Research Article: “Real life” use of raltegravir during pregnancy in France: The Coferal-IMEA048 cohort study

Date Published: April 24, 2019

Publisher: Public Library of Science

Author(s): Pierre Gantner, Babacar Sylla, Laurence Morand-Joubert, Pierre Frange, Karine Lacombe, Marie-Aude Khuong, Claudine Duvivier, Odile Launay, Marina Karmochkine, Cédric Arvieux, Amélie Ménard, Lionel Piroth, Ana Canestri, Dominique Trias, Gilles Peytavin, Roland Landman, Jade Ghosn, Robert Güerri-Fernández.

http://doi.org/10.1371/journal.pone.0216010

Abstract

Limited “real life” data on raltegravir (RAL) use during pregnancy are available. Thus, we aimed at describing effectiveness and safety of RAL-based combined antiretroviral therapy (cART) in this setting.

HIV-1-infected women receiving RAL during pregnancy between 2008 and 2014 in ten French centers were retrospectively analysed for: (1) proportion of women receiving RAL anytime during pregnancy who achieved a plasma HIV-RNA (pVL) < 50 copies/mL at delivery, and (2) description of demographics, immuno-virological parameters and safety in women and new-borns. We included 94 women (median age, 33 years) of which 85% originated from Sub-Saharan Africa and 16% did not have regular health insurance coverage. Sixteen women were cART-naïve (median HIV diagnosis at 30 weeks of gestation), whereas 78 were already on cART before pregnancy (40% with pVL < 50 copies/mL). RAL was initiated before pregnancy (n = 33), during the second trimester (n = 11) and the third trimester of pregnancy (n = 50). No RAL discontinuations due to adverse events were observed. Overall, at the time of delivery, pVL was < 50 copies/mL in 70% and < 400 copies/mL in 84% of women. Specifically, pVL at delivery was < 50 copies/mL in 82%, 55% and 56% of cases when RAL was started before pregnancy, during the second or third trimester of pregnancy, respectively. Median term was 38 weeks of gestation, no defect was reported and all new-borns were HIV non-infected at Month 6. RAL appears safe and effective in this “real-life” study. No defect and no HIV transmission was reported in new-borns.

Partial Text

In addition to the large decrease in HIV/AIDS-related mortality and morbidity, another major and early success of combined antiretroviral therapy (cART) has been the dramatic decrease of HIV mother-to-child transmission (MTCT). Indeed, current MTCT rates globally fall below 5% [1], this risk reaching almost zero for women on successful cART before pregnancy and maintaining success until delivery [2]. However, despite major improvements in antiretroviral drugs, the composition of cART during pregnancy remains challenging [3]. No antiretroviral drug can be considered totally safe during pregnancy, and several severe adverse events have been reported in new-borns exposed to cART in utero, such as heart defects with zidovudine (ZDV) exposure [4], neonatal adrenal dysfunction with lopinavir/ritonavir exposure [5], discrepant results between preclinical and clinical studies about neurologic defects with efavirenz [4, 6, 7], which is now considered as safe as other cART [8], risk of cancer during childhood with didanosine exposure [9] and alteration of DNA repair and telomere maintenance genes with ZDV/tenofovir exposure [10]. Until recently, international and French guidelines recommended the use of two nucleoside reverse transcriptase inhibitors (NRTI), namely emtricitabine plus tenofovir disoproxil fumarate (TDF/FTC) or abacavir plus lamivudine (ABC/3TC) in combination with a ritonavir-boosted protease inhibitor (bPI), as preferred regimen during pregnancy [11–13]. The availability of integrase strand-transfer inhibitors (INSTI), together with some concerns about a potential association between the use of bPI and premature delivery [14–16], could be a “game changer” in the field of cART during pregnancy. Indeed, the ability of INSTI to rapidly control HIV replication is very appealing [17, 18], especially in late presenting women (i.e. women who arrive late in the pregnancy follow-up for HIV care). However, the use of dolutegravir in the periconceptional period, which has been associated with neural tube defects [19] and need to be further confirmed, has recently raised some concerns about INSTI usage during pregnancy. Conversely, no signal for birth defects in pre-clinical studies was associated with the use of raltegravir (RAL); the first available INSTI, that was neither mutagenic nor clastogenic in a series of in vitro and animal screening tests [20, 21]. In 2015, when the Antiretroviral Pregnancy Report had gathered data sufficient enough to rule out a two-fold increase in risk of overall birth defects, RAL has been included as a preferred agent in pregnancy according to the U.S. Department of Health and Human Services [22]. Furthermore, European AIDS Clinical Society also included RAL use during pregnancy as a recommended option since 2017 [11–13]. In this context, to assess RAL use during pregnancy is both safe and effective; we conducted a retrospective cohort analysis of HIV-infected women who received a RAL-based regimen during pregnancy in France.

Recommended cART options remain limited for HIV-1 pregnant women despite the development of new antiretroviral drugs over the past decade. We report here a comprehensive retrospective analysis of HIV-1 infected women receiving a RAL-based cART during preganncy. Overall, a pVL < 50 copies/mL at the time of delivery was achieved in more than two third of women initiating RAL, although 60% of them were not virologically-suppressed at RAL initiation. Of major interest, this “real-life” study provides data for specific populations usually excluded from clinical trials. In particular this analysis: (i) included women initiating a RAL-based regimen at different time points, including late presenters, (ii) is representative of socio-demographic characteristics of HIV-infected pregnant women epidemiology in France, thus including a high proportion of Sub-Saharan Africa migrants, and (iii) described data for women with no regular health care insurance, who therefore cannot participate in clinical trials.   Source: http://doi.org/10.1371/journal.pone.0216010

 

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