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HIV and ageing

Dr Marta Boffito MD, PhD

Head of Clinical Trials, St. Stephen’s Centre (SSAT) Consultant Physician, Chelsea and Westminster Hospital

Reader, Imperial College

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Summary1 Managing older patients could be quite challenging

2 Do patients with HIV age prematurely?

3 What do we know from cohort studies

4 Setting up an over 50 clinic: my experience at C&W

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Mr W.• 61 y.o. MSM • HIV + since 2001 • VL<50, CD4 821 • Transfer of care in 2011 on TDF + 3TC + DRV/r • AUG 2015 switched to TDF/FTC + DTG • Baseline RT not available but no Hx of failure

reported

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Mr W.

Medical Hx: Depression, hypertension, peripheral neuropathy, hypercholesterolemia, benign prostatic hyperplasia, osteoporosis.

Co-medications: Citalopram, amitryptiline, amlodipine, bisoprolol, tamsulosin, vitamin D. He is intolerant to statins and therefore on rosuvastatin 5mg

At the last visit: Serum creatinine 154 microM/L; eGFR 40 mL/min. It was 57 six months ago and deteriorated BP 145/95

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Increasingage,

ageingprocess1

Lifestyle(drugs,

alcohol)1

Drug toxicity(e.g. TDF and

Nephrotoxicity1

)

Persistentimmune

dysfunctioninflammation1 PREMATURE

AGEING1

Polypharmacy1

Cancer1,3

Bonedisease1,5

Kidney disease1,7

Neurological Impairments1,2

CVD1,4

Liver disease1,6

1. Deeks SG et al. BMJ 2009;338:a31722. McArthur JC et al. Ann Neurol 2010;67:699–714

3. Nguyen ML et al. 18th IAC. Vienna, Austria 2010. Abstract WEAB01054. Freiberg MS et al. JAMA Intern Med 2013;173:614–22

5. Brown TT et al. AIDS 2006;20:2165–746. Towner WJ et al. JAIDS 2012;60:321–77. Lucas GM et al. Clin Infect Dis 2014;59

Do patients with HIV age prematurely?

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AANCC2

(age-associated non-communicable co-morbidities)

NCD1 (Non-communicable

disease)

Terms used in studies on comorbidities among PLWHIV

NICM3

(non-infectious comorbidity) NADI4

(non-AIDS-defining illness)

NADM/C5

(non-AIDS-defining malignancies/cancers)

Comorbidities in PLWHIV: today’s definitions

1. Smit M et al. Lancet Infect Dis 2015;15(7):810–82. Schouten J et al. Clin Infect Dis 2014:59:1787–97

3. Guaraldi G et al. Clinicoecon Outcomes Res 2013;5:481–8.4. Mocroft A et al. J Acquir Immune Defic Syndr. 2010;55:262-70

5. Shiels MS et al. J Natl Cancer Inst. 2011;103:753-62

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Part

icip

ants

(%)

45-49 50-54 55-59 60-64 ≥65 . 45-49 50-54 55-59 60-64 ≥65

0 12 3+

Age (years) 45–49 50–54 55–59 60–64 ≥65 45–49 50–54 55–59 60–64 ≥65

Mean number of AANCC 0.83 1.18 1.34 1.52 1.96 0.79 0.75 1.11 1.08 1.51

Number of participants 184 126 97 58 55 193 130 84 66 41

HIV-infected (N=540)Mean AANCC/person = 1.3 (SD 1.14)

HIV-uninfected controls (N=524)Mean AANCC/person = 1.0 (SD 0.96)

AANCC incidence stratified by age in the AGEhIV Cohort Study, 2010–2012

Schouten J et al. Clin Infect Dis 2014:59:1787–97AANCC, age-associated non-communicable co-morbidities

Comorbidities are prevalent among ageing PLWH

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16,000

4,000

2,000

2010 20302015

Num

ber o

f peo

ple

6,000

14,000

12,000

10,000

2020 20250

3 or more

Year

Co-morbidities: 2 1 0

8,000

The number of PLWHIV with NCDs is predicted to rise

• Proportion of PLWHIV with ≥1 NCD predicted to increase

o 2010 29%

o 2030 in 84%

• Driven by

o CVD in 78%

o Diabetes in 17%

o Malignancies in 17%

Predicted burden of NCDs in PLWHIV 2010–2030*

*Predictive model based on data from the ATHENA cohort (n=10,278)NCDs, non-communicable diseases

Smit M et al. Lancet Infect Dis 2015;15(7):810–8

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Age (years)

20 30 40 50 60 70+

No medications ART onlyART + 1 comedication ART + 2 comedicationsART + 3 comedications ART + 4 comedicationsART + 5 comedications

Number of co-medications by age

100

80

60

40

20

0

Patie

nts (

%)

In the Positive Voices Survey (2015), among PLWHIV seen at HIV clinics (n=778), 64% reported ≥1 chronic condition, increasing to 77% among those >50 years of age

The most common co-medications were anti-depressants, antihypertensives and statins

Kall M et al. and the Positives Voices Study Group. EACS 2015

PLWHIV are taking medications in addiction to their ARVs

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Knowledge on aging with HIVMajority of clinical trial populations include people under the age of 50 years and very few (if any?) above 60 years Our knowledge limited to

▪ Cohort studies (e.g. AGEhiv, POPPY, etc) ▪ Clinical experience

Trial Drug(s) Study population Median age

GS - 104&1111 ECFTAF vs ECFTDF Naïve 33

ARTEMIS2 DRV/r vs LPV/r Naïve 36

SPRING-23 DTG vs RAL Naïve 37

STAR4 EFV vs RPV Naïve 37

FLAMINGO5 DTG vs DRV/r Naïve 34

GS-US-292-01126 ECFTAF Switch 58

GS-US-292-1826* TDF based regimen to ECFTAF

Switch >60*recruiting

1 Wohl, Lancet 2015; 385. 2 Orkin, HIV Med. 2013. 3 Raffi, Lancet 2013; 381. 4 Cohen  Journal of the International AIDS Society 2012. 5 Cloet Lancet 2014. 6 Pozniak JAIDS 71, 2015

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What do we know from cohort studies

Cancer

Bonedisease

Kidney disease

Neurological Impairments

CVD

Liver disease

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Central nervous system

Hypotheses tested

Despite suppressive cART, compared to an appropriate control population, HIV+ individuals will have evidence of:

• Poorer cognitive performance • Grey and white matter atrophy • White matter microstructural abnormalities

Structural brain and cognitive abnormalities would occur together and be more common in HIV+ individuals

HIV + N = 134 – HIV – N = 79 All underwent: cognitive testing and MRI scanning (several modalities) AGE (median, IQR; years) HIV + = 55, 51-62 – HIV- = 57, 52-64

Brain MRI changes associated with poorer cognitive function in treated HIV-infection1

Underwood et al. CROI 2016

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Cognitive function

p < 0.001 p = 0.01

p < 0.01 p < 0.001

p < 0.001

p = 0.4 p = 0.4

20

30

40

50

60

70

80

Attention Executivefunction

Language Memory Motorfunction

Processingspeed

Global

Cog

nitiv

e do

mai

n T

scor

e

HIV-status

HIV-

HIV+

Boxplots of demographically adjusted cognitive domain T-scores by HIV-serostatus. P values calculated using Wilcoxon rank sum test.

Underwood et al. CROI 2016

PLWHIV have poorer scores in almost all tasks except language and memory compared to controls

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Conclusions

HIV+ individuals have evidence of cognitive impairment, grey matter atrophy and white matter microstructural injury

• despite fully suppressive cART • compared to an appropriate control population

Structural brain abnormalities tend to occur together • found more commonly in HIV+ individuals • associated with poorer cognitive function • associated with markers of immune dysregulation

Limitations – cohort study • unmeasured differences could confound group comparisons • but mitigated against this with an appropriate HIV- control group

Underwood et al. CROI 2016

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1. Anastos K et al. Antivir Ther 2007;12(7):1049–58, 2. McComsey GA et al. Clin Infect Dis 2010;51(8):937–46,3. Triant VA et al. J Clin Endocrinol Metab 2008;93(9):3499–504, 4. Bedimo R et al. AIDS 2012;26:825–31

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Antiretroviral exposure and risk of osteoporotic fractures: 1996–20094

Haz

ard

Ratio

1.2

1.1

1.0

0.9

0.8TDF ABC ZDV/D4T NNRTI rPI

Fracture prevalence PLWHIV and non-infected controls3*

Frac

ture p

revale

nce/

100 p

erson

s7.06.05.04.03.02.01.00.0

Male

20–29 30–39 40–49 60–6950–59Age

p<0.0001(overall comparison)

Frac

ture p

revale

nce/

100 p

erson

s

7.06.05.04.03.02.01.00.0

Female

30–39 40–49 50–59 70–7960–69Age

p=0.002(overall comparison)

HIV Non-HIV

Increased BMD issue risk from HIV infection

Increased BMD issue risk from HIV treatment

*U.S. healthcare system data

• PLWHIV have lower bone mineral density (BMD) than the uninfected population1

• Prevalence of fractures of the spine, hip, and wrist, sites commonly associated with osteoporosis can be 60% higher in PLWHIV compared with the uninfected3

PLWHIV are at increase of low BMD and fractures

• ARVs can exacerbate low BMD issues

• Initiation of therapy is associated with a 2–6% decrease in BMD over the first two years of treatment2

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Fractures Occur at a Younger Age in HIV+ Men

Gonciulea A, et al. CROI 2016. Boston, MA. #699

MACS Study (2001-2015)In

cide

nce

Rat

e/10

00 p

erso

n-yr

0

7.5

15

22.5

30

Overal

l40

-49 Yr o

f Age

50-59

Yr of A

ge≥6

0 Yr o

f Age

Overal

l40

-49 Yr o

f Age

50-59

Yr of A

ge≥6

0 Yr o

f Age

OverallHIV-negativeHIV-infected

All fractures Osteoporotic fracturesIncidence Rates of All Fractures and Osteoporotic Fractures

Overall Overall40-49 40-4950-59 50-59 ≥60≥60Age (Years)

The increase in incidence of all fractures and osteoporotic fractures occurred at an earlier age in HIV+ men compared to uninfected controls. This analysis highlights the importance of early screening for

osteoporosis in HIV+ men, particularly after the age of 50.

Ongoing, prospective cohort study of ART-treated HIV+ (n=1221) and HIV- (n=1408) men age ≥40 ▪ Incidence of all fractures and osteoporotic fractures was similar among younger HIV+ and HIV-

men, but increased at an earlier age in HIV+ (age 50-59) vs HIV- men (age ≥60 years) ▪ Compared to HIV- men (age 40-49), HIV+ men (age 50-59) and (age ≥60) had higher adjusted

incidence rate ratios of all fractures (1.99 and 1.84, respectively); similar trends were seen for osteoporotic fractures.

▪ eGFR <60 was associated with higher risk of all fractures

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PLWHIV have higher risk of CKD

• Data from Danish cohort 1995 - 2014 o 5897 cases o 53073 matched controls

The age-standardised risk of chronic kidney disease Increased with time after cART Initiation.

Rasmussen et al Lancet HIV 2015aIRR = adjusted incidence rate ratio

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… and higher risk of CV disease

Rasmussen et al Lancet HIV 2015aIRR = adjusted incidence rate ratio

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CardiovascularCardiovascular (CV)-related/AIDS-related death ratio and age of death in the HIV Outpatient Study (HOPS) trial,4 between 1996 and 2004.

Freiberg MS et alJAMA Intern Med 2013

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6

5

4

3

2

040 45 50 55 60 65

Age (years)

Rela

tive

haza

rd o

fde

velo

ping

CV

D

Reducing systolic BPb

Reducing cholesterola

Smoking cessation

Relative risk of CVD

Model for change in relative risk of CVD in a cohort of 24,323 HIV-positive individuals without prior CVD (D:A:D Study)

Effective treatment of modifiable risk factors can significantly reduce an individual’s CVD risk

aReduced by 1 mmol/L; bReduced by 10 mmHg

Reducing traditional CDV risk factors can decrease risk of CVD in older PLWHIV

Petoumenos K et al. HIV Med 2014;15:595–603

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PLWHIV are diagnosed with cancer at an earlier age than uninfected adultsM

ean

age

of

canc

er d

iagn

osis

0

20

40

60

80

5345

52514142

52

7161

6967656658

SCC, squamous cell carcinoma, SEER, Surveillance, Epidemiology and End Results 1. National Cancer Institute Fact Sheet. HIV Infection and Cancer Risk. National Institutes of Health. 2013, 2. Nguyen ML et al. 18th IAC, 2010. Vienna, Austria. Abstract WEAB0105

Average age at cancer diagnosis for 516 HIV-positive individuals and uninfected individuals (SEER database), by cancer type, 2000–20072

Uninfected (SEER database)

HIV-positiveindividuals

Anal/rectal SCC

Non-Hodgkinlymphoma Liver Head

and neck Lung Breast Prostate

p=0.0001 for all comparisons

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Polypharmacy

• Has been variously defined

• In research studies a commonly applied definition has been the concomitant use of five or more drugs

• Has been linked to heightened risk of occurrence of drug-related problems (toxicities and DDIs) and a detrimental health outcome

≥ 5

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Mechanism of PK drug-drug interaction

Roden DM & George AL, Jr. Nat Rev Drug Discov 2002;1:37–44

Absorption

Metabolism

Excretion

Inhibition/induction of intestinal cytochromes or drug transporters Gastric pH

Food, mineralsupplements

Inhibition of renaldrug transporters

Inhibition/inductionof hepatic

cytochromes,glucuronidation,

or drug transporters

Enterocyte

Small intestineKidney

Liver

Portal vein

Systemic circulation

Bile

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Drug interaction resources HIV

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25HIV=human immunodeficiency virus; TDM=therapeutic drug monitoring; CACS=coronary artery calcium scores; BMD=bone mineral density

Waters L, et al. Int J STD AIDS 2012;23:546‒52

…full medication and drug interactions review, neurocognitive assessment, adherence self-

assessment and investigations, including TDM, CACS and BMD.

…osteoporosis……prostate cancer…

The clinic has improved general practitioner (GP) liaison…

A dedicated clinic for the over 50’s at C&W

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1 – Drug history• N of drugs • Type of drugs

o Prescribed o OTC o Herbals o Recreational o Alcohol

• Drug interactions

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2 – Endocrine systemMEN

Check for hypogonadism • low libido • depression • osteoporosis

WOMEN Menopausal clinic • depression • osteoporosis • ….

Transexual • symptomatology • drug interactions

TestosteroneTotal and FREE

Full hormonalprofile

Full hormonalprofile with

appropriate referral

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3 - Cancer screening

MEN • PSA • Anal cytology • Referral to anoscopy

clinic if cytology is abnormal

WOMEN • Cervical smear* • Ensure mammography

is done or planned

*cervical smear test is recommended every year regardless of patient’s age

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3 - Cancer screening

… anal cytology results reflected the fact that an ageing HIV-positive population is more at risk of having abnormalities; it is important that this group continues to be offered regular screens and educated about anal malignancy.

Mohabeer-Hart EACS 2015

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4 – CV risk assessmentCoronary artery calcification score

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5 – Bone mineral density• DEXA scan • Vitamin D • FRAX score

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5 – Bone mineral density

BHIVA 2012

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6 – Cognitive assessment▪ HIV Associated Neurocognitive Disorder (HAND)▪ SOCIAL SITUATION: combination of all social factors that come into play

at any one time

Are you concerned about your memory/concentration/cognition?Has anybody around you expressed concern about your memory/concentration/cognition?

PHQ – 9GAD - 7

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6 – Cognitive assessment: EMQ

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6 – cognitive assessment

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Questions?• Are we ready to manage an aeging HIV

population? • Do we need to pay particular attention when it

comes to choose the right ARV regimen, to avoid adding toxicity?

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HIV duration of 20 Years in 75 year olds doubles multimorbidities & polypharmacy ratesSilver champions from the GEPPO cohort (GEriatricPatients living with HIV/AIDS): A case control study of people above 75 years of age addressing Multimorbidity Polypharmacy and Antiretrovirals’ Prescription in old HIV patients

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Results• A total of 492 patients were included (292 HIV+ and

200 HIV-neg • At logistic regression analysis HIV duration above 20

years was an independent predictor of MM (OR=2.31) and PP (OR=2.36)

• Less drug regimens (LDR) were used in 101 patients (35.31%) and included dual therapy in 82 (28.67%) and mono therapy in 19 subjects (6.64%)

• PP was a significant predictor of LDR (aOR=3.08`0 • Tenofovir was used in only 8 patients (2.7%) and NRTI-

sparing and booster free regimens in 163 (56.4%) and 127 (59.3%)

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Questions?