Estradiol Levels Are Altered in Human Immunodeficiency Virus-Infected Pregnant Women Randomized to Efavirenz-Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy

Abstract

Background: Combination antiretroviral therapy (cART) use in pregnancy has been associated with hormonal dysregulation. We performed a secondary retrospective analysis of longitudinal progesterone and estradiol levels in pregnancy using specimens from the Protease Inhibitors to Reduce Malaria Morbidity in HIV-infected Pregnant Women study, which randomized Ugandan human immunodeficiency virus (HIV)-infected ART-naive women to initiate either lopinavir/ritonavir (LPV/r)-based or efavirenz (EFV)-based cART.

Methods: Three hundred twenty-six women (160 randomized to the EFV arm and 166 women to the LPV/r arm) with at least 1 plasma sample collected during pregnancy were included. Enrollment samples collected prior to cART initiation were used as a cART-naive comparator group. Hormone levels were quantified by enzyme-linked immunosorbent assay.

Results: Estradiol levels were differentially affected by the 2 cART regimens. Exposure to LPV/r was associated with an increase in estradiol (P < .0001), whereas exposure to EFV was associated with a decrease in estradiol (P < .0001), relative to the cART-naive gestationally matched comparator group. Lower estradiol levels correlated with small for gestational age (SGA) (P = .0019) and low birth weight (P = .019) in the EFV arm, while higher estradiol levels correlated with SGA in the LPV/r arm (P = .027). Although progesterone levels were similar between treatment arms, we observed an association between SGA and lower progesterone in the LPV/r arm (P = .04). No association was observed between hormone levels and preterm birth in either arm. Levels of progesterone and estradiol were lower in cases of stillbirth, and levels of both hormones declined immediately prior to stillbirth in 5 of 8 cases.

Conclusions: Combination ART regimens differentially affect estradiol levels in pregnancy, a hormone critical to the maintenance of a healthy pregnancy. Identifying cART regimens that minimize perinatal HIV transmission without contributing to hormonal dysregulation represents an urgent public health priority.

Clinical trials registration: NCT00993031.

Keywords: HIV; combination antiretroviral therapy; estradiol; pregnancy; progesterone.

© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Flowchart of study participants and maternal plasma samples processed in this study. Abbreviations: ART, antiretroviral therapy; EFV, efavirenz; HIV, human immunodeficiency virus; LPV/r, lopinavir/ritonavir.

Figure 2.

Women receiving lopinavir/ritonavir (LPV/r)–based combination antiretroviral therapy (cART) have higher plasma estradiol in comparison with women receiving efavirenz (EFV)–based cART. Loge-transformed levels of plasma progesterone (A) and estradiol (B) across pregnancy in human immunodeficiency virus–infected women receiving EFV or LPV/r-based cART.

Figure 3.

Estradiol levels are higher in lopinavir/ritonavir (LPV/r)–treated women and lower in efavirenz (EFV)–treated women compared with levels in gestational week–matched combination antiretroviral therapy (cART)–naive women (prerandomization). Loge-transformed estradiol levels in plasma collected between gestational week (GW) 16 and <20 (A), 20 and <24 (B), and 24 and <28 (C). Data shown in circles (red for those who went on to be randomized to EFV and gray for those who went on to be randomized to LPV/r) are from prerandomization samples collected prior to cART initiation (enrol), data in red squares are from samples exposed to EFV, and data in gray triangles are from samples exposed to LPV/r. Statistical significance assessed by Kruskal-Wallis test with Dunn posttest.

Figure 4.

Progesterone levels and adverse birth outcomes in efavirenz (EFV) and lopinavir/ritonavir (LPV/r)–treated women. Loge-transformed plasma progesterone in average for gestational age (AGA) and small for gestational age (SGA) outcomes (A and D), average birth weight (ABW) and low birth weight (LBW) deliveries (B and E), and term and preterm (PTB) deliveries (C and F). Data are from women on EFV-based combination antiretroviral therapy (cART) (A–C) and from women on LPV/r-based cART (D–F). All samples analyzed were from women on treatment. Figures depict mean and standard deviations by gestational age category. Statistical significance assessed by 2-way analysis of variance (ANOVA) with Holm posttest. For (D), P = .04 for SGA by 2-way ANOVA. #P = .10 for posttest.

Figure 5.

Estradiol levels and adverse birth outcomes in efavirenz (EFV) and lopinavir/ritonavir (LPV/r)–treated women. Loge-transformed levels of plasma estradiol in average for gestational age (AGA) and small for gestational age (SGA) outcomes (A and D), average birth weight (ABW) and low birth weight (LBW) deliveries (B and E), and term and preterm (PTB) deliveries (C and F). Data are from women on EFV-based combination antiretroviral therapy (cART) (A–C) and from women on LPV/r-based cART (D–F). All samples analyzed were from women on treatment. Figures depict mean and standard deviations by gestational age category. Statistical significance assessed by 2-way analysis of variance (ANOVA) with Holm posttest. For (A), P = .0019 for SGA by 2-way ANOVA and *P < .05 for posttest. For (B), P = .019 for LBW by 2-way ANOVA, *P < .05 for posttest. For (D), P = .027 for SGA by 2-way ANOVA, #P = .07 for posttest.

Figure 6.

Plasma estradiol and progesterone levels in cases of stillbirth. Loge-transformed estradiol (A) and progesterone (B) levels in plasma samples in live birth and cases of stillbirth in women receiving efavirenz or lopinavir/ritonavir–based treatment combined. Figures depict mean and standard deviations by gestational age category. Statistical significance assessed by Wilcoxon rank-sum test.