109 DXA Scan Results: Hip BMD
37
Change From Baseline to Week 48 All Participants (N=1,354)
Me
dia
n %
Ch
an
ge
in
BM
D (
Q1
, Q
3)
p <0.001
E/C/F/TAF
TDF-Based Regimen
Regardless of prior treatment regimen, differences between arms were statistically significant
More than 1.6% difference between arms at Week 48
Mills, et al, IAS 2015, Vancouver July 2015
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-21 -18
-33
-52
10 9
18 19
-60
-50
-40
-30
-20
-10
0
10
20
30
UPCR UACR RBP: Cr Ratio B2MG: Cr Ratio
Me
dia
n %
Ch
an
ge
GS-US-292-0109 Renal Safety Results
Statistically significant improvements for participants who switched from either E/C/F/TDF or from
boosted ATV + FTC/TDF
Serum creatinine (p <0.001); eGFR (p <0.001)
Fractional excretion of phosphate, FEPO4 (p=0.05); fractional excretion of uric acid, FEUA (p <0.001)
Changes began by Week 2 and persisted to Week 48
38 UPCR: urine protein: creatinine ratio; UACR: urine albumin: creatinine ratio; RBP, retinol-binding protein; β-2-m:Cr , beta-2 microglobulin.
E/C/F/TAF
TDF-Based
Regimen
RBP:Cr β-2-m:Cr UPCR UACR
Tubular Proteinuria
Each difference between treatment arms
was statistically significant (p <0.001).
Mills, et al, IAS 2015, Vancouver July 2015
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Do HIV-positive persons age faster than
HIV-uninfected persons?
vs.
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Chronic disease drivers (known and suspected) act in concert
ART
Toxicity
Host
Clinical
Chronic
Co-morbidity
AGING
Lifestyle (smoking etc)
Genetic
May HIV and ART in Addition Interact with Biological Aging?
HIV
Persistent
Immune Dysregulation
& Inflammation
in treated
HIV disease
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Hallmarks of Biological Aging
Lopez-Otin et al Cell 2013 153, 1194-1217 Torres RA & Lewis W, Lab.Investigation 2014;94:120-28
ART (nRTI/PI)
HIV & ART (nRTI)
HIV? &ART?
ART(nRTI/PI)
HIV & ART (nRTI/PI)
ART (PI)
HIV & ART (PI)
HIV
ART (PI)
Several of these may be affected by HIV and/or ART
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The COHORTS
POPPY: ‘Pharmacokinetic
and Clinical Observations in
People over Fifty’
Status: • Recruited over 900 subjects
• 500 +ve over 50 • 200 +ve under 50 • 200 controls over 50
• Recruitment continue until end 2015 • Expect recruit 2000 subjects • First output last month at BHIVA meeting
Status: • Fully recruited and in follow up phase
• 598 +ve over 45 • 550 controls over 45
• Several outputs from this cohort including 3 publications
AMSTERDAM LONDON
COBRA: the clinical studies are run as sub-studies of POPPY and AGEhIV: • Collecting the extra information required • Whilst utilising the existing infrastructure
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• FP7 project of 4 year duration with 12 partners from 6 countries • Primary research question: are HIV-infected patients on successful cART
prone to develop AANCC at an earlier age (accelerated ageing) ? • Establish link between HIV and AANCC:
o longitudinal HIV cohort studies in Amsterdam and London o biomarkers and neuro-imaging studies
• Elucidate causative link between HIV and AANCC o “Humanised Immune System” (HIS) mouse model
• Clarify pathogenic mechanisms underlying link between HIV and AANCC o Promising biomarkers, including those coming out of the FP7
MARK-AGE project
Summary of the COBRA project
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C3NL
Neuroimaging modalities
T1-weighted
Diffusion Tensor
Imaging (DTI)
FLAIR T2-weighted Proton density
Voxel-based
morphometry Cortical thickness
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C3NL
Brain age - Methods
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C3NL
Brain age – Preliminary results
• Group comparisons of PAD score
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MARK-AGE Project
1 April 2008 – 30 September 2013
(HEALTH-F4-2008-200880)
www.mark-age.eu
Project full title:
European Study to Establish Biomarkers of Human Ageing
Scientific Co-ordinator:
Alexander Bürkle
University of Konstanz,
Konstanz, Germany
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Projections of burden of disease
- Proportion with at least one NCD increase from 29% in 2010 to 84% in 2030. - Proportion with 3 or more NCDs increase from 0.3% in 2010 to 28% in 2030. - In 2030 only 16% will have none of the NCDs investigated in this study
The increase in NCDs will be driven by CVD mainly - In 2010 19% of patients are
diagnosed with some CVD compared to 78% in 2030.
Smit M, et al, on behalf of the ATHENA observational cohort; Lancet Infect Dis 2015
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The impact of antiretroviral treatment on the age composition of the HIV epidemic in sub-Saharan Africa.
Hontelez JAC. et al. AIDS 2012, 26 (Suppl 1):519-530 & NCHIV 2012, poster 44.
Aging with HIV will Increasingly Occur in
Resource-limited Settings as well
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www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Regional Ranking of leading causes of years of life lost
(YLL), 2010
Global Burden of Disease Study 2010, modified from Lancet 2012; 380:2095-2128
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Summary and Conclusions • Burden of various co-morbidities consistently increased in
HIV • Traditional risk factors play an important role. Needs to be
reflected in our clinical management and care • Independent associations with HIV are observed for some
but not all co-morbidities • Longer time spent at low CD4 counts, rather than longer
overall exposure to ART, generally contributes to greater co-morbidity risk. Early HIV diagnosis and treatment now definitively shown to beneficially modify this risk.
• Persistent inflammation and innate immune activation generally seem to additionally contribute towards risk
• Pathogenic pathways involving effects on the biology of aging need further exploration
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Do not regret growing older.
It is a privilege denied to many
Author Unknown
All our study participants
EU 7th FP for research, technological development
and demonstration under grant agreement no 305522
Grant nrs 300020007 & 2009063
2010039
2012023