Cahill, LS

Copp, AJ

Delgado-Olguín, P

Greene, NDE

Guzman Lenis, M

Laurette, EY

Leung, K-Y

Mohan, H

Sanghvi, T

Serghides, L

Sled, JG

Tejada, O

English

UCL Discovery

EBioMedicine 66 (2021) 103334Contents lists available at ScienceDirectEBioMedicinejournal homepage: www.elsevier.com/locate/ebiomLetterIn response to the Letter to the Editor by Romach et al. re our publication“Dolutegravir in pregnant mice is associated with increased rates of fetaldefects at therapeutic but not at supratherapeutic levels”H. Mohana, M. Guzman Lenisa, E.Y. Laurettea, O. Tejadaa, T. Sanghvia, K.-Y. Leungb, L.S. Cahillc,d,J.G. Sledc,e,f, P. Delgado-Olguínf,g,h, N.D.E. Greeneb, A.J. Coppb, L. Serghidesa,i,j,*a Toronto General Hospital Research Institute, University Health Network, Toronto, Canadab Developmental Biology & Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UKcMouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canadad Department of Chemistry, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, CanadaeDepartment of Medical Biophysics, University of Toronto, Toronto, Ontario, Canadaf Translational Medicine, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canadag Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, CanadahHeart & Stroke Richard Lewar Centre of Excellence, Toronto, Ontario M5S 3H2, Canadai Department of Immunology and Institute of Medical Sciences, University of Toronto, Toronto, Ontario, CanadajWomen’s College Research Institute, Women’s College Hospital, Toronto, Ontario, CanadaA R T I C L E I N F OArticle History:Received 22 March 2021Accepted 24 March 2021Available online xxxWe appreciate the comments of Romach et al. on our recent publi-cation [1].In response to the comments on our study design, our objectivewhen we designed our study was not to repeat pre-clinical studiesperformed as part of the regulatory approval process for dolutegravir(DTG), but to emulate the clinical scenario as closely as possible. Ourstudy design was motivated directly by the Tsepamo study findingsof higher incidence of neural tube defects (NTDs) in pregnant womenreceiving a DTG-based regimen from conception [2]. We do not agreethat this is a sub-optimal study design for our research question.Pregnant women living with HIV receiving a DTG-based regimentake their medication as one or more pills orally. Fetal defects in thesewomen are compared to rates in the general population, i.e. womennot receiving DTG-based antiretroviral therapy (ART). In this real-world scenario, the “treated” group would not be receiving DTG as asingle drug, but in combination with a dual nucleos(t)ide reversetranscriptase inhibitor (NRTI), such as the one used in our study -tenofovir (TDF)/emtricitabine (FTC). TDF/FTC is a very commonlyused NRTI combination that has not been associated with higher inci-dence of NTDs in the many years of widespread use by pregnantDOI of original article: http://dx.doi.org/10.1016/j.ebiom.2021.103335, http://dx.doi.org/10.1016/j.ebiom.2020.103167.* Corresponding author at: 101 College Street, 10-359, Toronto, Ontario, M5G 1L7,Canada.E-mail address: lena.serghides@utoronto.ca (L. Serghides).https://doi.org/10.1016/j.ebiom.2021.1033342352-3964/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article unwomen living with HIV. Further, the “control” group would not betaking inactive excipients. To best replicate this clinically relevantscenario we selected to crush the actual pills that pregnant womenreceive, to administer DTG with TDF/FTC  the most commonly usedNRTI backbone in the Tsepamo study, and to administer all drugsorally. We chose a dose that yielded DTG Cmax concentrations simi-lar to those seen in pregnant women (3000 ng/ml). Further, as thehigher rates of NTDs were observed in women who received DTG-based ART from conception, we selected to treat our animals for theentire duration of pregnancy (unlike what was performed in thestudies by Stanislaus et al. [3]). Our control group was handled identi-cally to the treated group (i.e. gavaged daily with equal amounts ofwater) but did not receive any drug  to best model the clinical com-parator group of pregnant women not taking DTG-based ART whilecontrolling for effects of gavage on the pregnancy.For our dose-response experiments we chose to administer DTGat a 5x dose which yielded a 4-fold increase in Cmax levels(12,000ng/ml). We chose to not increase the dose of TDF/FTC  thusonly DTG was increased in our higher dose treatment arm. To oursurprise we observed a non-monotonic dose response, with higherrates of defects observed at the 1x-dose of DTG-based ART vs. at the5x-dose. While Romach et al. express concern that “the explanationfor the non-dose responsive developmental defects are contrary tothe established principles of teratology”, our findings speak to theimportance of testing under conditions that mimic the clinical condi-tions and not extrapolating from foundational work. We were alsosurprised by our findings but are not willing to alter the interpreta-tion of our data to fit “established principles of teratology”. We per-formed a highly powered study, including a much larger number ofanimals than traditionally used in pre-clinical teratogenic studies,and we observed higher rates of defects in our lower dose treatmentarm compared to our higher dose treatment arm. There are severalder the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)2 H. Mohan et al. / EBioMedicine 66 (2021) 103334examples in the literature of non-monotonic dose responses on fetaldefects, as noted in the Discussion of our paper [1], and our observa-tions add to that literature. It is of interest that a non-monotonic doseresponse was also observed for the effects of DTG on folate binding tofolate receptor 1 in the presence of human serum albumin and/or cal-cium in the study by Cabrera and colleagues [4]. We think that itwould be unscientific to dismiss our findings of a relationshipbetween therapeutic levels of DTG-based ART and an increase in fetaldefects simply because it does not fit the expectation of a classic doseresponse. We would also like to note that the one NTD observed inthe rabbit fetotoxicity study by Stanislaus et al. [3] was observed inthe lowest DTG dose treatment arm.Unfortunately, we cannot comment on the study by Posobiec et al.[5] as this was only presented as a conference abstract. We encouragepublication of these embryo culture experiments so these data can beadded to the available literature on DTG and fetal defects.On the suggestion by Romach et al. that a minimal effect on folatewould somehow rule out a role for DTG-based ART in NTDs, we dis-agree. Not all NTDs are sensitive to folate status, and NTDs that arenon-responsive to folic acid supplementation have been identified.Further, even small effects on maternal folates  which are underhomeostatic control may raise a concern.We welcome discussion of our findings and challenge of our con-clusions  this is the nature of science and peer review. However, westand by our study design and by our conclusion that our findingsprovide support for DTG usage in pregnancy being associated with asmall increase risk of NTDs.ContributorsLS and HM drafted the letter. All authors reviewed and edited theletter.Declaration of Competing InterestThe authors have no competing interests. AJC acted as consultantfor ViiV Healthcare Limited, with fees going to support his researchprogram. LS received personal support for participating in a ViiVorganized Think Tank.References[1] Mohan H, et al. Dolutegravir in pregnant mice is associated with increased rates offetal defects at therapeutic but not at supratherapeutic levels. EBioMedicine2021;63:103167.[2] Zash R, et al. Neural-tube defects and antiretroviral treatment regimens in Bot-swana. N Engl J Med 2019;381:827–40.[3] Stanislaus DJ, Posobiec LM, Laffan SB, Solomon HM, Ziejewski MZ, Romach EH.Absence of developmental and reproductive toxicity in animals exposed to dolute-gravir. Birth Defects Res 2020;112:245–61.[4] Cabrera RM, et al. The antagonism of folate receptor by dolutegravir: developmen-tal toxicity reduction by supplemental folic acid. AIDS 2019;33:1967–76.[5] Posobiec LM, Chapman SP, Murzyn S, Rendemonti JE, Stanislaus DJ, Romach B.Using whole embryo culture to address risk to patients taking dolutegravir Teratol-ogy Society 59th Annual Meeting Birth Defects Res 2019;111:490.

In response to the Letter to the Editor by Romach et al. re our publication "Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels"

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In response to the Letter to the Editor by Romach et al. re our publication "Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels"

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