Carole Dufouil (1,2), Laura Richert (1,2), Mathias Bruyand(1,3),
Hélène Amieva (1,2), Frédéric-Antoine Dauchy (3),
Carine Greib (4), Jean-François Dartigues (1,2,3),
Didier Neau (3), François Dabis (1,2,3), Philippe Morlat (1,2,3),
Fabrice Bonnet (1,2,3), Geneviève Chêne (1,2,3) and the ANRS CO3
Aquitaine Study Group
(1) INSERM, Bordeaux School of Public Health (ISPED), Centre INSERM
U897 & CIC-EC7, F-33000 Bordeaux, France
(2) Univ. Bordeaux, ISPED, Centre INSERM U897, F-33000 Bordeaux, France
(3) CHU de Bordeaux, F-33000 Bordeaux, France
(4) CHU de Bordeaux, F-33000 Pessac, France

HIV-infected patients receiving combination
antiretroviral therapy
 Higher prevalence of vascular risk factors :
hypercholesterolemia, diabetes, smoking
 Higher risk of cardiovascular morbidity
 Accelerated/accelerated aging notably of cognitive
functions

Link between cardiovascular risk factors and
cognition
 Well established from studies on population-
based studies on ageing
 Rarely investigated in HIV-infected cohorts

Type 2 Diabetes : heterogeneous metabolic disorder
 Reduced insulin sensitivity and relative insulin deficiency

Pre-diabetes (intermediate hyperglycemia)
 High risk state for diabetes
 Insulin resistance and b-cell dysfunction

Target organs
 Kidney, eyes, arteries, heart
 Brain :
• Accelerated cognitive decline (main domains: executive
functions, psychomotor speed and attention)
• Risk of Alzheimer's disease : 50-100% higher in T2 diabetics

In a large hospital-based cohort of HIV
infected patients, the ANRS-CO3 Aquitaine
cohort, to evaluate the association between
 Diabetes and cognitive function at baseline and
over time
 Pre-diabetes and cognitive function at baseline
and over time

ANRS CO3 Aquitaine Cohort
 Patients recruited through a hospital-based information system
on HIV-1 infection in the Bordeaux University Hospital
(Aquitaine region, South Western France) since 1987
 In- or out-patients of the participating hospitals
 HIV-1 infection confirmed by Western blot testing
 Informed consent signed
 Sub-study on cognition
 Baseline 2007-2009, Follow-up at 2 years
 No acute opportunistic infection or cancer under
treatment
 400 adult patients included
 Follow-up at 2-years : 288 participants

Assessment of several cognitive domains
 "Trail making test" : Attention and executive functions
 "Digit Symbol Substitution test" : Psychomotor speed
 "Purdue Pegboard Test" : Manual dexterity and coordination
 "Rey complex figure test" : Visuospatial abilities
 "Digit span" : Working memory
 "Grober & Buschke" : Episodic memory
 "Isaac Set Test" : Semantic Fluency
 Categories for glycaemia status
 Diabetes : at least two glycaemia >7 mmol/L or at least one glycaemia
>11.1 mmol/L or use of anti-diabetic drug prior inclusion
 Impaired glycaemia : at least two measures of glycaemia between 6.1 and
7 mmol/L prior inclusion
 Normal : otherwise

Polytomous logistic regression computed to investigate the
association between glycaemia status and neurocognitive
impairment categories (Revised research criteria for HIVassociated neurocognitive disorders; Frascati, 2007)

Covariance analysis computed to investigate the association
between glycaemia status and
 Raw cognitive test scores
 Annualized percentage of change in cognition

Adjusting for age, gender, education, depression, HIV transmission
category, CD4+ lymphocytes count, HIV-RNA, exposure to ART
(including Stavudine, Didanosine, Indinavir), AIDS stage, and
hypertension, hypercholesterolemia, BMI, smoking status

Inverse probability weighting to correct for attrition
Baseline (N=400)
Age in years (Standard Deviation)
47.3
(10.3)
% Male gender (N)
79.2
(320)
% Hypertension (N)
20.3
(81)
% Hypercholesterolemia (N)
44.0
(177)
8.0
9.5
(32)
(38)
% On antiretroviral treatment (N)
89.0
(356)
% AIDS stage (N)
24.0
(96)
% Current HIV-1 RNA level <500 copies/ml
85.0
(340)
Median CD4 nadir/mm3 (IQR)
260
(154-385)
Median CD4 count/mm3 (IQR)
515
(350-700)
Glycaemia status % Impaired (N)
% Diabetes (N)
Baseline (N=400)
Age in years (Standard Deviation)
47.3
(10.3)
% Male gender (N)
79.2
(320)
% Hypertension (N)
20.3
(81)
% Hypercholesterolemia (N)
44.0
(177)
8.0
9.5
(32)
(38)
% On antiretroviral treatment (N)
89.0
(356)
% AIDS stage (N)
24.0
(96)
% Current HIV-1 RNA level <500 copies/ml
85.0
(340)
Median CD4 nadir/mm3 (IQR)
260
(154-385)
Median CD4 count/mm3 (IQR)
515
(350-700)
Glycaemia status % Impaired (N)
% Diabetes (N)
- 26 treated
- 12 elevated
glyc. levels
Mean Age in years (SD)
Baseline
Baseline
Total
Followed vs. Dropouts
N=400
N=288
N=112
47.3 (10.3)
47.6 vs.
46.5
% Male gender (N)
79.2 (320)
82.3 vs.
72.4
% Hypertension (N)
20.3
(81)
20.4 vs.
19.8
% Hypercholesterolemia
(N)
Glycaemia status
% Impaired (N)
% Diabetes (N)
44.0 (177)
43.2 vs.
46.6
8.3 vs.
9.7 vs.
7.1
8.9
8.0
9.5
(32)
(38)

Prevalence of neurocognitive impairment
▪ Asymptomatic neurocognitive disorders (ANI): 21.0% (n=84)
▪ Mild neurocognitive disorder (MND):
32.0% (n=126)
▪ HIV-associated dementia (HAD):
6.7% (n=27)
Normal
N=163
NCI Categories
ANI
MND+HAD
N=84
N=153
GLYCAEMIA STATUS
NORMAL (N=330)
88.5
4.2
7.3
PRE-DIABETES (N=32)
78.6
9.5
11.9
DIABETES (N=38)
77.1
11.8
11.1
P=0.44, in multivariable analyses
Performance at Trail Making
Test B is measured through a
time to perform a task.
The higher the time, the worse
the performance
COGNITIVE TESTS
DISTRIBUTION
Baseline (N=400)
Mean
(SD)
Trail Making Test B
4.80
(4.63)
Digit Symbol
Substitution
44.6
(13.1)
Purdue Pegboard Test
48.7
(2.6)
Rey complex figure test
17.7
(6.5)
Digit Span
4.10
(1.28)
Grober and Buschke
12.3
(2.5)
Isaac Set test
47.3
(9.6)
COGNITIVE TESTS DISTRIBUTION
Baseline (N=400)
Mean
(SD)
Mean annualized
percentage of change
N=288
Trail Making Test B
4.80
(4.63)
-0.44 %
Digit Symbol
Substitution
44.6
(13.1)
+1.16%
Purdue Pegboard Test
48.7
(2.6)
+0.07%
Rey complex figure test
17.7
(6.5)
+0.52%
Digit Span
4.10
(1.28)
+3.5%
Grober and Buschke
12.3
(2.5)
+0.19%
Isaac Set test
47.3
(9.6)
+2.02%
No significant
change
Multivariable models adjusted for age, gender, education,
depression, HIV transmission category, CD4+ lymphocytes
count, HIV-RNA, exposure to ART (current and past,
including Stavudine, Didanosine, Indinavir), AIDS stage,
and hypertension, hypercholesterolemia, BMI, smoking
status
GLYCAEMIA STATUS
Normal
N=330
Diabetes
N=38
Impaired P value
N=32
P value
Trail Making Test B (Executive
functions)
5.3 (0.9)
7.3 (1.2)
6.9 (1.2)
0.01
0.04
Digit Symbol (Psychomotor
speed)
43.5 (2.2)
36.6 (2.8)
40.5 (2.8)
0.0003
0.04
Purdue Pegboard (Manual
dexterity)
48.6 (0.5)
46.9 (0.7)
47.4 (0.7)
0.0002
0.02
Rey complex figure
(Visuospatial)
16.0 (1.2)
11.8 (1.5)
14.3 (1.6)
<0.001
0.12
Digit Span (Working memory)
4.0 (0.3)
3.7 (0.3)
4.1 (0.3)
0.33
0.64
Grober and Buschke
(Episodic memory)
11.7 (0.5)
10.2 (0.6)
11.9 (0.6)
0.0002
0.61
Isaac Set test (Semantic
45.4 (1.8)
41.7 (2.4)
43.1 (2.4)
0.02
0.04
GLYCAEMIA STATUS
Normal
N=330
Diabetes
N=38
Impaired P value
N=32
P value
Trail Making Test B (Executive
functions)
5.3 (0.9)
7.3 (1.2)
6.9 (1.2)
0.01
0.04
Digit Symbol (Psychomotor
speed)
43.5 (2.2)
36.6 (2.8)
40.5 (2.8)
0.0003
0.04
Purdue Pegboard (Manual
dexterity)
48.6 (0.5)
46.9 (0.7)
47.4 (0.7)
0.0002
0.02
Rey complex figure
(Visuospatial)
16.0 (1.2)
11.8 (1.5)
14.3 (1.6)
<0.001
0.12
Digit Span (Working memory)
4.0 (0.3)
3.7 (0.3)
4.1 (0.3)
0.33
0.64
Grober and Buschke
(Episodic memory)
11.7 (0.5)
10.2 (0.6)
11.9 (0.6)
0.0002
0.61
Isaac Set test (Semantic
45.4 (1.8)
41.7 (2.4)
43.1 (2.4)
0.02
0.04
GLYCAEMIA STATUS
Normal
N=330
Diabetes
N=38
Impaired P value
N=32
P value
Trail Making Test B (Executive
functions)
5.3 (0.9)
7.3 (1.2)
6.9 (1.2)
0.01
0.04
Digit Symbol (Psychomotor
speed)
43.5 (2.2)
36.6 (2.8)
40.5 (2.8)
0.0003
0.04
Purdue Pegboard (Manual
dexterity)
48.6 (0.5)
46.9 (0.7)
47.4 (0.7)
0.0002
0.02
Rey complex figure
(Visuospatial)
16.0 (1.2)
11.8 (1.5)
14.3 (1.6)
<0.001
0.12
Digit Span (Working memory)
4.0 (0.3)
3.7 (0.3)
4.1 (0.3)
0.33
0.64
Grober and Buschke
(Episodic memory)
11.7 (0.5)
10.2 (0.6)
11.9 (0.6)
0.0002
0.61
Isaac Set test (Semantic
45.4 (1.8)
41.7 (2.4)
43.1 (2.4)
0.02
0.04
GLYCAEMIA STATUS
Normal
N=330
Diabetes
N=38
Impaired P value
N=32
P value
Trail Making Test B (Executive
functions)
5.3 (0.9)
7.3 (1.2)
6.9 (1.2)
0.01
0.04
Digit Symbol (Psychomotor
speed)
43.5 (2.2)
36.6 (2.8)
40.5 (2.8)
0.0003
0.04
Purdue Pegboard (Manual
dexterity)
48.6 (0.5)
46.9 (0.7)
47.4 (0.7)
0.0002
0.02
Rey complex figure
(Visuospatial)
16.0 (1.2)
11.8 (1.5)
14.3 (1.6)
<0.001
0.12
Digit Span (Working memory)
4.0 (0.3)
3.7 (0.3)
4.1 (0.3)
0.33
0.64
Grober and Buschke
(Episodic memory)
11.7 (0.5)
10.2 (0.6)
11.9 (0.6)
0.0002
0.61
Isaac Set test (Semantic
45.4 (1.8)
41.7 (2.4)
43.1 (2.4)
0.02
0.04
Multivariable models adjusted for baseline age, gender,
education, depression, HIV transmission category, CD4+
lymphocytes count, HIV-RNA, exposure to ART (current
and past, incl. Stavudine, Didanosine, Indinavir), AIDS
stage, and hypertension, hypercholesterolemia, BMI,
smoking status
4
2
0
-2
-4
-6
-8
Trail Making Digit symbol
Test B
Purdue
Pegboard
Normal
Rey complex
figure
Diabetes
Digit span
Impaired
Grober and Isaac Set test
Buschke
4
2
0
-2
-4
-6
-8
Trail Making Digit symbol
Test B
Purdue
Pegboard
Normal
Rey complex
figure
Diabetes
Digit span
Impaired
Grober and Isaac Set test
Buschke
4
2
0
-2
-4
-6
-8
Trail Making Digit symbol
Test B
Purdue
Pegboard
Normal

Rey complex
figure
Diabetes
Digit span
Grober and Isaac Set test
Buschke
Impaired
No change in findings after using inverse probability weighting to take
into account attrition
 In
summary
 Largest study with follow-up available
 Diabetic patients perform worse on average on cognitive tests especially
those assessing executive functions, attention and psychomotor speed
 No association with other cardiovascular risk factors (results not shown)
 Not evidenced when all categories of NCI are used
 Published
findings In HIV patients :
 Diabetes and dementia (Valcour 2005)
 Diabetes and NCI in older patients (McCutchan 2012)
 Potential



mechanism
Brain Micro- or macro-vascular damages
Neuro-Inflammation
Implications for daily clinical practice


Detect and control diabetes at the earliest possible stage,
Healthy lifestyle, limit prescription of ARV treatment associated with
diabetes
 Future


analyses
Impact of glycaemia control (glycaeted hemoglobin) and change in
glycaemia status
Longer neurocognitive follow-up and brain imaging
ANRS CO3 Aquitaine Cohort
Composition of the Groupe d’Epidémiologie Clinique du Sida en Aquitaine (GECSA):
Coordination: F. Dabis
Scientific committee: F. Bonnet, S. Bouchet, F. Dabis, M. Dupon, G. Chêne, H. Fleury, V. Gaborieau, D. Lacoste, D.
Malvy, P. Mercié, I. Pellegrin, P. Morlat, D. Neau, JL. Pellegrin, S. Tchamgoué, R. Thiébaut.
Epidemiology and Methodology: M. Bruyand, G. Chêne, F. Dabis, S. Lawson-Ayayi, R. Thiébaut, L. Wittkop.
Infectious Diseases and Internal Medicine:
CHU de Bordeaux: P. Morlat (F. Bonnet, N. Bernard, M. Hessamfar, D. Lacoste, MA. Vandenhende) ; M. Dupon (FA.
Dauchy, H. Dutronc) ; M. Longy-Boursier (P. Mercié, P. Duffau, J. Roger Schmeltz) ; D. Malvy (T. Pistone, MC Receveur) ;
D. Neau (C. Cazanave, A. Ochoa, T. Pistone, MO. Vareil) ; JL. Pellegrin (JF. Viallard, C. Greib, E. Lazaro)
CHG d’Arcachon : A. Dupont.
CHG de Dax : Y. Gerard, K. André, L. Caunègre
CHG de Bayonne : F. Bonnal, S. Farbos, MC. Gemain.
CHG de Libourne : J. Ceccaldi, S. Tchamgoué
CHG de Mont-de-Marsan : S. De Witte, C. Courtault
CHG de Pau : E. Monlun, V. Gaborieau
CHG de Périgueux : P. Lataste, JP. Meraud
CHG de Villeneuve-sur-Lot : I. Chossat.
Immunology: JF. Moreau, I. Pellegrin.
Virology: H. Fleury, ME. Lafon, B. Masquelier, P. Trimoulet.
Pharmacology: D. Breilh, S. Bouchet, M. Molimard, K. Titier.
Drug monitoring: F. Haramburu, G. Miremont-Salamé.
Data collection and processing: MJ. Blaizeau, M. Decoin, J. Delaune, S. Delveaux, C. D’Ivernois, C. Hanappier, O.
Leleux, E. Lenaud, B. Uwamaliya-Nziyumvira, X. Sicard.
Computing and Statistical analysis: V. Conte, A. Frosh, S. Geffard, J. Leray, I. Louis, G. Palmer, D. Touchard.
Members of the GECSA-COGLOC Study Group: M. Allard, H. Amieva, M. Auriacombe, S. Auriacombe, E. Bestaven, F.
Bonnet, M. Bruyand, M. Campoy, G. Catheline, G. Chêne, G. Coldefy, F. Dabis, J.-F. Dartigues, F.-A. Dauchy, S.
Delveaux, P. Dehail, C. Dufouil, C. Greib, C. Lewden, J. Macua, F. Marquant, F. Matharan, P. Mercié, C. Milien, P. Morlat,
N. Raoux, L. Richert.