HIV, Co-morbidity and Ageing - fgcasal.orgfgcasal.org/VIH_SIDA_V/VIH_SIDA_V_Peter_Reiss.pdf · HIV, Co-morbidity and Ageing “A good head and a good heart are always a formidable

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

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

Changing Age Structure of Population with HIV

in Care in The Netherlands

42% older than 50 yrs; 14% older than 60 yrs

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

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

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?

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


AGEING

Lifestyle (smoking etc)

Genetic

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

• 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

Populations’ Age Structure

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

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

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


Comorbidity in relation to age


Osteopenia/osteoporosis in 3 bone locations

K. Kooij et al, J Infect Dis, 2014

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

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

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

Neurocognitive impairment

AIDS. 2015 Mar 13;29(5):547-57

Comorbidity in relation to age


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)

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

Chronic disease drivers, known and suspected


AGING

ART

Toxicity

Host

Clinical

Chronic

Co-morbidity HIV

Persistent


& Inflammation

in treated

HIV disease


Genetic

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

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



AGING

ART

Toxicity

Host

Clinical

Chronic

Co-morbidity HIV

Persistent


& Inflammation

in treated

HIV disease


Genetic

“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



AGING

ART

Toxicity

Host

Clinical

Chronic

Co-morbidity HIV

Persistent


& Inflammation

in treated

HIV disease


Genetic

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/

ARV toxicities may accentuate the clinical expression of certain co-morbidities Some examples:

Some PI’s

ABC (?)

TDF ATV/r,LPV/r,(DRV/r?)

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

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

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

-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

Do HIV-positive persons age faster than

HIV-uninfected persons?

vs.

Chronic disease drivers (known and suspected) act in concert

ART

Toxicity

Host

Clinical

Chronic

Co-morbidity

AGING


Genetic

May HIV and ART in Addition Interact with Biological Aging?

HIV

Persistent


& Inflammation

in treated

HIV disease

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

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

• 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

C3NL

Neuroimaging modalities

T1-weighted

Diffusion Tensor

Imaging (DTI)

FLAIR T2-weighted Proton density

Voxel-based

morphometry Cortical thickness

C3NL

Brain age - Methods

C3NL

Brain age – Preliminary results

• Group comparisons of PAD score

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

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

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

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

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

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

Documents

HIV, Co-morbidity and Ageing - fgcasal.orgfgcasal.org/VIH_SIDA_V/VIH_SIDA_V_Peter_Reiss.pdf · HIV, Co-morbidity and Ageing “A good head and a good heart are always a formidable