Evaluation of the risk of birth defects among children exposed to raltegravir in utero in the ANRS-French Perinatal Cohort EPF J. Sibiude1,2, J. Warszawski1,3, S. Blanche4,5, O. Dialla1 A. Faye6,7, C. Dollfus8, L. Mandelbrot1,7,9, R. Tubiana10,11 for the ANRS-EPF CO1/CO11 Study group 1INSERM, CESP 1018, Le Kremlin Bicêtre, 2APHP-Hôpital Cochin Port Royal, Paris, 3Université Paris Sud, Le Kremlin Bicêtre, 4APHP Hôpital Necker, Paris,  5Université Paris Descartes, Paris, 6APHP Hôpital Robert Debré, Paris,  7Université Paris Diderot, Paris,  8APHP Hôpital Trousseau, Paris,  9APHP Hôpital Louis Mourier, Colombes, 10APHP Hôpital Pitié Salpétrière, Paris,  11Sorbonne Universités, UPMC Université Paris 6, Paris

Conflict of Interest No conflicts of interest to declare

Background Methods Results Conclusion ARVs and birth defects Conflicting literature concerning ARVs widely prescribed such as efavirenz or zidovudine (Sibiude CID 2015, Williams JAMA ped 2015, Sibiude Plos Med 2014, Ford AIDS 2014) Increasing proportion of women treated at conception Wide range of drugs received at conception Raltegravir : 10% EPF ANRS CO1/CO11 EPF ANRS CO1/CO11 - 2013

Integrase inhibitors and birth defects Background Methods Results Conclusion Integrase inhibitors and birth defects No published literature on raltegravir and birth defects Largest report = Antiretroviral Pregnancy Registry (APR interim report through Jan 2017) 263 exposed in the 1st trimester 7 BD = 2.7% No difference with 2nd-3rd trimester (8/250, 3.2%) Evidence of placental transfer for raltegravir (Vinot Antiviral Agents Chemo 2016)

The French Perinatal Cohort Background Methods Results Conclusion The French Perinatal Cohort National multicenter ongoing prospective cohort (100 sites) All HIV-positive pregnant women are included 1000 inclusions/year, more than 20 000 mother-child pairs since 1985 Coverage 70% of HIV+ pregnant women in France Since 1985 : EPF HIV + pregnant women Uninfected children Until 2 years Infected children Until 18 years

Study of Birth Defects Variables collected systematically Background Methods Results Conclusion Study of Birth Defects Variables collected systematically At birth : specific question concerning birth defects At each visit : all clinical events are reported No additional imaging on account of the study Coding of BD according to EUROCAT system (ICD 10) Minor defects are excluded Exposure to raltegravir 1st trimester vs 2nd and 3rd trimester

Study population N=479 exposed to raltegravir Between 2008 and 2015 Background Methods Results Conclusion Study population N=479 exposed to raltegravir Between 2008 and 2015 Earliest trimester of exposure N % 1st Trimester 140 29.2 2nd or 3rd Trimester 339 78.8 Characteristics of pregnancies N % Stillbirths 6 1.3 Late miscarriage 2 0.4 Termination of Pregnancy Preterm 68 14.2 Twin pregnancies 10 2.1 Nb of ARV regimens during pregnancy N % 1 238 49.7 2 160 33.4 3 or more 81 17.9

Background Methods Results Conclusion Rates of birth defects p=0.29 p=0.42 Birth defects Raltegravir OR 95% CI p 1st trimester 1.6 (0.7-4.1) 0.29 2-3rd trimester 1 No significant difference between 1st and 2nd or 3rd trimester

Exposed 2nd or 3rd Trimester Background Type of birth defects Methods Results Conclusion Exposed 1st Trimester N Exposed 2nd or 3rd Trimester Hypoplasia of pulmonary arteries* 1 Atrio-ventricular Canal Anomalous pulmonary venous return Pulmonary valve stenosis Patent ductus arteriosus Coarctation of aorta Polydactyly 2 3 Congenital hip dislocation Posterior urethral valves Multicystic dysplastic kidneys Kidney Cyst* Splenic cyst Ovarian cyst Down syndrome CHARGE association Congenital CMV

Discussion Strengths Limitations Background Methods Results Conclusion Discussion Strengths Largest number of children exposed in utero to raltegravir With homogeneous evaluation of birth defects : standardized follow-up Multicenter National Cohort Limitations No information on pregnancies < 14 WG Associated drugs used

Background Methods Results Conclusion Conclusion No evidence of association between birth defects and exposure to raltegravir in utero Findings are reassuring in the context of prescription of this drug for young women with few therapeutic alternatives Continuous epidemiological surveillance of new drugs for the risk of birth defects is needed

Acknowledgments Active contributors to ANRS-EPF : APHP Hôpital Louis Mourier, Colombes; APHP Hôpital Beaujon, Clichy; Hôpital Sainte Musse, Toulon; CHG Marechal Joffre, Perpignan; CHU Caremeau, Nîmes; CHD les Oudairies, La Roche / Yon; Centre Hospitalier William Morey, Chalon sur Saône; Centre Hospitalier, Vernon; Centre Hospitalier Intercommunal de Cornouaille, Quimper; Centre Hospitalier Universitaire, Brest; Centre Hospitalier, St Brieuc; Centre Hospitalier Universitaire, Rennes; Centre Hospitalier Bretagne Atlantique, Vannes; Centre Hospitalier de Bretagne Sud, Lorient; Centre Hospitalier de la région d’Annecy, Annecy; Centre Hospitalier Intercommunal, Montfermeil; Centre Hospitalier Intercommunal, Montreuil; APHP Hôpital Cochin-Port Royal, Paris; APHP Hôpital Bichat, Paris; Centre Hospitalier Intercommunal, Créteil; Hôpital de la Croix Rousse, Lyon; Centre Hospitalier Pellegrin, Bordeaux; CHU Les Abymes, Pointe à Pitre; Centre Hospitalier Général, Creil; CHI la Seyne sur Mer, La Seyne sur Mer; Hôpital de Haute Pierre, Strasbourg; Centre Hospitalier Général, Longjumeau; Hôpital Paule de Viguier, Toulouse; Centre Hospitalier de la Côte Basque, Bayonne; Centre hospitalier intercommunal, Villeneuve St Georges; Centre Hospitalier Intercommunal, Poissy Saint Germain en Laye; Centre Hospitalier Général, Fontainebleau; Centre Hospitalier Robert Ballanger, Aulnay; Hôpital Civil, Strasbourg; Centre Hospitalier Victor Dupouy, Argenteuil; APHP Hôpital Tenon, Paris; Centre Hospitalier Général, Saint-Denis; APHP Hôpital Necker, Paris; Centre Hospitalier Sud Francilien, Evry Corbeil; Centre Hospitalier Sud Francilien, Evry Corbeil; Centre Médico-chirurgical et Obstétrical, Schiltigheim; CHR American Memorial Hospital, Reims; APHP Groupe Hospitalier Pitié Salpêtrière, Paris; Centre Hospitalier René Dubos, Pontoise; APHP Hôpital Béclère, Clamart; Centre Hospitalier Marc Jacquet, Melun; Centre Hospitalier Général/, Evreux; APHP Hôpital Jean Verdier, Bondy; Centre Hospitalier de Meaux, Meaux; CHU de l’Archet, Nice; Centre Hospitalier Saint Joseph, Paris; Centre Hospitalier François Quesnay, Mantes La Jolie; CHU Hôpital Nord, Amiens; Hôpital de la Conception, Marseille; CHU de Brabois-Hôpital des Adultes, Vandoeuvre les Nancy; APHP Hôpital Trousseau, Paris; Hôpital Charles Nicolle, Rouen; APHP Hôpital Robert Debré, Paris; APHP Hôpital de Bicêtre, Le Kremlin-Bicêtre; CHRU Hôpital Saint Jacques, Besançon; CHU de Nantes, Nantes; CHRU Hôpital du Bocage, Dijon; CHRU Hôpital Clemenceau, Caen; Centre Hospitalier de Lagny, Lagny; Hôpital André Mignot, Le Chesnay; CHRU de Tours; Institut d'Hémato-Oncologie Pédiatrique, Lyon; Hôpital Nord, Saint Etienne; Centre Hospitalier Général, Bastia; Centre Hospitalier Universitaire, Angers; Centre Hospitalier Régional, Orléans; APHP Hôpital Lariboisière, Paris; CHR Arnaud de Villeneuve, Montpellier; Centre Hospitalier Général, Orsay; Centre Hospitalier de Saint Martin, St Martin; CHR Jeanne de Flandres, Lille; CHU - Maison de la Femme et de l'Enfant, Fort de France. We thank all families and patients who agreed to participate in these cohorts. ANRS (Agence Française de Recherche sur le VIH/SIDA et les hépatites virales) Steering commitee of ANRS-EPF Coordinating center of ANRS-EPF, INSERM U1018-CESP, Le Kremlin-Bicetre All participating women and children