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

Smith, Marie Soleil R; Mohan, Haneesha; Ajaykumar, Abhinav; Hsieh, Anthony Y Y; Martineau, Lou; Patel, Ronil A.; Gadawska, Izabella; Sherwood, Christopher; Serghides, Lena; Piret, James M.; Côté, Hélène

doi:10.1093/infdis/jiac386

Cited by 10 publications

(10 citation statements)

References 37 publications

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“…This aligns with what is known about the timing of organogenesis, which is complete by 12-14 weeks of gestation. In support of the hypothesis that in utero INSTI exposure could trigger abnormal fetal development, one research group has presented preliminary data showing that cultured human embryonic stem cells experience apoptosis, reduction in viability and/or loss of pluripotency after in vitro exposure to various drugs from the INSTI class at therapeutic and sub-therapeutic concentrations [27,28].…”

Section: Discussionmentioning

confidence: 99%

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Congenital malformations and preeclampsia associated with integrase inhibitor use in pregnancy: A single-center analysis

Smith¹,

Fought²,

Sung³

et al. 2023

PLoS ONE

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Background Antiretroviral therapy (ART) decreases perinatal HIV transmission, but concerns exist regarding maternal and infant safety. We compared the incidence of congenital malformations and other adverse outcomes in pregnancies exposed to integrase inhibitor (INSTI) versus non-INSTI ART. Setting Single-site review of all pregnancies among women living with HIV between 2008 and 2018. Methods We used binomial family generalized estimating equations to model the relationship of congenital anomalies and pregnancy outcomes with exposure to INSTI or dolutegravir (DTG) versus non-INSTI ART. Results Among 257 pregnancies, 77 women received ≥1 INSTI (54 DTG, 14 elvitegravir, 15 raltegravir), 167 received non-INSTI, and 3 had missing data. Fifty congenital anomalies were identified in 36 infants. Infants with first-trimester DTG or any first-trimester INSTI exposure had higher odds of congenital anomalies than infants with first-trimester non-INSTI exposure (OR = 2.55; 95%CI = 1.07–6.10; OR = 2.61; 95%CI = 1.15–5.94, respectively). Infants with INSTI exposure after the second trimester had no increased odds of anomalies. Women with INSTI exposure had higher odds of preeclampsia (OR = 4.73; 95%CI = 1.70–13.19). Among women who received INSTI, grade ≥3 laboratory abnormalities were noted in 2.6% while receiving the INSTI and 3.9% while not receiving the INSTI, versus 16.2% in women who received non-INSTI. There was no association between INSTI exposure and other pregnancy outcomes. Conclusion In our cohort, first-trimester INSTI exposure was associated with increased rates of congenital anomalies and use of INSTI during pregnancy was associated with preeclampsia. These findings underscore the need for continued monitoring of the safety of INSTI in pregnancy.

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Section: Discussionmentioning

confidence: 99%

“…Pregnancies were categorized as having DTG or any INSTI exposure if a mother received these drugs at any time between conception and delivery. ART was categorized by timing of receipt, in the first (gestational age �13 weeks), second (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), or third (28-delivery) trimesters.…”

Section: Data Managementmentioning

confidence: 99%

Congenital malformations and preeclampsia associated with integrase inhibitor use in pregnancy: A single-center analysis

Smith¹,

Fought²,

Sung³

et al. 2023

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…In support of the hypothesis that in utero INSTI exposure could trigger abnormal fetal development, one research group has presented preliminary data showing that cultured human embryonic stem cells experience apoptosis, reduction in viability and/or loss of pluripotency after in vitro exposure to various drugs from the INSTI class at therapeutic and sub-therapeutic concentrations. [26, 27]…”

Section: Discussionmentioning

confidence: 99%

Congenital Malformations and Preeclampsia Associated with Integrase Inhibitor Use in Pregnancy

Smith

Fought

Sung

et al. 2022

Preprint

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Background: Antiretroviral therapy (ART) decreases perinatal HIV transmission, but concerns exist regarding maternal and infant safety. We compared the incidence of congenital malformations and other adverse outcomes in pregnancies exposed to integrase inhibitor (INSTI) versus non-INSTI ART. Setting: Single-site review of all pregnancies among women living with HIV between 2008 and 2018. Methods: We used binomial family generalized estimating equations to model the relationship of congenital anomalies and pregnancy outcomes with exposure to INSTI or dolutegravir (DTG) versus non-INSTI ART. Results: Among 257 pregnancies, 77 women received ≥1 INSTI (54 DTG, 14 elvitegravir, 15 raltegravir), 167 received non-INSTI, and 3 had missing data. Forty-nine congenital anomalies were identified among 36 infants. Infants with first-trimester DTG or any first-trimester INSTI exposure had higher odds of congenital anomalies than infants with first-trimester non-INSTI exposure (OR=2.55; 95%CI=1.07-6.10; OR=2.61; 95%CI=1.15-5.94, respectively). Infants with INSTI exposure after the second trimester had no increased odds of anomalies. Women with INSTI exposure had higher odds of preeclampsia (OR=4.73; 95%CI=1.70-13.19). Among women who received INSTI, grade ≥3 laboratory abnormalities were noted in 2.6% while receiving the INSTI and 3.9% while not receiving the INSTI, versus 16.2% in women who received non-INSTI. There was no association between INSTI exposure and other pregnancy outcomes. Conclusion: First-trimester INSTI exposure may be associated with increased rates of congenital anomalies. Use of INSTI during pregnancy was also associated with preeclampsia in our cohort. These findings underscore the need for continued monitoring of the safety of INSTI in pregnancy.

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“…A number of studies explored the teratogenic effects of dolutegravir. Pre‐clinical animal studies conducted as part of the dolutegravir development programme showed no effect on embryonic or foetal development [ 2 ]; however, recent animal and cell‐model studies suggested possible increased risks for embryonic and foetal toxicity [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of dolutegravir on folate, vitamin B12 and mean corpuscular volume levels among children and adolescents with HIV: a sub‐study of the ODYSSEY randomized controlled trial

Barlow‐Mosha,

Ahimbisibwe,

Chappell

et al. 2023

J Int AIDS Soc.

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IntroductionDolutegravir‐based antiretroviral therapy (ART) is the preferred antiretroviral treatment for children and adolescents living with HIV. A large surveillance study in Botswana previously raised concerns about an association between pre‐conception dolutegravir and neural tube defects. Before these concerns were subsequently resolved, we set up a sub‐study to look at the effect of dolutegravir on levels of folate and vitamin B12 in children and adolescents within the randomized ODYSSEY trial, as folate and vitamin B12 are known to play a crucial role in neural tube development.MethodsWe conducted the sub‐study among Ugandan ODYSSEY participants and compared folate and vitamin B12 between children randomized to dolutegravir‐based ART (DTG) and non‐dolutegravir‐based standard‐of‐care treatment (SOC). Plasma folate was measured at enrolment and week 4 on stored samples; in addition, plasma and red blood cell (RBC) folate and vitamin B12 were assayed at week ≥96 in prospectively collected samples. RBC mean corpuscular volume (MCV) was measured 24‐weekly in all ODYSSEY participants. Samples analysed in the sub‐study were collected between September 2016 and October 2020.ResultsA total of 229 children aged ≥6 years were included in the sub‐study with median age at trial enrolment of 12.3 (interquartile range [IQR] 9.0, 14.7) years, and CD4 count of 501 (IQR 228, 695); 112 (49%) children were male. Most participants (225/229, 98%) had plasma folate results at enrolment and 214 (93%) children had results available for RBC folate, vitamin B12 and plasma folate at week ≥96. MCV results were analysed on 679 children aged ≥6 years enrolled in ODYSSEY. At week 4, mean plasma folate was significantly higher in the dolutegravir arm than in SOC (difference [DTG‐SOC] 1.6 ng/ml, 95% CI 0.8, 2.3; p<0.001), and this difference persisted to week ≥96 (2.7 ng/ml, 95% CI 1.7, 3.7; p<0.001). Mean RBC folate at ≥96 weeks was also higher in the DTG arm (difference 73 ng/ml, 95% CI 3, 143; p = 0.041). There was no difference in the treatment arms for vitamin B12 levels at ≥96 weeks or change in MCV through trial follow‐up.ConclusionsPlasma and RBC folate levels were higher in children and adolescents receiving dolutegravir‐based ART than on other ART regimens. Further studies are needed to clarify the mechanisms of these interactions and the clinical implications of increased blood folate levels.

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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

Cited by 10 publications

References 37 publications

Congenital malformations and preeclampsia associated with integrase inhibitor use in pregnancy: A single-center analysis

Congenital malformations and preeclampsia associated with integrase inhibitor use in pregnancy: A single-center analysis

Congenital Malformations and Preeclampsia Associated with Integrase Inhibitor Use in Pregnancy

Effect of dolutegravir on folate, vitamin B12 and mean corpuscular volume levels among children and adolescents with HIV: a sub‐study of the ODYSSEY randomized controlled trial

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