Abnormalities of the Hematopoietic Stem Cell Compartment in Children After in Utero Exposure to AZT

Abstract 1123

Mother to child HIV-1 transmission prophylaxy with antiretroviral (ARV) during pregnancy is remarkably effective. Although now based on various ARV-combinations, azydothymidine (AZT) remains the cornerstone drug in all guidelines. AZT hematologic toxicity after in utero exposure consisted in a reversible anemia but also in a persistant slight decrease on platelet, neutrophils and lymphocytes count up to 2 years of age. This long lasting biological effect evokes an alteration of the hematopoietic stem cell compartment. The very long term impact is unknown.

Twenty six neonates from HIV-1 infected mothers treated with an AZT based combination during pregnancy in Paris area were included in the study and compared to 20 neonates from healthy mothers. Umbilical cord blood was sampled after obtaining written informed consent from the mother. The experimental scheme included phenotypical and functional analysis of the hematopoietic compartment as well as transcriptome analysis of hematopoietic progenitors. Phenotypic analysis revealed a tendancy to higher numbers of CD34+ cells in the AZT group as compared to the control group. A similar finding was observed for hematopoietic stem cells defined on the basis of a Lin-CD34+ CD38loCD90+CD45RA- phenotype. Multipotent progenitors Lin-CD34+ CD38loCD90-CD45RA- were also increased at a statistically significant level. Affymetrix analysis of gene expression profiles was performed on CD34+ cells sorted from 8 AZT and 6 controls. Ingenuity analysis revealed significant differences in genes involved in hematopoiesis and cell cycle. Among hematopoietic genes for which differences of expression were noted between the two groups, 14 have a known role in the maintenance and differentiation of hematopoietic stem cells. Quantitative RT-PCR are actually ongoing to further characterize the gene expression profile of AZT CD34+ cells.

These results support the hypothesis of an alteration of the hematopoietic stem cell compartment in children after in utero exposure to AZT. Potential hematotoxicity of other ARV drugs must be evaluated to delineate the safest as possible mother to child HIV-1 transmission prophylaxy.