Safety of protease inhibitors in HIV-infected pregnant women

Chougrani, Imène; Luton, Dominique; Matheron, Sophie; Mandelbrot, Laurent; Azria, Élie

doi:10.2147/hiv.s33058

Cited by 10 publications

(4 citation statements)

References 86 publications

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“…To extend our in vitro findings to an in vivo model, we treated pregnant mice with a dual-NRTI regimen, ZDV + 3TC, provided as Combivir (dual-NRTI), or a PI-based cART regimen, ZDV + 3TC with RTV-boosted LPV, provided as Combivir/Kaletra (PI-cART). This PI-cART regimen was selected because it is a recommended first-line regimen in pregnancy and the most commonly used PI-based regimen in both high and low-income countries [ 29 ]. Pilot studies were performed to optimize PI dosing.…”

Section: Resultsmentioning

confidence: 99%

HIV Protease Inhibitor Use During Pregnancy Is Associated With Decreased Progesterone Levels, Suggesting a Potential Mechanism Contributing to Fetal Growth Restriction

et al. 2014

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Background. Protease inhibitor (PI)–based combination antiretroviral therapy (cART) is administered during pregnancy to prevent perinatal human immunodeficiency virus (HIV) transmission. However, PI use has been associated with adverse birth outcomes, including preterm delivery and small-for-gestational-age (SGA) births. The mechanisms underlying these outcomes are unknown. We hypothesized that PIs contribute to these adverse events by altering progesterone levels.Methods. PI effects on trophoblast progesterone production were assessed in vitro. A mouse pregnancy model was used to assess the impact of PI-based cART on pregnancy outcomes and progesterone levels in vivo. Progesterone levels were assessed in plasma specimens from 27 HIV-infected and 17 HIV-uninfected pregnant women.Results. PIs (ritonavir, lopinavir, and atazanavir) but not nucleoside reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors reduced trophoblast progesterone production in vitro. In pregnant mice, PI-based cART but not dual-NRTI therapy was associated with significantly lower progesterone levels that directly correlated with fetal weight. Progesterone supplementation resulted in a significant improvement in fetal weight. We observed lower progesterone levels and smaller infants in HIV-infected women receiving PI-based cART, compared with the control group. In HIV-infected women, progesterone levels correlated significantly with birth weight percentile.Conclusions. Our data suggest that PI use in pregnancy may lead to lower progesterone levels that could contribute to adverse birth outcomes.

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Section: Resultsmentioning

confidence: 99%

HIV Protease Inhibitor Use During Pregnancy Is Associated With Decreased Progesterone Levels, Suggesting a Potential Mechanism Contributing to Fetal Growth Restriction

et al. 2014

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“…PIs are highly protein-bound and subject to backward transport through P-glycoprotein, so any adverse effects on fetal growth in utero cannot be explained by placental transfer, which is minimal or even non-existent [ 21 ]. A recent study on sex steroid hormones offered another hypothesis for exposure to PI and SGA [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Preconception use of cART by HIV-positive pregnant women increases the risk of infants being born small for gestational age

et al. 2018

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BackgroundThe benefits of combination anti-retroviral therapy (cART) in HIV-positive pregnant women (improved maternal health and prevention of mother to child transmission [pMTCT]) currently outweigh the adverse effects due to cART. As the variety of cART increases, however, the question arises as to which type of cART is safest for pregnant women and women of childbearing age. We studied the effect of timing and exposure to different classes of cART on adverse birth outcomes in a large HIV cohort in the Netherlands.Materials and methodsWe included singleton HEU infants registered in the ATHENA cohort from 1997 to 2015. Multivariate logistic regression analysis for single and multiple pregnancies was used to evaluate predictors of small for gestational age (SGA, birth weight <10th percentile for gestational age), low birth weight and preterm delivery.ResultsA total of 1392 children born to 1022 mothers were included. Of these, 331 (23.8%) children were SGA. Women starting cART before conception had an increased risk of having a SGA infant compared to women starting cART after conception (OR 1.35, 95% CI 1.03−1.77, p = 0.03). The risk for SGA was highest in women who started a protease inhibitor-(PI) based regimen prior to pregnancy, compared with women who initiated PI-based cART during pregnancy. While the association of preterm delivery and preconception cART was significant in univariate analysis, on multivariate analysis only a non-significant trend was observed (OR 1.39, 95% CI 0.94−1.92, p = 0.06) in women who had started cART before compared to after conception. In multivariate analysis, the risk of low birth weight (OR 1.34, 95% CI 0.94−1.92, p = 0.11) was not significantly increased in women who had started cART prior to conception compared to after conception.ConclusionIn our cohort of pregnant HIV-positive women, the use of cART prior to conception, most notably a PI-based regimen, was associated with intrauterine growth restriction resulting in SGA. Data showed a non-significant trend in the risk of PTD associated with preconception use of cART compared to its use after conception. More studies are needed with regard to the mechanisms taking place in the placenta during fetal growth in pregnant HIV-positive women using cART. It will only be with this knowledge that we can begin to understand the potential impact of HIV and cART on the fetus, in order to be able to determine the optimal individualised drug regimen for HIV-infected women of childbearing age.

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“…PI effects on autophagy in placental cells may disrupt normal placental development and function. PI use during pregnancy has been variably associated with premature delivery, low birth weight, small for gestational age, maternal and neonatal endocrine dysfunction, and neonatal hematologic abnormalities [44][45][46][47][48][49] as well as abnormal placental morphology, cord insertion, and vasculature [48,[50][51][52]. ER stress underlies many toxicities associated with PI, and ER stress is important to the physiology and pathophysiology of the placenta [53].…”

Section: Lopinavir/ritonavirmentioning

confidence: 99%

Antiretroviral Drugs Impact Autophagy with Toxic Outcomes

Cheney

Barbaro

Berman

2021

Cells

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Antiretroviral drugs have dramatically improved the morbidity and mortality of people living with HIV (PLWH). While current antiretroviral therapy (ART) regimens are generally well-tolerated, risks for side effects and toxicity remain as PLWH must take life-long medications. Antiretroviral drugs impact autophagy, an intracellular proteolytic process that eliminates debris and foreign material, provides nutrients for metabolism, and performs quality control to maintain cell homeostasis. Toxicity and adverse events associated with antiretrovirals may be due, in part, to their impacts on autophagy. A more complete understanding of the effects on autophagy is essential for developing antiretroviral drugs with decreased off target effects, meaning those unrelated to viral suppression, to minimize toxicity for PLWH. This review summarizes the findings and highlights the gaps in our knowledge of the impacts of antiretroviral drugs on autophagy.

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Safety of protease inhibitors in HIV-infected pregnant women

Cited by 10 publications

References 86 publications

HIV Protease Inhibitor Use During Pregnancy Is Associated With Decreased Progesterone Levels, Suggesting a Potential Mechanism Contributing to Fetal Growth Restriction

HIV Protease Inhibitor Use During Pregnancy Is Associated With Decreased Progesterone Levels, Suggesting a Potential Mechanism Contributing to Fetal Growth Restriction

Preconception use of cART by HIV-positive pregnant women increases the risk of infants being born small for gestational age

Antiretroviral Drugs Impact Autophagy with Toxic Outcomes

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