snaes and aging: contribution of art versus lifestyle factors
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SNAEs and aging: contribution of ART versus lifestyle factors. Dominique Costagliola Institut Pierre Louis d’Epidémiologie et de Santé Publique, UMR-S 1136, INSERM et Sorbonne Universités, UPMC Univ Paris 06 . Disclosures. - PowerPoint PPT PresentationTRANSCRIPT
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