SNAEs and aging: contribution of ART versus lifestyle factors

Dominique CostagliolaInstitut Pierre Louis d’Epidémiologie et de Santé

Publique, UMR-S 1136, INSERM et Sorbonne Universités, UPMC Univ

Paris 06 

Disclosures

• I have received travel grants, consultancy fees, honoraria and study grants from:– Bristol-Myers-Squibb – Gilead Sciences – Janssen-Cilag – Merck-Sharp & Dohme-Chibret– ViiV Healthcare

Ageing in the HIV population

COHERE in EUROCOORD

Median age 31 35 38 41 43 45 (years)

Ageing in the HIV population

Myocardial Infarction

Relative risks of MIHIV+ versus General Population

Islam et al, HIV Medicine 2012

Results confirmed in Freiberg et al, JAMA Internal Med 2013 and Silverberg et al, JAIDS 2014

Risk factors for MI in HIV infected individuals

HDL- chol mmol/L : OR = 0.67 (95% CI, 0.12-1.12)

BMI < 21 kg/m2 : OR = 1.62 (95% CI, 1.10-2.37)Lang et al, Clin Infect Dis 2012

Smoking NoSmoking Yes

Family History of CAD NoFamily History of CAD Yes

Hypertension NoHypertension Yes

Hypercholesterolemia NoHypercholesterolemia Yes

HDL cholesterol level, mmol/L

Diabetes NoDiabetes Yes

BMI< 21 kg/m2 BMI 21-23 kg/m2

BMI 24-26 kg/m2

BM1 ≥ 27 kg/m2

Cocaine and/or IDU NoCocaine and/or IDU No

Risk factors for MI in HIV infected individuals

VL > 50 copies/mL OR = 1.51 (95% CI, 1.09-2.10)

CD4 Nadir (log2) : OR = 0.90 (95% CI, 0.83-0.97)

CD8 > 1150 cells /mm3 : OR = 1.48 (95% CI, 1.01-2,.18)

VL ≤ 50 copies/mLVL > 50 copies/mL

CD4 T cell Nadir (log2)

CD8 T cell ≤ 760/mm3

CD8 T cell 761-1150/mm3

CD8 T cell >1150/mm3

10 year PI exposure

Lang et al, Clin Infect Dis 2012

Result on nadir also seen in Silverberg et al, JAIDS 2014

Effect of cART

• Consistent association of cumulative exposure to older PI with the risk of MI– Mary-Krause et al AIDS 2003; Friis-Møller et al, NEJM

2003; Friis-Møller et al, NEJM 2007; Lang et al, Arch Intern Med 2010; Worm, JID 2010

– No association found for atazanavir in DAD (D’Arminio Monforte et al, AIDS 2013)

• but was cumulative exposure long enough?

– No data on Darunavir

• Conflicting results on abacavir• No data on integrase inhibitors

Non-AIDS defining cancers

Relative risks of non-AIDS defining cancers in the cART era HIV+ vs

General PopulationCancer Nb study SIR (95% CI) Heterogeneity

HL (EBV) 6 19 (13-27) <0.001

Anus (HPV) 5 47 (22-100) <0.001

Liver (HBV/HCV) 5 7.5 (4.2-14) <0.001

Lung 6 3.5 (2.6-4.6) <0.001

Breast 6 0.6 (0.5-0.8) 0.003

Prostate 5 0.6 (0.4-0.7) 0.08

Shiels et al. JAIDS 2009; 52:611-22.

The role of immunodeficiency in the risk of NADC

Guiguet M et al. Lancet oncology 2009; 10:1152–59.

Frequent non-AIDS defining cancers

HodgkinIRR (95%CI)

N=149

Lung*IRR (95%CI)

N=207

Liver +IRR (95%CI)

N=119

Last CD4 >500 350-500 200-350 100-200 50 -100 <50

1.01.2 (0.7-2.2)2.2 (1.3-3.8)4.8 (2.8-8.3)

7.7 (3.9-15.2)5.4 (2.4-12.1)

1.02.2 (1.3-3.6)3.4 (2.1-5.5)4.8 (2.8-8.0)

4.9 (2.3-10.2)8.5 (4.3-16.7)

1.0 2.0 (0.9-4.5)4.1 (2.0-8.2)

7.3 (3.5-15.3)6.6 (2.4-17.6)7.6 (2.7-20.8)

Model adjusted on age, sex and risk, and migration from SubSaharan Africa* Independent of smoking or + independent of HBV/HCV infection in sensitivity analyses

What is the risk in people with CD4 > 500/mm3?

Risk when current CD4 >=500/mm3

Kaiser permanente HL Anal Lung Liver

RR in HIV+ with recent CD4 >= 500/mm3 compared with HIV-

13.5 (7.2–25.1)

33.8 (17.8–64.3)

1.2 (0.7–1.9) 1.0 (0.4–2.4)

Silverberg et al, Cancer Epidemiol biomarkers Prev 2011Hleyhel et al, AIDS 2014

FHDH ANRS CO4 HL Anal Lung Liver

SIR in HIV+ with recent CD4 >= 500/mm3 for more than 2 years compared with HIV-

9.4(7.9-16.8)

- 0.9 (0.6-1.3) 2.4 (1.4-4.1)

Age, sex and race adjusted

Age and sex adjusted

The role of smoking • Several studies have suggested that HIV infection is associated

with lung cancer after adjusting for cigarette smoking – Chaturvedi et al, AIDS 2007; Engels et al, J Clin Oncol 2006; Kirk et

al, Clin Infect Dis 2007; Helleberg et al, AIDS 2014

• A recent study (Helleberg et al, AIDS 2014) looked at the impact of smoking and HIV on the risk of cancer among HIV-infected individuals compared to the background population: – the risk of cancer is increased in HIV patients compared to

the background population • Smoking-related cancers IRR

2.8 (1.6-4.9) • Virological cancers IRR

11.5 (6.5-20.5)– adjusted for sex, age and smoking status

– In absence of smoking, the increase in risk is confined to cancers related to viral infections

– whereas the risk of other cancers is not elevated and does not seem to be associated with immune deficiency

Effect of cART

• Inconsistent evidence of a deleterious effect of PI exposure on the risk of anal cancer or of efavirenz exposure on the risk of Hodgkin disease– Chao et al, AIDS 2012; Bruyand et al, CROI

2013; Mbang et al, CROI 2013; Powles et al, J Clin Oncol, 2009

Fractures and Low BMD

Relative risks of fractureHIV+ versus General Population

Adapted from Mallon, Curr Opin HIV AIDS 2014

Low BMD and fractures risk factors

• Low BMI, African ethnicity, current smoking• HIV infection independently associated with lower BMD at femoral

neck, total hip and lumbar spine after adjustment for demographic/lifestyle factors and BMI– Cotter et al, AIDS 2014

• Effect of initiating cART on BMD decline up to 4%, mainly in the first year– Duvivier et al, AIDS 2009; van Vonderen et al, AIDS 2009; Stellbrink et al, CID

2010; Mc Comsey et al JID 2011

• Greater losses in BMD with use of tenofovir and protease inhibitors – less so with raltegravir (Brown T et al, CROI 2014,Bloch et al, HIV Med 2014)

• Association of low BMD with the risk of fractures in HIV infected individuals (Battalora et al, Antiviral Therapy, 2013)

Accelerated aging

Are SNAEs occurring at an earlier age in HIV patients?

Age (yrs) at onset of cancer of AIDS patients and uninfected individuals

Cancer AIDS GP Observed difference

(Years)Rectal 46 69 -23

Anal 50 62 -12

Larynx 48 65 -17

Lung 50 70 -20

Ovarian 42 63 -21

Testicular 35 34 +1

Hodgkin lymphoma

42 37 +5

Myeloma 47 70 -23

Shiels et al, Ann Intern Med 2010 A Justice, CROI 2012

A Difference in age distribution

FHDH ANRS CO4 and the population in France

Age (yrs) at onset of cancer of AIDS patients and age matched uninfected individuals

Cancer AIDS GP ObservedDifference

(Years)

Age Adjusted

GP

Real Difference

(YearsRectal 46 69 -23 51 -5

Anal 42 62 -20 45 -3

Larynx 48 65 -17 52 -4

Lung 50 70 -20 54 -4

Ovarian 42 63 -21 46 -4

Testicular 35 34 +1 38 -3

Hodgkin lymphoma

42 37 +5 40 +2

Myeloma 47 70 -23 52 -5

Shiels et al, Ann Intern Med 2010

Looked at 26 different cancer diagnoses, no difference (p>0.05) for 18. Differences for remaining cancers were <5 years.

Age (yrs) at Diagnosis in VACS

Comorbid Disease HIV+ HIV- Difference(Years)

Lung Cancer 57 59 -2

MI 56 56 0

Renal Failure (eGFR<45)

59 63 -4

Fragility Fracture 53 52 +1

Liver Cirrhosis 57 58 -1

A Justice, CROI 2012

Mainly male population

Observed age HIV+(a)

Observed ageGeneral

population (b)

Observed difference

(years) (b-a)

Expected ageGeneral

population(c)

Real difference

(years)(c-a)

P-value

Lung 49(43-57)

68(58-73)

-18.3 52.5(47.5-62.5)

-3.3 <10-4

Hodgkin 42(36-48)

38(28-58)

+4.1 42.5(32.5-47.5)

-0.9 0.04

Liver 47(43-54)

73(63-78)

-25.1 57.5(52.5-62.5)

-10.1 10-4

Anus 46(39-51)

68(58-78)

-21.9 47.5(42.5-57.5)

-1.9 0.12

Age at cancer diagnosis among HIV-infected patients and the general population in France between 1997 and 2009

Hleyhel M et al, AIDS 2014 FHDH ANRS CO4

Age at myocardial infarction diagnosis among HIV-infected patients and the general population in

France between 2000 and 2006

MenSMR = 1.4 (IC 95%, 1.3-1.6)

Women SMR = 2.7 (IC 95%, 1.8-3.9)

Median age

(IQR) (years)

MenHIV+ 47.2 (42.3-53.9)

Expected age GP

47.5 (42.5-57.5)

Women

HIV+ 42.5 (40.4-46.8)

Expected age GP

47.5 (42.5-55.0)

Lang S et al, AIDS 2010 FHDH ANRS CO4

Conclusions• Even in the absence of excess risk, the number of HIV-

infected individuals with several SNAEs will increase because of aging, raising issues on the optimal management of multimorbidity and multidrug exposures.

• The risk of age-associated SNAEs is higher in HIV infected patients

• This is partly explained by a higher prevalence of traditional risk factors

• An effect of some ART has been shown for MI, and bone diseases

• The risk of some SNAEs for an individual with CD4 cell count recovery under cART might not be elevated

• The effect of HIV infection on age at diagnosis of common SNAEs is not uniform– It depends on comorbidities, sex and other risk factors

Acknowlegments

• Members of my team – Clinical Epidemiology of HIV infection:

Therapeutic strategies and comorbidities at the Pierre Louis Institute

– S Grabar, M Hleyhel, S Lang, M Mary-Krause

• Amy Justice• Patrick Mallon