Mira Hleyhel1, Stéphanie Goujon, Clémence Delteil, Alexandre Vasiljevic, Stéphanie Luzi, Jean-Louis Stephan, Véronique Reliquet, Sarah Jannier, Roland Tubiana, Catherine Dollfus, Albert Faye, Laurent Mandelbrot, Jacqueline Clavel, Josiane Warszawski, Stéphane Blanche. 1. aEpidemiology and Population HealthCenter, Institut National de la Santé et de la Recherche Médicale (INSERM), Le Kremlin-Bicêtre bEpidemiology and Biostatistics, INSERM UMR1153, Sorbonne Paris Cité Research Center, Epidemiology of Childhood and Adolescent Cancers Team (EPICEA), Université Paris Descartes cFrench National Registry of Childhood Cancers, Villejuif dEast Center of Pathology and Neuropathology, Hospices Civils de Lyon, Bron eRadiology Unit, Pediatric Department, Hôpital Necker-Enfants Malades, AP-HP, Institut IMAGINE and Faculté Paris Descartes fPediatric Oncology Unit Centre Hospitalier Universitaire, Saint-Etienne gInfectious Diseases Department, Centre Hospitalier Universitaire, Nantes hPediatric Oncology Unit, Hôpital Universitaire Hautepierre, Strasbourg iInfectious Diseases Department, Hôpital Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris (AP-HP) jPediatric Department, Hôpital Trousseau, AP-HP kPediatric Department, Hôpital Robert Debré, AP-HP and Université Paris Diderot, Sorbonne Paris-Cité, Paris lGynecology and Obstetrics Department, Hôpital Louis Mourier, Hôpitaux Universitaires Paris Nord Val de Seine, AP-HP, Colombes mHôpital Bicêtre, AP-HP and Université Paris Sud, Le Kremlin-Bicêtre nImmunology Hematology Rhumatology Unit, Pediatric Department, Hôpital Necker-Enfants Malades AP-HP and Université Paris Descartes, Paris, France. *Members are listed in the Acknowledgements.
Abstract
BACKGROUND: Evaluation of long-term tolerance to antiretroviral exposure during pregnancy is required. An increased risk of cancer has been suggested in children exposed in utero to didanosine. METHODS: Updated evaluation of cancer incidence in uninfected children exposed to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in the French perinatal study of children born to HIV+ mothers, by cross-checking with the National Cancer Registry. Associations between cancer risk and exposure to NRTIs were evaluated by univariate survival analysis and Cox proportional hazard models. Standardized incidence ratios (SIR) were used for comparison with the general population. RESULTS: A total of 21 cancers were identified in 15 163 children (median age: 9.9 years [interquartile range (IQR): 5.8-14.2]) exposed to at least one NRTI in utero, between 1990 and 2014. Five children were exposed to zidovudine monotherapy, and 16 to various combinations, seven including didanosine. Didanosine accounted for only 10% of prescriptions but was associated with one-third of cancers. In a multivariate analysis, didanosine exposure was significantly associated with higher risk [hazard ratio = 3.0 (0.9-9.8)]. The risk was specifically linked with first-trimester exposure [hazard ratio = 5.5 (2.1-14.4)]. Overall, the total number of cases was not significantly different from that expected for the general population [SIR = 0.8 (0.47-1.24)], but was twice that expected after didanosine exposure [SIR = 2.5 (1.01-5.19)]. CONCLUSION: There are strong arguments to suggest that didanosine displays transplacental oncogenicity. Although not extrapolable to other NRTIs, they stress the need for comprehensive evaluation of the transplacental genotoxicity of this antiretroviral class.
BACKGROUND: Evaluation of long-term tolerance to antiretroviral exposure during pregnancy is required. An increased risk of cancer has been suggested in children exposed in utero to didanosine. METHODS: Updated evaluation of cancer incidence in uninfected children exposed to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in the French perinatal study of children born to HIV+ mothers, by cross-checking with the National Cancer Registry. Associations between cancer risk and exposure to NRTIs were evaluated by univariate survival analysis and Cox proportional hazard models. Standardized incidence ratios (SIR) were used for comparison with the general population. RESULTS: A total of 21 cancers were identified in 15 163 children (median age: 9.9 years [interquartile range (IQR): 5.8-14.2]) exposed to at least one NRTI in utero, between 1990 and 2014. Five children were exposed to zidovudine monotherapy, and 16 to various combinations, seven including didanosine. Didanosine accounted for only 10% of prescriptions but was associated with one-third of cancers. In a multivariate analysis, didanosine exposure was significantly associated with higher risk [hazard ratio = 3.0 (0.9-9.8)]. The risk was specifically linked with first-trimester exposure [hazard ratio = 5.5 (2.1-14.4)]. Overall, the total number of cases was not significantly different from that expected for the general population [SIR = 0.8 (0.47-1.24)], but was twice that expected after didanosine exposure [SIR = 2.5 (1.01-5.19)]. CONCLUSION: There are strong arguments to suggest that didanosine displays transplacental oncogenicity. Although not extrapolable to other NRTIs, they stress the need for comprehensive evaluation of the transplacental genotoxicity of this antiretroviral class.
Authors: Jennifer Jao; Denise L Jacobson; Wendy Yu; William Borkowsky; Mitchell E Geffner; Elizabeth J McFarland; Kunjal Patel; Paige L Williams; Tracie Miller Journal: J Acquir Immune Defic Syndr Date: 2019-07-01 Impact factor: 3.731
Authors: Robert Klitzman; Claude A Mellins; Morgan M Philbin; Elaine J Abrams; Robert H Remien Journal: Am J Public Health Date: 2016-06-16 Impact factor: 9.308