1. No Evidence for Recent Abacavir/Lamivudine Use in Promoting Inflammation, Endothelial Dysfunction, Hypercoagulability, or Insulin Resistance in Virologically Suppressed HIV-infected patients: A Sub-study of the BICOMBO Randomized Clinical Trial
E. Martínez, M. Larrousse, I. Pérez, M. Loncá,
D. Podzamczer, F. Gutiérrez, R. Deulofeu, R. Casamitjana,
J.C. Reverter, J. Mallolas, J. Pich, J.M. Gatell,
for the BICOMBO Study Group
SPAIN

2. ABACAVIR AND CV DISEASE
Abacavir use identified as a marker of cardiovascular disease in several cohort studies (1-3), although it is currently unclear whether its role is causative or not.
Potential pathogenetic mechanisms are also unclear. Abacavir has not been asociated with insulin resistance (4) or lipoatrophy (4, 5) and its lipid impact is lower than that of stavudine (5) or protease inhibitors (6), although higher than that of tenofovir (7).
Several potential mechanisms affecting biological mechanisms associated with cardiovascular dysfunction have been suggested (6-8) but studies to date may have been subjected to bias.
1. D:A:D Study Group. Lancet 2008; 371:
2. The SMART/INSIGHT and the D:A:D Study Groups. AIDS 2008; 22: F17-F24
3. Obel N, et al. HIV Medicine 2009 (Epub ahead of print)
4. Shlay JC, et al. JAIDS 2005; 38:
5. Podzamczer D, et al. J Acquir Immune Defic Syndr. 2007; 44:
6. Martinez E, et al. N Engl J Med 2003; 349:
7. Smith KY, et al. AIDS 2009; 23:
6. Hsue PY, et al. AIDS. 2009; 23:
7. Satchell C, et al. 16th CROI, Montreal, Canada. Abstract 151LB
8. Kristoffersen US, et al. HIV Medicine 2009 (Epub ahead of print)

3. D:A:D STUDY: ABC, TDF, and MYOCARDIAL INFARCTION
Cumm.
use
Recent
use
1.9
1.5
1.5
RR yes/no 95%CI
1.2
1.2
RR per year 95%CI ** 1 1
0.8
0.8
0.6
0.6
ZDV
ddI
ddC
d4T
3TC
ABC
TDF
#PYFU:
138,109
74,407
29,676
95,320
152,009
53,300
39,157
#MI:
523
331
148
405
554
221
139
J Lundgren & DAD Study Group et al CROI 2009 LB abstr 44

4. MECHANISMS FOR MYOCARDIAL INFARCTION
TDF 3
Initiation
Progression
Complication
Inflammation
Endothelial dysfunction
Insulin resistance
Hypercoagulability
ABC
1-3
1. D:A:D Study Group. Lancet 2008.
2. The SMART/INSIGHT and the D:A:D Study Groups. AIDS 2008.
3. D:A:D Study Group. CROI 2009.

5. POTENTIAL SOURCES OF CONFOUNDING AND BIAS
Drug prescription not random
Pre-existing CV disease or DM
Uncontrolled HIV infection or AIDS

6. BICOMBO STUDY DESIGN Primary Analysis, Week 48
Patients randomized (n=335)
PI=34
NNRTI=301
Stable 3TC-based ART for > 6 months
HIV-RNA < 200c/mL
No HLA screening
ABC/3TC (n=167)
TDF/FTC (n=168)
Excluded (n=0)
Excluded (n=2)
ABC/3TC (n=167)
TDF/FTC (n=166)
Primary Analysis, Week 48
Discontinue ABC/3TC
(n=30, 18%)
Discontinue TDF/FTC (n=22, 13%)
Continue on ABC/3TC
(n=137, 82%) *
Continue on TDF/FTC
(n=144, 87%)
* 1 patient with virological failure and 1 with a new AIDS event
Martinez E et al. J Acquir Immune Defic Syndr 2009.

7. Endothelial dysfunction
METHODS
Patients
Baseline and 48w serum samples available
No history of symptomatic CV disease or DM
No virological failure or AIDS events during follow-up
Laboratory markers
Statistical analyses
Wilcoxon rank Sum test for comparisons
Punctual estimation and 95% confidence interval of difference in medians (methodology of Hodges-Lehman, using the distribution-free of Moses).
Spearman test for correlations
Initiation
Progression
Complication
Inflammation
Endothelial dysfunction
Insulin resistance
Hypercoagulability
hsCRP, MCP-1
OPG, IL-6
TNF-alpha
IL-10
D-dimer
ICAM-1, VCAM-1
Selectin E, Selectin P
Adiponectin, Insulin

8. POPULATION CHARACTERISTICS
BICOMBO Sub-study
BICOMBO Study
ABC/3TC
(n=46)
TDF/FTC
(n=34)
Patients in the Sub-study
(n=80)
Patients not in the Sub-study
(n=253)
Age (years)
44 (39-52)
42 (37-49)
43 (38-48)
Male gender (n, %)
38 (82.6)
26 (76.5)
64 (80.0)
195 (77.1)
Years of ART
4.5 ( )
3.7 ( )
3.9 ( )
3.9 ( )
PI at baseline (n, %)
4 (8.7)
2 (5.9)
6 (7.5)
24 (9.5)
Active smoker (n, %)
12 (26.1)
8 (23.5)
20 (25.0)
68 (26.9)
Systolic BP (mmHg)
125 ( )
122 ( )
124 ( )
125 ( )
Total chol (mg/dL)
205 ( )
205 ( )
205 ( )
205 ( )
HDL chol (mg/dL)
49 (44-64)
50 (41-61)
49 (42-63)
49 (42-62)
Framingham score
5.5 ( )
3.8 ( )
4.4 ( )
4.3 ( )
P>0.05 for all comparisons between groups (ABC/3TC vs TDF/FTC) in the Sub-study.
P>0.05 for all comparisons between patients in the Sub-study vs patients from the BICOMBO study not in the Sub-study.

9. BIOMARKERS AT BASELINE and 48 WEEKS
Median laboratory marker
(units)
ABC/3TC
(n=46)
TDF/FTC
(n=34)
P value for comparisons between baseline values
P value for comparisons between 48 week values
Baseline
48 weeks
hsCRP (mg/L)
0.13
0.14
0.10
0.91
MCP-1 (pg/mL) 76 71 83 87
0.27
0.17
OPG (pmol/L)
4.1
4.2
4.3
0.89
0.56
IL-6 (pg/mL)
0.70 1
IL-10 (pg/mL)
3.9
0.47
0.42
TNF- (pg/mL)
1.6
0.54
ICAM-1 (ng/mL)
198
188
194
213
0.58
0.45
VCAM-1 (ng/mL)
394
372
410
413
0.43
0.22
Selectin E (ng/mL )
119
115
121
126
0.92
0.44
Selectin P (ng/mL)
114
104
122
0.28
0.69
Insulin (mU/L)
8.9
8.3
9.7
10.3
0.18
Adiponectin (g/mL)
8.0
7.8
9.6
0.40
0.33
D-dimer (mg/L)
0.20
0.21
0.06
0.24

10. CORRELATIONS BETWEEN BASELINE PARAMETERS
Spearman Correlation Coefficient
P-value
Selectin E – Selectin P
0.63
<0.0001
ICAM-1 – VCAM-1
0.51
OPG – Adiponectin
0.29
0.015
Insulin - Adiponectin
-0.25
0.030
Spearman Correlation Coefficient
P-value
Framingham – OPG
0.31
0.008
Framingham – Selectin E
0.29
0.016
Framingham – Selectin P
0.26
0.032

11. CHANGE IN BIOMARKERS FROM BASELINE TO 48 WEEKS
Median Laboratory marker
(units)
ABC/3TC
(n=46)
TDF/FTC
(n=34)
P value for comparisons between absolute changes
P value for comparisons between percent changes
Median difference of percent change ABC/3TC minus TDF/FTC
[lower confidence interval, upper confidence interval]
Percent change
hsCRP (mg/L)
-3.9
0.0
0.76
0.26
26.4 [-15.4, 100]
MCP-1 (pg/mL)
5.9 4
0.35
0.52
9.5 [-14.2, 30.4]
OPG (pmol/L)
5.1
-2.8
0.51
0.59
2.9 [-8.7, 14.4]
IL-6 (pg/mL)
0.49
0 [0, 0]
IL-10 (pg/mL)
0.11
0.12
0 [0, 2]
TNF- (pg/mL)
0.28
0.31
ICAM-1 (ng/mL)
6.6
5.2
0.65
0.84
-15.9 [-17.1,16.2]
VCAM-1 (ng/mL)
0.02
-0.01
0.88
0.73
-0.02 [-0.16, 0.11]
Selectin E (ng/mL )
-0.4
7.8
0.19
0.13
-8.5 [-17.3, 2.1]
Selectin P (ng/mL)
4.6
12.6
0.37
0.33
-7.9 [-21.3, 6.3]
Insulin (mU/L)
-2.5
8.8
0.67
0.69
7.4 [-27.9, 38.4]
Adiponectin (g/mL)
-2.2
15.4
0.10
-15.9 [-36.3, 4.0]
D-dimer (mg/L)
0.00
0 [-18.0, 5.6]

12. CHANGE IN HIGH-SENSITIVITY CRP
Because hsCRP is the marker with more widespread clinical use, we performed additional analyses.
Absolute hsCRP increase at 48 weeks: 18(39%) and 11 (32%) patients in the ABC/3TC and TDF/FTC groups respectively (P=0.62).
hsCRP higher than 0.5 mg/dL at 48 weeks: 4(9%) and 1 (3%) patients in the ABC/3TC and TDF/FTC groups respectively (P=0.39).
hsCRP increase at 48 weeks 25% higher than that at the baseline: 16(35%) and 9 (26%) patients in the ABC/3TC and TDF/FTC groups respectively (P=0.61). 12

13. CONCLUSIONS
In otherwise healthy, virologically suppressed HIV-infected patients from the BICOMBO study, the initiation of ABC/3TC did not lead to significant changes after 48 weeks in markers of inflammation, endothelial dysfuntion, insulin resistance, or hypercoagulability as compared with the initiation of TDF/FTC.
These results argue against any of these mechanisms as involved in the higher risk of MI associated with recent ABC use in some cohort studies. 13

14. ACKNOWLEDGEMENTS
Supported in part by research grants from Gilead Sciences and GlaxoSmithKline
Participating centers and investigators (in alphabetical order):
Hospital de Bellvitge, L’Hospitalet (Patricia Barragán, Elena Ferrer, Daniel Iñiguez, Gabriela Leibenger, Daniel Podzamczer)
Hospital Clínic, Barcelona (Mireia Arnedo, José L Blanco, Marta Calvo, José M Gatell, Montserrat Laguno, María Larrouse, Agathe León, Montserrat Loncá, Josep Mallolas, Esteban Martínez, María Martínez, Ana Milinkovic, José M. Miró, Tomás Pumarola)
Hospital Clínico de San Carlos, Madrid (Mónica Fuster, Victor Roca†)
Hospital General Universitario de Elche, Elche (Enrique Bernal, Félix Gutiérrez, Mar Masiá, Sergio Padilla).
Hospital Germans Trías i Pujol, IrsiCaixa Foundation, Badalona (Isabel Bravo, Bonaventura Clotet, Patricia Echeverría).
Hospital Gregorio Marañón, Madrid (Juan Berenguer, Jaime Cosín, Isabel Gutiérrez, Margarita Ramírez, Matilde Sánchez)
Hospital Universitari de Tarragona Joan XXIII, Universitat Rovira i Virgili, Tarragona (Joaquim Peraire, Francesc Vidal)
Hospital del Mar, Barcelona (Hernando Knobel, Alicia González)
Hospital de Mataró, Mataró (Luis Force, Pilar Barrufet)
Hospital de Mútua de Terrassa, Terrassa (Mireia Cairó, David Dalmau, Carol García)
Hospital Parc Taulí, Sabadell (Esperanza Antón, Eva Penelo, Ferran Segura)
Hospital Universitario La Paz, Madrid (José R Arribas, Juan Miguel Castro, María Montes)
Hospital Universitario de La Princesa, Madrid (Raquel Carrillo, Ignacio de los Santos)
Hospital Príncipe de Asturias, Alcalá de Henares (Jose A Arranz, Esperanza Casas, Julio de Miguel, José Sanz)
Hospital Sant Jaume, Calella (Josep M Llibre, Silvia Valero)
Hospital Son Llàtzer, Palma de Mallorca (Antoni Payeras)
Hospital de Sierrallana, Torrelavega (Francisco Galo)
Hospital Vall d’Hebron, Barcelona (Esteban Ribera, Adrià Curran)
Special thanks to study patients 14