Going the full 360: on our understanding of ageing

Dr James BrownDr Tom Levett

The Going Beyond Undetectable 2019 meeting is organised and funded by Gilead Sciences Europe Ltd. Date of Preparation: June 2019Job Code: 001/IHQ/19-02//1076w

Longevity and frailty: considerations for the futureDr James BrownDirector, Aston Research Centre for Health Ageing, Aston University, UK@afatscientist

Beyond Undetectable: Going the full 360 is organised and funded by Gilead Sciences Europe Ltd. Date of Preparation: June 2019Job Code: 001/IHQ/19-02//1076w

Plan

1. What is ageing (biologically speaking)?

2. Successful and unsuccessful ageing

3. The frailty syndrome: detection

4. The frailty syndrome: prevention and treatment

Longevity and Healthspan

1. Office for National Statistics, Living longer: how our population is changing and why it matters 2018. Available at: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/ageing/articles/livinglongerhowourpopulationischangingandwhyitmatters/2018-08-13 [Accessed June 2019]; 2. Office for National Statistics. Health state life expectancies, UK: 2015 to 2017, 2018. Available at: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healthandlifeexpectancies/bulletins/healthstatelifeexpectanciesuk/2015to2017 [Accessed June 2019].

We’re living longer (on average)1.

We’re not living healthier (on average)2.

5 million in UK over 85 by 20661

By 2030, 16.4% of the world’s population will be over 601

Health expectancy is increasing at a slower rate2

Males can expect 63.1 years of good health out of 79.2 years

(80% of their lives)2

Females can expect 63.6 years of good health out of 82.9 years

(77% of their lives)2

Is Ageing Universal?

1. Human Ageing Genomic Resources. AnAge: The Animal Ageing and Longevity Database 2017. Available at: https://genomics.senescence.info/species/ [Accessed June 2019].

Do all organisms age the same?

Several organisms are extremely long lived1 and possibly immortal

Rockfish 205 years

Sturgeon 152 years

Aldabra Tortoise 152 years

Bowhead Whale 211 years

Red sea urchin 200 years

Arctica islandica >507 years (one of 7 thought not to age at all)

Why Do We Age?

1. Chmielewski P. Anthropological Review 2017;80(3):260 –0.

Ageing is programmed

(antagonistic pleiotropy)

Accumulation of damage

(wear and tear)

Both theories allow for cellular senescence

Healthspan for womenhas changed over the last century

• Lifespans are increasing1,2

• Delaying and compressing the at risk period for frailty may extend healthy life3

1. Bell FC and Miller ML. Life Tables for the United States Social Security Area 1900-2100, 2005;120(11-11536):pages; 2. Human Mortality Database 2016. Available at: https://www.mortality.org/ [Accessed June 2019]; 3. Opinion piece: Olshansky SJ. JAMA 2018;320(13):1323-1324.

Delaying and compressing the at risk period for frailty may extend healthy life3

Successful and unsuccessful ageing

Real World Examples

• 103

• Non-frail

• Independent

• Extended lifespan, more years in good health

• Is this ‘successful ageing’?

• 87

• Frail

• Increasingly dependent

• Cost NHS >£130,000 in last 10 years

• Extended lifespan, more years in poor health

• Is this ‘unsuccessful ageing’?

Influences on ‘Successful’ Ageing

1. Steves CJ, et al. Age and Ageing 2012;41(5):581.

Genetic Epigenetic Environmental

Environmental Influences on Successful Ageing

1. Steves Js et al. Age and Ageing 2012;41(5):583; 2. WHO. Report on Ageing and Health 2015. Geneva; 3. Theou O et al. J Aging Res 2011;1-19.

These factors impact epigenetic influences on successful ageing

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The Frailty Syndrome

What is Frailty?

1. Fedarko S. Clin Geriatr Med 2011;27(1):27–37; 2. Buckinx et al. Archives of Public Health 2015;73(1):19; 3. Clegg A et al. Lancet 2013;381(9868):752–762.

• Frailty is a geriatric syndrome characterized by weakness, weight loss, and low activity that is associated with adverse health outcomes1

• Increasing risk with age2

• Higher in women (9.6%) than in men (5.2%)3

• Increases in prevalence to 86–90 year olds (25.7%) then reaches a “stable” level2

• Failure in homeodynamics1

• Clinical manifestation of a biological process1

• Excellent term for classifying unsuccessful ageing

Influences on Unsuccessful Ageing (Frailty)

1. Steves Js et al. Age and Ageing 2012;41(5):581.

Genetic Epigenetic Environmental

v

Environmental Influences on Frailty

1. Steves Js et al. Age and Ageing 2012;41(5):583. 2. Bauer J et al. J Am Med Dir Assoc. 2013; 14(8):542-59; 3. Theou O et al. J Aging Res 2011;1-19. 4. Veronese N et al. J Am Med Dir Assoc 2017;18(7):624–628.

Healthy diet Protein intake? Activity levelsIssues of comorbidity

and polypharmacy

Frailty and HIV

1. Willig et al. Total patient care in HIV & HCV 2016;1(1):6–17.

• Frailty has become widely recognized among middle-aged and older adults with HIV

• As many as 4–10% of PLWH may be frail (MACS study) and possibly >50% of older PLHV

• Frailty is associated with significant morbidity among PLWH (contributing to depression, decreased ability for self-care, and poor quality of life)

So…1. Frailty is now an issue for PLWH2. Frailty generally occurs at a younger age in PLWH

Can We Measure Frailty?

Frailty Tests

1. NSCP Health. The Edmonton Frailty Scale. Available at: https://www.nscphealth.co.uk/edmontonscale-pdf [Accessed June 2019].

Frailty domain Item 0 point 1 point 2 points

CognitionPlease imagine that this pre-drawn circle is a clock. I would like you to place the numbers in the correct positions then place the hands to indicate a time of ‘ten after eleven’

No errorsMinor

spacing errors

Other errors

General health status

In the past year, how many times have you been admitted to a hospital? 0 1–2 ≥2

In general, how would you describe your health?‘Excellent’,

‘Very good’, ‘Good’‘Fair’ ‘Poor’

Functional independenceWith how many of the following activities do you require help? (meal preparation, shopping, transportation, telephone, housekeeping, laundry, managing money, taking medications)

0–1 2–4 5–8

Social support When you need help, can you count on someone who is willing and able to meet our needs? Always Sometimes Never

Medication useDo you use five or more different prescription medications on a regular basis? No Yes

At times, do you forget to take your prescription medications? No Yes

Nutrition Have you recently lost weight such that your clothing has become looser? No Yes

Mood Do you often feel sad or depressed? No Yes

Continence Do you have a problem with losing control of urine when you don’t want to? No Yes

Functional performanceI would like you to sit in this chair with your back and arms resting. Then when I say ‘GO’, please stand up and walk at a safe and comfortable pace to the mark on the floor (approximately 3m away), return to the chair and sit down’

0–10s 11–20s

One of >20s, or patient

unwilling or requires assistance

Totals Final score is the sum of column totals

Scoring

0–5 = Not Frail6–7= Vulnerable8–9 = Mild Frailty

TOTAL /1710–11 = Moderate Frailty12–17 = Severe Frailty

Administered by: ________________________

The Edmonton Frailty Scale

Can We Measure Frailty Simply?

Gait Speed Test

1. Barry et al. BMC Geriatrics 2014, 14:14; 2. Lee L et al. Can Fam Physician 2017;63(1):e51–e57; 3. Lower Extremity Review. Self-selected gait speed: A critical clinical outcome. Available at: https://lermagazine.com/article/self-selected-gait-speed-a-critical-clinical-outcome [Accessed June 2019].

• Gait speed can be measured by asking an individual to take a simple test used to assess mobility and requires both static and dynamic balance and strength1

• Gait speed can predict frailty when combined with grip strength (87.5% accuracy)2

Scores3

>1 m/s = normal mobility

<1 m/s = benefit from falls prevention

<0.6 m/s = future risk of falls/hospitalisation

<0.4 m/s or less = requires extensive support

Hand Grip Strength (HGS)

1. Dodds RM et al. PLOS ONE 2014;9(12):e113637; 2. Lee L et al. Can Fam Physician 2017;63(1):e51–e57; 3. Beyer SE et al. PLOS ONE 2018;13(3):e0193124. Image provided with presenter’s permission.

• Weak grip strength forms a key component of frailty1

• Can predict frailty (87.5% accuracy) when combined with gait speed2

• It is associated with cardiac events3 and even mortality risk1 in older subjects

• Normative data for age and gender ranges have been identified from large meta-analyses3

Grip strength across the lifespan: a highly effective measure of frailty

SWS, Southampton Women’s Survey, ALSPAC, Avon Longitudinal Study of Parents and Children, ADNFS, Allied Dunbar National Fitness Survey, UKHLS, UK Household Longitudinal Study, SWSmp, Southampton Women’s Survey mothers and their partners, T07, West of Scotland Twenty-07 Study, ELSA, English Longitudinal Study of Ageing, NSHD, Medical Research Council National Survey of Health and Development, HCS, Hertfordshire

Cohort Study, HAS, Hertfordshire Ageing Study, LBC1936, LBC1921, Lothian Birth Cohorts of 1921 and 1936, N85, Newcastle 85+ Study.

1. Adapted from Dodds RM et al. PLOS ONE 2014; 9(12): e113637.

Cross-cohort centile curves for grip strength

Males Females

0 20 40 60 80 1000

20

40

60

80

100

Gri

p s

tren

gth

(kg

)

0 20 40 60 80 100

Age (years)

Study (ordered by age at first wave of data collection, youngest first):

SWS ALSPAC ADNFS UKHLS SWSmp T07 ELSA NSHD HCS HAS LBC1936 LBC1921 N85

0

20

40

60

80

100

Gri

p s

tren

gth

(kg

)

Age (years)

What Can We Do To Prevent/Reverse Frailty?

Control your environment

1. Gale CR et al. Age and Ageing 2018;47:392–397.

Diet Exercise Social interaction

Considerations for diet to increase muscle mass and strength in an ageing population

IGF-1, Insulin growth factor 1, ESPEN, European Society for Clinical Nutrition and Metabolism

1. Report: World Health Organisation (WHO) 2007. WHO Technical Report Series 935; 2. Hallal PC et al. Lancet 2012 Jul 21; 380(9838):247-57; 3. Bauer J, et al. J Am Med Dir Assoc. 2013; 14(8):542-59. 4. Schurch MA, et al. Ann Intern Med 1998;128:801e809. 5. Deutz NE et al. Clin Nutr 2014;33(6):929-36.

• Current recommended daily allowances for protein intake (0.8g per kilogramme of body weight) do not consider age1

• Those >60 years spend more hours sitting per day than younger adults2, and physiological changes that can include, anabolic resistance, insulin resistance, gastrointestinal disturbances, inflammation3

• Increase in protein intake has been shown to improve bone mass density, muscle mass and slower bone and muscle loss,4 and to improve physiological impact of ageing, e.g. increase serum IGF-13,4

• Recommendations by the International PROT-AGE Study Group3, and ESPEN5 are for healthy lifestyles in populations >65 years include 1.0–1.2g of protein per kilogramme of body weight, further increasing to 1.5g with illness, injury or malnutrition

In The Real World…

1. University of Bath. BBC’s Trust Me I’m a Doctor tackles ‘exercise snacking’ at Bath. Available at: https://www.bath.ac.uk/announcements/bbcs-trust-me-im-a-doctor-tackles-exercise-snacking-at-bath/ [Accessed June 2019].

This doesn’t have to be throwing massive weights around and it’s never too late!

• 5 minutes of home based exercise for 28 days in adults aged 65–80 years

• Leg strength and power increased by 5% and 6% respectively

Exercise works so let’s do it now!

Summary

1. Author’s personal opinion.

1. Increases in longevity mean that some live their later years in poor health

2. People can age well (successful ageing)…

or age with health issues (unsuccessful ageing)

3. Frailty is a good working definition of unsuccessful ageing

4. Increasing physical activity and dietary protein intake can help prevent and possibly even reverse frailty in older adults

Frailty and longevityin the setting of HIVDr Tom Levett, Senior Lecturerin Medicine and Frailty

Brighton and Sussex Medical School

Beyond Undetectable: Going the full 360 is organised and funded by Gilead Sciences Europe Ltd. Date of Preparation: June 2019Job Code: 001/IHQ/19-02//1076w

Disclosures

• Honoraria for lectures and consultation for Gilead.

• Research grant from the British HIV Association (BHIVA).

Objectives

• What does longevity look like from an HIV perspective?

• What factors limit longevity in PLHIV?

• Exploration of frailty in the context of HIV:

– Prevalence

– Risk factors

– Clinical presentations and consequences

– Management – an introduction to comprehensive geriatric assessment

PLHIV, people living with HIV.

The proportion of PLHIV aged 50+ is increasing globally

PLHIV, people living with HIV.Autenrieth CS et al. PLoS ONE 2018;13(11): e0207005.

Proportion of PLHIV aged 50 years and older, by region (2000 to 2020)

2000 2002 2004 2006 2008 2010 2012 2014 2016 2018 20200%

10%

20%

30%

40%

50%

Asia and the Pacific

Latin America and the Caribbean

Sub-Saharan Africa

Eastern Europe and central Asia

Middle East and North Africa

Western and central Europe and North America

What is driving the ageing ‘epidemic’?

ART, antiretroviral therapy.1. Preparing for an ageing HIV epidemic. Lancet 2017; 4(7): Pe277. Available at: https://doi.org/10.1016/S2352-3018(17)30114-5 [Accessed June 2019]; 2. ECDC/WHO. HIV/AIDS Surveillance in Europe 2018 – 2017 data. Available at: https://ecdc.europa.eu/en/publications-data/hivaids-surveillance-europe-2018-2017-data [Accessed June 2019].

The success of ART in prolonging lifespan of those on treatment1

Decreasing HIV incidence in younger individuals shifts burden of disease to older ages1,2

• Success of treatment as prevention

• Safe sex campaigns targeted at younger age groups

New HIV infections occurring later in life1

• Lack of HIV screening and safe sex campaigns targeting older age groups

•Biological changes, e.g. vaginal thinning, increased risk of mucosal damage

50+

Approximately 20% of new HIV diagnoses are in people aged over 50

ECDC/WHO. HIV/AIDS Surveillance in Europe 2018 – 2017 data. Available at: https://ecdc.europa.eu/en/publications-data/hivaids-surveillance-europe-2018-2017-data [Accessed June 2019].

Note: Germany did not report data for 2017; 0 cases were reported by Liechtenstein

<15 years

15-19 years

20-24 years

25-29 years

30-39 years

40-49 years

50+ years

RomaniaIcelandCyprus

Czech RepublicHungary

PolandIreland

BulgariaNetherlands

SpainSweden

United KingdomEU/EEA

ItalySlovakiaAustria

DenmarkFranceEstoniaCroatia

PortugalNorwayBelgiumSlovenia

LatviaGreece

LithuaniaLuxembourg

FinlandMalta

0% 20% 40% 60% 80% 100%

Diagnosis at an older age is more frequentlydue to heterosexual transmission

ECDC/WHO. HIV/AIDS Surveillance in Europe 2018 – 2017 data. Available at: https://ecdc.europa.eu/en/publications-data/hivaids-surveillance-europe-2018-2017-data [Accessed June 2019].

New HIV diagnoses, by transmission mode and age group, EU/EEA, 2017

Heterosexual (n = 8397)

0% 20% 40% 60% 80% 100%

Injecting drug use (n = 928)

Sex between men (n = 9691)

15-19 years

20-24 years

25-29 years

30-39 years

40-49 years

50+ years

Diagnosis rates in the 50+ age group are not decreasing

ECDC/WHO. HIV/AIDS Surveillance in Europe 2018 – 2017 data. Available at: https://ecdc.europa.eu/en/publications-data/hivaids-surveillance-europe-2018-2017-data [Accessed June 2019].

15-19 years

20-24 years

25-29 years

30-39 years

40-49 years

50+ years

New HIV diagnoses, by sex and age group, EU-EEA, 2008-2017

New

dia

gno

ses

per

10

0,0

00

po

pu

lati

on

14

12

10

8

6

4

02008 2009 2010 2011 2012 2013 2014 2015 2016 2017

2

Year of diagnosis

Men Women

New

dia

gno

ses

per

10

0,0

00

po

pu

lati

on

20

15

10

5

02008 2009 2010 2011 2012 2013 2014 2015 2016 2017

Year of diagnosis

Advanced disease at diagnosis is mostcommon in 50+ age groups in Europe

*Diagnosed late = CD4 < 350 cells/µL at diagnosis; CD4, cluster of differentiation 4.ECDC/WHO. HIV/AIDS Surveillance in Europe 2018 – 2017 data. Available at: https://ecdc.europa.eu/en/publications-data/hivaids-surveillance-europe-2018-2017-data [Accessed June 2019].

Proportion diagnosed late with HIV by age, EU/EEA, 2017

Dia

gno

sed

late

(<3

50

cel

ls/µ

L) (

%)

50

40

30

20

10

0

60

70

Total 15–19 20–24 25–29 30–39 40–49 50+

Age group (years)

EU-28 Life expectancy at birth

LE, life expectancy, EU-28, 28 countries included in the Eurostat classification.1. Eurostat. Life expectancy at birth by sex 2019. Available at: https://ec.europa.eu/eurostat/web/products-datasets/-/sdg_03_10 [Accessed June 2019]. 2. Office for National Statistics. Health state life expectancies, UK: 2015 to 2017, 2018. Available at: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healthandlifeexpectancies/bulletins/healthstatelifeexpectanciesuk/2015to2017 [Accessed June 2019].

Life expectancy (LE) for the general population in 20171:

• Average 80.9 years

• Women 83.5 years

• Men 78.3 years

• Healthy life expectancy is lower than life expectancy2

• Country variation2

2002 2004 2006 2008 2010 2012 2014 201672

74

76

78

80

82

84

86

Life expectancy at birth1

(Years, EU-28, 2002–2017)

Women Men

Expected age at death of PLHIV starting ART aged 20 years, by period of initiation

ART, antiretroviral therapy; CD4, cluster of differentiation 4; PLHIV, people living with HIV.*Expanded age at death were based on mortality during 3 years of follow up.The Antiretroviral Therapy Cohort Collaboration. Lancet HIV 2017;(4):e349–356.

Antiretroviral Therapy Cohort Collaboration data

• 18 cohorts in Europe and N. America

• All-cause mortality greatest in first year of ART

• Around 10-year increase in average age of death when mortality based on second and third year of ART

• Expected age at death of a 20-year-old 1-year after starting ART = 78·0 years (77·7–78·3)

– ART commencing 2008-2010 and CD4 > 350 cells/µL

1996–99

80

2000–03 2004–07 2008–10

75

70

65

60

55

0

Men, 3 years of follow-up

Women, 3 years of follow-up

Men, second and third years of follow-up

Women, second and third years of follow-up

Period of ART initiation

Exp

and

ed a

ge a

t d

eath

(yea

rs)

PLHIV with CD4+ cell count >350 and VL <400achieve UK general population life expectancy – UK CHIC data

ART, antiretroviral therapy; CD4, cluster of differentiation 4; LE, life expectancy; PLHIV, people living with HIV; UK CHIC, UK Collaborative HIV Cohort; VL viral load. May MT et al. AIDS 2014;28(8):1193–1202.

85

80

75

70

65

60

55

0 1 2 3 4 5

Years since start of ART

Male LE 78 years

85

80

75

70

65

60

55

0 1 2 3 4 5

Years since start of ART

Female LE 82 years

CD4 ≥ 350 CD4 200- 349 CD4 < 200VL ≤ 400

CD4 ≥ 350 CD4 200- 349 CD4 < 200VL > 400

50 50

What affects life expectancy in PLHIV?

Results from Gompertz parametric survival regression models. Univariate analyses based on 16,532 patients. CI, confidence interval. –, not estimated due to large amount of missing data or small number of patients and deaths.cART, combination antiretroviral therapy; CD4, cluster of differentiation 4; CI, confidence interval; PLHIV, people living with HIV.Gueler A et al. AIDS 2017;31(3):427–436.

Life expectancy (95% CI)

Monotherapy (1988–1991) Dual therapy (1992–1995) Early cART (1996–1998) Later cART (1999–2005) Recent cART (2006–2013)

Overall life expectancy 11.8 (11.2–12.5) 20.8 (19.4–22.2) 44.7 (42.2–47.3) 50.8 (48.5–53.3) 54.9 (51.2–59.6)

Education

Higher education – 26.7 (22.2–31.6) 53.0 (46.9–59.0) 58.2 (53.4–63.2) 60.0 (53.4–67.8)

Vocational training – 25.3 (23.0–27.7) 44.4 (41.4–47.7) 49.2 (46.5–52.1) 52.6 (48.3–57.9)

Compulsory school – 24.3 (21.3–27.5) 38.9 (35.1–43.0) 46.5 (43.1–50.3) 52.7 (46.4–60.1)

Main source of income

Work – 32.8 (29.2–36.5) 55.0 (50.9–58.9) 63.9 (59.3–68.4) 62.9 (56.2–70.9)

Welfare benefits – 15.8 (13.6–18.4) 31.5 (29.0–34.1) 39.4 (36.9–42.0) 48.0 (43.4–53.0)

HIV transmission group

MSM 8.9 (8.1–9.8) 22.9 (20.5–25.4) 52.7 (48.6–57.1) 57.3 (53.5–61.5) 56.8 (51.8–63.6)

Heterosexual contact 15.3 (13.7–17.21) 29.6 (26.1–33.3) 49.5 (45.8–53.6) 53.1 (50.2–56.2) 56.7 (51.7–62.8)

Injection drug use 12.4 (11.5–13.3) 15.7 (14.2–17.4) 27.3 (25.3–29.5) 31.3 (28.8–33.4) 35.8 (30.6–41.5)

Injection drug use

Never 11.3 (10.4–12.2) 25.1 (23.1–27.2) 51.9 (49.0–55.1) 54.6 (52.2–57.1) 57.2 (53.1–62.5)

Former 12.2 (11.4–13.1) 16.9 (15.0–18.9) 29.9 (27.4–32.5) 33.5 (30.9–36.3) 39.6 (34.4–45.1)

Current 12.2 (10.6–14.0) 15.2 (12.9–17.7) 24.7 (21.7–27.9) 29.0 (25.8–32.4) –

Smoking

Never – – – 65.2 (60.1–70.6) 59.0 (53.5–65.7)

Former – – – 56.4 (51.2–62.1) 54.6 (48.2–61.8)

Current – – – 42.8 (40.7–45.2) 49.4 (45.2–54.6)

Presentation at enrolment

CD4+ cell count <200 cells/μl 3.2 (2.9–3.6) 6.5 (5.5–7.6) 35.1 (30.2–40.3) 46.7 (42.6–51.2) 47.6 (41.9–54.3)

200–349 cells/μl 11.2 (9.9–12.5) 26.0 (21.7 –30.6) 48.0 (40.3–55.6) 50.2 (45.0–55.9) 54.0 (47.0–63.0)

≥350 cells/μl 25.2 (23.5–27.1) 44.5 (40.2–48.6) 59.9 (52.8–66.0) 53.0 (48.7–57.9) 63.9 (54.8–76.0)

Late presentation 6.1 (5.6–6.7) 12.1 (10.6–13.6) 41.1 (36.8–45.5) 48.7 (45.5–52.3) 53.2 (48.2–59.5)

Presentation with advanced HIV disease 3.5 (3.2–3.9) 7.3 (6.2–8.4) 36.0 (31.2–41.0) 46.5 (42.7–50.8) 49.1 (43.5–55.5)

Presentation with AIDS 2.4 (2.2–2.7) 4.4 (3.7–5.2) 29.1 (23.4–35.3) 42.1 (37.1–47.7) 46.3 (38.4–54.9)

Estimated life expectancy at age 20 years in the Swiss HIV Cohort Study, by treatment eraEstimated life expectancy in years when matched to the general population (95% Confidence Interval), N=16,532

Early start of cART and effective smoking-cessation programs could improve life expectancy for PLHIV

cART, combination antiretroviral treatment; CD4, cluster of differentiation 4; PLHIV, people living with HIV; CI, confidence interval.Gueler A et al. AIDS 2017;31(3):427–436.

Life expectancy (95% CI)

Monotherapy (1988–1991) Dual therapy (1992–1995) Early cART (1996–1998) Later cART (1999–2005) Recent cART (2006–2013)

Overall life expectancy 11.8 (11.2–12.5) 20.8 (19.4–22.2) 44.7 (42.2–47.3) 50.8 (48.5–53.3) 54.9 (51.2–59.6)

Education

Higher education – 26.7 (22.2–31.6) 53.0 (46.9–59.0) 58.2 (53.4–63.2) 60.0 (53.4–67.8)

Vocational training – 25.3 (23.0–27.7) 44.4 (41.4–47.7) 49.2 (46.5–52.1) 52.6 (48.3–57.9)

Compulsory school – 24.3 (21.3–27.5) 38.9 (35.1–43.0) 46.5 (43.1–50.3) 52.7 (46.4–60.1)

Main source of income

Work – 32.8 (29.2–36.5) 55.0 (50.9–58.9) 63.9 (59.3–68.4) 62.9 (56.2–70.9)

Welfare benefits – 15.8 (13.6–18.4) 31.5 (29.0–34.1) 39.4 (36.9–42.0) 48.0 (43.4–53.0)

HIV transmission group

MSM 8.9 (8.1–9.8) 22.9 (20.5–25.4) 52.7 (48.6–57.1) 57.3 (53.5–61.5) 56.8 (51.8–63.6)

Heterosexual contact 15.3 (13.7–17.21) 29.6 (26.1–33.3) 49.5 (45.8–53.6) 53.1 (50.2–56.2) 56.7 (51.7–62.8)

Injection drug use 12.4 (11.5–13.3) 15.7 (14.2–17.4) 27.3 (25.3–29.5) 31.3 (28.8–33.4) 35.8 (30.6–41.5)

Injection drug use

Never 11.3 (10.4–12.2) 25.1 (23.1–27.2) 51.9 (49.0–55.1) 54.6 (52.2–57.1) 57.2 (53.1–62.5)

Former 12.2 (11.4–13.1) 16.9 (15.0–18.9) 29.9 (27.4–32.5) 33.5 (30.9–36.3) 39.6 (34.4–45.1)

Current 12.2 (10.6–14.0) 15.2 (12.9–17.7) 24.7 (21.7–27.9) 29.0 (25.8–32.4) –

Smoking

Never – – – 65.2 (60.1–70.6) 59.0 (53.5–65.7)

Former – – – 56.4 (51.2–62.1) 54.6 (48.2–61.8)

Current – – – 42.8 (40.7–45.2) 49.4 (45.2–54.6)

Presentation at enrolment*

CD4+ cell count <200 cells/μl 3.2 (2.9–3.6) 6.5 (5.5–7.6) 35.1 (30.2–40.3) 46.7 (42.6–51.2) 47.6 (41.9–54.3)

200–349 cells/μl 11.2 (9.9–12.5) 26.0 (21.7 –30.6) 48.0 (40.3–55.6) 50.2 (45.0–55.9) 54.0 (47.0–63.0)

≥350 cells/μl 25.2 (23.5–27.1) 44.5 (40.2–48.6) 59.9 (52.8–66.0) 53.0 (48.7–57.9) 63.9 (54.8–76.0)

Late presentation 6.1 (5.6–6.7) 12.1 (10.6–13.6) 41.1 (36.8–45.5) 48.7 (45.5–52.3) 53.2 (48.2–59.5)

Presentation with advanced HIV disease 3.5 (3.2–3.9) 7.3 (6.2–8.4) 36.0 (31.2–41.0) 46.5 (42.7–50.8) 49.1 (43.5–55.5)

Presentation with AIDS 2.4 (2.2–2.7) 4.4 (3.7–5.2) 29.1 (23.4–35.3) 42.1 (37.1–47.7) 46.3 (38.4–54.9)

Life expectancy at age 20 years in the Swiss HIV Cohort Study, by treatment era.

Results from Gompertz parametric survival regression models. Univariate analyses base on 16,532 patients. CI, confidence interval. –, not estimated due to large amount of missing data or small number of patients and deaths.

SociodemographicsLife expectancy (95% CI)

Recent cART (2006–2013)

Education

Higher education 60.0 (53.4–67.8)

Vocational training 52.6 (48.3–57.9)

Compulsory school 52.7 (46.4–60.1)

Main source of

income

Work 62.9 (56.2–70.9)

Welfare benefits 48.0 (43.4–53.0)

BehavioursLife expectancy (95% CI)

Recent cART (2006–2013)

Injection drug

use

Never 57.2 (53.1–62.5)

Former 39.6 (34.4–45.1)

Smoking

Never 59.0 (53.5–65.7)

Former 54.6 (48.2–61.8)

Current 49.4 (45.2–54.6)

HIV parametersLife expectancy (95% CI)

Recent cART (2006–2013)

Presentation

CD4 <200 cells/µL 47.6 (41.9–54.3)

CD4 200-349 cells/µL 54.0 (47.0–63.0)

CD4 ≥350 cells/µL 63.9 (54.8–76.0)

Late presentation 53.2 (48.2–59.5)

Presentation with AIDS 46.3 (38.4–54.9)

Overall life expectancy 54.9 years (Recent cART 2006 – 2013)

Challenges to longevity and ageing well in PLHIV

PLHIV, people living with HIV.Karris MY et al. Poster presented at: IDSociety 2017. Available at: https://ein.idsociety.org/media/resources/publications/posters/2018/Karris_HIVandAging_2017.pdf [Accessed June 2019].

Barriers to ageing well

Adverse Lifestyle factors

Mental Health Issues

Co-infections Social & financial

disadvantage

Stigma and discrimination

Premature ageing

Uncertainty

Institutional preparedness

HIV service provision

Inequalities among key

groupsFrailty Co-morbidities Late diagnosis

Challenges to longevity: Effects of HIV control, comorbidity, and substance misuse

Obel N et al. PLoS ONE 2011;6(7):e22698.

0- HIV negative

1- HIV positive, well controlled

2- HIV positive, not controlled

3- HIV positive, not controlled + comorbidity

4- HIV positive, not controlled + comorbidity + drug/alcohol abuse

Age (years)

0.030 70605040

0.2

0.4

0.6

0.8

1.0

Pro

bab

ility

of s

urv

ival

Group 0Group 1

Group 2

Group 3

Group 4

Well-treated PLHIV may lose more life yearsthrough smoking than through HIV

Exce

ss m

ort

alit

y ra

te p

er 1

00

0

per

son

yea

rs

50

0

Nu

mb

er o

f lif

e ye

ars

lost

9

0

40

30

20

10

8

7

6

5

25 35 45 55 65

1

2

3

4

Smoking HIV-related factors

Smoking was associated with excess mortality and more lost life years in European and North American cohorts (n=17,995 men living with HIV more than 1 year after ART initiation)

25 35 45 55 65

ART, antiretroviral therapy; PLHIV, people living with HIV.Helleberg M et al. AIDS 2015;29(2):221-229.

Age (years) Age (years)

Age-specific excess mortality rates associated with smoking and HIV-related factors

Number of lost life years associated with smoking vs. HIV-related factors

Smoking HIV-related factors

Where are we now?

MDT, multi-disciplinary team; PLHIV, people living with HIV.Author’s opinion.

HIV has become a long term condition:

• Long term outcome of treated HIV unknown- new issues may arise

• Stigma is still an issue and may influence service choice

• A proportion of PLHIV have complex needs (advanced disease, resistance, co-infection)

Current issues:

• Level of experience in dealing with elderly care issues generally

• Comorbidities have become major part of HIV care

• Expertise, links to community/MDT services, funding

• Elderly medicine services may not be designed to cater for a younger “ageing” population, e.g. >50 years

Guaraldi and Rockwood. Clin Infect Dis 2017;65(3):507–9; Singh et al. Clin Infect Dis 2017;65(3):501–6.

Geriatric-HIV Medicine is Born.Guaraldi G and Rockwood K. Clin Infect Dis 2017;65(3):507–9.

From One Syndrome to Many: Incorporating Geriatric Consultation Into HIV Care.Singh et al. Clin Infect Dis 2017;65(3):501–6.

Incorporating geriatric consultation into HIV care

BHIVA, British HIV Association; DDI, drug-drug interaction; EACS, European AIDS Clinical Society; MM, multimorbidity; PLHIV, people living with HIV, IU, international unit.1. British HIV Association. BHIVA guidelines for the routine investigation and monitoring of adult HIV-1-positive indiviudals (2019 interim update). Available at: https://www.bhiva.org/file/DqZbRxfzlYtLg/Monitoring-Guidelines.pdf[Accessed June 2019]; 2. EACS Society. EACS Society Guidelines Version 9.1 October 2018 (English). Available at: http://www.eacsociety.org/files/2018_guidelines-9.1-english.pdf [Accessed June 2019]; 3. Singh HK et al. Clin Infect Dis 2017;65(3):501-506. Author’s opinion.

• Ageing cannot be defined/measured by the presence of disease

• Impact of MM is not the same as adding the impacts of multiple individual comorbidities

• Ageing-related (geriatric) syndromes are distinct from classic medical syndromes

• Geriatric syndromes can be seen among PLHIV before they are chronologically elderly

• To date, there is no formal guidance on incorporating geriatric care principles into care for PLHIV

Some recommendations on the “geriatric approach”3:

Guidelines addressing ageing in PLHIV

Updates to guidelines reflect the needs of an ageing population of PLHIV

Guidelines RecommendationsBHIVA Standards 2019:1 >40 years: Annual cardiovascular risk,

metabolic and lipids assessment >50 yearsFracture risk assessment (FRAX) and medication review for potential DDIs, population cancer screening

EACS Society Guidelines 2018:2 Reduce fracture risk in PLHIV by assessing fall risks, ensure 1–1.2 g daily calcium and 800–2,000 IU daily vitamin D intake, osteoporosis screening

Geriatric syndromes arevariously defined1,2

* Text in red are conditions associated with classical frailty syndromes1. Inouye SK et al. J Am Geriatr Soc 2007;55(5):780–791; 2. British Geriatrics Society. Comprehensive Geriatric Assessment Toolkit for Primary Care Practitioners 2019. Available at: https://www.bgs.org.uk/sites/default/files/content/resources/files/2019-03-12/CGA%20Toolkit%20for%20Primary%20Care%20Practitioners_0.pdf [Accessed June 2019].

Frailty

Falls

Immobility

Functional impairment

Incontinence

Cognitive impairment –acute (delirium) and chronic

Polypharmacy and increased risk of iatrogenic harm

Multi-morbidity

Mood disorder

A word on geriatric syndromes

Inouye SK et al. J Am Geriatr Soc 2007;55(5):780–791.

Clinical conditions in older persons that do not fit into discrete disease categories

and instead

cross organ systems and discipline-based boundariesSK Inouye 2007

• They are common

• They are often defined by a single symptom (e.g. urinary incontinence)

• Single aetiologies may precipitate multiple syndromes

– e.g. pneumonia precipitating falls and delirium

• Individual syndromes may have multiple aetiologies:

– Delirium might be caused by an infection, dehydration, constipation

• Older patients often have multiple geriatric syndromes at one time

How geriatric syndromes differ from classic syndromes:

What is frailty?

Clegg A et al. Lancet 2013:381(9868):752–762.

Underpins the ‘non-specific nature’ of some medical presentations in older adults

Age-related decline in multiple physiological systems

Threshold of homeostatic reserve reached, resulting in:

• An ‘at risk’ state

• Vulnerability to minor stressor events

Disproportionate changes in health status:

• From mobile to immobile

• From lucid to confused

• From independent (‘managing’) to requiring help

An increasedrisk of adverse events

HIV-positive HIV-negative Odds ratio Odds ratio

Study or subgroup Frail Total Frail Total Weight M-H, random, 95% CI M-H, random, 95% CI

Akgün 2014 102 3472 86 3043 10.2% 1.04 [0.78, 1.39]

Althoff 2013 257 898 220 1048 10.5% 1.51 [1.23, 1.86]

Desquilbet 2007 34 245 28 1905 9.1% 10.80 [6.42, 18.17]

Ding 2017 21 345 2 345 4.3% 11.12 [2.59, 47.78]

Gustafson 2016 251 1449 58 579 10.2% 1.88 [1.39, 2.55]

Kooji 2016 55 466 14 513 8.6% 4.77 [2.61, 8.70]

Margolick 2017 109 842 26 230 9.5% 1.17 [ 0.74, 1.84]

Pathai 2013 48 248 34 256 9.3% 1.57 [0.97, 2.53]

Piggot 2015 57 387 42 939 9.7% 3.69 [2.43, 5.60]

Terzian 2009 110 1206 46 573 10.0% 1.15 [0.80, 1.65]

Young 2015 7 61 0 27 1.6% 7.57 [0.42, 137.44]

Zhang 2015 18 39 18 40 7.0% 1.05 [0.43, 2.54]

Total (95% CI) 9658 9498 100.0% 2.22 [1.50, 3.28]

Total events 1069 574

Heterogeneity: Tau2 = 0.36; Chi2 = 101.34; df = 11 (P <0.00001); I2 = 89% Test for overall effect: Z = 4.01 (P <0.0001)

Frailty is more prevalent amongst PLHIV, compared to those without HIV

CI, confidence interval; M-H, Mantel-Haenszel; OR, odds ratio; PLHIV, people living with HIV. Pool E, et al. Global Health Day 2017 Conference, UCL London, UK. Provided by Imperial College London.

Meta-analysis of 12 studies; comparison of frailty prevalence according to HIV status

OR: 2.22

95% CI: 1.50–3.28

p<0.0001

0.01 1 100100.1

HIV-negative HIV-positive

Predictors of frailty in HIV

Age

HIV-related factors:• Longer duration

• Greater immune suppression (lower CD4, current and nadir)

• Detectable viral load

• AIDS diagnosis

• Use of protease inhibitors

• Low CD4:CD8 ratio

BMI, body mass index; CD4, cluster of differentiation 4; HANA, HIV-associated non-AIDS conditions; VL, viral load. Adapted from: Brothers TD et al. J Infect Dis 2014;210(8):1170–9.

Social factors:• Lower education

• Unemployment

• Low income

Body composition:• Low BMI

• High BMI

• Lipodystrophy

Comorbidities:• Hepatitis C

• Diabetes

• Kidney disease

• Depression

• Cognitive impairment

Inflammaging(Markers of immune activation, senescence and inflammatory cytokines)

Viral load> 50 copies/mL

CD4 count< 750 cells/μL

Immune deficiency/activation

AIDS- and non-AIDS-associated conditions Clinical spectrum of disease

Pre

vale

nce

of

frai

lty

Age

HIV factors and age were notassociated with frailty transition

*Frailty scores were assessed by Fried criteria, including low physical activity, exhaustion, weight loss, weak grip strength, slow walking speed.Hrouda N et al. 2018. Poster presented at: Fourth Joint Conference of BHIVA with BASHH 2018. Available at: https://www.bhiva.org/file/NHnoEYPSrTCAw/P176.pdf [Accessed June 2019].

12656.5%

5223.3%

4520.2%

Direction of transition

Proportion of participants who transitioned between different frailty scores, n %

Clinicians should focus their interventions on the non-infectious complications of HIV in this ageing population.

Increasing score (propensity to frailty) associated with:

• Lesser education (p=0.041)

• Being out of work (p=0.016)

• Greater number of comorbidities (p=0.009)

• Greater number of medications used (p=0.004)

• Greater mood symptoms (p=0.033)

• Lower physical activity, as measured by grip strength (p=0.037) and walking speed (p=0.006)

No change More frail Less frail

Frailty trajectories in 1 year in PLHIV in a 50+ age group• 253 participants were recruited

• 223 participants (88%) were followed up at 1 year

• An overall frailty score* (0–5) was assigned to record change in 1 year

Early initiation of tolerable ARTAggressive risk factor controlAddressing health disparities

Is there anything we can do about frailty?

ART, antiretroviral therapy. Personal communication, Dr. Tom Levett, November 2018.Escota GV et al. Int J Infect Dis 2018;66:56-64.

No single treatment as such,

but consensus say yes:

• Improve physical function

• Improve nutrition

• Improve psychological status

• Treat medical conditions

• Manage pain

• Novel approaches/interventions? Drug candidates?

Successful ageing in HIV

ART-induced toxicity, inflammation, immune dysfunction, monocyte activation

Traditional factors – smoking, poor diet, inadequate physical activity

HIV-related risk factors

Active engagement with lifeAvoidance of disease

and disease-related disability

High cognitive and physical functional capacity

Positive lifestyle factors

Future potential frailty intervention targets

Exercise1,2

• Resistance – designed to improve core strength

• Aerobic – designed to improve exercise capacity

• Combination

Nutrition3-6

• Global dietary modification

• Protein supplementation

• Specific nutrients/micronutrients - turmeric, fisetin and quercetin (flavonoids)

Hormonal modification7

• Testosterone, growth hormone, ghrelin

Immunomodulation/cellular11-15

• Stem cell transplant (autologous)

• Blood serum markers

• Superoxide dismutase

• Tyrosine kinase inhibitors

Specific drugs8-10

• Metformin

• Statins

• ACE inhibitors

ACE, angiotensin-converting enzyme; G-CSF, granulocyte-colony stimulating factor.1. Travers J et al. Br J Gen Pract 2019;69(678):e61-e69; 2. Apóstolo J et al. JBI Database System Rev Implement Rep 2018;16(1):140–232; 3. Clegg A et al. Lancet 2013;381(9868):752–762; 4. Coelho-Junior HJ et al. Nutrients2018;10(1334): doi:10.3390/nu10091334; 5. Bonnefoy M et al. J Nutr Health Aging 2015;19(3):250-7; 6. Yousefzadeh MJ et al. EBioMedicine 2018;36:18–28; 7. Giannoulis MG et al. Endocr Rev 2012;33(3):314–377; 8. Wang C et al. J Endocrinol Diabetes Obes 2014;2(2):1031; 9. Pilotto et al. PLoS One 2015;10(6):e0130946; 10. Goldwater DS and Pinney SP. Clinical Medicine Insights: Cardiology 2015:9(S2) 39–46; 11. Schulman IH et al. Front Nutr2018;5:108; 12. . Xu M et al. Nat Med 2018;24(8):1246–1256; 13. Saedi AA et al. Clin Interv Aging 2019;14:389–398; 14. Deepa SS et al. GeroScience 2017;39(2):187–198; 15. Zhu Y et al. Aging Cell 2015; 14:644–658: doi: 10.1111/acel.12344.

What can we do about frailty?

Klotz SA et al. J Int Assoc Provid AIDS Care 2019;18:1-3.

It is anticipated that anti-retroviral therapy now being administered at the time of diagnosis, cure of hepatitis C and use of current HIV therapies with fewer side effects [compared with early HIV treatments] will diminish the incidence and prevalence of frailty associated with HIV infection.Klotz et al. 2019

Some of the data presented here is investigational, and Gilead encourages use of medicines only for licenced indications.HAND, HIV associated neurocognitive disorder; PLHIV, people living with HIV; RCT, randomised controlled trial; VIP, Video Information Provider. 1. Veeravelli S et al. J Vis Exp 2016;116:e54275; 2. Available at: https://clinicaltrials.gov/ct2/show/NCT03182738 [Accessed June 2019]; 3. Available at: https://clinicaltrials.gov/ct2/show/NCT02965469 [Accessed June 2019]; 4. Available at: https://clinicaltrials.gov/ct2/show/NCT03277222 [Accessed June 2019].

Exergaming1

• N=10 PLHIV aged >50 years; 6 weeks of graded exercise driven by computer programme

• Frailty assessed by Fried phenotype

• Showed improved balance, gait speed and pain scores

Video Information Provider (VIP) for HIV-Associated Non-AIDS Symptoms (HANA)2

• RCT currently recruiting 100 adults with HIV in the USA

• VIP app delivering HIV-related symptom strategies vs VIP app alone

• Primary outcome – PROMIS-29 at 3 and 6 months;Secondary outcome – Frailty (phenotype)

Psychosocial Stress and Ageing in HIV USA3

• RCT completed late 2017, N=42 PLHIV aged >21

• Usual care vs. mobile phone-delivered stress reduction intervention (‘Breathe2relax’ app)

• Correlation between perceived stress & both ageing (incl. frailty) and HIV-specific outcomes

HAND IN Insulin-001: Intranasal Treatment of HIV-associated Neurocognitive Disorders4

• Commenced November 2018, N=45, HIV+ adults with HAND

• RCT intranasal insulin, twice daily, 4 months

• Primarily outcome – effect on cognition; secondary outcome – change in frailty (index)

Comprehensive Geriatric Assessment

A process not an event

• Interdisciplinary

• Multidimensional

• Produces problem lists

• Integrated plan for treatment, rehabilitation, support and long term care

British Geriatrics Society. Comprehensive Geriatric Assessment Toolkit for Primary Care Practitioners 2019. Available at: https://www.bgs.org.uk/sites/default/files/content/resources/files/2019-03-12/CGA%20Toolkit%20for%20Primary%20Care%20Practitioners_0.pdf [Accessed June 2019].

Creation of problem list

Personalised care plan

Intervention

Regular planned view

AssessmentCurrentReactive

Disease-focussedFragmented

DesiredProactiveHolistic

Preventative

Care Planning

Socioeconomic/environmental

Functional

Physical

Psychological/mental

Medication review

Mobility/balance

Proactive rather than reactive care

Conclusions: Aspects of ageing impact PLHIV earlier,and there is more that can be done

1. Autenrieth CS et al. PLoS ONE 2018;13(11): e0207005; 2. ECDC/WHO. HIV/AIDS Surveillance in Europe 2018 – 2017 data. Available at: https://ecdc.europa.eu/en/publications-data/hivaids-surveillance-europe-2018-2017-data [Accessed June 2019]; 3. Author’s personal opinion. 4. Greene M et al. J Acquir Immune Defic Syndr 2015;69(2):161–167

PLHIV are living longer than they used to a decade ago1

A move towards diagnosis of HIV at an older age, and in different demographic groups2 needs to be reflected in the care provided3

PLHIV now face issues associated with ageing4

Clinical performance-oriented assessments of the indicators of ageing will help to improve our ability for proactive, preventive interventions3

Potential future targets, include exercise, diet, hormone modulation and are likely include use of new technologies3