No Evidence for Recent AbacavirLamivudine Use in Promoting Inflammation, Endothelial Dysfunction, Hy

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No Evidence forRecent Abacavir/Lamivudine Use in
Promoting Inflammation, Endothelial Dysfunction,
Hypercoagulability, or Insulin Resistance in
Virologically Suppressed HIV-infected patientsA
Sub-study of theBICOMBO 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

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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. DAD Study Group. Lancet 2008 371
1417-1426 2. The SMART/INSIGHT and the DAD
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 38 147-155 5.
Podzamczer D, et al. J Acquir Immune Defic Syndr.
2007 44 139-147 6. Martinez E, et al. N Engl J
Med 2003 349 1036-1046 7. Smith KY, et al. AIDS
2009 23 1547-1556 6. Hsue PY, et al. AIDS.
2009 23 2021-2027 7. Satchell C, et al. 16th
CROI, 2009. Montreal, Canada. Abstract 151LB 8.
Kristoffersen US, et al. HIV Medicine 2009 (Epub
ahead of print)
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DAD STUDY ABC, TDF, and MYOCARDIAL INFARCTION
Cumm. use
1.9
Recent use
1.5
1.5
RRyes/no 95CI
1.2
RR per year 95CI
1.2

1
1
0.8
0.8
0.6
0.6
J Lundgren DAD Study Group et al CROI 2009 LB
abstr 44
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MECHANISMS FOR MYOCARDIAL INFARCTION
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TDF
Initiation
Progression
Complication
Inflammation
Hypercoagulability
Endothelial dysfunction Insulin resistance
1-3
ABC

• 1. DAD Study Group. Lancet 2008.
• 2. The SMART/INSIGHT and the DAD Study Groups.
  AIDS 2008.
• 3. DAD Study Group. CROI 2009.

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POTENTIAL SOURCES OF CONFOUNDING AND BIAS

• Drug prescription not random
• Pre-existing CV disease or DM
• Uncontrolled HIV infection or AIDS

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BICOMBO STUDY DESIGN
Patients randomized (n335) PI34 NNRTI301

• Stable 3TC-based ART for gt 6 months
• HIV-RNA lt 200c/mL
• No HLA screening

TDF/FTC (n168)
ABC/3TC (n167)
Excluded (n2)
Excluded (n0)
ABC/3TC (n167)
TDF/FTC (n166)
Primary Analysis, Week 48
Discontinue ABC/3TC (n30, 18)
Discontinue TDF/FTC (n22, 13)
Continue on ABC/3TC (n137, 82)
Continue on TDF/FTC (n144, 87)
1 patient with virological failure and 1 with a
new AIDS event
Martinez E et al. J Acquir Immune Defic Syndr
2009.
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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
D-dimer
hsCRP, MCP-1 OPG, IL-6 TNF-alpha IL-10
ICAM-1, VCAM-1 Selectin E, Selectin
P Adiponectin, Insulin
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POPULATION CHARACTERISTICS
Pgt0.05 for all comparisons between groups
(ABC/3TC vs TDF/FTC) in the Sub-study. Pgt0.05 for
all comparisons between patients in the Sub-study
vs patients from the BICOMBO study not in the
Sub-study.
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BIOMARKERS AT BASELINE and 48 WEEKS
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CORRELATIONS BETWEEN BASELINE PARAMETERS
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CHANGE IN BIOMARKERS FROM BASELINE TO 48 WEEKS
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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 (P0.62).
• 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 (P0.39).
• 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
  (P0.61).

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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.

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ACKNOWLEDGEMENTS

• Supported in part by research grants from Gilead
  Sciences and GlaxoSmithKline
• Participating centers and investigators (in
  alphabetical order)
• Hospital de Bellvitge, LHospitalet (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)

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