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.
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.
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% , this risk reaching almost zero for women on successful cART before pregnancy and maintaining success until delivery . However, despite major improvements in antiretroviral drugs, the composition of cART during pregnancy remains challenging . 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 , neonatal adrenal dysfunction with lopinavir/ritonavir exposure , discrepant results between preclinical and clinical studies about neurologic defects with efavirenz [4, 6, 7], which is now considered as safe as other cART , risk of cancer during childhood with didanosine exposure  and alteration of DNA repair and telomere maintenance genes with ZDV/tenofovir exposure . 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  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 . 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