No Evidence for Recent Abacavir/Lamivudine Use in Promoting Inflammation, Endothelial Dysfunction, Hypercoagulability, or Insulin Resistance in Virologically.

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

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: 1417-1426

2. The SMART/INSIGHT and the D:A:D Study Groups. AIDS 2008; 22: F17-F243. Obel N, et al. HIV Medicine 2009 (Epub ahead of print)4. Shlay JC, et al. JAIDS 2005; 38: 147-1555. Podzamczer D, et al. J Acquir Immune Defic Syndr. 2007; 44: 139-1476. Martinez E, et al. N Engl J Med 2003; 349: 1036-10467. Smith KY, et al. AIDS 2009; 23: 1547-15566. Hsue PY, et al. AIDS. 2009; 23: 2021-20277. Satchell C, et al. 16th CROI, 2009. Montreal, Canada. Abstract 151LB8. Kristoffersen US, et al. HIV Medicine 2009 (Epub ahead of print)

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

RRyes/no 95%CI 1

1.9

1.5

1.2

0.8

0.6

1

1.5

1.2

0.8

0.6

RR per year 95%CI**

J Lundgren & DAD Study Group et al CROI 2009 LB abstr 44

D:A:D STUDY: ABC, TDF, and MYOCARDIAL INFARCTION

Recentuse

Cumm.use

Initiation Progression Complication

InflammationEndothelial dysfunction

Insulin resistance

Hypercoagulability

ABC

TDF

MECHANISMS FOR MYOCARDIAL INFARCTION

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.

3

1-3

POTENTIAL SOURCES OF CONFOUNDING AND BIAS

• Drug prescription not random

• Pre-existing CV disease or DM

• Uncontrolled HIV infection or AIDS

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=2)Excluded (n=0)

ABC/3TC (n=167) TDF/FTC (n=166)

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%)

Primary Analysis, Week 48

BICOMBO STUDY DESIGN

Martinez E et al. J Acquir Immune Defic Syndr 2009.

* 1 patient with virological failure and 1 with a new AIDS event

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

InflammationEndothelial dysfunction

Insulin resistance

Hypercoagulability

hsCRP, MCP-1OPG, IL-6TNF-alpha

IL-10ICAM-1, VCAM-1

Selectin E, Selectin PAdiponectin, Insulin

D-dimer

POPULATION CHARACTERISTICS

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.

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) 43 (38-48)

Male gender (n, %) 38 (82.6) 26 (76.5) 64 (80.0) 195 (77.1)

Years of ART 4.5 (2.2-6.4) 3.7 (2.1-6.3) 3.9 (2.1-6.2) 3.9 (2.1-6.4)

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 (111-142) 122 (106-140) 124 (109-141) 125 (107-142)

Total chol (mg/dL) 205 (166-225) 205 (177-227) 205 (175-227) 205 (176-229)

HDL chol (mg/dL) 49 (44-64) 50 (41-61) 49 (42-63) 49 (42-62)

Framingham score 5.5 (1.8-9.7) 3.8 (2.9-10.3) 4.4 (1.9-10.3) 4.3 (1.9-10.1)

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 Baseline 48 weeks

hsCRP (mg/L) 0.13 0.14 0.13 0.10 0.91 0.14

MCP-1 (pg/mL) 76 71 83 87 0.27 0.17

OPG (pmol/L) 4.1 4.2 4.2 4.3 0.89 0.56

IL-6 (pg/mL) 0.70 0.70 0.70 0.70 1 1

IL-10 (pg/mL) 3.9 3.9 3.9 3.9 0.47 0.42

TNF- (pg/mL) 1.6 1.6 1.6 1.6 1 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) 121 114 104 122 0.28 0.69

Insulin (mU/L) 8.9 8.3 9.7 10.3 0.13 0.18

Adiponectin (g/mL) 8.0 7.8 8.0 9.6 0.40 0.33

D-dimer (mg/L) 0.17 0.17 0.20 0.21 0.06 0.24

Spearman Correlation Coefficient

P-value

Selectin E – Selectin P 0.63 <0.0001

ICAM-1 – VCAM-1 0.51 <0.0001

OPG – Adiponectin 0.29 0.015

Insulin - Adiponectin -0.25 0.030

CORRELATIONS BETWEEN BASELINE PARAMETERS

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

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

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) 0.0 0.0 0.49 0.51 0 [0, 0]

IL-10 (pg/mL) 0.0 0.0 0.11 0.12 0 [0, 2]

TNF- (pg/mL) 0.0 0.0 0.28 0.31 0 [0, 0]

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 0.12 -15.9 [-36.3, 4.0]

D-dimer (mg/L) 0.00 0.0 0.67 0.73 0 [-18.0, 5.6]

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).

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.

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