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
• 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
Median age
31
35
COHERE in EUROCOORD
38
41
43
45
(years)
Ageing in the HIV population
Myocardial Infarction
Relative risks of MI
HIV+ versus General Population
Results confirmed in Freiberg et al, JAMA Internal Med 2013
and Silverberg et al, JAIDS 2014
Islam et al, HIV Medicine 2012
Risk factors for MI in HIV infected individuals
Smoking No
Smoking Yes
Family History of CAD No
Family History of CAD Yes
Hypertension No
Hypertension Yes
Hypercholesterolemia No
Hypercholesterolemia Yes
HDL cholesterol level, mmol/L
Diabetes No
Diabetes Yes
BMI< 21 kg/m2
BMI 21-23 kg/m2
BMI 24-26 kg/m2
BM1 ≥ 27 kg/m2
Cocaine and/or IDU No
Cocaine and/or IDU No
HDL- chol mmol/L : OR = 0.67 (95% CI, 0.12-1.12)
Lang et al, Clin Infect Dis 2012
BMI < 21 kg/m2 : OR = 1.62 (95% CI, 1.10-2.37)
Risk factors for MI in HIV infected
individuals
VL ≤ 50 copies/mL
VL > 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
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)
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 Population
Cancer
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
Hodgkin
Lung*
Liver +
IRR (95%CI)
N=149
IRR (95%CI)
N=207
IRR (95%CI)
N=119
Last CD4
>500
350-500
200-350
100-200
50 -100
<50
1.0
1.2 (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)
1.0
1.0
2.2 (1.3-3.6)
2.0 (0.9-4.5)
3.4 (2.1-5.5)
4.1 (2.0-8.2)
4.8 (2.8-8.0) 7.3 (3.5-15.3)
4.9 (2.3-10.2) 6.6 (2.4-17.6)
8.5 (4.3-16.7) 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
3
CD4 > 500/mm ?
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)
HL
Anal
Lung
Liver
9.4
(7.9-16.8)
-
0.9 (0.6-1.3)
2.4 (1.4-4.1)
Age, sex and race adjusted
FHDH ANRS CO4
SIR in HIV+ with recent
CD4 >= 500/mm3 for
more than 2 years
compared with HIVAge and sex adjusted
Silverberg et al, Cancer Epidemiol biomarkers Prev 2011
Hleyhel et al, AIDS 2014
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 fracture
HIV+ 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
Observed
Difference
(Years)
Age
Adjusted
GP
Real
Difference
(Years
Rectal
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
Looked at 26 different cancer diagnoses, no difference (p>0.05) for 18.
Differences for remaining cancers were <5 years.
Shiels et al, Ann Intern Med 2010
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
Mainly male population
A Justice, CROI 2012
Age at cancer diagnosis among HIV-infected patients and
the general population in France between 1997 and 2009
Real
P-value
Observed Observed age Observed Expected age
difference
General
General
difference
age
(years)
population
HIV+
population
(years)
Lung
Hodgkin
Liver
Anus
(a)
(b)
(b-a)
(c)
(c-a)
49
68
52.5
(43-57)
(58-73)
-18.3
-3.3
<10-4
42
38
(36-48)
(28-58)
-0.9
0.04
47
73
(43-54)
(63-78)
-10.1
10-4
46
68
(39-51)
(58-78)
-1.9
0.12
Hleyhel M et al, AIDS 2014
+4.1
-25.1
-21.9
(47.5-62.5)
42.5
(32.5-47.5)
57.5
(52.5-62.5)
47.5
(42.5-57.5)
FHDH ANRS CO4
Age at myocardial infarction diagnosis among HIVinfected patients and the general population in
France between 2000 and 2006
Men
SMR = 1.4 (IC 95%, 1.3-1.6)
Median
age
(IQR)
(years)
Lang S et al, AIDS 2010
Men
Women
Women
SMR = 2.7 (IC 95%, 1.8-3.9)
HIV+
47.2 (42.3-53.9)
Expected age
GP
47.5 (42.5-57.5)
HIV+
42.5 (40.4-46.8)
Expected age
GP
47.5 (42.5-55.0)
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