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ARV induces long-acting effects? Neurological symptoms AZT +/- 3TC Blanche et al Lancet 1999 Persistent hyperlactatemia AZT +/- 3TC Noguera et al Ped Inf.

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Presentation on theme: "ARV induces long-acting effects? Neurological symptoms AZT +/- 3TC Blanche et al Lancet 1999 Persistent hyperlactatemia AZT +/- 3TC Noguera et al Ped Inf."— Presentation transcript:

1 ARV induces long-acting effects? Neurological symptoms AZT +/- 3TC Blanche et al Lancet 1999 Persistent hyperlactatemia AZT +/- 3TC Noguera et al Ped Inf Dis J 2003 Altered hematopoïesis AZT +/- 3TC Lechenadec et al AIDS 2003 Altered myocardal contractility AZT +/- 3TC Lipshultz et al J Am Coll Cardiology 2011

2 Neutrophils count in perinatally AZT exposed children until 8 years AZT exposed ECS AIDS 2005;19:1071 AZT unexposed

3 AZT-induced long-lasting impairment of hematopoieisis Is there hematopoietic stem cell CD34+ genotoxic alteration ? I Schmutz Andre, E Six, M Cavazzana-Calvo, S Kaltenbach F Mavillio, Paris and Modena Lechenadec AIDS 2003, ECS AIDS 2004, Pacheco J Inf Dis 2006…etc

4 Validation by qRT-PCR Cord blood cells CD34 + cells Affymetrix Gene chip analysis Bioinformatic analysis Transcriptional profiling analysis of CD34+ hematopoietic stem cells HIV neg AZT- exposed and control newborn Gene expression in CD34 + cord blood cells of AZT exposed newborn Maternités : A. Béclère, L. Mourrier, Bichat, Lariboisière, Cochin, Necker.

5 ** * Cord blood cell immunophenotyping: hematopoietic stem cells (HSC) and multipotent progenitors(MPP ) Lin-CD38-CD34+CD90- Lin-CD38-CD34+CD90+ CD34+

6 213 genes up- regulated in ARV- treated cells 90 genes down- regulated in ARV- treated cells ND vs ARV pvalue 0.05 Fold Change 1.5 Gene expression profiles Control vs AZT-exposed CD34+

7 Genes functions Ingenuity® functional clustering analysis

8 Cellular Growth and Proliferation Cell Death Cell Cycle DNA Replication, Recombination and Repair ALOX12 CCL5 AXLCASP1AXLCCNE1 BAMBICASP3CCNE1CD180 C7orf68CCL2CCNE2IL1B CASP1CCL5CDK1ITGB3 CASP3CCR1DDX17MDM2 CCL2CDK1EGFORC6 CCL5CTTNGDF15PDE5A CCNE1EGFH19PDGFA CCNE2GDF15HMGA2TFPI2 CCR1GIMAP5ID1VPRBP CD36HMGA2ID2WRN CDK1ICAM1IL1B COL4A1ID1ITGB3 DDX17IL1BKLHL2 EGFITGB3KNTC1 GBP1ITGB5MDM2 GDF15LGALS8MDM4 HMGA2MDM2ORC6 ICAM1MDM4PDK3 ID1NFIL3PRKCA ID2PDGFAPTAFR IL1BPF4RPS6KA2 ITGA2BPPBPVPRBP ITGB3PRKCAWRN ITGB5PTAFR KDM4C MDM2 MDM4 PDE5A PDGFA PF4 PLD1 PRKCA PTAFR PTCH1 PTGS1 PTPRJ TFPI2 VPRBP WRN

9 The effect involves particularly regulator genes of chromosomal instability –centrosome amplification (Cyclin E1 and E2) –checkpoint defect (Rae1) –dysregulation of cell-cycle proteins (Mdm2) –microtubule attachment and chromosome segregation (TUBB, MARK4) These major cell cycle regulators are involved in chromosome segregation

10 Stem Cells and DNA Damage: Persist or Perish? A. Lane Cell 2010;142, 360–362142,

11 Increased aneuploidy in cord blood lymphocytes from AZT-exposed newborn Proportional increase of micronuclei Median (%): 6.6 vs 18.7 p<0.001

12 Summary These findings are reminiscent of cellular and animal AZT exposure experiments Aneuploidy appears as the result of DNA damage induced by AZT integration They confirm significant in vivo genotoxicity in cord blood cells after exposure to AZT in utero Unknown long-term clinical consequences

13 Signification clinique ? Hématopoïèse à long terme ? Risque de cancer hematopoïétique ? Autre cancer ?

14 AZT in utero exposure and risk of cancer To date, no global increased risk 9127 AZT or AZT+3TC exposed children Median age : 5.4 y >53 000 patient- year 10 cases observed vs 9.6 expected French Cohort. Benhammou AIDS 2008

15 6 nouveaux cas de cancers repérés depuis lanalyse de 2007 Nouveau croisement avec registre SFCE prévu

16 Suites…. Données de Primeva Comparaison de différentes combinaisons dARV avec ces outils moléculaires –Observationnelles –Randomisées ?


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