Safety of protease inhibitors in HIV-infected pregnant women

Abstract

The dire conditions of the human immunodeficiency virus/acquired immune deficiency syndrome epidemic and the immense benefits of antiretroviral prophylaxis in prevention of mother-to-child transmission far outweigh the potential for adverse effects and undeniably justify the rapid and widespread use of this therapy, despite incomplete safety data. Highly active antiretroviral therapy has now become standard care, and more than half the validated regimens include protease inhibitors. This paper reviews current knowledge of the safety of these drugs during pregnancy, in terms of maternal and fetal outcomes. Transfer of protease inhibitors across the placenta is known to be minimal, and current data about birth defects and fetal malignancies are reassuring. Maternal liver function and glucose metabolism should be monitored in women treated with protease inhibitor-based regimens, but concerns about the development of maternal resistance, should treatment be discontinued, have been shown to be groundless. Neonates should be screened for hematologic abnormalities, although these are rarely severe or permanent and are not usually related to the protease inhibitor component of the antiretroviral combination. Current findings concerning pre-eclampsia and growth restriction are discordant, and further research is needed to address the question of placental vascular complications. The increased risk of preterm birth attributed to protease inhibitors should be interpreted with caution considering the discrepant results and the multitude of confounding factors often overlooked. Although data are thus far reassuring, further research is needed to shed light on unresolved controversies about the safety of protease inhibitors during pregnancy.

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

“…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.…”

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

“…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 ].…”

Antiretroviral Drugs Impact Autophagy with Toxic Outcomes

“…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].…”