Dolutegravir and rat whole embryo culture

Copp, Andrew J.; Greene, Nicholas D. E.; Jao, Jennifer; Zash, Rebecca; Mohan, Haneesha; Dontsova, Valeriya; Serghides, Lena

doi:10.1002/bdr2.1969

Birth Defects Research

2021

DOI: 10.1002/bdr2.1969

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Dolutegravir and rat whole embryo culture

Andrew J. Copp

Nicholas D. E. Greene

Jennifer Jao

et al.

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This author reply is in reference to the recent correspondence entitled "Dolutegravir and rat whole embryo culture" (Copp et al, 2022) regarding the article entitled "No developmental toxicity observed with dolutegravir in rat whole embryo culture" (Posobiec et al, 2021). Copp et al did not include updated data (Zash, 2019) from the clinical study in Botswana.

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confidence: 99%

Author reply to Copp et al. (2022) correspondence

Posobiec

2022

Birth Defects Research

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mentioning

confidence: 99%

Author reply to Copp et al. (2022) correspondence

Posobiec

2022

Birth Defects Research

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Metabolic implications and safety of dolutegravir use in pregnancy

et al. 2023

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Second-Generation Human Immunodeficiency Virus Integrase Inhibitors Induce Differentiation Dysregulation and Exert Toxic Effects in Human Embryonic Stem Cell and Mouse Models

Smith

Mohan

Ajaykumar

et al. 2022

The Journal of Infectious Diseases

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Background Each year, approximately 1.1 million children are exposed in utero to HIV antiretrovirals, yet their safety is often not well characterized during pregnancy. The Tsepamo study reported a neural tube defect signal in infants exposed to the integrase inhibitor (InSTI) dolutegravir from conception, suggesting that exposure during early fetal development may be detrimental. Methods The effects of InSTIs on two human embryonic stem cell (hESC) lines were characterized with respect to markers of pluripotency, early differentiation, and cellular health. Additionally, fetal resorptions following exposure to InSTIs from conception were analyzed in pregnant mice. Results At sub-therapeutic concentrations, second-generation InSTIs bictegravir, cabotegravir, and dolutegravir decreased hESC counts, pluripotency, and induced dysregulation of genes involved in early differentiation. At therapeutic concentrations, bictegravir induced substantial hESC death and fetal resorptions. Notably, first-generation InSTI raltegravir did not induce any hESC toxicity or differentiation, at any concentration tested. Conclusions Exposure to some InSTIs, even at sub-therapeutic concentrations, can induce adverse effects in hESCs and pregnant mice. Given the increasingly prevalent use of second-generation InSTIs, including in women of reproductive age, it is imperative to further elucidate the effect of InSTIs on embryonic development, as well as their long-term safety following in utero exposure.

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Dolutegravir and rat whole embryo culture

Cited by 3 publications

References 6 publications

Author reply to Copp et al. (2022) correspondence

Author reply to Copp et al. (2022) correspondence

Metabolic implications and safety of dolutegravir use in pregnancy

Second-Generation Human Immunodeficiency Virus Integrase Inhibitors Induce Differentiation Dysregulation and Exert Toxic Effects in Human Embryonic Stem Cell and Mouse Models

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