Marianne Leruez-Ville1, Idir Ghout2, Laurence Bussières3, Julien Stirnemann4, Jean-François Magny5, Sophie Couderc6, Laurent J Salomon4, Tiffany Guilleminot1, Philippe Aegerter2, Guillaume Benoist7, Norbert Winer8, Olivier Picone9, François Jacquemard10, Yves Ville11. 1. Equipe d'Accueil 73-28, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Laboratoire de Microbiologie Clinique, Assistance publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France; Centre National de Réfèrence Cytomegalovirus-Laboratoire Associé, Paris, France. 2. Assistance publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Unité de Recherche Clinique et Département de Santé Publique, Boulogne, France; Université Versailles Saint Quentin, Unité Mixte de Recherche-S 1168, Université Versailles St-Quentin-en-Yvelines, Montigny, France. 3. Equipe d'Accueil 73-28, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Unité de Recherche Clinique, Assistance publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France. 4. Equipe d'Accueil 73-28, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Maternité, Unité de Médecine Fœtale, Assistance publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France. 5. Equipe d'Accueil 73-28, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Réanimation Néonatale, Assistance publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France. 6. Hôpital Intercommunal de Poissy-Saint Germain, Maternité, Poissy, France. 7. Hôpital Universitaire de Caen, Maternité, Caen, France. 8. Hôpital Universitaire de Nantes, Département d'Obstétrique et de Médecine Fœtale, Nantes, France; UMR 1280 Physiologie des Adaptations Nutritionnelles, Institut National de Recherche Agronomique, Université de Nantes, France. 9. Hôpital Foch, Service de Gynécologie-Obstétrique, Suresnes, France. 10. Hôpital Américain de Paris, Unité de Médecine prénatale, Neuilly Sur Seine, France. 11. Equipe d'Accueil 73-28, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Maternité, Unité de Médecine Fœtale, Assistance publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France. Electronic address: Ville.yves@gmail.com.
Abstract
BACKGROUND: Congenital infection with human cytomegalovirus is a major cause of morbidity and mortality. A randomized controlled trial showed that high-dosage valacyclovir prevents cytomegalovirus disease in transplant recipients. Fetuses showing ultrasound features of infection are at high risk of being symptomatic at or before birth. In a pilot study, oral administration of high-dosage valacyclovir to mothers significantly decreased viral load and produced therapeutic concentrations in the blood of infected fetuses. A randomized controlled trial comparing prenatal treatment with valacyclovir against placebo in infected fetuses failed to recruit because women declined randomization. Randomized controlled trials in fetal medicine have often proven unacceptable by women who decline termination of pregnancy and are not prepared to resign themselves to the odds of the natural history of the disease. OBJECTIVE: We evaluated the efficacy of oral valacyclovir, 8 g daily, for pregnant women carrying a symptomatic cytomegalovirus-infected fetus, targeting a high-risk group for developing both neurosensory and neurological impairment. STUDY DESIGN: We designed a multicenter, open-label, phase II study with 1 arm, using one of Simon's optimal 2-stage designs. Symptomatic fetuses were defined by the presence of measurable extracerebral or mild cerebral ultrasound symptoms. They were treated in utero from prenatal diagnosis at a median of 25.9 weeks' gestation until delivery or termination of pregnancy. Fetuses with severe brain anomalies on ultrasound were not included as were cases completely asymptomatic at presentation, because treatment was unlikely to modify either outcome. The primary endpoint was the proportion of asymptomatic neonates born to treated mothers. RESULTS: At the interim analysis, 8 of 11 women delivered an asymptomatic neonate (required: ≥7). In step 2, 32 additional cases were included for a total of 43; the final number of asymptomatic neonates was 34, more than the 31 required to indicate efficacy according to the Simon 2-stage design. They remained asymptomatic at 12 months. High-dosage valacyclovir given for a median of 89 days to pregnant women carrying a moderately infected fetus was efficient at giving birth to asymptomatic neonates. Fetal blood viral loads decreased and platelet counts increased, both significantly (P = .01 and P < .001, respectively), between treatment initiation and birth after treatment completion, regardless of duration of fetal infection. Compared with a historical cohort obtained by a metaanalysis of the literature, the use of valacyclovir (8 g daily) significantly increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment. Although the pill burden was high (16 pills a day) adherence to treatment was >90%. Finally, valacyclovir at this high dosage was extremely well tolerated. CONCLUSION: Our results indicate that high-dosage valacyclovir given in pregnancy is effective for improving the outcome of moderately symptomatic infected fetuses. Although this study is not a randomized controlled trial, this is the first study reporting the efficacy of an antiviral drug to treat cytomegalovirus-infected fetuses. Moreover, this first study will allow new trials to be conducted, using valacyclovir as a baseline safe and effective treatment in pregnancy, to be compared to the new emerging and more potent anticytomegalovirus drugs that have not currently been tested in pregnancy.
RCT Entities:
BACKGROUND:Congenital infection with human cytomegalovirus is a major cause of morbidity and mortality. A randomized controlled trial showed that high-dosage valacyclovir prevents cytomegalovirus disease in transplant recipients. Fetuses showing ultrasound features of infection are at high risk of being symptomatic at or before birth. In a pilot study, oral administration of high-dosage valacyclovir to mothers significantly decreased viral load and produced therapeutic concentrations in the blood of infected fetuses. A randomized controlled trial comparing prenatal treatment with valacyclovir against placebo in infected fetuses failed to recruit because women declined randomization. Randomized controlled trials in fetal medicine have often proven unacceptable by women who decline termination of pregnancy and are not prepared to resign themselves to the odds of the natural history of the disease. OBJECTIVE: We evaluated the efficacy of oral valacyclovir, 8 g daily, for pregnant women carrying a symptomatic cytomegalovirus-infected fetus, targeting a high-risk group for developing both neurosensory and neurological impairment. STUDY DESIGN: We designed a multicenter, open-label, phase II study with 1 arm, using one of Simon's optimal 2-stage designs. Symptomatic fetuses were defined by the presence of measurable extracerebral or mild cerebral ultrasound symptoms. They were treated in utero from prenatal diagnosis at a median of 25.9 weeks' gestation until delivery or termination of pregnancy. Fetuses with severe brain anomalies on ultrasound were not included as were cases completely asymptomatic at presentation, because treatment was unlikely to modify either outcome. The primary endpoint was the proportion of asymptomatic neonates born to treated mothers. RESULTS: At the interim analysis, 8 of 11 women delivered an asymptomatic neonate (required: ≥7). In step 2, 32 additional cases were included for a total of 43; the final number of asymptomatic neonates was 34, more than the 31 required to indicate efficacy according to the Simon 2-stage design. They remained asymptomatic at 12 months. High-dosage valacyclovir given for a median of 89 days to pregnant women carrying a moderately infected fetus was efficient at giving birth to asymptomatic neonates. Fetal blood viral loads decreased and platelet counts increased, both significantly (P = .01 and P < .001, respectively), between treatment initiation and birth after treatment completion, regardless of duration of fetal infection. Compared with a historical cohort obtained by a metaanalysis of the literature, the use of valacyclovir (8 g daily) significantly increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment. Although the pill burden was high (16 pills a day) adherence to treatment was >90%. Finally, valacyclovir at this high dosage was extremely well tolerated. CONCLUSION: Our results indicate that high-dosage valacyclovir given in pregnancy is effective for improving the outcome of moderately symptomatic infected fetuses. Although this study is not a randomized controlled trial, this is the first study reporting the efficacy of an antiviral drug to treat cytomegalovirus-infected fetuses. Moreover, this first study will allow new trials to be conducted, using valacyclovir as a baseline safe and effective treatment in pregnancy, to be compared to the new emerging and more potent anticytomegalovirus drugs that have not currently been tested in pregnancy.
Authors: Anca Maria Ciobanu; Nicolae Gica; Corina Gica; Radu Botezatu; Mirona Furtuna; Gheorghe Peltecu; Anca Maria Panaitescu Journal: Maedica (Bucur) Date: 2020-06