Effects of Initiating Raltegravir-Based Versus Efavirenz-Based Antiretroviral Regimens During Pregnancy on Weight Changes and Perinatal Outcomes

NICHD P1081

Conrado Milani Coutinho, PhD; Meredith G. Warshaw, MA; Geraldo Duarte, PhD; Alice Stek, MD; Avy Violari, FCPaed(SA); Cristina B. Hofer, PhD; Jaime G. Deville, MD; James Samwel Ngocho, PhD; José Henrique Pilotto, PhD; Mario Dias Correa, Jr, PhD; David E. Shapiro, PhD; Trevon L. Fuller, PhD; Nahida Chakhtoura, MD; Mark Mirochnick, MD; Esaú C. João, PhD

Disclosures

J Acquir Immune Defic Syndr. 2022;91(4):403-409. 

In This Article

Abstract and Introduction

Abstract

Background: Integrase inhibitors have been associated with excess gestational weight gain that may lead to adverse pregnancy outcomes (APOs). This post hoc analysis of NICHD P1081 compared antepartum changes in weight and body mass index (BMI) in pregnant women initiating raltegravir- or efavirenz-based combined antiretroviral therapy (cART) and examined associations between rates of weight gain and APOs.

Setting: NICHD P1081 enrolled antiretroviral-naive pregnant women living with HIV in the second and third trimester in Brazil, Tanzania, South Africa, Thailand, Argentina, and the United States.

Methods: Two hundred eighty-one women enrolled between 20 and 31 gestational weeks were randomized to raltegravir- or efavirenz-based cART and followed for ≥4 weeks. A low rate of weight gain was defined as <0.18 kg/wk and high as >0.59 kg/wk. We compared weight gain and BMI increase between treatment arms using Kruskal–Wallis tests. Logistic regression was used to investigate the association between weight gain and APOs.

Results: Raltegravir-based cART was associated with significantly higher antepartum weight gain (median 0.36 kg/wk versus 0.29 kg/wk, P = 0.01) and BMI increase (median 0.14 kg/m2/wk versus 0.11 kg/m2/wk, P = 0.01) compared with efavirenz-based treatment. Women on raltegravir had less low weight gain (18% versus 36%) and more high weight gain (21% versus 12%) (P = 0.001). Women with low weight gain were more likely than those with normal weight gain to have small for gestational age infants or a composite of APOs.

Conclusions: A raltegravir-based antiretroviral regimen was associated with significantly higher antepartum rate of weight gain and BMI increase compared with efavirenz-based treatment in antiretroviral-naive pregnant women.

Introduction

HIV suppression is critical during pregnancy for maintenance of maternal health and prevention of both secondary sexual and perinatal HIV transmission. Initiation of combined antiretroviral therapy early in pregnancy with a potent and safe pregnancy regimen is of paramount importance.[1] The integrase inhibitors raltegravir and dolutegravir are currently recommended as part of preferred initial antiretroviral regimens for pregnant women based on their demonstrated efficacy, straightforward posology and acceptability, available pharmacokinetic data, and low toxicity.[1] Raltegravir was the first integrase inhibitor to be studied during pregnancy. Pregnancy pharmacokinetic data demonstrate adequate plasma exposures with the use of standard adult doses of 400 mg twice daily, its use is known to result in rapid viral load decline in antiretroviral-naive late presenters compared with efavirenz- or lopinavir/ritonavir-based regimens, and raltegravir has a favorable safety profile, with no concerns regarding teratogenicity described to date.[2–4]

Mounting experience with integrase inhibitor use in nonpregnant populations has raised concern of potential adverse metabolic effects. Increases in weight, body fat, and body mass index (BMI) and greater risk for diabetes have been reported both after integrase inhibitor initiation in treatment-naive adolescents and adults[5–8] or after switching to integrase inhibitors in suppressed individuals when compared with non-nucleoside reverse transcriptase inhibitors and protease inhibitors.[9,10] These associations seem greater for patients receiving dolutegravir and tenofovir alafenamide. However, these same effects have not been observed by other researchers in similar studies.[11–13] Regarding pregnancy, increased antepartum and postpartum weekly weight gain was reported for dolutegravir compared with efavirenz in an African population but still below the average weight gain of women not living with HIV.[14,15]

Gestational weight gain is a potentially modifiable risk factor for immediate adverse pregnancy outcomes and has long-term implications. Low gestational weight gain has been linked to fetal growth restriction, preterm birth, and perinatal mortality,[16,17] while increased weight gain has been associated with diabetes during pregnancy, hypertensive disorders, preterm birth, macrosomia, labor dystocia, Cesarean delivery, postpartum weight retention, and offspring obesity.[17–21] Moreover, women living with HIV are also at risk for noncommunicable diseases during reproductive age and throughout their lives, because of the intricate interactions between the virus, antiretrovirals, and chronic inflammation, adding to the burden of possible integrase inhibitor-induced metabolic adverse events.[22,23] Therefore, it is of utmost importance to understand the potential impacts of integrase inhibitor use in pregnant women and in their offspring.

Weight gain related to integrase inhibitor use in pregnancy and its consequences have not yet been described for raltegravir. This study is a secondary analysis of a subset of participants in the NICHD P1081 trial. The parent study compared clinical outcomes of antiretroviral-naive pregnant women randomized to receive a raltegravir- or efavirenz-based antiretroviral regimen starting between 20 and 36 weeks of gestation. This sub study only included those who started between 20 and 31 weeks' gestation and were on study for at least 4 weeks. The objectives of this analysis are to compare antepartum changes in body weight and BMI between treatments and to assess the associations between weight gain and adverse pregnancy outcomes.

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